VictorJuiz/thesis huggingface dataset:
The role of ASPP2 in intestinal homeostasis and tumourigenesis
Keywords: ASPP2
Organoid
Colorectal Cancer
Inflammation
Intestinal Stem Cell

The intestinal epithelium represents one of the most actively renewing tissues in the body, and is widely used as a model system to study epithelial cell biology. ASPP2, a member of the ASPP (apoptosis stimulating protein of p53) protein family, has been shown to act as a regulator of epithelial cell polarity and tumour suppressor. This study investigated whether the dual function of ASPP2 is involved in the regulation of intestinal homeostasis and tumourigenesis, with a particular interest in the distinction between epithelial cell autonomous and non-autonomous mechanisms.
Germline and intestinal epithelial cell-speciﬁc ASPP2 conditional knockout mice were employed in this study. Deﬁciency of ASPP2 in the intestinal epithelium resulted in delayed recovery from dextran sulfate sodium (DSS)-induced acute colitis, concurrent with a reduction in the expression of proinﬂammatory cytokines such as interleukin (IL)-1β and IL-6. Moreover, ASPP2-deﬁcient mice showed increased susceptibility to Azoxymethane/DSS-induced colorectal tumourigenesis. While wild-type and ASPP2-deﬁcient crypts showed similar incidence of tumour formation, the local immune microenvironment of ASPP2-deﬁcient mice favoured tumour progression.
The intestinal organoid culture was established to supplement in vivo experiments. The feasibility of the system was demonstrated with small intestinal organoids, in the context of proliferation, differentiation, and cell death. Using the established workﬂow, a colonic organoid-based tissue regeneration model was developed. The intrinsic susceptibility of organoids to DSS-induced cell death was not affected by the loss of ASPP2. However, ASPP2-deﬁcient colonic organoids were less responsive to the pro-proliferative effects of IL-6, but were more sensitive to tumour necrosis factor-α-induced cell death in the presence of IL-22.
In conclusion, this project undertook parallel examinations of animal models and organoids, demonstrating that a deficiency of ASPP2 in the intestinal epithelium results in dysregulated epithelial–immune cell interactions. This may partially explain the pathological conditions observed in ASPP2-deficient mice. Importantly, this study highlights the possibility of using organoids to investigate epithelial cell non-autonomous factors implicated in intestinal pathogenesis.
Stationary and temporal structure of antibody titer distributions to human influenza A virus in southern Vietnam
Keywords: Protein microarray
Influenza
Sero-epidemiology
Antibody titers

Seroepidemiology aims to understand population-level exposure and immunity to infectious disease. Serological results are normally presented as binary outcomes describing the presence or absence of antibody, despite the fact that many assays measure continuous quantities. A population's antibody titers may include information on multiple serological states – naiveté, recent infection, non-recent infection, childhood infection – not just seropositivity or seronegativity. In the first part of this thesis, I investigate 20,152 general-population serum samples from southern Vietnam collected between 2009 and 2013 from which I report antibody titers to the influenza virus HA1 protein using a continuous titer measurement from a protein microarray assay. I describe titer distributions to subtypes 2009 H1N1 and H3N2, and using a model selection approach for mixture distributions, I determine that 2009 H1N1 is best described by four titer subgroups while H3N2 is best described by three titer subgroups. For H1N1, my interpretation is that the two highest-titer subgroups correspond to recent and historical infection, which is consistent with pandemic attack rates. For H3N2 however, right-censoring of titers makes interpretations difficult to validate. To move beyond this stationary interpretation of titers, I developed two methods for analyzing this serum collection as a time series. First, I attempted to analyze mixture categories in individual time windows. This approach did not lead to a consistent temporal picture of titer change; results differed by site and were sensitive to assumptions in the mixture fitting. Second, I attempted to fit a hybrid-dynamical model with free incidence parameters. This inference was robust to parameter assumptions, consistent across sites, and in agreement with the incidence reported in Vietnam's influenza surveillance network. In addition, my new approach showed evidence that there was a second silent wave of the 2009 influenza pandemic that was not recorded in national surveillance, which is this thesis' main novel result.
Sensitivity and specificity of molecular methods for detecting markers of  antimalarial drug resistance in clinical  samples of Plasmodium falciparum: a systematic review
Keywords: Meta-analysis
Drug resistance
Diagnostic test accuracy
Narrative synthesis
Malaria
Molecular methods
Systematic review
Plasmodium falciparum

Background Each year infection with Plasmodium causes millions of clinical cases of malaria, and hundreds of thousands of deaths. Resistance to different antimalarial medications continues to develop and spread, threatening effective prophylaxis and treatment. Monitoring of resistance is required to inform health policy and preserve effective antimalarials; molecular methods can be used to determine likely parasite susceptibility. There is no consensus on the most accurate methods; large variation exists in practice. The goal of this systematic review was to identify the sensitivity and specificity of each molecular method for detecting antimalarial resistance markers.
Methods All diagnostic accuracy studies that examine at least two molecular methods for detecting selected markers of antimalarial resistance in blood samples from patients diagnosed with, or suspected of having malaria were included. MEDLINE, EMBASE, BIOSIS, and Science Citation Index were searched. Methodological quality was evaluated using QUADAS-2. Sensitivity and specificity were calculated and results synthesised and compared narratively.
Results 27,575 search results returned 18 eligible studies, examining 13 index tests, against five reference tests, for their accuracy in detecting 24 molecular markers. Some markers and tests were investigated multiple times, but rarely in the same combinations. Characteristics of studies were poorly reported. Generally, risk of bias and applicability concerns were unclear. Estimates of sensitivity and specificity were calculable for most evaluations, confidence intervals were generally wide.
Discussion Estimates of the accuracy of molecular methods are generally imprecise, contributing to uncertainty. Many methods may be close to 100% in sensitivity or specificity. Most methods require specialist equipment unlikely to be available in many low resource settings. High quality study design focusing on methods useable in low resource settings, prospective registration, and reporting according to STARD 2015 guidelines are essential for future studies.
Soft chemical control of layered oxychalcogenides
Keywords: Oxide chalcogenides
Magnetism
Magnetic order
Solid-state chemistry
Oxychalcogenides

The structure, magnetic behaviour and chemistry of layered oxychalcogenides of composition A2MO2X2Ch2 (where A = Sr, Ba; M = Mn, Co, Ni, Cu, Zn; X = Cu, Ag and Ch = S, Se, Te) has been investigated by the synthesis of new compounds of this type and control of the properties of these compounds by oxidative deintercalation of Cu/Ag.
I2 can be used to oxidatively deintercalate Cu from Sr2MnO2Cu1.5S2, forming Sr2MnO2Cu1.33S2, an incommensurately modulated compound, with a completely different Cu/vacancy ordering and antiferromagnetic ordering structure to the parent. This reaction is also probed in real-time, using in situ powder X-ray diffraction.
Sr2MnO2Ag1.5Se2 was found to have an A-type magnetic ordering structure, similar to Sr2MnO2Cu1.5Se2. Sr2MnO2Cu1.8Te2 on the other hand with a lower Mn oxidation state shows only two-dimensional magnetic correlations, rather than long-range order.
Extending the reaction with I2 to several Co-containing analogues revealed that &Tilde; 25% Ag could be removed from Sr2CoO2Ag2Se2, sufficient to observe a change in magnetic behaviour, from antiferromagnetic to ferromagnetic. By contrast only &Tilde;11% Cu can be deintercalated from Sr2CoO2Cu2S2 and even less (&Tilde;5%) from Sr2CoO2Cu2Se2. Neutron diffraction was used to examine the resultant changes in magnetic ordering.
The novel compounds Sr2CuO2Cu2Se2 and Ba2CuO2-xCu2Se2 are related by substitution of the alkali-earth metal, but while Sr2CuO2Cu2Se2 is a stoichiometric compound with metal-like character, Ba2CuO2-xCu2Se2 is an oxygen-deficient semiconductor, with tuneable oxygen content.
Unusual features are observed in the magnetic susceptibility measurements of Sr2NiO2Cu2Se2 that appear unrelated to this compound's long-range magnetic ordering, as probed by neutron diffraction. Furthermore, unusual peak splitting is observed in low-temperature powder X-ray diffraction patterns of this compound; this may plausibly be due to a photon-induced effect arising from the use of a high-energy beamline; although further measurements are required to examine this.
Overall the work shows the flexibility and range of behaviour exhibited by a series of the transition metal oxide chalcogenides.
Altered function of CCK-positive interneurons in mice over-expressing the schizophrenia risk gene neuregulin 1
Keywords: Neurophysiology
Neuregulin
Schizophrenia
Hippocampus
Interneurons
Physiology

The Neuregulin 1 (NRG1)-ErbB4 signalling pathway is implicated in critical processes for the development and function of neuronal circuits. Post mortem studies have reported that elevated expression of NRG1 type 1 isoform is associated with schizophrenia. Importantly previous behavioural studies in mice that overexpress the NRG1 type 1 isoform (NRG1tg-type-I) have suggested a schizophrenia endophenotype including impairment in the hippocampus-dependent spatial working memory, prepulse inhibition (PPI) of the startle reflex and alterations in the gamma band rhythmogenesis This study aims to reveal the cellular targets of the NRG1-ErbB4 signalling pathway and putative alterations in the function of the hippocampal network in NRG1tg-type-I mice.
Immunocytochemical analysis showed that the NRG1 receptor ErbB4 is predominantly localized in interneurons comprising parvalbumin positive (PV) and cholecystokinin (CCK) expressing cells. Comparison of the density of ErbB4-positive cells between the hippocampus of wild type (WT) and NRG1tg-type-I mice suggested that NRG1 over-expression resulted in decreased number of ErbB4 immunopositive hippocampal interneurons. This is consistent with the proposed role of the NRG1-ErbB4 signalling in the migration of GABAergic cells during neurodevelopment and with the NRG1-mediated internalisation of the ErbB4 receptors. CCK- positive cells are a major target of NRG1-ErbB4 signalling, and therefore the NMDA receptor and AMPA receptor components of glutamatergic transmission were analysed in this population of cells by performing whole cell recordings of evoked and miniature excitatory post synaptic currents. Glutamatergic neurotransmission in CCK-positive cells was found to be compromised in the hippocampus of NRG1tg-type-I mice. This change was attributed to hypofunction of NMDA receptors but not AMPA receptors post-synaptically. Next, the inhibitory output of CCK-positive cells to pyramidal cells was examined. Analysis of the optogenetically elicited inhibitory post synaptic currents (IPSCs) did not reveal any changes in the properties of the GABAergic synapse formed by these cells due to NRG1 over-expression Finally, the effects of this NMDA receptor hypofunction in the recurrent inhibition were analysed by performing whole cell recordings during the gamma relevant optogenetic entrainment of the hippocampal network. It was found that the disynaptic inhibition, a key synaptic interaction for the generation of gamma oscillations, depends on the NMDA receptors and was altered in the hippocampus of NRG1tg-type-I mice.
Together these data point out a key modulatory role of the NRG1-ErbB4 signalling in the neurodevelopment of cortical microcircuits and a link between ErbB4 and NMDA receptor function with a possible association to schizophrenia pathogenesis.
Between cosmopolitan and classical: Persian in early colonial India, c.1757-1857
Keywords: Colonial India
Persianate World

This thesis investigates the significance of Persian learning in Britain and India during the period of colonial expansion under the East India Company, from 1757 to 1857. It seeks to situate Persian in its wider social context in north India, and understand the significance and function of the language during a period which is typically described in terms of the decline of the Persianate world. It does so by studying Persian literary production and language-learning by a range of actors at different sites in north India. By examining the presence of Persianate texts and individuals in spaces and endeavours which are typically classified as modern (orientalist textual production in the colony, the rise of linguistic studies, colonial education and nineteenth-century Indian printing), this thesis emphasizes the ways in which Persianate relationships and sensibilities shaped these sites of Indian modernity, and were themselves altered in the process. This thesis shows that the reasons for the continued usage of Persian in late eighteenth and early nineteenth-century India went beyond its symbolic value as a marker of earlier Mughal power. Persian played an important role in shaping and constructing cosmopolitan literary and scholarly identities, as well as enabling spatial and social mobility. In so doing, this thesis hopes to contribute to the historiography of the Persianate world, as well as the histories of language, printing and education in colonial South Asia more broadly. In making these arguments, this thesis suggests a reappraisal of the ways in which the relationship between Indian modernity and cosmopolitan cultures now seen as 'classical' - such as that of Persian - is conceived. Rather than viewing Persian as a mere symbol of Mughal rule, a socially-grounded understanding of the Indian and colonial engagement with Persian is suggested. Understanding Persian in its social context in India, and recognizing the variety of spaces, languages and groups it interacted with challenges any neat categorization of the language as 'classical' or 'foreign' to India, or in opposition to vernacular or indigenous languages.
MAIT cells in sterile and non-sterile inflammation
Keywords: Salmonella
MAIT
Cancer

Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that recognize bacteria-derived metabolites presented on MR1, but can also be stimulated in a T cell receptor (TCR)-independent manner by pro-inflammatory cytokines. Therefore, their role in both sterile and non-sterile diseases are of great interest and only just beginning to be explored. To understand the role of MAIT cells in non-sterile inflammation, we utilized a controlled human infection model of live Salmonella enterica serovar Paratyphi A. We observed that at the time of diagnosis MAIT cells had an activated phenotype, which was maintained even after antibiotic treatment. We analysed the TCR repertoire of MAIT cells in diagnosed individuals to determine if the MAIT cell response to infection was antigen- driven. We found that infection led to redistribution of the repertoire, with transient contraction of the over-represented clones at the peak of infection. To understand the role of MAIT cells in sterile inflammation we examined cancer sections and found that MAIT cells infiltrate tumours derived from various tissues and that the source of MAIT cells was from tissue-resident MAIT cell subsets. We also determined that MAIT cells may respond to BCG immunotherapy of bladder cancer, as they are both present and activated in the bladder following treatment. Finally, we wanted to determine the extent to which both the TCRα and TCRβ usage affected MAIT cell responses. We found that the TRAJ usage, which relatively defines circulating versus tissue-resident MAIT subsets, has a large impact on the MAIT TCR response to both bacterial and ligand stimulation. We also investigated selected TCRβ clonotypes identified in Salmonella-infected individuals and found that the MAIT cell clonotypes that expanded after infection had stronger TCR-dependent activation than did contracted clonotypes from the same individual. In conclusion, we have characterised the function and phenotype of MAIT cells in human infection, cancer and cancer immunotherapy as well as provide insight into the usage and importance of the specific MAIT cells TCRα and TCRβ chains.
Nomads in the liberal state: liberal approaches to the problem of Roma and traveller itinerancy
Keywords: multiculturalism
minority rights
Roma and Travellers
gens du voyage
liberalism
Brian Barry
Will Kymlicka
nomadism

May the state, from a liberal point of view, operate laws and institutions that impede the mobile lifestyle of nomadic Roma and Travellers, or should the state take steps to accommodate their nomadic way of life? This is the essence of the problem of Roma and Traveller itinerancy and the question that is at the heart of this three-partite dissertation.
The first part of the dissertation looks at public policy in France and the United Kingdom and describes the six public policy problems that constitute the problem of Roma and Traveller itinerancy. These problems concern the education of children, the French travel permits system, the legal conditions for voter registration and for GP registration, the housing benefits system, and the public provision of halting sites.
The second part looks at liberal political theory. It suggests that contemporary liberalism divides into two strands that take different views on the entitlements of cultural and religious minorities, and it provides a detailed outline of the prime articulations of each approach, namely the multiculturalist liberalism of Kymlicka and the classic neutrality liberalism of Barry.
The third part investigates what the two said liberalisms imply for the six policy problems from part 1. These analyses suggest that the two liberalisms have slightly diverging implications for the halting sites problem, the housing benefits problem and the problem of GP registration. They suggest furthermore that the two accounts converge on the question of voter registration and agree that the voter registration system must accommodate nomads, and may not make the possession of a fixed residence an absolute condition for voter registration. And the analyses suggest finally that the two liberalisms also converge over the education question and the travel permits question, but here support polices that are potentially inimical to Roma and Traveller itinerancy. The broader implications of these findings are that liberalism is potentially, but not necessarily and not intrinsically, inimical to Roma and Traveller nomadism, and that the disagreement between classic neutrality liberalism and multiculturalist liberalism is weak insofar as public policy is concerned.
An arterial spin labelling method for the measurement of myocardial perfusion in humans at 3 tesla
Keywords: Magnetic Resonance Imaging
Arterial Spin Labelling
Myocardial perfusion

The assessment of Myocardial Blood Flow (MBF) is an important measure in clinical practice for evaluating the health of the heart. Multiple imaging methods have been employed to measure MBF, including applications of nuclear medicine, x-ray and contrast enhanced Magnetic Resonance Imaging (MRI). However, each of these modalities suffers from drawbacks, such as invasiveness due to radiation or intravenous contrast injection, difficulty in quantitation, and limited repeatability.
The aim of this thesis was to develop a non-invasive, quantitative and repeatable MRI method for the measurement of MBF, by applying the techniques of Arterial Spin Labelling (ASL). A novel cardiac ASL sequence was designed and thoroughly tested by simulation and phantom experiment. The method was applied in vivo in three slices of the human heart, to our knowledge the first cardiac ASL acquisition in multiple slices, in ten healthy volunteers. The resulting values of mid-ventricular MBF, averaged over multiple measurements, compared well with the literature values from multiple modalities. Repeat measures were then used in order to characterise the reproducibility and variation inherent in the method, showing that the expected change in MBF would be detectable with the ASL sequence. Segmental values of MBF, according to the AHA standard model, were also calculated and these compared well to previous PET literature. This work has been published in the journal Magnetic Resonance in Medicine.
Further to this work, the new cardiac ASL sequence was optimised with the ultimate goal of single breath hold acquisitions. The optimised sequence was shown to improve the results in terms of the balance between good signal-to-noise ratio and reducing spatial and temporal variation in MBF values. Though improvements were made, there remained a large variation in the measured values of MBF, meaning single breath hold acquisition in a clinical context is not yet practical. In addition to the optimisation, the online scanner reconstruction software was altered to produce parametric maps of both T1 and MBF direct to the scanner operator. The sequence, along with online reconstruction is available for use in our laboratory for future clinical trials in the heart and liver.