VictorJuiz/thesis huggingface dataset:
Control of intestinal progenitor cell fate by the microenvironment
Keywords: Stem cell biology

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organisational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. I look at evidence to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment. Selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. The Wnt, BMP and Hedgehog pathways are explored in terms of epithelial and mesenchymal compartmentalisation and cross-talk, both in homeostasis and inflammation. Interactions between BMP and Hedgehog pathways are studied in vivo and in vitro. The BMP antagonist GREM1 is discussed, and the effect of a compartmental switch in its expression in humans (Hereditary Mixed Polyposis Syndrome) and in mouse models. This leads to ectopic crypts with supposed stem cell activity, and evidence for stem cell activity is interrogated using lineage tracing models and organoid cultures. The functionality of Sox9, a marker of ectopic crypts, is explored. An epithelial Sox9 knockout model is studied in terms of its effect on ectopic crypt formation. The role of Sox9 in intestinal restitution is also examined by using a chemical colitis model and a biopsy wounding model.
Novel methods of measuring and modifying perception of and satisfaction with body size: a clinical translational approach
Keywords: eating disorder
bulimia nervosa
anorexia nervosa
body dissatisfaction

Body dissatisfaction is a risk factor for subsequent eating disorders, weight gain and low mood. It is resistant to treatment and, untreated, predicts relapse to eating disorders. Measurement of its perceptual and cognitive components currently relies predominantly on self-report questionnaires.
This thesis describes the development and testing of a novel brief intervention designed to change perception of and satisfaction with own body size. Three studies demonstrate and replicate the finding that whether one-off, or repeated over the course of a week, exposure to over- or normal- weight images leads to participants subsequently perceiving others’ bodies as smaller, in comparison to those shown underweight bodies. One-off exposure to images of overweight, compared to normal or underweight, women also leads to participants viewing their own bodies as smaller, and being more satisfied with their body size; however, repeated exposure over the course of a week does not have this effect, and in fact leads to women perceiving their own bodies as larger. Such repeated exposure to over- rather than underweight bodies does however increase women’s ideal body size.
The thesis also describes two studies concerning the development and testing of novel measures of body size and satisfaction with body size in healthy women and those with an eating disorder. Using an Avatar to demonstrate real and ideal body size, and a novel behavioural measure of body satisfaction using outfits, both correlated well with existing measures of body size and satisfaction, and there were differences on these measures between individuals with and without eating disorders. The novel implicit tasks (Implicit Association Tasks and a Lexical Decision Task) also correlated with existing measures of body size and satisfaction, however, there were no differences on these measures between individuals with and without eating disorders.
The findings suggest that exposure to images of women of different sizes is effective in changing perception of what constitutes a normal weight, but has less predictable effects in relation to perception of and satisfaction with own size. Implicit measures of body size and satisfaction do not appear to be useful in distinguishing between women with and without eating disorders, but a novel behavioural measure using outfits, and using Avatars to demonstrate perceived own size, does show promise.
Descent methods and torsion on Jacobians of higher genus curves
Keywords: Hyperelliptic curve
Torsion
Jacobian
Descent

In this thesis we accomplish four main results related to Jacobians of curves.
Firstly, we find a large number of hyperelliptic curves of genus 2, 3 and 4 whose Jacobians have torsion points of large order. The genus 2 case is particularly well-studied in the literature, and we provide a new example of a geometrically simple Jacobian of a genus 2 curve with a point of order 25, an order which was not previously known. For geometrically simple Jacobians of curves of genus 3 and 4, we extend the known orders of points, increasing the largest known order in both cases to 91 and 88, respectively.
Secondly, we find an explicit embedding of the Kummer variety of a genus 3 superelliptic curve into projective space. This is a natural extension of the embeddings that are already known for the Kummer varieties of hyperelliptic curves of genus 2 and 3.
Thirdly, we classify the genus 2 curves whose Jacobians admit a (4,4)- isogeny. We find an infinite family of genus 2 curves for which the elements of the kernel of the (4,4)-isogeny are defined over the ground field, and make partial progress on classifying the genus 2 curves with this property. We also extend Flynn’s example of a genus 2 curve whose Jacobian admits a (5, 5)-isogeny to infinitely many geometrically nonisomorphic curves.
Finally, we extend Schaefer’s algorithm for computing the Selmer group of a Jacobian to carry out a (4, 4)-descent on Jacobians of curves that admit a (4, 4)-isogeny.
First measurements of inclusive muon neutrino charged current differential cross sections on argon at 0.8 GeV average neutrino energy with the MicroBooNE detector
Keywords: neutrino
liquid argon time projection chamber
microboone
cross section
particle physics

Current and next-generation precision neutrino oscillation experiments aim to determine the neutrino mass ordering, to measure the extent of CP violation in the lepton sector and to probe beyond Standard Model physics, such as sterile neutrinos. These experiments rely on models for neutrino interactions with matter that are complicated by nuclear effects and final state interactions. To date, these effects cannot be modelled precisely, especially for heavy target nuclei, typically used in modern neutrino experiments. Many future experiments will employ detectors based on the liquid argon time projection chamber technology. As a consequence, neutrino-argon cross-section measurements are of the outmost importance, especially given the relative scarcity of neutrino-argon data, due to the novelty of the technology.
This thesis presents the first measurement of muon-neutrino charged-current inclusive cross section on argon at a mean neutrino energy of 0.8 GeV. Data were collected using the MicroBooNE liquid argon time projection chamber in the Fermilab Booster neutrino beam during a period of six months, corresponding to an exposure of 1.6 x 1020 protons on target. The measured cross section is presented as a function of the outgoing muon momentum, using multiple Coulomb scattering as a measurement technique, as well as the muon angle with respect to the beam direction. A comparison of the measured cross section obtained with two different configurations of the Genie neutrino event generator is performed, and better agreement is found when using nuclear-effect modelling in the theoretical calculations. Additionally, the total flux integrated cross section is measured to be 0.693 ± 0.010 (stat.) ± 0.165 (syst.) x 10-38 cm2.
Characterising the small heat shock proteins: structure and regulation
Keywords: Motor neuropathy
Phosphorylation
Domain swapping
Molecular dynamics
Oxidation
Alpha crystallin
T151I
Beta2 strand
NMR
Native mass spectrometry
Cyclic voltammetry
Square wave voltammetry
HSPB1
Molecular chaperone
Oligomerisation
Chaperone assays
Alpha-crystallin domain
Disulphide bond
Core domain
Disulfide bond
Ion mobility
Mass spectrometry
Protein crystallography
R136W
T164A
Regulation
Proteostasis
Small Heat Shock Protein
HSP27
SDS-PAGE

The small heat shock protein HSP27 is expressed throughout the body and involved in a variety of cellular processes. Its multiple roles may all be mediated by its ability to chaperone partially folded protein substrates, and its malfunction is implicated in a range of diseases such as motor neuropathy and neurodegeneration. Here I describe structural, dynamical and functional investigations into this protein, particularly regarding its regulation by oxidation and phosphorylation. The foundations of this work were a protein crystal structure obtained on the oxidised core domain of the wild-type protein, which forms a disulphide-locked dimer, and additional structures that contain neuropathy-associated mutations. Observations of a structurally variable region, namely the β2-strand at the beginning of the core domain, led us to probe the nature of this region in solution and examine whether phosphorylation at the nearby phosphoserine site led the β2 to bind more strongly to the core domain, as phosphorylation elicits HSP27 oligomer disruption and activity modulation. I am able to postulate on the structural effect of mutation using the mutant crystal structures, and report the first structure showing the interface formed by the HSP27 core domain dimer in the ‘antiparallel III’ register. This finding, in tandem with the unusual nature of the intact intra-subunit disulphide bond reported here, motivated studies into the role of this disulphide in the redox response of the HSP27 chaperone. These include dynamical studies on the subunit exchange of the protein and functional investigations showing that the disulphide is formed in the cell and that chaperone behaviour depends on the oxidation state. Moreover, I show that the redox potential of the disulphide is affected by mutation, as is the change in chaperone response on oxidation. Taken together, I suggest that HSP27 is regulated by oxidation through the intra-dimer disulphide, which allows it to respond to oxidative stress within the cell.
Chordal sparsity in control and optimization of large-scale systems
Keywords: Large-scale systems
Distributed control
Decomposition methods
First-order methods
Chordal sparsity

Many large-scale systems have inherent structures that can be exploited to facilitate their analysis and design. This thesis investigates how chordal graph properties can be used to develop scalable methods for solving three classes of problems: sparse semidefinite programs (SDPs), distributed control of networked systems, and sum-of-squares (SOS) programs. By exploiting the properties of chordal graphs and sparse positive semidefinite matrices, we present decomposition methods that are able to scale these problems to much larger instances.
The first part of this thesis proposes a new conversion framework for large-scale SDPs characterized by chordal sparsity. This framework is analogous to standard conversion techniques for interior-point methods, but is more suitable for the application of first-order methods. We develop efficient algorithms based on the alternating direction method of multipliers (ADMM) for sparse SDPs in either primal or dual standard form, and for their homogeneous self-dual embedding. The algorithms are made available in the open-source conic solver CDCS. CDCS is the first open-source first-order solver that exploits chordal decomposition and can detect infeasible problems. We demonstrate the performance of CDCS in standard analysis problems of large-scale networked systems.
The second part of this thesis is concerned with solution scalability and model privacy in distributed control of networked systems. Specifically, we apply chordal decomposition in sparse Lyapunov-type linear matrix inequalities arising from structured stabilization and optimal decentralized control of networked systems. We introduce a sequential method based on the clique-intersection property of a clique tree for structured stabilization. This strategy greatly improves the computational efficiency for large-scale sparse systems. In addition, we propose an ADMM algorithm that can maintain model privacy when solving the optimal decentralized control problem.
Finally, we consider large-scale SOS programs. We identify an inherent partial orthogonality in the formulation when recasting general SOS programs using the standard monomial basis. In addition, we extend the well-established chordal decomposition/completion results for sparse positive semidefinite matrices to a subset of SOS matrices. Using a new graph-theoretic viewpoint, we build an explicit relationship between chordal decomposition in SOS optimization and two other recent techniques — DSOS and SDSOS optimization. We demonstrate that chordal decomposition can bring significant speed-ups for large-scale sparse SOS programs.
A cognitive approach to assessment for learning: assessing the impact of changing formative assessment practices in a secondary school science faculty.
Keywords: MLT
MLT2018

This research and development project took place across a science faculty in a UK state secondary school. Following trials, an assessment intervention was introduced to all science classes across key stages three and four in one academic year. The intervention sought to improve on an aspect of formative assessment, regular short tests, by combining literature on formative and summative assessment design and implementation with evidence from cognitive science relating to the nature of learning over time and how to improve it. The design of the intervention came from applying ideas from research to the specific context of the school, science faculty, staff and students at School X.
Quantitative analysis suggests an improvement in examination performance for students of all abilities in years 9 and 10 but a slight decrease in examination performance for students in years 7 and 8. Student and teacher opinion about the intervention is that it benefits learning. The primary reasons for this benefit are identified as improved diagnostic feedback as a result of increasing the inferential capacity of the assessment and improvements in the self-regulatory behaviour of students.
To what extent can girls' levels of academic risk-taking be raised in Year 6 maths lessons.
Keywords: MLT
MLT2018

When starting my first teaching job at an all girls’ school, I was struck by the disparity that I saw in the classroom between the number of times that pupils were willing to put their hands up in maths lessons compared to English lessons. It was clear that something was preventing the girls from fully participating in maths and that they generally seemed less confident. One year later, after carrying out a scoping study, it was clear that there was a difference in opinion between many parents and teachers over mistakes, success and what should motivate children. For me, this was of greater significance as my class were aged between 10 and 11, about to go through puberty and its associated self-image changes and were soon to leave Junior School for Senior School. Thus, this research and development project emerged with an aim to merge the home and school views on risk-taking, success and failure, and ultimately to help the girls to take more academic risks.
The study centered around a school-based intervention which was administered to all pupils in my class. The risk-taking lessons were designed to educate the girls about what risk-taking was and allowed the girls to analyse their motivation, their responses to failure and success, and the changes that they could make to help improve these. All of this lesson material was then sent to participating parents, who were able also to become educated over the school attitudes towards risk-taking. Pupils were encouraged to explain these lessons to their parents to strengthen this home-school link.
Parent and pupil questionnaires and lesson observations were used to collect data, which started to show some positive changes. Some pupils started to put their hands up more often, they responded more positively in lessons to failures or disagreements, and they became more aware of what risk-taking was. In addition, parents felt more able to support risk-taking at home, reflected some similar language surrounding risk-taking to pupils, and some felt that their daughters were less upset by failures. However, the study was limited by that fact that interviews were not included and follow up interviews would be necessary to validate some of the findings. It would also be of benefit to extend the study period, so that subtle changes over a greater time could be studied.
Modulators of MHC class I-related protein 1-mediated antigen presentation
Keywords: Antigen Presentation
MAIT cells
MR1

The monomorphic MHC class I-related protein 1 (MR1) presents bacterial metabolites to mucosal-associated invariant T (MAIT) cells, an innate-like subset of T lymphocytes. The known MAIT-activating MR1 ligands are intermediates of riboflavin synthesis, a pathway specific to certain fungi and bacteria and, thus, intrinsically non-self for humans. Here, a combination of hypothesis-generating and hypothesis-testing approaches was used to identify novel modulators of this non-classical antigen presentation pathway. In particular, a functional genetic screening technique based on insertional mutagenesis of the near-haploid human cell line HAP1 was employed to discover novel players in MR1 antigen presentation and trafficking. The most significant positive regulator of MR1 surface expression identified in this screen was β2-microglobulin, confirming its indispensable role in the surface translocation of MR1. A number of other putative regulators of MR1 trafficking were taken forward into a CRISPR/Cas9-based validation approach and the ER-localised transporter ATP13A1 was found to affect MR1-mediated antigen presentation by modulating the size of the intracellular pool of MR1. In addition, the role of the soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) Sec22b in MR1-mediated antigen presentation was investigated as knock-down of Sec22b has previously been reported to control MHC class I-mediated cross-presentation. MR1 surface expression was reduced upon Sec22b knock-down and while the SNARE itself did not appear to play a role, RNA sequencing of a Sec22b deficient cell line revealed a number of potential regulators of MR1. Lastly, the capacity of cellular riboflavin transporters to mediate MR1 ligand import was investigated. Treatment with the riboflavin analogue lumiflavin resulted in decreased MR1 surface expression in various human cell lines by a mechanism that appeared to be independent of the inhibition of riboflavin import. Together, these data contribute to an increasing understanding of MR1-mediated antigen presentation, which is essential for harnessing the therapeutic potential of MAIT cells.
An action research study of learning centred leadership in an American High School
Keywords: MLT
MLT2016

This study examines the leadership practices of a number of leaders in an American High School. The school is currently engaged in a major change process with the introduction of three action plans which will have significant implications for its teaching and learning process.
An essential aim of the study was to provide an informed view of how leaders were responding to the challenges of these changes, and in particular, how their practices were impacting on staff learning. In doing so, it was hoped that findings would inform and support the future directions of leadership in the school.
Knowledge of the school, strongly suggested that leadership practices at the school are consistent with a developing model of leadership that may be defined as 'learning centred'. A learning centred leadership model, after Southworth (2003) was used as the analytical framework for the research. The principles and practices of this model were explored in relation to how the leaders at the school were 'leading learning' and developing as 'leaders of learning'.
This is an interpretative action research project. Through this process I sought to answer questions with regard to the school's developing leadership practices and how these were impacting on the teaching and learning process in the school. The action research required a collaborative working in a cyclic process. A range of data was collected and triangulation was used in its analysis.
My findings are indicative of broad based practice in the school, where leaders are engaged in leading learning in a purposeful collaborative culture, with developing and supporting one another's practice as the norm.
Evidence demonstrates also, that leaders are continuing to develop their practices as leaders of learning, and as such, my conclusions are, that learning centred leadership is continuing to develop at the school, in ways consistent with its principles and practices.
The mechanism of action and physiological role of PLCζ at fertilisation
Keywords: Fertilisation
Polyspermy
Embryology
Gene editing
Calcium signalling
CRISPR/Cas9
Phospholipase C Zeta.
Alternative pathway in egg activation

Activation of the egg by the sperm is a key developmental event that in mammals triggered by the sperm-induced calcium oscillations. This has been proposed to be caused by the sperm-factor phospholipase C isoform zeta (PLCζ), although this remained a matter of debate for nearly 15 years.
The first part of this thesis demonstrates the successful use of the novel CRISPR/Cas9 gene editing technology in targeting the coding sequence of PLCζ gene in mouse embryos that subsequently has led to the creation of the first mouse model lacking the functional expression of PLCζ.
The main part of the thesis investigates the phenotype of the produced homozygous knockout male mutants. Functional analysis showed no adverse effects from the mutation on spermatogenesis, and normal sperm functional parameters. Although PLCζ-null sperm failed to trigger Ca2+ oscillations following ICSI procedures, experiments involving in vitro fertilisation, or fertilisation in vivo by natural mating, revealed that live offspring can still be conceived, albeit at greatly reduced efficiency and after a significant time delay. These findings suggest a yet-to-be identified PLCζ-independent route in mammalian egg activation that is completely dependent on sperm-egg membranes interactions.
Lastly, oocytes fertilised in vivo and in vitro by PLCζ-null sperm were found to be polyspermic. The significant finding supports the role of PLCζ protein in generating the standard Ca2+ oscillations that which govern the cortical and zonal reactions and membrane establishment following fertilisation. Oolemmal membrane localisation of Juno proteins post fertilisation showed complete dependency on sperm-oocyte interaction. However, Juno shedding mechanism failed to block the polyspermic fertilisation caused by lacking the expression of PLCζ. Thus, contradicting the proposed roles of Juno in establishing oocyte membrane block to supernumerary fertilisation in mammals.