VictorJuiz/thesis huggingface dataset:
Earthquakes and active faults in Central Asia

This thesis presents the results of research centred on three large Central Asian earthquakes from recent decades: the 1985 Wuqia (China), 1992 Suusamyr (Kyrgyzstan) and 2015 Pishan (China) earthquakes. For the Pishan earthquake I construct a fault slip model based on coseismic interferograms. It shows that the earthquake took place on a well-established fault that is visible in a seismic reflection profile. However, the coseismic and early postseismic deformations are misaligned with the longer-term topographic uplift pattern. Therefore, other mechanisms must be considered to explain the growth of topography. In a reinvestigation of the Wuqia earthquake, I combine data from several techniques to show that although surface ruptures were produced along a well-known fault, the existing models of that fault are not compatible with the earthquake’s focal mechanism or depth. Instead, most of the earthquake’s moment was released below a detachment. The detachment acts as a barrier to geomorphic expression of the basement fault, even though the observations require slip to have taken place both above and below the detachment within a month or less. In a study on the 1992 Suusamyr earthquake, I examine the significance of surface ruptures more closely. I use remote sensing and field observations to measure the extent and scarp height of the fresh ruptures, and to construct a paleoseismic record for the fault. The results reveal significant variability in the surface rupture pattern between successive earthquakes on the fault. Finally, I use those results to inform a broader study on the Suusamyr Basin. I map the tectonic structures across the entire basin and provide a slip rate estimate for the Suusamyr Fault. Overall this thesis extends the body of knowledge on continental reverse faulting earthquakes, and demonstrates the challenges and complexities of interpreting the fault structure and seismic hazard of an area based on surface observations.

Advisor: Walker, R
Parsons, B
Elliott, J
Optimising statistical methodologies for estimating antimalarial efficacy for uncomplicated Plasmodium falciparum malaria

Plasmodium falciparum malaria remains one of the greatest causes of mortality and morbidity globally. Estimates of treatment efficacy provide critical information for optimising treatment guidelines. The aim of this thesis was to quantify the magnitude of variation in the derived estimates attributable to study design and analytical approaches in uncomplicated P. falciparum in patients treated with artemisinin combination therapies (ACTs). This thesis utilised individual patient data collated from 92 clinical trials, including 31,507 patients treated with ACTs extracted from WorldWide Antimalarial Resistance Network (WWARN) repository.
This thesis presents a number of novel findings relevant to clinical researchers and policy makers. The current recommended follow-up period of 28 days with artemether-lumefantrine regimen missed an estimated 58% [95% Confidence Interval (CI): 47% – 74%] of treatment failures in Africa and 32% [95% CI: 15% – 45%] in Asia. For dihydroartemisinin-piperaquine (DP) regimen, a study with 42 day follow-up was estimated to miss 47% [95% CI: 19 – 90%] of the treatment failures in those who were adequately dosed. These results confirmed that studies adhering to the current follow-up recommendations provide an overestimate of the drug efficacy and longer follow-up is warranted for these regimens to adequately capture treatment failures.
The derived estimates were further vulnerable to analytical approaches adopted. Kaplan-Meier (K-M) approach, the currently recommended method, overestimated treatment failure by up to 3.6% compared to a competing risk survival analysis approach. Simulation studies demonstrated that the magnitude of this overestimation increased with declining drug efficacy in high transmission areas, where a substantial fraction of patients develop new infections. Similarly, excluding patients with indeterminant outcomes (i.e. whether parasite recurrence is a treatment failure or new infection cannot be determined) was associated with an upwards bias in the derived estimate of efficacy by up to 1.7% compared to using the sophisticated methods of multiple imputation and inverse probability weighting for dealing with the indeterminant outcomes.
This thesis highlighted that the choice of analytical approaches led to variability around the derived estimates of drug efficacy. The findings of this thesis are discussed with regards to current World Health Organization guidance to change treatment policy.

Keywords: Malaria
Efficacy
Advisor: Guerin, P
Price, R
Simpson, J
Stepniewska, K
Hume's problem, Kant's solution

These essays are four independent contributions to scholarship on David Hume’s and Immanuel Kant’s metaphysics, epistemologies, and philosophies of mind. They converge on Kant’s response to Hume’s causal scepticism. By ‘Hume’s causal scepticism’, I mean: first, Hume’s doubt that we can cognise causation a priori (what Kant called ‘the Humean doubt’); second, Hume’s doubt that the justification of induction is rational (Hume’s so-called ‘problem of induction’).
Essay 1, ‘Hume’s Alleged Lapse on the Causal Maxim’, argues that Hume was prima facie justified in doubting the ‘absolute’ necessity for the impression of any event to be preceded by the impression of a cause. Essay 2, ‘Kant’s Humean Problem’, argues that Kant, recognising the coherence of Hume’s doubt that we can cognise causation a priori and not just empirically, took his own Transcendental Analytic to directly refute Hume’s doubt. Essay 3, ‘Kantian Objectivistic Nonconceptualism’, argues that the ‘nonconceptualist’ reading of Kant’s Transcendental Deduction—on which intuiting objects does not require applying a priori concepts—is incorrect because it does not directly refute Hume’s doubt that we can cognise causation a priori. Essay 4, ‘Did Kant Solve Hume’s Problem of Induction?’, argues that Kant offered resources for a limited solution to Hume’s ‘problem of induction’, i.e., the demand to rationally justify our presupposition that any object or event resembling those perceived as conjoined with a specific quality is also conjoined with that quality.

Keywords: Induction
Nonconceptualism
Causation
Hume
Kant
Scepticism
Advisor: Kail, P
Gomes, A
Order, motion and relaxation in radical pair compass magnetoreception

Traditionally, biological systems are thought to be governed by classical, rather than quantum behaviour. In the warm, aqueous environment of a cell, the thermal energy kBT is much larger than the spacing of quantum energy levels and there are many processes, such as molecular motion, that can rapidly destroy delicate quantum coherences. An exception may be the remarkable ability of birds to navigate using the Earth's pervasive but extremely weak magnetic field; an ability that is thought to depend on the spin-selective reactions of photochemically-generated radical pair species.
Despite substantial (although inconclusive) evidence pointing towards a radical pair mechanism of avian magnetoreception, whether, and how, spin coherence can be maintained long enough to produce a field-dependent compass signal remains a key question. It becomes even more critical in light of recent work, presented in this thesis, showing that coherence lifetimes > 10 microseconds reveal `spiky' features in the compass signal that could explain the astonishing precision of the avian compass and its sensitivity to radiofrequency noise. In the first half of this thesis, two different models are used to explore the resilience of the compass to restricted rotational motion of individual radicals, with a focus on the flavin and tryptophan radicals in the proposed magnetoreceptor, cryptochrome. Fast, highly constrained motion is found to be crucial for the flavin radical, whilst the tryptophan radical can be allowed greater motional freedom, in keeping with its position near the surface of the protein. However, even in an optimised system, very little compass information is likely to survive in the presence of realistic relaxation, suggesting that our current understanding of the radical-pair mechanism may be incomplete.
Chapter 7 investigates how relaxation effects could be exploited to probe the function of cryptochrome. An experiment in which relaxation rates are locally enhanced by the presence of the biomimetic, superparamagnetic nanoparticle magnetoferritin is proposed and assessed. This experiment could provide much-needed evidence for the identity of the magnetoreceptor, allowing for more focused investigation of the compass mechanism.
Finally, the requirements for highly restricted motion and long-range ordering of the magnetoreceptors make the radical pair compass inherently sensitive to polarized light. This is potentially problematic because natural variations in skylight polarization could compromise detection of the magnetic field. A combination of algebraic and biological arguments are used to demonstrate how unwanted information can be filtered out of the compass signal by taking the ratio of signals from two neighbouring cells related by a 180° rotation about their line-of-sight. The combination of magnetic field patterns from the two cells additionally helps to pinpoint a precise heading.

Keywords: Spin Chemistry
Redfield Theory
Magnetoreception
Spin Relaxation
Radical Pair Mechanism
Advisor: Hore, P
Coherent terahertz Smith-Purcell radiation generated by the microbunched electron beam

The main objective of the thesis is to investigate the generation of coherent terahertz (THz) Smith-Purcell radiation using microbunched electron beams. Several ways of generating electron microbunches were considered and a method to monitor the separation between microbunches was developed. Microbunch trains, with picosecond (or sub-picosecond) periodicities, were generated through a variety of methods, including the modulation of a long electron bunch in a plasma channel, direct generation of microbunches from a photocathode (at KEK-LUCX, Japan), and the modulation of a long bunch (with an initial density modulation) using the longitudinal space charge forces during its propagation in the beamline (at TTX, China). The method to monitor the periodicity of microbunch trains was based on the analysis of coherent Smith-Purcell radiation and experiments were carried out with two microbunches to confirm its validity. Furthermore, the generation of coherent THz Smith-Purcell radiation using microbunch trains with tunable periodicities was investigated. The properties of the radiation generated were studied. Numerical simulations and experimental measurements have confirmed that the microbunching of electron bunches results in the intensity of the generated coherent Smith-Purcell radiation concentrating at around the microbunch frequency. These proof of concept studies demonstrate the possibility of the generation of high power, broadly tunable THz radiation using microbunched electron beams.

Advisor: Konoplev, I
Characterisation of the differentiation process of induced pluripotent stem cells (iPSCs) into mesenchymal stem cells (iMSCs)

Mesenchymal stem cells (MSCs) are adult stem cells derived from soft tissue or bone marrow (BM) and are widely investigated due to their multi-potential differentiation and immunomodulatory abilities. They are skeletal lineage progenitors, being able to differentiate into various cell types including osteoblasts, adipocytes, chondrocytes, myocytes and more. However, MSCs are limited for use in clinical settings and for in vitro purposes. The main limitation for in vitro-based research is cell senescence, which occurs during sub-culturing of MSCs. MSC-like cells, termed induced MSCs (iMSCs), are derived from induced pluripotent stem cells (iPSCs) and display similar characteristics as MSCs. Yet, these iMSCs are not restricted by senescence, making them an attractive alternative source. The differentiation of iPSCs into iMSCs has been recently described, however mechanisms that underlie this process and the comparison between iMSCs and BM-MSCs are largely lacking.
This study aimed to identify a suitable protocol for the differentiation of iPSCs into iMSCs. The chosen protocol consists of a 14-day phase 1 followed by a passaging protocol, thus selecting for cells primed for stable differentiation into the mesenchymal lineage. Detailed characterisation of the mechanistic actions during the differentiation was documented. Moreover, iMSCs were compared to BM-MSCs on a proteomic and transcriptomic level. Known mesenchymal stem cell (MSC) and pluripotency markers expression levels were measured using mass cytometry (CyTOF) and RNA sequencing techniques. Results display a gradual loss of pluripotency gene and protein expression as well as an upregulation of MSC markers, indeed indicating a shift towards a more mesenchymal-like stem cell type. However distinct features between bone-marrow derived MSCs and iMSCs are observed, including an apparent lack of adipogenic differentiation in iMSCs despite osteogenic differentiation potential.

Advisor: Oppermann, U
Philpott, M
How can a peer mentoring programme be developed in order to help meet a school's pastoral care development priorities?

This research project explores the development of a peer mentoring programme in my school during the academic year 2017-18. The main focus of the project is how the peer mentoring programme can be aligned to help fulfil my school’s pastoral care priorities. The importance of encouraging a whole-school approach to well-being is also considered. There is currently a growing awareness of pastoral issues such as mental health in schools, and the research regarding peer mentoring is developing concurrently. For instance, recent governmental guidelines (2017) encourage peer support as a proactive tool to tackle mental health issues, and studies demonstrate that peer mentoring can develop resilience in young people. However, the research regarding peer mentoring is limited.
Action research was employed for this project in order to ensure a continued focus on the development of the peer mentoring programme and to ensure regular collaboration with both pupils and staff, allowing for both feedback on interventions and suggestions for the future. Three cycles were undertaken, with a key focus on pastoral priorities for each cycle. Mixed methods surveys were employed in order to allow for both quantitative and qualitative data. This provided a broad range of responses from the pupils and staff which the programme engages with.
This project resulted in significant changes to the peer mentoring programme in my school setting. Working in collaboration with a range of pupils and staff has allowed me to re-structure the peer mentoring programme for the next academic year, focussing on the quality rather than quantity of peer mentoring available, and employing participatory action research has encouraged a more meaningful engagement with the development of the programme. A whole-school approach to well-being is, over time, being developed in my school setting, and the peer mentoring programme will play a proactive part in that.

Keywords: MLT2018
MLT
What is the impact of collaborative working between teachers on their classroom practice?

Socio-cultural theorists and empirical studies suggest teachers increase their expertise through collaborative learning in environments with specific modi operandi and ways of thinking. However, few of these studies examine the classroom impact of this collaboration. In this inquiry, the factors which enable and constrain collaborative task design between teachers in a large modern languages faculty are explored. The classroom impact of this collaboration and the reasons for differences between colleagues are then examined. Classroom impact appeared most significant when colleagues had the autonomy to choose their area for development, based on an immediate gap identified in their pupils’ knowledge and when a menu of research-informed classroom tasks to bridge that gap was provided. Factors such as trust between participants, teacher agency and beliefs, the extent to which managers relinquished their power and competing demands on teachers’ time also explained differences in classroom outcomes. An additional finding, often neglected in the write-ups of action research, are the challenges faced in data-collection and interpretation, when the researcher and the participants’ line manager are one and the same person.

Keywords: MLT2018
MLT
Intrinsic motivation: exploring the effect of praise and reward on pupil engagement

Motivating pupils to learn in the classroom has been on the agenda in schools and academic research for decades. This case study takes a look at school where pupils are not fully engaging in their education and implements an intervention with a view to increase the pupil motivation, and more specifically the pupils’ intrinsic motivation. Findings from the intervention show that there is a strong causal link between pupil motivation in the classroom and praise and reward.

Keywords: MLT
MLT2018
Phenotypic and genotypic characterisation of juvenile myelomonocytic leukaemia

Paediatric myelodysplastic syndromes and Juvenile Myelomonocytic Leukaemia (JMML) are very rare haematological diseases of childhood, with an estimated incidence of 1 case per million. Due to their rarity there is relatively little known about their natural history and disease biology. As a result, there are often significant challenges in establishing a diagnosis and there are very few treatment options available for these children. The only curative treatment is bone marrow transplantation but even this is associated with a high risk of disease relapse, particularly in JMML where relapse rates are approaching 35%.
In the work described here, I first set up a national observational study to prospectively collect serial patient samples in order to phenotypically and molecularly characterise these patients at diagnosis and to establish the basis for a prospective natural history study. The clinical and molecular characterisation of these diseases allowed me to devise new diagnostic and management algorithms for paediatric MDS and JMML.
In order to understand more about the biology of this group of disorders I decided to focus on JMML as this was the largest distinct group of patients enrolled in the study. My specific aim has been to identify and characterise the disease-propagating population in JMML (the JMML 'leukaemic stem cells, LSC); which is a crucial step in understanding the disease evolution and dynamics of relapse. Prior to this work, there was almost nothing known about the haematopoietic hierarchy in JMML and the impact of JMML-associated mutations on haematopoiesis. With this study I analysed the JMML haematopoietic stem cell and progenitor cell (HSPC) compartments gaining new insights into the architecture of the JMML HSPC and their lineage potential. Using a single cell genotyping approach I was able to map the JMML mutations onto the haematopoietic hierarchy identifying for the first time the cellular compartment in which the JMML-associated mutations originate. The stem cell capacity of candidate JMML LSC was assessed with in vitro and in vivo stem cell assays establishing the identification of the disease propagating population(s). Molecular techniques, including RNA sequencing, then allowed me to molecularly characterise the JMML LSC and identify putative disease-specific targets and biomarkers that might be utilised in the future for disease burden monitoring and more effective treatments.

Keywords: Targeted sequencing
Single cell genotyping
Leukaemia stem cell
Stem cell assays
Advisor: Roberts, I
Mead, A
Genetic dissection of the regulation of chloroplast protein import by SP1-type ubiquitin E3 ligases

Chloroplasts are photosynthetic organelles in plants, and their functions are dependent on the import of thousands of proteins from the cytosol. These proteins engage with the translocon at the outer envelope membrane of chloroplasts (TOC), which acts as a selective conduit for the first stage of their import across the double membrane system. Mutations affecting the TOC components, such as plastid protein import 1 (ppi1) of Arabidopsis thaliana, can hinder the efficiency of import activity, and have consequences for organelle development. A screen for second-site suppressors of ppi1 identified a novel regulator of the TOC machinery called suppressor of ppi1 locus 1 (sp1). Two homologues of SP1, SP1-Like1 (SPL1) and -2 (SPL2), were identified in Arabidopsis based on sequence similarity. In this thesis, the function of these two homologues was characterized in relation to chloroplast biogenesis. While spl1 null mutations had no profound effect on the ppi1 mutant, knockdown of SPL2 exhibited a weak suppression phenotype that could be attributed to a recovery in protein import activity and chloroplast development. Immunoprecipitation results revealed a strong physical interaction between SPL2 and the TOC components. Manipulation of SPL2 gene expression caused phenotypes reminiscent of those caused by SP1 manipulation during the dynamic process of leaf senescence. In vitro ubiquitination analysis showed that SPL1, unlike SP1 and SPL2, does not possess E3 ligase activity, but rather has an inhibitory effect on SP1 activity via an unknown mechanism. Accordingly, spl1 null mutants displayed an opposite phenotype to sp1 mutants during leaf senescence (i.e., senescence was accelerated), suggesting that SPL1 may be a negative regulator of SP1. However, SPL1 is only observed within the Brassicaceae family, which raises questions about the wider relevance of its role across different species. Lastly, a screen for new sp1 enhancer mutants was conducted, and this identified three putative sp1 enhanced chlorophyll (spec) mutants that display elevated chlorophyll levels, intermediate between those of sp1 ppi1 and wild-type plants. Mapping of the spec mutations by whole-genome sequencing identified several gene candidates in each case, which will require further analysis in order to conclude final identification of the causal locus in each case. Overall, the results revealed new regulatory mechanisms governing the chloroplast protein import machinery.

Advisor: Jarvis, P
Langdale, J
How does leukemia disrupt hematopoiesis?

Acute myeloid leukemia (AML) is an aggressive hematological malignancy which, if left untreated, results in complete bone marrow (BM) failure characterised by anemia, neutropenia and thrombocytopenia. Although the symptoms of AML can occur at low levels of disease burden, their manifestation is often attributed to a loss of functioning hematopoietic cells via physical displacement. Evidence now suggests, however, that leukemic populations are capable of directly interfering with supportive BM niches and neighbouring hematopoietic cells. This therefore proposes that mechanisms unrelated to displacement may play a role in hematopoietic disruption during AML.
A clinically accurate, kinetically tractable model of AML was generated through the transplantation of mutant Cebpa leukemic cells into recipient mice. At the onset of disease, committed BM erythroid progenitors were impaired immunophenotypically and functionally, and was an effect also observed hierarchically upstream in erythroid-forming Gata1-EGFP+ progenitors. In contrast, committed myeloid progenitors were expanded as a result of leukemic cell-expressed FLT3L and CCL6. Moreover, HSCs displayed no long-term defects in multi-lineage reconstitution once removed from the leukemic environment. Of note, sinusoidal BM vascular endothelial cells (VECs), demarcated by their expression of VCAM1, were reduced in frequency during leukemic development, whereas arteriolar VECs were expanded. Lastly, aged mice were capable of supporting leukemogenesis, which was accompanied by significant immunophenotypic and transcriptional changes to BM niches. Collectively, the findings presented in this study shed new light on the global immunophenotypic, functional and transcriptional changes that occur across several distinct BM populations during leukemia and ageing.

Advisor: Nerlov, C
Milne, T