VictorJuiz/thesis huggingface dataset:
The sedimentology, mineralogy and geochemistry of the ~1.4 ga Roper Superbasin Northern Australia
Keywords: precambrian
mesoproterozoic
McArthur Basin
Velkerri Formation
Sherwin Ironstone
Black Shale
Tijunna Group
Iron Formation
Roper Group
sedimentology
Geology

Eukaryotic life arose around 1.6 billion years ago, but for much of Earth history has been ecologically and biologically conservative. There is a gap of around a billion years between the first eukaryotic fossils and their rise to ecological prominence around 800 million years ago. The causes of this delay in eukaryote evolution are widely debated, but in recent years the role of oxygen, has been proposed as a major driver in the evolution of complex life. Oxygen drives metabolism for energy intensive organisms like eukaryotes, it is also a key component of eukaryotic biomolecules. Oxygen is also a key player in the cycling of essential bio-limiting nutrients such as phosphorus. Some have hypothesized that in the low oxygen Proterozoic world, phosphorus was scarce and thus limited primary productivity, slowing the oxygenation of the Earth and locking the planet into a billion-year long period of environmental stasis. Additionally, the iron rich oceans are proposed to have sequestered phosphorus in sediments as iron phosphate minerals. To date, neither of these hypotheses have been robustly tested against the sedimentary record.
To test these two hypotheses, I conducted a high-resolution study of exquisitely preserved ~1.4 - 1.3 Ga sedimentary rocks from the Roper Superbasin (RSB), northern Australia. I find no evidence of sedimentary sequestration of phosphorus as Fe-phosphate in the examined sediments. Additionally, I find that sediments were deposited under ferruginous and oxic conditions, contrary to published work. Also, in contrast to previous work, I find that the RSB is a restricted basin and underwent periods of disconnection from the global ocean. As an epicratonic basin enclosed on multiple sides, the RSB is unsuitable for investigating global ocean conditions in the Proterozoic. However, such locations appear to be commonnly preserved in this interval, and may have been important sites for phosphorus deposition. Regardless of ocean connection the RSB, and locations like it, are where we find eukaryote fossils, and so were obviously an important part of eukaryote evolution. The questions raised by this study highlight how much is left to learn about Earths distant past and the organisms that inhabited the planet at that time.
Investigations into inflammation and nerve regeneration in a human model system of neuropathic pain
Keywords: Nerve Regeneration
Inflammation
Neuropathic Pain
Pain
Nerve Injury

Neuropathic pain is a serious and debilitating disease affecting a large proportion of the population. The disease is caused by direct damage to the nervous system and is often chronic in nature. Neuropathic pain is typically poorly treated, with patients often experiencing inadequate relief from symptoms. Part of this issue stems from ineffective treatment options while a lack of understanding of the disease pathology also presents as a major issue.
Recent findings have emerged which implicate the immune system in the initiation and generation of neuropathic pain. These studies have highlighted the role of inflammatory mediators including cytokines and immune cells as being heavily involved in the development of neuropathic pain. The majority of this work has been conducted in pre-clinical animal models where severe nerve injury paradigms are used. These experiments have proven useful in identifying the role of inflammation in neuropathic pain but do not necessarily reflect the nerve injury present in humans. Furthermore, preclinical findings do not always translate to patients in the clinic, which has resulted in a deficit in novel, effective neuropathic pain therapies. The mechanisms of nerve regeneration that occur after nerve injury are also incompletely understood. Similar to neuropathic pain, much work has been done using animal model systems of nerve regeneration, however human nerve regeneration presents with unique challenges and is often incomplete. Further studies are therefore required in humans to elucidate the precise role and action of inflammation in patients with neuropathic pain and to determine the mechanisms that are driving nerve regeneration after injury.
Carpal tunnel syndrome is an entrapment neuropathy commonly occurring in patients which presents as a unique model system with which to study neuropathic pain. Due to the unparalleled opportunity to collect tissues from these patients, both inflammation and nerve regeneration can be explored in the context of neuropathic pain. This thesis will firstly endeavour to describe and characterise inflammatory associations with neuropathic pain in patients with carpal tunnel syndrome using both genetic and molecular approaches. Using these same approaches, I will also investigate nerve regeneration after injury to uncover mediators stimulating nerve growth and determine associations with inflammation in this process.
Model-driven reconstruction in atom probe tomography
Keywords: atom probe tomography
boundary element methods
semiconductor imaging
FEM-BEM coupling
continuum modelling
image registration
level set methods
image reconstruction

This thesis presents a new continuum model for predicting results from atom probe tomography (APT) experiments. Unlike previous atomic-scale approaches, this continuum approach makes realistic specimen simulation computationally tractable, enabling direct quantitative comparison with experiment. Here, specimen evaporation resembles a moving boundary problem, where the electrostatic field at the surface and in the surrounding vacuum must be solved throughout time. Tracking the surface implicitly as a contour in a scalar field ensures numerical stability of surface faceting and evaporation of voids (cavities). The electric field is efficiently solved by a boundary integral equation. Proof-of-concept submodels for laser-assisted evaporation, crystallographic faceting, and material dielectricity are also considered. Predictions are shown to agree well with experiment.
The application of the model to directly performing data reconstruction is also considered. A protocol is proposed where the specimen model for an APT analysis is calibrated against experimental data by solving a generalised image registration problem. Here, model parameters are constrained by maximising the similarity between the model and experimental data, measured using mutual information (MI). Through this proposed method, large-scale trajectory distortions are shown to be corrected for two experimental semiconductor devices: a multilayer structure and a fin field-effect transistor (FinFET) structure.
Atom probe tomography of irradiated zirconium alloys
Keywords: irradiation induced precipitation
corrosion
atom probe tomography
heavy ion irradiation
neutron irradiation
Zr-2.5Nb
proton irradiation
clusters
CANDU
zirconium alloys
irradiation
MUZIC-3

Zirconium alloys are used for nuclear reactor fuel cladding and structural components, but aqueous corrosion of these components is a significant life-limiting factor. A mechanistic understanding of the corrosion of zirconium alloys is sought which could aid in alloy development, and explain the improved in-reactor corrosion performance of Zr-Nb alloys compared to Zircaloy (Zr-Sn-Fe-Cr). This project was carried out as part of the third Mechanistic Understanding of Zirconium Corrosion (MUZIC-3) programme, which was established to work towards this goal.
Zirconium alloy corrosion is highly sensitive to small differences in alloy chemistry, and the C4 model has shown that oxidation kinetics are determined by aliovalent dopants in the oxide from the alloying elements. This indicates the importance of the elements in the base metal, such as niobium and iron, which are in low concentration in α-Zr and challenging to quantify. This project was carried out using atom probe tomography (APT) to quantify the nanoscale changes to the alloy chemistry in a Zr-2.5Nb pressure tube alloy before and after irradiation. A key aim was to quantify the solute niobium and iron concentration left behind in the α-Zr matrix after irradiationinduced clustering.
This thesis contains three experimental chapters corresponding to the irradiation of the same Zr-2.5Nb alloy by neutrons, protons, and krypton ions. Irradiation-induced clusters were found to separate into two distinct categories with increasing dose; iron-rich clusters with a range of compositions consistent with the Zr(Nb,Fe)2 Laves phase, which reject iron with increasing dose and become niobium-rich clusters of β-Nb composition. The concentration of niobium and iron was significantly lower in the α-Zr matrix as a result of the clustering. Before irradiation, the β-Zr phase had decomposed into β-Nb and α-Zr, and the β-Nb phase was found to be highly stable under high temperature neutron irradiation, contributing to corrosion resistance.
The development of novel therapeutic vaccines for chronic hepatitis B infection
Keywords: HBV
vaccine
ChAdOx1
hepatitis B

Chronic infection with Hepatitis B virus (HBV) remains a significant health problem, infecting millions of people worldwide. Cirrhosis and hepatocellular carcinoma, the sequalae of longstanding HBV infection, have a high mortality. Current therapy controls HBV replication but does not eradicate the virus, and therefore most people require life-long treatment. A robust adaptive immune response is required to control acute HBV but is dysfunctional in individuals that go onto develop chronic infection. The immune response is an attractive target for novel HBV therapies, which aim to induce functional cure of HBV in finite treatment courses by restoring HBV specific immunity. Therapeutic vaccination, which describes the process of delivering non-infective HBV antigen into the body in order to induce or boost cellular immune responses to HBV, is one strategy under investigation for chronic HBV treatment.
In this thesis I evaluate the novel vaccines ChAdOx1-HBV and MVA-HBV as candidates for HBV therapeutic vaccination. I investigate their immunogenicity in heterologous prime-boost strategies in healthy mice, describing in detail the fine specificity, functionality and phenotype of vaccine induced T cell responses in the blood and the liver. I also describe the safety and immunogenicity ChAdOx1-HBV in a phase-1 open label clinical trial in healthy volunteers and patients with chronic HBV infection. This work is important to inform the development of therapeutic strategies using ChAdOx1-HBV and MVA-HBV in patients with chronic HBV going forward.
Ubering while poor: the socio-political implications of digital platforms in underdeveloped contexts
Keywords: Algorithmic Control
Development
Politics of Platforms
Digital Platforms
Platform Strategy
Ride-hailing Platforms
ICT for Development
Algorithms

Digital platforms that employ algorithmic technologies to facilitate transactions have become popular in many contexts characterised by underdevelopment. What does it mean for society and its politics when people in such contexts become pervasive users of digital transaction platforms?
I address this by venturing out to Manila and Jakarta—Southeast Asia’s largest megacities—to study ride-hailing platforms through interviews, ethnography, and document analysis. I present three studies, which tackle different aspects of the question. The first study examines how digital platform companies employ strategies to win legitimacy in new markets. The second study investigates how the adoption of digital transaction platforms affects the social clamour to improve public systems. The third study explores the strategies that consumers develop to protect themselves against the algorithms and rules that represent the platform’s interests.
I make two important contributions to digital platforms research. First, I uncover previously unexamined ways in which platforms’ characteristics provide powerful advantages to platform companies in shutting down opposition and strengthening society’s reliance on their services. For example, since workers buy assets for the platform, the investment compels them to defend the platform’s interests, enhancing the platform’s power to resist and influence authorities. Second, I show how adverse conditions shape the socio-political impacts of digital platforms by amplifying the advantages of platform companies, sometimes triggering socio-political feedback loops that perpetuate underdevelopment. For example, deficiencies in pre-existing public systems can drive platform users to politically support technological solutions that benefit few, while devaluing public systems that benefit many, thus weakening the social clamour for improvements in public services.
The lessons from underdeveloped contexts need not be confined to developing countries. Adverse conditions that hinder people from living a good life exist everywhere, even in so-called developed countries. Thus, my findings can help many governments and societies who are “Ubering while poor”—that is, using digital platforms in adverse contexts—to better understand the perils and potentials of digital technologies.
What the f*ck do I know?: Knowledge of and encounters with English profanity by Japanese learners
Keywords: EFL taboo language
EFL cursing
EFL swearing
EFL profanity

Little research has been done on knowledge of and encounters with English profanity in EFL populations. Moreover, no research has been done in Japanese EFL learners, whose language background creates unique challenges to understanding and learning this language. Therefore, a two-part research design was used to provide insight on this topic with this group of learners. First, a questionnaire was developed to study three aspects of profanity knowledge, background factors related to this knowledge, and frequency of encounters with profanity in various daily life activities. Results found low productive scores and that overall higher scores were significantly related to the factors of English proficiency and time spent living in English-speaking countries. Participants reported the situations where they most frequently encountered profanity to be from watching movies and reading comments online. Using results from the questionnaire, two simulated real-world scenarios were designed to study what elements negotiated learner engagement with profanity when encountered in these two situations. Data was collected via a stimulated recall interview and analyzed to find 7 contributory factors that negotiated engagement with taboo language: stimulus format, subtitles, word form, emotional impact, frequency, L1, and abroad experience. The addition of three deviant cases allowed for one further element of attitude to be found. Results are followed by implications for pedagogy, materials design, and future research.
Note. Please be advised that this study contains frequent usage of strong language both in English and in Japanese.
Elucidating the mechanism of action of novel small molecule activators of differentiation in acute myeloid leukemic cells
Keywords: acute myeloid leukemia
differentiation

Acute Myeloid Leukaemia (AML) is a haematopoietic malignancy which comprises of different genetic subtypes with a common hallmark of differentiation arrest. In abnormal haematopoiesis, overcoming the differentiation blockade has emerged as an attractive therapeutic strategy. While current approaches target specific genetic mutations, herein we were interested in identifying novel agents which may be effective in multiple patient populations. In a small phenotypic screen, compounds were identified which increased the expression of CD11b- a cell surface receptor known to indicate differentiation of myeloid lineages. In an assay with six genetically distinct AML cell lines, clinical histone deacetylase inhibitors (HDACi) and some novel derivatives were observed to cause an upregulation in CD11b expression. These were further validated by a change in cell morphology and a block in proliferation, with a cell cycle arrest at G1 phase. The novel derivatives were successfully resynthesized along with potential inactive ones devoid of the zinc ion active site binding motif. Recombinant HDAC inhibitory assays and in situ HDAC inhibitory assays were performed which allowed to understand the profile of all the derivatives synthesized and be distinguished as HDACi and non HDACi. To elucidate the mechanism of action of these novel HDACi in detail, we explored various cell cyclins and cell cyclin inhibitors related to G1 arrest. By western blot it was seen that the novel HDACi causing G1 arrest did not cause the concomitant increase of cell cyclin inhibitor p21 unlike mocetinostat, suggesting a potential secondary downstream target for some of the effects observed. Further work using RNA sequencing allowed us to better understand the molecular events that underpin these responses and helped us confirm the selectivity of our novel HDACi. It was interesting to observe that the derivatives serving as mechanistic probes devoid of zinc ion active site binding motif were not HDACi but still initiated differentiation, further confirmed by the observed block in proliferation and the change in morphology and were recognised as non HDACi. However, the cell cycle arrest with these non HDACi was observed at G2 phase in HL60 cells. Moreover, the sequencing results of these derivatives highlighted the role of cell cycle regulatory kinases leading to G2 arrest and the concomitant increase in CD11b expression suggesting these may be future therapeutic targets for differentiation agents in AML.
Divergence and mismatches in Portuguese morphology and syntax
Keywords: diachronic
Lexical Functional Grammar (LFG)
mismatches
syntax
Portuguese
Paradigm Function Morphology (PFM)
Romance linguistics
morphology

This thesis proposes an integration of Paradigm Function Morphology (PFM) as the morphological component within the Lexical-Functional Grammar (LFG) architecture, applying the combined theoretical framework LFG-PFM to account for diachronic data. The theory is developed by application to two case studies from Portuguese involving mismatches between different levels of grammatical structure and resulting in divergence between varieties of the language. In each case, I give a new presentation of the Portuguese phenomena, which have not previously been treated in LFG or PFM.
The first case study is the double past participle phenomenon, in which an arbitrary set of verbs unexpectedly have two past participle forms split between active and passive contexts, where most verbs only have one form. There is significant variability in the application of the phenomenon to lexemes over time and across varieties of Portuguese. I show that this can be successfully analysed in LFG-PFM using lexical specification and inflection classes. In addition, I clarify the role of irregular stem roots in the double past participles and identify possible trajectories of change. The second case study is Portuguese grammaticalised pronouns, which have developed from noun phrases and show interesting mismatch behaviour in their agreement patterns. My analysis uses distinctions in the PERSON feature at the levels of semantic structure and functional structure to capture various mismatch patterns seen across varieties of European and Brazilian Portuguese, including differences in the choice of coreferent pronouns and verb agreement.
The two case studies together demonstrate the success of the LFG-PFM approach of treating separate modules of the grammar independently. This allows a fine-grained account of the incremental changes that contribute to the development of distinct varieties of a language, and offers new insights into the morphological and syntactic phenomena at issue.
Development of all-in-one CRISPR/Cas9 and CRISPRi AAV constructs to treat autosomal dominant retinitis pigmentosa
Keywords: rhodopsin
crispr-cas9
retinitis pigmentosa
crispr
gene therapy
aav
gene silencing
crispr/cas9
crispri

Dominant mutations in RHO (rhodopsin) are the most common cause of autosomal dominant retinitis pigmentosa (RHO-adRP). RHO-adRP causes progressive loss of rod cells, followed by cone cells, leading to blindness. This disease is a candidate for CRISPR gene editing, as reduction of mutant rhodopsin is associated with phenotypic rescue. This thesis optimises all-in-one CRISPR/Cas9 and CRISPRi adeno-associated viruses (AAVs) and explores their potential as RHO-adRP gene therapy vectors.
Following construct optimisation in vitro, a CRISPR/Cas9 and CRISPRi plasmid carrying SaCas9 and dSaCas9.KRAB, respectively, were generated. Both demonstrated knock down of endogenously expressed EGFP in a transgenic cell line. For allele-specific knock down of RHO, the CRISPR constructs must target a region unique to the mutant allele. Bioinformatic screening of RHO identified seven non-pathogenic single nucleotide polymorphisms (SNPs) that were targetable with SaCas9. Two of these SNPs could be targeted allele-specifically, with high CRISPR/Cas9 gene disruption and CRISPRi gene repression rates of 38.5-73.2 % and 43.1-65.8 %, respectively. In heterozygous patients, targeting the SNP on the mutant RHO offers a mutation-independent allele-specific targeting strategy.
As a proof-of-concept for targeting rod cells, the AAV were subretinally injected into Nrl-EGFP mice, in whom enhanced green fluorescent protein (EGFP) expression is limited to rod photoreceptors. To restrict Cas9 expression to rods cells only, a novel 154 bp rod cell-specific promoter was identified. This shortened promoter from the PDE6B gene was active in human retinal explants, the human retinoblastoma-derived cell line Y79, and drove strong rod cell-specific expression in mice. The CRISPRi AAV was unable to repress EGFP, despite high transgene expression. The CRISPR/Cas9 AAV however, drove strong EGFP disruption. It produced 4.1 % EGFP indels, resulting in a reduction of EGFP mRNA and fluorescence of 55.3% and 36.5 %, respectively. The all-in-one CRISPR/Cas9 AAV is therefore able to drive strong gene disruption in rod cells in vivo, making it a useful vector for the treatment of RHO-adRP.
This thesis describes in detail the development of these all-in-one CRISPR/Cas9 and CRISPRi AAV vectors from proof-of-concept to in vivo study and advances the potential for using such therapies in future treatments of RHO-adRP.