VictorJuiz/thesis huggingface dataset:
Optimising CRISPR for targeting of primary haematopoietic stem cells
Keywords: Haematopoiesis
CRISPR
Leukaemia
Genome Editing

CRISPR (clustered regularly interspaced short palindromic repeats) offers an unprecedented array of genetic tools for treating and modelling haematological disorders. However, there are concerns about its safety. CRISPR-based editing can induce upregulation of TP53 associated pathways, a finding particularly important for clinical applications. The impact of CRISPR-based editing on haematopoietic stem cells (HSCs) has not, however, been interrogated in detail.
In the work described in this thesis, I initially optimised the CRISPR approach in mouse haematopoietic stem and progenitor cells (HSPCs) by targeting the fluorescent reporter tdTomato, as this enabled lineage tracking of edited HSCs. I then sorted edited HSCs for RNA-Sequencing (RNA-Seq) 24 hours post-editing. This allowed me to assess the immediate transcriptional consequences of genome editing. Using in vivo transplantation, I serially tracked the contribution of edited cells to all blood lineages. I carried out RNA-Seq on edited HSCs 18 weeks post-transplant which allowed me to assess whether the short-term changes in transcriptional profiles were maintained long-term.
To demonstrate the applicability of the genome editing approach I had optimised to a disease model setting, I targeted the NF-1 gene which harbours loss of function mutations in 15% of JMML patients. While mouse models exist for this disorder, most lack a human fetal context. I first optimised targeting of the NF-1 locus in a GM-CSF dependent cell line (TF-1). I then carried out in vitro NF-1 targeting studies using human cord blood (CB) to establish a GM-CSF hypersensitivity phenotype. Finally, I set up in vivo transplants of NF-1 edited human CB to establish whether this could propagate the myeloid biased expansion characteristic of JMML.
In this way, I applied the CRISPR genome editing approach to study both normal and malignant haematopoiesis: first to establish the molecular and functional consequences of genome editing on normal haematopoietic output and second to model the consequence of NF-1 loss of function in a human fetal-like context.
Engineering a noise-free quantum memory for temporal mode manipulation
Keywords: Physics
Quantum memories
Quantum
Atom-light interactions

An optical quantum memory, a device which can store and retrieve on demand an arbitrary quantum state at the single photon level, has been identified as a significant cornerstone of photonic quantum technologies. The development of such a memory would allow the creation and development of a large number of quantum technologies. These would range from the ability to synchronise processing steps in an optical quantum computer, to the construction of a quantum repeater which would allow faithful transmission of quantum states over arbitrarily long distances.
In this thesis I investigate broadband light storage in a room-temperature Raman memory for purposes of quantum information processing with photons. During the course of this thesis, a novel scheme to suppress four-wave mixing noise is simulated, based on equations derived to describe the physics of the memory interaction. The experimental arrangement to test the suppression method is described and an original method using photon statistics is demonstrated. The results of these experiments prove the ability of the memory to retrieve and maintain the non-classicality of the state, given a single photon input.
Following the affirmation that, using this noise suppression technique, the memory can function at the single-photon level, I go on to consider how the temporal-spectral properties of a pulsed mode of light may be manipulated using the memory. There are two primary reasons for this investigation: 1) Increasing the efficiency of the read-in process by carving the optimum mode of the memory 2) Using the memory as a device operating in a high dimensional quantum information basis. The restrictions of such applications are considered and a method to test the efficacy of transformations in this basis is devised and experimentally tested. I also perform demonstrations of light storage using conventional temporal modes using a novel method of velocity selection within warm vapour.
Finally I detail further experiments that are achievable with the Raman quantum memory given the progress that has been achieved during my DPhil research. The results show that the Raman memory is a viable candidate for a practical route towards low-noise quantum storage and for manipulation of temporal modes of light.
Exploitation, technology and function of plant resins in Oceania: molecular analysis of ethnographic museum artefacts and the implications for archaeological resin analysis
Keywords: Canarium resin
Oceania
Xanthorrhoea resin
Resin analysis
Spinifex resin
Triterpenoid
Diterpenoid
Ethnobotany
Australia
Agathis resin
Hafting
Archaeology
Gas chromatography - mass spectrometry

Oceania has an extremely diverse and unique flora that includes many endemic species of restricted geographic range. This flora comprises coniferous, deciduous, and monocot plants and trees that include many resin-producing species. Plant resins have a long ethnobotanical history in Indigenous Oceania, as is recognised by some rare archaeological finds as well as a rich ethnographic record. In this study, gas chromatography-mass spectrometry (GC-MS) has been employed to chemically investigate resins of ethnobotanical importance in Oceania including Australia. A total of 173 samples of resinous material from ethnographic artefacts, currently held in museums, was analysed alongside botanically identified reference materials from in and around the area. The aim was to both contribute to our understanding of the role of resins in Indigenous Oceania, and provide a framework for efficiently and effectively analysing valuable resinous archaeological finds from the region.
Four main types of resin were found to be regularly used in various regions of Oceania, namely conifer-type diterpenoid, non-conifer-type diterpenoid, triterpenoid and phenolic resins. A number of samples have been identified to source family, genus and in some cases species, by comparison with authenticated resin samples collected from botanic gardens and herbariums. The results show that a much wider range of plant resins have been exploited in Oceania than has been generally recognised, particularly in reference to the descriptions of resin use in the ethnographic literature. The chemical characterisation of a range of resins including samples from three species that were previously unpublished has been presented. Also presented are the chromatographic profiles of ethnographically collected putative spinifex (Triodia) and northern ironwood (Erythrophleum chlorostachys) resins. The range of functions served by plant resins in Indigenous Oceania is discussed with an emphasis on both hafting and non-hafting uses.
Modelling the Late Devonian Climate: Implications for evolution and extinction
Keywords: Paleoclimate Modelling
Physical Oceanography
Devonian

The Devonian period (419.2 - 358.9 Ma) was characterised by a warm greenhouse climate which transitioned towards glaciation throughout the Late Devonian. This period in Earth’s history was punctuated by repeated environmental and biotic crises. A common feature accompanying these events was widespread ocean anoxia, typically recorded in the geological record by periodic organic-rich laminated shales. However, the relationship between climate, evolution and extinction in the Late Devonian remains unclear.
In the first part of this thesis, Late Devonian (375 Ma) boundary conditions are applied to an Ocean General Circulation Model (OGCM) forced by monthly atmospheric surface forcing to determine ocean circulation and likely regions of ocean anoxia. The model simulation oscillates between two quasi-stable states: (1) an unventilated phase where the ocean circulation is dominated by shallow tropical/sub-tropical cells; (2) a ventilated phase with globally strong deep ocean overturning. In the second part of this thesis, Late Devonian boundary conditions are applied to a Coupled Atmosphere-Ocean-Ice General Circulation Model (CGCM) and an Atmospheric Slab Ocean General Circulation Model (ASGCM). Comparisons of the atmospheric results highlight the importance of a dynamic ocean in transporting heat polewards. The CGCM ocean also exhibits two ocean states, although the ‘unventilated’ equivalent is termed the partly-ventilated state since there is a weak, deep overturning circulation restricted to the Northern Hemisphere.
Machine learning applied to prediction, control and planning from dynamic epidemiological models
Keywords: intervention planning
disease modelling
machine learning
malaria control

We are ever aware of the global impact of infectious disease transmission in shaping the reality of the world around us. For much of human existence transmitted infections have been the principle cause for loss of human life. Through their very nature, the transient threats of pandemics or endemic disease transmission remain a constant challenge to epidemiologists and are also at the forefront of shaping public policy decisions.
In order to bring the benefits of Machine learning (ML) to tasks such as optimal prediction, control and planning from epidemiological models of disease transmission, we need to define how principles, advancements and knowledge can be directed towards real-world progress.
This work outlines steps towards making better decisions based on learn- ing from epidemiological models under uncertainty. It considers how we can automate and scale epidemiological model value using Machine learn- ing. The thesis investigates a range of methods from Multi-Armed Bandit approaches to sequential decision making using Reinforcement learning (RL) based on simulation. We use Gaussian Process Regression for sample efficiency in learning value-functions, improving model predictions via Bayesian optimisation of epidemiological model parameters and develop surrogate model descriptions for sharing, abstraction and combination of models as learning environments. Finally, the necessary computational infrastructure for sharing and running models at scale is considered.
Essays on corporate finance in continuous time
Keywords: corporate finance
asset pricing
real options
contract theory

This thesis provides three contributions to theoretical corporate finance in continuous time. The first contribution focus on regulation over patent litigation, the second on management dismissal, and the third on the capital structure of financial institutions.
First, I study the effects of the Hatch-Waxman Integrity Act over the set of admissible financial positions available to an informed agent that requests an inter partes review to challenge a patent but wants to prevent expected losses of litigation. This Act requires that a person that short-sells the shares of a patent-holding company must wait ninety days before requesting an inter partes review. Enacting this Act does not harm informed agents. Instead, it decreases the percentage of the defendant's equity that a plaintiff must short-sell in order to hedge her expected loss of requesting the inter partes review. Also, short-selling hedging positions are smaller if the patent can inexpensively be converted into a commercial product, and if the value of this commercial product has low volatility.
Second, I develop a continuous time model to study the Leicester-Pearson phenomenon, that is, the atypical cases of managerial dismissal triggered by high firm performance. My explanation proposes that differences in the knowledge and exerted effort between a firm's incumbent manager and an outsider candidate can cause this phenomenon. The firm has an option to replace the incumbent which is exercised when the outsider is considered better for the existing cash-flow level after paying replacement costs. I derive the level of cash-flows that triggers dismissal and identify the key condition that sustains dismissal with increasing cash-flow performance. The incumbent always faces this phenomenon if the outsider has comparative advantage in the effort attribute for which it suffices to have lower outsider's risk aversion and effort costs.
Third, I study the relationship between three regulatory measures imposed in Europe after the 2008 crisis and the capital structure decisions of regulated banks. I analyse the increase of the level of coverage of Deposit Insurance Schemes, the introduction of the Private Sector Acquisition resolution tool, and the introduction of the bail-in tool. The introduction of these measures incentivises banks to decrease the ratio of equity over assets and to increase the ratio of deposits over total debt. Lastly, introducing the bail-in tool generates a recapitalisation option, that is, banks unable to rebalance their capital structure may have an incentive to increase ex-ante the weight of bail-inable debt over total debt if they expect that a potential bail-in will result in a value-enhancing recapitalisation.
Je m'ai fait mal quand j'ai tombé: a real- and apparent-time study of auxiliary alternation in intransitive and pronominal verbs in spoken Montréal French (1971-2016)
Keywords: multivariate analysis
variationist methodology
sociolinguistics
auxiliary verbs
Montréal French
alternation

My thesis investigates auxiliary alternation in spoken Montréal French between avoir ‘have’ and être ‘be’ in the twenty or so intransitive verbs that prescriptively require the latter (tomber ‘to fall’, partir ‘to leave’, rester ‘to stay’, etc.):
(1) J’ai tombé (AVOIR) vs Je suis tombé (ÊTRE) I fell/have fallen
This phenomenon has been documented in virtually all the French-speaking communities of North America. Sankoff & Thibault (1977, 1980) observed a rate of avoir generalization of 34% in the Sankoff-Cedergren Montréal Corpus (1971), and hypothesized that greater exposure to the standard “acts as a brake on the regularization of conjugation through the extension of avoir” (1980: 345). Using a trend study, I attempt to determine whether their ‘prediction’ is confirmed in real time and in apparent time. I also explore the alternation between auxiliary avoir and être within pronominal forms because they were not studied by Sankoff & Thibault:
(2) Je m’ai fait mal (AVOIR) vs Je me suis fait mal (ÊTRE) I (have) hurt myself
In 2016, I interviewed 48 native speakers of Montréal French and, with the mixed-effects statistical software Shiny Rbrul (Johnson 2017), I test various (socio)linguistic factors on the recorded intransitive and pronominal periphrastic tense tokens in order to determine the main influences on avoir selection.
The real-time comparison of my results with those of Sankoff & Thibault (1977, 1980) reveals that the auxiliary alternation observed in intransitive verbs has, overall, significantly decreased in Montréal French. The absence of any age effect in apparent-time suggests that in 2016 the change to être has almost reached completion, despite the lingering of a small stable variation in the lowest SPS. My data also show that avoir use in the periphrastic tenses of pronominal verbs is highly socially marked. This decline of avoir in Montréal French appears to illustrate a (re)alignment with standard French or dévernacularisation, thus confirming Sankoff & Thibault’s conclusions.
I then triangulate these findings through an analysis of grammaticality judgements performed by my 48 participants and of self-reporting judgements on auxiliary choice from 821 Montréalers of the crowdsourced corpus Français de nos régions (Avanzi et al. 2016). My 48 speakers were much more willing to accept avoir variants, with pronominal verbs even more so than with intransitive ones, than what could have been inferred from their own actual auxiliation patterns. As for the self-reporting judgements, the effects of the level of education of the participants and their gender were highly significant on the choice of auxiliary verb.
By investigating both intransitive and pronominal verbs and by analysing newly collected (production and grammaticality judgement) data, this sociolinguistic study of auxiliary alternation in Montréal French is the first of its kind.
Metamorphoses of bodies and desire: Making queer heterotopias in contemporary Japanese cinemas
Keywords: heterotopia
Japanese queer cinema
gender
family

This thesis discusses ‘queer’ and ‘heterotopic’ within the context of contemporary Japanese cinemas. So far, queer studies have proved how ‘queer’ is in itself peculiar and hard to pin down through a universal definition. Studying ‘queer’ thus requires multiple lenses and interdisciplinary approaches. This study argues that ‘queer’ is more than a theme confined to sex or sexuality, but also a methodology applicable to film studies and cultural studies in general. It suggests that when used to denote sexuality, ‘queer’ has become a norm and a social convention through the continuous historical reconstructions of it in relation to the changing socio-cultural context. Thus, by coupling ‘queer’ and ‘heterotopic’, this thesis talks about ‘queer’ but at the same time deconstructs it so as to break free the confinements that have been enforced upon queer studies. It further argues that ‘heterotopic’ indicates a state of fluidity and non-hierarchical openness. Therefore, by using ‘queer’ as a method to deconstruct and bring together these two paradigms in film analysis, it is possible to produce a powerful deconstructive effect and refresh our understanding of conventional concepts such as family, love, and intimacy.
Instead of analysing human interactions following orthodox patterns based on institutions like lawful marriage and registered family, this study reconfigures interpersonal connectivity and proposes a heterotopic mode of love, intimacy and family that rejects hierarchy and any normalised framework. It argues that through this mentality, film studies can transcend the boundary posed by heteronormativity and eventually release visual art from its confinements.
Galaxy formation and evolution from deep optical and infrared surveys
Keywords: Galaxy Evolution

In this thesis, I present results from population studies conducted on galaxies across most of cosmic time. Using the unique depth and area combination of modern, ground-based surveys allows for strong constraints to be placed on the number density of the most massive and luminous galaxies between redshifts of 0.1
First, I measure the stellar mass function of galaxies from 0.1
Second, I measure and examine the ultraviolet luminosity function of galaxies in the redshift range 3.5 -24) are high, generating a steep power law slope -2.1 < αAGN < -1.7. I propose that the large rise in space density of AGN over this time period can be attributed to a global increase in the number density of active black holes. Measurements of the galaxy population are found to match models which suggest that a steep bright-end slope is driven by dust obscuration and that mass-dependent quenching from AGN feedback is not yet significant at this time.
Methods of attributing human mobility to climate change: evidence from East Africa
Keywords: climate change
extreme weather events
human mobility
attribution

East Africa’s population is vulnerable to weather and climate-related events because of its reliance on pastoralism for livelihoods, economic security, and development. Recent weather and climatic extremes have included both recurring droughts and floods. This is paired with an ongoing humanitarian crisis, poverty, and conflict prompting changes in existing human mobility. However, the processes involved in these changes and the extent to which human-induced (anthropogenic) climate change plays a role are not yet understood. Despite awareness of climate impacts on society and the economy, weather and climate-related events and attributable links to anthropogenic climate change have received limited attention in research and policy. To circumvent this issue, an integrated attribution approach is developed which assesses the full chain of causality with human mobility as outcome, weather and climate-related events as human mobility drivers and potential inputs of anthropogenic climate change. This thesis focusses on the concepts, tools and techniques needed for the attributability of weather and climate-related events and human mobility in East Africa to anthropogenic climate change. It emphasizes the need for general models to account for the complexities of human mobility and how these can be applied in the context of a range of weather and climate-related events facing this region. These range from disentangling the diverse drivers of human mobility, to characterising climate-related human mobility, to modelling the probability and attributability of anthropogenic climate change. There is a need and responsibility to redesign climate science outputs to be proactive, agile, and socially just when confronted with increasingly likely compounding risks. New approaches must be utilised to feed into this need of science for society and regional decision-makers alike. Here, several examples of such approaches are presented which outline practical steps to improve our understanding of climate-related human mobility in East Africa and attributable links to anthropogenic climate change. This thesis concludes that an integrated attribution approach can be used to attribute weather and climate-related events and human mobility to anthropogenic climate change and is a promising method for modelling future implications of climate-related human mobility.
Investigating protein-protein interactions of the Bloom Syndrome complex
Keywords: Bloom Syndrome
DNA damage

Bloom Syndrome is a rare recessive chromosomal instability disorder, caused by loss-of-function mutations in the BLM helicase tumour suppressor. Patients develop a variety of developmental defects and have an increased predisposition to all cancers.
BLM interacts with TOP3A, RMI1 and RMI2 to form the BTR complex, which functions to promote the restart of stalled forks and the dissolution of double Holliday junctions during homologous recombination repair to the prevent the formation of sister chromatid exchanges.
Since most patient mutations abrogate all of BLM’s functions, it is unknown which specific function(s) are important for tumour suppression. Moreover, the functions of the unstructured regions are poorly defined. To address this, I aim to identify and characterize separation-of-function mutations within conserved motifs of the unstructured regions of the BTR complex.
Firstly, I identified several RPA binding motifs in BLM and RMI1 which are important for cellular resistance to HU but are not important the dissolution of dHJs. Secondly, I found that highly conserved FTF residues within the N-terminus of BLM are important for interactions with TOP3A, RMI1 and RMI2, which are partially functional in resistance to hydroxyurea treatment and suppression of sister chromatid exchanges. Thirdly, I found that conserved residues within the N-terminal dimerization helical bundle are important for BLM dimerization and that these residues are partially functional for resistance to HU treatment and suppression of sister chromatid exchanges.
My results demonstrate that there are several conserved unstructured motifs in BLM that mediate specific protein-protein interactions. Furthermore, my data proposes several models of how these motifs and interactions regulate several cellular functions of the BTR complex. This work may provide a future insight into which specific cellular functions of BLM are important for preventing tumorigenesis in future animal models in which the conserved regions we have studied are mutated.