VictorJuiz/thesis huggingface dataset:
Portfolio of compositions and critical writing
Keywords: composition
environment
Gerhard Richter
20th century music
opera
aesthetics
contemporary music
Margaret Atwood
The handmaid's tale
Valentyn Silvestrov
photography
glaciology
Roland Barthes

The portfolio of compositions comprises six pieces: a chamber opera, an orchestral piece and four shorter chamber works. These pieces are diverse and distinct from one another but collectively explore aesthetic tensions relating to tonality, aura and ontology. The largest piece is a chamber opera setting Margaret Atwood's novel, The Handmaid's Tale, which has been flexibly scored as a series of fragments in order to reflect the quality of her text. The remaining pieces draw influence from poetry, landscape and the environment. They all encompass a series of material contrasts but attempt to simply contain these tensions in some way, leaving them partially unresolved.
The thesis is a re-assessment of the music of the Ukrainian composer, Valentin Silvestrov, in particular, his 'metamusic' approach to composition that treats pre-existing styles as a form of musical metaphor. Through a series of comparisons with landscape and photography, I offer new vantage points for approaching the aesthetic issues present in his work, relating to aura, imitation and historical reference. The metaphors of landscape and photography might appear far removed from his work, but mediated by the work of the artist Gerhard Richter, offer a basis for critically analysing Silvestrov's approach. Furthermore, by drawing upon the theories of Walter Benjamin, Roland Barthes and the geographer, Stephan Harrison, I demonstrate how concepts from other disciplines can be recast in order to be effective for approaching both Silvestrov and Richter. As a form of conclusion, I consider the role of photography in the production of CD covers and how this relates to the reception of Silvestrov's metamusic in a commercial setting.
Numerical solution of nonlinear boundary value problems for ordinary differential equations in the continuous framework
Keywords: Chebfun
automatic differentiation
Frechet derivatives
deflation
automatic linearity detection
nonlinear boundary value problems

Ordinary differential equations (ODEs) play an important role in mathematics. Although intrinsically, the setting for describing ODEs is the continuous framework, where differential operators are considered as maps from one function space to another, common numerical algorithms for ODEs discretise problems early on in the solution process. This thesis is about continuous analogues of such discrete algorithms for the numerical solution of ODEs.
This thesis shows how Newton's method for finite dimensional system can be generalised to function spaces, where it is known as Newton-Kantorovich iteration. It presents affine invariant damping strategies for increasing the chance of convergence for the Newton-Kantorovich iteration.
The derivatives required in this continuous setting are Fréchet derivatives, the continuous analogue of Jacobian matrices. In this work, we present how automatic differentiation techniques can be applied to compute Fréchet derivatives. We introduce chebop, a Matlab solver for nonlinear boundary-value problems, which combines damped Newton iteration in function space and automatic Fréchet differentiation.
By proving that affine operators have constant Fréchet derivatives, it is demonstrated how automatic linearity detection of computed quantities can be implemented. This is valuable for black-box solvers, which can use the information to determine whether an iteration scheme has to be employed for solving a problem.
Like nonlinear systems of equations, nonlinear boundary-value problems can have multiple solutions. This thesis present two techniques for obtaining multiple solutions of operator equations: deflation and path-following. An algorithm combining the two techniques is proposed.
Studies of piRNA synthesis
Keywords: RNA silencing

RNA silencing is a form of post-transcriptional gene regulation, in which a small RNA guides a member of the Argonaute protein family in an effector complex to repress target gene expression. piRNAs, found in germ cells, are the most recently discovered major subset of small RNAs. A key known function of piRNA is to repress the transposable elements in the germline and maintain the germline genome integrity. The defining features of the piRNAs are 1) they are ubiquitously methylated at the 3’-end of the 2’-OH group by methyltransferase Hen1; 2) they associate exclusively with the Piwi subfamily Argonaute proteins. Much is not understood about the biogenesis and the regulation of the piRNA pathway. One of the fundamental questions is how the 3’-end of the piRNA is generated and recognised specifically by Piwi but not by Ago subfamily Argonaute proteins. In this thesis, the high resolution crystal structure of the Aubergine PAZ domain, a domain from a Piwi subfamily Argonaute, bound to a 7 mer single-stranded methylated piRNA ‘mimic’, reveals the mode of recognition for the 3’-end of piRNAs by Piwi subfamily Argonautes. The structure provides the molecular basis for why Piwi but not Ago PAZ domains preferentially bind to RNAs with 2’-O-methylation at the 3’-end, thus conferring substrate specificity. The structural results are confirmed by biochemical studies. Biochemical and biophysical studies on the methyltransferase Hen1 have provided insights into substrate specificity for piRNA 3’-end methylation and revealed a potential regulatory role for the C-terminal region of the protein. Extensive biochemical analysis defined a minimal active Hen1/short RNA complex, though crystallisation screening yielded no crystals for structure determination. Overall, this study provides insights into the generation and molecular recognition of the piRNA in animals.
edison - a novel model of otitis media
Keywords: deafness
mouse
otitis media
genetics

Otitis media (OM) is characterised by inflammation of the middle ear and is a common cause of conductive hearing impairment that places a substantial social, medical and economic burden on healthcare systems globally. Despite the importance of the disease, the aetiology of chronic middle ear inflammatory disease remains poorly understood. The development and persistence of chronic OM is multi-factorial with a significant genetic component. A new mouse model of chronic OM, edison, was generated by N-ethyl-N-nitrosourea (ENU) mutagenesis and discovered in a recessive screen at MRC Harwell.
Homozygous edison mice have craniofacial abnormalities, an emphysema-like lung phenotype and spontaneously develop a conductive hearing loss at 28 days as measured by ABR. Histological analysis shows the hearing loss is associated with the development of chronic OM in the middle ear, characterised by mucosal inflammation and highly cellular ear exudates. Similar to the Jeff and Junbo mutants, edison shows raised levels of Vegfa, Tnfα and Il-1β in middle ear fluids. A putative functional mutation was identified, resulting in a missense Leu972Pro change in a relatively unknown gene, Nischarin (Nisch). The identification of additional ENU-induced Nisch alleles, and subsequent characterisation, validated Nisch as the causative gene in edison.
NISCH selectively binds ITGA5, which is thought to have a role in modulating VEGF signalling through SRC and FAK kinases. A significant genetic interaction between Nisch and Itga5 exists and impacts upon development of chronic OM. Mice heterozygous for Itga5-null and homozygous for edison alleles show a significantly increased penetrance and severity of chronic OM. Analysis of downstream pathways suggests that the edison allele is impacting upon both RAC1 and TGF-β/SMAD signalling.
I also explored the potential use of the edison mouse as a model for bacterial challenge with the human otopathogen, NTHi. Similar to the Junbo infection model at MRC Harwell, the edison mouse was identified as a robust OM model for bacterial NTHi infection.
The edison mouse highlights a new candidate gene for susceptibility to chronic OM and will provide further insight into the genetic pathways and pathogenic processes involved in chronic OM.
Network pharmacology of the MPP+ cellular model of Parkinson’s disease
Keywords: systems biology
network pharmacology
mitochondrial dysfunction
Parkinson's disease
autophagy
MPP+

Parkinson's disease (PD) is an incurable neurodegenerative motor disorder caused by the inexorable loss of dopamine neurones from the substantia nigra pars compacta. Cell loss is characterised by the perturbation of multiple physiological processes (including mitochondrial function, autophagy and dopamine homeostasis) and much of this pathophysiology can be reproduced in vitro using the mitochondrial toxin MPP+ (1-methyl-4-phenylpyridinium). It was hypothesised that MPP+ toxicity could be modelled using protein-protein interaction networks (PPIN) in order to better understand the interplay of systems-level processes that result in eventual cell death in MPP+ models and PD.
Initially, MPP+ toxicity was characterised in the human, dopamine-producing cell line BE(2)-M17 and it was confirmed that the neurotoxin resulted in time and dose dependent apoptosis. A radio-label pulse-chase assay was developed and demonstrated that MPP+ induced decreased autophagic flux preceded cell death. Autophagic dysfunction was consistent with lysosome deacidification due to cellular ATP depletion.
Pertinent PPINs were sampled from publically available data using a seedlist of proteins with validated roles in MPP+ toxicity. These PPINs were subjected to a series of analyses to identify potential therapeutic targets. Two topological methods based on betweenness centrality were used to identify target proteins predicted to be critical for the crosstalk between mitochondrial dysfunction and autophagy in the context of MPP+ toxicity.
Combined knockdown of a subset of target proteins potentiated MPP+ toxicity and the combined resulted in cellular rescue. Neither of these effects was observed following single knockdown/overexpression confirming the need for multiple interventions. Cellular rescue occurred via an autophagic mechanism; prominent autophagosomes were formed and it was hypothesised that these structures allowed for the sequestration of damaged proteins. This thesis demonstrates the value of PPINs as a model for Parkinson's disease, from network creation through target identification to phenotypic benefit.
A lexical-functional analysis of Swahili relative clauses
Keywords: LFG
lexical-functional grammar
relative clauses
Swahili
resumptive pronouns
syntax

After an overview of Swahili's linguistic situation and a basic description of its nominal morphology, verbal morphology, and syntax, I focus on a description of relative clauses. The two basic relative clause formation strategies (the first utilizing the '-o of Reference' as a verbal infix, and the second involving 'amba-') are examined, along with their use in various semantic contexts. I then examine canonical examples of relative clauses from the literature and from corpora in order to highlight the various constraints and generalizations on the use of the different relativization strategies. The goal of these discussions is an analysis of the strategy distribution from within the syntactic framework of Lexical-Functional Grammar (LFG), which itself receives a brief overview. For the analysis, I lay out the basic phrase structure rules that characterize Swahili syntax from the perspective of LFG. Important questions are the status of the '-o' particle and the word 'amba-'. I argue, contrary to e.g., Barrett-Keach (1980), where amba- is considered to be a verb, that amba- is in fact a relative pronoun appearing in the specifier of CP. This structural configuration triggers the activation of various rules which predict the grammaticality of relative clause word orders. In other words, the difference between verbal infix relatives and amba- relatives is primarily structural; in verbal infix relative constructions, -o is also taken to be a relative pronoun. This analysis is made coherent by claiming that Swahili syntax regularly makes use of resumptive pronouns, e.g., when both amba- and -o are used in a single construction, and this notion is formalized using LFG's 'r-structure' (reference structure). In evaluating the analysis given in this thesis, I point out problems with the data used in the literature to argue for different positions. It is in many cases uncertain whether there is a clear grammaticality judgment, and this opens up the possibility that competing analyses capture the data in non-insightful ways. That being said, this work shows that an analysis of the facts within the framework of LFG is not only possible but also renders the linguistic claims made by the analysis more perspicuous than on other approaches.
HIV-1 transmission between T cells and macrophages: consequences for viral pathogenesis.
Keywords: HIV-1
phagocytosis
CD4 T cells
immune activation
macrophages

Within the paradigm of HIV-1 infection, macrophages play a crucial role as long-lived viral reservoirs. However, cell-free virus infection is inefficient and is unlikely to explain the levels of infection observed in vivo. To investigate the hypothesis that macrophages might be infected via direct contact with HIV-1-infected T cells, macrophage and HIV-1-infected T cell cocultures were imaged in real time. I observed that macrophages preferentially phagocytosed HIV-1-infected T cells and, using long-term culture assays, I established that following coculture the macrophage became productively infected. Phagocytosis of HIV-1-infected cells occurred independently of viral tropism; however, productive infection following T cell phagocytosis was restricted by viral tropism. Imaging flow cytometry showed that macrophages primarily phagocytose dying HIV-1-infected T cells. However, a significant population of HIV-1-infected 'healthy' cells were also taken up. Furthermore, ICAM-1 was identified as mediating the uptake of HIV-1-infected T cells. These results indicate that apoptosis plays a significant, but not sufficient, role in the mechanism for recognition and uptake of HIV-1-infected T cells.
The response of macrophages to HIV-1 infection remains controversial. Using both primary macrophages and a monocyte/macrophage NFκB reporter line assay, I demonstrated that macrophages are activated in response to HIV-1-infected T cells. In addition, during coculture with HIV-1-infected T cells, macrophages upregulated secretion of Th1 cytokines, with associated dysregulation of regulatory cytokines. Finally, data presented suggest that polarisation of macrophages towards M1 and M2 phenotypes alters the susceptibility to HIV-1 infection in the cell-to-cell route.
Taking sides: impartiality, norm contestation and the politics of UN peacekeeping 
Keywords: norms
United Nations
Congo
impartiality
peacekeeping

Impartiality has long been a core norm of United Nations peacekeeping. However, since 2000 the dominant conception of impartiality has changed, leading to more coercive forms of peacekeeping. Claims to impartial authority are no longer based exclusively on terms to which all parties consent. Instead, they are premised on a more ambitious and expansive set of norms related to human rights, around which consensus is presumed but not always affirmed.
This dissertation critically examines the change in both the conception and practice of impartiality, which, it argues, is an integral part of the emergence of a more assertive liberal internationalism. In doing so, it challenges dominant constructivist approaches within IR that conceive of norms as linear and static. It advances a framework for a multi-level analysis of impartiality as a “composite” and “contested” norm. Through this framework it elucidates the macro-level politics surrounding the norm’s institutionalisation at the UN, as well as the micro-level politics surrounding its implementation in the specific case of the UN mission in Congo (MONUC).
The analysis of the processes of both institutionalisation and implementation reveals an absence of consensus over the norm itself, and over the purposes of and actions involved in contemporary peacekeeping. This contestation, together with varying expectations and incentives created by the norm amongst local actors, frequently results in unintended consequences, which are contrary to the norm’s original intent. And yet, despite these consequences, the very nature of assertive impartiality makes it difficult for those who claim such authority to change course.
Given that the legitimacy of peacekeeping derives both from whether it is seen to reflect and promote shared values, as from the degree to which it is actually effective, this difficulty raises troubling questions for peacekeeping itself and for the UN, the institution to which it has become so symbolically linked. This dissertation argues that, ultimately, the UN’s role may be to reflect, rather than to resolve, the differences of normative interpretation among its member states. It concludes that a more practical and prudent conception of impartiality – one which recognises that impartiality is necessarily and inextricably political – will be necessary if scholars and practitioners alike are to navigate the normative tensions inherent to a more assertive liberal international order.
The role of polycomb repressive complex 2 in postnatal subventricular zone neural stem/progenitor cell self-renewal and multipotency
Keywords: Subventricular zone
Neural Stem Cells
Epigenetics

The murine subventricular zone (SVZ) in a brain contains a population of stem cells and daily produces tens of thousands of neurons throughout lifetime. However, the mechanisms of SVZ neural stem/progenitor cell (NSPC) maintenance, differentiation and cell-fate specification are still not clear. To understand these parameters via histone methylations with bivalent mechanism, the SVZ NSPCs were first isolated by using a culture technique called neurosphere assay (NSA). It has been a challenge to culture pure cell populations of SVZ subtypes, so the NSA was initially validated. The H3K27me3 mark, which has a dominant role in the bivalent mechanism, has not been studied in postnatal and adult SVZ in vivo, yet their role has been implicated to control the shift of embryonic cortical neurogenesis to gliogenesis. Therefore, we have first investigated whether H3K27me3 marks are present in the postnatal and adult SVZ NSPC population and whether their marks have been changed after stroke or demyelination in central nervous system (CNS) by immunohistrochemistry. With the confirmation of H3K27me3 mark present in SVZ NSPCs, the presence of H3K27me3 catalyzer, called polycomb repressive complex 2 (PRC2) core components (Eed, Ezh2, Suz12) including Jarid2, was investigated and confirmed in postnatal SVZ in vitro by qRT-PCR and Western blot. To understand the role of PRC2 enzymatic activity in postnatal SVZ neurosphere self-renewal and multipotency, Eed was down-regulated by using lentiviral mediated delivery of shRNA. Also, PRC2 dependent or independent function of Jarid2 was examined via knockdown approach. The lack of Eed in the neurospheres resulted the attenuation of self-renewal and oligodendrogenesis, whereas the Jarid2 knockdown neurospheres showed the decreased proliferation with no SVZ NSPC differentiation. Based on these knockdown studies, it suggests Eed and Jarid2 might not share their function in the postnatal SVZ NSPCs to govern postnatal SVZ NSPC self-renewal and multipotency.
An ion-binding approach to asymmetric allylation reactions
Keywords: allylation
catalysis
asymmetric synthesis
organocatalysis

Ion-binding organocatalysis is an emerging field that has the potential to control the stereochemical outcome of any transformation that goes via charged intermediates. The aim of this project was to explore how this concept could be applied to an asymmetric allylation reaction.
Chapter 2 of this thesis discusses anion-binding catalysis and investigates a chiral cooperative thiourea catalyst that could bind to fluoride to control allylation using an allylsilane. Optimization using a non-chiral thiourea (Schreiner’s catalyst) demonstrated that the reaction proceeded in high yield with TBAT onto an N-benzoylhydrazone. A chiral cooperative thiourea catalyst library was then synthesized but unfortunately, although the allylation using these catalysts proceeded in excellent yield, the product was isolated as the racemate (Scheme 1).
Scheme 1: Anion-binding catalysis gave allylated products in high yields but gave no stereocontrol.
Chapter 3 examines a chiral quaternary ammonium fluoride as an example of chiral cation-directed catalysis. We hypothesized that an allylsilane activated by fluoride would generate an allyl anion species that would associate with the chiral quaternary ammonium cation through electrostatic interactions. Extensive optimization found that the allylation reaction proceeded in good yield in chloroform at reflux with N-benzoylhydrazones. Different fluoride catalysts were prepared using an ion-exchange resin, and cinchonidine-derived catalysts performed the best. This methodology was extended to a phase-transfer catalyzed process, where solid cesium fluoride exchanged with chloride in situ, removing the need to synthesize and isolate ammonium fluoride catalysts (Scheme 2).
Scheme 2: Cation-directed asymmetric allylation.
In Chapter 4 cation-directed asymmetric catalysis was extended to an intramolecular allylation reaction. Substrate synthesis was attempted by cross metathesis but the reaction was capricious and yields were low. Intramolecular allylation with these materials gave promising results (Scheme 3) but a lack of material prevented optimization.
Scheme 3: Intramolecular allylation results.
Plasma vertical position control in the COMPASS–D tokamak
Keywords: Position Control
Plasma Modelling
Tokamak
System Identification

The plasma vertical position system on the COMPASS–D tokamak is studied in this thesis. An analogue P+D controller is used to regulate the plasma vertical position which is open loop unstable. Measurements from inside the vessel are used for the derivative component of the control signal and external measurements for the proportional component.
Two main sources of disturbances are observed on COMPASS–D. One source is 600Hz noise from thyristor power supplies which cause large oscillations at the control amplifier output. Another source is impulse–like disturbances due to ELMs (Edge Localized Modes) and this can occasionally lead to loss of control when the control amplifier saturates.
Models of the plasma open loop dynamics were obtained using the process of system identification. Experimental data is used to fit the coefficients of a mathematical model. The frequency response of the model is strongly dependent on the shape of the plasma. The effect of shielding by the vessel wall on external measurements when compared with internal measurements is also observed. The models were used to predict values of gain margins and phase crossover frequencies which were found to be in good agreement with measured values.
The harsh reactor conditions on the proposed ITER tokamak preclude the use of internal measurements. On COMPASS–D the stability margins of the loop decrease when using only external flux loops. High order controllers were designed to stabilize the system using only external measurements and to reduce the effect of 600Hz noise on the control amplifier voltage. The controllers were tested on COMPASS–D and demonstrated the improved performance of high order controllers over the simple P+D controller.
ELMs cause impulse–like disturbances on the plasma position. The optimal controller minimizing the peak of the impulse response can be calculated analytically for COMPASS–D. A multiobjective controller which combines a small peak impulse response with robust stability and noise attenuation can be obtained using a numerical search.