VictorJuiz/thesis huggingface dataset:
Evolved P450 mutants as general oxidation catalysts

The thesis describes the use of a library of mutant P450BM3 variants for the biocatalytic oxidation of a range of structurally diverse substrates and the efforts toward the total synthesis of trigoxyphin K and L, employing biocatalytic C-H oxidation as a key step.
Chapter 1 explores the P450BM3-catalysed oxidative cyclisation of α-amino (thio)acetamides for the synthesis of bicyclic imidazolidin-4-(thi)ones with P450BM3 variantcontrolled regio- and diastereoselectivity attainable in some cases. A method was developed for the Lewis acid-mediated ring-opening functionalisation of these compounds employing a variety of nucleophiles.
Chapter 2 discusses the P450BM3-catalysed para-hydroxylation of three sulfonanilidederived herbicides and the expansion of this transformation to a number of substituted anilides. Regioselectivity of hydroxylation was possible for certain substrates, with selectivity possible for para-hydroxylation or benzylic hydroxylation.
Chapter 3 details the successful approach to the core structures of the natural products trigoxyphin K and L and an investigation into the use of the library of mutant P450BM3 variants for late-stage oxidation of intermediates to enable synthesis of the natural products themselves.
Finally, the P450BM3-mediated oxidation of a structurally diverse collection of small molecules and commercially available herbicides was examined with transformations including benzylic hydroxylation, acetal formation, S-oxidation, and nitro-group reduction.

Advisor: Robertson, J
Wong, L
Free energy calculations in drug design: application to bromodomains

Computer simulations of biomolecules have been improving at a pace that is faster than Moore’s law for microprocessors in the last few decades. Thanks to advances in theory, hardware, and algorithms it is increasingly possible to study biological processes at relevant spatial and temporal resolutions, and to exploit simulation for quantitative predictions. One area that can potentially benefit greatly from such computational predictions is that of drug discovery. Since the inception of the concept of rational drug design, the prediction of how tightly an organic molecule binds to a macromolecular partner has been one of the chief objectives of computational chemistry. Computers already play a fundamental support role during the drug discovery process, and today many novel approaches that aim at studying the details of drug binding and predicting binding affinity are being actively investigated. In this thesis, I report a series of studies that aim to evaluate the potential utility of free energy calculations based on molecular simulations for drug design. In particular, I focus on the prediction of small-molecule binding affinities to the epigenetic target of bromodomains. Bromodomains are small protein modules that have been found in 46 human proteins involved in gene regulation. Given their role in various diseases, in particular cancer and inflammation, a number of bromodomain inhibitors are currently being investigated both in the laboratory and the clinic. Here, it is shown how thorough calculations based on explicit-solvent simulations and all-atom force fields can accurately reproduce binding free energies for this protein family. Rigorous free energy calculations are also compared to more approximate methods based on the post-processing of the simulation trajectories in implicit solvent. Finally, a recently proposed method for the estimation of water binding free energy is employed to study water displaceability from bromodomain binding pockets.

Advisor: Biggin, P
Knapp, S
A robust approach to pricing-hedging duality and related problems in mathematical finance

In this thesis, we pursue a robust approach to pricing and hedging problems in mathematical finance. The general goal of this approach is to develop a pricing and hedging theory, which is based mainly on the market information than on a specific probabilistic belief about the future evolution of the risky assets. Motivated by the notion of prediction set in Mykland (2003), we include in our framework modelling beliefs through a set of paths to be considered, e.g. super-replication of a contingent claim is required only for paths falling in the given set. Our framework thus interpolates between model--independent and model--specific settings and allows quantifying the impact of making assumptions or gaining information.
The first part of the thesis is concerned with robust fundamental theorem of asset pricing, pricing--hedging duality and their applications in a discrete-time setting in which some underlying assets and options, are available for dynamic trading and a further set of European options, possibly with varying maturities, is available for static trading.
In the second part of the thesis, we consider the robust pricing--hedging duality problem with options in a continuous-time setting where underlying assets are assumed to have continuous paths. Our results include an "unconstrained" pricing--hedging duality, in the absence of options and beliefs, and a general but approximated pricing-hedging duality result. Moreover, when all put options are available for static hedging, the pricing problem is connected to the martingale optimal transport problem and our duality results in this thesis include the martingale optimal transport duality of Dolinsky and Soner (2013) and extend it to multiple maturities and multiple assets.

Advisor: Obloj, J
Towards extracellular vesicle based gene therapy for Huntington's disease

Huntington's disease (HD) can be regarded as a model neurodegenerative disorder to screen potential genetic based therapeutics and their carriers. It is an autosomal dominant disorder caused by a mutation in a single gene that leads to progressive neurodegeneration caused in part by protein misfolding. The mutation codes for an expanded polyglutamine tract within the Huntingtin gene (HTT) which leads to neuronal loss through a pathological cascade of events. Current treatment strategies include symptom management but no disease-modifying therapies exist.
Research has shown that nucleic acid based therapeutics aimed at decreasing HTT expression can prevent, or reverse, the phenotype. Translating such therapies to the clinic is hindered by the blood brain barrier (BBB) and the lack of an easily administrable, non-toxic, immunologically inert delivery vehicle capable of bypassing the BBB. This study examines a range of nucleic acid based therapeutics for their potency and toxicity, and evaluates extracellular vesicles (EVs) as a delivery vehicle through investigation of the biodistribution of brain targeted EVs and an analysis of EV loading.
A small interfering RNA (siRNA) targeting a region upstream of the repeat induced potent non-toxic silencing of HTT. In examining EVs as a carrier for therapeutics for neurological diseases including HD, it was found that targeting can increase brain accumulation of EVs but that the physiological characteristics of EVs which make them susceptible to clearance by the reticuloendothelial system (RES) must be further evaluated to bioengineer modified EVs to avoid fast clearance. Lastly, loading by electroporation was found to induce siRNA aggregation which can lead to overestimation of loading by increasing siRNA content in an ultracentrifugation pellet, but cholesterol-conjugated siRNA mixed with EVs was capable of generating silencing in vitro.
This thesis examined EV based treatment for HD through the selection of a nucleic acid cargo to silence HTT, and examination of EVs as a delivery vehicle via biodistribution and loading studies. If the loading can be optimised and fast clearance avoided, there is promise in the use of EVs as a carrier of siRNA for HD.

Keywords: siRNA
Gene Therapy
Huntington's
Advisor: Wood, M
Revealing physiological changes through colour

This dissertation extends remote vital sign monitoring by examining whether it is possible to track oxygen saturation with visible-light video cameras by filming an exposed skin region (the face). Two further questions are also investigated as part of the presentation of this thesis: the in uence of skin melanin on the ability of video cameras to track oxygen saturation, and the ability of video cameras to assess the absolute value of oxygen saturation at any given point in time.
A study involving human volunteers was designed to answer these research questions in a controlled environment, and 46 subjects were recruited. The subjects were divided into six different skin phenotype groups (Fitzpatrick Scale I{VI). For a period of up to one hour, the volunteers' oxygen saturation was varied between 80% and 100% and videos of their faces were recorded in that time. The volunteers' reference oxygen saturation was recorded using two pulse oximeters placed on the index fingers of each hand. Another study was carried out in a neonatal high-dependency unit to test the algorithms for remote vital sign monitoring in a challenging clinical setting.
A theoretical basis for the derivation of oxygen saturation monitoring algorithms is developed throughout the dissertation, and two methods (baseline and RoR) were built upon this. The baseline method has parallels with oximetry and is based on tracking overall changes in the colour of the skin while minimising the effect of lighting, while the RoR method mimics pulse oximetry in form and assesses the relative change in amplitude as measured by each colour channel while oxygen saturation changes. Both methods are found to work well for subjects of Fitzpatrick phenotypes I{IV (average coeficient of determination r2 of 0.79 and 0.71 for baseline and RoR respectively across all Type I{IV subjects), variably for Type V subjects (average r2 values of 0.64 and 0.48), and not work for Type VI subjects (average r2 values of 0.19 and 0.01). Although the RoR method yields noisier results than the baseline method, it was found that the timecourse of the latter varied with respect to the oxygen saturation.
A simple linear model used to derive oxygen saturation directly from the video camera data was thus devised using the RoR method only, and applied to Type I{V subjects. The subjects were divided into randomly generated but equally split training sets and test sets and the model parameters learned from the training set were evaluated in the test set. This was repeated over 10 iterations and the overall mean absolute error between the estimated oxygen saturation using the video camera data and the reference oxygen saturation using the pulse oximeters was, for Type I{V subjects respectively: 3.0%, 2.3%, 2.5%, 2.5%, and 4.6%.

Advisor: Tarassenko, L
Counterpoint, 'fuge', and 'air' in the instrumental music of Orlando Gibbons

This thesis develops an analytical approach to the instrumental music of Orlando Gibbons (1583-1625) based on close readings of historical theory sources, primarily by Thomas Morley, John Coprario and Thomas Campion. Music of the early seventeenth century can be difficult to analyse, since it falls between the more extensively studied and theorised practices of classic vocal polyphony and common-practice tonality. Although English music theory of this period is recognised as strikingly modern in many respects, innovative aspects of English compositions from the same period receive little attention in standard accounts of the seventeenth century. I argue that concepts taken from this body of historical theory provide the basic terms of a technical vocabulary for analysis, which should be further refined through application to real compositions. Successive chapters deal with common counterpoint models or patterns, imitative invention and disposition, cadential progressions, and overall tonal structure. I argue that these analyses show Gibbons's music to be a contribution to new ways of conceiving of instrumental polyphony and tonal structure, which deserves re-evaluation in the context of broader seventeenth-century trends.
In particular, Gibbons's use of extended cadential expectations as an expressive element, fascination with sequential progressions, and sectional structuring by harmonic area have clear parallels with later practices. At the same time, early seventeenth century style allows the composer considerably more freedom of harmonic procedures and implications than the musical styles which immediately followed it. Analysis grounded in historical theory provides the best approach to understanding and appreciating this unique musical language.

Keywords: Seventeenth-century music
Cadences
Counterpoint
Mode
Keyboard music
Tonality
Imitation
Viol consort music
Fugue
English music
Advisor: Dreyfus, L
Metabolism of exogenous ketones

As metabolic substrates, ketone bodies provide an alternative to glucose in order to pro- long survival during starvation. A low carbohydrate, high fat diet can be used to promote ketogenesis without fasting, but long-term compliance can be difficult. Dietary ketone bod- ies may be an alternative method to induce ketosis, so the aim of the work in this Thesis was to investigate the metabolism of exogenous ketones. In the first experimental Chap- ter, the effects of ketone ester and salt drinks on blood β-hydroxybutyrate (βHB), glucose, lipids, electrolytes and pH were determined in healthy humans at rest. Blood D-βHB levels were higher following ketone ester drinks, but it was found that total βHB levels with ke- tone salts were similar, as over 50% of βHB delivered in the salt was the L-isoform, which was only slowly removed from the blood. Circulating glucose and lipid concentrations fell following both ketone drinks. Blood pH fell following ketone ester consumption, but rose following ketone salt drinks, whilst both compounds raised blood sodium and chloride, and lowered potassium. Work in the second Chapter investigated the repeatability of ketone es- ter metabolism with food, successive drinks or continuous nasogastric (NG) infusion. Peak D-βHB levels were repeatable between- and within- subjects at rest but were lower after a meal, although blood acetoacetate, breath acetone and urine βHB were unaffected by feed- ing. βHB kinetic parameters were not altered by existing hyperketonemia from successive ketone ester drinks and total βHB uptake was identical when isovolumetric amounts of ketone ester were continuously infused through a NG tube. The third Chapter explored side-effects of ketone drinks: ketone ester drinks decreased appetite compared to isocaloric dextrose; which may have been linked to effects of βHB on enteroendocrine cells. Fur- thermore, both ester and salt drinks were found to be unpalatable, and to cause a few, mild gastro-intestinal effects that increased with intake. As exogenous ketones could be a per- formance enhancing supplement in sport, the fourth Chapter used a survey to investigate supplement use by endurance athletes. The results demonstrated widespread supplement use, which was highest at the elite level. In the final Chapter, the effect of glycogen lev- els on the oxidation of βHB was determined in isolated perfused rat hearts. Low cardiac glycogen levels decreased βHB oxidation and levels of the intermediates of glycolysis and the Krebs cycle, whilst increasing muscle amino acid levels, suggesting that low glycogen may have impaired anaplerosis. In conclusion, this work extends current understanding of the novel physiological ketosis that occurs following exogenous ketone consumption.

Keywords: Metabolism
Ketosis
Ketones
β-hydroxybutyrate
Ketone ester
Advisor: Clarke, K
Evans, R
Cox, P
Representing the Algerian woman in Francophone literature of the late-colonial period: une dissymétrie s'évoque

This thesis seeks to discuss the ways in which canonical Francophone Algerian authors, writing in the late-colonial period (1945 – 1962), namely Kateb Yacine, Mohammed Dib, Mouloud Feraoun, Mouloud Mammeri and Assia Djebar, approached the representation of Algerian women through literature. The thesis, divided into five chapters, each focusing on the late-colonial oeuvre of one writer, initially makes use of Bourdieusian conceptions relating to a gendered "dissymétrie fondementale" and concomitant Spivakian notions of representation, to argue that a masculine domination of public fields of representation contributed to, if not ensured, a post-colonial marginalization of women and a reduction of their public role. However, it is the principal argument of this thesis that the canonical writers of the period, who were mostly male, both textually acknowledge their inability to articulate the experiences and subjectivity of the feminine Other, to represent women, and deploy a remarkable variety of formal and conceptual innovations in an attempt to tentatively produce evocations of Algerian femininity that seek to upset or highlight the structural imbalance of masculine symbolic hegemony in literary and socio-political milieux. Though this thesis does not shy from investigating those aspects of its corpus that produce ideologically conditioned masculinist representations, it chiefly seeks to articulate a shared reluctance concerning representativity and an omnipresent literary subversion of a masculine subject pole. It deploys formal narrative analysis, Lacanian psychoanalytical frameworks and a conceptualisation of "pessimistic" form to achieve these ends and to argue that the texts of its corpus discreetly militate for a communal feminine self-representation to be inaugurated, before outlining in its conclusion a post-colonial Algerian feminine literary tradition, in particular contemporary symbolic conduits such as la bande dessinée that might serve as effective motors for progression in gender relations.

Keywords: Assia Djebar
Kateb Yacine
representation
Mouloud Mammeri
Mouloud Feraoun
Pierre Bourdieu
Mohammed Dib
Jacques Lacan
Advisor: Hiddleston, J
Urban climate change adaptation pathways for short to long term decision-making

Climate resilience is increasingly an attribute of competitive global cities. Cities that are most responsive to change will continue to prosper. To achieve this, governance structures and decision-making approaches that promote flexible and/or robust adaptation action are required. This thesis introduces a framework for urban adaptation planning that links medium-term risk management with the development and appraisal of long-term adaptation pathways. A long-term plan informed by the appraisal of a range of plausible pathways provides the opportunity to retain the flexibility to respond to future uncertainties, whilst also demonstrating how a city could manage future climate risk. This provides stakeholders with confidence that long-term risk is adequately considered, even if there is not a need to act immediately.
To demonstrate how adaptation pathways can support adaptation decision-making in an urban system, the approach and methods developed as part of this thesis are applied in London. Adaptation pathways in response to water scarcity, surface water flood and heat risk were developed, and their appraisal presented as pathways diagrams. These diagrams provide a visual representation of the sequencing of decision points and plausible adaptation actions that may be implemented in the future. Pathways diagrams present climate risk and adaptation information for decision-makers in a salient and actionable manner. The pathways responding to individual risks in London are then brought together to demonstrate how an integrated assessment framework may be used to appraise city-scale adaptation pathways that respond to multiple climate risks.
The growing emphasis within adaptation planning on approaches that can react flexibly to change increases the need to better understand the dynamics of climate risk and embed learning about the effectiveness of adaptation actions. To complement the pathways and adaptation decision-making research presented in this thesis, a framework that links adaptation monitoring and evaluation (M&E;), risk assessment and decision-making is presented and explored to highlight the potential benefits of, and mechanisms for, adaptation M&E; to inform and strengthen iterative risk-based adaptation planning. Demonstrated for the Thames Estuary, where concepts of adaptation planning have been pioneered but the opportunities of linking to monitoring and evaluation have not been extensively explored, we show how the framework can highlight actions and factors that are contributing to improving adaptation outcomes and those that require strengthening.
This thesis contributes to the literature on urban climate change adaptation planning under conditions of uncertainty. This thesis also contributes to the evidence base needed to justify long-term planning and realise the benefits of climate risk reduction through the implementation of flexible, long-term integrated urban adaptation plans.

Keywords: Climate risk management
flooding
decision-making under uncertainty
heat risk
water supply
integrated urban planning
Adaptation pathways
Advisor: Hall, J
The cosmological aesthetics of Tomás Saraceno's atmospheric experiments

This dissertation proposes cosmological aesthetics as a critique of and contribution to geologic, geomorphic and geographical aesthetics. This argument is developed in the context of human geographers' growing interests in the dark, imperceptible and unknown forces and fields of Earth and the cosmos. Attention to such cosmic phenomena amplifies the porosity of distinctions between humans, nonhumans and matter; therefore we require an aesthetic theory at the limits of sensing. In developing this aesthetics, this dissertation draws conceptual support in particular from the non-anthropocentric philosophy of Alfred North Whitehead and from Isabelle Stengers' "ecologies of practice". At the same time, the elaboration of cosmological aesthetics emerges from a site-based creative ethnography of Studio Tomás Saraceno in Berlin, and more specifically, from a series of experiments in transdiciplinary collaboration, writing and teaching with Tomás Saraceno. This dissertation interrogates how the surfaces, webs, envelopes and interstices populating and propagating in Saraceno’s artwork affect the transmission and distribution of sensation across spaces and scales: in short, how these forms become technologies of cosmo-aesthetic adventure. By engaging with Saraceno's art projects, from On Space Time Foam to hybrid webs and the Aerocene, and by participating in the atmospheric experiments of aerosolar sculptures, this dissertation articulates two core propositions of cosmological aesthetics: first, that aesthetic experience can create tangible, sensible relations with contexts that are far removed, or much wider than, the particular conditions in which we experiment. And second: such adventures in aesthetics emerge from practices bound together by the forces of obligation, attachment and crucially, imagination. Employing foremost the device of the web, cosmological aesthetics explores propositions for bodies to be creatively extended in a vast and vibrating cosmos.

Keywords: Air
Art
Saraceno
Aesthetics
Experiment
Cosmological
Atmosphere
Advisor: McCormack, D