VictorJuiz/thesis huggingface dataset:
New asymmetric metal-catalysed addition processes for amine synthesis

This thesis concerns the development of novel catalytic approaches for the construction of stereocentres bearing a nitrogen atom. In 2011, the Dixon group reported a Ag(I)/cinchona-derived amino phosphine catalytic system for the activation of isocyanoacetates in asymmetric aldol and Mannich reactions. During this thesis work it was sought to extend the scope of this catalytic system to Mannich additions of other isocyanide pronucleophiles, then the focus was broadened to include Reformatsky and α-alkylation reactions of ketimine substrates.
Chapter 1 gives an overview of the state of the art with particular emphasis on catalytic enantioselective additions to ketimines and the use of activated isocyanides as pronucleophiles.
Chapter 2 describes the application of the Ag-catalysed enantio- and diastereoselective aldol reaction of isocyanoacetates to the concise asymmetric synthesis of the antibiotic chloramphenicol, which possesses a chiral stereodefined α-amino β-hydroxy motif.
Chapter 3 details our efforts to expand the scope of the Ag(I)/amino phosphine catalytic system to the activation of more challenging isocyanides lacking an electron-withdrawing group in the α-position by investigating aldol and Mannich reactions of benzyl isocyanide.
Chapter 4 describes how the scope of the Ag(I)/amino phosphine catalytic system was successfully extended to another pronucleophile, the versatile p-toluenesulfonylmethyl isocyanide (TosMIC). The first catalytic enantio- and diastereoselective addition of TosMIC to N-diphenylphosphinoyl (N-DPP) ketimines was developed, affording 2-imidazolines possessing two contiguous stereocentres with high yields and excellent levels of stereocontrol.
Chapter 5 describes the development of a Ni(II)-catalysed Reformatsky reaction of N-DPP ketimines with ethyl bromoacetate and diethylzinc, providing racemic amines bearing a quaternary stereocentre in the α-position in good yields.
Chapter 6 reports the serendipitous discovery of the α-alkylation of N-DPP ketimines with ethyl bromoacetate using visible light photoredox catalysis. The transformation, catalysed by ruthenium(II) and nickel(II) complexes under mild conditions, was optimised, its scope assessed and the mechanism investigated.

Keywords: Isocyanides
Addition to ketimines
Photoredox catalysis
Silver catalysis
Advisor: Dixon, D
Functional genetics of cancer and congenital disorders

The genetic architectures of cancer and congenital disorders are heterogeneous and incompletely mapped. Rare and low-frequency variants of incomplete penetrance are emerging as an important class of germline and somatic variation, but their contribution to disease remains poorly characterised. This thesis aims to identify and assess pathogenic mutations in the 1q41q42 microdeletion syndrome, neural tube defects, neuropsychiatric disorders and cancer. Rare microdeletions at the 1q41q42 locus cause a clinically heterogeneous syndrome characterized by developmental delay, characteristic dysmorphic features and brain morphological abnormalities. Examining new and published patients with 1q41q42 microdeletions, we found that TP53BP2, encoding ASPP2, is a strong candidate for being the gene responsible for brain morphological abnormalities of the syndrome. Mice deficient for Trp53bp2 show multiple abnormalities overlapping the features of the 1q41q42 microdeletion syndrome such as dysmorphic lateral ventricles, heart and urogenital abnormalities. ASPP2 deficiency also causes neural tube defects, hopping gait, and male-specific motion hyperactivity in mice. We further identify candidate pathogenic TP53BP2 duplications, implicating TP53BP2 dosage sensitivity in the ganglionic eminences of the developing brain, manifested by structural abnormalities in the striatum and lateral ventricles of both deletion and duplication patients. ASPP2 controls neuroepithelial cell polarity via Par3 and genetic disruption of aPKC-Par3 interaction by rare missense variants was implicated in human neural tube defects. An integrative analysis of cancer genomic data revealed that PPP1R13B, encoding ASPP1, bears many hallmarks of a tumour suppressor gene, despite being mutated at a low absolute frequency. A subset of missense somatic mutations in ASPP genes genetically interact with TP53 mutations, disrupting an autoinhibitory mechanism to modulate p53-dependent transcription. In summary, this work identified novel candidate pathogenic variants in developmental disorders and cancer, and explored the mechanisms underlying their respective genotype-phenotype links.

Keywords: 1q41q42 microdeletion syndrome
Rare variant
ASPP
Advisor: Lu, X
Teijaro, J
Characterisation of a novel mouse model of mitochondrial disease – a hypomorphic Wars2 ENU-induced allele

Mitochondrial aminoacyl-tRNA synthetases (mtRS) are vital for mitochondrial translation. mtRSs catalyse the aminoacylation of mitochondrial tRNA with their cognate amino acid. Mutations in mtRS genes are associated with distinct clinical pathologies in humans. Studying mtRS mutations in model organisms is difficult because mtRS knock-out alleles are haplosufficient and cause embryonic lethality in their homozygous state. In this study, we phenotypically and mechanistically characterised a hypomorphic, ENU-induced Wars2 allele (Wars2-V117L) in mouse with the aim to determine the cause of the tissue-specific penetrance of mtRS mutant alleles.
The Wars2-V117L allele caused tissue-specific pathology in mice. Wars2V117L/V117L mice developed hypertrophic cardiomyopathy, sensorineural hearing loss, reduced adiposity, increased glucose tolerance and systemic changes in metabolism. Furthermore, we showed that the Wars2V117L/V117L allele causes abnormal adipose tissue pathology as shown by 'browning' of WAT depots and lipid accumulation in BAT in Wars2V117L/V117Lmice.
The Wars2V117L/V117L allele disrupts Wars2 mRNA splicing, resulting in reduced full-length Wars2 (Wars2-FL) mRNA in Wars2V117L/V117L tissues and cells. Reduced Wars2-FL mRNA caused tissue-specific reductions in mt-TrpRS protein and mitochondrial OXPHOS deficiencies in Wars2V117L/V117L mice in vivo. OXPHOS deficiencies lead to activation of the Integrated Stress Response (ISR) in Wars2V117L/V117L heart and liver. Activation of the ISR in Wars2V117L/V117L heart caused up-regulation of Fgf21 mRNA and increased plasma FGF21, leading to systemic changes in metabolism. Finally, we showed that up-regulation of Pgc1a and mitochondrial biogenesis prevented inhibition of mitochondrial translation in Wars2V117L/V117L skeletal muscle and mouse embryonic fibroblasts.
Overall, we have characterised the first mouse model of mitochondrial disease caused by a global, hypomorphic, mutation in an mtRS gene. We showed that the tissue-specific pathology observed in Wars2V117L/V117L mice was due to activation of tissue-specific stress response mechanisms that either lead to disease pathology, such as activation of the ISR in the heart, or protection against inhibition of mitochondrial translation, such as up-regulation of Pgc1a in iWAT and MEFs. This study provides some evidence that up-regulation of mitochondrial biogenesis could be utilised as a therapeutic strategy to treat human patients with mtRS mutations in the future.

Advisor: Cox, R
Pears, C
Clinical translation of hyperpolarized magnetic resonance for cardiovascular and metabolic diseases

Cardiovascular diseases continue to pose an unacceptable societal burden, mandating the development of new and improved methods for their diagnosis, monitoring and treatment. Current cardiovascular magnetic resonance imaging techniques provide exquisite structural and functional information, but their ability to assess the molecular processes underlying cardiac function in health and disease is limited by inherent insensitivity. Hyperpolarized magnetic resonance is a new technology which overcomes this limitation, creating molecular contrast agents with an improvement in magnetic resonance signal of up to five orders of magnitude. One key molecule, hyperpolarized [1-13C]pyruvate, shows particular promise for the assessment of cardiac energy metabolism and other fundamental biological processes with clinical relevance.
This thesis describes a programme of translational research in hyperpolarized magnetic resonance conducted with the aims of identifying priority disease states for translational hyperpolarized MR studies, and of enabling first human cardiovascular studies using the technique. We identify important and new potential roles for hyperpolarized magnetic resonance in both the diagnosis, and potentially treatment, of heart disease associated with metabolic diseases and also in ischaemic heart disease.
Hyperpolarized [1-13C]pyruvate also has high potential for rapid clinical translation from the laboratory to patients with cardiovascular disease, though the production and administration of clinical-grade hyperpolarized molecules poses significant challenges. We present strategies to overcome these challenges, and describe the first human cardiovascular experience with hyperpolarized magnetic resonance.

Advisor: Neubauer, S
Tyler, D
Rider, O
Mechanisms of Xist-dependent Polycomb recruitment

The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental gene regulation, functioning, at least in part, by catalyzing specific histone modifications, H2AK119u1 and H3K27me3, respectively. The hierarchical model of Polycomb recruitment proposes that PRC2 is recruited to target loci by sequence specific factors and/or non-coding RNAs, and that PRC1 recruitment occurs subsequently as a consequence of recognition of H3K27me3 by the PRC1 subunit CBX. However, non-canonical PRC1 complexes, defined by the presence of different PCGF subunits, lack the CBX subunit and are therefore recruited independently of PRC2 activity. Moreover, recent evidence has shown that H2AK119u1 catalyzed by non-canonical PRC1 can directly recruit PRC2, establishing a reverse model of Polycomb recruitment. I analyzed Polycomb recruitment using a classical model system, X chromosome inactivation mediated by Xist RNA. Previous reports suggested that Polycomb recruitment to the inactive X chromosome is initiated by a direct interaction of PRC2 subunits with Xist RNA, and that PRC1 is then recruited via interaction of the CBX subunit with PRC2 mediated H3K27me3. This model has been challenged, since it does not account for all experimental observations. In this thesis, I provide evidence that Polycomb recruitment by Xist RNA is initiated by deposition of H2AK119u1 by noncanonical PRC1 complexes. PRC2 is therefore recruited indirectly, presumably by binding to H2AK119u1. I also show that all non-canonical PRC1 complexes are enriched on the inactive chromosome, albeit with different dynamic behaviors. PCGF3- and PCGF5-PRC1 complexes, which have a slower dynamics on the inactive chromosome as determined by FRAP, are necessary for the initiation of Polycomb domain formation on the inactive chromosome, presumably through direct recruitment by Xist RNA or through an adaptor protein that mediates this interaction. Subsequent enrichment of other non-canonical PRC1 complexes relies predominantly on H2AK119u1 recognition by RYBP/YAF2, which also contributes to the enrichment of the more dynamic fraction of PCGF3- and PCGF5-PRC1 complexes on the inactive chromosome. Altogether, these observations overturn existing models for Polycomb recruitment by Xist RNA, and thereby, provide new insights into the dynamics and mechanisms for Polycomb recruitment by non-coding RNAs.

Advisor: Brockdorff, N
Against comparativism about mass in Newtonian Gravity - a case study in the metaphysics of scale

This thesis concerns the metaphysics of scale. It investigates the implications of a physical determinable being dimensionful. In particular, it considers the case study of mass, as it features within Newtonian Gravity. Nevertheless, most of the terminology, methodology and arguments developed should be relatively straightforwardly applicable to other determinables and theories.
Weak Absolutism about mass holds that mass ratios obtain in virtue of absolute masses. Weak Comparativism denies this. In the first five chapters I argue in favour of Weak Absolutism over Weak Comparativism. The sixth chapter argues against reducing mass to other non-mass facts. The overall conclusion is Strong Absolutism about mass within Newtonian Gravity: mass ratios obtain in virtue of absolute masses, which themselves are fundamental (i.e. they do not require anything further in order to obtain).
Comparativism promises to recover all the virtues of absolutism, in particular its empirical adequacy, but at a lower 'metaphysical cost'. Special attention is given to Dasgupta's recent comparativist proposal. Dasgupta interprets the requirement of empirical adequacy in terms of the undetectability of the absolute mass scale. I argue that undetectability is an unsuitable way of understanding empirical adequacy and that we would do better to understand it in terms of a theory's ability to correctly generate the set of empirically possible worlds (or at least the actual world). I refute Dasgupta's comparativism both on my terms and on his own terms. I subsequently develop and strongly criticise alternative versions of comparativism. Chapter five sheds doubt on the supposed 'metaphysical parsimony' of comparativism.
This debate should be of particular interest to readers who engage with the substantivalism-relationalism debate. These debates are much more entwined than previously acknowledged, which provides a significant source of mutual inspiration, although I do also draw out some important disanalogies.

Keywords: Mass
Scaling Symmetry
Reductionism
Absolutism vs Comparativism
Newtonian Gravity
Advisor: Pooley, O
Wallace, D
Caulton, A
Temporal expectations in healthy ageing &amp; neurological disorders

Previous research has shown that orienting attention in time can help to improve behavioural outcomes. However, the extent to which temporal orienting can be preserved in ageing and in the context of neurological disorders remains unresolved. This thesis therefore explores temporal expectations in the healthy ageing and diseased brain by taking a neuropsychological approach. To begin, I provide an overview of the literature in Chapter 1 most relevant for the following investigation. Four chapters of experiments then follow. To examine the effects of ageing on temporal expectation, the performance of healthy young adults and healthy older adults is presented and the results are discussed in Chapter 2 and 3. Though it had been previously shown that older adults seem to experience an expectation deficit on temporal expectation tasks, these chapters demonstrate the preservation of temporal expectation in ageing. On their own, these findings represent an important and novel contribution to the literature; however, this research is incapable of establishing the causal mechanisms involved in temporal expectation. To explore the causal role of relevant brain regions in temporal expectation, Chapter 4 and 5 investigate the effects of temporal orienting in participants with damage to the basal ganglia — a brain region strongly implicated in temporal processing. In Chapter 4, the role of the basal ganglia in temporal expectations is examined using data collected from participants with Parkinson’s disease and contrasts their performance with age-matched healthy controls. To complement this investigation, and to provide converging evidence for the basal ganglia’s role in temporal expectations, Chapter 5 investigates the behavioural performance of individuals with focal lesions to the basal ganglia. The findings in this thesis are discussed in their wider context in Chapter 6, and directions for future research are proposed.

Keywords: Temporal Orienting
Basal Ganglia
Stroke
Temporal Expectation
Anticipation
Attention
Parkinson's Disease
Advisor: Nobre, K
Gillebert, C
Development and aerothermal investigation of integrated combustor vane concept

This work focuses on the interface of combustor and high-pressure turbine of power generation gas turbines with individual can combustors. More specifically the thesis presents the development and aerothermal investigation of the integrated combustor vane concept. In this novel concept, first introduced in 2010, the conventional nozzle guide vanes (NGVs) are removed and flow turning is achieved by vanes that extend the combustor walls. The concept was developed using the inhouse CFD code TBLOCK. Aerothermal experiments were conducted using the Oxford combustor-turbine high-speed research facility. The linear cascade is comprised of two can combustor transition ducts and either four conventional vanes (CVs) or two integrated vanes (IVs). The experimental study validates the linear numerical simulations of the integrated vane development. Annular full stage simulations, used to evaluate aerodynamics and stage efficiency, confirm the trends of the linear numerical and experimental results and thus demonstrate the concept's potential for real gas turbine applications. Results show a reduction of the total pressure loss coefficient at the exit of the stator vanes by more than 25% due to a reduction in profile and endwall loss. Combined with an improved rotor performance demonstrated by unsteady stage simulations, these aerodynamic benefits result in a gain in stage efficiency of 1.5%. A distinct reduction in HTC levels on vane surfaces and endwalls on the order of 40%-50% is observed. This is attributed to the transferral of the combustor wall's boundary layer onto the integrated vane and to the removal of the horse-shoe vortex system. Furthermore it is shown that engine-realistic combustor flow with swirl leads to a slight, non-detrimental shift in the heat transfer coefficient distributions and to a less homogenous turning distribution downstream of the integrated vanes. Three-dimensional vane profiling is suitable to modify the downstream turning and thus counteract the increased losses downstream of the two-dimensional integrated vanes incurred by the combustor's swirl. The experimental and numerical investigation of the newly developed integrated vane's endwall and leading edge cooling geometries shows a superior surface coverage of cooling effectiveness, and the cooling requirements for the first vane are expected to be halved. Moreover, by halving the number of vanes, simplifying the design and eliminating the need for vane leading edge film cooling, manufacturing and development costs can be significantly reduced.

Advisor: Rosic, B
Essays on industrial organisation and behavioural economics

This thesis is composed of three chapters each of which deals with markets with agents who are not fully rational.
The first chapter aims to understand the relationship between Word- of-Mouth marketing and traditional advertisement. With the advent of internet and social network web-sites, the cost of Word-of-Mouth marketing reduced dramatically. This chapter mainly analyses the effect of this change on the traditional advertisement efforts.
The second chapter analyses the market implications of manipulable consumers. Manipulable consumers are defined as the consumers whose beliefs about the future can be altered by advertisement decisions of firms. The equilibrium outcome is given and extensions are discussed.
The last chapter of the thesis studies the consumers who decide which firm to approach by sampling the price information offered by firms. Consumers do not conduct a rational evaluation but use one of the procedures which are motivated by axioms reflecting their limited understanding of the strategic environment. I analyse the market implications of such procedures and conduct several comparative statics.

Advisor: Armstrong, M
Essays in microeconomics

This thesis consists of two theoretical chapters, focusing on dynamic games, and one empirical chapter. In Chapter 1, I consider a repeated game in which, due to imperfect monitoring, no collusion can be sustained. I add a self-interested monitor who commits to generating an imperfect private signal of firms’ actions and sends a public message. The monitor makes an offer specifying the precision of the signal generated and the amount to be paid in return. I show that with low monitoring cost, collusive equilibria exist. In the monitor's favorite collusive equilibrium, firms’ payoffs are decreasing in the discount factor. My model helps explain the cartel agreements between the mafia and firms in legal industries in Italy and America.
In Chapter 2, I consider a bargaining game with two types of players – rational and stubborn. Rational players choose demands at each point in time. Stubborn players are restricted to choose a bargaining strategy from a proper subset of strategies available to rational players. In the simplest case, stubborn players are restricted to choose from the set of "insistent" strategies that always make the same demand and never accept anything less. However, their initial choice of demand is unrestricted. I characterize the equilibria in this game, showing how the flexibility of the stubborn type changes equilibrium predictions.
Chapter 3 estimates the effect of longer prison sentences on criminal asset recovery, using administrative, cross-sectional data on confiscation orders in the UK. Confiscation orders request convicted offenders to pay the value of their criminal assets, and specify a prison sentence to be served in the case of non-payment. Using a fuzzy RDD, I exploit discontinuous changes in the legal maximum of this prison sentence. There is evidence that longer prison sentences incentivize offenders to pay.

Advisor: Eso, P
Mukerji, S
Tracking authorship and creativity in orchestral performance

This thesis takes as its starting point the observation that the authorship of the creative product of orchestral performances has been, and continues to be, over-attributed to the conductor. This is reflected both in popular perceptions and in the scholarly attention given to the conductor's leadership role, as well as in orchestral practices which privilege the conductor’s artistically superior position within the orchestra through rehearsal and performance rituals and in remuneration and marketing. Although existing research has challenged the perception that the authority of the conductor is absolute, none has offered alternative explanations for how best to attribute the authorship of orchestral performances. Through a three-phased mixed-methods empirical study including an online questionnaire, in-depth interviews, and a newly developed method of data collection utilising an online variation of video-stimulated recall to capture musician experiences in real-life rehearsal and performance settings, this research contributes to an understanding of the social psychology of orchestral performance by identifying what prompts musicians' decision-making regarding how and when to play their parts. The analysis of the data has resulted in the development of a theoretical Framework of Influence and Action in Orchestral Performance that offers a new way of conceptualising authorship in performance through a 'theory of influence'. It concludes with an exploration of the implications of this revised view of authorship for existing orchestral practices, group creativity research, and our understanding of how the relationships enacted in the micro-socialities of orchestral performance reflect larger social formations.

Keywords: Music Psychology
Creativity
Orchestral Music
Social-Psychology of Music Performance
Music Performance
Authorship
Advisor: Clarke, E