VictorJuiz/thesis huggingface dataset:
Developing inhibitors of bromodomain-histone interactions
Keywords: isoxazole
cancer
acetyl-lysine
post-translational modification
histone
bromodomain

Lysine acetylation is a widespread protein post-translational modification that influences diverse cellular processes. An association between acetylation of histone N-terminal tails and transcriptional activation has been recognised since the 1960s. However, it has only become apparent since 2000 that many of the effects of histone acetylation are mediated by proteins that bind to acetyl-lysine through a specialised acetyl-lysine recognition domain, the bromodomain. Small-molecule inhibitors of bromodomain-histone interactions can greatly assist studies into the functions of bromodomain-containing proteins, and show promise as treatments for several diseases, including cancers. Herein I describe the discovery and development of a novel chemical series of bromodomain-binding ligands containing the 3,5-dimethyisoxazole moiety. This heterocycle acts as an acetyl-lysine bioisostere, mimicking key interactions formed between acetyl-lysine and the bromodomain. Optimised compounds show sub-micromolar affinities for bromodomains of the BET family, a class of transcriptional co-regulators. Crystallographic and structure-activity relationship studies shed light on the structural requirements for potent and selective BET ligands. Furthermore, the compounds show cellular effects consistent with BET bromodomain inhibition: cytotoxicity studies in a range of cell lines, including the NCI-60 human tumour cell line screen, reveal differential activity, with leukaemias showing particular sensitivity. 3,5-Dimethylisoxazole-containing compounds were also shown to downregulate known BET target genes.
Further studies investigated the effect of modifying or replacing the methyl groups of 3,5-dimethylisoxazole on BET bromodomain affinity, which indicated that the 3-methyl group is necessary for affinity. Finally, three novel isoxazole-containing amino acids were synthesised and incorporated into histone peptides as potential bromodomain-binding, non-hydrolysable, acetyl-lysine mimics. These amino acids might be useful in uncovering the function of individual acetylated lysine residues.
The identification of methyl-isoxazoles as acetyl-lysine-mimetic bromodomain ligands represents a significant advance in our understanding of structure-activity relationships for these important proteins. The confirmed cellular activity of these compounds will enable their use in future biological studies.
The zero-turbulence manifold in fusion plasmas
Keywords: turbulence
nuclear fusion
plasma physics
subcritical turbulence

The transport of heat that results from turbulence is a major factor limiting the temperature gradient, and thus the performance, of fusion devices. We use nonlinear simulations to show that a toroidal equilibrium scale sheared flow can completely suppress the turbulence across a wide range of flow gradient and temperature gradient values. We demonstrate the existence of a bifurcation across this range whereby the plasma may transition from a low flow gradient and temperature gradient state to a higher flow gradient and temperature gradient state. We show further that the maximum temperature gradient that can be reached by such a transition is limited by the existence, at high flow gradient, of subcritical turbulence driven by the parallel velocity gradient (PVG). We use linear simulations and analytic calculations to examine the properties of the transiently growing modes which give rise to this subcritical turbulence, and conclude that there may be a critical value of the ratio of the PVG to the suppressing perpendicular gradient of the velocity (in a tokamak this ratio is equal to q/ε where q is the magnetic safety factor and ε the inverse aspect ra- tio) below which the PVG is unable to drive subcritical turbulence. In light of this, we use nonlinear simulations to calculate, as a function of three parameters (the perpendicular flow shear, q/ε and the temperature gradient), the surface within that parameter space which divides the regions where turbulence can and cannot be sustained: the zero- turbulence manifold. We are unable to conclude that there is in fact a critical value of q/ε below which PVG-driven turbulence is eliminated. Nevertheless, we demonstrate that at low values of q/ε, the maximum critical temperature gradient that can be reached without generating turbulence (and thus, we infer, the maximum temperature gradient that could be reached in the transport bifurcation) is dramatically increased. Thus, we anticipate that a fusion device for which, across a significant portion of the minor radius, the magnetic shear is low, the ratio q/ε is low and the toroidal flow shear is strong, will achieve high levels of energy confinement and thus high performance.
Essays in development economics: land rights, ethnicity and birth order
Keywords: peer effects
birth order
Philippines
Development economic
Tanzania
ethnicity
property rights

Aside from the introduction and conclusion, this thesis comprises four core chapters: The first chapter investigates the presence of endogenous peer effects in the adoption of formal property rights. Using data from a unique land titling experiment held in an unplanned settlement in Dar es Salaam, Tanzania. I show a strong, positive impact of neighbour adoption on the household’s choice to purchase a land title. I also show that this relationship holds in a separate, identical experiment held a year later in a nearby community, as well as in administrative data for approximately 45,000 land parcels in the same city. I also discuss possible channels, including the possibility of complementarities in the reduction in expropriation risk.
The second chapter examines the relationship between ethnic heterogeneity and the demand for formal land tenure. Using a unique census of two highly fractionalised settle- ments in Dar es Salaam, I show that households located near coethnics are significantly less likely to purchase a limited form of land tenure recently offered by the government. I attempt to address one of the chief concerns, endogenous sorting of households, by con- ditioning on a households choice of neighbors upon arrival in the neighborhood. These results suggest that close-knit ethnic groups may be less likely to accept state-provided goods if they can generate reasonable substitutes.
The third chapter is a short chapter which presents results from a recent policy experi- ment in Tanzania where formal land titles were provided to informal settlers at randomised prices. Land owners were also randomly assigned conditional discounts, which could only be applied if a woman was designated as owner or co-owner of the land in question. Results show that conditionality has no adverse effects on demand for land titles, yet drastically increases the probability a woman is included. We discuss the implications of these results for the expected bargaining power impacts of the intervention.
The final chapter investigates birth order effects on both anthropometric and edu- cation outcomes in a longitudinal survey of children from the Philippines. Birth order effects are present early in life for both outcomes, but attenuate as children approach adulthood. There is also evidence for nonlinear birth order effects, with both firstborn and lastborn children holding an advantage over middleborn children. These results are at odds with prevalent theories of birth order which predict lasting and monotonic differences in outcomes across children.
Reading herem texts as Christian scripture
Keywords: Bible
Joshua
hermeneutics
1 Samuel
religion and violence
Old Testament
Deuteronomy
reception history
herem
genocide

The thesis investigates the interpretation of some of the most problematic passages of the Hebrew Bible/Old Testament, i.e. passages involving the concept or practice of herem. The texts under consideration contain prima facie divine commands to commit genocide as well as descriptions of genocidal military campaigns commended by God. The thesis presents and analyses the solutions that Christian interpreters through the ages have proposed to the concomitant moral and hermeneutical challenges. A number of ways in which they have been used to justify violence and war are also addressed.
For the patristic and early medieval eras the thesis aims to be as comprehensive as possible in identifying and analysing the various interpretative options, while for later periods the focus lies on new developments. In addition to offering the most comprehensive presentation of the Wirkungsgeschichte of herem texts to date, the thesis offers an analysis and critical evaluation of the theologico-hermeneutical assumptions underlying each of the several approaches, and their exegetical and practical consequences. The resulting analytical taxonomy and hermeneutical map is an original contribution to the history of exegesis and the study of the interplay between religion and violence.
The cognitive dissonance herem texts cause for pious readers is introduced as an inconsistent set of five propositions: (1) God is good; (2) the bible is true; (3) genocide is atrocious; (4) according to the bible, God commanded and commended genocide; (5) a good being, let alone the supremely good Being, would never command or commend an atrocity. If proposition (4) is assumed, at least one of the deeply-held beliefs expressed in the other four must be modified or given up.
The introduction is followed by four diachronic chapters in which the various exegetical approaches are set out: pre-critical (from the OT to the Apostolic Fathers), dissenting (Marcion and other ancient critics), figurative (from Origen to high medieval times), divine-command-ethics,(from Augustine to Calvin) and violent (from Ambrose to Puritan North America). A concluding chapter presents near contemporary re-iterations and variations of the historic approaches.
Can social contract theory fully account for the moral status of profoundly mentally disabled people?
Keywords: social contract
social justice
moral status
mental disability

My hypothesis is that social contract theory does not satisfactorily explain why we owe a serious concern or respect to profoundly mentally disabled individuals (PMD). This is a problem for social contract theories if we assume, like I do in this dissertation, that the PMD possess a robust moral status (RMS).
My dissertation will explore the main strategies deployed by contractarian and contractualist theorists to bring the PMD within the purview of the social contract, in order to clarify why some aspects of their claims are promising but why they nonetheless fail to fully explain the robust moral status of the PMD. I notably find that they leave morally important dimensions of human relations out of the contractual frame, which means that they exclude the PMD from the scope of justice and morality when they claim that this contractual frame offers the only valid explanation to be a subject of justice and a moral patient.
I do not conclude that this requires us to reject social contract theory altogether, nor do I count it as a reason to question whether the PMD have a robust moral status. In my concluding chapter, I will rather suggest a theoretical frame that has the potential of incorporating both contractual and non-contractual relations within the spheres of morality and justice, because both kinds of relation vehicle important intuitions about what is of value in human life.
This dissertation will contribute to orientate future research on the moral and political grounds for the rights of profoundly mentally disabled people, as well as question or curtail the breadth of certain key assumptions of social contract theories.
Assessment of collateral blood flow in the brain using magnetic resonance imaging
Keywords: magnetic resonance imaging
vessel-selective
perfusion imaging
collateral blood flow
angiography
pulse sequence development
arterial spin labelling

Collateral blood flow is the compensatory flow of blood to the tissue through secondary channels when the primary channel is compromised. It is of vital importance in cerebrovascular disease where collateral flow can maintain large regions of brain tissue which would otherwise have suffered ischaemic damage. Traditional x-ray based techniques for visualising collateral flow are invasive and carry risks to the patient. In this thesis novel magnetic resonance imaging techniques for performing vessel-selective labelling of brain feeding arteries are explored and developed to reveal the source and extent of collateral flow in the brain non-invasively and without the use of contrast agents.
Vessel-encoded pseudo-continuous arterial spin labelling (VEPCASL) allows the selective labelling of blood water in different combinations of brain feeding arteries that can be combined in post-processing to yield vascular territory maps. The mechanism of VEPCASL was elucidated and optimised through simulations of the Bloch equations and phantom experiments, including its sensitivity to sequence parameters, blood velocity and off-resonance effects.
An implementation of the VEPCASL pulse sequence using an echo-planar imaging (EPI) readout was applied in healthy volunteers to enable optimisation of the post-labelling delay and choice of labelling plane position. Improvements to the signal-to-noise ratio (SNR) and motion-sensitivity were made through the addition of background suppression pulses and a partial-Fourier scheme. Experiments using a three-dimensional gradient and spin echo (3D-GRASE) readout were somewhat compromised by significant blurring in the slice direction, but showed potential for future work with a high SNR and reduced dropout artefacts.
The VEPCASL preparation was also applied to a dynamic 2D angiographic readout, allowing direct visualisation of collateral blood flow in the brain as well as a morphological and functional assessment of the major cerebral arteries. The application of a balanced steady-state free precession (bSSFP) readout significantly increased the acquisition efficiency, allowing the generation of dynamic 3D vessel-selective angiograms. A theoretical model of the dynamic angiographic signal was also derived, allowing quantification of blood flow through specified vessels, providing a significant advantage over qualitative x-ray based methods.
Finally, these methods were applied to a number of patient groups, including those with vertebro-basilar disease, carotid stenosis and arteriovenous malformation. These preliminary studies demonstrate that useful clinical information regarding collateral blood flow can be obtained with these techniques.
Cherubim and Seraphim in the Old Testament
Keywords: Old Testament
Seraphim
Angels
Cherubim

This thesis is the first modern joint study of biblical Cherubim and Seraphim. I begin by setting out the recent history of their interpretation, before taking each of the biblical texts in turn. Chapter 1 looks at the references to Cherubim in Ezekiel. I argue that the Cherubim in Ezek. 1-11 are based upon the two large Cherubim in the sanctuary in Jerusalem. I investigate the different traditions represented by LXX and MT versions of Ezek. 28 and identify a tradition which may account for the MT of this chapter. Chapter 2 covers the other descriptions of living Cherubim in the biblical texts in Gen. 3 and Ps. 18. I argue for a conscious link with the Jerusalem Temple in both texts but for their independence from each other. All the references to Cherubim in the Temple and the Tabernacle are looked at in Chapter 3, and I offer a radical re-imagining of the two large Cherubim in the Solomonic Temple and on the Kapporeth in the Mosaic Tabernacle. In Chapter 4 I question the validity of translating the Cherubim Formula as “enthroned upon the Cherubim”, and offer an alternative translation which makes reference to all the Cherubim mentioned in the text. In Chapter 5, looking at the references to saraph, I follow Joines and others in arguing for a serpentine form for the Seraphim, but argue that this identity was forgotten at an early stage of the textual transmission, and that they were then seen as part of Yhwh's heavenly host. Finally, I argue that the role of Cherubim and Seraphim is similar, being primarily apotropaic, but that both are associated with theophany and, less frequently, with heavenly worship.
Price modelling and asset valuation in carbon emission and electricity markets
Keywords: Forward-Backward Stochastic Differential Equation
Electricity
Commodity Market
Derivative Pricing
Emission Market
Non-linear Partial Differential Equation

This thesis is concerned with the mathematical analysis of electricity and carbon emission markets.
We introduce a novel, versatile and tractable stochastic framework for the joint price formation of electricity spot prices and allowance certificates. In the proposed framework electricity and allowance prices are explained as functions of specific fundamental factors, such as the demand for electricity and the prices of the fuels used for its production. As a result, the proposed model very clearly captures the complex dependency of the modelled prices on the aforementioned fundamental factors. The allowance price is obtained as the solution to a coupled forward-backward stochastic differential equation. We provide a rigorous proof of the existence and uniqueness of a solution to this equation and analyse its behaviour using asymptotic techniques. The essence of the model for the electricity price is a carefully chosen and explicitly constructed function representing the supply curve in the electricity market.
The model we propose accommodates most regulatory features that are commonly found in implementations of emissions trading systems and we analyse in detail the impact these features have on the prices of allowance certificates. Thereby we reveal a weakness in existing regulatory frameworks, which, in rare cases, can lead to allowance prices that do not conform with the conditions imposed by the regulator.
We illustrate the applicability of our model to the pricing of derivative contracts, in particular clean spread options and numerically illustrate its ability to "see" relationships between the fundamental variables and the option contract, which are usually unobserved by other commonly used models in the literature.
The results we obtain constitute flexible tools that help to efficiently evaluate the financial impact current or future implementations of emissions trading systems have on participants in these markets.
The mirror of Tacitus? Selves and others in the Tiberian books of the 'Annals'
Keywords: Roman historiography
early principate
Tacitus
civil war

This thesis considers the geographical and chronological forms of ‘mirroring’ that offer a way of reading 'Annals' 1-6. It looks at how Tacitus’ depictions of non-Romans reflect back on Rome, and at the echoes of Rome’s past and future that can be discerned within his description of Tiberius’ principate. After an introduction that discusses key thematic and methodological questions, Chapter 1 shows that Tiberius’ accession and the Pannonian and German mutinies described in 'Annals' 1 echo Tacitus’ account in 'Histories' 1 of events of AD 69. Moreover, when the Romans attempt to conquer Germany, the Germans’ resistance to this and to other efforts to rule them shows up Roman responses to civil war and autocracy. Chapter 2 begins by examining potential similarities between Roman and both Parthian and Armenian history, and then focuses on Germanicus’ voyage in the east, recounted in 'Annals' 2. His actions associate him with many late republican and early imperial Roman figures, which suggests that there are continuities between those two eras. Chapter 3 extends this theme by discussing the echoes of Sallust and Caesar in the central books of the Tiberian hexad. Intertexts with Sallust’s 'Bellum Catilinae' especially hint that earlier civil conflicts are about to be replayed in some form, as the appearance of Sejanus, the ‘new Catiline’, confirms.
Chapter 4 further considers Tacitus’ inferences about the overlap between republican and imperial history, and then examines anti-Roman revolts in 'Annals' 2, 3 and 4. Foreign rebels’ relative success in attempting to reclaim their freedom correlates with their distance from Rome, and this has clear implications for the status of Roman 'libertas' under Tiberius. Finally, the outbreak of ‘civil war within the principate’, and indeed within the imperial house, is analysed. Chapter 5 traces the continuation of this ‘civil war’, and proposes that the last book of the Tiberian hexad again looks directly to 69, as well as to the excesses of other Julio-Claudians. It also considers Tacitus’ account of Roman intervention in Parthia: this episode confirms imperial Rome’s propensity for autocracy and civil war. There follows a short conclusion in which some speculation is offered about how some of the themes discussed in this thesis with reference to the Tiberian hexad may have been represented in the lost central books of the 'Annals'.
Analysis of b cell responses to blood-stage malaria antigens in humans following immunization with candidate vaccines and controlled human malaria infection
Keywords: vaccines
malaria
B cell

The apicomplexan parasite Plasmodium falciparum is the causative agent of the most severe and deadly form of human malaria. The production of an efficacious malaria vaccine is seen as one of the key steps towards the eradication of the disease, however to date only one candidate has progressed to application for licensure. Candidate malaria vaccines target the different stages of the P. falciparum lifecycle through induction of a functional immune response. Vaccines targeting the blood-stage parasite require induction of high titre neutralising antibodies. To achieve this, vaccine regimens have been designed specifically to maximise antibody induction and maintenance in humans. The ultimate test of any candidate vaccine is clinical efficacy and controlled human malaria infection (CHMI) is a powerful tool for measuring this. This model can also be used to study how vaccine induced antigen-specific components of the immune system respond to native antigen exposure in the context of parasitic infection
In this Thesis I describe the induction and maintenance of B cell responses, including memory B cells (mBC) and antibody secreting cells (ASC) to the candidate blood-stage malaria antigens MSP1 and AMA1 following vaccination with a variety of regimens and CHMI. These B cell populations along with peripheral blood T follicular helper (Tfh) cells correlate strongly with antibody induction. Within these populations I have identified a number of phenotypically distinct subsets which contribute to a functional response to vaccine and/or parasite antigen. From single cell sorting of ASC at day seven post-boost I have managed to produce the first fully human monoclonal antibodies (hmAbs) specific for AMA1, one of which shows significant growth inhibitory activity (GIA).
Despite promise the vaccine candidates MSP1 and AMA1 have been disappointing in terms of human efficacy. In this Thesis I have attempted to provide explanations on a cellular level as to why there is such disparity between pre-clinical and human data and ultimately why these candidates may have failed to provide efficacy. Such work will provide a strong basis for analysing future clinical trials of alternative candidate blood-stage vaccines and allow accurate characterisation of immune correlates and clinical efficacy when it is achieved.