VictorJuiz/thesis huggingface dataset:
Molecular imaging of DNA damage repair
Keywords: molecular imaging
cancer
PARP
DNA damage response
radiofluorination
ATM
PET

Nuclear imaging has the ability to non-invasively probe target expression, drug pharmacokinetics, and monitor treatment response. With many cancer therapies inducing DNA damage to overwhelm tumour cells into arrest, there has been a push to investigate the DNA damage response with regards to understanding the key proteins involved and the development of DDR inhibitors to enhance current DNA damaging therapies. The use of DDR inhibitor radiotracers with PET or SPECT could allow scientists to quickly collect information on tumour phenotype, DDRi drug interactions and pharmacokinetics, calculate levels of DNA damage as a result of previous therapies, and could ultimately improve patient stratification. With some key targets of the DDR such as γH2AX and PARP, already under investigation for nuclear imaging, this thesis aimed to investigate ATM as a potential new target for DDR nuclear imaging, as well as expanding the selection of PARPi radiotracers to allow imaging of tumours in the brain. This body of work highlights the key challenges faced in the chemistry and radiochemistry of developing new radiotracers and demonstrates the limitations of ATM as an imaging target. It is the hope that this research will pave the way for further development of ATMi radiotracers to verify whether ATM is a suitable molecular imaging target and to promote the development of BBB-penetrable PARPi tracers.
Optimal investment, valuation and hedging under model ambiguity
Keywords: model ambiguity
basis risk
stochastic volatility

In this thesis, we study several utility maximisation problems under model uncertainty, involving optimal investment, valuation and hedging.
We first derived martingale distortion representations for classical utility maximisation problems in a non-Markovian stochastic factor model, with power, logarithmic and exponential utilities.
We then study multiple priors power utility maximisation problems when the reference model is a non-Markovian stochastic factor model, and derive a BSDE representation of the value process, optimal strategy and least favourable model.
We also study a variational preferences logarithmic utility maximisation problem when the reference model is a non-Markovian stochastic factor model, and when the plausible models are penalised by an additive entropic penalty function. The robust problem is transferred to a classical utility maximisation problem with a power utility whose risk aversion is dependent on the model ambiguity aversion parameter. We then fully solve the robust problem and perform numerical tests comparing several classical and robust strategies for a Stein-Stein stochastic volatility model and for a Heston model.
Finally, we study robust exponential valuation and hedging problems in a basis risk model, using both the multiple priors approach and the variational preferences approach with a multiplicative penalty function. Specialising to a constant parameter basis risk model, the robust problems admit explicit or approximate solutions, thus we are able to conduct large-scale simulation based tests on performances of various pricing and hedging strategies.
Searching for axionlike particles with gamma-ray observations of blazars
Keywords: Beyond the Standard Model
Axionlike particles
Axions
Blazars
Gamma rays

Many theories beyond the Standard Model of particle physics predict the existence of axionlike particles (ALPs) that mix with photons in the presence of a magnetic field. Searching for the effects of ALP-photon mixing in astrophysical gamma-ray observations of blazars—jetted active galactic nuclei with their jets pointed towards us—has provided some of the strongest constraints on ALP parameter space so far. The focus of this thesis is a type of search where the magnetic field of the blazar jet itself, as opposed to the various other mixing environments usually used, is the dominant region for ALP-photon mixing. I show that mixing in jets can be important for an un-probed region of ALP parameter space at high masses (close to the ALP dark matter space), making them promising mixing environments for an actual search. In order to perform such a search, however, the modelling of the jet field structure, and the effects of photon-photon dispersion within the jet, must be understood. I develop a framework to investigate and address these challenges. This framework is then used to perform an ALP search. In previous searches, only individual sources have been analysed. I perform a search with a combined analysis of Fermi Large Area Telescope data of three bright, flaring flat-spectrum radio quasars. For the first time, I include a full treatment of photon-photon dispersion within the jet, and account for the uncertainty in the B-field model by leaving the field strength free in the fitting. Overall, I find no evidence for ALPs, but am able to exclude ALP masses, m ≲ 200 neV, and ALP-photon couplings, g ≳ 5 × 10^−12 GeV^−1, with 95% confidence. This is an improvement on previous gamma-ray constraints in this mass range. Finally, I develop a proof-of-concept for an ALP search based on population-level observations of blazars, as opposed to individual source spectra. From simulated number counts with and without ALPs, I show that this method could potentially allow couplings down to g ∼ 1 × 10^−12 GeV^−1 to be probed for masses m ∼ 10 neV.
Aspect and event structure: the morphosyntax of Polish verbs from a cross-linguistic perspective
Keywords: event structure
aspect
linguistics
syntax
Polish
Distributed Morphology
morphology
Russian
Slavic

This thesis presents a detailed analysis of Polish verb stems from a cross- linguistic perspective, couched in the framework of Distributed Morphology (Halle and Marantz 1993 et seq.). Polish verbs are decomposed into a number of functional projections responsible for aspect (perfective vs. imperfective) and event structure (simple event vs. complex change of state). The first part of the thesis focuses on the morphosyntax of event structure. Polish is classified as a weak satellite-framed language in a tripartite version of Talmy’s typology (Acedo-Matellán, 2016). Just like Latin and Classical Greek, Polish has resultative prefixes, but no complex AP or PP resultatives. The properties of weak satellite-framed languages are captured by an M-Merger Parameter, which requires a non-branching resultative X/XP to incorporate into the verb at PF (Matushansky, 2006). The second part of the thesis turns to the morphosyntax of aspect, investigating the relationship between verbal affixes and the value of aspect in Polish and other Slavic languages. I discuss and dismiss proposals based on syntactic agreement (Biskup, 2019, 2022) and a semantic mapping from event structure to aspect (Klein, 1995; Ramchand, 2008a; Tatevosov, 2018, 2022). Instead, I develop a novel movement-based analysis, whereby vP-internal prefixes raise to AspP to license perfectivity. Special attention is paid to the function of secondary imperfective morphology, such s the suffix -yw. I argue that there is no such thing as a ‘secondary imperfective operator’ at the level of syntax/semantics, and that the secondary imperfective is a dissociated morpheme in the sense of Embick (1997), inserted only at PF. The emerging picture is consistent with a grammatical architecture in which morphology interprets the output of narrow syntax, but is not fully isomorphic with it. Morphological operations may filter out well-formed syntactic representations or insert morphemes that are absent from narrow syntax and LF.
Using machine learning for dynamic resource orchestration & task scheduling, in a radio access network based edge environment
Keywords: ceph
artificial intelligence
containers
task scheduling
mobile edge computing
cloud computing
energy reduction
federated cloud
mMTC
URLLC
5G
machine learning
cloud-based/ Centralized Radio Access Network (C-RAN)
multi-access edge computing
eMBB
MEC orchestration

The evolution in mobile wireless communication generations, continues to gift the world with new telecommunication capabilities towards how people live and work. For instance, the roll out of the fifth generation (5G) promises a much-enhanced cloud-native application service, through improved communication speed, higher bandwidth, improved capacity for more connected devices and many more. These exciting new 5G features have given numerous vertical and horizontal industries a reason to explore different ways of delivering value, through emerging cloud-native applications that run on access devices (i.e. the Internet of Things (IoTs) and mobile devices). These cloud-native applications such Virtual Reality, Vehicle to everything communication (V2X), artificial intelligence, video analytics and so on however have strict performance requirements for extremely low latency (10 milliseconds and below) and higher bandwidth, that 5G alone cannot deliver. Unfortunately, the traditional cloud computing and radio access network setups do not sufficiently address these key communication needs which are crucial to the performance of these cloud-native applications. There is therefore an urgency to enhance and optimize the traditional mobile telecommunication network architecture, to meet these performance needs. This thesis seeks to demonstrate how we have developed a facility called Multi-Access Edge Computing with Cloud Radio Access Networks (MECRAN) to address this issue. MECRAN is based on the edge computing paradigm and uses machine learning to optimize the round-trip delivery of data at low latency, by dynamically scheduling cloud-native applications, to run in close proximity to a mobile user, at the edge of the radio access network.
The crusade against the Staufer in Germany, 1246-51
Keywords: crusade against the Staufer
Holy Roman Empire
Henry Raspe
Hohenstaufen
crusade against Christians
1248
crusade against the Staufen
1247
Archbishop of Cologne
crusade against the Hohenstaufen
William of Holland
Archbishop of Trier
political crusade
crusade against political enemies
Archbishop of Mainz
1246
Innocent IV
13th century
Staufer
Hohenstaufen Crusade
1250
1251
1239
Pope
Holy Roman Emperor
crusade against Christian enemies
Frederick II
Conrad IV
Staufen
crusade
Germany 13th century
Staufer Crusade
1249
Gregory IX
Germany

In the conflict between Holy Emperor Frederick II and Pope Innocent IV, the papal argument that this change of power was a crusade and thus a holy war with an important spiritual dimension largely failed to take hold in Germany. Instead, the way the crusade unfolded in practice was determined by the logic of attaining royal power in Germany, while the political and legal necessities for Frederick II’s deposition determined how Pope Innocent IV chose to phrase the justification for war. Politics drove religious ideology in a way that made it distinct from other crusades. Thus, the crusade against the Staufer merits description as a ‘political crusade.’
The analysis is based on thirteenth century chronicles and annals, mainly produced in Germany but also beyond, as well as charters issued by protagonists of the conflict. Most chronicles and annals did not report the military campaigns by using language typical of crusading. Hence chronicles create a dissimilar picture of the same events to papal letters, which are often prescriptive. The difference in language between the sources has shaped the historiography on the crusade until this day.
The crusade was shaped by the prerequisites of becoming the new King of the Romans, and of putting rulership into practice. Henry Raspe conceptualised his military strategy as a direct fight to overthrow Conrad IV, while William of Holland strengthened his rule after his coronation by conquering imperial lands and property, especially royal palaces. Juxtaposing their strategies highlights their different approaches to affecting a change of power in Germany.
By addressing this hitherto neglected subject, the thesis contributes to two disciplines: to crusader studies by analysing the crusade against the Staufer in its German context, and to German history by explaining the role the crusade played in the conflict between Emperor Frederick II and the papacy.
Developing recombinant overlapping peptides of prostate-specific antigen as vaccine
Keywords: immunotherapy
prostate cancer
peptide vaccine

Immunotherapy has become a new approach for prostate cancer (PCa) due to its selectivity and efficacy. With immunogenic properties, PSA has been found to be overexpressed in PCa and its enzymatic activity enhances the growth and progression of PCa cells. Furthermore, dendritic cell (DC) based therapies against PSA have been approved for clinical use which makes PSA a desirable target for recombinant overlapping peptides (ROPs) vaccine development. Based on combining multiple T cell epitopes, ROPs involves identifying a set of overlapping amino acid sequences constituting a single-chain peptide representing the sequence of PSA. Between each overlapping region is an enzymatic cleavage site specific for cathepsin S which is a key protease located in endolysosomes of DC. This strategy harnesses DC’s potential of priming both CD4+ and CD8+ naïve T cells by its ability to be presented by MHC class I and II molecules, triggering robust cell-mediated anti-tumour immunity. This project aims to develop and optimise the process of ROP-PSA expression and purification, and subsequently study the mechanism of activation of DCs in vitro using dendritic cell line DC2.4 by cytokine array assays. Here we demonstrate the successful expression of ROP-PSA from E. coli, the solubilisation of the recombinant ROP-PSA protein in urea, sarkosyl and arginine, and purification of ROP-PSA from E. coli expression system, which was validated by SDS-PAGE and western blot. Biocompatibility and stability of the buffer were tested by viability assay in vitro with the cell line to optimise buffer proportion in medium before cytokine array. Upon endotoxin removal, the concentration of ROP-PSA was accurately measured by bicinchoninic acid (BCA) assay for the calculation of treatment dose. Cytokine profiles have shown cytokine and chemokine release (e.g. TNF-α and significantly from CC chemokine family) from DC2.4 after treatment with ROP-PSA in cytokine array. Cathepsin S digestion assay and mass spectrometry analysis concluded some cleavage at cathepsin specific linker. The project provides a strong foundation for in vivo preclinical murine studies.
Compression of models and data in deep learning
Keywords: image compression
neural network quantization
deep learning
data compression
neural network pruning
quantization

We face many challenges in deploying high-performance neural networks in practice. These challenges are predominantly due to the size of neural networks and apply to both training and inference. Compressing neural networks to make them train and run more efficiently is therefore crucial and has been a parallel line of research from the early days of neural networks development. The two main compression techniques in deep learning, which are the focus of this thesis, are pruning and quantization. This thesis explores how the information from higher-order gradients (meta-gradients) be used to improve deep learning compression. We start by identifying a fundamental limitation in the formulation of pruning: Although many methods, such as saliency-based pruning, follow pruning by a training or fine-tuning stage, parameter saliencies only look at a snapshot of parameters without taking into account the "trainability" of the parameters. We show how meta-gradients can be used as a more informative signal to find better trainable subnetworks at initialization. We then look at quantized neural networks and show how meta-gradients can be used in a regularization scheme to "learn" models with inherent robustness against post-training quantization. Finally, we look at the dual compression problem, i.e. using neural networks to compress data sources. We start with images and propose a simple autoencoder-free architecture where we store weights of a neural network instead of RGB values of image pixels. We then use meta-gradients to meta-learn a base network to amortize the cost of training one network per input. A significant advantage of our learning compression is that it becomes agnostic to the data type, and we present results on various data types beyond 2D images. Importantly, we evaluate the usefulness of standard DNN compression techniques, e.g., quantization, for this new type of neural network.
Investigating the role of lipids and small-molecule ligands in hedgehog signalling using molecular dynamics simulations
Keywords: simulation
HHAT
molecular dynamics
smoothened
biophysics
structural biology
patched
cancer
hedgehog

The Hedgehog (HH) signalling pathway orchestrates cellular patterning during embryonic development and adult stem cell programming. Sonic hedgehog (SHH) is the principle morphogenic ligand responsible for paracrine induction of HH signalling. Pathway dysregulation results in multiple cancer pathologies and ineffective tissue partitioning, leading to severe developmental diseases. SHH is directly conjugated to two lipids; a N-terminal palmitate and a C-terminal cholesterol moiety. Unique bilipidation of SHH occurs within the endoplasmic reticulum via autocatalytic cholesterylation and Hedgehog acyl-transferase (HHAT) catalysed palmitoylation steps, after which SHH is released from cells. SHH binds to and inhibits the tumour suppressor protein Patched1 (PTCH1) to relieve PTCH1 mediated inhibition of the Class F G-protein coupled receptor (GPCR) Smoothened (SMO). Small-molecule ligands, notably cholesterol and palmitate, are inextricably linked to HH signalling, inducing a perplexing range of signalling outputs. This thesis outlines a conveyor-belt tour of HH membrane proteins for SHH processing, engagement, and pathway initiation. Molecular dynamics (MD) simulations of PTCH1, SMO and HHAT are employed to rationalise the, often counter-inductive, roles of small-molecules in HH signalling. Simulations are coupled with structural and biochemical data, demonstrating how the SHH-cholesterol contributes to PTCH1 inhibition. Simulations and free energy calculations are used to provide energetic contextualisation of PTCH1 cholesterol transport models and predict ion-coupling stoichiometries. Additionally, we find simulation and biochemical evidence for cooperativity between cholesterol binding sites on SMO. Finally, simulations are used to assist HHAT structural interpretation, elucidating roles for residues in solvent gating, product exit and priming HHAT catalysis. Bioinformatics and simulations were also employed to assess structural divergence between HHAT and related homologues. Biological insights were assisted by concurrent development of computational methodologies for characterisation of protein-lipid interactions, their affinities and integration with experimental data. Thus, this thesis spotlights the diverse roles lipids and small-molecules play in HH pathway regulation – from activators to allosteric modulators and inhibitors, illuminating new avenues for therapeutic intervention.
Tranquillity, transcendence, and retreat: the transformative practice of listening at Evensong
Keywords: music listening
sacred music
choral Evensong

Choral Evensong is sung every day in Anglican churches across the UK, attracting thousands of people each week to its congregations. In the context of declining Anglican church attendance overall, Evensong’s appeal has been attributed, anecdotally, to its music. This thesis reports the findings of a musicological study conducted to investigate why people go to Evensong, what they experience while they are there, and how the music of Evensong is implicated in these motivations and experiences.
The study took an interdisciplinary approach based on the sociology, and the social and applied psychology, of music. It adopted a multi-method approach incorporating participant observation, 43 in-depth interviews; an immersive, real-time experimental study involving 26 participants; and two surveys which elicited more than 2,100 responses.
Drawing on the findings of each of these methods, the thesis locates Evensong within the framework of music in everyday life, as a powerful and trusted technology of the self. It argues that emotional and cognitive transformation are central to many people’s experiences of the service, and it demonstrates that the attainment of tranquillity, transcendence, and a sense of retreat are particularly highly valued and frequently reported outcomes. It suggests that these are pursued through an active and sophisticated listening practice involving both agency and its relinquishment, and argues that notwithstanding participants’ often parallel practices, objectives, and results, their experiences of Evensong are characterised as much by plurality as similarity. It is proposed that it is the multiplicity of ways of listening that Evensong affords that enables so many ‘sorts and conditions’ of listener to be satisfied by it.
The thesis has ramifications for our understanding of the types, modes and practices of music listening in which people engage to pursue cognitive and affective objectives; of the mechanisms by which the same music can elicit different experiences among diverse groups of co-present listeners; and of the creative uses to which listeners can put live musical events.
Links between the unfolded protein response and the DNA damage response in hypoxia
Keywords: senataxin
unfolded protein response
reactive oxygen species
transcription
nucleolin
nucleolus
hypoxia
DNA damage response
tumour microenvironment
R-loops
rDNA

Hypoxia is a common feature of solid tumours and is associated with poor patient prognosis, therapy resistance and metastasis. Severe hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication stress/DNA damage response (DDR) and the unfolded protein response (UPR). However, we carried out a systematic literature review using PRISMA guidelines and concluded that no previous mechanistic links were reported between the hypoxic DDR and UPR. We demonstrated for the first time that secondary structures called R-loops increase in hypoxia and contribute to hypoxia-induced replication stress. Interestingly, we found that the putative RNA/DNA helicase SETX, which resolves R- loops, is induced in hypoxic conditions and that this occurs in a UPR-dependent manner through the PERK/ATF4 axis. Upon depletion of SETX in hypoxia, R-loop levels increase, DNA damage accumulates and replication rates decrease. Therefore, these data establish SETX and R-loops as novel links between the UPR and DDR in hypoxia. These findings also led us to question both the mechanism and consequence of hypoxia-induced R-loops. Here, we show that hypoxia-induced R-loops regulate the nucleolar stress response. Specifically, R-loops accumulate on the rDNA in hypoxia and block rDNA transcription in hypoxic conditions. The nucleolar stress protein nucleolin translocates from the nucleolus to the nucleoplasm in hypoxia and this translocation is also dependent on R-loops. Furthermore, we determined that the accumulation of R-loops in hypoxia is dependent on reactive oxygen species (ROS) as ROS scavengers partially rescued rDNA transcription repression and nucleolin translocation. Together, these data led us to hypothesise that the hypoxic UPR, in an attempt to shut down protein synthesis, also downregulates the production of ribosomes, an energy-demanding process, through the ROS dependent accumulation of R-loops at the rDNA.