VictorJuiz/thesis huggingface dataset:
Exploring the relationship between cancer metabolism and oncolytic adenoviruses

Tumour cells exhibiting the Warburg effect rely mostly upon aerobic glycolysis for ATP production and have a notable addiction to anaplerotic use of glutamine for macromolecular synthesis. This strategy maximises cellular biosynthetic potential and provides an attractive anabolic environment for viral infection. Here, we evaluate infection of highly permissive cells (A549 cells) and poorly permissive cells (SKOV3) with wildtype adenoviruses, and the oncolytic chimeric adenovirus enadenotucirev (EnAd) to probe the role of metabolism on the success of oncolytic virotherapy with EnAd.
All adenoviruses caused an increase in glucose and glutamine uptake along with increased lactic acid secretion in their host cells, mirroring the canonical Warburg effect phenotype. Through identifying the IC50 of a panel of cancer cells, we identify a correlation showing that cells which rely upon aerobic glycolysis tend to be more permissive to EnAd oncolysis.
The virus lifecycle of both wildtype adenoviruses and EnAd were critically dependent on exogenous glutamine. Virus activity in glutamine-free cells was rescued with exogenous membrane-permeable α-ketoglutarate, but not pyruvate or oxaloacetate, suggesting an essential role for reductive carboxylation in glutamine usage. We propose that this unusual glutamine metabolism is beneficial for the production of biosynthetic intermediates, particularly under conditions of hypoxia or decreased cellular respiration as is often seen during adenovirus infection.
Counterintuitively, restricting glycolysis using 2-deoxyglucose or by limiting glucose supply strongly improved virus activity in both cell types. Antagonism of glycolysis also boosted EnAd replication and transgene expression within human tumour biopsies, and in xenografted tumours in vivo. We further bolstered this finding through weaning SKOV3 cells off of glucose. This process created a cell line which is highly permissive to EnAd infection and lysis. Finally, we engineered an “armed” EnAd expressing the glycolysis inhibitor TIGAR which was able to lyse cells whilst expressing TIGAR without causing acidification of the media.
These findings emphasise the importance of metabolism on productive viral infections which is of particular significance for viruses restricted to replicate in tumours, that already display aberrant metabolic phenotypes.

Keywords: oncolytic virotherapy
cancer immunotherapy
tumour metabolism
virology
gene therapy
metabolism
oncolytic
oncology
Advisor: Seymour, L
Stone, E
Rational structures on multiple zeta values

Motivated originally by the question of defining a rational canonical associator, we study rational structures associated to multiple zeta values. In particular, we focus on the question of providing an explicit description of the motivic Lie algebra associated to the projective line minus three points via new families of motivic relations among multiple zeta values.
Inspired by results obtained by considering depth-graded multiple zeta values, we attempt a similar approach. We introduce the block filtration on the space of multiple zeta values and show that it agrees with the coradical filtration induced by the motivic coaction. By considering the associated graded Lie algebra of the motivic Lie algebra with respect to this filtration, we obtain an isomorphic Lie algebra bg with canonical representatives for its generators in Q0,e1>. This provides a possible route to defining canonical generators of the motivic Lie algebra by finding a section of the projection induced by this isomorphism.
We then consider relations among block graded motivic multiple zeta values, finding several new families of relations and providing a complete description of bg in low block degree. We use the motivic coaction to lift these relations to genuine relations among motivic multiple zeta values, providing new families of relations and generalising previously known relations such as those due to Borwen, Bradley, Broadhurst and Lisonek.
Finally, we consider the implication of previously known relations on the p-adic valuation of coeffcients of a rational associator, providing a bound on the growth in terms of weight and block degree. We also present a partial solution to the question of canonical generators via the introduction of an inner product.

Keywords: motivic periods
multiple zeta values
number theory
shuffle algebra
Advisor: Brown, F
Epicurus' human beings - beyond person and self

Epicurus’ philosophical project is predicated on its eudaimonistic efficacy. His letters and maxims are not only describing a way of life, they actually instantiate his practice of care and reform. To memorise and understand them is meant to actually improve on one’s capacity to reach and maintain a state of ataraxia. They are written and designed to have an impact. Thus, to read Epicurus solely as a theoretician is to turn a blind eye to his agenda. This thesis advocates a stronger reading that takes Epicurus’ intentions at face value. It brings the doctrine closer to its application, through an examination of the readers and intended practitioners of Epicurus’ philosophy: human beings.
The corpus is made of the three letters and the doctrines transmitted by Diogenes Laertius in book 10 of the Lives of Eminent Philosophers. Each chapter is dedicated to one of these texts and subdivided into two main sections. In the first section, close readings and textual interpretations with philosophical focus build a heuristic analysis of Epicurus’ conception of what human beings are and do. In the second one, lexical analysis and a review of person deixis offer a text-centred counterpart. Together, they delineate the human beings according to, and in, Epicurus’ philosophy. In the case of the chapters on the Letter to Pythocles and the corpus of the Kuriai Doxai, special attention is paid to the problem of their respective authenticity by focusing on the function of those texts, also essential in assessing their form and content.
This research yields important insights into the pragmatics of Epicurus’ writings, especially with respect to their use, their format, and their functioning in one’s efforts to become and stay happy. Such results are invaluable to our understanding why, and how, Epicurus thought that his teaching can be efficacious and therapeutic.

Keywords: Epicurean epistemology
Person deixis
Kuriai Doxai
Philosophical efficacy
Epitomai
Letter to Herodotus
Philosophy as care
Epicurus
Letter to Menoeceus
Pragmatic philosophy
Epicurean ethics
Letter to Pythocles
Self-reform
Advisor: Reinhardt, T
No longer slaves: weak hamartiology in Bethel Music

Since 2009, Bethel Music has become one of the best-selling Christian worship outfits in the world. Bethel have produced a large number of pop worship songs, such as ‘Forever’ and ‘No Longer Slaves,’ that have been incorporated into contemporary worship services across the globe, as the pop idiom has become more popular in Christian worship. Critiques of pop worship music have, thus far, generally failed to identify any theological shortcomings of the musical idiom itself.
In this thesis, I argue that the pop idiom of contemporary mainstream worship music conveys a weak hamartiology that undermines the ongoing relevance of the doctrine of sin, and subsequently instrumentalises worship in the pursuit of “tangible” assurance of salvation (for example through positive affect or charismata). I demonstrate this by presenting three musico-theological devices, ubiquitous throughout the genre, which Bethel Music utilise to this end: cosmic ambience, erotic infantilism and triumphalist climax. These devices are created using musical features such as harmony, rhythm, melody and instrumentation. This use of the pop idiom shapes Bethel’s theological message in such a way as to actively hinder the communication of a more robust hamartiology. In making this argument, I combine musicological and theological analysis in a method unused, so far, in theological analyses of pop music.
I begin by situating Bethel’s Charismatic theology within the tradition of Methodism and Pentecostalism, before elucidating Bethel’s distinctive hamartiology through a comparison with John Wesley’s. I then outline the functions of pop worship, and three models of musical meaning. Two musico-theological chapters subsequently argue that Bethel’s worship music conveys a therapeutic ambience that eclipses the significance of sin, and presents sin as a retrospective quality for justified Christians. I close with reflections on how Christian pop worship might strengthen its own doctrine of sin without abandoning the pop idiom.

Keywords: John Wesley
Christian congregational music
pop music
Bethel Church
Bethel Music
hamartiology
Charles Wesley
music
worship
Advisor: Rasmussen, J
Towards an engineered autologous cellular therapy for RAG2 deficiency

Severe combined immune deficiency (SCID) caused by RAG deficiency is a genetically-determined immune deficiency characterized by the virtual absence of adaptive immune cells. Unless treated with a hematopoietic stem cell transplantation (HSCT), RAG deficient patients succumb to severe infections early in life. HSCT, however, carries risks of graft-versus-host disease. Moreover, a high rate of graft failure and poor immune reconstitution have been reported after unconditioned HSCT. Expression of the RAG genes is tightly regulated, and preclinical attempts of gene therapy with heterologous promoters have led to controversial results. Using patient-derived induced pluripotent stem cells (iPSCs), patient hematopoietic stem and progenitor cells (HSPCs) and an in vitro artificial thymic organoid system as a model, here we demonstrate that gene editing rescues the progressive T-cell differentiation potential of RAG2 deficient cells to normal levels, with generation of a diversified T cell repertoire. These results suggest that gene editing may represent a novel autologous therapeutic option for correction of this immunodeficiency.

Keywords: cell therapy
organoids
immunodeficiency
CRISPR
RAG2 deficiency
immunotherapy
Advisor: Acuto, O
Notarangelo, L
Refugees and local politics: Elite and citizen responses to asylum seekers

How do voters and candidates arrive at their immigration stances? Although immigration is at the center of current political debates, we know surprisingly little about how these attitudes are formed. This is because research on immigration attitudes in political behavior relies mainly on expressed preferences and aggregate election results. This thesis attempts to innovate by using outcomes that have real policy effects and are possible to measure at the micro-level with causal identification strategies.
The first paper makes use of unique Finnish Voting Advice Application data that measure candidates' support for different policies. I measure the over-time evolution of candidates' revealed preferences with which they try to attract voters in local elections after receiving or not receiving asylum seekers in the constituency. The results suggest that politicians in affected rural areas update their stances to be more pro-immigration upon realising the socio-economic benefits of refugee intake. In the second paper I use this setting to measure what kinds of immigration policies are rewarded by the electorate. I propose three different ways to measure the anti-immigration vote and conclude that measuring party support brings different results from measuring individual-level policy support. All ways of measurements, however, corroborate that rural reactions to asylum seekers are more positive than urban reactions. The third paper tests the citizen-level mechanisms of this rural—urban division and concludes that people in rural areas are more receptive to asylum seekers because they experience more contact with them, don't associate them with crime, and they also economically profit more from their reception.
Together, these three papers question the thus far unanimous belief that rural areas are more hostile to immigration than cities and also highlight how aggregation and analyzing parties' vote shares cloud our understanding of the formation of immigration preferences.

Keywords: rural-urban divisions
refugees
Asylum seekers
causal inference
immigration
Advisor: Kosmidis, S
Dinas, E
The pottery of Late Helladic IIIC and its significance

The thesis is an attempt to view the pottery of the Late Helladic IIIC period as a whole, particularly in terms of the relationships between different regions of the Mycenaean world and of their effect on the processes of ceramic change. It begins with an historical introduction in which the role of pottery in general and of LH IIIC in particular in the study of the Aegean Late Bronze Age down to the early 1970s is discussed briefly. This is followed by a short resume of the LH IIIA-B background.
The main body of the work begins with a detailed look at material from sites or regions where stratigraphical evidence for the chronological development of LH IIIC pottery is available. From this it is concluded that the pottery of the period can most usefully be divided into three broad stages of development. There then follows a more general discussion of sites or regions without stratigraphical information, the aim of which is to gain some impression of the form taken by each of the broad developmental stages already outlined in the pottery of each region or site, and of its stylistic character and affiliations.
The thesis ends with a summary of the conclusions reached in the various regional chapters. The three main stages are discussed in terms of the rate of ceramic change in various parts of the Mycenaean world. A discussion of the extent and directions of contact between regions in the three main stages of LH IIIC, and of their effect on the spread of ceramic ideas, is accompanied by some comparative statistical analyses designed to illustrate the varying degrees and directions of inter-regional similarity during the three stages. Finally, the patterns of ceramic trade and influence which appear to obtain in LH IIIC are contrasted with those of earlier periods, and discussed briefly in terms of possible changes in the political and economic organisation of the Mycenaean world.

Keywords: Helladic
Mycenaean
pottery
IIIC
Advisor: Popham, M
Neuroimaging of neonatal nociception

Newborn infants undergo painful procedures during standard clinical care. However, pain assessment in non-verbal infants is challenging. Improving understanding of infant pain neurophysiology, including anticipating pain responses, is central to improving pain management. Magnetic resonance imaging (MRI) is an ideal technique for examining the structure and function of the infant pain system, allowing whole-brain coverage at relatively high spatial resolutions. However, major differences between the adult and infant brain necessitate the use of infant- optimised data analysis methods.
The first study involved outlining and validating an optimised infant noxious- response functional MRI data analysis pipeline to improve data quality. Using a cohort of 15 healthy newborn infants, five key analysis steps were assessed. Adopting the Developing Human Connectome Project functional MRI preprocessing pipeline improved motion and distortion correction and spatial normalisation outputs, and including spatial ICA-based denoising and minimal spatial filtering furthered these improvements. Of three term infant haemodynamic response function parameterisations, the double gamma function was most suitable. Relative to a standard adult analysis pipeline adapted for infants, the infant-optimised pipeline significantly improved data quality.
The second study involved predicting infants’ cerebral haemodynamic noxious- response amplitudes from resting-state activity demonstrating the potential for infant-unique brain activity to inform infant pain management. Using a cohort of 18 healthy newborn infants, nine resting-state networks were robustly identifiable, and the infants’ resting-state network amplitudes predicted noxious-response amplitudes with statistically significant accuracy. Noxious-response amplitudes were related to white matter complexity using diffusion MRI, suggesting the response amplitudes were infant trait effects. Finally, the specific pattern of functional and structural neural correlates of the haemodynamic noxious-response amplitudes suggested the responses reflected brain maturity.
This work advances our understanding of the newborn infant’s pain system, un- derscores the central importance of MRI in furthering this basic understanding, and helps form the foundations on which further infant pain research can be conducted.

Keywords: developing human connectome project
fMRI
infant
functional magnetic resonance imaging
preprocessing
diffusion magnetic resonance imaging
noxious
dMRI
pain
Advisor: Slater, R
Duff, E
Jbabdi, S
Environmental protection in the Canadian High Arctic: Tallurutiup Imanga/Lancaster Sound as a case study for re-conceptualising governance

The diminishing ice cover has accelerated the ability for commercial shipping through the navigable routes of the Northwest Passage in the Canadian High Arctic. Shipping movement through ecologically fragile marine areas represents new environmental risks that could result from oil spills in these northern waters. Yet, existing preparedness and response systems have not been tested, as no response has been required to a large-scale spill in this region. The empirical research undertaken reveals that the Government of Canada is under mounting pressure to demonstrate how damage to marine ecosystems and northern peoples’ lifestyles would be mitigated. Broad actor consensus is that systems are not in place to reduce the risks of detrimental environmental impacts that could dramatically change the community livelihoods and lifestyles. Compounding pressure on the government, research findings indicate conflicting perspectives within indigenous northern communities concerning commercial development of the Canadian Arctic. In confronting this challenge, this thesis introduces a new governance paradigm to the field of Arctic stewardship that applies pre-emption and precautionary logic to protect this vulnerable environment from problems associated with commercial development and the emergence of environmental risks. Existing frameworks for managing unintended impacts are disrupted by repositioning new and existing actors into new constructs of shared knowledge, power over decision-making, responsibility for resource management and wellbeing. The prevailing ‘top-down’ and rigid hierarchical structure dominated by the federal branch of the Government of Canada is disrupted by a shift towards an emergent arrangement to allow actors to facilitate interactions to operationalise agreed upon measures. This innovative form of governance can enable debate on the merits of reconstructing epistemological scales to conceptualise environmental protection measures in the context of global environmental change and the potential impact to local communities.

Keywords: Nunavut
Oil Spill
Lancaster Sound
Environmental Governance
Inuit
Canadian Arctic
Advisor: Powell, R
Structural studies of the PIR and RIFIN families from malaria-infected erythrocytes

Malaria, caused by the Plasmodium parasite, is responsible for the deaths of close to half a million people a year. During the course of infection, the parasite invades and remodels the host red blood cell, often requiring the export of a number of proteins to the erythrocyte surface. These include the RIFIN family of Plasmodium falciparum, which have been shown to directly modulate the host immune response through interactions with inhibitory immune receptors such as LILRB1 and LAIR1. Additionally, the PIR family of a number of human- and rodent-infective Plasmodium species have been implicated in the determination of parasite virulence and the outcome of infection, along with cytoadhesion of infected erythrocytes to the vasculature. Here, I present the structure of the variable region of a RIFIN in complex with LILRB1. This is the first structure of any member of the RIFIN family and reveals that the RIFIN utilises a conserved mode of binding, which can be blocked through a single mutation in all RIFINs tested, and which mimics the interaction of MHC class I, the native ligand of LILRB1. The RIFIN is also able to mimic the effect of MHC binding both on signalling through LILRB1, and on inhibition of NK cell activation at the immunological synapse. I also present the structure of the extracellular domain of a PIR protein from Plasmodium chabaudi, the first for a member of this family, revealing a novel α-helical fold. Sequence analysis and homology modelling show conservation of this fold across PIRs from 4 human- and 3 rodent-infective Plasmodium species, as well as excluding the RIFINs and STEVORs from membership of the PIR family. These findings provide both a molecular mechanism for RIFIN function, along with a structural definition of the PIRs, giving valuable insight into 2 major families of Plasmodium variant surface antigens.

Keywords: PIR
LILRB1
RIFIN
plasmodium
CIR
falciparum
malaria
Advisor: Higgins, M
Garman, E
The literary culture of the Moriscos, 1492-1609 : a study based on the extant manuscripts in Arabic and Aljamía

That no one should hitherto have attempted to collect together in one place the evidence which is available on the subject of the literary culture of the Moriscos is scarcely surprising. The primary reason for such an omission has doubtless been the inferior nature of so much of what was written by the Moriscos, whether in Arabic or in aljamía; a secondary factor contributing to this neglect has been that these studies do not fall entirely within the purview of any one established discipline. It is clearly desirable that information about Morisco writings, whether in Arabic or aljamía should be brought together; this study is an attempt to fill this gap.
An Introduction (pp. 1-26) examines and defines the terms Morisco and aljamía: Morisco, (somewhat improperly as is explained) is applied to the converted Muslims living on in Spain after 1492, aljamía is Spanish written in Arabic characters. The object of the present study is to investigate the literary culture of the Moriscos between 1492 and 1609 in the extant ms. sources, both Arabic and aljamiado.
The study is divided into two parts, the first listing and discussing the sources of our knowledge of the literature of the Moriscos, the second analysing and interpreting these materials.
Continued in thesis ...

Keywords: culture
Moriscos
Arabic
manuscripts
intellectual
literary
Aljamía
literature