VictorJuiz/thesis huggingface dataset:
Investigating the effects of IFNγ signalling on transcriptional, epigenetic and enhancer landscapes
Keywords: gene expression
regulatory elements
IFNγ
enhancers
PD-L1

IFNγ signalling can have contradictory roles in a tumour microenvironment. Predominantly, IFNγ has an anti-tumour function, activating the immune system against the cancer. However, pro-tumour activities of IFNγ have also been observed. Its choice between the two opposing outcomes appears to be context dependent and the mechanism instructing this choice isn’t well understood. One prevailing determinant comes from the IFNγ-induced upregulation of PD-L1, an immunosuppressive ligand. Binding of PD-L1 to its receptor, PD-1, inhibits immune cells despite the presence of other activating signals, enabling cancer immune evasion. Increased knowledge of IFNγ-induced gene expression within cancer cells, including the regulation of PD-L1, would enable a more accurate prediction of IFNγ’s behaviour in the tumour microenvironment.
This thesis examines the effect of IFNγ signalling on the transcriptional, epigenetic and enhancer landscape in a hepatocellular carcinoma cell line, Hep3B. Using a variety of genome-wide sequencing techniques, I find that IFNγ orchestrates differential gene expression and enhancer activity dynamically in at least three distinct phases within 24 hrs of treatment. IFNγ treatments were found to regulate more enhancers than genes, with a large proportion of these enhancers becoming primed but not fully activated. Capture-C, a 3C based technique, revealed that IFNγ treatments significantly increase promoter:enhancer interactions, adding a further level of gene regulation.
IFNγ treatments induced upregulation of PD-L1 in Hep3B cells. Capture-C revealed that the PD-L1 promoter interacts with the closest neighbouring promoter and a CTCF site downstream of the gene. Neither of these interactions appeared to regulate IFNγ-induced PD-L1 expression. Instead, this thesis proposes that the proximal promoter may be sufficient for IFNγ-induced upregulation of PD-L1. Altogether, this study increases our understanding of IFNγ-induced gene regulation.
Atomic force microscope-based methods for the nano-mechanical characterisation of hydrogels and other viscoelastic polymeric materials for biomedical applications
Keywords: magneto-mechanical coupling
fullerene
polymeric materials
mechanical properties
AFM
viscoelasticity
hydrogels
biomedical applications
atomic force microscopy
elasticity
polymers
chitosan

Hydrogels, porous hydrated polymeric materials, are being increasingly used in biomedical applications. The mechanical properties of hydrogels play an important role in the success of many of these applications (e.g. tissue engineering and drug delivery), and can be modulated by external stimuli and/or by changing hydrogel structure and composition. Therefore, it is important to measure and understand these mechanical properties at cellular length scales (nano/micro-scale) to improve the efficacy of hydrogels in biomedical applications.
Hydrogels are often studied in terms of their elasticity. In this thesis, elastic properties of hydrogels were studied in terms of their elasticity via Atomic Force Microscopy (AFM) quasi-static micro-indentations. It is important to consider that hydrogels are not just elastic, but exhibit viscoelasticity, a time-dependent mechanical behaviour typical of hydrogels and polymeric materials in general. In this thesis, a novel AFM-based technique was developed to measure nano/micro-scale viscoelasticity.
First, changes in the local elastic properties of chitosan (a biopolymer) hydrogels in response to an external magnetic field were measured, demonstrating magneto-mechanical coupling. Second, this coupling was further explored by incorporating magnetic nanowires into the hydrogels. Both experiments suggest this coupling could be exploited to control hydrogel mechanics. Third, elasticity of hydrogels based on fullerenes was measured, and depended on the size of the fullerene used. Hydrogel elasticity in all three experiments matched that of biological tissues, suggesting biomechanical compatibility. The possibility of controlling hydrogel properties either by external stimuli or by composition, opens the door for all three of these materials to be used for therapeutic applications. Lastly, a novel technique based on photothermal excitation of the AFM cantilever was developed and proved to quantify viscoelasticity of polymeric materials over a frequency range up to five orders of magnitude (0.2 Hz to 20200 Hz), in good agreement with macroscopic data, revealing a promising tool for the viscoelastic characterisation of hydrogels.
Numerical modelling of laterally loaded piles in clay
Keywords: Finite Element Limit Analysis
Laterally Loaded Piles
Offshore Pile Design
Monopiles

The rapid expansion of the offshore wind industry in recent decades has led to an increased scrutiny of methods traditionally used to design piles in the offshore environment. Investigations by the industry have been performed using a multitude of methods including finite element analysis (FEA), centrifuge testing, and large scale field testing. In this thesis, a novel numerical technique termed finite element limit analysis (FELA) is used to investigate the limiting capacity of laterally loaded piles in clay and the mechanisms that contribute to this resistance.
Finite element limit analysis is a modelling technique that permits rapid optimization-based analysis of plastic collapse mechanisms of boundary value problems with complex loading, structural geometry and soil parameter profiles. Unlike traditional FEA where the accuracy of a given solution is unknown, FELA provides lower and upper bound solutions between which the exact solution must lie within a known bracketing error. An additional benefit of FELA is that runtimes are significantly shorter than equivalent FEA models allowing large parametric studies to be performed in a fraction of the time.
Methods previously used for predicting ultimate resistance are revisited and compared to FELA; such as the moment equilibrium method used by Broms (1964) to calculate total capacity and the widely used Matlock (1970) methodology for determining p-y curves in clay. Relationships between key dimensionless groups of geometry and soil parameters are explored and recommendations about pile capacity are provided. Soil strength profiles including homogeneous conditions, strength gradients and abrupt changes in strength are considered, with recommendations provided on predicting the profile of limiting resistance in each case. An update to the traditional moment equilibrium approach for calculating pile capacity is proposed incorporating additional resistance mechanisms such as shear and moment resistance at the pile base, and a distributed moment resistance acting on the shaft of the pile. Finally, some case studies demonstrating use of the recommendations are presented with a comparison to some of the recently performed pile tests in the PISA joint industry project as a check on the validity of the proposed approach.
Ocular harpsichord: colour-sound analogy at large in The Enlightenment
Keywords: Enlightenment
ocular harpsichord
Castel
synesthesia
rhetoric
Voltaire
senses
Rameau
history of music
history of colour

The ocular harpsichord was a notable cultural phenomenon of the European Enlightenment, but its precise chronology and contemporary reception have since become obscure. Proposed in 1725 by Louis-Bertrand Castel (1688-1757, a Jesuit scientist and writer at the Journal de Trévoux), it was meant to play ‘colour music’. However, the exact sensory and aesthetic effect that it was meant to have upon an audience is difficult to gauge, because it inspired such extensive controversy and excitement—evidenced in books, academic lectures, reviews, journal articles, libertine satires, personal anecdotes, and private correspondence. Was it inspired by Newton, and what assumptions did it imply about the senses? While the ocular harpsichord is sometimes mentioned in connection to synaesthesia, there was no eighteenth-century equivalent for this late nineteenth-century term derived from the emerging discourse of psychology, which indicates that contemporary responses to Castel’s clavecin oculaire had other pre-occupations, motivations and goals. Complicating matters is the fact that Castel was a polarizing and polemical figure in the lives of Voltaire, Diderot, Rousseau, Rameau, Fontenelle and Montesquieu. While some philosophes who had quarrels with Castel described him as crazy, or ‘fou’, they also made perplexing remarks about his contraption that typically resist straightforward interpretation. The ocular harpsichord’s mechanics as a concept and as a machine have been further obscured by Castel’s elaborate style of writing, whose organizing principles and institutional and cultural contexts are alien to modern readers. Yet Castel wrote many works about his device, using it to construct his persona and generate publicity for his œuvre and universal system. This thesis combines close reading of primary sources, intellectual history, and literary analysis using the tradition of classical rhetoric to explain what the ocular harpsichord was, how its history as a material instrument unfolded, and what it meant to Castel and his readers.
Characterization of VIP+ interneurons in the mouse whisker barrel cortex during development
Keywords: cortical development
interneuron
long-range
vasoactive intestinal peptide
connectivity
Prox1
VIP

GABAergic interneurons (INs) are thought to be important players in normal cortical circuit development, with a body of data highlighting the role of two major IN classes – parvalbumin and somatostatin-positive (PV+ and SST+) subtypes – in neonatal mouse sensory cortices (Marques-Smith et al., 2016; Takesian and Hensch, 2013; Tuncdemir et al., 2016). More recent evidence supports a developmental role for a third class of IN, defined by the expression of vasoactive intestinal peptide (VIP+ INs) (Batista-Brito et al., 2017; Goff and Goldberg, 2019; Mossner et al., 2017). This IN subtype has been shown to play a role in sensorimotor integration via preferential targeting of SST+ cells and consequent disinhibition of pyramidal cells in the mature cortex (e.g., Lee et al., 2013). However, it is unknown how and when VIP+ INs integrate into the local and long-range circuitry during early development.
To address this, I first investigated the integration of VIP+ cells into the local circuit in postnatal whisker barrel cortex (S1BF). Data show that, while VIP+ INs acquire mature electrophysiological properties and integrate in the local glutamatergic network over the first two postnatal weeks, they engage with other INs and pyramidal cells already in the first postnatal week. Second, I employed a viral optogenetic strategy to test the emergence of long-range inputs from anterior-motor areas onto S1BF VIP+ cells. Data show that VIP+ INs start to be recruited already in the first postnatal week, but they are fully integrated in the long-range circuitry only at the end of the second postnatal week.
Finally, I have used the VIP-Cre;Prox1c/c conditional knockout model (Miyoshi et al., 2015) to investigate whether genetic perturbation of VIP+ INs has an impact on synaptic integration and in vivo activity. Data suggest that conditional deletion of Prox1 leads to reorganisation of the local but not long-range glutamatergic input, and increased activity upon whisker stimulation. These findings define the emergence of the VIP+ circuitry and show their early influence in circuit maturation, further supporting the importance of IN signalling in cortical development.
Molecular scale patterning of photonic structures via conformational control
Keywords: Aggregation Induced Emission
nano-optics
beta-phase of Polyfluorenes
Patterning
Photoluminescence Quantum Yield/Efficiency (PLQE)
Aggregation
Fluorenone Oligomers
Excimers
Thin film optical devices
microscale photoluminescence (micro-PL)
Absorption
Photonics
Photoluminescence

This thesis comprises a number of studies into controlling the photonic properties of materials by way of controlling their molecular conformation.
The absorption and emission behaviours of fundamental AIE molecules TPE and HPS were probed in solutions with varying degrees of aggregation. It was found, in contrast to the existing RIR hypothesis, that the monomers were able to emit in good solutions with minimal aggregation, and continued to do so upon low levels of aggregation. The monomer emission of TPE was found to be more prevalent than that of HPS due to the difference in conjugation pathways offered by each molecule. These results suggested that the term AIE is misleading, with the assumption that the molecular emission ‘switches on’ upon aggregation disregarding the fact that the more efficient fluorescence actually results from a quenching process (excimer formation), with RIR causing the increase in efficiency.
A new method for controlling the aggregation in fluorene/fluorenone oligomers was also investigated. Water was found to be highly effective for screening the fluorenone aggregation, with fractions of only 10% sufficient to eliminate the excimer emission. The fluorenone was then successfully reaggregated to varying degrees as the water fraction was increased, due to non-solvent effects. Investigating solutions of thermally oxidised FFF also revealed the method’s ability to identify the presence of fluorenone moieties when there was no indication of oxidation in the absorption or PL.
Lastly, dip-pen nanolithography was employed to pattern photonic structures in PFO thin films. Beta phase dots with diameter 548nm were achieved, demonstrating the potential of DPN in photonic device fabrication, however there were issues with consistency of feature size and damage to the film. An outline of the development of the microscale PL set-up used to analyse the patterns, and the steps taken to maximise its resolution and spectral contrast is also given. The set-up was found to be well suited to highlight the beta phase of PFO, however there were issues with reproducibility of the PL maps, as well as a trade-off between signal strength and photodegradation of the sample. When compared to patterns imaged on a different set-up, it was clear that the set-up designed here produced too low a signal to accurately compare the new patterns. Further work in sample fabrication, DPN operation and microscale PL optimisation was therefore identified to improve the quality and reproducibility of the patterns.
Battles for the Yangtze: the riverine defence of China, 1927-1945
Keywords: Diffusion of military power
Riverine Defence
the Yangtze River
the Sino-Japanese War
Amphibious Warfare
the Second World War

This research is a military-strategic history on the Kuomintang’s riverine defence against Imperial Japan along the Yangtze River during the Second World War. While challenging various views regarding actual military operations, this research emphasizes the importance of the riverine environment and offers a new interpretation to the main historiography of the Second World War in China. It does so by filling an important gap the historiography of riverine and amphibious warfare and by providing the essential story of the defending side. In 1932, the Shanghai Incident made the Kuomintang realise that China was threatened by the Japanese from the land, sea, and the Yangtze. The Kuomintang, advised by German and Italian advisors, prioritised the defence of Central China and formulated a strategy to turn Central China into a bulwark. However, the military preparations guided by the strategy was problematic. The escalation of the war in Shanghai in 1937 was the result of the offensive war plans of both China and Japan. Before the fall of Madang, China’s riverine defence focused primarily on the riverine front. After Madang, China realised the importance of the landward front, but its adaptation was nullified by their own unconventional method of making artificial floods. During the war, China and the Allies tried conventional, unconventional, symmetrical, and asymmetrical methods to deny Japan from using the Yangtze. The air interdictions succeeded in damaging Japanese riverine transport and contributed to the collapse of the Japanese wartime economy. Based on archival and published materials from China, Japan, Britain, the US, and Germany, this research aims to demonstrate that the Chinese hybrid riverine defence, meaning the combination of conventional, unconventional, symmetrical, and asymmetrical methods with the militarisation of terrain, was an essential part of the Second World War in China.
Pigskin politicking: The American presidency and the changing politics of sport
Keywords: Gerald R Ford
presidents
athletes
football
political history
baseball
1970s
permanent campaign
sport and leisure
National Football League
20th century history
1960s
pigskin politics
political culture
politics
Richard M Nixon
American presidency
sports history
U.S. history

This thesis is concerned with the American presidency and what I call ‘pigskin politicking’, or the practice of deploying professional football and other sports for political gain. Pigskin politicking can be observed in presidential traditions that have become commonplace: phoning teams after important victories, inviting players and coaches to the White House, attending games, and more generally basking in the reflected glory of successful teams and athletes. Such practices have become so seamlessly ingrained in the American political apparatus that they have been largely overlooked in both the political and historical scholarship on the public presidency and the rise of what political scientists call the permanent campaign.
I argue that the origins of pigskin politicking can be traced to the Nixon-Ford administrations. A passionate sports fan, President Richard Nixon and his aides took entrepreneurial politics to a new and innovative level by publicising his fandom in ways that previous presidents would have considered trivial or politically unnecessary. The parallel rise of professional football and the television presidency in the late 1960s and early 1970s had lasting implications for American politics, and the Nixon administration capitalised on this convergence. Nixon’s pigskin politicking ultimately set a precedent for his successors, each of whom—at some point or another—have turned to both football and baseball with the hope of projecting a masculine ‘just folks’ image to the public. I conclude that the Nixon-Ford era marked the beginning of a transformation in presidential self-promotion and showmanship in which the world of sport played a winning role.
Identifying biophysical determinants of virus-cell fusion through live-cell imaging
Keywords: Restriction factors
Virus fusion
IFITM

The biophysical properties of both enveloped virus and cell membranes must be favourable for successful fusion and entry of the virus into its host. Characterising these properties in cells and virions is critical for understanding and manipulating target cell susceptibility to infection, as well as blocking infection by cell-autonomous antiviral proteins. To characterise such properties, we developed imaging assays multiplexing genetically-encoded biosensors concomitant with single virus tracking in live cells to uncover a link between the host cell membrane biophysical landscape, host metabolic state, and virus fusion. Expanding the utility of these assays, we characterised a conserved GxxxG oligomerisation motif in antiviral protein interferon-inducible transmembrane 3 (IFITM3), linking the oligomeric state of IFITM3 and its antiviral activity to its ability to rigidify host cell membranes. Interestingly, the GxxxG motif is not intact in human IFITM5, and this IFITM protein is traditionally not associated with antiviral immunity. Therefore, we restored the GxxxG motif in IFITM5 to determine if its oligomerisation capacity and antiviral activity was potentiated. Collectively, the results described in this dissertation connects the fusion of viruses with the biophysical properties of membranes of the host cell, which are dependent on host metabolic state and the ability of IFITM proteins to oligomerise and rigidify membranes.
The social and ecclesiastical significance of church seating arrangements and pew disputes, 1500-1740
Keywords: disputes
church
pews
pew

This thesis examines the seating arrangements of English parish churches between 1500 and 1740 in order to define their basis, the reflection of society through them and areas of tension made apparent in pew disputes.
It begins by charting the development of the ecclesiastical law in the early seventeenth century. Unusually this is seen to have been based upon cases prohibited to the common law on the basis of prescription. Chapter Three then examines the procedure of the ecclesiastical courts and shows that the scope of their interest was far wider than legal theory implies. The courts are shown to have been most concerned with the physical appearance of seats and their convenient placement. This was never organised into a coordinated campaign until the 1630’s, but even the Laudians failed to end the ingrained abuses of the pew system because of the passive resistance of the parish authorities.
Pew disputes and the deciding of titles to seats was a significant part of the ecclesiastical courts’ business. The motivation these cases differed under the office and instance procedure. The former type of case was concerned only with the punishment of disruption or disobedience; the latter with the actual question of title.
The assigning of seats is shown to have been undertaken mainly by the churchwardens, either through the formation of a composite picture of an individual or on the basis of a life-payment or rent. Both systems are examined and their workings and differences analysed. Chapter Five examines the correlation between the church’s seating arrangements and society as a whole and shows this to have been good but not perfect. In the final chapter, the reasoning behind pew disputes is analysed. This reveals pew disputes as essentially the preserve of the gentry of market towns and as a form of honour conflict.