VictorJuiz/thesis huggingface dataset:
Understanding the anti-tumour immune response to radionuclide therapy using PSMA targeting radiopharmaceuticals in a prostate cancer model

The ability of external beam radiation (EBRT) to modulate the tumour immune microenvironment is becoming increasingly well understood, leading to the development of combinatorial EBRT and immunotherapeutic combinations to improve patient responses. Despite this, there is very limited understanding of if, and how, the related modality of targeted radionuclide therapy (TRT) can interact with the immune system. Given its similarities with EBRT it seems likely that immune factors may play a role in the response to TRT. However, differences between the two radiotherapeutic modalities may result in some interesting differences that may be exploitable in combination therapies. As such, I sought to assess the impact of TRT on the tumour immune microenvironment, with the ultimate aim of identifying synergistic TRT and immunotherapy combinations.
Here, I have established a TRT targetable, immunocompetent prostate cancer model in our lab, namely PGLS allografts. This enabled evaluation of the immune response to the clinically relevant radiopharmaceutical [177Lu]-PSMA-I&T. Using this model, I was able to show for the first time that [177Lu]PSMA-I&T is capable of inducing changes to the TIME, with a notable reduction in immune cells 72 hours post treatment followed by a return to no-treatment levels by day 12 with a trend towards an increase. Strikingly this initial decline was not observed for EBRT treatment, though a similar increase in immune cells was seen by day 12. I went on to investigate the potential mechanisms involved in this interaction with the immune system, demonstrating that both TRT and EBRT can induce immunogenic cell death in this model. Interestingly, this ability to eliminate tumour growth in a vaccination study was absent in the treatment of established tumours, suggesting other factors in the TIME are limiting the capacity of TRT to induce a functional immune response. Finally, I investigated potential combinations with immunotherapies to eliminate possible barriers. Transcriptional analysis of a large prostate cancer patient cohort demonstrated a strong correlation of TGFβ expression with worse outcomes highlighting this protein as a potential target for combination therapeutics. However, no synergistic effect was observed in in vivo studies. Strikingly, I demonstrate that TRT can cause a remarkable increase in PDL1 expression suggesting that this may be an important mechanism of radioresistance, thus I suggest that combination of TRT with anti-PDL1 and potentially TGFβ could be a valuable avenue to explore. Ultimately, this work provides evidence that the immune response to TRT is a field worthy of persuing and highlights several key areas of interest for further exploration.

Keywords: Immunotherapy
Radionuclide
Radiotherapy
Advisor: Vallis, K
Structural & biophysical characterisation of M. tuberculosis MmpL3

Tuberculosis (TB) is the leading cause of death from a single infectious agent, with a staggering 10 million people estimated to have contracted the disease in 2019 alone. Whilst treatments for TB exist, continual emergence of drug-resistant strains necessitates urgent development of next-generation antituberculars. A promising new target is the essential glycolipid exporter mycobacterial membrane protein large 3 (MmpL3), a member of the resistance-nodulation-division (RND) superfamily. MmpL3 is required for construction of the distinctive Mycobacterium tuberculosis (Mtb) cell envelope; a complex lipid-rich assembly critical to mycobac- terial viability. Despite discovery of numerous MmpL3 inhibitors, including one in clinical trials, a structural understanding of the transporter, and by extension the variants identified to confer resistance to said experimental agents, has remained elusive. To this end, the research herein presents a 3.0 Å reconstruction of Mtb MmpL3; the culmination of a project structurally pursuing the RND exporter through construct design & characterisation, in vitro binder selection, nanodisc reconstitution, in meso & in surfo crystallisation trials, and imaging by Cryo-EM. Unexpectedly monomeric, the Mtb MmpL3 atomic model provides insights into the evolutionary co-option of RND architecture for lipophile transit. Most notably, the protein houses an extensive periplasmic cavity with putative functional rel- evance as the glycolipid translocation conduit. A detergent molecule resolved within the cavity plausibly sheds light on interactions employed by MmpL3 to coordinate its native substrate. Additionally, comprehensive mapping of known resistance-conferring substitutions suggests the existence of at least two routes, operant within different domains, by which antituberculars inhibiting MmpL3 can be mutationally circumvented. Taken together, the data reported in this thesis set the stage for an era of structure-based drug design against MmpL3; guided by an enhanced appreciation of the underlying resistance landscape.

Keywords: Nanodiscs
Nanobodies
MmpL3
Cryo-EM
Membrane Protein
MmpL
Tuberculosis
Drug Resistance
LMNG
Mycolic Acid
Antitubercular
Sybodies
RND Transporter
Advisor: Newstead, S
Fowler, P
Diboron-enabled high-precision protein engineering

Boronic acids are versatile synthetic building blocks, widely applied in molecular sensing applications and have more recently attracted attention as warheads in medicinal chemistry. Yet, boron containing organic compounds are rarely found in nature. Despite boron being considered a “probably essential” element which is found across all domains of life, organoboron compounds have only been reported to occur naturally in form of boric acid esters. These compounds are known to fulfil several biological functions, including cell-wall strength modulation and quorum sensing. In fact, boronic acids display unique reactivity towards Lewis bases, allowing for the dynamic and reversible formation of covalent interactions with suitable ligands. Precisely engineered boronic acids placed within biomacromolecules, such as proteins, could allow for altered or novel, previously not accessible, function and enable the selective manipulation of biological systems through specific programming of de novo binding.
Herein, methods for the selective modification of proteins through diboron reagents are described.

Keywords: chemical biology
Bal
boronic acid
chemistry
dehydroalanine
protein modification
diboron
protein
boron
protein chemistry
Dha
boronoalanine
Advisor: Davis, B
Gouverneur, V
Popular periodicals, common readers and the 'grand march of intellect' in London, 1819-34

Between the 1780s and the 1830s increasing amounts of agency were assigned to - and claimed by - the English common people in their own intellectual improvement and moral reform. In the years between 1819 and 1834, this sense of ‘popular agency’ (the capacity of the common people to assert control over aspects of their lives) was increasingly embodied in - and cultivated by - London’s ‘popular periodical’ press. It was in this popular press (comprising cheap weekly magazines costing three-pence or under and stamped, seven-penny Sunday newspapers - both aimed at ‘common readers’) that the concept of a ‘march of intellect’ was most strongly contested as a narrative of popular intellectual and moral progress, a categorization of knowledge forms and a description of improving practice.
This thesis attempts to rethink the ‘march of intellect’ as a socio-political complex through an analysis of its discursive properties and material bases, as revealed in the popular periodical. Asking questions about the origins, nature, timing, reality and significance of the ‘march’, it argues that although the trope was rich raw material for reformist rhodomontade and reactionary satire, it was also a widely-recognized shorthand for a range of experienced imperatives and practices. In this context, the popular press was frequently depicted as cultivating a latent ‘common readership’ of lower-middling and labouring-class Londoners; as making the cultural world of the common people a focus of enquiry; and as providing a medium through which the ‘common writer’ could articulate a sense of personal intellectual agency. This re-imagination of the common reader as an active historical agent was, however, circumscribed by the nature of the popular periodical itself. No simple link between the overall growth of a popular periodical market and the perceived increase in popular agency can therefore be confidently made.
This thesis concludes that the march of intellect was the product of a specific historical moment: a linguistic and conceptual framework through which the public image of the common people was being reworked - and a repertoire of practices experienced - in the context of profound economic, technological and demographic changes. Slower and more haphazard than its champions claimed, the ‘march’ was nonetheless the locus of a crucial debate during the ‘age of reform’ about the place of the common people in English society: a debate in which at least some of these people articulated their opinions.

Keywords: journalism
nineteenth century
London
Popular periodicals
intellectual life
common readers
19th century
politics
newspapers
A study of compact objects: stellar evolution models and X-ray binaries

Compact and double compact binary systems are excellent natural laboratories for the study of a variety of physical phenomena. In this Thesis I study black hole binary systems and neutron star low-mass X-ray binaries in order to investigate binary stellar evolution pathways and accretion mechanisms.
Estimating the binary black hole merger rate and comparing it with predictions from gravitational-wave observatories is an important method to constrain binary stellar evolution channels. I investigate the chemically homogeneous evolution of close binary systems consisting of rapidly rotating, massive stars at low metallicities, by combining, for the first time, realistic binary models with detailed cosmological calculations of the chemical and star-formation history of the Universe. By constraining the population properties and determining the cosmological and detection rates of binary black hole mergers more precisely than before, I find that the chemically homogeneous evolution pathway can be an important source of aLIGO events.
Probing accretion processes in neutron star low-mass X-ray binaries offers unique tests of general relativity and helps to constrain the elusive equation of state of neutron stars. In the next part of the Thesis, I explore one of the most promising models to explain the accreting quasi-periodic oscillations observable in the power density spectra of neutron stars and black holes in binary systems: the relativistic precession model. I analyse the RXTE data of the neutron star X-ray binary 4U1608-52, presenting the first case study where more than one usable set of the necessary three quasi-periodic oscillations (a so-called triplet) are found for one single source, and for which multiple tests of the relativistic precession model can be carried out. I find that the mass and spin values resulting from such triplets cluster around physically realistic values, which can be considered reliable estimates of the neutron star fundamental parameters. If confirmed, my results indicate that 4U1608-52 would be one of the heaviest neutron stars known to date.
Finally, I analyse the RXTE data of the 11 Hz accreting pulsar IGR J17480-2446. Previous studies failed to find in this source the very low-frequency quasi-periodic oscillation associated with frame-dragging in the relativistic precession model, thus casting doubt on the validity of the model itself. In this study I find previously undetected very low-frequency quasi-periodic oscillations and show that these are consistent with being produced via frame-dragging, thus re-establishing the validity of the relativistic precession model.

Advisor: Motta, SE
Fender, R
Decidability in extensions of Fp((t))

In this thesis we primarily consider the first-order theory of the local field F_p((t)) and the question of whether it is decidable. To this end we expand the language of valued fields together with a constant symbol for t by adding predicates R_f representing the existence of a root of the multivariable polynomial f \in F_p(t)[X_1, ..., X_n], hoping in this way to control the behaviour of purely wild extensions of valued fields (which has historically caused problems in this area), and seek to prove a quantifier elimination result for a proposed axiomatisation of F_p((t)) (originally, we believe, due to F-V. Kuhlmann). This proceeds along classical lines, à la Shoenfield (used in Macintyre’s celebrated proof of quantifier elimination for the p-adic numbers Q_p). We obtain a conditional result, sketching a proof that if a particular technical condition is satisfied by an arbitrary \aleph_1-saturated model of our theory, then we will indeed obtain quantifier elimination and thereby (via the existence of an algebraically prime model) decidability of the first-order theory of F_p((t)). However, this technical condition is still largely mysterious. We sketch an (unsuccessful) attempt at an unconditional proof and highlight where difficulties arise.
In Chapter 1 we introduce the area in general, and our question and approach more specifically. Chapter 2 contains necessary preliminaries for the rest of the thesis, on valuation theory, model theory, Galois theory, and a smidgen of algebraic geometry; we have intended to keep these preliminaries as brief as possible. Chapter 3 starts with an explanation of our approach and contains sections (among others) introducing and analysing our candidate axiomatisation, proceeding to a conditional Shoenfield-style quantifier elimination proof (Theorem 3.4.2) and presenting (in \S 3.5) a sketch of where difficulties arise when trying an unconditional proof. Chapter 4 introduces several notions which we feel may be helpful in future study of this area, as well as discussing ultraproducts of generalised Laurent series fields in relation to extremality. Chapter 5 includes a self-contained examination of the structure and first-order theory of some distinguished fields extending F_p((t)), this time with p-divisible value group. We conclude with some brief remarks in Chapter 6.

Keywords: logic
extremal valued fields
decidability
valuation theory
model theory
Advisor: Koenigsmann, J
The geodesy and geology of earthquakes and aseismic slip

In this thesis, I explore the geodetic and geologic evidence of earthquake ruptures and aseismic fault deformation in different settings in order to understand: 1) the distribution of seismic or aseismic slip, and 2) the physical factors that influence the mechanics of faulting. In a case study of the Tien Shan (Central Asia), mapping and paleoseismology of faults along a supposed 400-km signal of fault creep paints a more nuanced picture than existing regional studies. With data from the field and high-resolution digital elevation models, the 3-5 mm/yr N-S shortening gradient in GPS data appears to be distributed variably across different basins in the mountain belt. From an apparently creeping rangefront fault in Karkara, more structures to the west accommodate active deformation. Distributed folding and thrust faults in the middle of the neighboring wide basin of Issyk-Kul takes up the majority of internal basin shortening. In the narrow basins further southwest (Karakudzhur and eastern Naryn), fresh-looking fault scarps indicate Holocene activity, with along-strike morphology and extents that could be from rupture that have generated magnitude (M) ~7 earthquakes. Moving to the Philippines, analyzing the deformation field from satellite radar interferometry (InSAR) data and inverting for the source parameters of a series of four Mw 6.4--6.8 earthquakes in late 2019 reveals a previously unrecognized seismogenic conjugate fault system on the island of Mindanao. The distribution of blind and surface fault ruptures correlates with the heterogenous geology in the shallow crust. Finally, detailed InSAR time-series analysis and modeling of the mode of slip on the creeping segment of the Philippine Fault shows that while ~100 km of the fault creeps on Leyte island throughout the seismogenic zone, a 20-km long seismogenic asperity exists in the middle. This asperity ruptured in a Mw 6.5 earthquake in July 2017. Fluids on the faults and rate-strengthening lithologies can promote interseismic aseismic slip (and impede seismic slip), while seismogenic potential shows up in structurally complex sections of the seismogenic crust in these different cases.

Keywords: faults
creep
aseismic slip
earthquakes
InSAR
Advisor: Walker, RT
Parsons, BE
Numerical simulation and modeling of shock tube experiments

Shock tube experiments are a key method of reproducing the flow conditions encountered by hypersonic flight vehicles and are the primary source of known thermochemical reaction rates. However, because of the complex nature of hypersonic flows, and also due to the many subtle complexities of the shock facilities themselves, full characterization of the flows they produce is elusive. This work develops a numerical method for the simulation of shock tube experiments using a novel technique of shock tracking to improve the resolution and decrease the computational cost of such simulations. An axisymmetric, Navier-Stokes shock tube simulation code entitled FROSST keeps the shock and contact discontinuity each stationary in their own zone of refinement that slides along a coarse background mesh of the entire facility. Using this solver, the role of shock history in the formation of nonuniformities in shock tube test gases is investigated in the context of ideal gas simulations. Shock speed variations from -29% to +33% are found to influence temperatures in the test slug by as much as 55% in an Argon test gas with a tube-end 2100 m/s. These results give rise to the observation that nearly all nonuniformities in the test gas originate with variations in shock speed along the tube. Based upon this observation, a novel method is devised to use experimentally measured shock speed to predict test flow properties for each experiment. This method tracks the influence of waves associated with shock speed variation upon isentropic slices of shock-processed gas. By tracking a number of such slices, the entire test slug is reconstructed to a high degree of accuracy. The analytical methodology, entitled LASTA, is extensively validated against simulated ideal Argon data and also experiments performed in the Oxford T6 Stalker shock facility with both Argon and thermochemically reacting air. LASTA is found to capture the shot-to-shot nonuniformities to within 1% within minutes on a single core. Real-world application of LASTA is already leading to improved understanding of radiative emissions from shock tube experiments.

Keywords: ground test
shock tube
thermodynamics
high temperature
thermochemistry
hypersonic
Advisor: Di Mare, L
McGilvray, M
The subversive power of laughter: Plato and Aristotle on humour

Plato explicitly theorises about laughter in three dialogues: Republic (388a-389a, 605c-607a); Philebus (47e-50b); and Laws (816d-817a, 935a-936a). Although it is not possible to construct an overarching Platonic “theory” of laughter, this thesis argues, based on Platonic moral psychology and epistemology, that Plato is preoccupied with the subversive potential of laughter in the soul and state (subversive laughter) while also allowing for a socially and ethically positive form of laughter (playful laughter). Aristotle is generally seen as taking a more positive view of humour and laughter than Plato: he includes εὐτραπελία (wittiness) as a virtue in the Nicomachean Ethics (1127b34-1128b9). This thesis will show how Aristotle’s philosophising on laughter emerges, converges, and diverges from Plato’s “theories” of laughter, arguing that laughter for Aristotle can be either subversive or playful, and that the latter always has the potential to turn into the former. Finally, this thesis will show how the influence of Plato and Aristotle on modern humour theory (the Superiority Theory and the Incongruity Theory) should not be underestimated and so sheds further light on why we laugh and whether it is possible for laughter ever to be free from subversive potential.

Keywords: Philebus
virtue ethics
paideia
superiority theory
subversion
katharsis
Incongruity theory
the laws
moral psychology
tripartition of the soul
poetics
rhetoric
Phaedrus
Plato
Hobbes
Nicomachean ethics
republic
laughter
Aristotle
Advisor: Nielsen, KM
Metal-metal bonding in low-dimensional structures

This thesis presents two computational investigations into the properties and behaviour of transition metal compounds. The first focuses on bond- ing patterns in endohedral Zintl clusters, and the second on structural processes in low-dimensional perovskites. Working across the ionic and co- valent bonding paradigms, and molecular and periodic structures, we gain deeper insights into the chemical manifestations of fundamental principles of transition metal chemistry. We employ electronic structure theories and analytical tools which allow us to compare the behaviour of transition ele- ments, and particularly the contrast between open and closed shell atoms, in a broad range of chemical environments. The majority of the research herein is performed in collaboration with experimental efforts, where we use theoretical insights to guide synthesis, aid analysis, and join the dots of experiment to draw a complete picture of the underlying chemistry.

Keywords: density functional theory
transition metal
computational chemistry
Advisor: McGrady, J
Philodemus and Seneca on anger

This thesis compares two Roman philosophical treatments of On Anger, one written in Greek by the Epicurean Philodemus, the other in Latin by the Stoic Seneca. It seeks to resolve three problems between the two authors’ conception of anger: (1) the “definitional” problem, which outlines the deciding factors that makes anger what it is and distinguishes it from all the other non-anger psychological processes; (2) the “cognitive” problem, which clarifies the relationship between anger and the judgments that cause, underlie, and constrain the occurrence of the emotion; (3) the “motivational” problem, which focuses on the involvement of desire in anger and how it leads people to feel and act in certain ways. By investigating how Philodemus and Seneca each handles the three problems in their works, I aim at giving a thorough examination of the two authors’ understanding of the nature of anger, especially in the cognitive and motivational respects, meanwhile demonstrating the intersections and differences between the two theoretical systems.

Keywords: anger
cognition
emotion
motivation
Seneca
Philodemus
Advisor: Bown, A