VictorJuiz/thesis huggingface dataset:
The impact of ageing on trauma-related bleeding and coagulopathy

The epidemiology of major injury is changing as the population ages, revealing gaps in our understanding of the management of older patients with trauma-related bleeding. Physiology and haemostasis alter with normal ageing and could attenuate the response to bleeding in an older person. The aim of this thesis was to explore the impact of the ageing trauma demographic on the presentation and management of bleeding and coagulopathy in trauma.
I conducted a systematic review to explore the evidence across age for the use of blood transfusion strategies in acute trauma haemorrhage. I identified 10 randomised controlled trials; older patients were not well represented. There were no randomised trials in older people or trials that evaluated interventions for different age groups.
A Delphi study was undertaken to develop a new consensus research definition for major bleeding in trauma. This definition was applied to the Trauma Audit Research Network registry to assess the effect of age on risk factors for major bleeding. I found older patients with bleeding were less likely to present with tachycardia than younger patients. Multivariable logistic regression using seven risk factors (age, male gender, penetrating injury, mechanism of injury, hypotension and tachycardia and unstable pelvis) showed all were independently significantly associated with bleeding. I also identified a negative interaction between age and penetrating injury, and age and mechanism of injury. Multiple imputation was used to handle missing data and the significance of the risk factors in the imputation model was broadly similar to the complete case analysis model.
The effect of age on coagulation and fibrinolytic parameters was assessed in a multicentre cohort study. In patients who did not receive tranexamic acid, after adjusting for key covariates including presence of bleeding and injury severity, I found older age was associated with heightened fibrinolytic activity and fibrinogen levels compared with younger age.
The programme of work in this thesis has provided new data showing that age has a significant effect on the clinical presentation and risk factors for bleeding. Furthermore, coagulation and fibrinolytic parameters appear altered across age. These data are exploratory and hypothesis-generating. They inform future research areas to assess the effectiveness of different interventions including tranexamic acid across age, develop age-adapted transfusion protocols and prediction models for bleeding that take age into consideration.

Keywords: haemorrhage
trauma
coagulopathy
ageing
Advisor: Stanworth, S
Curry, N
Yu, L
Two-dimensional Bose gases in systems with pointlike disorder

The effect of disorder on many-body physics is important for our understanding of real-world systems. In particular, the behaviour of phase transitions between superfluid, normal and insulating phases is an area with many unanswered questions and experimental evidence remains scarce in certain important cases. In this thesis, we focus on systems of two-dimensional (2D) Bose gases subjected to a pointlike disorder potential. We trap atoms in radiofrequency dressed potentials and apply the technique of multiple-radiofrequency dressing to create a double-well potential into which we load the ultracold atoms. Matter-wave interferometry allows us to directly probe the local relative phase and its fluctuations between the clouds in the two potential wells. A pointlike disordered optical potential is produced by a high-intensity laser beam which is shaped by a programmable mirror array and passes through clouds in both of the wells. We adiabatically apply disordered potentials of increasing strength to observe their effect on the superfluids in equilibrium in a double-well. We observe that above a critical disorder strength the superfluid undergoes a transition to the normal phase at a lower temperature than that of the disorder-free case, and we characterise this disorder-induced transition. We also study the flow of a 2D superfluid cloud around both a single defect and a random potential and measure the dissipation induced by the obstacles. The absence of dissipation is observed below a critical velocity in the case of a single defect but we find no such dissipationless regime for the disordered potential. We describe the development of a software simulation package for modelling cold-atom systems and the implementation of particle collisions, magnetic trapping and evaporative cooling. Finally, we report on the initial work towards construction of a new cold-atom apparatus, capable of faster sequence times and greater atom numbers, to continue our investigation of many-body physics.

Keywords: Bose-Einstein condensate
matter-wave interferometry
Superfluidity
disorder
many-body physics
Berezinskii-Kosterlitz-Thouless
ultracold atoms
Advisor: Foot, C
MEASURING and utilising visible light scattering functions for the lunar regolith using the visible Oxford space environment goniometer

An accurate description of how visible light scatters from the lunar surface enables 1) constraints to be placed on the physical and compositional properties of the surface, using a photometric model such as the Hapke BRDF model, which has nine free parameters related to compositional and physical properties, and 2) more realistic scattering function inputs to be set within thermal models. Until a recent study by Foote et al. in 2010, lunar visible light scattering functions had been theoretically derived using limited laboratory measurements. Within thermal models, unrealistic scattering functions may be partly responsible for modelled temperature discrepancies of up to ~15-50 K (dependent on location)—when compared to remote sensing data from Diviner, onboard the Lunar Reconnaissance Orbiter—in regions such as polar craters, where light scattering due to surface topography dominates heat transfer. In this project, a laboratory goniometer setup was developed, which was used to measure a suite of visible light scattering functions for Apollo 11 (10084) and Apollo 16 (68810) lunar regolith samples across a wider range of viewing angles than has previously been measured. These samples were characterized in terms of their surface roughness and porosity profiles, and this enabled two of the free parameters within the Hapke BRDF model to be constrained. By fitting the model to the dataset, Hapke parameters could be deduced for the two representative (mare and highlands) regolith samples, and further constraints could be placed on the ‘practical’ size-scale of the model’s slope angle parameter. Thus, the dataset enabled Diviner’s visible-wavelength off-nadir data to be interpreted in a novel way, due to the reduction of free terms within the model. This led to surface roughness and compositional deductions (via the Hapke parameters h_s, b and θ ̅) for seven Diviner targets. Finally, the dataset was used to set more realistic scattering functions within the Oxford 3D Thermal Model, and it was demonstrated that this 1) could affect modelled high-latitude lunar surface temperature profiles by up to ~30 K—as compared to using previously assumed scattering functions—and 2) could increase the minimum depth at which water ice is predicted to be stable in the lunar subsurface by up to ~0.8 m. Hence, this dataset may help to constrain the possible distribution of water ice on the lunar surface, and this may be crucial for future lunar exploration missions such as Luna-27 and Artemis.

Keywords: regolith
lunar
sensing
moon
planetary
solar
apollo
system
photometry
remote
Advisor: Bowles, N
Warren, T
Embedding of Selmer group associated to relative Frobenius morphism of an abelian variety into the group of homomorphism of vector bundles

In this thesis we show that the Selmer group of the relative Frobenius morphism of an abelian variety defined on the function field of a projective and smooth curve C
over a finite field k0
of characteristic p>0
can be embedded into the group of homomorphisms between two natural vector bundles over C
.

Keywords: Selmer group
abelian variety
relative Frobenius morphism
Advisor: Rössler, D
Regenerative agriculture practices and their influence on soil organic carbon and farm productivity in temperate regions

Global food production is currently contributing to numerous environmental challenges including anthropogenic climate change, biodiversity loss and widespread declines in soil health. Regenerative Agriculture (RA) is an emerging paradigm which proposes that restoring soil health, by adopting a suite of management practices that align with so-called ‘regenerative’ principles, will not only improve agricultural productivity but also contribute to climate change mitigation through increased soil organic carbon (SOC). Despite a plethora of policies and suggested practices emerging over the past decade to support the introduction of RA across the world, there is still remarkably little scientific evidence to quantify potential improvements in soil organic carbon or agricultural productivity as a result of adopting ‘holistic’ RA systems. This represents a large knowledge gap that I set out to address in my DPhil thesis using currently available evidence for individual management practices.
Research for my thesis was divided into four parts. First, I used gold-standard systematic review methods to collate the state of current knowledge and assemble datasets from published studies of management practices forming part of a RA approach. My study area was temperate oceanic regions and I examined papers that considered the following RA approaches: reduced tillage intensity, cover cropping and ley-arable rotations in arable systems, and rotational grazing, multi-species or herbal leys, and agroforestry in pasture systems. Second, using the datasets obtained from these published studies, I conducted Bayesian meta-analyses of the impact of these practices on SOC and agricultural productivity (crop yields, herbage production, livestock growth). I found that adoption of rotational grazing and herbal leys can increase herbage dry matter production and livestock growth rates in pasture systems, but there is currently insufficient evidence to determine their impact on SOC. Conversely, my results identified clear potential for RA practices in arable systems to increase SOC but no evidence of a SOC-yield win-win. Third, using this finding I simulated adoption of these arable RA practices across Great Britain using the soil carbon model RothC, and found that in the UK there is the potential to mitigate 16-27% of current agricultural emissions through soil carbon sequestration. Finally, I conducted semi-structured interviews with industry representatives and livestock farmers in England to further understand advantages and disadvantages of implementing rotational grazing, herbal leys, ley-arable rotations and trees on farms. This final part of my research highlighted potential constraints on the ability to realise the theoretical advantages demonstrated from my earlier analyses.

Keywords: regenerative agriculture
meta-analysis
sustainable agriculture
soil organic carbon
systematic review
RothC
agroecology
Advisor: Willis, K
Petrokofsky, G
Computational models of assembly, structure and damage to collagen IV networks

Collagen IV networks play a key structural role in the human ocular lens capsule. However, their structure is not well understood, and is hypothesised to undergo significant changes over a lifetime, resulting in a loss of ability to accommodate different focal depths. In this thesis, a range of computational models and methods are developed, which aim to help better understand the properties of 2D networks of biopolymers, especially inspired by collagen IV.
The available experimental images of collagen-containing networks are assessed and an image analysis protocol is developed. A Monte Carlo method is designed, which introduces disorder into simplified graph-based networks by switching edges. In addition, Molecular Dynamics is used to simulate coarse-grained polymers which attract one another at their headgroups. These coarse-grained polymers are shown to self-assemble into a variety of interesting network structures. The coarse-grained polymer approach is combined with a Molecular Statics scheme to calculate mechanical properties of the network, and understand how the networks behave when stretched. A model that can mimic the ageing of the network over a lifetime is developed. To better understand how lens capsule motion may damage collagen IV networks, the rupturing behaviour of the polymer networks is examined by stretching ordered hexagonal networks linearly and sinusoidally until they break. This is compared to the rupturing behaviour of networks containing defects.
The MD method is used to assess the surface roughness and dimensionality of polymer networks, which is quantified by a fractal dimension. Finally, a new type of persistence diagram is used to quantify and visualise damage to ring structures in a network over time.

Keywords: monte carlo
persistent homology
2d networks
collagen
molecular dynamics
Advisor: Wilson, M
Pt(IV) anticancer prodrugs and liposomal encapsulation

This work describes the development of several photoactivatable platinum based anticancer prodrugs. The use of liposomes as a method of drug encapsulation for a known platinum complex is also explored. Finally, the synthesis of a microbubble-liposome conjugated system and the sonoluminescence effect of microbubbles are assessed. Chapter 1 discusses the fundamental properties of platinum, how it is currently utilised in chemotherapy, and the potential benefits of light-activated platinum compounds. The use of liposomes in medicine, with particular focus on drug encapsulation, is discussed in detail. The clinical applications of microbubbles are also explored. Chapter 2 describes the development and characterisation of two novel photoactivatable PtIV complexes. The solubilities, photochemical properties and pKa values of these compounds are compared to those of two previously reported complexes. Chapter 3 reviews the use of liposomes for the encapsulation of the drug iproplatin, with exploration of the best active loading method for this compound, and how the composition of the liposomes can be adapted to improve drug retention. Chapter 4 discusses the optimisation of synthesis for a conjugated microbubble-liposome drug delivery system. The phenomenom of sonoluminescence, and it’s potential use for activating photosensitive compounds is also explored. Chapter 5 describes the conclusions for this work, and what the next steps of this research would involve. Chapter 6 provides the experimental procedures and synthetic methods used in this work.

Keywords: platinum
microbubbles
anticancer
photoactivation
prodrugs
DIPG
liposomes
Advisor: Farrer, N
Copper-mediated radiosynthesis of 18F- and 123I-radiolabelled PARP inhibitors

This thesis aims to develop copper-mediated radiosynthesis to incorporate fluorine-18 and iodine-123 into FDA-approved poly(ADP-ribose) polymerase (PARP) inhibitors for cancer diagnosis and treatment, consisting the development of 18F-radiolabelled rucaparib for positron emission tomography (PET) application in cancer diagnosis and development of 123I-radiolabelled rucaparib and olaparib analogues as potential theragnostic agents for Auger therapy.
Chapter I presents a general introduction of DNA damage, PARP and PARP inhibitors.
Chapter II starts with a brief overview of PET, and 18F-fluorination of (hetero)arenes, and discusses two copper-mediated radiosynthesis approaches of 18F-radiolabelled rucaparib from pinacol boronic ester precursors. Full radiosynthesis of the most successful approach is demonstrated. In vitro data, in vivo dynamic PET imaging and ex vivo biodistribution of [18F]rucaparib are presented subsequently.
Chapter III provides a summary of Auger therapy and current methodologies to access 123I-radiolabelled (hetero)arenes. Development of 123I-rucaparib analogue and 123I-olaparib analogue via copper-mediated 123I-iodination from pinacol boronic ester precursors are discussed separately.
Chapter IV provides experimental data for compounds and procedures of radiosynthesis discussed in this thesis.

Advisor: Gouverneur, V
Establishment of an ex vivo precision-cut lung slice model for the evaluation of drug-radiation responses

Background: We hypothesized that the ex vivo precision-cut lung slices could provide a novel model for studying the biological responses of normal tissue to ionizing radiation and additionally provide important mechanistic insights into drug-radiation combinations.
Aims: 1) To establish an ex vivo model of lung tissue slices from mice. 2) To evaluate DNA damage responses in ex vivo lung slices compared with in vivo responses in lungs. 3) To determine the impact of NU7441, a pharmacological inhibitor of DNA-PK, on the DNA damage response.
Methods: Left lungs from female C57BL/6 mice (6-12 weeks old) were dissected and perfused with 4% low gelling temperature agarose. Lungs were sliced (250 µm) and incubated ex vivo for up to seven days. Lung slices were irradiated (137Cs) in the presence or absence of a DNA-PK inhibitor (NU7441). Fixed tissue sections were stained for histological markers (γH2AX and 53BP1) of DNA double-strand breaks (DSBs).
Results: We established culture conditions that maintained tissue viability for up to 7 days and structural integrity for at least 3 days. We showed that DNA damage responses to ionizing radiation were similar in ex vivo lung slices and lungs irradiated in vivo. Treatment with NU7441 was associated with an increase in long-lived DNA DSBs consistent with pharmacological inhibition of DNA repair. Unexpectedly, we found that a subset of lung epithelial cells (alveolar Type II) had low levels of γH2AX and 53BP1 staining following irradiation, which may have been associated with rapid repair of DNA DSBs.
Conclusion: The DNA damage response to ionizing radiation in lung tissue is similar in ex vivo and in vivo. The ex vivo lung slice model is a novel and highly tractable experimental system for studying the biological effects of drug-radiation combinations where the ability to carefully control experimental variables gives it clear advantages over in vivo models.

Keywords: DNA-PK
gH2AX
lung models
ex vivo
radiation
FFR
PCLS
DNA damage response
53BP1
DDR
Advisor: Ryan, A
The effect of domain geometry and long-range dispersal on the motion of hybrid zones

We consider two different population models that relate to hybrid zones. In both cases individuals in the population can be of one of three types: aa which may be fitter than AA, and both fitter than the aA heterozygotes. The hybrid zone is the region separating a subpopulation consisting entirely of aa individuals from one consisting of AA individuals.
First, we investigate the interplay between the motion of the hybrid zone and the shape of the habitat, both with and without genetic drift (corresponding to stochastic and deterministic models respectively). In the deterministic model, we investigate the effect of a wide opening and provide some explicit sufficient conditions under which the spread of the advantageous type is halted, and complementary conditions under which it sweeps through the whole population. As a standing example, we are interested in the outcome of the advantageous population passing through an isthmus. We also identify rather precise conditions under which genetic drift breaks down the structure of the hybrid zone, complementing previous work that identified conditions on the strength of genetic drift under which the structure of the hybrid zone is preserved.
The second set of results regard the study of how hybrid zones are affected by long-range dispersal of the individuals in the population, assuming both homozygotes are equally fit. We ignore genetic drift and use a deterministic model, the fractional Allen-Cahn equation to study the population. We show not only that under a suitable rescaling the motion of hybrid zones converges to motion under mean curvature flow, but also that there is a family of possible rescalings that gives this result. To overcome technical difficulties arising from the heavy-tailed nature of the stable distribution, we couple ternary branching stable motions to ternary branching Brownian motions subordinated by truncated stable subordinators, and use this coupling to quantify how the large jumps of the stable motion affect our main result.

Keywords: probability
hybrid zones
population genetics
SLFV
Advisor: Etheridge, A
Beretycki, J
Label-free tracking and mass measurement of single protein complexes on lipid bilayers

Protein-protein interactions are essential for biological processes, but can display a level of polydispersity that is difficult to study with bulk measurements. Recently, mass photometry, a label-free single molecule imaging technique, has been used to quantify protein-protein interactions by measuring the mass of single proteins. So far, however, measurements are limited to solution-based systems and nM concentrations. Here, we aim to expand the applications of mass photometry to proteins on lipid bilayers, and to increase the concentration range of solution-based measurements.
We implement a surface passivation protocol that reduces non-specific binding by up to four orders of magnitude, and apply further surface function- alisation strategies aimed at accessing measurements at μM concentrations. Next, we develop a mass photometry-based method for tracking individual protein complexes on lipid bilayers, thereby demonstrating quantification of oligomer-dependent kinetics and mobilities. We then extend this method to interactions of the HIV-1 envelope glycoprotein (Env) with broadly neutral- ising antibodies. Using our assay, we resolve polydisperse anitbody-induced cross-linking and quantify the corresponding binding affinities. We show that lipid bilayers give access to mass photometry measurements at μM protein concentrations, and demonstrate specific pull-down of target proteins from complex mixtures. Finally, we discuss aspects of the data analysis for these assays with a specific focus on systematic errors in the diffusion and mass measurements, and outline strategies for their correction.

Keywords: single molecule pull-down
optical microscopy
surface passivation
single particle tracking
lipid bilayers
mass photometry lipid
HIV
Advisor: Kukura, P
Struwe, W
Benesch, J