VictorJuiz/thesis huggingface dataset:
Investigating the role of suppressed hydrolases during Pseudomonas syringae infection
Keywords: plants
proteases
plant immunity

The apoplast, the extracellular space outside the plasma membrane of plant cells, is an important battleground for plant-pathogen interactions. Plants secrete hydrolytic enzymes into this space which are targeted by pathogen inhibitors. Previous work used activity-based protein profiling coupled to mass-spectrometry (ABPP-MS) to monitor hydrolase dynamics in the apoplast of Nicotiana benthamiana upon infection with virulent Pseudomonas syringae pv. tomato DC3000. This work detected 171 hydrolase activities, including 60 that were suppressed upon bacterial infection. We hypothesised that suppression by a bacterial inhibitor may have evolved in response to a role in immunity for some of these hydrolases.
This thesis aimed to uncover novel immune hydrolases by testing six of the suppressed hydrolases for their role in plant immunity using ‘agromonas’ assays. We identified NbPR3, a glycosyl hydrolase with a role in bacterial immunity despite its annotation as an endochitinase. We identified a Nicotiana-specific substitution in the catalytic general base of NbPR3 that is essential for this resistance function. A hypothesis-driven approach to identify the substrate of NbPR3 uncovered a potential role in release of a bacterial elicitor to trigger the oxidative burst.
We also identified NbRD21, a papain-like cysteine protease whose function in bacterial resistance appears to be dependent on effector-triggered immunity. We used transient NbRD21 expression combined with rd21 knockout by CRISPR-Cas9 to test potential mechanisms of NbRD21 function. Proteomics data uncovered a role for NbRD21 in processing of receptor-like kinases.
Finally, we developed a high-throughput assay for monitoring NbRD21 activity and used it to confirm that NbRD21 is inhibited during P. syringae infection. We presented evidence that the inhibitor is novel, likely proteinaceous, and produced by multiple bacterial species. Overall, this work has identified two novel and distinct plant immune hydrolases, demonstrating the potential of ABPP-MS to uncover molecular plant-pathogen interactions in the apoplast.
Synthetic studies towards sesquiterpenoids
Keywords: total synthesis
sesquiterpenoid

Chapter 1 explores synthetic efforts carried out during this project towards α-bulnesene. Several radical cyclisation methods are discussed for constructing the 5,7-fused bicyclic framework. A concise and enantiospecific route to 5-epi-α-bulnesene, combining a new reductive rearrangement method, is presented.
Chapter 2 focuses on the total synthesis of daphnenoid A. A unique strategy towards this cage-like tetracyclic structure is developed via an intramolecular Diels–Alder reaction and a 20-step synthesis leading to an advanced intermediate to daphnenoid A is presented.
Shrines and special graves in Britain and Ireland c.600-850
Keywords: Christianity
shrines
conversion
funerary practice
special graves
early medieval
Ireland
Britain
cemeteries
cult of the saints
religious change
stone sculpture

This thesis offers a reappraisal of the development of the cult of the saints in Britain and Ireland in the period 600-850, by situating the written, sculptural, and archaeological evidence for saints’ graves in the context of wider patterns of funerary practice between the fifth and ninth centuries. It also argues that there was great variety in the way that saints’ remains were presented in this period. The experience of visiting shrines depended on the audience, aspirations, and functions of the cult, as well as the cultural and economic context of the church in which it was situated. Saints’ graves were part of a spectrum of special graves that existed in the early medieval Insular world. Before the later seventh century, special graves were found at church sites and in traditional cemeteries, or in isolated landscape contexts. By the eighth century, special graves were created almost exclusively within ecclesiastical contexts. However, even within church sites the distinction between the grave of a saint and that of another honoured individual was not always obvious and unchanging. The location of the grave and the way it was marked was not necessarily a reliable indicator of saintly status. By comparing saints’ graves with other kinds of special graves, the similarities of form and function are revealed, demonstrating that the cult of the saints was adapted to local contexts and incorporated existing practices. The thesis argues that the influence of local burial practices and funerary monuments explains the variation in the types of shrines across Britain and Ireland as well as the unique forms of Insular shrines. This argument modifies and updates previous understandings of the development of the cult of the saints which have over-emphasised the influence of Frankish and Late Antique Mediterranean forms and neglected the contribution of Insular traditions.
Neural mechanisms of state-dependent sensory processing
Keywords: recurrent neural networks
decoding
all-optical microscopy
calcium imaging
neural variability
perception
working memory
E/I balance
optogenetics

A key purpose of the central nervous system is to transform sensation into action. During this process, identical stimuli can cause variable behavioural responses because of changes in the condition -- or, state -- of the brain. This response variability is a common phenomenon, yet the underlying neural mechanisms of how sensory information differentially interacts with varying network states remain obscure. In this thesis, we consider three such mechanisms in depth: inhibition stabilisation, neural variability and predictive learning. First, we analyse all-optical experiments where we were able to simultaneously record and insert neural activity in somatosensory cortex in vivo. Our results show that population activity is stabilised by inhibition, thereby allowing faint sensory stimulation to be detected and propagated downstream. In mice trained to detect these stimuli, we further observe that the neural variability across neurons modulated their perceptual performance, whereas this effect did not occur during passive stimulation. Therefore, maximising the cortical signal-to-noise ratio of behaviourally relevant stimuli is critical to facilitate activity propagation and perception. Separately, in a study of artificial neural networks, we demonstrate that it is advantageous for networks to continuously predict upcoming sensory information, as this facilitates learning of more complex working memory tasks. This could explain recent experimental findings showing that cortical neurons engage in predictive learning even when reward is absent. In sum, this thesis explores how sensory information interacts with ongoing neural activity in both biological and artificial neural networks, and explains mechanisms that underpin the variability of our behavioural response.
Developments in unitary quantum theory

Keywords: heisenberg picture
everett
unitary quantum theory
relative-state formalism
everettian quantum theory
unorthodox quantum theory
chronology-violating regions
deutsch hayden descriptors
closed timelike curves
quantum multiverse

This thesis describes advancements in unitary quantum theory. These can be divided into three main topics: Everett’s relative-state formalism, the Page–Wootters construction, and unorthodox quantum theory.
Everett’s relative-state formalism allows one to express the state of one quantum system relative to the state of another with which it is entangled. This formalism has only recently been translated to the Heisenberg picture by myself & Deutsch (2021). Our construction makes explicit the locality of Everettian multiplicity and demonstrates that the relative-states of a quantum system are fully fledged quantum systems in their own right. For instance, the observables of a relative state satisfy an appropriate form of a system’s characteristic algebra, and the relative states can store locally inaccessible information, just like the absolute system.
The Heisenberg-picture relative-state formalism has been used by me (Kuypers (2022a)) to refine a construction due to Page & Wootters (1983). In their construction, it is shown that an external time parameter is unnecessary for explaining change and dynamics in quantum theory because one can instead rely on ‘clock time’ – i.e. the time as represented by a clock. This makes time manifestly physical: clock time is an observable attribute of a clock, whereas the time parameter is not an attribute of anything physical. I have shown (Kuypers (2022a)) that the Page–Wootters construction is a ‘calculus for q-numbers’; that is to say that within that construction, one can define functions of q-numbers (which can be represented by matrices or operators on a Hilbert space) as well as derivatives of such functions.
Both the Page–Wootters construction and Everett’s relative state formalism are here treated in the Heisenberg picture because that picture has the crucial advantage that it is a local description of quantum theory (see §2.5). Therefore, the Heisenberg picture has been used by me (Kuypers (2022b)) to describe quantum systems in chronology-violating regions of spacetime (i.e. regions of spacetime that contain closed timelike curves). The presence of closed timelike curves makes one of the axioms of ‘orthodox’ quantum theory problematic – namely, the axiom that the observables of spacelike-separated systems commute. In unorthodox quantum theory, that axiom is dropped. The foundations of unorthodox quantum theory are presented, and I demonstrate that this theory provides a resolution to the so-called grandfather paradox.
Immigration, altruism, and attitudes towards the welfare state
Keywords: immigration
attitudes
redistribution
welfare states

This study develops a theoretical argument to explain when, why, and how immigration affects attitudes towards the welfare state and tests this argument in countries in Western Europe. I first argue that individuals’ attitudes towards the welfare state are driven by two concerns: material self-interest and altruism. I then argue that individuals are more likely to empathize with and help the poor when the poor are more like them in terms of culture, and that altruistic concerns have a greater influence on the welfare attitudes of the rich than the poor. I also disaggregate the effects of immigration into two parts: (i) it can make the poor more culturally dissimilar, and (ii) it can create competition for scarce resources, such as jobs and social benefits and services.
The central argument of this dissertation is that the variation in rich and poor voters’ support for a generous and inclusive welfare state across countries and time is explained by the extent to which immigration increases cultural dissimilarity among the poor and competition for scarce resources. When immigration increases cultural dissimilarity among the poor, voters become less willing to help them. Rich voters will therefore reduce their support for a generous and inclusive welfare state, while poor voters support a generous but less inclusive welfare state for self-interested reasons. When immigration creates resource competition, poor voters will demand more social spending and/or more restrictive eligibility rules to protect themselves against it.
Using quantitative and experimental methods, this study will show how immigration affects feelings of economic threat and the willingness to help the poor. Further, it will look at how these motivations explain the attitudes towards the welfare state among rich and poor voters across industrialized democracies in Western Europe and over time, and within the United Kingdom, Ireland, and the Netherlands.
An assessment of the welfare of non-human primates used in neuroscience research 
Keywords: behaviour
ECG
neuroscience
macaque
accelerometer
3Rs
non-human primate
stress
general anaesthesia
animal welfare
cortisol

The Animals (Scientific Procedures) Act 1986 governs the use of animals in scientific research in the UK. Embedded within this is a requirement to implement the 3Rs: replacement, reduction, and refinement; a key mechanism for minimising the pain, suffering, distress, and lasting harm of research models. To adhere fully to these principles, it is imperative to assess animal welfare. Non-human primates (NHP) human similarities make them both an essential biomedical research model and a species particularly vulnerable to welfare challenges. This thesis investigates non-invasive, objective methods of welfare assessment and applies them alongside neuroscience research to monitor the welfare of rhesus macaques (Macaca mulatta).
Accelerometers monitored changes in activity levels following general anaesthesia (GA) and revealed a decline in activity for 5.7 days following GA alone. Additionally, 2.6 days of activity decline were observed after surgery under GA, followed by an activity increase, suggesting post-operative behavioural change. Additionally, accelerometers were used to create a rule-based model for automated behavioural assessment. This model groups macaque activity into 5 species-typical behavioural categories with an overall 69% accuracy.
Physiological welfare parameters were assessed by detecting cortisol in faeces and hair. Faecal cortisol levels were significantly elevated for several days following GA, with a longer and more profound increase after surgery. Hair samples are a valuable measure of chronic stress and cumulative experience, facilitating longitudinal cortisol assessment without influence from transient stressors. Hair cortisol levels were significantly elevated post-surgery and, in some cases, following social disruption.
A customised, neck-based ECG was designed to monitor heart rate variability. The ECG was trialled on anaesthetised and restrained NHPs, dogs, and sheep. Proof of concept was achieved, with R-waves detectable in all species.
Overall, this thesis demonstrates how welfare and neuroscience research can be conducted in parallel for a better understanding of the life-time experience of animal models. This is an essential step towards implementing refinements and improving welfare, which may ultimately improve public perception and help to form the evidence-base required to inform and drive policy change.
Zonal flow and spectra in two-dimensional Rayleigh–Bénard convection

Keywords: Fluid Dynamics
Dynamical Systems
Geophysical Fluid Dynamics
Rayleigh-Bénard Convection
Computational Physics
Turbulence

In this thesis, we study two-dimensional Rayleigh-Bénard convection at a wide range of Prandtl numbers.
Following two introductory chapters, the subsequent three chapters focus on a horizontally periodic domain with free-slip top and bottom boundaries. This configuration encourages mean horizontal flows of zero horizontal wavenumber, which can be considered as an idealisation of zonal flows in planetary atmospheres, tokamaks, and annular cylindrical convection experiments. In chapter 3, we study the onset of zonal modes from a steady state that emerges at the onset of convection. In our fourth chapter, we study the dynamics when zonal modes are present. Our study unveils the presence of several bifurcations within the turbulent regime, in particular, a sequence of bifurcations leading to reversals of a very strong zonal flow. Chapter 5 generalises our analysis from a previously studied two-dimensional flow to a quasi-two-dimensional flow. We introduce a third spatial direction, and explore how narrow the domain must be in this direction to render the flow truly two-dimensional.
In chapter 6, we study two-dimensional Rayleigh-B ́enard convection with periodic boundary conditions to emulate the dynamics far from walls. This chapter aims to understand how spectra, fluxes, and global variables vary with both the Rayleigh and Prandtl number.
Finally, the thesis concludes with a summary of the main findings together with an outlook on possible further research directions for each project.
The investigation of tendon ECM alterations in response to stress relaxation for improving the Ponseti method
Keywords: stress relaxation
Ponseti method
elastin
tendon
collagen crimp
clubfoot

Congenital clubfoot or congenital talipes equinovarus (CTEV) is a complex paediatric foot deformity which will lead to long-term disability, deformity, and pain if left untreated. At present, the Ponseti method composed of a series of manipulation and casting is recognized as the standard treatment for clubfoot. However, the evaluation for the treatment outcome is based primarily on the clinical examinations and functional parameters while no work has explored the material response and the alterations of extracellular matrix (ECM) of a clubfoot tendon in response to the treatment – a long term stress relaxation. Ex vivo stress relaxation experiments discovered time-dependent tendon lengthening and ECM alterations including crimp angle reduction and elastin fragmentation, which illustrated the mechanism behind the treatment – a material-based tissue lengthening resulted from elastin fragmentation. This proposed mechanism was further supported by the relaxation results using elastin-digested tendons which also found a positive contribution to stress relaxation and relaxation rate from elastin. As the changes in crimp and elastin structures will be influential in the function and health of the tendon tissue, the capability of recovery of these ECM alterations in a tendon became a critical examination. The in vivo results derived from stress-relaxed tendons of young rabbits observed restoration of the above-mentioned ECM alterations along with increased elastin and vascularity level, and the existence of inflammation, indicating process of healing and recovery from the tendon in reaction to the treatment over time. While the increased vascularity and persisted inflammation may potentially bring concerns to the tendon health, they are both important biological adaptation in response to the mechanical treatment. Additionally, cellular response derived from the in vitro experiment discovered increased gene expressions of COL1A1 and ELN, supporting the incidence of recovery. Overall, this study reveals the treatment mechanism and proves the efficacy of the Ponseti method to correct clubfoot from an ECM-oriented perspective.
The do's and don'ts of quantum memory in cryptanalysis
Keywords: post-quantum cryptography
quantum cryptanalysis
cryptanalysis

This thesis refines the estimates of the costs to attack three different cryptographic problems. To get there, I first survey some fundamental issues in quantum computing. This narrows the scope of the capabilities of quantum computers and the engineering costs to build and run them. I then focus on “QRAM”, a type of quantum memory. The question with QRAM is whether quantum computers could cheaply access memory in superposition. I argue that they could not, and that quantum computers must pay a steep price to access memory.
I then analyse circuits to attack elliptic curve cryptography with Shor’s algo- rithm. I find that even expensive QRAM improves these circuits. Next I provide some optimisations and parallelisation strategies for Kuperberg’s algorithm. This algorithm can attack “CSIDH”, a type of post-quantum cryptography. Again QRAM is an effective tool: huge classical co-processing costs offset the expense of each quantum memory access. Finally I provide an algorithm for the golden collision problem, a generalisation of “meet-in-the-middle” attacks. If stable, error- free memory exists, then this algorithm could acheive an exponential advantage in total cost. However, the run-time of this algorithm is too high, so I show a more effective use of massive arrays of quantum hardware. This second algorithm has a higher cost but parallelises nearly perfectly.
In search of lost time: development of rapid magnetic resonance methods to probe time-varying diffusion
Keywords: time-dependent diffusion
diffusion magnetic resonance
pre-clinical imaging
exchange

Diffusion MR methods are a powerful means to probe tissue microstructural features. Most diffusion MR methods and signal representations, however, do not explicitly acknowledge the inherent time-dependence of diffusion, although it is precisely this time-dependence which reveals the characteristics of the microstructure. More advanced diffusion MR methods have emerged to study time-dependent phenomena. Diffusion exchange spectroscopy (DEXSY) measures exchange between diffusive microenvironments, and temporal diffusion spectroscopy (TDS) measures the time-dependence of diffusion directly. These methods, while powerful, have various limitations, particularly in their high data requirement.
This thesis details the development and validation of rapid, information-rich methods to probe exchange and time-dependent diffusion and which improve upon DEXSY and TDS. To improve upon DEXSY, a rapid sub-sampling scheme called the `curvature' method is developed to isolate exchange from other effects such as restriction, while requiring as few as 5 total acquisitions. The speed of the method enables the study of exchange in near real-time and also permits the study of distributed exchange times, revealing new insights about the nature of exchange in tissue. To improve upon TDS, a single-shot method is developed to probe diffusion over sub-millisecond timescales while also avoiding off-resonance effects, called the static gradient, time-incremented echo train acquisition (SG-TIETA).
The methods are tested using a tabletop, permanent magnet system with a strong static gradient as well as pre-clinical scanners capable of imaging. Studies of simple liquids, tissue phantoms, yeast, ex vivo neonatal mouse spinal cord under various perturbations, and in vivo mice are presented to support the feasibility and utility of the developed methods. Of note, the exchange time is found to be linked to steady-state, metabolic activity in tissue, representing a potentially useful biomarker. Overall, novel diffusion MR methods sensitive to exchange and time-dependent diffusion are developed and validated in a series of pre-clinical experiments.
Total synthesis of complex natural products
Keywords: daphniphyllum alkaloids
himalensine A
natural products
prostaglandins
enantioselective desymmetrisation
total synthesis
clavine alkaloids

Chapter 1 describes the development of a new enantioselective synthesis of prostaglandins employing a recently developed rhodium-catalysed enantio- and diastereoselective Suzuki-Miyaura reaction of aracemic bicyclic allyl chloride and an alkenyl boronic acid. This new synthetic strategy was successfully applied for the preparation of Tafluprost, a synthetic analogue of PGF2α used for the treatment of intraocular pressure in open-angle glaucoma and ocular hypertension.
Chapter 2 details the development of the enantioselective synthesis of Daphniphyllum alkaloids based on the previous accomplishments of our research group. The combination of palladium/enamine cocatalysed enantioselective synthesis of the morphan core and Michael addition – ketone allylation – ringclosing metathesis sequence enabled a highly convergent total synthesis of Himalensine A. This approach also allowed the formal synthesis of several other members of this family. In addition, the synthesis of Daphlongamine E and Daphniyunnine D was investigated.
Chapter 3 introduces Clavine (Ergot) alkaloids and their previous syntheses before a new synthetic strategy towards this family of natural products is investigated. A convergent synthesis of an advanced tetracyclic intermediate was achieved by utilising the key intermediate from our synthesis of Daphniphyllum alkaloids, unlocking the potential for the collective synthesis of the Clavine alkaloids.