VictorJuiz/thesis huggingface dataset:
Modulating the heat-shock response : a potential therapy for lysosomal storage disorders

Lysosomal storage disorders (LSDs) comprise a broad disease group of inherited metabolic disorders, the majority of which are associated with CNS pathology, significant disability and reductions in life expectancy. LSDs are caused by mutations in genes encoding proteins critical for the correct functioning of lysosomal homeostasis. The disruption of lysosomal homeostasis results in the abnormal accumulation of lysosomal content, initiating intracellular pathological events, including calcium dysregulation and lysosomal membrane permeablisation (LMP) affecting cell function and inducing cellular death mechanisms. These pathological events are particularly damaging within the CNS, due to its limited capacity for regeneration. Despite intensive scientific research into these disorders, and an increased understanding of the pathological events underlying these diseases, effective treatments are still lacking for most LSDs. Several therapeutic approaches have been investigated in the last 30 years, including enzyme replacement therapy, bone marrow transplantation, substrate reduction therapy, chemical chaperones and gene therapy. However, the CNS pathology in many of the LSDs remains unaddressed due to the restricted ability of many therapeutic agents to cross the blood-brain barrier.
The heat-shock response (HSR) is an emerging element involved in the pathogenesis of a variety of disorders. The HSR is a physiological response to a wide range of cellular stresses. It functions to protect the cell from the aggregation of misfolded proteins and LMP. Of the HSR, several key players are integral to mounting a heat shock response, these include the heat-shock factor 1 (HSF-1) and HSP70.
In this thesis, we provide proof-of-principle for the use of recombinant HSP70, and the small molecule up-regulator of the HSR, arimoclomol in treatment of a range of LSDs. We show that HSP70 is able to access the CNS, and increase the degradative capacity of lysosomal hydrolases. This provides differential behavioural, biochemical and survival effects in LSD models of Niemann-Pick type C, Sandhoff and Fabry disease. Additional studies using the HSF-1 upregulator arimoclomol, show a complex dose-response between the different models, possibly reflecting essential differences in the calcium dysregulation between these disease states.
Combustor simulators for scaled turbine experiments

Gas turbine combustors employing a single lean combustion stage represent the next generation of design for reduced NOXemissions. These lean-burn combustors rely on swirl-stabilised flames resulting in highly non-uniform outflows. Non-uniform conditions adversely affect high-pressure turbine performance. 3D numerical simulations provide a means to understand and optimise engine design, however, the modelling of turbulence means experimental validation is crucial. Turbine test facilities operating at scaled, non-reacting conditions, with simulated combustor flows are an important source of validation data.
This thesis presents advances in combustor simulator design, testing and instrumentation relevant to the challenges of modern, highly-integrated turbine testing. The design of a lean-burn combustor simulator, characterised by swirl and non-uniform temperature, is presented. The design was based on measurements and predictions of engine conditions. Unsteady numerical simulations were employed as a predictive design tool.
An engine-scale combustor simulator was manufactured and characterised experimentally in a bespoke facility. Surveys of flow structure are presented, focusing on experimental turbine inlet data. These data confirmed that the combustor simulator reproduces the important features of a lean-burn combustor; e.g. swirling mainstream flow and high turbulence intensity. The lean-burn combustor simulator will be the first of its kind to be implemented in a rotating turbine test facility, and will provide important validation data.
Measurement techniques were developed alongside the core work. Miniaturised five-hole probe rakes for turbine inlet measurements were developed using additive manufacturing (AM). Building on this work, an open source AM five-hole probe design is presented with experimental validation. The problem of estimating pressure probe bandwidth was also addressed, and a simplified model is presented. These tools have direct applications in turbomachinery research.

Keywords: Aerospace
Advisor: Povey, T
Indirect interactions structuring ecological communities

Ecological communities are collections of species bound together by their influences on one another. Community structure, therefore, refers to the way in which these influences are organised. As a result, ecologists are mainly interested in the factors driving the structure, functioning, and persistence of communities. The traditional focus, however, has been on the feeding relationships among species (direct trophic interactions), whereas relationships mediated by a third species or the environment (indirect interactions) have been largely overlooked. I investigated the role of indirect interactions in structuring communities through a series of field experiments in a diverse assemblage of arthropods living on a Brazilian shrub species. I experimentally reduced the abundance of the commonest galler on the shrub and found that the perturbation resonated across the food web, affecting its structure and robustness. Since there was no potential for these effects to be propagated directly or indirectly via the documented trophic links, the effects must have spread non-trophically and/or through trophic links not included in the web. Thus, I investigated non-trophic propagation of effects in the system. I demonstrate that hatched galls of the commonest galler, which serve as habitat for other species, can mediate non-trophic interactions that feedback to the galler modifying its interactions with parasitoids and inquiline aphids. I performed further manipulative experiments, excluding ants, live galls and hatched galls, to reveal mechanisms for the non-trophic interaction modifications observed in this system. Finally, I explored how non-trophic interaction modification could affect the structure and stability of a discrete ecological community in the field. I investigated how the densities of certain pairs of groups relate to each other, and how their relationship changes in relation to a third group. Then, I assembled an "effect network" revealing, for the first time in an empirical community, a hidden web of non-trophic indirect interactions modifying the direct interactions and modifying each other. Overall, the thesis presents evidence that communities are strongly interconnected through non-trophic indirect interactions. This is one of the first empirical demonstrations of the context-dependent modification of interactions via non-trophic interactions. However, determining the mechanisms behind such interaction modifications may be unfeasible. Understanding how the observed effects relate to community structuring requires shifting our focus from bipartite interaction networks to a more holistic approach.

Keywords: Indirect interactions
Interaction network
Food web
Tropics
Parasitoids
Brazil
Insects
Advisor: Morris, R
Lewis, O
Redox controls on Cr isotopes in natural waters

Shifts in Cr isotope fractionations due to microbial activity provide valuable insights into the mechanisms of its cycling, and can be used to quantify biogeochemically mediated redox processes in the environment. In my thesis, microbial Cr isotope fractionations were determined, with a broad range of experimental variables, including species, electron donors, Cr concentration, pH and respiration pathways, and the information can be used to understand the natural environment. Cr isotopes are found to be very sensitive to the types of electron donors and bacterial respiration pathways, indicating that the bacteria employed di erent metabolic pathways to reduce Cr under those conditions. These also suggest the potential to develop Cr isotopes as a new tool to probe speci c biological processes. Cr isotope fractionation in metal-microbe-mineral interactions is also studied. The addition of the minerals did not lead to a significant change on bacterial Cr isotope fractionations, though Cr reduction rates were significantly impacted. This indicates that although metabolic rates were altered by the interactions with the minerals, similar reduction pathways were still used by the bacteria. Based on these studies, the potential of combining a whole cell bioreporter, which can be used to assess the toxicity of Cr, and Cr isotope techniques, which can be applied in monitoring bio-reduction processes in contaminated sites, were explored. The whole cell bioreporter was found to be efficient in indicating Cr toxicity at different concentration levels and Cr isotopes were independent of toxicity levels. Therefore, it can be used to monitor bioremediation processes of Cr(VI) with different concentrations.

Advisor: Porcelli, D
Thompson, I
Natural enemies and the diversity of plant communities

The processes that determine the structure of plant communities are of considerable practical and theoretical interest. Natural enemies such as herbivores, seed predators and pathogens provide one potentially important influence on plant diversity. I investigated the effects of natural enemies on plant diversity in two contrasting, species-rich plant communities (tropical forests in Panama and temperate grasslands in the UK), focusing on pre-dispersal seed predation by insects, and the mortality of seeds and seedlings caused by soil fungi. In Panama I found that pre-dispersal insect seed predators generate significant levels of mortality in multiple tropical tree species, with high heterogeneity in predation rates among individuals and at different forest sites. Insect seed predators were highly host-specific, consistent with a role in enhancing plant diversity. At Upper Seeds, a calcareous grassland site in the UK, I used manipulative experiments to show that soil fungi increase the diversity of plants propagating from soil seed banks. A parallel experiment in Panama, mimicking germination under light gap conditions, revealed differential effects of fungi among sites, with fungicide treatment appearing to increase the diversity of propagated seedlings at some sites but reducing it at others. These results suggest that the influence of soil fungi on pre-emergence mortality can alter plant diversity, even when post-emergence mortality from fungal pathogens is limited. In Panama, I also tested whether enemy-mediated mortality increases with rainfall, potentially contributing to the positive regional correlations widely observed between precipitation and plant diversity. In contrast to predictions, neither pre-dispersal insect seed predation nor the influence of soil fungi on seedling recruitment were affected significantly by site humidity, or (for soil fungi) with experimentally manipulated soil moisture levels. Overall, my results provide evidence that pre-dispersal seed predators and soil fungi can affect plant recruitment and diversity at early life stages, with potential consequences for the community structure of adult plants.

Keywords: grassland
tropical forest
plant diversity
insect
pathogen
plant soil feedback
seed predator
rainforest
seedling
community ecology
density dependence
Panama
Wytham Woods
Advisor: Lewis, O
Aero-thermal performance and enhanced internal cooling of unshrouded turbine blade tips

The tips of unshrouded, high-pressure turbine blades are prone to significantly high heat loads. The gap between the tip and over-tip casing is the root cause of undesirable over-tip leakage flow that is directly responsible for high thermal material degradation and is a major source of aerodynamic loss within a turbine. Both must be minimised for the safe working and improved performance of future gas-turbines.
A joint experimental and numerical study is presented to understand and characterise the heat transfer and aerodynamics of unshrouded blade tips. The investigation is undertaken with the use of a squealer or cavity tip design, known for o↵ering the best overall compromise between the tip aerodynamics, heat transfer and mechanical stress. Since there is a lack of understanding of these tips at engine-realistic conditions, the present study comprises of a detailed analysis using a high-speed linear cascade and computational simulations. The aero-thermal performance is studied to provide a better insight into the behaviour of squealer tips, the e↵ects of casing movement and tip cooling. The linear cascade environment has proved beneficial for its o↵ering of spatially-resolved data maps and its ability to validate computational results. Due to the unknown tip gap height within an entire engine cycle, the e↵ects of gap height are assessed. The squealer's aero-thermal performance has been shown to be linked with the gap height, and qualitative different trends in heat transfer are established between low-speed and high-speed tip flow regimes.
To the author's knowledge, the present work is the first of its kind, providing comprehensive aero-thermal experimental research and a dataset for a squealer tip at engine-representative transonic conditions. It is also unique in terms of conducting direct and systematic validations of a major industrial computational fluid dynamics method for aero-thermal performance prediction of squealer tips at enginerepresentative transonic conditions.
Finally, after recognising the highest heat loads are found on the squealer rims, a novel shaped squealer tip has been investigated to help improve the thermal performance of the squealer with a goal to improve its durability. It has been discovered that a seven percent reduction in tip temperature can be achieved through incorporating a shaped squealer and maximising the internal cooling performance.

Keywords: Gas turbines
turbine blade
High-speed
Aerodynamics
CFD
Experimental
Computational Fluid Dynamics
aero-thermal
tip leakage flow
engine realistic
cooling
blade tip
Heat transfer
compressible
Advisor: He, L
Obstructions to arithmetic properties of rational points on varieties

The aim of this thesis is to develop further the theory of obstruction sets, which is used in the study of the arithmetic behaviour of rational points on nice varieties over number fields.
Let X be a nice variety over a number field k. In the first part of this thesis, we characterise in pure descent-type terms some inequivalent obstruction sets refining the inclusion X(Ak)ét Br ⊂ X(Ak)Br1 . More precisely, we apply ideas from papers by Skorobogatov and Demarche to new cases, by proving a comparison theorem for obstruction sets. We then show that descent under unipotent linear algebraic groups over k does not give any obstruction at all. This allow us, among other things, to characterise the étale-Brauer set in terms of descent under (non-necessarily connected) reductive linear algebraic groups and to characterise descent under solvable linear algebraic groups in terms of a Brauer-type set.
The second main part is motivated by the need of finding new obstruction sets, as the current finest one - the étale-Brauer set - is not sufficiently small to explain all the violations of the Hasse principle (there is a counterexample by Poonen for which there are no rational points but the étale-Brauer set is non-empty). We iterate the algebraic étale-Brauer set for any nice variety X over a number field k with πét1 (X̄) finite and we show that the iterated set coincides with the original algebraic étale-Brauer set. This provides some evidence towards the conjectures by Colliot-Thélène on the arithmetic of rational points on nice geometrically rationally connected varieties over k and by Skorobogatov on the arithmetic of rational points on K3 surfaces over k; moreover, it gives a partial answer to an algebraic analogue of a question by Poonen about iterating the descent set.

Advisor: Flynn, V
The biological treatment of metalworking fluids: insights into carbon removal mechanisms and integration with biocide toxicity mitigation strategies

The biological treatment of metalworking fluids (MWFs) is a cost effective alternative to conventional waste disposal processes. While research has proven that this process is capable of treating large volumes of wastes with high organic concentrations, there are uncertainties about the mechanisms by which the treatment occurs, and there are limitations that must be overcome.
There is a need to understand the importance of the mechanisms by which carbon (and hence COD) is removed from the wastewater. This will allow for waste practitioners to make better decisions for optimizing the process, and for disposing of waste (i.e sludge) that is generated.
The biological treatment process is also susceptible to biocides present within formulations. These compounds either need to be removed before the treatment process, or the bioreactors need to be made more resistant to them to ensure that their presence does not hinder the reactor functioning.
This study aims to answer the uncertainties about the carbon removal mechanisms involved in the treatment of oil-containing MWFs. In the first experimental chapter, it is shown that the predominant mechanism of carbon removal is oil/water separation induced by emulsifier degradation, and hence the bioprocess treatment rate is significantly affected by the biodegradability of surfactants and by the presence of cations found naturally in the water that used to prepare the emulsions.
The study then provides insights into the potential that coagulation and coalescence has for removing inhibitory components commonly found in MWFs. Coagulation and coalescence is shown to effectively remove biocides with low aqueous solubility (iodopropynyl butylcarbamate) and those that partition themselves into the oil phase (o-phenyl phenate and its sodium salt).
Finally, to improve the resistance of reactors to inhibitory compounds, factors influencing the development of fixed-film reactors are investigated. A micro-cosmic system is used to study the both physico-chemical effects and nutritional factors on the development of biofilm reactors. It is shown that biofilm yields can be controlled through pH adjustment, and that these yields are maximized with phosphate stimulation and ammonium limitation. It is then shown that fixed-film reactors are able to treat metalworking fluids even under conditions deemed to be inhibitory.
In summary, this project provides insights into further understanding and enhancing the biological treatment of MWFs.

Advisor: Hankins, N
The emergence of the Cantigas d’Amor. A philological investigation of poets, genres, manuscripts and their compilers

The cantigas d'amor are a genre within medieval Galician-Portuguese lyric. It is numerically expressive and was seemingly considered the highest poetic form in its time. This thesis explains its rise and history, focusing on its manuscript tradition, its compilation history and its formal characteristics. It opens with a codicological analysis of the thirteenth-century songbook Cancioneiro da Ajuda. This chapter complements previous studies, offering new information on the mise-en-page and analysing variation occurring throughout the manuscript. It concludes that the manuscript does not constitute a single unity, but should be explained as an evolving work of at least two different teams. The second chapter builds on this conclusion in order to reconstruct the songbook's lacunae. Missing folios are reconstructed based on mise-en-page conventions and its variation. It reviews the problem of putative lacunae for which there is no textual evidence, arguing that the Cancioneiro da Ajuda is less damaged than previously admitted. Chapters 3 and 4 compare the Cancioneiro da Ajuda with other manuscripts, proposing a theory on how the cantigas d'amor were gradually assembled. Chapter 3 develops a general theory on compilation which accounts for all three surviving songbooks. It infers the contents and structure of three lost songbooks. Chapter 4 provides specific details on how the corpus of each poet who composed cantigas d'amor was compiled. Chapter 5 provides a literary analysis of the cantigas d'amor composed by the earliest poets (c.1180-c.1240). It explains the emergence of this genre by drawing a poetic profile of twenty-five poets, analysing their corpora and accounting for their compilation. Overall, the study offers extensive explanations on the structure of existing and lost songbooks, on the compilation history of the cantigas d'amor, on how the genre emerged in direct relationship with other lyric genres and on the range of formal possibilities explored by the poets.

Advisor: Parkinson, S
The moral agency of corporations and its implications for criminal law theory

This thesis analyses the corporation, a business entity, as a form of group agent and considers its treatment under criminal law. I use group agency theory, drawn from the philosophy of action, to explain how a corporation can be a rational, moral agent with an existence separate from its individual human members' existence. Sceptics about corporate entity often tie moral agency to emotional capacity, something that many theorists, including many who defend the existence of corporate agency, find that the corporation lacks. As against this, I argue that corporations are indeed emotional entities, drawing group-level emotional states from the emotions of various members. Critics of corporations also argue that there are structural reasons why corporations are essentially immoral, or bad moral agents. As against this, I argue that while there are strong reasons why corporations tend to do bad things, they are structurally neutral.
In the second half of the thesis, I use the conceptual framework of the corporate moral agent to attempt to bring clarity to various problems within the criminal law as it applies to corporations. While corporations can be brought up on charges of committing acts that require a mens rea element, the law and legal theorists have long struggled with how to locate mens rea within the corporation. I build on collectivist theories of mens rea to explain a form of corporate recklessness, as an instance of corporate mens rea. The applicability of excuses to corporations is also an undertheorized area. I show how, in very limited circumstances, a corporation may be able to make out the excuse of duress, though that excuse relies on the accused acting from the emotion of fear. Finally, I consider the applicability of various theories of punishment to the corporation.

Advisor: Gardner, J
Roberts, J