VictorJuiz/thesis huggingface dataset:
Molecular characterisation of autophagy deficits in a LRRK2-BAC transgenic rat  model of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. PD is characterised by the preferential loss of dopaminergic neurons in the Substantia Nigra pars compacta in the midbrain accompanied by progressive motor dysfunction. The precise aetiology of PD is unknown, however a causative role of Leucine-rich repeat kinase 2 (LRRK2) has been proposed. Mutations in the LRRK2 gene are the most frequent cause of familial PD and are also an independent risk factor for sporadic PD. Although the function of LRRK2 is not well characterised, a role of LRRK2 in the autophagy pathway has been suggested. The disruption of the autophagy pathway by LRRK2 pathogenic mutations has been described. However, the literature is often contradictory and the exact underlying mechanisms remain unknown. In this study, primary cortical cultures were generated from three bacterial artificial chromosome (BAC) transgenic (TG) rat models of PD harbouring either the whole human wild-type LRRK2 gene, the G2019S mutant (the most common LRRK2 mutation) or the R1441C mutant (the LRRK2 mutation leading to a more aggressive pathology). After characterising the autophagy pathway it was observed that the presence of either hWT-LRRK2 or LRRK2-G2019S inhibits autophagosome biogenesis in primary cortical cultures. hWT-LRRK2 and LRRK2-G2019S each localise to the Golgi apparatus where autophagy signalling complexes are situated, which may underlie the inhibitory effect on autophagosome biogenesis. The presence of LRRK2-R1441C, however, induces a lysosomal deficit that causes an accumulation in autophagosomes and decreased autolysosome maturation and lysosomal protein degradation. LRRK2-R1441C also increases lysosomal pH levels and causes lysosomal Ca2+ release deficits. Furthermore, hWT-LRRK2 and LRRK2 G2019S were found to bind to the a1 subunit of the v-type ATPase pump (vATPase a1) which is responsible for modulating lysosomal pH. Whereas LRRK2-R1441C showed a loss of binding capacity to this subunit, which was associated with a decrease in a1 subunit protein expression and cellular mislocalisation. Lastly, the Zn2+ ionophore, clioquinol, was able to rescue the LRRK2-R1441C-mediated lysosomal phenotypes through modulating lysosomal zinc levels and increased vATPase a1 expression which re-acidified lysosomes, corrected localised calcium release and increased autolysosome maturation. These data describe a novel functional link between LRRK2 and vATPase a1, and define critical mechanisms underlying the inhibition of autophagy by different pathogenic LRRK2 mutations. These findings demonstrate a novel mode of action by which drugs may rescue lysosomal dysfunction and alleviate blockage in autophagic flux. These results demonstrate the importance of LRRK2 in lysosomal biology, as well as the critical role of the lysosome in PD and the potential of lysosome-targeting compounds as a novel therapeutic for the disease.

Advisor: Wade-Martins., R
Connor-Robson, N
Computational and experimental studies of exotic magnets and superconductors

The advent of metalworking during the bronze age marked a transition in humankind’s relationship with materials: instead of materials existing only as they were found in nature, one could now manipulate their physical properties to make them fit for purpose. With the discovery of quantum mechanics, the new opportunities to manipulate materials were manifold. The collective behaviour of electrons inside a solid is much more than the sum of its parts; as such, in some bulk materials, new quantum mechanical behaviour can emerge. We can use our knowledge of quantum mechanics to manipulate these quantum materials, and thus we find ourselves not in the bronze or the iron age, but in the quantum age.
This thesis is a series of four studies on a range of quantum materials.
I begin with emergent magnetic monopoles in spin ice. While there have been many bulk studies of monopoles, there is yet to be a microscopic measurement of small ensembles of these emergent quasiparticles. I use Monte Carlo methods to simulate the expected magnetic field fluctuations arising from small numbers of monopoles passing close to a probe near the surface of a spin ice, and show that the presence of monopole excitations produces unique features in the magnetic noise spectrum. I also propose several experiments which may be able to detect these features.
I then move onto CoTi2O5. Using muSR and neutron powder diffraction, as well as theoretical calculations, I find that this material undergoes a transition to an antiferromagnetic state, which is coupled to a spontaneous breaking of structural symmetry. This makes CoTi2O5 the lowest-known-symmetry crystal to undergo the spin Jahn-Teller effect. I then present a possible magnetostructural coupling regime.
The remaining studies examine the importance of topology in the successful understanding of quantum material systems. I use μSR to investigate both the ACa2Fe4As4F2 (A = K, Rb, or Cs) and LuxZr1-xB12 families of superconductors. It is possible to alter the topological character of the superconducting gap in these families, either by manipulating the chemical spacer layers in the crystal structure of ACa2Fe4As4F2 or by changing x in LuxZr1-xB12. Along with the gap topologies, both the penetration depths and critical temperatures of these compounds appear to be sensitive to these chemical manipulations. I investigate how these topological crossovers are linked to the other superconducting properties of these materials, and discuss the consequences for our wider understanding of superconductivity.

Keywords: Superconductivity
Magnetism
Advisor: Blundell, S
The language of kingship under Henry III: civilian, canonical, and dictaminal ideas in practice, c.1230-c.1252

This thesis is a study in how the political culture of the reign of Henry III was conditioned by its engagement with wider continental ideological and administrative developments. Within the shared legal and cultural space of ‘Europe’, a number of factors contributed to the development of a language of power both secular and spiritual, including the growth of universities, the study of Roman civil and canon law, the development of dictamen and the increasing prominence of the mobile curial administrative elite. I propose that these influences were of signal importance for the reign of Henry III in its own right, and also in the longer-term development of later medieval English political culture.
The chapters of the thesis evaluate these influences through three sections: prosopographical, textual and linguistic. Chapter 1 examines the personnel of royal government, exploring both the contributions to royal government made by foreign clerks, and the participation of other royal servants in European cultural networks. Chapter 2 turns to analysis of legal and dictaminal manuscripts, exploring the challenges in reconstructing medieval reading culture. In Chapter 3, the circulation of such manuscripts over the longer thirteenth century is evaluated to demonstrate their influence on royal government. In Chapter 4, the thesis turns to linguistic influence during the period of the personal rule, 1230-1250, exploring the impact of Romano-Canonical legal concepts on the discussion of royal power. Chapter 5 looks at the impact of the same concepts on discussion of the wider political community. The final chapter considers the influence of dictamen on the rhetoric of royal government. Bringing these strands together, the thesis shows that a cultivated and cosmopolitan elite, serving Henry III and knowledgeable in the learned laws and rhetoric, adapted that knowledge to their portrayal and implementation of royal government, with lasting significance for this reign and beyond.

Keywords: canon law
civil law
dictamen
kingship
Advisor: Watts, J
Stulrajterova, K
The Phytomonas cell surface proteome: Insights into the evolution of the parasite-host interface in Trypanosomatids

The trypanosomatids are a diverse group of obligate parasitic eukaryotes that have adapted to colonise multicellular and unicellular hosts that span the eukaryotic tree of life. The genetic resources that have enabled trypanosomatids to colonise such a diverse range of hosts are largely unknown. However, there is precedent that adaptation is in part facilitated through the evolution of families of cell surface proteins. The aim of this thesis was to broaden our knowledge of how trypanosomatids have adapted their cell surface to colonise different hosts through a combination of proteomic and bioinformatic approaches. The principal body of work is focussed on Phytomonas, a globally distributed genus of plant infective trypanosomatids that are transmitted by insects. As a sister group to Leishmania parasites of animals, this study of Phytomonas informs our understanding of how trypanosomatids have evolved from a monoxenous parasite of insects to adapt to both mammalian and plant hosts. To provide further resolution, a second species, Trypanosoma carassii (an extracellular parasite of cyprinid fish) was also analysed. T. carassii occupies an informative position in the phylogenetic tree of trypanosomatids as an outgroup to the salivarian and stercorarian Trypanosoma species. The results of the bioinformatic analysis presented in this thesis reveal that there is a conserved core of trypanosomatid cell surface proteins, the majority of which have no known function. Bioinformatic and proteomic results show that the cell surface of T. carassii is covered in one or more novel and unique families of GPI anchored proteins. The study of P. serpens indicates that while evolution to parasitise plants was facilitated though adaptation of the cell surface, there was no evidence for the innovation of large families of cell surface proteins as is observed in Trypanosoma and Leishmania species. Placed in an evolutionary context, the results presented in this thesis provide some insight into how these enigmatic parasites evolved from a single common ancestor to parasitise a broad host range from coconuts to crocodiles.

Keywords: Proteomics
Trypanosomatid
Parasites
Plant Pathology
Advisor: Kelly, S
The normativity of obligations: trust, blame, and interpersonal agency

This dissertation defends Deontic Pragmatism -- the view that the normativity of obligations is grounded in reasons to engage in interpersonal agency. I defend an account of obligations as correctness standards grounded in specific kinds of reasons. On this view, all obligations are directed from one person to another because these reasons are facts about a specific bipolar relation between people. To be a moral person is, in part, to comply with one's obligations for such reasons, by caring about other people and how they rely on oneself. Such caring attitudes are constitutive of the kinds of relationships people have reasons to have with one another. Indeed, the trusting attitudes such relationships also constitutively involve presuppose that others hold such caring attitudes towards us. In turn, the blaming responses to which trust disposes us presuppose that people fail to respond to such reasons, by failing to hold such caring attitudes.
I argue that this nexus between obligations, trust, blame, and relationships is played out across the entire moral domain. I then defend an account of the reasons people have to hold such attitudes. On this view, reasons that ground correctness standards, including obligations, are shared by people in virtue of their engagement in activities. Specifically, it is correct for people to have moral relationships, because they have reasons to intend to engage in interpersonal activities that involve mutual dependence relations. And they have those reasons, I argue, whatever other activities they are engaged in. Since such dependence is presupposed by the attitude of reliance involved in trust, the reasons that ultimately ground our obligations are grounded in a relation that is itself presupposed by the attitude of trust.

Keywords: Ethics
Moral
Obligation
Normativity
Advisor: Hills, A
Crisp, R
Nickel stable isotope fractionation in planetary materials

Nickel is a moderately siderophile and refractory first row transition metal, and a relatively new addition to the field of investigation of mass dependent stable isotope fractionation processes. Nickel is compatible in the magnesium-rich silicate minerals that constitute most upper mantle lithologies. This work provides the first detailed study of Ni stable isotopic compositions for such materials, with a particular focus on ultramafic xenoliths, oceanic basaltic rocks and lunar samples. The methods use ion exchange chromatography and multi-collector ICPMS with double spiking, adapting procedures of Gall et al., 2012. It is found that Ni isotopic compositions are not fractionated by partial melting or fractional crystallisation. There are no significant fractionations between mantle minerals. However, there are variations within the terrestrial mantle and in basalts from the Earth and Moon. On Earth, the deviations toward lighter compositions in enriched mid ocean ridge basalts show a relationship with the presence of enriched trace element chemical compositions. Ocean island basalts also display isotopic heterogeneities. In ultramafic samples it is the more metasomatised and iron-rich lithologies that are isotopically lightest, the most extreme being pyroxenitic material. This provides evidence that recycling of basaltic materials into the mantle leaves a signature of isotopically light Ni. Nickel isotopic compositions can therefore behave as a tracer for the composition of the mantle source region, uncomplicated by melting processes, redox changes, or time since enriched material was added to the mantle source region. On the Moon, variations in Ni isotopic composition have been shown not to relate to cosmogenic effects. The lunar Ni isotopic compositions appear to relate to the abundance of plagioclase and incompatible elements in the sample. Nickel isotopes, therefore, behaved differently in the lunar environment and were fractionated by processes that are insignificant or do not occur on Earth, probably in the lunar magma ocean.

Advisor: Halliday, A
Barling, J
Probing the risks of moral enhancement

Attempting to improve fundamental moral dispositions with technology is prone to unexpected consequences. These dispositions are complex, and fragile when faced with technological interventions. For instance, a drug increasing the disposition to co-operate between individuals can unexpectedly lead to group conflict because it can increase parochialism. Furthermore, these interventions might be detrimental to a person’s psychological unity over time and thus might undermine interests whose realisation is sensitive to the continuation of this unity over time. Likewise, they might be detrimental to interests sensitive to the continued chain of human generations. Notwithstanding these risks, there are strong reasons in favour of attempting to improve moral dispositions; it could significantly decrease a wide range of extreme risks that arise from our moral failings (for example, nuclear war from lack of global co-operation). Appealing to a form of virtue theory as a guiding framework is likely to avoid these risks and to address other concerns expressed in the literature. If we apply such a framework, technological interventions aimed at improving fundamental moral dispositions are extremely desirable.

Keywords: virtue theory
moral enhancement
moral psychology
Advisor: Savulescu, J
Crisp, R
Seismic design and evaluation of moment resisting frames using elastomeric dampers

This study evaluates the characteristics of elastomeric dampers, and assesses their eectiveness in mitigating the eects of dynamic loading. As part of this evaluation a series of characterization tests were carried out in order to extract the main mechanical properties of the elastomer material in a range of strain amplitudes, loading frequencies, and ambient temperatures, since it has been proved that elastomeric materials depend on these parameters. It was found that strain amplitude was the most dominant factor not only regarding the values of their mechanical properties (shear storage modulus, and loss factor) but also with regard to the shape of the hysteresis loops. At the same time frequency was shown to have only a minor eect on their behaviour.
Based on the Generalised Maxwell Model, a new hysteretic model was developed and proposed in this thesis which is able to capture the behaviour of the material. As part of this model an equation was derived which describes the force-displacement relationship of the Generalised Maxwell Model for N Maxwell elements in time domain, and formed the basis for the proposed model.
The seismic performance of a 10 storey steel moment resisting frame was evaluated, and the eect of the dampers on the frame's performance was examined. The dampers were designed to provide an additional 10% damping to the Eurocode 8 compliant building. The structure was tested with and without dampers for two dierent levels of earthquake intensity. It was shown that the elastomeric dampers led to signicant decrease of displacements, accelerations, base shear forces, and permanent damage of the structure, even after ground motions scaled to the Maximum Considered Earthquake level.
Lastly, Real Time Substructure tests were performed in order to further validate the proposed hysteretic model. Both SDOF and MDOF systems equipped with elastomeric dampers were tested under scaled version of the ElCentro ground motion and the corresponding force-displacement relationship of the dampers was compared with the analytical model. The results showed that the proposed model is able to capture the dynamic performance of the dampers under realistic earthquake conditions.

Keywords: Real Time Substructure Test
seismic retrofit
Elastomeric dampers
passive diisipation devices
Generalized Maxwell Model
Advisor: Williams, M
‘What if a spirit or an angel has spoken?’ Narrative modelling of the treatment of dreams and visions in the Acts of the Apostles

The reports of dreams and visions in the Book of Acts are widely accepted to portray moments of divine-human communication that demonstrate God’s continuing involvement in the life of His church. However, within the narrative there are inconsistencies between repeated reports of visionary experience (e.g. Acts 9, 22, 26), cases of prophecy being ignored (e.g. Acts 21:10-14), mixed responses to dream-visions (e.g. Acts 2, 10, 11, 15, 22), and nuances that suggest more is going on in the text than what would be required simply to show God’s hand at work.
This thesis will analyse the dream-vision reports within the Acts of the Apostles, assessing the extent to which they reflect wider first century attitudes towards dreaming, and their function within the narrative itself. It will be argued that at both of these levels of enquiry, the reports of dreams and visions demonstrate an awareness of the challenges that these phenomena pose for individuals and communities. This is reflected not only in the struggle to appropriately interpret dreams and visions, but also in the recognition of the potential risks posed by these phenomena. Indeed, it will be suggested that the inherent ambiguity and uncertainty that surrounds dreams and visions is something that is heightened rather than diminished within the upside-down world of the Acts of the Apostles. It will be argued that one finds a movement from the idealised representation of dreams and visions in the account of the first Christian Pentecost, to its more complex practical outworking. Through engagement with this story the reader/hearer is offered a means of understanding how dreams and vision might be treated, mutatis mutandis, within the context of their own community.

Keywords: Religious Experience
Ambiguity
Authority
Narrative Criticism
Acts of the Apostles
Dreams and Visions
Advisor: Rowland, C
Agent-based modelling in healthcare operations

Introduction:Simulation is a common approach in healthcare operations research. In recent years, a new simulation method, Agent-based Modelling (ABM), has gained increasing popularity due to its flexible ‘bottom-up’ framework. For all the hypes around ABM, it is unclear to what extent it is being used in healthcare operations, if it is being utilised to full potential and whether it provides robust evidence for change. The aim of this review is to systematically evaluate its state of the art.
Research Questions: What are the topic addressed by ABM and their associated characteristics? What was the quality of these studies? How were these models implemented?
Methods: A comprehensive interdisciplinary search strategy was developed to account for materials not published in traditional journals, and double screening was applied. A data extraction form was developed to enable standardised description of studies across topic areas. An easy-to-use quality assessment tool was developed in line with the academic principles and industry experience.
Results: Thirty-one studies met the inclusion criteria. 11 studies are about service efficiency, 9 on nosocomial infection, 4 on care coordination, and the rest are on hospital layout design, patient choice, and payment model. Although ABM is not evidently advantageous in studies on service efficiency, it demonstrated unique properties for studies on other topic areas (e.g. care coordination) where patients and providers enjoy greater autonomy. The quality of these studies was quite low, on average meeting 2 out of 7 quality items. In particular, most studies failed to justify their conceptual model and the time horizon chosen for model execution. Only two studies on hospital layout have been implemented and even the study of highest quality was not.
Conclusion: Future studies should improve the quality of conduct and reporting, and find new ways to make an impact on healthcare operations and eventually population health.

Advisor: Oke, J