VictorJuiz/thesis huggingface dataset:
Harnessing the immunomodulatory capacity of dendritic cells differentiated from human induced pluripotent stem cells and the therapeutic potential of dendritic cell-derived exosomes for the treatment of lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a collection of disorders that feature the pathological accumulation of substrate frequently due to an enzymatic defect within the lysosomes. The most effective treatment regime for LSDs is enzyme replacement therapy. However, this treatment has faced two main challenges which have limited its treatment efficacy and clinical impact. One challenge constitutes the potential immunogenicity of the replaced enzyme, which can lead to the induction of an antibody response that prevents its effective targeting. Therefore, this thesis investigated the potential to derive patient-specific autologous dendritic cells (ipDCs) from fibroblasts which were obtained from a healthy donor and from a patient diagnosed with infantile-onset Pompe disease and were reprogrammed into induced pluripotent stem cells (iPSCs). This study demonstrated the feasibility of differentiating these iPSCs into ipDCs and investigated the potential to modulate their immunogenicity using a variety of agents. Using IL-10, this work was able to show the feasibility of generating patient-specific ipDCs with pro-tolerogenic characteristics which may be exploited for the induction of tolerance towards therapeutic enzymes. Secondly, the delivery of therapeutic enzymes to the central nervous system (CNS), which is frequently involved in disease pathogenesis, is limited by the selective-permeability of the blood brain barrier. As specifically-labelled exosomes have been shown capable of targeting to the CNS for the delivery of therapeutic molecules, this study has shown the possibility of harvesting exosomes from ipDC cultures. The potential of exploiting the endocytic capacity of dendritic cells for the loading of enzyme into exosomes was explored. Furthermore, this study has found that the administration of syngeneic and allogeneic exosomes from mouse bone-marrow derived DCs and ipDCs elicited an antibody-mediated immune response which may limit the clinical application of exosomes further highlighting the need for tolerance induction. Altogether, this study constitutes a first step towards potential improvements in the treatment of LSDs.

Advisor: Fairchild, P
Citizens and states: considering the concept of citizenship

This thesis is an investigation into the concept of citizenship, or, more precisely, the core concept of citizenship. It attempts to show how certain key debates within citizenship theory can (and should) be framed once the core concept has been clarified. Its central claim is that citizenship is primarily an institutional relationship between an individual and the laws and organs of government to whose authority she is subject. All other 'aspects', 'dimensions', 'senses', or conceptions of citizenship, should be oriented in relationship to this core meaning.
Understanding citizenship as primarily an institutional relationship affects how we should approach a number of issues in citizenship theory. The first issue I consider has to do with the limits of both citizenship theory and the extension of citizenship in practice. Specifically, can the conceptual category of citizenship apply to non-human animals, or, indeed, for animals to be citizens in sense that is substantively on par with human citizens?
I next consider what the core concept tells us about the moral aspect of citizenship and the relationship between co-citizens. I ask whether one’s membership in a morally bounded community could be either necessary or sufficient for a kind of citizenship, and whether citizens owe each other special obligations qua citizens.
Finally I ask who might have a moral claim to citizenship in a given state. I consider the possible moral claims a person might have to each of citizenship’s two primary elements—what I call democratic membership (i.e. to be included in the demos of a democratically governed polity), and basic membership (i.e. the rights to live and work within the territory of a polity). The first sort of claim brings us into contact with the debate over what is known as the democratic boundary problem, while the second leads us to consider the practice of birthright ascription.

Advisor: Green, L
The climate of Mars from assimilations of spacecraft data

The Mars climate has been explored using two reanalysis datasets based on combining spacecraft observations of temperature and dust with the UK version of the LMD Mars GCM. The semiannual oscillation (SAO) of zonal-mean zonal wind was studied using the existing Mars Analysis Correction Data Assimilation reanalysis during Mars Years (MYs) 24-27. The SAO of zonal-mean zonal wind was shown to exist and extend over a wide range of latitudes. The dynamical driving processes of the SAO in the tropics were investigated, and the forcing due to meridional advection appeared to be the main contributor to the SAO. The study also highlighted some phenomena associated with perturbations of the global circulation during the MY 25 global dust storm (GDS). The meridional advection term was shown to be weaker in the first half of GDS year MY 25 than in the following year, but the forcing due to meridional advection and westward thermal tides both appeared to intensify during the MY 25 GDS.
The capabilities of the Mars data assimilation system were also extended in this thesis, 1) to represent dynamic dust lifting and dust transport during the assimilation and 2) to assimilate measurements of the dust vertical distribution. The updated reanalysis was then used to study several major dust events during MY28-29. It proved able to reproduce a southward-moving regional dust storm without the overwhelming assistance of the assimilation. Dust devil lifting was found to at least partly provide the initial pattern of dust of this moving dust storm. The cold anomaly of the cooling zone beneath this dust storm could be as large as &Tilde; 2 K similar to the magnitude of what was found during the MY 25 GDS. Using the reanalysis, the life cycle of the planet-encircling global dust storm in MY28 was also studied. The Noachis dust storm that occurred just before the MY 28 GDS was found to be the joint result of a travelling Chryse storm, enhanced by dust lifting along its path and local dust lifting in Noachis itself. The adiabatic heating associated with the north polar warming that occurred during MY 28 GDS was up to &Tilde; 3 times as large as that found during the non-GDS year MY 29. The wind stress dust lifting was shown to in strong correlation with the global average dust loadings, and significantly decreased when the GDS decayed.

Keywords: numerical model
Mars Climate
dust climatology
Data Assimilation
Advisor: Read, P
Genetics of colonisation in the common wall lizard

In this thesis I set out to further our understanding of the causes and consequences of genetic variation after colonisation events. Specifically, I focused on how historical processes shape genetic diversity and to what extent we can link colonisation history, genetic diversity, individual fitness and population viability. To achieve this, I used a combination of molecular markers, analytical tools and the common wall lizard, Podarcis muralis as a study system. I first infer the origin and genetic architecture of isolated population on islands at the range margin, in relation to mainland populations, to determine whether their current distribution and genetic structure are a result of a historical colonisation event or a more recent introduction. I then unravel the details of human-mediated introductions of P. muralis in England to further test which factors affect their genetic structure. I ask about the contribution of multiple introductions and admixture, the importance of number of founders and the year since their introduction and whether bottleneck events during primary and /or secondary introduction predict the level of genetic diversity in the non-native range. Throughout this study I obtain information on population genetic structure and composition from both native and non-native ranges. This is essential since the (complex) phylogeographic structure of P. muralis in the native range determines the distribution and structure of genetic diversity from which colonists are drawn and the details of colonisation will then reflect in the genetics of non-native populations. Lastly, I assess the consequences of colonisation on reproductive fitness and test for heterozygosity fitness correlations at the individual and population level. Overall, this thesis demonstrates why reconstructing the colonisation history is important when aiming to understand the causes and consequences of genetic variation during colonisation. This information is critical when assessing the relationship between genetic diversity and establishment success. Whether non-native populations have retained sufficient evolutionary potential to adapt to their new climate their long-term viability will be dictated by availability of suitable habitat rather than by internal population factors.

Advisor: Uller, T
Investigation of the neurochemical, molecular and behavioural properties of the putative lithium-mimetic, ebselen

Lithium is the first choice drug for the treatment of bipolar disorder and it is also used as supplementary therapy for treatment-resistant depression. A leading candidate target of lithium is inositol monophosphatase (IMPase) which is critically involved in signalling via the phosphoinositide cycle (PI). Ebselen, first developed as an anti-inflammatory and anti-oxidant drug, has recently been shown to inhibit IMPase and therefore is a putative lithium-mimetic.
This project aimed to investigate the neuropharmacological effects of ebselen in mouse models relevant to depression. Initial studies examined the function of 5-HT2A and 5-HT2C receptors, which signal through PI cycle. Ebselen attenuated the responses of systemically administered 5-HT2A agonists at the behavioural and molecular level; specifically the induction of head twitches and ear scratches and increased immediate early gene (IEG) expression. Lithium produced similar effects to ebselen in the same experiments. In addition, an IMPase inhibitor but not a GSK-3 inhibitor mimicked the effect of ebselen at the behavioural model of 5-HT2A receptor function. Ebselen also reduced 5-HT2C receptor function, as assessed using IEG expression, and lithium had a similar effect. Ebselen was also found to increase 5-HT synthesis in mouse brain regions as previously reported for lithium. In microdialysis studies, ebselen tended to enhance the increase in extracellular 5-HT levels induced by the SSRI citalopram in hippocampus. This finding was consistent with the observation that ebselen and citalopram increased IEG-expression when administered together but not when administered separately. Lastly, ebselen when administered repeatedly increased the abundance of a variety of gene markers of neuronal plasticity in mouse brain regions. Lithium also increased the abundance of markers of neuronal plasticity.
Overall, the present study found that ebselen attenuated 5-HT2 receptor function and partially augmented the effects of citalopram, while it increased markers of neuronal plasticity. These effects of ebselen were largely mimicked by lithium. These findings show that ebselen has similar neuropharmacological effects to lithium across a range of mouse models relevant to depression. The antidepressant potential of ebselen is discussed.

Advisor: Sharp, T
Imaging lipid phase separation in droplet interface bilayers

The spatiotemporal organization of membrane proteins is implicated in cellular trafficking, signalling and reception. It was proposed that biological membranes partition into lipid rafts that can promote and control the organization of membrane proteins to localize the mentioned processes. Lipid rafts are thought to be transient (microseconds) and small (nanometers), rendering their detection a challenging task. To circumvent this problem, multi-component artificial membrane systems are deployed to study the segregation of lipids at longer time and length scales. In this thesis, multi-component Droplet Interface Bilayers (DIBs) were imaged using fluorescence and interferometric scattering microscopy. DIBs were used to examine and manipulate microscopic lipid domains and to observe, for the first time, transient nanoscopic lipid domains. The techniques and results described here will have important implications on future research in this field.

Advisor: Wallace, M
The Hofstadter model and other fractional chern insulators

Fractional Chern insulators (FCIs) are strongly correlated, topological phases of matter that may exist on a lattice in the presence of broken time-reversal symmetry. This thesis explores the link between FCI states and the quantum Hall effect of the continuum in the context of the Hofstadter model, using a combination of nonperturbative, perturbative and numerical methods. We draw links to experimental realisations of topological phases, and go on to consider a novel way of generating general FCI states using strong interactions on a lattice.
We begin by considering the Hofstadter model at weak field, where we use a semiclassical analysis to obtain nonperturbative expressions for the band structure and Berry curvature of the single-particle eigenstates. We use this calculation to justify a perturbative approximation, an approach that we extend to the case when the amount of flux per plaquette is close to a rational fraction with a small denominator. We find that eigenstates of the system are single- or multicomponent wavefunctions that connect smoothly to the Landau levels of the continuum. The perturbative corrections to these are higher Landau level contributions that break rotational invariance and allow the perturbed states to adopt the symmetry of the lattice. In the presence of interactions, this approach allows for the calculation of generalised Haldane pseudopotentials, and in turn, the many-body properties of the system. The method is sufficiently general that it can apply to a wide variety of lattices, interactions, and magnetic field strengths.
We present numerical simulations of the Hofstadter model relevant to its recent experimental realisation using optical lattices, noting the additional complications that arise in the presence of an external trap.
Finally, we show that even if a noninteracting system is topologically trivial, it is possible to stabilise an FCI state by introducing strong interactions that break time-reversal symmetry. We show that this method may also be used to create a (time-reversal symmetric) fractional topological insulator, and provide numerical evidence to support our argument.

Keywords: Fractional Chern insulators
The Hofstadter model
Advisor: Simon, S
Manuscript recipe collections and elite domestic medicine in Eighteenth-Century England

Collecting recipes was an established tradition that continued in elite English households throughout the eighteenth century. This thesis is on medical recipes and advice, and it addresses the evolution of recipe collecting from the seventeenth century and throughout the eighteenth century. It investigates elite domestic medicine within a cultural history of medicine framework and uses social and material history approaches to reveal why elites continued to collect medical recipes, given the commercialisation of medicine. This thesis contends that the meaning of domestic medicine must be understood within a wider context of elite healthcare in order to appreciate how the recipe collecting tradition evolved alongside cultural shifts, and shifts within the medical economy. My re-appraisal of the meaning of domestic medicine gives elite healthcare a clearer role within the narrative of the social history of medicine. Elite healthcare was about choice. Wealthy individuals had economic agency in consumerism, and recipe compilers interacted with new sources of information and products; recipe books are evidence of this consumer engagement. In addition to being household objects, recipe books had cultural significance as heirlooms, and as objects of literacy, authority, and creativity. A crucial reason for the continuation of the recipe collecting tradition was due to its continued engagement with cultural attitudes towards social obligation, knowledge exchange, taste, and sociability as an intellectual pursuit. Positioning the household as an important space of creativity, experiment, and innovation, this thesis reinforces domestic medicine as an important part of the interconnected histories of science and medicine. This thesis moreover contributes to the social history of eighteenth-century England by demonstrating the central role domestic medicine had in elite healthcare, and reveals the elite reception of the commercialisation of medicine from a consumer perspective through an investigation of personal records of intellectual pastimes and patient experiences.

Keywords: Healthcare
Remedies
Recipe Books
Elite
Domestic Medicine
Advisor: Charters, E
Gauci, P
Muddy waters: political tensions and identity in the writings of Xu Wei (1521-1593)

The late Ming artist and poet Xu Wei 徐渭 (1521-1593) is most well known for his self-representation as a cultured "mountain hermit" and "eccentric", pursuing the literary ideals of originality, simple language and direct emotional expression. His wild ink-brush paintings, mental instability, numerous suicide attempts and the murder of this third wife all helped to consolidate Xu's image as China's Van Gogh. However, later hagiographies of Xu as the "patron saint of eccentrics" have led to a one dimensional view of Xu.
This thesis presents Xu as someone who explored and wrestled with different and sometimes contradictory self-representations against a thorny political and social backdrop. It moves away from Xu's "eccentric" persona, instead examining his writings within the political context of the 16th century.
Against the backdrop of Mongol and pirate invasions, Xu's close friend Shen Lian was executed by the Chief Grand Secretary Yan Song and his clique. Yet only a month after his friend’s execution, Xu switched sides and worked as a ghost-writer for Hu Zongxian, a protégé of Yan Song. Yet with the fall of Yan Song in 1562 and the arrest of Hu Zongxian, this became an embarrassment for Xu. Fearing that he would be implicated with the Yan Song clique, Xu distanced himself from his flattering ghost-written poems. Overwhelmed by feelings of guilt, he explored the complexities of loyalty and identity in his poetry.
Xu's career is representative of many Ming scholars who were frustrated by examination failure and the inability to find an official post. His literary ideals contradicted with lived reality. Xu is unique among Ming literati in voicing these contradictions.

Keywords: self-representation
Late Ming cultural history
Xu Wei, 1521-1593
Advisor: Ditmanson, P
Towards storage and retrieval of non-classical light in a broadband quantum memory - An investigation of free-space and cavity Raman memories

Photonic quantum information processing has emerged as a powerful platform for realising quantum-enhanced technologies. In order to be scalable, many of these technologies depend on the availability of a suitable quantum memory for the coherent storage and on-demand retrieval of photonic quantum states.
In this thesis, I investigate broadband light storage in a room-temperature Raman memory, implemented both in free space and, for the first time, inside a low-finesse optical cavity designed for low-noise operation.
The ability of the Raman memory to preserve phase coherence was tested by storing coherent polarisation states in two spatially separate atomic ensembles. Polarisation storage with a fidelity of up to 97 ± 1% was demonstrated by performing full process tomography on the system.
The Raman memory was then interfaced for the first time with a spontaneous parametric downconversion (SPDC) source of heralded, GHz-bandwidth single photons. The memory performance was characterised by measuring the second-order autocorrelation of the retrieved fields. While the SPDC input photon statistics showed a clear influence on the statistics of the retrieved field, four-wave mixing (FWM) noise, stimulated by spontaneous Raman scattering, prevented the preservation of non-classical photon statistics during read-out.
Suppressing this source of noise represents the last remaining challenge for realising a broadband single-photon Raman memory suitable for quantum information applications. To this end, I demonstrate a novel cavity implementation of the Raman memory which reduces the FWM contribution relative to the signal field by re-distributing the density of states into which the noise photons can be scattered. Cavity-enhanced memory operation was investigated using weak coherent input states, showing a significant improvement of the signal-to-noise ratio compared to the free-space memory implementation. This proof-of-principle demonstration suggests that cavity Raman memories may offer a practical route towards low-noise, high-bandwidth quantum storage at room temperature.

Keywords: Quantum memory
Temporal multiplexing for photonic quantum information processing
Advisor: Walmsley, I
The role of rest and stress cardiac energy metabolism and ectopic lipid deposition in diabetic cardiomyopathy

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of heart failure and cardiovascular mortality even in the absence of coronary artery disease. Although the reasons for this are not clear, impaired cardiac high energy phosphate metabolism, coronary microvascular dysfunction and ectopic lipid deposition have emerged among the candidate mechanisms. Cardiac magnetic resonance imaging (CMR) and magnetic resonance spectroscopy (MRS) are powerful tools to characterise these conditions.
The findings here suggest that, in diabetes, coronary microvascular dysfunction may potentially exacerbate derangement of cardiac energetics under conditions of increased workload. The relationships amongst ectopic adiposity (myocardial, epicardial and hepatic), myocardial metabolic changes and left ventricular remodelling in T2DM were determined using proton magnetic resonance spectroscopy (1H-MRS), cardiac computer tomography (CT) and multi-parametric liver MR. It was found that cardiac steatosis independently predicted left ventricular concentric remodelling and impairment of systolic strain in patients with T2DM. This work also demonstrated that ectopic adiposity is linked to insulin resistance, liver fibrosis and inflammation, and cardiac contractile dysfunction in diabetes, and that the coexistence of obesity and T2DM leads to higher epicardial fat volumes and significant non-alcoholic fatty liver disease compared to T2DM alone. These findings suggest that, since cardiac steatosis and ectopic adiposity are modifiable, strategies aimed at reducing myocardial triglyceride levels may reverse concentric remodelling and improve contractile function in the diabetic heart. The work on field strength effects on cardiac 31P-MRS has shown that 7T is feasible and reliable with reduced error and increased signal to noise compared to 3T.
In summary, the work in this thesis demonstrates the powerful role of CMR and MRS in elucidating the detrimental effects that originate from the metabolic abnormalities in the diabetic heart.

Advisor: Clarke, K
Neubauer, S