VictorJuiz/thesis huggingface dataset:
The role of seminal fluid extracellular vesicles in human endometrial receptivity

Embryo implantation is a key limiting factor to In Vitro Fertilization (IVF) success, the main treatment of subfertility. A successful embryo implantation requires the endometrium to be receptive, which involves embryo-endometrium crosstalk, decidualisation, and modulation of the maternal immune system. Research data showed maternal exposure to seminal fluid improved clinical pregnancy rates. The seminal fluid contains extracellular vesicles that facilitate cell-cell communication through their cargo. This thesis aimed to investigate seminal fluid extracellular vesicles (SF-EVs) and their role in human endometrial receptivity.
SF-EVs, isolated by ultracentrifugation, were characterised and purified using size- exclusion chromatography. SF-EVs ranged between 15 to 300 nm and were a heterogenous group of EVs. Four populations were described based upon morphology while protein expression identified three CD63+ SF-EV populations and suggested another four populations by co-localization and correlation studies respectively. Importantly, purified SF-EVs were demonstrated to be a good representation of physiological SF-EVs after analysing extracellular vesicles in unprocessed seminal fluid.
The role of SF-EVs in endometrial receptivity was then investigated. Bio-maleimide labelled SF-EVs bound to Ishikawa cells (endometrial adenocarcinoma cell line) and primary endometrial epithelial and stromal cells. SF-EVs bound more to untreated than progesterone treated Ishikawa cells, and, unlike previously described for progesterone- treated cells, SF-EVs did not induce dephosphorylation of CREB S133 in untreated Ishikawa cells. In addition, SF-EVs enhanced endometrial stromal cells secretion of prolactin throughout the days of decidualisation and increased total HCK Tyr411 phosphorylation in non-decidualised stromal cells. Bio-maleimide labelled SF-EVs also bound to primary endometrial immune cells. CD4+ and CD8+ T cells bound more SF-EVs than NK cells and regulatory CD4+ T (Treg) cells showed higher SF-EV binding than non-regulatory CD4+ T cells. SF-EVs did not change CD3 and CD25 Treg cell expression levels, which are involved in T cell receptor (TCR) mediated activation. Endometrial Treg cells also did not increase TGF-β1 expression after TCR mediated activation.
These DPhil thesis reports for the first time that SF-EVs interact with endometrial cells and play a role in endometrial receptivity suggesting they might be used as adjuvants to assist human embryo implantation in IVF. It also highlights the need for further research to understand endometrial Treg cellular physiology.

Advisor: Granne, I
Southcombe, J
Tropical-extratropical teleconnections and atmospheric drivers of European drought events

Atmospheric dynamics are important in tropical-extratropical teleconnections. Using maximum covariance analysis (MCA), we investigate the leading modes of covariability between the tropical outgoing longwave radiation and the extratropical geopotential height. Using observed data, the leading mode of covariability on the seasonal timescale is associated with the El-Ni~no Southern Oscillation. Using a Met Office climate model (GC3) control run, although the leading tropical mode is still ENSO, the extratropical pattern shows large differences in the North Pacific-American region.
GC3 has a large North Pacific jet bias, which according to ray tracing can affect wave propagations from the tropics. Using a barotropic model with the same ENSO tropical forcing but linearized upon the different basic states of reanalysis and GC3, the largest differences in the response are in the North Pacific-American region and agree with the MCA differences. The result is also supported by baroclinic experiments. Our finding may contribute to resolving the signal-tonoise paradox in some climate predictions.
Next, we test the mechanism of influence from the tropics to European droughts, to find potential tropical drivers of Rossby waves that are consistent between observations and the idealized models. We identify a northward shift in the tropical Atlantic precipitation and a weakening of the tropical eastern Pacific precipitation, which significantly influence about 60% of European drought events.

Keywords: Teleconnections
Advisor: Woollings, T
Investigation of nanoscopic dynamics and potentials by interferometric scattering microscopy

The advent of single-particle tracking and super-resolution imaging techniques have brought forth a revolution in the field of single-molecule optical microscopy. This thesis details the development and subsequent implementation of the technique known as interferometric scattering microscopy as a novel single-molecule tool to study nanoscopic dynamics and their underlying potentials. Specifically, Chapter 2 lays out the theoretical framework and draws comparisons between this technique and other state-of-the-art single-molecule optical approaches. Chapter 3 provides a detailed description for the design and implementation of an interferometric scattering microscope including alignment, instrumentation, hardware interfacing, image processing and respective characterisation to achieve the highest levels of performance. The following two chapters use model systems, namely the diffusion of receptor GM1 in a supported lipid bilayer and the movement of molecular motor myosin 5a, to demonstrate the intrinsic shot-noise limited nature of the technique, its ability to decouple the temporal resolution from localisation precision, and highlight the importance of taking both parameters into consideration when drawing conclusions about the dynamics of each model system. Chapter 6 provides a proof-of-concept study on the limits of sensitivity and demonstrates for the first time the all-optical label-free imaging, detection and tracking of a single protein. In the last chapter, interferometric scattering microscopy is used to quantitatively study dynamic heterogeneous systems in situ at the single particle level and thus serves as a proof of principle for future label-free studies beyond the realms of biophysics.

Keywords: single-molecule microscopy
interferometric microscopy
myosin 5a
label-free detection
single particle tracking
Advisor: Kukura, P
Assessment and optimisation of the pancreas allograft

Background
In this thesis, I have sought to improve the understanding of how pancreases are assessed with a particular focus on organ steatosis and allograft pancreatitis. Whole organ pancreas transplantation is a transformative treatment option, but despite the benefits since its inception, little evolution has been made tackling the change in donor habitus. With continued high morbidity and falling rates of referral, pancreas transplantation remains a niche treatment rather than a mainstay for patients with diabetes.
Aim
The key aim of the thesis is to assess current trends in pancreas organ utilisation nationally, and see how these compare with other international programs. I have started off by identifying areas of optimisation and considering factors that may be relevant, and I have then applied particular focus on assessment in regards to pancreas steatosis and associated allograft pancreatitis, thereafter focusing on how better to assess and optimise patients with this morbidity.
Results
• Lack of pancreases is not the primary issue when considering utility. Assessment of fatty pancreases in the context of organ steatosis is a key factor in the decision-making process with a very high percentage of donor organs assessed as unfit for purpose.
• Pancreas steatosis is common, heterogeneous and focal, with the use of MRI being quantitative and potentially clinically useful.
• Allograft pancreatitis is a common morbidity with an incidence of 44%. Day 5 CRP appears to be a suitable surrogate marker, with alternative methods of assessment also possible with further work (FACBC and glutathione).
• Inflammatory patterns suggest allograft pancreatitis may be a distinct process to native pancreatitis with classical monocytes and macrophages playing an important role.
Conclusion
Current donor utilisation and methods of assessment are imprecise, in particular, the causal associations between pancreas steatosis and the adverse outcome remains unproven. The need to minimise postoperative morbidity has clear merit with early organ dysfunction, due to allograft pancreatitis being shown to be associated with long-term graft loss. There is a clear clinical need to identify and test strategies that abrogate early graft inflammation in order to improve outcome.

Advisor: Ploeg, R
Sharples, E
"They won't let us starve but they won't let us live": the politics of hunger and aid dependence in Malawi

The importance of aid to economic, social and political development has been widely debated. Arguments have tended to focus either on the question of aid effectiveness or the political effects of aid. This thesis seeks primarily to contribute to the question of the political impact of aid on relationships of representation and interactions between citizens and the state; but it also demonstrates the importance of the politics of aid to its effectiveness. I take the literature on aid and politics as my starting point, which focuses on the interactions between donors and governments and the manner in which these undermine political sovereignty (Whitfield 2009; Abrahamsen 2000; Williams and Young 2012). This literature conceptualises aid interactions as taking place around a negotiating table or in the state’s bureaucracy, within a ‘sovereign frontier’ (Harrison 2007).
Using Malawi’s agricultural sector – a politically important sector in a heavily aid-dependent country – as my case study, I build on this literature in two ways. Firstly, I contend that developments in aid modalities and donors’ efforts to restructure the Malawian state have resulted in more substantive infringements of sovereignty than previously argued. Donors have become constitutive of domestic politics. Aid negotiations and resistance to conditionalities now occur at all levels of the state and within domestic political systems. Thus, resistance to aid conditionalities, formal and informal, has shifted from the bureaucratic into the political realm, where it has frequently become the prerogative of the executive. Secondly, in order to fully appreciate the effects of aid dependence, primarily how it alters everyday interactions between citizens and the state, studying down the state is imperative. Here, aid dependence has profound effects on state-society relationships and political representation in Malawi, thereby preventing a move towards more responsive policy-making and away from patronage.

Advisor: Alexander, J
Graphene tunnel junctions for nanoelectronics and biosensing: intrinsic electronic noise and response to environmental factors

This thesis is concerned with the investigation of Graphene Tunnel Junctions (GTJs) and their applications. GTJs are fabricated by feedback-controlled electroburning, which results in the controllable formation of nanometric tunnelling gaps. Tunnelling currents have been widely used to study electron transport through single molecules, however the scope of their practical applications remains limited.
The main aim of this thesis is to assess the feasibility of the use of GTJs for biosensing. The first research chapter summarises the results demonstrating that GTJs are highly sensitive to their local electrostatic environment. Under cryogenic conditions with reduced perturbations from the environment, the devices are used to study the dynamics of nearby charge traps. Measurements show features of Two Level Fluctuation and Lorentzian Noise. This verifies that in optimum situation the junctions are capable of detecting single electron dynamics.
The second research chapter describes the emergence of 1=f noise resulting from the superposition of fluctuators upon the increase of temperature. This chapter also presents the impact of noise on the measurement sensitivity and resulting limits of detectable sensing signals on the order of 1-10 nA. In the next chapter the impact of a liquid environment is studied. Water polarisation effects at graphene-water interface lead to decreased current levels due to electrostatic screening, and to increased noise due to molecular fluctuations.
Next, the viability of biosensing using GTJs is demonstrated by the detection of single nucleotides at nM concentrations in water solutions. The detection of deoxy-guanine and thymine triphosphates moving around junctions due to Brownian motion is demonstrated, with specifc tunnelling current spikes in the range of 1-100 nA.
Finally, I present an outlook on the development of GTJ sensing devices, including the fabrication protocol and device geometry of suspended GTJs capable of sequencing linear DNA strands. Furthermore local side-gate devices with enhanced sensing performance are proposed.

Keywords: Graphene nanodevices
Advisor: Mol, J
Briggs, A
The social and cultural conception of space in early modern European utopias

This research attempts a new analysis of the early modern utopianism’s space based on the Ptolemaic tripartite division of space into geos, topos and choros. This study unfolds through a selection of sources that represent the various patterns and the diversity of the uses of space not only in early modern utopian literature but also in intentional communities and colonial projects of the period. In the beginning, it examines the association of utopia with the newly discovered lands of the Americas and the Terra Australis and how the existence of these ‘empty’ in the eyes of the Europeans spaces gave new impetus to dreams for an alternative, better society. It then proceeds to an examination of the complex relationship that various expressions of utopianism had with the geographical space and natural environment underlining how their differences are manifested in their perception of nature. Additionally, based on the Ptolemaic cartographic practices, this thesis provides an overview of utopian space that, illuminates the different functions it fulfilled in early modern visions of ideal societies, thus highlighting the importance that was given to space for providing solutions to the various problems that the period’s European societies faced. Hence, moving away from the traditional view that understands utopian space as unimaginative, symbolic and static and this thesis emphasises how realistic the utopian space was and how important this element was for the articulation of realistic alternative political and social paradigms. For this reason, great care is given to understand and illuminate the open dialogue that early modern utopias maintained with the real world, through their mutual concern for the best possible utilisation of their space—a mutual dialogue that influenced various fields such as architecture and public health policies both in utopia and the real world.

Advisor: Iliffe, R
Use of patient-derived cellular models to investigate the mechanistic basis of circadian dysfunctions and chronomodulatory drugs in bipolar disorder

Bipolar disorder is a highly incapacitating neuropsychiatric disorder, where patients exhibit cycling episodes of mania and depression. In addition to these characteristics, sleep and circadian rhythm disruptions are frequently observed through changes in physiology and behaviour. Lithium treatment remains effective in inducing acute and long-term mood stabilisation, yet there is ambiguity as to how it exerts its therapeutic benefits. As lithium induces significant chronomodulatory effects, one possible mechanism may be via the alteration of circadian rhythms. Using virally transduced bipolar patient-derived fibroblasts, we investigated basal circadian rhythms, as well as the cellular responses to chronomodulatory agents in order to identify any aberrancies. We then went on to investigate the mechanism via which lithium induces its chronomodulatory effects.
The use of patient-derived fibroblasts revealed the presence of circadian abnormalities, manifesting as a broad distribution of period lengths. Further, patients with a longer period phenotype exhibited muted chronomodulatory changes following lithium treatment. These changes were not restricted to lithium and were also observed with two novel chronomodulators. Remarkably, these compounds also exhibited changes to circadian rhythms and displayed lithium-like behaviours in vivo, highlighting their translational potential. We subsequently went on to confirm that lithium inhibited two major receptor coupled systems: inositol monophosphatase and adenylate cyclase. Using immortalised cell lines, we showed that lithium induces period lengthening predominantly via perturbing the phosphoinositide pathway, which elevates expression of the transcription factor C/EBPα. Whilst we found that adenylate cyclase signalling plays a contributory but subordinate role in mediating period effects, such information may be vital in informing future drug discovery processes, as it could enable the identification of mechanistically novel mood- stabilisers with fewer undesirable side effects. Thus, in this DPhil thesis, we present data highlighting that patient-derived fibroblasts could be instrumental tools which could perpetuate the drug discovery process, and suggest that C/EBPα may be responsible for lithium-induced circadian period lengthening.

Keywords: circadian rhythms
fibroblasts
lithium
bipolar disorder
chronomodulation
Advisor: Vasudevan, S
A principled approach for engineering privacy by design

Privacy is a multi-faceted concept that has several aspects. It is subjective in nature, not least because it is influenced by a variety of factors, including societal demands, which evolve over time, and technological developments. With the advent of information technologies, legal frameworks and standards alone are not sufficient to preserve the privacy of data subjects. As a response, Privacy by Design (PbD) has emerged as a proactive approach for embedding privacy into the early stages of the design process. Challenges involved in engineering PbD include a lack of holistic methodologies that address the plurality and contextuality of privacy and support the translation of its principles into engineering activities. In this dissertation, we investigate various methods for engineering PbD that capture and address privacy issues in the early stages of the design process. We also investigate how to model the key aspects of abstract privacy principles stated in legal frameworks and standards to bridge the semantic gap between technical and normative concepts. This gives rise to the Abstract Personal Data Lifecycle (APDL) model, which serves as an abstract model for personal data lifecycles. We also define a UML profile for the APDL model to represent data-processing activities in a way that is amenable to risk analysis and compliance checking. In addition, we develop a privacy risk model that defines the main factors that have impacts on privacy risks along with their assessable attributes and conceptual relationships. Based on this, we develop analysis and assessment approaches that illustrate how combinations of these factors are analysed and used as inputs to assess the levels of risk. Furthermore, we characterise privacy protection as a quality attribute by means of a general quality attribute scenario to avoid non-operational or overlapping definitions. Based on this, we develop a tactical approach that identifies privacy architectural strategies as collections of tactics, which are described through design patterns, to support the adoption of Privacy-Enhancing Technologies (PETs), and to specify, implement and justify various levels of privacy protection. Together, these contributions give rise to a principled approach for engineering PbD that captures privacy concerns in a comprehensive manner; addresses these concerns at an architectural level; and reasons about the compliance of architectural choices with legal frameworks and standards. It is aided by techniques and tools, which provide procedures with a prescribed language and notation, to accomplish its activities.

Advisor: Simpson, A
The resurrection of Durga: Indira Gandhi's spectacular politics in the 1980s

The cult of personality around Prime Minister Indira Gandhi has traditionally been explained with reference to her role in the Bangladesh War, the Emergency, and Operation Blue Star. Moreover, historiographical narratives woven around these episodes largely portray her as a champion of ‘socialism’ and the poor. Going beyond these characterisations, this thesis is organised around four ‘state spectacles’ that captured Indian middle class imagination in the early 1980s – the Asian Games in New Delhi (1982), the launch of the Maruti-Suzuki ‘family car’ (1983), the Festival of India in Britain (1982), and the Non-Aligned Movement Summit in New Delhi (1983). The production and reception of these spectacles is analysed against the context of the Emergency imposed by Mrs Gandhi in 1975. During this period, public opinion swayed against the incumbent Congress Party and Mrs Gandhi, who was consequently ousted in the 1977 elections.
In certain ways, Mrs Gandhi’s ‘political resurrection’ in January 1980 reaffirmed her position as a popular national leader. However, she was conscious of the fragility of her dominance, and her dented image in public and the media. The primary objective of this thesis is to examine how Mrs Gandhi, through the visual medium of the ‘spectacle’, sought to remake her image from a ‘dictator’ of the Emergency days to a symbol of stability, aspirations, and national pride upon re-election. Additionally, it questions the success of this political project by turning its gaze toward the spectator-consumer – in this case a pre-liberalisation, urban middle class in India.
Consulting a range of textual and visual archives, the thesis argues that the above ‘mega-media-events’ and their carefully constructed associations with consumption, leisure, and entertainment enabled Mrs Gandhi to secure legitimacy amongst established and emerging categories of the middle class in India. In doing so, it seeks to portray another dimension of Mrs Gandhi’s constructed image as a leader of this influential demographic in ‘the long 1980s’, a period which brought enduring shifts in the Indian socio-economic landscape a full decade before the era of liberalisation.

Keywords: state spectacle
middle class
political performance
consumption
liberalisation
Indira Gandhi
Advisor: Devji, F