VictorJuiz/thesis huggingface dataset:
Sterile activation of invariant natural killer T cells by ER-stressed antigen presenting cells
Keywords: cancer
ER-stress
iNKT cells

Invariant NKT (iNKT) cells are a subset of innate-like lymphocytes that recognize lipid antigen presented on monomorphic CD1d molecules. These cells have the unique ability to shape immunity during anti-tumour immune responses and other forms of sterile and non-sterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and non-sterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Given that ER-stress is prevalent during tumourigenesis coupled with the intersection between the ER-stress pathways and lipid metabolism, we hypothesized that ER-stressed CD1d+ cells might present immunogenic self-lipid(s) on CD1d molecules to activate iNKT cells in sterile conditions. We demonstrate that ER-stressed dendritic cells activated iNKT cells in a CD1d-dependent manner, which in turn promotes dendritic cell maturation. We illustrate that PERK signalling increases CD1d-mediated presentation of immunogenic endogenous lipid species. We demonstrate that the immunogenic self-lipid(s) are likely ceramide-based and loaded onto CD1d in the endosomal/lysosomal compartments. We also investigate the relevance of this mechanism in a human tumour setting by analysing iNKT cell responses to multiple myeloma cell lines and identifying ER-stressed myeloid cells in the tumour microenvironment. In conclusion, this work defines a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation, with a potential role in human health and disease.
Enantioselective desymmetrisation towards the synthesis of daphniphyllum alkaloids
Keywords: Asymmetric catalysis
Dual catalysis
Organocatalysis
Natural product synthesis
Alkaloids
Enantioselective desymmetrisation
Total synthesis

Chapter One introduces the Daphniphyllum alkaloids and the Calyciphylline A- type alkaloid sub-family, including proposed biosyntheses and recently reported total syntheses. The morphan core is introduced, and methods for its synthesis are dis- cussed, with a focus on enantioselective desymmetrising cyclisations.
Chapter Two details the development of a Pd(II)/secondary amine co-catalysed desymmetrising cyclisation for the enantioselective synthesis of the morphan core. The method addresses several limitations of previous methods, and provides access to a broad range of products including trisubstituted alkenes.
Chapter Three details the preparative synthesis of the morphan core via an enantioselective desymmetrisation reaction on up to 20 g scale. Functionalisation of the bicyclic core is discussed, including a diastereoselective hydrogenation to afford the desired stereochemical configuration.
Chapter Four describes the synthesis of the tetracyclic core common to many Daphniphyllum alkaloids. An intramolecular Michael addition reaction is used to form the five-membered lactam, while the seven-membered ring is constructed by ring closing metathesis.
Chapter Five details a range of synthetic strategies investigated in an attempt to construct the pentacyclic core of the Calyciphylline A-type alkaloids in an effort to achieve a total synthesis. Some of the key approaches investigated include an aldol condensation, a 5-endo-dig cyclisation, and a [3+2] cycloaddition.
Biodegradable pulsatile release technologies for viral vector based vaccinations
Keywords: malaria
viral vectors
microparticles
vaccines
biodegradable

Vaccines are arguably the greatest public health intervention of modern era medicine. Most vaccines, in order to be effective require multiple doses. This is disadvantageous as there is an increasing trend towards non-compliance with subsequent doses. Viral vectored vaccines represent arguably the next generation of vaccines but they too often require a heterologous prime-boost approach such as the use of Adenoviral-MVA vectors. This thesis describes work utilising biodegradable microparticulate and non-microparticulate technologies to attempt to transform vaccination regimes from multiple into one single injection. Both technologies were tested using the heterologous Adenoviral-MVA prime-boost regime. A novel and virus-tailored encapsulation using the solvent triacetin and qPCR-based quantification methodology is proposed for the microencapsulation of MVA virus in biodegradable PLGA or PLA microparticles. Immunogenicity studies comparing routine prime-boost using 2 injections compared to single-dose administration of soluble Adenovirus with encapsulated MVA virus in PLA microparticles, showed comparable immune responses after 8 weeks. However true pulsatile release kinetic based on T-cell and antibody response kinetics was not observed. When experimentally tested with malarial sporozoite challenge the same formulation failed to provide comparable protective immune responses with a single immunisation after 5 weeks. Further work is still required to manufacture more uniform and reproducible formulations. This work is a significant improvement in the field of viral vector encapsulation in solid polymeric matrices, which could benefit not only human vaccination but also veterinary, including fish vaccination, improving quality of life, reducing public health costs and ultimately saving more lives.
Evaluating the effects of dengue virus and  iminosugar treatment on  cellular unfolded protein response  and redox homeostasis
Keywords: unfolded protein response
iminosugars
dengue virus

Dengue virus (DENV) infections cause significant morbidity worldwide. The complex host-viral interactions affecting viral replication and the host immune response result in variable disease severity in affected individuals. This thesis focuses on two such host responses implicated in DENV pathogenesis; unfolded protein response (UPR) and oxidative stress. DENV preferentially activated the proviral and pro-inflammatory IRE1-XBP1 arm of the UPR in monocyte-derived macrophages in vitro. Investigation of redox homeostasis revealed induction of reactive oxygen species and increase in total antioxidant capacity in DENV- infected macrophages. Further evaluation of peripheral blood mononuclear cells during early DENV-infection revealed increased XBP1s and reduced DDIT3 and HSPA5 transcripts in affected individuals who later developed severe dengue disease. Proteomics performed on the cell lysates revealed upregulation of the IRE1-mediated UPR pathway and differential expression of several protein markers in individuals who developed severe disease compared to non-severe disease potentially providing a foundation to develop markers of DENV disease severity.
Iminosugars are broad spectrum antivirals targeting host ER glucosidases causing antiviral effects against DENV. The effects of iminosugars have not previously been studied in DENV-infected dendritic cells. The percentage of infected cells and secretion of DENV were reduced in dendritic cells treated with three DNJ-derived iminosugars in a dose-dependent manner. The specific infectivity was reduced at iminosugar doses exceeding 3.16 M which inhibited -glucosidase I. Furthermore, DENV-induced TNF levels were reduced with iminosugar treatment. Evaluation of the UPR in DENV-infected and 2THO-DNJ treated macrophages revealed a reduction in XBP1s levels compared to untreated cells and an increase in EDEM1 and ERDJ4 transcripts. However, the UPR was not required for the antiviral or anti-inflammatory effects of the iminosugar 2THO-DNJ. ROS levels and antioxidant capacity were also reduced in DENV-infected macrophages following treatment with 2THO-DNJ and MON-DNJ.
Overall, this thesis describes the role of the UPR and oxidative stress in DENV infection and the effect of iminosugars on these host responses.
General Dental Practitioners’ knowledge encounters: how do dentists build their knowledge-in-practice?
Keywords: Systematic review
Video ethnography
Qualitative
Interviews
General Dental Practice
Faceted classification
Bliss Bibliographic Classification
Practice knowledge
Dentistry
Mixed methods
knowing in practice
Observation

Evidence-based practice suggested that, to deliver good clinical care, clinicians should consult up to date clinical research whilst drawing on their own expertise and experience and the values and aspirations of patients. Despite there being a large interest in generating more robust research evidence and finding ways to disseminate it, there has been relatively little research interest in the moment-to-moment practice it is intended to be incorporated into. John Gabbay and Andrée Le May theorised that the work of good general practitioners was guided by internal, tacit, socially reinforced mindlines. The organisational literature developed concepts of practice as a provisional, ephemeral and socio-material accomplishment. This thesis was inspired by these works to explore the complexity of knowing and interaction when practising as a healthcare professional and, specifically, as a general dental practitioner. It reviews the development of the concept of practice before reporting on three studies: a mixed studies systematic review of how healthcare professionals encounter information and experiences; a mixed methods study of the sources of information and experience GDPs use; and a video-ethnographic study of how knowing in practice arises in clinical encounters in general dental practice. Together, these studies show how knowing in practice arises as GDPs, patients, nurses and things interact in time and space; how the GDPs’ performances in these practices are generated from their embodied and in-the-moment knowing; and how diverse the sources of knowing are that healthcare professionals interact with in developing their ostensive and performative knowing. The thesis discusses the implications of taking a more practice-orientated approach to how we think about quality improvement in general dental practice and professional learning generally.
Border contagion: transit migration from the Mediterranean to the Atlantic c. 1860-1914
Keywords: Border controls
Transit migration
Mediterranean
Transatlantic migration
Borders

My thesis looks at transit migration from the Mediterranean to the Atlantic in the late nineteenth and early twentieth centuries. I follow the development of both the legal and illegal trade in order to account for the persistence of clandestine flows despite the liberalisation of emigration, with the removal of bans on exit in emigration countries and the transition to the bureaucratic regulation of migration flows. This includes examining not only the causes behind clandestine migration, but also the ways in which clandestinity was legislated for, policed, classified and ultimately archived. Documentary checks on identity are thus considered alongside migration laws, the policing of emigration agents, the regulation of the hospitality industry in ports of transits, controls at embarkation and sanitary policy. Its chronology extends from the beginning of mass transatlantic migration from the Mediterranean, starting in the 1870s and 1880s, until the outbreak of World War One, which saw a sudden decrease in migration from Europe (including the Mediterranean) to the Americas and the hardening of migration controls in both countries of origin and arrival for the purpose of conscription and defence. This time arc was punctuated by various crises in migration control, resulting from a number of factors, such as disease epidemics or the feverish spread of propaganda. Although the thesis takes a comparative and interactionist approach to Mediterranean transit flows, ranging from the Ottoman empire and Greece in the east to the Levant in the south and Italy in the west, it focuses primarily on the ‘western transit corridor’ that linked the port cities of Beirut, Naples and Marseilles.
An investigation of relaxor ferromagnets
Keywords: Magnetism
Solid-state Chemistry

Q–dependent diffuse scattering was observed at low angles in a neutron diffraction experiment performed on the relaxor ferromagnet La3Ni2SbO9 using a spin–polarised beam. The nuclear component could be modelled using direct Monte–Carlo methods if it was assumed that short (~5.5 Å) Sb–Sb contacts were energetically disfavoured. The magnetic component of the diffuse scattering at 110 K (TC = 108 K) was analysed using both direct and reverse Monte–Carlo techniques. When antiferromagnetic nearest–neighbour coupling was assumed to be dominant in this perovskite, second neighbour coupling was found to be weak but non–zero with third–neighbour coupling being negligible. The short–range structural and magnetic orderings were found to have correlation lengths of 15 and 9 Å, respectively.
The consequences of replacing d10 Sb5+ by d0 pentavalent cations were investigated; all the compounds reported are isostructural with La3Ni2SbO9. La3Ni2TaO9 was found to be a relaxor ferromagnet but La3Ni2NbO9 behaved as a spin glass below 35 K. Solid solutions La3Ni2SbxTayNb1–x–yO9 were synthesised and characterised. It was again shown that the relaxor behaviour is incompatible with the presence of Nb5+ in the system. In contrast, doping La3Ni2B’O9 (B’ = Sb, Ta or Nb) with Cu2+ cations was found to increase TC and the bulk magnetisation. For example, La3Ni1.75Cu0.25NbO9 exhibits ferrimagnetic behaviour below ~90 K with the development of long–range G–type magnetic ordering. It is proposed that relaxor regions and long–range ordered regions coexist in this system.
The sensitivity of cation ordering, and hence magnetic behaviour, to the charge difference between Ni2+ and the diamagnetic six–coordinate cation was studied by replacing Sb5+ by Te6+ or W6+. Electron microscopy revealed a significant level of cation disorder in a severely–twinned sample of SrLa2Ni2TeO9; spin–glass and antiferromagnetic phases coexist below 35 K. The Ni2+ cations in CaLn2Ni2WO9 (Ln = La, Pr or Nd) form a spin glass, although the behaviour of each composition reflects the magnetic properties of Ln3+.
Automated analysis of system-wide malware propagation
Keywords: Program analysis
Security
Taint analysis
Malware
Reverse engineering

In contrast to most benign applications, malware infects its host system. It does so via system-wide execution by injecting code into otherwise benign applications, executing via code-reuse attacks, dynamically generating code and much more. These unconventional, albeit perfectly valid, execution paradigms are used for evasion and obfuscation tactics and pose significant problems to automatic malware analysis environments.
In this thesis, we investigate the problem of system-wide malware execution. We focus on building general and precise techniques to analyse malware that execute throughout the entire system. To demonstrate our techniques, we implement them as part of a malware analysis system called Minerva. We use Minerva to perform extensive empirical studies based on synthetic benchmarks that explore corner-case behaviours as well as real-world malware samples collected from the wild.
The core idea behind our techniques is to analyse system-wide malware execution with a bottom-up approach. To this end, we develop a fundamental technique for capturing the system-wide execution trace of a given malware sample that is independent of the techniques malware use to propagate through the system. We then incrementally build abstractions upon this trace to identify code injections, malware droppers, code-reuse attacks, packed malware and more.
In the final part of our thesis, we extend Minerva with several capabilities to perform large-scale studies. We use these features to characterise system-wide malware propagation at large and extract many interesting high-level views on malware based on our precise and general analysis.
Ricci flow in Milnor frames
Keywords: Partial differential equations
Geometric flows

In this work, we are going to find sufficient conditions on the initial metric on some 4-dimensional manifolds foliated by homogeneous S3 for a Type I singularity to occur when it is flowed under the Ricci flow. This work generalises the study on rotationally symmetric manifolds done by Angenent and Isenberg as well as the work of Isenberg, Knopf, and Sesum, in which they introduced some ansatz for the problem setup. In the latter study, a global frame for the tangent bundle called the Milnor frame was used to set up the problem. We begin with some discussions on the symmetries of the manifold and its ansatz metric derived from Lie groups as well as the global tangent bundle frame developed by Milnor. The curvature quantities and the Ricci flow equation of this ansatz metric will then be explicitly computed. Numerical simulations of the Ricci flow on these manifolds are done, which provides insight and conjectures for the main problems. Some analytic results will be proven for the manifolds S1xS3 and S4 using maximum principles from parabolic PDE theory and sufficiency conditions for a neckpinch singularity will be provided. Finally, a problem from general relativity with similar metric symmetries but endowed on manifolds homeomorphic to CPM2\B4 and B4 will be discussed, which will provide a possible direction for future work.
Home data security decisions
Keywords: Security design
Security
Decision making
Security behaviour
Usable security
Grounded Theory

The most common solution to securing data in the home remains increased awareness. However, studies and increasing numbers of cyberattacks targeting the home point to very limited success of this intervention. Awareness campaigns can lead to information overload, do not impart security skills, implicitly assume that every home user is an administrator, and are largely ignorant of the specific context of the user. Unfortunately, little research has been done to understand the home user, the home context, and related security practices in order to inform the design of appropriate security interventions. A more grounded understanding of the home and security practices therein is required to address this gap.
The research presented in this dissertation focuses on understanding security practices in the home, and how they can inform the design of appropriate security technology to support such practices. The work was conducted in three steps: (a) empirical exploration of security support behaviours and factors that influence the outcome of security decisions in the home through 65 semi-structured interviews followed by a survey of 1128 UK participants; (b) development of a framework to guide the design of security technology for the home; and (c) a case study demonstrating applicability of the framework to the design of a network security toolkit for the home.
Grounded Theory was applied to analyse data from the interviews focussing on understanding security support behaviours. Thematic Analysis was also used to analyse the interview data to identify important concepts for understanding the security context in the home and factors that influence security decisions. Data from the survey was analysed using descriptive and inferential statistics to validate the previous qualitative results. Key findings include evidence of: (1) social networks serving as informal support networks in home security; (2) perceived competence being used to evaluate the quality of security support sources and work; and (3) visibility of harm influencing security decisions.
From this research, we propose the Home-Appropriate Network and Digital Security (HANDS) framework: a data-driven descriptive framework that enables designers of home technology to ground their design decisions in relevant contextual information. We demonstrate its application in a Case Study designing a network security toolkit for the home. The design was evaluated through 4 focus groups of 3 participants each, followed by a survey involving 616 UK participants. Thematic analysis was used to analyse data from the focus groups, while descriptive and inferential statistics were applied to analyse the quantitative data.
A study of stellar populations in the last 5 billion years using Integral Field Spectroscopy
Keywords: Integral Field Spectrogphy
Galaxy Quenching
Initial Mass Function
Galaxy Formatiom
Galaxy Evolution
Galaxy Environment
Stellar Populations

In this thesis, I study the properties of quiescent and star-forming galaxies with integral field spectroscopy. The study of quiescent galaxies focuses on inferring the low-mass end of the stellar initial mass function (IMF). To accomplish this, we make spatially resolved measurements of a number of “gravity-sensitive” absorption features in the spectra of three nearby early-type galaxies. These vary in strength between otherwise identical (low-mass) dwarf and giant stars, allowing for measurement of the dwarf-to-giant ratio and hence the low-mass IMF.
In NGC 1277 and IC 843, I use the Oxford SWIFT instrument to study the variation of these features as a function of radius. I find strong gradients in NaI0.82 absorption but flat FeH0.99 profiles in both cases, although the data cannot distinguish between chemical abundance gradients or a gradient in the IMF being the cause. I then fit models to the integrated spectrum of each galaxy, finding an IMF slope of x = 2.27±0.17 IC 843 and x = 2.69±0.11 in NGC 1277. Next, I use MUSE to make quantitative inferences about an IMF gradient in NGC 1399. I use full spectral fitting in 18 annular bins to measure a super-Salpeter IMF slope in the galaxy’s centre, which is radially constant out to 0.7 effective radii before becoming consistent with a Milky-Way IMF at Re. These findings add weight to the theory of a two-stage formation process for massive elliptical galaxies.
I then introduce K-CLASH, which uses KMOS to observe star-forming galaxies in four galaxy clusters from the CLASH survey. I describe the observations, data reduction and analysis process, and present a novel probabilistic method of determining whether a target resides in a cluster or field environment. I compare and contrast the properties of field and cluster galaxies, finding that the cluster sample follow a star-formation rate “Main Sequence” relation which is offset to smaller SFR by 0.18 dex. Furthermore, I measure the size of galaxies in optical light and Hα emission and find the average ratio r50Hα/r50Rc to be significantly smaller in cluster galaxies than in the field comparison sample. I find no significant differences in ISM conditions. These observations are evidence for environmental reduction of star-formation, al- though deeper observations are required to discriminate between a global effect (due to ISM heating) or outside-in processes (such as ram-pressure stripping).