VictorJuiz/thesis huggingface dataset:
Responsive theranostic nanoparticles
Keywords: nanomaterials
chemistry

The development and use of nanotechnology towards theranostics (all-in-one disease diagnostics and therapeutic delivery) have been increasing in popularity in recent years, in particular the use of high capacity of nanomaterials to transport both imaging and therapeutic agents into pathological tissues or abnormal cells. In this work, biocompatible mesoporous silica nanoparticles (MSNs) that can be reliably endocytosed by cells are employed in the investigation of novel cancer treatment and magnetic resonance imaging (MRI). One of the principal aims is to develop T1 contrast nanoparticles not only with extraordinarily high MRI contrast characteristics, but also tunability through surface chemistry and functional protein conjugation. In coupling paramagnetic Gd3+-centres to MSNs, one can effectively marry the advantages afforded by increased molecular bulk with those engendered by confined water environment inside the porous network. Specifically, through exclusively biasing paramagnetic Gd3+-centres in the internal spaces of nanoparticles, their mobility and interaction with water protons can be altered, significantly, with beneficial changes in molecular tumbling (τR), proton exchange (τM) and water diffusion (τD) within relaxation dynamics. These MRI nanoparticles with internalised Gd3+-centres are additionally used in the development of tunable/responsive contrast agents through vectoring protein conjugation. The relaxivity of MSNs can be tailored depending on the separation distances between proteins and nanoparticles; significantly, the simultaneous retention of both high MRI contrast and protein vectoring is achieved by the insertion of long polyethylene glycol (PEG) chain. The image contrast can also be reversibly gated through the competitive displacement of surface proteins by their partner proteins. Specifically, these responsive nanoparticles possess a low contrast resulting from restricted water accessibility when protein moieties are conjugated on the particles, whereas the removal of proteins causes a transition of contrast from a low to high state. The MSNs synthesised in this work are used not only in diagnostic imaging but also in the delivery of therapeutic agents for cancer therapy. The agents can be either physically encapsulated inside the pores or chemically conjugated on the nanoparticles. For the former, their loading and release efficiencies are tunable by the electrostatic interactions with particle surface functional groups; while in the latter case, their retention on nanoparticles, as opposed to being released, plays an important role in the effectiveness of cancer treatment that is achieved by trigging programmed cell death (apoptosis) in this work. This nanoparticle conjugation secures the proteins’ activity by facilitating their bypass of proteolytic degradation. Significantly, specially designed nanoparticles that demonstrate endo/lysosomal escape capability can reliably deliver therapeutic cytochrome c to cell cytosols for the initiation of a caspase cascade within apoptosis with high efficacy.
Antigenic variation and its evolution in P. falciparum malaria
Keywords: Plasmodium falciparum
malaria
PfEMP1
var genes
antigenic variation

This thesis investigates antigenic variation and its evolution in Plasmodium falciparum, the cause of the most deadly form of human malaria. Antigenic variation is a strategy for evading immunity by switching between antigenic variants during infection. In P. falciparum, such variable antigens confer different binding phenotypes that may affect parasite survival and have also been linked to pathology. Here, a new statistical method is described for determining the switching patterns that underlie antigenic variation. This method is then applied to experimental data to yield a full description of an antigenic switching network in P. falciparum. In light of the findings, theoretical modelling is used to show how immune selection and binding phenotypes may have contributed to the evolution of antigenic repertoire structure, expression order and virulence. Related models are also used to investigate parasite population diversity, providing possible explanations for observations reported here and elsewhere, with implications for vaccine design. Together, these chapters advance understanding of P. falciparum immune evasion and how it relates to pathology. This work further reinforces the role of host immunity in shaping pathogen population diversity at multiple levels.
Rewriting community for a posthuman age in the works of Antoine Voloine, Michel Houellebecq, and Maurice G. Dantec
Keywords: Bernard Stiegler
Jean-Luc Nancy
Michel Houellebecq
Maurice G. Dantec
Late Capitalism
Antoine Volodine
Prosthetics
Posthuman
Globalisation
Technology and Literature
Community

The heterogeneous field of posthuman theory allows for an account of community under the convergence of late capitalism and high technology and its spread to a global scale. Spanning bioconservative fears of a potential loss of agency and a human ‘essence’ through advances in technology, ‘transhumanist’ hopes for a biological transformation that would fulfil liberal goals for human development, as well as postmodern, feminist interpretations of the posthuman as instantiating a liberating break with liberal ideology and patriarchal structures, theories of the posthuman offer a productive starting point for exploring the transformations in understandings of human subjectivity and community at the turn of the twenty-first century. Placing the concept of community against a background of past totalitarianism and a possible future of an uncontested globalised neoliberal regime that high technology risks intensifying, the present study enquires into the possibility of a community that would escape the metaphysical logic of mastery subtending both past and present models of community and suggests that problematizing representations of the creation of what a strand in contemporary philosophy terms a non-totalising ‘communauté désoeuvrée’ and implicit proposals not for the revival of community as a teleological ‘oeuvre’, but for its rewriting may be found in works by Maurice G. Dantec, Michel Houellebec, and Antoine Volodine, works which have been labelled posthuman themselves by virtue of their incorporation of posthuman themes or structures that come in the shape of representations and problematisations of high technology and its intersection with late capitalism and narrative structures that mimic or subvert conceptions of subjectivity that can loosely be termed posthuman. These novelists write in a context of an ideological, technological, and commercial constraint that hampers literary and political agency and which is problematized both implicitly and explicitly in the use these writers make of representations of violence and literary strategies such as irony, ambiguity, and hermeticism. These representations and strategies, it will be suggested, could be read as subtle attempts to bypass those constraints and restore the potential of literary production to comment on and even intervene in the creation of community in a posthuman age.
Reweighting methods in high dimensional regression
Keywords: statistical methodology
machine learning

In this thesis, we focus on the application of covariate reweighting with Lasso-style methods for regression in high dimensions, particularly where p ≥
n. We apply a particular focus to the case of sparse regression under a-priori grouping structures.
In such problems, even in the linear case, accurate estimation is difficult. Various authors have suggested ideas such as the Group Lasso and the Sparse Group Lasso, based on convex penalties, or alternatively methods like the Group Bridge, which rely on convergence under repetition to some local minimum of a concave penalised likelihood. We propose in this thesis a methodology that uses concave penalties to inspire a procedure whereupon we compute weights from an initial estimate, and then do a single second reweighted Lasso. This procedure -- the Co-adaptive Lasso -- obtains excellent results in empirical experiments, and we present some theoretical prediction and estimation error bounds.
Further, several extensions and variants of the procedure are discussed and studied. In particular, we propose a Lasso style method of doing additive isotonic regression in high dimensions, the Liso algorithm, and enhance it using the Co-adaptive methodology. We also propose a method of producing rules based regression estimates for high dimensional non-parametric regression, that often outperforms the current leading method, the RuleFit algorithm. We also discuss extensions involving robust statistics applied to weight computation, repeating the algorithm, and online computation.
The historical archaeology of post-medieval water supply in Oxfordshire
Keywords: Oxfordshire
water supply
historical archaeology

Surprisingly, clean mains water has only been universally available to the population of Oxfordshire since the second half of the 20th century. This thesis explores the different methods by which water was obtained between the end of the medieval period and the establishment of the contemporary water companies; it shows how archaeological remains can inform understanding of how different groups lived and interacted during that period. It attempts for the first time to catalogue water supply features within the county, having 910 entries to date. Patterns emerging from the data have been used to suggest themes for further study.
Statistics and GIS mapping have demonstrated that the availability and quality of water, including the incidence of early holy and healing wells, are dominated firstly by geology and then by differences between the social classes and between urban and rural areas. Themes explored include the relationship between water and disease, whether water supplies differ between ‘open’ and ‘closed’ parishes, the evolution of holy wells into spas, water in leisure activities, its association with memorials and changing attitudes to hygiene. The thesis also examines the various designation systems in place for protecting historic monuments, the level of recording of water features on local and national lists of monuments and how appropriate this framework is for helping the conservation of a valuable resource.
Cosmic ray backgrounds for dark matter indirect detection
Keywords: galactic cosmic rays
dark matter indirect detection

The identification of the relic particles which presumably constitute cold dark matter is a key challenge for astroparticle physics. Indirect methods for their detection using high energy astro- physical probes such as cosmic rays have been much discussed. In particular, recent ‘excesses’ in cosmic ray electron and positron fluxes, as well as in microwave sky maps, have been claimed to be due to the annihilation or decay of dark matter. In this thesis, we argue however that these signals are plagued by irreducible astrophysical backgrounds and show how plausible con- ventional physics can mimic the alleged dark matter signals.
In chapter 1, we review evidence of, and possible particle candidates for, cold dark matter, as well as our current understanding of galactic cosmic rays and the state-of-the-art in indirect detection. All other chapters contain original work, mainly based on the author’s journal publications. In particular, in chapter 2, we consider the possibility that the rise in the positron fraction observed by the PAMELA satellite is due to the production through (hadronic) cosmic ray spallation and subsequent acceleration of positrons, in the same sources as the primary cosmic rays. We present a new (unpublished) analytical estimate of the range of possible fluctuations in the high energy electron flux due to the discreteness of plausible cosmic ray sources such as supernova remnants. Fitting our result for the total electron-positron flux measured by the Fermi satellite allows us to fix the only free parameter of the model and make an independent prediction for the positron fraction. Our explanation relies on a large number of supernova remnants nearby which are accelerating hadronic cosmic rays. Turning the argument around, we find encouraging prospects for the observation of neutrinos from such sources in km^3-scale detectors such as IceCube.
Chapter 3 presents a test of this model by considering similar effects expected for nuclear secondary-to-primary ratios such as B/C. A rise predicted above O(100)GeV/n would be an unique confirmation of our explanation for a rising positron fraction and rule out the dark matter explanation.
In chapter 4, we review the assumptions made in the extraction of the `WMAP haze' which has also been claimed to be due to electrons and positrons from dark matter annihilation in the Galactic centre region. We argue that the energy-dependence of their diffusion means that the extraction of the haze through fitting to templates of low frequency diffuse galactic radio emission is unreliable. The systematic effects introduced by this can, under specific circumstances, reproduce the residual, suggesting that the ‘haze’ may be just an artefact of the template subtraction.
We present a summary and thoughts about further work in the epilogue.
Environmental and behavioural determinants of geographic variation in coronary heart disease in England: an ecological study
Keywords: synthetic estimates
geographic variation
coronary heart disease
inequality

Coronary heart disease rates show substantial geographic variation in England, which could be due to environmental variables (e.g. climate, air quality) or behavioural risk factors for coronary heart disease within populations. Previous work investigating this geographic variation has either used ecological analysis (i.e. areas as units of observation) or individual-level analysis. Ecological studies have been unable to account adequately for differences in behavioural risk factors within populations; individual-level studies have been under-powered at the area-level to include all potentially explanatory environmental variables. This thesis reports on ecological multi-level and spatial error regression analyses of coronary heart disease mortality and hospitalisation rates for all wards in England using environmental variables and synthetic estimates of the prevalence of behavioural risk factors as explanatory variables. Existing sets of synthetic estimates were subjected to studies of their validity. Validated synthetic estimates of the prevalence of smoking, low fruit and vegetable consumption, raised blood pressure, obesity and raised cholesterol were combined into a single index of unhealthy lifestyle to take account of collinearity between them. Final models successfully explained around 80% of large scale geographic variation (i.e. variation between wards in different areas of the country) in mortality rates for coronary heart disease and 60% in hospitalisation rates, and around 20% of the small scale geographic variation (i.e. variation between wards in close proximity) in mortality rates, and 30% in hospitalisation rates. The climate explained around 15% of large scale geographic variation in coronary heart disease rates after adjustment for the index of unhealthy lifestyle and socioeconomic deprivation. Urbanicity and air pollution explained a small amount of small scale geographic variation in coronary heart disease rates. The majority of explained geographic variation was due to the index of unhealthy lifestyle and deprivation. The results of this thesis confirm and extend findings from the British Regional Heart Study, report on the validity of synthetic estimates currently used to guide healthcare resource allocation, and introduce an index of unhealthy lifestyle that could be used in future ecological studies of chronic disease.
Red Tārā: lineages of literature and practice
Keywords: Tibet
iconography
Buddhist goddesses
new religious movements
Tara
ritual
Tibetan Buddhism

Tārā is arguably the most popular goddess of the Tibetan Buddhist pantheon. She is well known in her Green, White, and Twenty-one forms. However, the numerous red aspects of the divinity have long been overlooked in both popular and academic literature on the goddess. This thesis aims to redress this balance.
This thesis presents the various manifestations of Red Tārā in the form of a survey of the literary and practice lineages of this goddess throughout Tibetan Buddhist history. The intention of the thesis is to examine individual forms of Red Tārā, excluding Kurukullā (who has received previous scholarly attention), in order to prove the hypothesis that not all Red Tārās are Kurukullā. The research has identified a preliminary historical order of Red Tārā lineages from the eleventh century works on Pīṭheśvarī and the Sa-skya-pa Red Tārās, through to the nineteenth and twentieth century forms of the goddess authored by the dGe-lugs-pas and A-paṃ gter-ston in the A-mdo region of Tibet. The red forms of Tārā are more 'worldly' than her Green or White incarnations, and the soteriological component of her worship is not always clear. Accordingly this allows a glimpse into the subjugating/ magnetising ritual process.
The thesis comprises three sections. Section One provides a general introduction to Tārā and Kurukullā, followed by a survey of the literature pertaining to Red Tārā identified in the course of this research. Section Two takes four lineages of Red Tārā literature as its focus. Each chapter refers to an individual lineage: Pīṭheśvarī, Sa-skya-pa, the Twenty-one Tārās, and A-paṃ gter-ton's gter-ma cycle. Section Three deals with modern-day practice of the goddess in the Chagdud Gonpa Foundation and the Flaming Jewel Sangha.
The thesis relies on translation of primary sources from the Tibetan language, participant observation, and New Religious Studies methodology, and covers a wide range of areas including subjugation rituals, iconography, body-maṇḍala rituals, the adoption of Buddhism in the West, and New Religious Movements. It adds to current knowledge in a variety of fields including ritual, goddess studies, the Tibetan pantheon and its iconography, and Buddhism in the West.
A clinical/immunological neuromyelitis optica association study
Keywords: Neuromyelitis optica
NMO
aquaporin-4

Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are associated with the disease-specific autoantibody aquaporin-4 (AQP4-Ab), which is thought to be pathogenic. Some NMO/NMOSD patients do not have this antibody and may have different clinical and immuno-pathological disease characteristics, but previous clinical NMO/NMOSD studies have been confounded by inclusion of such patients.
To define better the characteristics of AQP4-Ab disease, disease course, outcomes and predictors of disability were investigated in 106 AQP4-Ab positive NMO/NMOSD patients from the UK and Japan. AQP4-Ab positivity conferred a high risk of relapsing disease and substantial disability; age at disease onset and ethnicity were important predictors of disability type. Visual disability was more common in younger patients and those of Afro-Caribbean ethnicity whilst older patients and Caucasian patients were more at risk of motor disability.
To determine whether disease characteristics were influenced by AQP4-Ab binding specificities, the differential binding of patient AQP4-Ab against the two main AQP4 isoforms was investigated. Although the relative binding to the two isoforms differed between patients, there was no association between these differences and clinical features such as relapse type, severity, onset age and ethnicity.
The clinical and in vitro characteristics of AQP4-Ab negative NMO/NMOSD patients were studied. It was shown that these patients represent an aetiologically heterogeneous group. Some have other inflammatory and infectious disorders, some have low levels of AQP4-Ab and a significant proportion have antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab). Others have antibodies that bind to neurons or oligodendrocytes in primary cultures. Attempts to identify novel antigens by immunocapture techniques were made, but were not successful. Patients with MOG-Ab showed differences when compared to those with AQP4-Ab including higher proportion of males, younger age at disease onset and greater likelihood of conus involvement on imaging. Additionally, patients with MOG-Ab appear to have more favourable outcomes, with better improvement from the onset attack and a lower probability of subsequent relapses.
In conclusion, the work in this thesis has shown that AQP4-Ab disease is not synonymous with the term NMO and that seronegative NMO/NMOSD patients represent a clinically and aetiologically heterogeneous group and should therefore be classed separately from those with AQP4-Ab.
The mechanisms and effects of modifying attentional biases to threatening information
Keywords: cognition
neuroimaging
antidepressants
cognitive bias

Patients with both depression and anxiety show an increased tendency to deploy attention towards negative information. Cognitive models of the illnesses predict that these negative attentional biases are causally related to the symptoms of the disorders. Consistent with this, modifying attentional bias using either antidepressant medication or simple, computer based training tasks has previously been associated with altered symptomatology in both non-clinical and clinical populations. The current thesis aimed to investigate the mechanisms by which attentional bias training tasks alter attention. The investigations were conducted within an experimental neuroscience framework which has previously been successfully deployed in studies of antidepressant medication. The thesis then sought to use these initial results to improve the basic understanding of attentional control processes and, ultimately, guide the development of novel treatment strategies. The initial studies of the thesis characterised the behavioural and neural effects of attentional bias training. Behaviourally, a high degree of generalisation of the training effect was found across a range of emotional stimuli. Neurally, training was found to alter activity in a network of prefrontal regions known to be involved in the control of attention. Further analysis, utilising a computational learning model, suggested that the attentional control systems identified in this study could be understood in terms of expectation based processes. These studies therefore indicated that, in contrast to the predominately limbic effects of antidepressant medication, training initially altered the response of frontal control circuitry. The later studies of the thesis investigated possible strategies for extending the use of attentional bias training. Firstly, combining training with antidepressant medication was found to produce an interference effect on emotional memory suggesting that administering both interventions concurrently is likely to erode their cognitive impact. Lastly, attentional bias training was found not to alter attention in patients with bipolar disorder, with the results of the study indicating that standard assessments of attentional bias in this clinical population are likely to be unreliable. Overall, these studies indicate that attentional bias training may be used to alter the top-down control of attention to emotional information and suggest that such effects may interfere with the bottom-up effects of antidepressant drugs. More generally the work demonstrates the utility of using a cognitive-neuroscientific framework to explore the mechanisms and impact of novel therapeutic strategies.