VictorJuiz/thesis huggingface dataset:
Neutrality in political decision making

Liberal neutrality – as understood in current legal and political debates – has two underlying intuitions and therefore two distinct elements. On the one hand it refers to the intuition that there are matters the state has no business getting involved in (hands-off element). On the other hand it is motivated by the idea that the state ought to treat citizens as equals and show equal respect and for their different conceptions of the good life (equality element). This thesis defends this two-fold understanding of neutrality with reference to Rawls’ conception of society as a fair system of cooperation and the idea of citizens as free and equal persons. In particular, the idea that citizens are to be treated as free justifies the hands-off element and argues that the state must be involved in nothing but justice. In the context of political decision making this requires the state to be justificatorily neutral. Treating citizens as equals requires the state to grant its citizens equal political rights and also to ensure that these rights have “fair value.” Given the danger that cultural bias undermines the equal standing of citizens the state has to ensure procedures of political decision making that are able to take citizens’ different conceptions into account. Treating citizens as free and equal therefore requires that the state bans all considerations of the good from being part of the justification of state action while at the same time taking these considerations into account when deliberating the way how these regulations are to be implemented.

Keywords: neutrality
Rawls
Dworkin
Liberalism
multiculturalism
Advisor: McDermott, D
Friends and enemies of Poggio

This thesis assembles articles on Italian humanists (chiefly Tuscan and Roman) of the fifteenth century. Their origin lay in research into the letters of Poggio (1380-1459) and the context in which they were written. Chapter 1, designed as an introduction to those that follow, examines the nature of Poggio's epistolario and suggests ways of presenting it, with reference to a new edition. An appendix describes some unknown manuscripts of the letters. The first part of Chapter 2 publishes an early letter (1416) of Poggio, hitherto assigned to another humanist; the second prints and reconsiders the unpublished remnant of his history of Europe, which death cut short in 1459.
Chapter 3 discusses the invectives aroused by Poggio's closest friend Niccoli, and tries to assess the reality behind the persona of this enigmatic scholar. Emphasis is laid upon the attacks of another of Poggio's friends, Leonardo Bruni, and the defences mounted by Poggio himself. Chapter 4 prints a new letter of Bruni which refers to his feud with Niccoli, and thereafter disinters the figure of the bearer of the letter, the grammarian Mattia Lupi. The next chapter deals with another acquaintance of Bruni, Niccoli and Poggio, the scribe Giovanni Aretino, in an examination of two of Bruni's letters. Evidence of the relations of humanists with Poggio's colleague Giacomo Languschi is brought together in a second section of the chapter, which is completed by three appendices: a letter of Giovanni Aretino, the 'biography' of a manuscript written by him, and a new list of all manuscripts attributable to him.
The last chapter does not directly concern Poggio, but publishes letters between two of his most bitter enemies, Niccolo Perotti and Lorenzo Valla. They date from the period of the protracted polemics exchanged between them and him (1451-54). An effort is made to characterise the scribe of these letters, and to place him in the context of humanist education. New information on Valla and Perotti is also integrated into their biographies.
Design of a non-scaling fixed field alternating gradient accelerator for charged particle therapy

This thesis describes the design a novel type of particle accelerator for charged particle therapy. The accelerator is called a non-scaling, Fixed Field Alternating Gradient (ns-FFAG) accelerator, and will accelerate both protons and carbon ions to energies required for clinical use. The work is undertaken as part of the PAMELA project. An existing design for a ns-FFAG is taken as a starting point and analysed in terms of its ability to suit the charged particle therapy application. It is found that this design is particularly sensitive to alignment errors and would be unable to accelerate protons and carbon ions at the proposed acceleration rate due to betatron resonance crossing phenomena. To overcome this issue, a new type of non-linear ns-FFAG is developed which avoids resonance crossing and meets the requirements provided by clinical considerations. Two accelerating rings are required, one for protons up to 250 MeV and fully stripped carbon ions to 68 MeV/u, the other to accelerate the carbon ions up to 400-430 MeV/u. Detailed studies are undertaken to show that this new type of accelerator is suitable for the application. An alignment accuracy of 50 micrometers will not have a detrimental effect on the beam and the dynamic aperture for most lattice configurations is found to be greater than 50 pi.mm.mrad normalised in both the horizontal and vertical plane. Verification of the simulation code used in the PAMELA lattice design is carried out using experimental results from EMMA, the world's first ns-FFAG for 10-20 MeV electrons built at Daresbury Laboratory, UK. Finally, it is shown that the described lattice can translate into realistic designs for the individual components of the accelerator. The integration of these components into the PAMELA facility is discussed.

Keywords: particle therapy
particle accelerator design
Accelerator physics
Advisor: Peach, K
The role of non-coding regions of the alpha-synuclein gene in protein expression and the determination of alternatively spliced alpha-synuclein isoforms in oxidatively stressed cells

Parkinson’s disease (PD) is a neurodegenerative disorder caused by substantial loss of dopaminergic neurons and has been extensively linked to alpha synuclein (α-synuclein). This thesis has investigated the non-coding regions and alternatively spliced isoforms of α-synuclein and an improved cell model of PD in which this might be studied. The results indicate that there are several different 5’ untranslated region isoforms of α-synuclein expressed and that these stimulate significantly different levels of protein expression when analysed using a luciferase assay. Real-time PCR data indicates that these isoforms are differentially expressed; particularly isoform 202 which was up-regulated in both oxidatively stressed cells and a sample of cingulate gyrus from a dementia with Lewy body (DLB) patient. Interestingly this α-synuclein 202 isoform stimulated the lowest levels of protein expression in the luciferase assay. Three of the four previously reported splice isoforms of α-synuclein were detected; 112, 126 and 140 and the expression levels determined by real-time PCR. Results indicate that isoform 112 expression is up-regulated in oxidatively stressed cells and a sample of cingulate gyrus from a DLB patient but this is not seen when levels of total α-synuclein are normalised. The three spliced isoforms were also cloned and used to determine that a novel antibody was able to detect specifically the 126 α-synuclein isoform by western blotting. Finally, progress was made in developing a new protocol for the differentiation of induced pluripotent stem cells (iPSCs) into dopaminergic neurons using modified messenger RNAs encoding dopamine-specific transcription factors (TFs). Five of required TFs were cloned and ligated to the UTRs needed to produce RNA. Additionally we discovered that iPSCs could not only survive plating onto neuronal substrate in neuronal medium with two daily transfections, but they start to express neuronal markers after four days of culture.

Keywords: Parkinson's disease
5' untranslated regions
alpha synuclein
Advisor: Wood, M
Hallegger, M
Identifying causative elements within structural variants associated with developmental disorders

It has been well established that copy number variation contributes substantially to genetic variation within human populations. However, the extent to which de novo and inherited copy number variants (CNVs) underlie human disease is not well known. In this thesis, I investigate the role of de novo and inherited CNVs in a wide range of developmental abnormalities.
First, I compare disease associated and apparently benign CNVs for structural differences, with the aim of identifying distinguishing features of disease causing CNVs. I identified significant enrichments of protein-coding genes, protein-coding genes associated with disease in OMIM and miRNAs amongst disease associated disease. Conversely, inherited CNVs observed in healthy individuals show depletions of these features.
Following this, I employ functional enrichment approaches to identify the copy number variable genes within these de novo CNVs that contribute to the patient’s developmental abnormalities. I predict candidate genes for 143 different developmental abnormalities, with 65% of the candidate genes not having been previously associated with disease in OMIM. Through examining the distribution of these candidate genes within the patient’s CNVs, I found evidence of extensive pleiotropy and epistasis as well as a small number of simple additive effects.
Finally, I extend my analyses to examine the role of inherited CNVs as the underlying cause of human developmental disorders. I implicate inherited CNVs and their overlapping copy number variable genes in the underlying causes of 45 human developmental abnormalities. Additionally, I re-examine the patients possessing both de novo CNVs and inherited CNVs using functional enrichment analyses. I reveal significant enrichments for a greater number of human developmental abnormalities when combining both the de novo and inherited CNVs, suggesting it is de novo mutations in combination with the inherited genomic background that are responsible for many instances of human developmental abnormalities.

Keywords: genomics
genetics
CNVs
Advisor: Webber, C
Ponting, C
Thanks for that elegant defense

The end of the seventeenth century and the beginning of the eighteenth saw many women writers from numerous social ranks, political affiliations and religious denominations reading, writing, circulating and publishing polemical prose and poetry in defence of their sex. During this surge of protofeminist activity, many of these women decried 'Customs Tyranny' by advocating a more egalitarian status for themselves, especially in regard to marriage, education and religion. This thesis, then, is a socio-historic study of the lives and writings of several polemical women writers, namely, Mary Astell (1666-1731), Mary, Lady Chudleigh (1656-1710) and Elizabeth Thomas (1675-1731). It also considers how and why protofeminism evolved in the late seventeenth century and reached a climax between 1694, when Astell published A Serious Proposal to the Ladies, and 1710, when Chudleigh published Essays upon Several Subjects.
Until now, scholars of early women writers have labelled Astell the foremost English feminist of her day. Consequently, many of her contemporary protofeminist writers have been neglected. By contextualizing their lives and texts within the political and literary activity at the turn of the eighteenth century, this thesis ultimately argues that women polemicists, such as Chudleigh and Thomas, who followed Astell into print, were not merely echoes and disciples. Rather, they furthered the evolution and secularization of a genre that anticipates feminism proper, which began to develop in the late eighteenth and early nineteenth centuries.
In order to uncover and rediscover the personal and professional details of these women's lives their class, education, friendships and patronage relationships this thesis relied heavily upon material evidence such as letters, parish records, legal records, prison records and wills. As a result, it combines feminist, materialist inclinations with traditional methodology, such as historical and archival research.
The diligent dilettante

The thesis sets out to explain the presence of women writers in the book market of the late eighteenth and early nineteenth centuries. In order to do so, it examines the position of women writers in Germany - in the context both of their discursive and of their social reality. The thesis investigates the ideological and material background for women's writing, by exploring the areas of gender ideology, contemporary concepts of authorship, women's reading, and the literary market. The final chapter examines women's freedom of expression in different public circumstances. The thesis argues that women's position in the business of culture in general and literature in particular is not as unpromising as has often been claimed. By investigating less well-known texts on gender roles, such as eighteenth-century journal articles, it is possible to show that the rhetoric of prohibitions, for example regarding women's reading and writing, was by no means uniform, but fragmentary and frequently contradictory. Women's own responses to the conditions under which they were working are highlighted throughout the thesis, and examined on the basis of a range of texts, including unpublished correspondence. The examination of non-literary factors, such as the expansion of the literary market and the emergence of a newly diverse reading public, enables the identification of causes other than gender as determining women's position as writers during this period. In the course of this study, numerous neglected texts are considered, which broaden our understanding of this period of literature. The creative and successful use which women writers made of the opportunities they were afforded is emphasised throughout, thereby making an important contribution to the study of women writers.

Advisor: Watanabe-O'Kelly, H
Liver specific microRNA control of adenovirus serotype five

MicroRNAs are small non-coding RNA molecules that regulate mRNA translation by binding to complementary sequences usually within the 3’ un-translated region (UTR). By inserting four perfectly complementary binding sites for the hepatic specific microRNA mir122 into the 3’ UTR of adenovirus wild type 5 (Ad5 WT) E1A mRNA I show that the acute liver toxicity caused by Ad5 WT in mice can be significantly reduced. This virus, termed Ad5-mir122, is a promising virotherapy candidate and causes no obvious liver pathology whilst maintaining Ad5 WT replication in mir122 negative cells.
Data shows that repeat intravenous administration of Ad5-mir122 (2x1010vp) to HepG2 tumour bearing mice mediated significant anti-cancer efficacy. RT-QPCR for E1A mRNA demonstrated a 29-fold reduction when compared to Ad5 WT in murine liver whilst western blot confirmed that all E1A protein variants were knocked down. Viral genomic replication was also reduced in mouse liver by 25-fold compared to Ad5 WT. This control of virus activity reduced alanine and aspartate transaminase release by >15-fold and histological analysis showed little to no pathology in Ad5-mir122 infected livers.
Measurement of mature mir122 levels in Ad5-mir122 infected livers by RT-QPCR showed that the quantity of mir122 remained unaffected at therapeutic doses. Complete genome mRNA array profiling of infected livers showed that the transcript levels of >3900 different mRNAs were changed more than 2-fold following Ad5 WT infection whilst less than 600 were changed by Ad5-mir122. A non-replicating control adenovirus vector altered >550 mRNAs. No known mir122 target mRNAs were affected following infection with Ad5-mir122. Western blot analysis of a known mir122 regulated target (Aldolase A) confirmed these results, demonstrating no change in protein level despite infection with Ad5-mir122. These data combined demonstrate that the exploitation of microRNA mir122 regulation to control adenovirus replication is a safe method of control and does not alter the endogenous level or activity of the microRNA or its endogenous mRNA targets. Ad5-mir122 is a potent anti-cancer agent that replicates to wild-type levels in microRNA mir122 negative cells but is specifically and safely attenuated in hepatocytes.

Keywords: microRNA
oncolytic
virotherapy
adenovirus
Advisor: Seymour, L
The Role of the Prefrontal Cortex in Pain Modulation

Existing knowledge identifies the prefrontal cortex (PFC) as the modulatory area for pain. Previous neuroimaging studies suggest the existence of the cortico-cortical pathway, an alternative pain modulatory pathway distinct from the descending modulatory pathway of pain. However, little is known of the extent, mechanism and underlying substrate of the modulation. The objective of this study is therefore to explore the role of the PFC in pain modulation. To examine the extent of PFC involvement in pain, meta-analyses of imaging studies in healthy volunteers and patients with chronic pain were performed. Using Gaussian-process regression (GPR) analysis, brain maps were produced from foci of activation as reported in the studies. Since structure dictates function, our next study was to performprobabilistic tractography on diffusion-weighted brain images to ascertain the connection probability of lateral PFC subdivisions and pain-related brain regions as well as intrinsic PFC connections. Two behavioural studies were conducted to investigate cognitive modulation of pain. The first was a study to assess the subjective and physiological correlates of cognitive stress, as previously used in stress-induced analgesia studies. The second was to investigate the involvement of the endogenous opioid system inthe cognitive modulation of pain through effortful reappraisal and contextual modulation.
Meta-analyses in healthy volunteers and chronic pain patients revealed activation mainly in the lateral aspect of the PFC due to pain. Distinct pattern of activation was demonstrated in patients with significant ventrolateral PFC (VLPFC) activation across subtypes of chronic pain. Probabilistic tractography further illustrate the functional significance of lateral PFC subdivisions by demonstrating differential connection probability to pain-related brain regions; dorsolateral PFC (DLPFC) regions displayed higher connection probability with brain regions serving more sensory-discriminative function while VLPFC showed high connection probability with both sensory-discriminative and affective regions. Behavioural study of stress showed that cognitive stress failed to induce significant increases in biomarkers of stress, and was not affected by increased level of difficulty. Lastly, behavioural study on contextual modulation and reappraisal confirmed opioid mediation for contextual modulation while negating its involvement in effortful reappraisal.
Findings from this studyillustrate the extent of PFC involvement in pain modulation especially in chronic pain patients and provide further evidence of an alternative pathway distinct from the opioid-mediated descending inhibitory pathway.

Keywords: prefrontal cortex
pain
modulation
Advisor: Tracey, I
Wiech, K
Voltammetric sensing

Electrochemical analysis using mercury electrodes has been a prominent methodology since the beginning of voltammetry, however, due to its toxic nature their use is being slowly phased out in favour of environmentally friendlier alternatives. In this thesis, carbon electrodes feature heavily as a means to provide a cheaper and non-toxic approach to voltammmetric sensing. Pulse techniques have been used for the sensitive detection of commonly studied analytes, including antimony and iron.
A simple fabrication of a vibrating electrode is presented by modifying a commercially available vibrating toothbrush with platinum foil as a means to enhance mass transport for electroanalytical work.
Finally, pH determination at carbon electrodes is investigated. Carbon electrodes have been proposed as a simple sensor for pH determination by exploiting the pH sensitive nature of surface quinone groups intrinsic within carbon edge-plane like sites. Using this approach, both EPPG and GC electrodes are suggested as new materials for pH determination and can be used in aqueous solutions over the pH range 1.0 to 13.0, as a cheap and simple alternative to the classic glass electrode.

Keywords: Electroanalysis
Advisor: Compton, R
The innate immune effector cell response against HIV-1

Since being identified as the cause of AIDS in 1983, HIV-1 infection has reached pandemic proportions. Despite public awareness about prevention, the growing incidence of HIV-1 infection and the limitations of current antiretroviral therapy underscore the imperative need for a vaccine. Understanding the basis of an immune response that controls infection or provides sterilizing immunity remains a major goal in the search for effective vaccines or immunotherapies. Research into correlates of immunity to HIV-1 have largely focused on CD8+ T cells or neutralising antibodies (NAbs) but to date these responses have not proved effective in containing viral replication in vaccinees who become infected.
Natural killer cells (NKs), monocytes (MCs), and neutrophils (PMNs) are cells of the innate immune system with intrinsic cytotoxic function that can be enhanced by antibodies (Abs) in what is termed antibody-dependent cellular cytotoxicity (ADCC). In my studies I investigated the production of PMNs from human stem cells, the elimination of HIV-1 infected cells by these effector cells, the modulation of cellular cytotoxicity by Ab, and characterized how Abs facilitate a potent ADCC response. I developed a novel flow cytometry assay to measure cytotoxic activity against HIV-1 infected CD4+ T cells. Using this, effector cells were shown to have different cytotoxic capacities which were enhanced by Ab. Comparing ADCC mediated by patient serum revealed that higher levels correlated with IgG binding to infected cells. I observed no correlation between serum-mediated ADCC and markers of disease progression including patient status, viral RNA load, CD4+ T cell count, or NAb titers. The data presented here have implications for acquisition and control of early HIV-1 infection by NKs, MCs, and PMNs prior to activation of an adaptive immune response, at later stages in the presence of HIV-1-specific Abs, and are relevant to vaccine-induced anti- HIV-1 Ab-based effector mechanisms.

Keywords: AIDS
antibody-dependent cellular cytotoxicity
monocytes
neutrophils
HIV
NK cells
Stem Cells
Immunology
neutralising antibody
antibody
Advisor: Sattentau, Q
Ultra-small open access microcavities for enhancement of the light-matter interaction

The design, construction and characterisation of a novel, arrayed, open-access optical microcavity is described. Included in this thesis are the precise fabrication details, making use of the focused ion beam. A technique for analysing and optimising the microcavities constructed, making use of an atomic force microscope is also included. Results from the optical characterisation of the fabricated microcavities are presented, including quality factors of around 104, and fitnesses of around 400. The optical analysis then progressed onto coupling colloidal semiconductor nanocrystals to the microcavity modes. This yielded room temperature Purcell enhancements, single particle sensing, and also allowed for the characterisation of a second iteration of cavities. This improved set was shown to achieve fitnesses in excess of 1800 and quality factors with a lower limit of 15000. The optical identification of single NV centres in nanodiamond is discussed, along with the development of an optical apparatus to couple them to microcavities at cryogenic temperatures. Finally several results from finite difference time domain simulations will be presented, showing ultimate mode volumes of less than 0.5 cubic wavelengths are possible for this approach.

Keywords: cavity quantum electrodynamics
microcavities
microcavity
quantum dot
nanocrystal
diamond
nanodiamond
Advisor: Smith, J