VictorJuiz/thesis huggingface dataset:
Vascular disease in multiple sclerosis: impact on pathology and radiologic outcomes

Shared risk factors, immobility, and inflammation may predispose to systemic- and cerebro-vascular disease in Multiple Sclerosis (MS). On the other hand, vascular risk factors (VRF) and comorbidities may have a direct impact on MS pathology. A post mortem and an in vivo magnetic resonance imaging (MRI) study were set up as complementary approaches to test these hypotheses. In the first, objective measures of systemic and cerebro-vascular disease were obtained from a unique cohort of MS and non-MS cases in whom whole body autopsy reports and brain tissue were available for study. This work revealed that cardiovascular disease is less common, but has a stronger impact on cerebral small vessel disease (cSVD) in MS compared with non-MS, and associates with a lower burden of active plaques. Histological analysis showed an increased cSVD burden in those who die young with highly active MS and that periarteriolar hemosiderin deposition, enlarged spaces and inflammation are key features of MS pathology. In the in vivo brain MRI study imaging markers were compared between MS cases with and without VRF and non-MS cases with VRF. By doing so, imaging discriminators between MS and cSVD were identified. While MS does not seem to influence cSVD imaging markers, the different VRF have distinct effects on MS imaging markers: smoking and dyslipidaemia associating with a higher burden of these markers and diabetes having the opposite effect. Using this combined approach, this thesis advanced the knowledge of the contribution of vascular disease/VRF into MS radiological and pathological heterogeneity, identified markers that can be useful on MS differential diagnosis, and has evidenced that the cerebral microvasculature is structurally abnormal in MS and may be an important therapeutic target.

Keywords: Vascular disease
Brain Magnetic Resonance Imaging
Neuropathology
Multiple Sclerosis
Advisor: Palace, J
DeLuca, G
Interpretations of marks from draughting tools in some Italian renaissance drawings

The focus of this thesis is the examination of evidence left by draughting tools in Italian Renaissance drawings. Because of the archaeological evidence of tool marks it is possible to investigate artists’ use of design systems in a scien-tific manner, with almost forensic certainty. When evidence is sufficient and in-terpreted in the context of design traditions, the sequence of steps that the de-signer employed can be recreated, shedding light on the artists’ methods and the decisions that informed the design process.
The historical survey in Part I describes the origins and subsequent man-ifestations of two primary design systems that, I argue, were traditional among designers up to the Renaissance. These are the numerical and geometrical sys-tems of designs. Numerical systems involve simple ratios that derive from re-lationships found in nature, e.g. musical harmonies. Geometrical systems in-volve using a compass and straightedge to locate points and intersections that aid in building compositions. Part II contains analyses of physical evidence in drawings by Leonardo, Antonio da Sangallo, Palladio, Uccello, Michelangelo and Peruzzi.
My conclusion is that evidence from draughting tools can be brought to bear on the question of artists’ design procedures; that information on artists’ design procedures, thus obtained, cannot usually be found anywhere else; and that revealing the information requires the implementation of an investigative methodology. This methodology involves examining and recording the tool marks and determining the sequence of their creation by reference to the de-sign traditions. The results of the drawing analyses provide examples of artists design procedures revealed by this methodology.
As a draughtsman and designer myself, I have a special appreciation for drawings, compositions and the process of making them. It is my hope that others who share this appreciation and desire to investigate further, can benefit from the methodology and investigatory results of this thesis.

Keywords: harmonic numbers
design process
geometric design
Leonardo
architectural drawings
Palladio
Advisor: Kemp, M
How restorative justice ‘works’: psychological changes expected and experienced by victims who communicate with offenders

There is evidence that some victims benefit from communication with offenders, at least some of the time, but little is known about how these benefits occur. Many have theorised about the mechanisms by which restorative justice produces outcomes for victims, but few have empirically tested these theories. This thesis proposes five main types of psychological change generated for victims by a specific restorative justice practice (communication with the offender), which in turn lead to satisfaction and wellbeing. Three studies were designed to test whether victims expect and experience changes in their perceptions of 1) procedural justice, 2) punishment, 3) prevention, 4) the offender and 5) themselves. Analysis of quantitative data from a national victimisation survey and a complementary smaller-scale online survey demonstrated that four of the five types of victim perception predicted willingness to meet the offender. Victims were particularly motivated to meet the offender when they believed the criminal justice system had failed to fulfil their justice objectives. Analysis of qualitative data from interviews with forty people demonstrated that victims expected and experienced each of the five types of psychological change, and attributed improvements in their wellbeing and satisfaction to having experienced these five changes. This constitutes preliminary but promising evidence that together the five mechanisms explain how communication with the offender benefits victims. The thesis also provides conceptual clarity on the precise nature of the changes that take place during victim-offender communication, and a theoretical framework upon which future studies can build. Knowledge of the mechanisms by which victim-offender communication ‘works’ can help victims make informed choices about participating, can enhance preparation and facilitation, and can contribute to the wider conversation about how to deliver meaningful justice for victims.

Keywords: justice
crime
victim
perceptions of justice
restorative justice
victims of crime
Advisor: Hoyle, C
Bradford, B
Criminalising preparation: the limits of the law

This thesis evaluates the justifiability of preparatory offences: offences that target acts of preparation carried out with the intent to commit some further crime. The preventive turn in the criminal law has seen, amongst other changes, a broadening in the scope of preparatory offences. New offences reach far back into the early stages of preparation, targeting conduct that, but for the criminal intent, would often be entirely innocuous. Notable examples arise in the terrorist and child-sex offending contexts. Section 5 of the Terrorism Act 2006 criminalises any conduct in preparation for giving effect to an intention to commit acts of terrorism. Section 15 of the Sexual Offences Act 2003 criminalises communicating with a person under 16 and arranging to meet them, with the intention of committing a sexual offence against them in the future. The breadth of these offenses, and their focus on criminal intent, has led to concerns that they are akin to ‘thought crimes’ and thus represent an oppressive overreach of state power. This thesis begins by reviewing current theoretical thinking on the limits of the criminal law. It contributes to existing liberal accounts of the limits of the criminal law by exploring in more detail the specific issues raised by preparatory offences, structured as they are around an ulterior intent. The methodology will involve considering the familiar inchoate offences of attempt, conspiracy and possession with intent and the debates pertaining to their justifiability and scope. By engaging with the literature on these offences, this thesis moves the debate on the liberal limits of the criminal law forward by refining the constraints on criminalisation already identified by other theorists. More importantly, this thesis begins the difficult work of demonstrating how those constraints should be applied to specific offences: attempts, conspiracy and compound possession offences.

Advisor: Zedner, L
Public opinion and seditious language from the Wars of the Roses to the Pilgrimage of Grace, c.1461-1537

Although the traditional divide between the late medieval and the early modern periods has increasingly been addressed by scholars, this arbitrary division has long dictated historical research and it has inevitably affected the way we study public opinion and seditious language. While late medievalists have increasingly acknowledged that public opinion was indeed significant in the late medieval period, they do not always agree about its workings, fluctuations, intensity, and most importantly about who mattered in the public arena. Early modernists have increasingly argued against the Habermasian ‘public sphere’ in order to establish that England experienced a dynamic public debate in the sixteenth century. This study interacts with both groups of scholars and approaches public opinion and seditious language by surveying a variety of sources that combines legal records, private and official correspondence, chronicles, proclamations, legislation, and other texts that were directly or indirectly related to the contemporary public opinion. To illustrate the workings of public opinion, the popular attacks against the hegemonic voices of the ruling elites, and the interaction of these two features, this thesis resorts to a combined theoretical framework to examine five broad features: the rhetorical references to ‘the people’ and ‘the commons’, and the stereotypes about them; the profound and instinctive nature of rumour-mongering; the patterns of seditious language; the continuities and shifts in popular discourses across the period; and the government’s reactions and attempts to control all these different variants in the public realm. In other words, this study explores the workings of the communication system that underlay the interaction between rulers and ruled to explain how the tropes and discourses of the Wars of the Roses mostly remained in use and powerful during the early Reformation – and the extent to which some of these discourses shifted or intensified. Overall, this thesis argues that the continuities in how people criticised and reacted to crises throughout the period partly explain the peaks in records of complaint and rumour as well as provide significant insights into how government policy was more frequently reactive than proactive.

Keywords: public opinion
political culture
seditious language
Advisor: Watts, J
Understanding the structure and interactions of polycystin-2 through structural and simulation studies

Polycystin-2 (PC2) is a member of the transient receptor potential (TRP) superfamily of non-selective cation channels. It has a systemic distribution with relatively high expression in kidney tubules. PC2 shares a common transmembrane fold with other TRP channels, in addition to having a extracellular/luminal domain (TOP domain) unique to TRPP and TRPML channels. Mutations in PC2 are associated with autosomal dominant polycystic kidney disease (ADPKD), which is one of the most prevalent genetic disorders in human. Despite that the genetic link between PC2 and ADPKD is well established, the molecular basis of the disease is still elusive. It has been proposed that dysfunction of ciliary PC2 is the main mechanism of pathology of PC2-associated ADPKD. Given the complex organisation of ciliary membrane, it is important to establish how PC2 interacts with specific lipids in its membrane environment. Lipid binding assay results suggest that detergent-solubilised PC2 can bind a range of phosphatidylinositol phosphates but not other simple anionic (phosphatidylserine, phosphatidic acid) or zwitterionic (phosphatidylethanolamine, phosphatidylcholine) lipids. Combining cryo-electron microscopy (cyro-EM) and multiscale molecular dynamics (MD) simulations, we identified a hydrophobic pocket in PC2 formed between S3, S4 transmembrane helices and S4-S5 linker, which showed a preference for phosphatidylinositol bisphosphate (PIP2) binding. Simulations of other members of the TRP channel family suggest this lipid-binding site may be shared amongst a number of TRP channels. In addition, our cryo-EM maps revealed a binding site for cholesterol on PC2, which is further characterised with MD simulations. These results help to position PC2 within an emerging model of the complex roles of lipids in the regulation and organisation of ciliary membranes. Moreover, we used MD simulations to probe the ion selectivity of PC2. Our results suggest that PC2 is selective for Na+ over Ca2+, and not only the selectivity filter residues but also the TOP domain contribute to the selectivity of the channel.

Keywords: Molecular Simulations
Cryo EM
Advisor: Sansom, M
Carpenter, L
The reception of Aeschylus in Italy: translation, adaptation and performance

The present thesis seeks to address the neglect of Aeschylus’ reception in Italy. By putting Aeschylus back into the history of Classics in Italy, it becomes clear just how central a role this playwright (and in particular his Prometheus Vinctus and Oresteia) has played in the history of Italian theatre, in the forging of a strong national identity, and in the history of Italian scholarship.
In its seven chapters, this work fills a gap in the reception history of Aeschylus by ranging widely across the Italian histories of performance, translation and adaptation over five different centuries. Chapter One begins with the first translations of Aeschylus’ plays, from the first published in 1556 to two others that remained long unknown; Chapter Two focuses on the oft-neglected importance to theatre and the translation of the classics of Alfieri’s retelling of Aeschylus’ Oresteia; Chapter Three is about eighteenth- and nineteenth-century translations of Aeschylus’ plays and their importance in the forging of an artificial and aristocratic language for translation, a language that still burdens some translations of the classics today. Chapters Four and Five retrace the birth (1914–1921) and subsequent growth under Fascism (1924–1939) of the longest running modern festival of ancient drama at the ancient theatre of Syracuse, organised by the entity that is today known as INDA. Chapter Six focuses on the revolutionary and precursory work of Manara Valgimigli in re-conceptualising philology as essentially a ‘rethinking’ of humankind, always oscillating between past and present, because always in the making. Finally, Chapter Seven analyses the ground-breaking production of the 1960 Oresteia directed by Vittorio Gassman and Luciano Lucignani with a translation by Pier Paolo Pasolini.
This journey through five different centuries not only reveals how Aeschylus’ reception has contributed widely to Italian classical scholarship, intellectual history and history of theatre; it also contextually allows for the writing of an ‘unclassical’ – i.e. ‘uncommon’ and ‘unknown’ – account of not just Aeschylus, but of the ‘classic’ generally in Italian theatre, scholarship and translation.

Advisor: Macintosh, F
Genomic investigations of bacteriocins and bacteriophages in Streptococcus pneumoniae and other streptococci

Streptococcus pneumoniae (the “pneumococcus”) is a major public health problem, leading to significant morbidity and mortality worldwide. The global increase in antimicrobial-resistant pneumococci is of serious concern, which necessitates investigations into novel antimicrobial strategies. Two promising areas of research are the exploitation of phages (viruses that infect bacteria) and bacteriocins (antimicrobial peptides produced by bacterial species to kill other bacteria). This thesis uses genomic approaches to address questions related to the prevalence, diversity and molecular epidemiology of bacteriocins and prophages (phage genomes that are integrated into bacterial chromosomes).
The first part analysed >6,200 pneumococcal genomes and discovered 14 novel bacteriocin gene clusters. The molecular epidemiology of the bacteriocin clusters was investigated in the context of the pneumococcal population structure. The results revealed extraordinary bacteriocin diversity among pneumococci and the majority of bacteriocin clusters were also present in other streptococcal species. Genomic hotspots for the integration of different bacteriocin gene clusters were discovered. Bacteriocin genes were found to be transcriptionally active when the pneumococcus was under stress and when two different strains were co-cultured in broth.
The second part describes the molecular epidemiology of satellite prophages (prophages that rely on the host and an additional helper phage for survival) in a large global and historical pneumococcal dataset. Forty-four unique satellite prophages were newly identified, which had persistent associations with specific widely-circulating pneumococcal clonal complexes over many decades. Collaborative experimental work demonstrated that one of these satellite prophages was associated with virulence in a murine model of infection. RNA sequencing revealed that satellite prophage genes were overexpressed when pneumococci were grown planktonically versus in in vitro biofilm experimental conditions.
The final part analysed >1,300 genomes of 70 different Streptococcus species and identified nearly 800 prophages and satellite prophages. The data showed that prophages and satellite prophages were widely distributed among streptococci and constituted two distinct entities with little effective genetic exchange between them. Contrary to the current dogma that suggests prophages are bacterial species-specific, there was convincing evidence that transmission of prophages occurred between genetically different streptococcal species.
These results broaden our understanding of bacteriocins and phages among streptococci and uncover many areas for future studies.

Keywords: Phages
Genome Mining
Streptococcal bacteriocins
In silico Drug Discovery
Bacteriocins
Streptococcus
Prophages
PhageMiner
Peptide antibiotics
Phage discovery
Bioinformatics Tools
Streptococcal phages
Bacteriophages
Bioinformatics
Streptococcus pneumoniae
Advisor: Brueggemann, A
Klenerman, P
Regulation of expression of RNA polymerase II-transcribed human snRNA genes

Human small non-coding RNAs (snRNAs) are required for expression of the vast majority of our protein-coding genes due to their important role in pre-mRNA processing events. Transcription initiation of snRNA genes is mediated by transcription factors like Oct-1, which recognize the DSE element, and by PTF, which recognizes the PSE and nucleates a pre-initiation complex (PIC) comprising general transcription factors TFIIA, B, C, E, F and H, TBP and some TBPassociated factors, and Mediator. RNA polymerase II (pol II) is then recruited with the carboxylterminal domain (CTD) of the large subunit in a hypophosphorylated form. In humans, the CTD comprises 52 repeats of the consensus heptapeptide, Y1S2P3T4S5P6S7. After initiation, the pol II CTD is phosphorylated on S2, S5 and S7 as the polymerase progresses into elongation, which is mediated by the little elongation complex (LEC) and finally 3’ end formation and termination are mediated by recognition of the 3’ box RNA processing element by the Integrator complex. It has been shown that there is compulsory coupling between the promoter element PSE and the 3’ box; transcription by pol II must initiate from a PSE-containing promoter for the 3’ box to be recognised. However, the mechanism underlying this coupling is still unclear. In order to better understand how snRNA genes are regulated, I performed an unbiased dCas9-mediated pulldown approach to characterize the transcription machinery present on the DSE and PSE of the U2 snRNA gene. This analysis has identified some novel potential players in snRNA gene expression.
After initiation of transcription of protein-coding genes, phosphorylation of S5 of the pol II CTD by the cyclin-dependent kinase (CDK) 7 subunit of TFIIH facilitates promoter escape and 5' capping of the emerging transcript. CTD S2 phosphorylation by the CDK9 subunit of the super elongation complex (SEC) and CDK12 facilitates processive elongation, splicing and recognition of the polyadenylation (poly(A)) signal in the nascent RNA. It has been shown that the activity of CDK9 is required for recognition of the snRNA gene 3' box. However, the roles of other CDKs was unknown. Characterisation of the in vivo roles of the CDKs has now been facilitated by using CRISPR/Cas9 genome engineering to produce cell lines with analog-sensitive (as) versions of many of these CDKs. In order to determine the roles of several CDKs in snRNA gene transcription, I performed pol II chromatin immunoprecipitation (ChIP) assays, RNase protection assays and immunoprecipitation/mass spectrometry analysis after specific inhibition of analog-sensitive CDKs. I have confirmed the role of CDK9 in expression of the human U2 snRNA gene and uncovered redundant roles for CDK12 and CDK13 in recognition of the 3' box.

Advisor: Murphy, S
Impact of host restriction factors and capsid evolution on HIV disease progression

HIV-1 is responsible for the global HIV pandemic whereas HIV-2 has mostly been limited to West Africa. The key to their successful spread is their unparalleled ability to adapt to the host immune system. The contemporary HIV pandemics are the latest iteration in a millennia-long evolutionary arms race between retroviruses and their hosts. Two host restriction factors which have been important actors in this arms race are TRIM5α and its paralogue TRIM22. TRIM5α targets the retroviral capsid, whereas TRIM22 suppresses retroviral transcription indirectly.
The central hypothesis for the thesis is that the HIV capsid and TRIM restriction are associated with HIV disease progression. In this thesis we present findings from four projects. In chapter three we discuss the effect of TRIM genotype on disease outcomes in children and adolescents infected perinatally with HIV-1. We characterised TRIM genetic diversity in this cohort and found that TRIM22 genotype is associated with CD4+ T cell counts and, potentially, disease progression rates. Chapter four presents the outcomes of using CD4+ T cell kinetic data to stratify HIV-2 infected adults into disease progressor groups. Forty-six percent of patients were classified as fast progressors and 54% as slow progressors. Slow progressors advanced to AIDS at approximately half the rate of fast progressors, had higher CD4+ T cell levels and a slower CD4+ T cell decline rate. In chapter five we discuss the effect of TRIM genotype on HIV-2 disease outcomes in adults. TRIM22 genotype associated with significant effects on long-term CD4+ levels, though these effects were modest. Finally, we report that intrahost evolutionary rates of HIV-2 gag are significantly higher in fast progressors, that the p24 region evolves under negative selection and that evolutionary rates correlate negatively with CD4+ T cell percentage

Keywords: TRIM
Capsid
AIDS
Advisor: Rowland-Jones, S
Esbjornsson, J