VictorJuiz/thesis huggingface dataset:
Synthesis and properties of porphyrin nanotubes

Porphyrins, with their planar aromatic cores, are suitable and versatile building blocks to form functional nanostructures. This thesis describes the synthesis and properties of atomically precise porphyrin nanostructures with a specific focus on porphyrin nanotubes.
Chapter 1 introduces the key properties of porphyrins and discusses the template-directed synthesis of (conjugated) porphyrin nanostructures. Furthermore, it explores the "bottom up" synthesis of carbon nanotubes and its molecular analogues including those constructed from porphyrin building blocks.
Chapter 2 describes the assembly of a nested nanoring complex. Excitation energy is transferred from the inner nanoring to the outer nanoring. The inner porphyrin nanoring is used as a template to direct the synthesis of the outer nanoring from its linear precursor.
Chapter 3 explores different strategies for the synthesis of a nanotube consisting of 12 porphyrin subunits. An unprecedented method of ring-stacking of pre-formed 6-porphyrin nanorings is discussed as well as a template-directed procedure.
Chapter 4 describes the host-guest chemistry of a 12-porphyrin nanotube. C60 and C70 fullerenes are encapsulated in the cavity of the nanotube. Electron transfer from the nanotube host to the C60 guest is observed. The guests can be released when the molecular box is chemically opened.
Chapter 5 describes the synthesis and properties of porphyrin nanotubes with a mono acetylene connection between the conjoined 6-porphyrin nanorings. This link enables the synthesis of an 18-porphyrin nanotube; the longest p-conjugated molecular nanotube to date. Enhanced conjugation is found compared to analogous bis-acetylene linked tubes.
Chapter 6 explores DFT calculations on large p-conjugated porphyrin nanostructures. Size dependent bandgap oscillations in bis-acetylene linked porphyrin nanotubes are examined. TD-DFT studies on a 14-porphyrin nanoball provide insight into the electronic structure and agree with experimental observations.

Advisor: Anderson, H
Knowing politics: knowledge and democratic citizenship in South Africa's education system

This thesis brings together democratic theory’s calls for an understanding of the actually existing democratic state and anthropological work on innovative forms of citizen participation. Building on the work of Joao Biehl and Steven Robins, the research focuses on access to knowledge and claims of expertise as grounds upon which politicians and bureaucrats exclude citizen participation. It argues, using an ethnographic case study of South African student activist group Equal Education, that authors such as Max Weber, Michel Foucault, and James Scott are wrong to imply that citizens cannot train themselves in the technocratic manner frequently deployed by the state’s representatives. It also argues, however, that the state’s representatives are often not the technocrats they are hypothesised to be or that they claim to be, and their knowledge practices cannot be separated from politics. This makes the process through which citizens establish expertise and credibility with the government more complicated than simply training themselves in the government's knowledge practices.
Drawing on the work of Danielle Allen and Francesca Polletta, the thesis thus also examines how questions of personal experience and identity on grounds of lived experience as well as claimed or perceived identity often interact with claims to knowledge, opening up or shutting down citizens' ability to participate. Even when citizens are able to leverage their technocratic expertise to successfully influence policy creation, they may still find it difficult to effectively participate in the implementation thereof beyond external monitoring and accountability enforcement. The thesis concludes that the current democratic theory ought not be so pessimistic about the spectre of a know-nothing citizenry, but nor ought it presume that education and expertise alone will be sufficient for democratic governments to take seriously an involved and engaged citizenry.

Advisor: Alexander, J
On privacy

This thesis concerns the ethics and political philosophy surrounding privacy. It investigates what privacy is, what is at stake in its loss, and how it relates to other rights and values.
The first part sets the groundwork for the rest of the thesis. Chapter One delves into the origins of privacy. I argue that privacy is not a recent cultural product, but rather a need buried deep in our evolutionary and human history.
The second part of the thesis is dedicated to conceptual issues. Chapter Two clarifies the relation between privacy and the public and private divide. I argue against the popular belief that privacy is an issue that belongs solely to the private sphere. Chapter Three reviews the most influential definitions of privacy that have been offered in the legal and philosophical literature, and points out some of their shortcomings and strengths. In Chapter Four, I develop my own definition of privacy as remaining personally unaccessed, as well as an account of the right to privacy as a right to a robustly demanding good. I also map out the moral significance of privacy perceptions, and privacy-related obligations.
The third part of the dissertation concerns practical issues. Chapter Five inquires into the relationship between security and privacy. I argue that mass surveillance is a disproportionate, unnecessary, and ineffective response to the threat of terrorism. I also argue that encryption should be widely used, as it can curtail the mass surveillance of content and protect people without seriously obstructing criminal investigations. Chapter Six explores the relationship between privacy and transparency. I argue that transparency should sometimes be limited in the interest of privacy. Chapter Seven deals with the questions of whether we can lose privacy to computer algorithms, and whether decision-making algorithms can violate our right to privacy. I answer both questions in the negative, as algorithms are currently neither our peers nor moral agents responsible for their actions.
The conclusion sketches some of the lessons learnt over the course of this investigation.

Keywords: privacy
Advisor: Crisp, R
Fabre, C
Investigating resistance mechanisms to ATR inhibitors

The kinase activity of Ataxia-Telangiectasia and Rad3 related (ATR) protein plays a key role in controlling the DNA damage response (DDR) by acting through downstream targets to stabilise DNA replication forks, induce a transient cell cycle arrest to facilitate the repair of DNA, and thereby prevent premature mitosis in cells with unrepaired or unreplicated DNA. ATR is activated when single stranded DNA arises, for example, from stalled DNA replication forks or during the intermediate steps of double strand DNA break repair, and it is thought to mediate most of its responses through the downstream checkpoint kinase 1, CHK1. As ATR plays an important role in intra-S phase and G2/M cell cycle checkpoints, it has been proposed that inhibition of ATR activity selectively targets tumour cells that have defects in DNA damage-induced G1 cell cycle checkpoints by causing the accumulation of DNA damage and cell death.
AZD6738 is a selective ATR kinase inhibitor that is currently in early clinical development (phase 1). Since development of resistance has been universally observed with long-term use of kinase inhibitors in the clinic, we aimed to identify potential mechanisms of acquired resistance to AZD6738. In this study, we used an in vitro assay system using PC-9 human non-small cell lung cancer cells to generate independent clonal cell lines (SO25, SO45, and SO46) that were resistant to AZD6738. The resistant cells have increased relative cell viability in the presence of AZD6738 compared to the parental cells and, surprisingly, grow better in the presence of the inhibitor than in its absence. AZD6738 resistant cells are also cross-resistant to other chemically unrelated ATR inhibitors (VE-821 and VE-822) as well as CHK1/2 and WEE1 inhibitors, but not ataxia telangiectasia mutated (ATM) inhibitors. Together, cell cycle, DNA fibre, and RNA-sequencing analyses all point towards differential cell cycle regulation in the resistant clones while western blot analysis revealed activation of ATM signalling in the presence of AZD6738 in parental PC-9, but not in the resistant cells.
Western blot and RNA-sequencing analyses demonstrated that cyclins A2 and E1 are downregulated in the resistant cells. Knockdown of cyclin A2 and/or cyclin E1 using siRNA in parental PC-9 cells increased cell viability in the presence of AZD6738. We conclude that downregulation of cyclins A2 and E1 can confer resistance to ATR kinase inhibitors, and may also confer cross-resistance to other inhibitors targeting certain pathways downstream of ATR signalling (CHK1, WEE1).

Keywords: DDR (DNA damage response)
resistance
ATR
AZD6738
Advisor: Ryan, A
Technology and political speech: commercialisation, authoritarianism and the supposed death of the Internet's democratic potential

The Internet was initially seen as a metaphor for democracy itself. However, commercialisation, incorporation into existing hierarchies and patterns of daily life and state control and surveillance appear to have undermined these utopian dreams. The vast majority of online activity now takes place in a handful of commercially owned spaces, whose business model rests on the collection and monetisation of user data. However, the upsurge of political action in the Middle East and North Africa in 2010 and 2011, which many argued was facilitated by social media, raised the question of whether these commercial platforms that characterise the contemporary Internet might provide better venues for political speech than previous types of online spaces, particularly in authoritarian states.
This thesis addresses the question of how the commercialisation of online spaces affects their ability to provide a venue for political speech in different political systems through a mixed-methods comparison of the U.S. and China. The findings of this thesis support the hypotheses drawn from existing literature: commercialisation is negative for political speech but it is less negative, even potentially positive, in authoritarian systems. However, this research uncovers a surprising explanation for this finding. The greater positivity of commercialisation for political speech in authoritarian systems seems to occur not despite the government but because of it. The Chinese state’s active stance in monitoring, encouraging and crafting ideas about political speech has resisted its negative repositioning as a commercial product. In contrast, in the U.S., online political speech has been left to the market that sells back the dream of an online public sphere to users as part of its commercial model. There is still hope that the Internet can provide a venue for political speech but power, particularly over the construction of what it means to be a political speaker in modern society, needs to be taken back from the market.

Keywords: survey
social media
discourse analysis
Internet
public sphere
commercialisation
random sample
China
USA
Advisor: Bright, J
Dutton, W
Nash, V
Dissecting heterogeneity in GWAS meta-analysis

Statistical heterogeneity refers to differences among results of studies combined in a meta-analysis beyond that expected by chance. On the one hand, excessive heterogeneity can diminish power to discover genetic signals; on the other, moderate heterogeneity can reveal important biological differences among studies. Given its double-edged nature, this thesis dissects heterogeneity in genetic association meta-analyses from three vantage points. First, a novel multi-variant statistic, M is proposed to detect genome-wide (systematic) heterogeneity patterns in genetic association meta-analyses. This was motivated by the limited availability of appropriate methodology to measure the impact of heterogeneity across genetic signals, since traditional metrics (Q, I2 and τ2) measure heterogeneity at individual variants. Second, given that meta-analyses comprising small numbers of studies typically report imprecise summary effect estimates; GWAS-derived empirical heterogeneity priors are used to improve precision in estimation of average genetic effects and heterogeneity in smaller meta-analyses (e.g. ≤ 10 studies). Third, a critical evaluation of the Han-Eskin random-effects model shows how it can identify small effect heterogeneous loci overlooked by traditional fixed and random-effects methods.
This work draws attention to the existence of genome-wide heterogeneity patterns, to reveal systematic differences among the ascertainment criteria of participating studies in a meta-analysis of coronary disease (CAD) risk. Furthermore, simulation studies with the Han-Eskin random-effects model revealed inflated genetic signals at small effect loci when heterogeneity levels were high. However, it did reveal an additional CAD risk variant overlooked by traditional meta-analysis methods.
We therefore recommend a holistic approach to exploring heterogeneity in meta-analyses which assesses heterogeneity of genetic effects both at individual variants with traditional statistics and across multiple genetic signals with the M statistic. Furthermore, it is critically important to review forest plots for small effect loci identified using the Han-Eskin random-effects model amidst moderate-to-high heterogeneity (I2 ≥ 40%).

Keywords: meta-analysis
heterogeneity
prior distributions
coronary artery disease
genetic association meta-analyses
Bayesian meta-analysis
LPA
GWAS
Advisor: Farrall, M
Hopewell, J
Computational detection of electrophysiological abnormalities in hypertrophic cardiomyopathy for risk stratification

Hypertrophic cardiomyopathy (HCM) is a common cardiac genetic disease and a major cause of sudden cardiac death (SCD) in young adults. While most patients remain asymptomatic, others suffer from SCD triggered by ventricular arrhythmias. An accurate detection of these high-risk patients in order to provide them with appropriate treatment is therefore essential, and it remains a challenge as current electrocardiogram (ECG) biomarkers are not specific. In this thesis, we develop computational methods for the analysis and interpretation of electrophysiological clinical data in order to investigate the diversity of HCM phenotypes with the ultimate aim to improve risk stratification in HCM. First, by combining computational clustering and mathematical modelling, we identify four distinct ECG phenotypes exhibiting differences in hypertrophy distribution and risk of arrhythmia. The group with primary repolarization abnormalities and coexistence of apical and septal hypertrophy shows a higher HCM Risk-SCD score compared to other groups. Second, we explore the influence of structural and electrophysiological mechanisms on the ECG to explain the four HCM phenotypes identified, by using a whole-body personalized 3D computer simulation framework. We show that apico-basal repolarization heterogeneities explain the T wave inversions in the high risk group, and that an abnormal Purkinje system may explain the QRS abnormalities in another group. Finally, we further investigate the presence of repolarization biomarkers in HCM, specifically action potential alternans, and show that HCM cardiomyocytes do not overall exhibit more action potential alternans compared to controls, which may suggest other whole-organ mechanisms responsible for T wave alternans. Overall, this thesis contributes towards a better understanding of HCM phenotypic heterogeneity and the improvement of individual patient management.

Advisor: Rodriguez, B
Minchole, A
Law, poverty and time: the dynamics of poverty in constitutional human rights adjudication

Poverty is an event in time. Only dynamic thinking can fully capture its reality. This thesis contends that human rights case law is based on a static perception of poverty inconsistent with the dynamic perception of poverty in economics. Failing to notice its temporal aspects, the examined courts consequently produce judgments that overlook essential aspects of this socio-economic phenomenon. This is puzzling, since in other contexts of constitutional human rights adjudication the passage of time bears a significant role. This means that for courts to switch from a static perspective to a dynamic perspective of poverty does not require new legal tools. The duration of poverty and change in poverty can be incorporated into judicial thinking using familiar norms and doctrines.
The extent of poverty, whether it is transitory or a long-term situation, the chances of escaping it in the near future, the fluctuations in depth of poverty over the years, the probability that upon emerging from poverty one will be caught up in it again, the inheritance of poverty from parents to children: these are all time-related concerns that bear profound significance on the lives of poor people. A static examination not only overlooks these issues, but also neglects the essence of long-term poverty. Viewing poverty through the lens of time would reveal a broader and more complex human rights picture, producing a richer legal analysis, and, finally, leading to a more suitable remedy.
This study examines cases that consider claims relating to the economic situation of poor people, concentrating on examples from France, Canada and Israel. The analysis reveals the temporal approach of each judgment and suggests an alternative, dynamic reading of poverty.

Keywords: Israeli Law
Time
Canadian Law
Human Rights
Law and Economics
French Law
Poverty
Welfare Law
Advisor: Fredman, S
In modo guerrino: change and continuity in English elite conceptions of violence, 1450-1560

Debates over the issue of violence in late medieval and early modern England tend to focus on ways that the legal system and institutions attempted to control it, or on the influence of wider political or economic forces that generated violence and criminality. This overlooks, or minimises, the cultural and social meaning of violence, particularly as it was performed by members of the social elite. This thesis re-evaluates the meaning of violence for socially elite performers of violence, their victims, and their audiences through a survey of case studies drawn from the records of the central Court of King's Bench and other sources. Using research drawn from criminology, anthropology, and sociology, meaning is found in the performances of violence and their contexts. This method contrasts with previous attempts at studying violence quantitatively or through the lens of the civilizing process.
Violence is a form of communication and the way violence is performed communicates meaning and intent. This survey of cases shows how much these performances were influenced by the deeply ingrained values of martial culture and right-violence amongst socially elite performers. As the value and meaning of martial culture changed, so too did the ways in which those elites chose to perform violence. This thesis tracks some of those changes from the militarised, public, and communal performances of the last half of the fifteenth century towards the less militarised, more private and individualistic performances of violence in the first half of the sixteenth century, foreshadowing the duelling craze that followed.

Advisor: Gunn, S
(-)-Indolactam V and MO47: reducing heterogeneity in human iPSC culture

The induction of induced pluripotent stem cells (iPSCs) presents a paradigm shift for cell therapies, disease modelling, drug screenings and toxicology. Notably, the first clinical trials are attempting to bring iPSC derived therapy from bench to bedside. Consequently, the demand for iPSCs has seen a considerable surge, and thereby incentivised the scale- up from 2D to 3D culturing systems. Current iPSC culture in 2D is contact-dependent. This gives rise to a lack of uniformity in iPSC cultures: cells that experience overcompaction in the centre or a lack of external cues at the edge of iPSC colonies grow with different properties, and are prone to differentiation. Colony-independent culture is promising to reduce heterogeneity in 2D culture, enabling more reproducible iPSC growth, optimised differentiation and passaging. This research project argues for a chemical approach to improve 2D culturing: the disruption of iPSC colonies and cell-cell aggregates via two structurally related protein kinase C (PKC) activators, namely (-)-Indolactam V and MO47. As a proof-of-principle, the phenotypic effects of the small molecules were examined in 2D culture. Subsequently, the mechanism of action (MoA) of each compound was investigated by focusing on PKC and E-cadherin. Finally, we assessed whether serial treatment with MO47 would impair key iPSC characteristics. Treatment with MO47 and (-)-Indolactam V resulted in the disruption of iPSC colonies and the induction of a spread phenotype. The findings support a model, in which rearrangements of the actin cytoskeleton are accompanied by the flattening of the cytoplasm. This phenotype was strong, reproducible and reversible. Combined treatment of the PKC activators with the PKC inhibitor Gö6983 resulted in the disruption of these phenotypes. We could not confirm E-cadherin cleavage or internalisation via endocytosis as an underlying MoA. Importantly, the study provides strong evidence for the preservation of iPSC characteristics upon serial treatment with MO47. The spontaneous differentiation of MO47 treated iPSCs to endoderm, mesoderm and ectoderm in vitro resulted in the upregulation of gene signatures for all three germ layers (ScoreCard). These findings were corroborated by the successful directed differentiation to the ectodermal (cortical neurons) and the mesodermal (macrophages) lineage. Finally, the study paves the way to further studies in 3D culture with the question as to whether MO47 can prevent the formation of difficult-to-dissociate aggregates.

Advisor: Russell, A
Silpa, L
Nijman, S
Anti-CMV CD8+ T-cell epitope specificities and T-cell receptor repertoires in African study subjects

This work focuses on chronic viral infection in populations in sub-Saharan Africa. Although some of these viruses are endemic, there is a paucity of data charac- terising the immune responses in the relevant populations affected. The primary focus of this thesis is cytomegalovirus (CMV). Almost 90% of children in Africa are infected by the age of 12 months. A strong virus-specific immune response controls but does not clear CMV infection, and CMV typically remains latent; how- ever, reactivation is possible, particularly in the context of HIV infection and other states of immunosuppression. The high-frequency, immunodominant CD8+ T-cell responses, the CMV epitopes targeted, and the T-cell receptor repertoires underly- ing these responses have not previously been well defined in African populations. Furthermore, it is not known how the T-cell repertoire changes over the course of infection in response to CMV. To gain a better understanding of these aspects of CMV infection and immunity, I defined the immunodominant CMV-specific CD8+ T-cell responses within a cohort of sub-Saharan African study subjects (Chapter 3). Using next-generation sequencing of the CMV-specific CD8+ T-cell receptor (TCR) repertoire, focusing on a single immunodominant HLA-B*44:03-restricted response, I studied TCR repertoire bias (Chapter 4) and the changes in the TCR repertoire within children and adults followed longitudinally over 10 years (Chapter 5). Two other viruses, human Parvovirus 4 (PARV4) and Hepatitis B virus (HBV) are also endemic in these populations, may, like CMV, also be of particular signifi- cance in the setting of HIV co-infection, but are under-represented in the literature for Africa. I present data that I contributed to projects setting out to improve our understanding of the local epidemiology of these infections and to characterise relevant CD8+ T-cell responses (Chapter 6). Together, this work contributes to- wards a better understanding of immune responses that control chronic infections prevalent in African populations.

Advisor: Goulder, P
Matthews, P