VictorJuiz/thesis huggingface dataset:
Identification of novel players implicated in replication-dependent and independent DNA interstrand crosslink (ICL) repair
Keywords: DNA damage repair
DNA interstrand crosslink (ICL) repair
Fanconi Anaemia (FA) pathway
THYN1

The integrity of the genome is constantly under threat from within and without. Cells rely on the evolutionary conserved DNA damage response (DDR) mechanism to orchestrate the repair of DNA lesions and thus prevent the accumulation of mutations. One of the most deleterious types of DNA lesions, interstrand crosslink (ICL), occurs when a crosslinking agent forms covalent bonds with both strands of the double helix and tethers them together. The most well-studied among ICL repair pathways is the Fanconi Anaemia (FA) pathway, the disruption of which gives rise to a disorder of the same name. Both the FA pathway and the more recently-discovered NEIL3 pathway are replication-dependent. However, replication-independent pathways also exist and they are likely responsible for the repair of ICLs in non-dividing cells.
This thesis describes the optimisation of a purification scheme, which was designed to identify hitherto unknown players in ICL repair out of a pool of nuclear proteins. The scheme exploited the likely binding preference of such proteins for crosslinked over non-modified DNA probes. Two types of probes, linear and replication fork mimic, were designed to capture the proteins putatively associated with replication-independent and -dependent ICL repair pathways, respectively. The scheme was successfully used to identify UHRF1 and BOD1L1, two proteins with already known links to ICL repair, as well as THYN1, an EVE-domain-containing protein with no established roles in DDR. THYN1 is rapidly recruited to ICL sites in vivo and its absence confers hypersensitivity to psoralen-induced ICLs. THYN1 operates in the same pathway as FANCD2 in the repair of psoralen-derived lesions; however, unlike FANCD2, its activity is not cell cycle-dependent. Interestingly, THYN1 exerts a negative influence on MMC and cisplatin repair in FANCD2-deficient cells. Identification and analysis of putative THYN1 binding partners may help to explain this phenotype and to elucidate the molecular mechanisms which underpin THYN1-mediated repair.
Alkyne probes and natural products
Keywords: organic chemistry
synthesis

This thesis is split into two projects, both of which involve efforts to synthesise compounds containing alkynes. The first project is related to the synthesis of probes to label plant CYP450s, a key superfamily of enzymes involved in plant metabolism. The second project details efforts undertaken towards the synthesis of natural products isolated from the Laurencia genus of red algae.
Chapters 1 and 3 provide introductions to the respective projects. CYP450 enzymes and activity-based protein profiling (ABPP) are introduced in chapter 1. Chapter 3 provides some background to the Laurencia natural products; the biosynthetic postulates proposed for the formation of the diverse skeletons seen in the chemical structures are presented and a selection of interesting total syntheses carried out by numerous groups are also set forth.
Chapter 2 details the synthesis of CYP450 probes of a number of generations (termed G1 through G4) and outlines some of the challenges faced not only in the synthesis of these probes, but also with respect to observing labelling of the CYP450 enzymes in planta.
Chapters 4 and 5 concern the synthetic endeavours undertaken towards the total synthesis of ent-laurepinnacin, a natural product from the Laurencia genus, using a key silver(I)-mediated skeletal rearrangement involving complex oxonium ions as key intermediates. Chapter 6 concludes the thesis by detailing the development of an alternative protocol for the skeletal rearrangement, allowing access to alternative natural products ent-(E)-notoryne and laurendecumenyne B.
Democracy as procedure and principle: essays on social groups and democratization
Keywords: Political Elites
Social Identity
Democratization

p>How does inequality between social groups impact the politics of democratic change? Several scholars of democratization argue that individuals (a) intuit principles about procedural democracy that consequentially affect the distribution of benefits and; (b) form preferences between democracy and dictatorship based on which maximizes the utility of their social group. This thesis argues for a more comparative understanding of both (a) and (b) through three primary means. First, it compares and contrasts three different and contradictory principles of democracy namely the popular, liberal and associational principles. Second, it looks at a wider variety of social groups through studying gender, class and ethnic identity. Third, it considers a wider variety of inequalities that includes not only economic, but also social, political and demographic inequality.
The chapters of this thesis explore how different varieties of inequality between different social groups can impact the politics of democratic change. The first chapter provides a comparative overview of the role social identity plays in shaping individual preferences and compares and contrasts different principles of democracy. The second chapter introduces a new data set on political elite (WhoGov) which constitutes the largest database of political elite that is publicly available. The third chapter argues that civil and political empowerment of women each have differential impacts on the probability of democratic transition. The fourth argues that influence in democratic executive politics by the authoritarian elite is a function of the predatory economic legacies left by the previous authoritarian regime. The fifth argues that the size of an ethnic group to which an individual belongs does not predict support for democracy. Instead, group size influences the salience with which individuals view differing principles of democracy. The final concludes with policy implications for proponents of democratic change and discusses extensions for WhoGov that can enable scholars to better study how social identity and elite-level politics interact.
Robustness of evolutionary and glassy systems
Keywords: statistical physics
evolution
spin glass
genotype-phenotype maps
robustness
graph theory
maximum entropy
input-output maps

Systems which take in a sequence-based input to produce a nontrivial output are ubiquitous across science. One key property of such maps is the robustness of the output upon random changes of the inputs. Interestingly, recent work on genotype-phenotype maps in biology has shown that the robustness, defined as the probability that a point mutation to the genotype does not change the phenotypic output, is typically exponentially higher than a null expectation based on a random input-output pairings. This high robustness must arise from correlations in the input-output map. In this thesis, we investigate the origins of these correlations.
We first study spin glasses, defining the inputs as the set of interactions, and the outputs as the ground-state spin configurations. We find that the robustness in this generic model exhibits behaviour that is consistent with the scaling laws observed for the biological genotype-phenotype maps, suggesting that the robustness behaviour has a more universal origin.
Next, we use a maximum-entropy approach to study generic sequence-based input-output maps on Hamming graphs. If we constrain the global robustness, we find that there are two states, as a function of the strength of the constraint. The fragile phase is similar to the null-model based on completely random pairings, and has low robustness. By contrast, for a stronger constraint, there is a rather sudden change to a different correlated behaviour. Interestingly, this very simple model exhibits scaling of the robustness, the distribution of neutral component sizes, and the probability of obtaining a different output upon mutations that are remarkably similar to those found for a series of genotype-phenotype maps. Finding these detailed results in such a simple model suggests that they have near-universal origins in GP maps, and possibly in a wider set of real-world mappings.
Maximally robust neutral networks are then explored from a graph-theoretic perspective, elucidating connections between the robustness bound and a function from number theory. We then discuss trade-offs natural systems face in simultaneous optimisation of robustness and information content and robustness and population neutrality. Upon coarse-graining phenotypes, it has been observed that robustness decreases relative to what one might expect from the underlying finer-grained phenotypes. We explain this non-intuitive behaviour quantitatively. We then extend the notion of robustness to input-output maps with continuous inputs, predicting a novel natural scaling law for robustness in these systems. Recent numerical results from deep neural networks support our theory.
The thesis concludes with a return to spin glasses, now in the context of evolutionary adaptation. We study short-term evolution on glassy fitness landscapes following non-adiabatic perturbation of metastability and characterise how variances in epistatic and external interactions influence timescales and change in fitness.
Exploiting the structure of turbulence with tensor networks
Keywords: data-compression
quantum computing
tensor networks
computational fluid dynamics
optimisation
non-linear
turbulence
matrix product states

Turbulence is among the most important unsolved problems of physics. Its numerical solution is hindered by the extreme number of computational variables needed to accurately resolve the broad range of length-scales that become relevant during turbulent flow. It turns out that a similar challenge appears in a completely different branch of physics. Quantum many-body systems are described by elements of a vector space whose dimension grows exponentially with the number of particles, making direct simulation infeasible. However, the actual information contained in realistic quantum states is typically only polynomially large in the number of particles, which in principle makes it possible to represent them using a polynomial number of parameters. Tensor network methods do precisely this for quantum systems with local interactions by removing unrealised long-distance correlations from the solution space, which in turn enables accurate simulation of otherwise intractable quantum systems. In this thesis, a simple tensor network formalism known as the matrix product state (MPS) ansatz is transferred from quantum physics onto fluid dynamics and used to numerically examine two paradigmatic turbulent flows: the 2D temporally decaying jet and 3D collapse of the Taylor-Green vortex. We find both flows to be structured according to the classical, scale-local view of turbulence, where flow features of disparate scales are largely uncorrelated. We eliminate these unrealistic interscale correlations from the solution space through our MPS encoding of the velocity field, and then formulate a MPS algorithm for simulating turbulence. With this algorithm, we find that the incompressible Navier-Stokes equations can be accurately solved even when reducing the number of computational parameters by more than one order of magnitude compared to traditional direct numerical simulation. The outlook is threefold. Further work towards harnessing the power of tensor networks for turbulence simulation holds the promise of computational fluid dynamics calculations that are yet inconceivable in scale. Moreover, the close connection that our MPS algorithm has to quantum physics points towards the exciting prospect of solving the Navier-Stokes equations on a quantum computer. Finally, from a theoretical standpoint, this work also lays the foundations for studying the structures of turbulence using tensor network theory. One topic of particular interest here is what tensor network geometry is most appropriate for turbulence simulations and why. Answering this question will illuminate the structure of turbulence from a completely new angle, and perhaps help unravel the old riddle that is predicting the dynamics of turbulent flows.
Local order in conflict
Keywords: Statebuilding
Cooperation
Local Order
Competition
Territorial Strategy
Armed Conflict
Agency

This thesis examines the intersections of development and security in the implementation of infrastructure projects in Colombia. The study of infrastructure in armed conflict largely focuses on its potential to deliver security through statebuilding and tends to only examine armed groups when they target infrastructure to undermine state presence in the territory. Yet, armed groups and states also cooperate, coopt, or coexist during and after internal armed conflict. Without incorporating these interactions, we lack a complete picture on how development impacts security.
I build a theoretical framework to show four interactions between the state and armed group during infrastructure implementation on a spectrum between competition and cooperation. Depending on the interaction, the state and armed group use distinct territorial strategies to secure their presence that shape the local order. I develop this theoretical framework through a grounded approach, employing a most-similar subnational research design to examine state-led infrastructure implementation in areas occupied by armed groups in Colombia. Drawing from 82 interviews in the regions of Northern Antioquia and Pacific Nariño, I process trace the local impact of state and armed group interactions during infrastructure through the mechanism of territorial strategies.
By applying an infrastructural lens to armed conflict, I show that the most insecure local orders are at both ends of the spectrum: extreme competition and close cooperation. When the state and armed group are in the mid-range of the cooperative end of the spectrum, their territorial strategy produces security. Yet I show that development – through infrastructure implementation – produces security and agency only when the state and armed group are in competition, not cooperation.
Wisdom in the Qur'an
Keywords: Golden Rule
Agelomorphic Christology
Decalogue
late antiquity
rabbinic Judaism
Syriac Christianity
apocalyticism
patristics
quran
islam

This dissertation is an attempt to understand what the Qur’an means by the term ḥikmah. I argue that the Qur’an, when it uses the term, is engaging with biblical wisdom discourse, as it had been interpreted and understood in late antiquity. Wisdom texts are a category of books in the Hebrew Bible and Apocrypha, such as Proverbs and Sirach, that emphasize the importance of acquiring wisdom through contemplating the natural world and one’s own life experience. The presence of this wisdom genre in the Bible encouraged Hellenistic Jews and early Christians to embrace the Greek philosophical notion of natural law, the idea that what is morally right and wrong is known innately, and confirmed through divine revelation. Over subsequent centuries, church fathers and rabbis continued to debate what the relationship between divine revelation and natural law / wisdom ought to be. I argue that when the Qur’an invokes ḥikmah, it engages in that debate, and ultimately presents a relationship between scripture and natural law that is close to the Christian conception.
Towards polyyne rotaxanes and catenanes
Keywords: catenanes
cyclocarbons
acetylene
thermal stability
rotaxanes
polyynes
masked alkyne equivalents
template-directed synthesis

This thesis summarises attempts towards polyyne [n]rotaxanes and cyclocarbon [n]catenanes. Carbon allotropes built purely from sp carbon atoms have long fascinated chemists but have yet to be isolated or characterised due to their high reactivity. This thesis documents work towards isolating both linear and cyclic sp carbon chains.
Chapter 1 reviews the history of carbon allotropes, focussing on cyclic and linear forms of sp carbon. Synthetic strategies towards preparing acetylene-rich molecules, rotaxanes and catenanes are discussed.
Chapter 2 discusses development of a novel masked alkyne equivalent (MAE) with intrinsic metal binding abilities. A simple masked triyne can be synthesised in only three steps, but photochemical unmasking of this group could not be realised due to a competing dimerisation process.
Chapter 3 details new strategies for synthesising polyyne [3]rotaxanes with two macrocycles on the same polyyne thread. An active metal template route using dicobalt-masked precursors was developed to prepare two polyyne [3]rotaxanes. The thermal stabilities of the two rotaxanes were evaluated relative to the naked polyyne dumbbell and were found to be significantly more stable in decalin at 80 °C.
Chapter 4 presents a novel approach to cyclocarbon [n]catenanes and polyyne [n]rotaxanes. The coupling of a [2]rotaxane bearing two temporary bulky MAE stoppers provides access to precursors of cyclocarbon [n]catenanes and polyyne [n]rotaxanes. Early unmasking experiments have successfully afforded a polyyne bearing 24 contiguous acetylene units and indicate that larger polyynes should be viable using this route.
Chapter 5 summarises
Creating and functionalising a synthetic compartment in plants
Keywords: OSER
Synthetic biology
Endoplasmic reticulum
Synthetic organelles

Compartmentalisation is a universal feature of life, allowing organisms to separate their functions from each other and the environment. It enables greater control and complexity for cellular processes. Taking a cue from nature, engineered compartmentalisation has become one of the top priorities of synthetic biology. While many alternative strategies have emerged, building a synthetic membranous organelle de novo remains prohibitively difficult, despite its potential as a tool for metabolic engineering. This lack of an orthogonal synthetic organelle especially hampers the development of the nascent plant molecular farming industry. In this thesis, I describe the design and characterisation of a novel synthetic membranous compartment derived from the plant endoplasmic reticulum (ER), and proof-of-principle experiments to showcase its potential as a bioproduction platform in plants. The formation of the compartment is triggered by overexpression of a single recombinant scaffold protein, and I investigated the relationship between the structure of the scaffold protein and the morphology of the resultant compartment. I also compared the compartment to a conceptually similar ER rearrangement called organised smooth endoplasmic reticulum to determine their relation. Notably, the formation of the compartment had very little impact on the overall health of the host plant, and successful pilot experiments for the purification of the scaffold and other proteins anchored to it, as well as running enzymatic reactions on the surface of the compartment demonstrate the great potential of this system to serve as a plant synthetic biology tool. With further development, this platform could be a valuable asset to the plant biosynthesis and recombinant protein production industry.
Cowper's Olney Hymns: usefulness, locality, and the puritan context
Keywords: Eighteenth century revival
Evangelical revival
Poetry
Theology
William Cowper
Puritanism
Olney
John Newton
Olney Hymns
Evangelicalism
Buckinghamshire
Eighteenth Century
Hymns

This thesis argues that William Cowper’s Olney Hymns should primarily be read within their immediate context and according to the intent of their author: as local texts, written to be used for specific purposes by a specific readership and on specific occasions. In proposing this reading, it runs contrary to scholarly convention, which until now has largely understood the hymns to be effusions of spiritual feeling or psychological torment.
This argument is built upon a necessary redressal of our received understanding of Cowper himself, particularly during his hymn-writing period from 1768-72. Challenging traditional depictions of him as the ‘sick man of Olney’, the introductory section uncovers Cowper’s role as an active resident of his local parish, his work as an informal companion in ministry to John Newton, and his standing as a spiritual and theological authority within the Evangelical community at Olney.
Part One situates Cowper’s hymns within Olney and posits them as sophisticated and intentionally ‘usefull’ texts, emerging from their locale and responding to the needs, tastes, and reading contexts of their first readership: the members of John Newton’s weekly Evangelical prayer meeting. Part Two considers Cowper’s interactions with seventeenth- and eighteenth-century theological thought, and demonstrates that much of the content of his Olney Hymns is either influenced by or explicitly engaging with the work of several Puritan and Evangelical divines.
As a historicist and theological reading of Olney Hymns, this thesis approaches these issues via careful and extended use of sources close to the poet, authored by him, or belonging to his context.
Utilising anhydride reactivity to target endogenous human proteins
Keywords: Protein conjugation
Nanoassembly
Synthetic biology
Proximity labeling
Chemical biology
Protein engineering

Covalent conjugation between proteins has been used to develop novel drug delivery methods, enhance therapeutic efficacy, and improve diagnostic sensitivity. Proximity-directed ligation methods enable coupling to unmodified endogenous proteins. A diverse range of proteins contain autoproteolytic domains that cleave at an Asp-Pro bond via an aspartic anhydride intermediate. In this thesis, the anhydride is harnessed as an electrophilic warhead for targeted conjugation. I developed NeissLock, a technology that uses the self-processing module (SPM) of the FrpC protein from Neisseria meningitidis. SPM is fused to the C-terminus of the binder protein so that the anhydride generated upon calcium-induced activation reacts with proximal nucleophiles on the target. NeissLock, using the standard genetic code, enables rapid and specific coupling under mild conditions.
I discovered that the FrpA SPM variant has an enhanced activation rate compared to the first-generation NeissLock. I developed a bacterial surface display system for directed evolution of SPM, towards improving the cleavage yield and stability of the domain. Finally, I established the split SPM system by splitting the domain into 2 fragments to provide another level of control over SPM activation. The fusion of SpyTag003/SpyCatcher003 to the split SPM fragments increased the coupling efficiency. Split SPM facilitates the mammalian expression of binder-SPM fusions, broadening the applicability of NeissLock. I fused various human red blood cell-binding peptides to SPM to test for coupling to human red blood cells. Covalent conjugation of therapeutic proteins to red blood cells using NeissLock would increase the stability of coupling compared to non-covalent methods, potentially enhancing drug delivery using red blood cell carriers.