VictorJuiz/thesis huggingface dataset:
Design, synthesis and properties of multivalent DNA nanomaterials for cancer diagnostics and therapeutics

Aptamer-functionalised DNA nanostructures have been developed as drug nanocarriers for targeted cancer therapy and other in vivo applications. Among them, hierarchical DNA nanoflowers (DNA-NFs) with densely packed DNA that can self-assemble using rolling circle amplification (RCA) hold promise for cancer therapy. To expand the functionality of DNA-NFs, the inorganic core of the nanoflowers was chemically modified through substitution of Mg2+ with either Mn2+ or Co2+ during the RCA process, resulting in formation of nanomaterials in a range of morphologies. These nanoconstructs retain the stability against enzymatic degradation of their magnesium counterparts and the Mn2+ and Co2+ DNA-NFs were endowed with magnetic properties. Cyclic nucleic acid templates are essential substrates in RCA reactions, and are most commonly obtained via enzymatic cyclisation. However, the cyclisation efficiency mainly depends upon the length of the linear precursor and is inefficient when the linear oligonucleotide has complex secondary structures. To circumvent the limitations of enzyme-catalysed DNA cyclisation, three different chemical cyclisation approaches were explored for the preparation of single-stranded cyclic DNA constructs. These chemical cyclisation methods are cheaper and easier to carry out in a large scale than their ligase-mediated counterpart. They can also be carried out under denaturing conditions and are therefore particular valuable for cyclic DNA templates containing complicated secondary structure. The resulting cyclic DNA templates contain a single unnatural backbone linkage at the ligation site (triazole, phosphoramidate or amide). They were compared to unmodified cyclic DNA templates in RCA reactions using Ф-29 and Bst 2.0 DNA polymerases. The phosphoramidate-modified cyclic templates were particularly well tolerated by Ф-29 DNA polymerase, consistently performing as well as the unmodified natural backbone in RCA. In contrast, the cyclic templates containing a triazole backbone linkage generally showed lower and more variable yields of RCA products, a significant proportion of which were double-stranded DNA side-products. The performance of the amide-modified cyclic templates fell in between those of the triazole- and phosphoramidate-modified cyclic templates. Moreover, all cyclic templates containing modified backbone linkage could be used to produce DNA-NFs during the RCA process.

Keywords: DNA nanoflower
Aptamers
Chemical ligation
Cancer diagnostics and therapeutics
RCA
Cyclic oligonucleotides
Advisor: Brown, T
Molecular mechanisms relevant to the maintenance of locomotor control

The striatum, consisting of enkephalin-positive (Penk+) and substance P-positive subpopulations of medium spiny neurons (MSNs), integrates and drives information and function of the basal ganglia circuits, which is crucial for maintaining normal movement. Preferential degeneration of the Penk+ MSNs has been observed at early stage of Huntington disease (HD). Recently, selective deletion of TrkB, high affinity receptor of brain derived neurotrophic factor (BDNF), specifically in the Penk+ MSNs (TrkbPENK-KO) led to an age-dependent spontaneous hyperlocomotion, but not to neuronal loss, indicating that TrkB is essential to maintain normal locomotor control. However, the underlying molecular mechanism still remains unknown. Dissecting the molecular changes induced in the Penk+ MSNs in the context of absence of TrkB is imperative to understand mechanism of normal locomotor maintenance. We, therefore, have performed transcriptomics analysis by next generation sequencing (RNA-seq) on the purified Penk+ MSNs with and without ablation of TrkB at two ages. Subsequent bioinformatics analysis has revealed early energy metabolism and mitochondrial dysfunction specifically to the Penk+ MSNs, leading to the severe energy deficiency at later stage. We have then validated hits from the RNA-seq data by optimising comprehensive validation approaches. Interestingly, the bioinformatics analysis led to the discovery of dopamine dysregulation in mutants at early age that could contribute to an age-dependent hyperlocomotor phenotype. Amongst the hits we validated, an enzyme involved in the glutathione metabolism, was identified as a key gene with unique expression pattern driving transcriptomic changes of the Penk+ MSNs. Furthermore, by creating a Cre-dependent shRNA lentiviral vector, we selectively knocked down specific gene expression in the Penk+ MSNs in vivo at presymptomatic age. Excitingly, this significantly rescued the hyperlocomotor phenotype of the TrkbPENK-KO mice. These findings add knowledge to the molecular mechanisms underlying normal locomotor maintenance, and they also highlight related pathway as a potential target for the development of novel treatments to movement disorders.

Keywords: Enkephalinergic neurons
Striatum
locomotor behavior
Advisor: Minichiello, L
Orthodoxy, heterodoxy, and reform: constructing an Islamic universe in the British official mind, 1860-1914

This dissertation concerns conceptualizations of Islam produced by the world of the nineteenth century British colonial official. It argues that, contrary to much of the standard scholarship concerning Western engagement with Islam and Muslims in the age of empire, the British officials who staffed the empire perceived Islam as a religion riven by sectarian division. In order to come to terms with the diversity encountered across their Islamic empire, the ‘official mind’, a reflexive acknowledgement of the importance of the Muslim world in Britain’s imperial project, attempted to bring order to this conceptual chaos by anchoring its understanding of Islam in terms of orthodoxy, heterodoxy, and reform. In the process, the official mind became subject to several contexts, the most important of which were the religious, cultural, and educational background of the officials themselves; the significance of India as the location where the most intimate relationships with Muslims were built; and the influence of native Muslim voices, who in some cases won the ear of their British masters and helped shape colonial policy.
The reality of colonial governance drove a process whereby, from the rural hinterlands of the Punjab to the urban sophistication of Cairo, British officials became arbiters of Islam. In some places this involved imposing orthodoxy, in others encouraging reform. Everywhere, it involved engaging in doctrinal controversies, evaluating authenticity within Islam, and speculating on the nature of the dozens of consciously sectarian and reformist movements which were emerging from the world of Islam in the period under review. As the official mind attempted to make sense of the Islamic universe it was constructing, a burgeoning identification with Islam developed, culminating in the project to affect reformative change in the Muslim world in partnership with the sect or movement with the most potential to unleash Islam’s essentially progressive spirit.

Advisor: Devji, F
Practising the Irish enlightenment:  the role of medical men in Ireland’s learned societies, 1683-1801

This thesis examines the neglected practice of Enlightenment in Ireland through a study of the institutional character of Ireland’s Republic of Letters. It focuses on the unique and fundamental contribution made by medical men to the life of Ireland’s learned societies. It argues that Ireland had an Enlightenment and it was Irish. It contends that medicine and medical practitioners constituted a vitally important, yet unexamined, part within it.
It suggests that Ireland experienced a moderate Enlightenment (c.1683-1790), which was founded on the notion of improvement and a radical Enlightenment (c.1791-1801), which was rooted in republicanism and revolution. It proposes that Ireland’s learned societies institutionalised a vibrant patriotic and cosmopolitan Republic of Letters between 1683 and 1801 and that their members were self-conscious engines of the Irish Enlightenment.
It argues that Ireland’s men of letters shared a common identity and fundamental commitment to the concept of improvement and were united by their belief in the advancement of knowledge, peaceful reform and, as the century progressed, to the notion of increased religious toleration. It maintains that Ireland’s medics were the leading animators and beating heart of these learned societies. It demonstrates that Ireland’s medics were engaged in ambitious programmes of social, economic and political reform. It concludes that while the pursuit of medical and natural knowledge was not the only concern of the Irish Enlightenment, it was, nevertheless, a vital component and suggests that a medical Enlightenment was taking place in long eighteenth-century Ireland.
This thesis shows, not just that the ideas of the Enlightenment had been transferred, jug to mug style, into Ireland from abroad but that the flow of knowledge was never just one way. It demonstrates how Ireland’s medics contributed to key Enlightenment debates and were active participants in a transnational Republic of Letters and Enlightenment.

Keywords: Republic of Letters
Medical Practitoners
Ireland
Enlightenment
Learned Societies and Academies
History of Medicine
Advisor: Brockliss, L
New potential waveforms for cyclic and linear-sweep voltammetry

This thesis is concerned with the simulation of electrochemical systems in general and of voltammetry using various potential waveforms in particular. Chapter 1 introduces the fundamental principles of electrochemistry essential to the understanding of this thesis, and Chapter 2 outlines the methodology used in the numerical simulation of the systems of interest.
Chapters 3 and 4 discuss the application and benefit of a non-triangular/nonlinear potential waveform to run cyclic voltammetry/potential-sweep voltammetry. In both chapters, a one-dimensional macroelectrode system is modelled for a one-electron electrochemically reversible reaction. Chapter 3 investigates the effect of cosine-based potential waves on the capacitive and Faradaic currents and proposes new opportunities to determine the formal potential of a redox couple based on the peak-to-peak separation in measured voltammograms. Chapter 4 extends the concept of a non-linear potential wave and studies the effect of a semi-circular potential wave on the current response for increased sensitivity of detection in electroanalysis. In both chapters, an experimental verification of the method are provided.
Chapters 5 and 6 extend the semi-circular potential wave method to a twodimensional microelectrode system. Chapter 5 illustrates that the semi-circular potential wave method produces similar trends at a microelectrode as it does at a macroelectrode and shows the increased applicability of the method. Chapter 6 proposes a new method for determining the standard electrochemical rate constant through the application of a semi-circular potential wave at a microelectrode based on the voltammetric features.
Chapter 7 applies the semi-circular potential waveform to stripping voltammetry for a one-electron electrochemically reversible reaction and shows how the unique voltammetric curves resulting from the semi-circular potential wave markedly increase the sensitivity.

Advisor: Compton, R
The paribhāṣā, yadāgamās tadguṇībhūtās tadgrahaṇena gṛhyante in the Pāṇinian tradition

The current work studies a paribhāṣā “metalinguistic rule” about āgama “augment” within the scope of the Pāṇinian tradition of Sanskrit grammar (vyākaraṇa). One of the forms in which this paribhāṣā (“the yadāgamaparibhāṣā”) is found is yadāgamās tadguṇībhūtās tadgrahaṇena gṛhyante (e.g. #11 in Paribhāṣenduśekhara). The current work discusses various aspects of āgama (Chapter 2), translates and explains the texts found in the Mahābhāṣya and five Pāṇinian paribhāṣā treatises that deal with the yadāgamaparibhāṣā (Chapter 3-8), and presents, based on the treatment of these texts, evaluation and remarks (Chapter 9). It argues that Pāṇini must have assumed the effect of the yadāgamaparibhāṣā, but he may not necessarily have assumed an additional paribhāṣā like yadāgamās tadguṇībhūtās tadgrahaṇena gṛhyante or tadbhaktas tadgrahaṇena gṛhayate to achieve this effect, because this effect can already be achieved through elements within the Aṣṭādhyāyī itself, i.e. sūtra 1.1.46 and 1.1.56. Therefore, such an additional paribhāṣā can be assumed, but is not necessary. The current work may thus contribute to a better understanding of: <1> the concept and function of āgama in the Aṣṭādhyāyī system; <2> the yadāgamaparibhāṣā; <3> through the previous two points, the working of the Aṣṭādhyāyī system itself; and <4> the Pāṇinian paribhāṣā literature, e.g. how a paribhāṣā is interpreted and argued about by the commentators.

Keywords: paribhāṣā
Sanskrit
Pāṇini
yadāgamaparibhāṣā
āgama
vyākaraṇa
grammar
Aṣṭādhyāyī
Advisor: Benson, J
Mathematical modelling of lead-acid batteries

Electrochemical and equivalent-circuit modelling are the two most popular approaches to battery simulation, but the former is computationally expensive and the latter provides limited physical insight. A theoretical middle ground would be useful to support battery management, online diagnostics, and cell design.
In this thesis, we present a porous-electrode model of a lead-acid battery, which includes an extension of concentrated-solution theory that accounts for excluded-volume effects, local pressure variation, and a detailed microscopic water balance.
Asymptotic analysis of the one-dimensional model in the limit of small discharge rate produces three reduced-order models, which relate the electrical behaviour to microscopic material properties, but simulate discharge at speeds approaching an equivalent circuit. A lumped-parameter model, which neglects spatial property variations, proves accurate for small discharge rates (below 0.1C), while a spatially resolved higher-order solution retains accuracy at higher discharge rates (up to 5C). The reduced-order models provide improved insight into the battery's behaviour. The models are fit to experimental data, showing good agreement.
We then consider the three-dimensional model and exploit the limit of small aspect ratio to decompose the through-cell and transverse dimensions. Further asymptotic analyses in the limit of high conductivity and/or small discharge rate give new simplified models that capture transverse non-uniformities at reduced computational cost. In the simplest case, the current collectors act as series resistors.
In order to explore the behaviour of a lead-acid battery during recharge, we return to a one-dimensional model and add an oxygen reaction to the model. We find that the oxygen recombination must be diffusion limited in the negative electrode, leading to non-monotonic voltage increase during constant-current recharge. Reduced-order models in the limit of slow recharge provide good approximations to the full charging model.

Keywords: lead-acid batteries
asymptotics
Advisor: Chapman, S
Please, C
Howey, D
Monroe, C
Investigating the role of the anti-malarial drug Atovaquone in anti-cancer therapy

Radiotherapy (XRT) is used in over half of all cancer treatment regimens and can be administered alone or in tandem with chemotherapeutics to improve clinical outcomes. Sub-physiological levels of oxygen (hypoxia) is a feature of many solid tumours and can diminish the effectiveness of anti-cancer treatments. Though its detrimental impact on treatment efficacy was first realised over half a century ago, hypoxia endures as a significant barrier to improving clinical outcomes.
Historically, numerous approaches to alleviate or even exploit tumour hypoxia have been explored; however, none are in widespread clinical use today. Most strategies were predicated on therapeutic agents reaching hypoxic areas that are difficult to penetrate, yielding minimal clinical efficacy. Attempting to increase oxygen supply directly via hyperbaric chambers was similarly ineffective. An emerging alternative approach based on modulating cellular demand for oxygen was recently pioneered by our team. We theorised that reducing oxygen consumption of cells that are located in adequately perfused areas and peri-hypoxic regions might increase the concentration of unmetabolised oxygen able to diffuse across a tumour bed and into hypoxic areas.
Using a high-throughput small molecule screen, our team previously identified that the FDA-approved, anti-malarial drug Atovaquone (ATQ) reduces oxygen consumption, upregulates glycolysis, and alleviates tumour hypoxia in vivo. As a consequence of the alleviation of hypoxia, ATQ therapy was furthermore shown to synergise with XRT. ATQ is a ubiquinone analogue, suppressing oxidative phosphorylation via direct inhibition of Complex III subunit bc1 of the electron transport chain (ETC). ATQ is a well-studied anti-malarial agent and our team is actively undertaking multiple clinical studies to evaluate its suitability as a clinical hypoxia modifier.
This thesis builds on our teams’ previous work by exploring the broader effects of ATQ in an anti-cancer setting. The first experimental chapter (Chapter 3) probes the reversibility and tolerability of ATQ in vitro and in vivo before exploring preliminary mechanistic dependencies for how ATQ reverses hypoxia. Metabolic reprogramming towards a more glycolytic phenotype has long been implicated as a key promoter of aggressiveness and metastatic spread and so Chapter 4 probes the effects of ATQ on cancer cell migration in vitro and metastatic potential in vivo. In the last experimental chapter (Chapter 5), we reveal that ATQ potentiates the anti-cancer efficacy of platinum-class chemotherapy agents by modulating ETC-driven oxidative stress. Chapter 6 summarises the findings of the thesis as a whole and discusses future directions.
Together, the data presented in this thesis suggests that ATQ is a translationally viable and well-tolerated hypoxia modifying agent having pleotropic effects that are undoubtedly deserving of further study.

Keywords: Cancer
Electron Transport Chain
Metabolism
Radiobiology
ETC
Atovaquone
OXPHOS Inhibition
Hypoxia
Advisor: Higgins, G
McKenna, G
The asymptotic theory of the gauge of the step-indicator saturation estimator and its application to study the effect of deindustrialisation on real rates

This thesis is about Step-indicator Saturation, an algorithm that identifies and models location shifts which are changes in the intercept of time series regression models. It contributes both to the asymptotic theory as well as applications of the algorithm. On theory, we develop asymptotic results about the empirical gauge of Step-indicator Saturation which is the frequency of false positives. The ability to control the empirical gauge is essential to have confidence that the location shifts identified by Step-indicator Saturation are not statistical artifacts. On applications, we use Step-indicator Saturation to study the empirical relationship between deindustrialisation and the real interest rate.
Chapter 1. We set out the mathematical framework for the asymptotic theory of Step-indicator Saturation. We establish empirical process results for differenced residuals, which introduce a specific timeseries dependence between the indicator functions. We develop techniques to handle the time-series dependence within the traditional chaining argument that is used to show uniform convergence of empirical processes.
Chapter 2. We derive asymptotic results of the empirical gauge of a stylized version of Step-indicator Saturation that uses the split-half algorithm. We prove that the empirical gauge converges in probability to the population gauge which depends on the distribution of the error terms. Moreover, asymptotic distribution results of the empirical gauge are derived. We show that the asymptotic distribution the empirical gauge of Step-indicator Saturation is larger than for Impulseindicator Saturation.
Chapter 3. We present two new ways to use Step-indicator Saturation in an empirical study. We first show that location shifts can hide an empirical relationship between two macroeconomic variables, in our case the relationship between deindustrialisation and the real interest rate. Step-indicator Saturation identifies two step-indicators that suffice to uncover a highly significant empirical relationship. Second, we apply the catalyst method to study the causal transmission of terms of trade shocks which first hit the manufacturing sector before they transmit into the real interest rate. Step-indicator Saturation is used to construct the catalyst from the location shifts in the Britsh terms of trade. We estimate that deindustrialisation can explain a 419 basis point reduction of the real interest rate from 1990 to 2017.

Advisor: Nielsen, B
Sons of Adam, daughters of Eve: original sin and the evolution of sexual difference

Since the publication of Charles Darwin’s On the Origin of Species in 1859, there has been much scholarly interest in developing a coherent synthesis between the doctrine of original sin and scientific accounts of human origins. Despite the significant interest in integrating theories of evolution with a doctrine of original sin, there has been comparatively little effort devoted to reexamining original sin in light of information about the evolution of Homo sapiens as sexually differentiated, even though the doctrine has carried implications for gendered relationships since its earliest formulations. This project fills this gap in scholarly literature by developing an interdisciplinary conversation between evolutionary biology, New Feminist Materialism, and theology in order to articulate a way of thinking about original sin that takes seriously the nature of Homo sapiens as continually evolving in sexually differentiated ways. By engaging with developments in evolutionary theory and biological information about sexual difference, the project aims to cultivate a sense of wonder at the diversity and explosive unpredictability of human biology, a value for the role of creativity in the human participation that partially shapes our ongoing evolution, and humility about the extent to which we can predict and control the future of the evolution of our species. The biological investigations in this project illuminate the interdependencies that define creaturely life, the persistent entanglement of nature and culture, the centrality of desire to human identity and behavior, and the role played by biology in the transmission of sin. These biological insights confirm some of Augustine’s anthropological intuitions. In the second half of the project, John Paul II’s Theology of the Body is juxtaposed with New Feminist Materialism in order to develop a framework for a Christian Feminist Materialism that sees material life as evolving, generative, and “imbued with activity;” but also as simultaneously infected with sin and saturated with the divine.

Keywords: evolution
sexual difference
gender
original sin
Advisor: Ward, G