VictorJuiz/thesis huggingface dataset:
Targeting polymer coated adenovirus to tumour-associated vasculature

Tumour-associated vasculature provides an accessible target for systemic gene therapy using targeted adenoviruses. The aim of this thesis is to develop strategies for targeting adenovirus infection to tumour-associated endothelium.
Adenovirus expressing luciferase (Adluc) was coated with an amino-reactive polymer based on poly [N-(2-hydroxypropyl) methacrylamide] [pHPMA] to ablate normal infection pathways¬. This was a pre-requisite to redirecting virus tropism to infect endothelial cells via specific receptors.
Direct attachment to the pHPMA-adenovirus (pcAdluc) of ligands including vascular endothelial growth factor (VEGF165) and a monoclonal antibody (RAFL) recognising VEGF receptor 2 (VEGFR-2) retargeted infectivity to VEGFR-2-positive endothelial cells and not to receptor-negative cells. Specificity of transduction in vitro was shown by competition with excess antibody. In vivo however, the VEGF165-retargeted virus failed to transduce tumour-associated endothelia following systemic administration. Similarly, direct linkage of a monoclonal antibody against E-Selectin (MHES) demonstrated E-Selectin-specific transduction of tumour necrosis factor-α (TNF-α)-activated endothelial cells, although overall levels of infection were not increased compared to unmodified Adluc.
A two-component targeting system using protein A or protein G as ‘bridging’ agents was developed to ensure the required orientation of targeting antibodies. Using this system MHES mediated greater transduction of TNF-α-activated endothelial cells than Adluc. Conjugation using protein A also gave non-specific effects which were not seen with protein G. Whereas the unmodified Adluc virus failed to transduce TNF-α-activated endothelium in an umbilical vein model ex vivo, the MHES-protein G-pHPMA-adenovirus (MHES-StrepGpcAdluc) mediated good transduction. Similarly, StrepGpcAdluc retargeted with a chimeric P-Selectin Glycoprotein Ligand-1 (PSGL-1)-Fc fusion protein, showed good circulation kinetics and significant uptake into HepG2 xenografts following intravenous administration. Histological studies suggested selective targeting to tumour-associated endothelial cells.
Overall these findings support the assertion that tumour-associated vasculature is an accessible target for systemic gene delivery, and the use of protein G as bridging agent facilitates rapid screening of Fc-bearing ligands for retargeting pcAd infection to tumour-associated endothelium.

Keywords: pHPMA
VEGFR-2
adenovirus
E-Selectin
cancer
vascular targeting
gene delivery
Advisor: Seymour, L
Design, synthesis and biological evaluation of glycosidase inhibitors in an anti-cancer setting

The aim of the work described in this thesis was to explore the synthesis of glycosidase inhibitors and to evaluate their potential as anti-cancer agents. Glycosidases catalyze the fission of glycosidic bonds and are involved in vital biological functions. With regard to their potential for anti-cancer therapy, two glycosidases were identified: α-N-acetyl-galactosaminidase and β-N-acetyl-hexosaminidase. The former has been implicated in causing immunosuppression in advanced cancer patients by negating the effect of the macrophage activating factor (MAF), while the latter is secreted by invading cancer cells and hence associated with metastasis formation.
The synthetic focus was on generating piperidine and azetidine iminosugars, carbohydrate mimetics with their endocylic oxygen replaced by nitrogen. Their structural similarity to carbohydrates make iminosugars excellent inhibitors of glycosidases. Following synthesis of a pipecolic amide, its previously reported potent β-N-acetyl-hexosaminidase inhibition was confirmed. This data, along with inhibition profiles of several pyrrolidines, allowed the generation of a molecular model for predicting activity of β-N-acetyl-hexosaminidase inhibitors. The model was used to select azetidines in the D/L-ribo and D-lyxo configuration as suitable candidates to be explored in novel chemical space, leading to the first synthesis of a fully unprotected 3-hydroxy-2-carboxy-azetidine. The potent α-N-acetyl-galactosamindase inhibitor 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) was successfully derivatised via N-alkylation.
Important structural discoveries with regard to glycosylation of vitamin D3-binding protein, the precursor of MAF, were made using MALDI mass-spectrometry. By comparing the enzymatic and cellular inhibition of N-alkylated derivatives of DGJNAc and a pyrrolidine the following generalization on iminosugar biodistribution was found: N-butylation promotes uptake into the cell/organelles, while hydrophilic side-chains restrict cellular access. An in vitro assay evaluating cancer cell invasion was devised and β-N-acetyl-hexoamindase inhibitors were shown to retard cell migration, including with the highly metastatic breast cancer cell line MDA-MB-231. Additive effects where found when the iminosugar was combined with a protease inhibitor, suggesting potential for future combination therapy.

Keywords: extra cellular matrix
azetidine synthesis
carbohydrate
beta-N-acetyl-hexosaminidase
piperidine synthesis
glycosidase inhibitor
alpha-N-acetyl-galactosaminidase
anti-cancer
iminosugar
macrophage activation factor
Advisor: Fleet, G
Butters, T
'Movie-made generation': cinema-going and the novel in post-war Britain

This thesis examines how the reading and writing of the post-war British novel is altered by the emergence of an 'everyday' cinema-going culture amongst young people in the 1920s, 30s and 40s. The thesis demonstrates how viewing and reading practices converge in the twentieth-century and how the resulting modification of the visual literacy of this new, 'movie-made' generation of 'cinesthetic' writers and readers refigures realism in this period. Such cinesthetic realism can be differentiated from the modernist mode of the 'camera-eye' by how it elicits interactive (and often sexist) affects and leads to techniques such as 'indexical characterisation' and a consideration of 'extratextual' narratives. Thus, the thesis argues for the post-war period as one of literary innovation as opposed to the regressive, anti-modern epoch it is still widely labelled.
The work encompasses a broad range of novels and novelists: 'Invitations to a Candy-Floss World?' explains how John Braine's 'documentary' fiction engages with cinematic escapism, how Colin MacInnes incorporates cinema-going as an emblem of marginalisation, and how Alan Sillitoe positions cinema as a 'valid' literary influence; 'I Could Have Bitten Her' examines the influence of Philip Larkin's addiction to cinema in his debut novel, John Wain's investigation of the cinesthetic reification of the post-war novelist, and Kingsley Amis' extratextual and (surprisingly) feminist endeavours; 'Passionate Detachment' explores Muriel Spark's employment of cinema to represent a crisis in feminine ipseity, Lynne Reid Banks' use of 'sexist' cinema as a proto-feminist trope (in conjunction with an interview with Banks), and Iris Murdoch's relationship with cinema as 'Plato's Cave', which leads to refigurations of realism and feminist forms of escape.
Ultimately, this thesis aims to foreground an underestimated aspect of the transition between the 'late modernist' and the 'contemporary' in British fiction.

Keywords: postwar
novel
cinema
indexciality
realism
cinesthetics
Advisor: Marcus, L
Aqueous droplet networks for functional tissue-like materials

An aqueous droplet in a solution of lipids in oil acquires a lipid monolayer coat, and two such droplets adhere to form a bilayer at their interface. Networks of droplets have been constructed in this way that function as light sensors, batteries and electrical circuits by using membrane proteins incorporated into the bilayers. However, the droplets have been confined to a bulk oil phase, which precludes direct communication with physiological environments. Further, the networks typically have been assembled manually, which limits their scale and complexity. This thesis addresses these limitations, and thereby enables prospective medical and technological applications for droplet networks.
In the first part of the work, defined droplet networks are encapsulated within mm-scale drops of oil in water to form structures called multisomes. The encapsulated droplets adhere to one another and to the surface of the oil drop to form interface bilayers that allow them to communicate with each other and with the surrounding aqueous environment through membrane pores. The contents of the droplets can be released by changing the pH or temperature of the surrounding solution. Multisomes have potential applications in synthetic biology and medicine.
In the second part of the work, a three-dimensional printing technique is developed that allows the construction of complex networks of tens of thousands of heterologous droplets ~50 µm in diameter. The droplets form a self-supporting material in bulk oil or water analogous to biological tissue. The mechanical properties of the material are calculated to be similar to those of soft tissues. Membrane proteins can be printed in specific droplets, for example to establish a conductive pathway through an otherwise insulating network. Further, the networks can be programmed by osmolarity gradients to fold into designed shapes. Printed droplet networks can serve as platforms for soft devices, and might be interfaced with living tissues for medical applications.

Keywords: encapsulation
lipid monolayer
droplet interface bilayer
multisome
membrane
membrane protein
emulsion
lipid bilayer
3D printing
drug delivery
synthetic biology
Advisor: Bayley, H
Kapanidis, A
Dissecting the interactive effects of hypoxia and Kaposi's sarcoma-associated herpesvirus on microrna and mrna transcriptomes

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several tumours and hyperproliferative disorders. Hypoxia plays an important role in KSHV lifecycle, as hypoxia-inducible factors (HIFs) are involved in the latent/lytic switch and affect other KSHV genes, and as KSHV infection can in turn enhance cellular levels of HIFs. Two KSHV-associated tumours tend to develop in settings of relative hypoxia; Kaposi's sarcoma (KS) often occurs in the lower extremities and primary effusion lymphoma (PEL) exists in pleural effusions. A better knowledge of the pathways that regulate KSHV infection in hypoxia is therefore essential for an improved understanding of viral infection and pathogenesis. MicroRNAs (miRNAs) have been shown to play important roles in regulating the expression of genes in oncogenesis, and herpesviruses, including KSHV, encode for miRNAs.
This thesis describes a multidisciplinary approach toward understanding the mechanisms behind the hypoxia-regulated miRNA-mRNA networks in the context of KSHV infection. The question of miRNA and mRNA regulation through hypoxia, KSHV or both is addressed in this thesis by deep sequencing and gene expression assays as well as various transfection and functional assays. In chronically infected cells compared to uninfected controls, it is demonstrated that the majority of cellular miRNAs whose expression is affected are substantially down-regulated. A third of this down-regulation can be attributed to a single genomic region, 14q32 cluster, where miRNAs are lowly expressed in infected cells. In hypoxia, hsa-miR-210 is the only miRNA to be consistently up-regulated in the KSHVinfected cell lines subjected to deep sequencing in this study. Computational approaches additionally allowed for the investigation of mRNA targets. Inversely correlated miRNAmRNA target pairs were identified and distributed into canonical pathways and biological networks.
Taken together, these results suggest that miRNAs affected by hypoxic stress and/or viral infection are implicated in the pathogenesis of KSHV-related diseases. It is expected that the outcomes of these studies will change our understanding of how KSHV uses the host RNA silencing machinery to its advantage and how this intersects with the use of the cell's response to hypoxia.

Keywords: Kaposi's sarcoma-associated herpesvirus
microRNA
Next-Generation Sequencing
Genomics
Advisor: Pezzella, F
Ragoussis, J
Yarchoan, R
A comparative legal study of the war power in the constitutions of Australia, Canada, and the United States

It is the object of this dissertation to consider, as a problem of constitutional law, the nature and scope of the war power of the central government in Australia, Canada, and the United States. The war power is something of an anomaly in federal constitutional law. In exercising it the central government may transcend the federal division of powers which is described in the organic law, and, to an extent which varies with the degree of emergency which is present, may invade an area which is normally reserved to the regional governments. Under conditions of an emergency attributable to war, the central government may also enact war legislation which in normal times would be considered to fall within the prohibition of a constitutional limitation.
The constitutional systems of Australia, Canada, and the United States exhibit, sufficient similarities to make a comparative study of the war power profitable. In each the wax power is entrusted to the central government; in each the regional governments possess other reserved powers which in normal times may not be exercised by the central government; in each the federal judiciary has the last word in interpreting a written constitution. But certain basic dissimilarities dictate the pattern which this comparative study must follow.
[Please see pdf. for full abstract.]
An investigation into the role of methylation in mammalian X-chromosome inactivation

X-chromosome inactivation achieves dosage compensation of X-linked genes between male (XY) and female (XX) mammals. This process involves the down-regulation of most, but not all genes on one of the two X-chromosomes in the nucleus of each female somatic cell. The mechanism of X-inactivation has yet to be elucidated in full, but is known to involve the noncoding transcript of theXist gene, DNA methylation, histone hypo-acetylation and the condensation of higher order chromatin. Recent studies have established mechanisms linking methylation to repressive chromatin structures through methyl-binding proteins and histone deacetylase complexes.
In order to better understand the role of methylation in X-inactivation, the promoters of the human Pyruvate dehydrogenase El a (PDHA1) and the human and murine Norrie disease protein (NDP/Ndp) genes were subjected to direct methylation sequencing, allowing the definition of methylation profiles at nucleotide resolution. The promoter of the PDHA1 gene was found to be hyper-methylated on the inactive X-chromosome and hypo-methylated on the active X-chromosome in agreement with studies at the promoters of other X-linked housekeeping genes. Methylation at the promoters of the NDP/Ndp genes was extensively investigated in a range of primary tissues and cell lines. The Ndp promoter was found to be methylated on both active and inactive X-chromosomes, but hypo-methylated in the proximal promoter exclusively in tissues that expressed the Ndp gene. The NDP promoter was found to be unmethylated on the active X-chromosome and hyper-methylated across the proximal promoter on the inactive X-chromosome in expressing cell lines and human retinal tissues. The novel promoter sequences of the human and murine SMCX/Smcx genes were isolated for comparative analysis and to provide a future resource for studying methylation at the promoters of genes which escape the X-inactivation process.
Promoter sequences of the PDHA1, NDPI Ndp and SMCX/Smcx genes were screened for putative transcription factor binding sites and for conserved CpG-dinucleotide content. Promoter-reporter gene constructs for these genes were transfected into mammalian cells establishing that the sequences studied were functional promoters. Artificial methylation of these constructs was shown to repress their promoter activities.
Single photon avalanche diodes for optical communications

In order to improve the sensitivity of an optical receiver, the gain and the collection area of the photo-detectors within the receiver should be increased. Detectors with internal gain such as avalanche photodiodes (APD) are usually used to increase the sensitivity of the receiver. One problem with APDs is the sensitivity of their gain to their bias voltage, which makes them challenging to be fabricated in a standard CMOS process due to variations in their gain. However, when an APD is biased over its breakdown voltage, it is sensitive to a single photon, hence, referred to as a single photon avalanche diodes (SPAD). The SPADs are photon-counting detectors, which are less sensitive to their bias voltage, and can be integrated with rest of the electronic circuitry that form an optical receiver. An avalanche diode requires dedicated circuits to be operated in the SPAD mode. These circuits make the diode insensitive to an incident photon for a duration that is known as deadtime. Unfortunately, The collection area of the PD, APD, and SPADs are limited to their capacitance. Hence, a large photo-detector leads to a larger capacitance, which reduces the bandwidth of the receiver.
In this thesis, a photon counting optical receiver based on an array of SPADs is proposed which increases the collection area with a low output capacitance. The avalanche diode and peripheral circuits which operate and readout-out the SPAD array are fabricated in the commercially available UMC 0.18 μm CMOS process. Initially, the avalanche diode is tested and characterised. A high performance circuit is then designed and tested which is able to achieve short deadtimes up to 4 ns. Once the photon counting operation of the SPAD is verified, a numerical model is developed to investigate the influence of several factors, including the deadtime, on the performance of the photon-counting detector in a communication link. Based on the simulation results, which show the advantages of an array over a single detector, a prototype detector array of 64 asynchronous SPADs is designed and tested. This array uses a high-speed readout mechanism which is inspired by the current steering digital-to-analogue converters. Bit error ratio tests (BERT) verify the photon counting capability of the proposed detector, and a bit error rate of 1E-3 has been achieved at data rate of 100 Mbps. In addition, the array of SPAD is compatible with a front-end of conventional optical receiver which uses a photodiode as a photo detector.

Keywords: poisson channels
mixed analog digital integrated circuits
optical receivers
single photon avalanche diode
CMOS
Advisor: Collins, S
China and Ethiopia: the political dynamics of economic relations in the new global order

How can political science account for the decision of African states to strengthen their ties with China, often at the expense of other alliances and often in the face of economic risks? This thesis explores this question in the context of relations between Ethiopia and China, especially in the context of investments made by Chinese sovereign wealth funds in the Ethiopian economy. To begin to answer this question this thesis recasts the China-Africa debate to focus on African, i.e. Ethiopian, agency. The focus is on how Ethiopia's political leaders make foreign policy decisions and on the factors that shape their preferences. This focus reveals the influence of cognitive variables on their foreign policy decisions; the influence of their guiding ideology, 'revolutionary democracy,' is especially key. An analysis of Ethiopia's formal institutions demonstrates they are inadequate to explain the policy choices of Ethiopian leaders; they have been designed to reflect the concepts of revolutionary democracy.
Using the language of prospect theory, a descriptive theory of decision-making under risk, this thesis contends that Ethiopian leaders select foreign policy options by weighing their possible outcomes as gains or losses relative to revolutionary democracy as their reference frame. Ethiopian leaders sanctioned China's finance of the Ethiopian Telecommunications Corporation despite the monopoly it gave to China and its impact on Ethiopia's debt. They formed a front company between Ethiopia and China's military industrial complexes despite its negative effects on economic development. They opened Ethiopia’s regions to Chinese capital although capital flows only to state-owned enterprises. Yet in each case, ideological objectives were advanced.
This examination demonstrates how non-structural factors play a critical role in a bureaucratized state. Theoretical frameworks that account for these factors, like prospect theory, are therefore valuable to more robust understandings of Ethiopia, and Africa's, deepening relations with China.

Keywords: foreign policy
Ethiopia
prospect theory
China
ideology
sovereign wealth funds
Advisor: Anderson, D
"This Mecca for the Pilgrims of Pleasure": tourism, modernity, and Victorian London, 1840-1900

This dissertation argues that during the nineteenth century, the journey to London revealed a world undergoing systemic change as industrialisation steadily eroded the traditional rhythms of the countryside in favour of urban modernity; indeed, London is regarded as a synecdoche for the forces shaping the wider world. This work uses tourist narratives to London as investigative tools to examine the ways in which individuals comprehend the modern changes occurring around them, as represented by the British capital, and does so in a comparative fashion, investigating the British Empire, the United States, Britain itself, and continental Europe. In so doing, it addresses two questions: first, whether one’s acceptance or rejection of modernity was predicated upon specific social and national preconditions; and second, whether the idea of nineteenth-century modernity was itself a non-universal construction dependent upon a variety of socio-cultural outlooks. The evidence for this study is drawn from the published and unpublished narratives of tourists from the four different contexts mentioned above, and divided into four chapters to focus upon each group. This study is grounded in a theoretical context which establishes a correlation between the methods used to interpret the city’s spaces, and the methods used to interpret modernity more generally. I conclude that the changes occurring from the interaction between global modernity and local culture were regarded with ambivalence and uncertainty, judgments influenced by London’s impact on the visitors mentioned above. The city gives a physical dimension to the travellers’ imagined fears, benefits, or concerns over future progress. Victorian London is thus one focus for a transformation affecting large segments of the nineteenth-century world, illustrating that modern industrial changes were ultimately perceived as being ambiguous and ambivalent forces.

Keywords: tourism
industrial society
technology
visitor perceptions
modernity
international travel
London
Advisor: Davis, J