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Accelerating SARS-CoV-2 Translational Research Workflows for Molecular Diagnostics, Immune Monitoring and Host Response
No full textThe emergence of SARS-CoV-2 created a global crisis, prompting unprecedented efforts by the scientific and medical communities to develop and roll-out diagnostic assays, therapeutics, and vaccines. These efforts significantly reduced viral transmission and saved lives. In 2020, rapid RT-qPCR diagnosis of SARS-CoV-2 became fundamental for pandemic control. However, global demand for testing threatened the testing capacity of Irish hospitals. To address this, we developed a viral RNA extraction workflow with medium-to-high throughput capacity, high reproducibility, and high sensitivity and specificity compared to commercial platforms. This Viral RNA Extraction Kit (VREK) was ready to supply to local hospitals if needed. Quantifying neutralising capacity of circulating SARS-CoV-2 antibodies is essential for evaluating protective immune responses generated post-infection and post-vaccination. We developed a novel medium-throughput flow cytometry-based micro-neutralisation test (Micro-NT) to evaluate neutralisation titres (NT50) against live SARS-CoV-2 Wild Type and Variants of Concern (VOC) in convalescent or vaccinated populations. Micro-NT achieves results comparable to traditional Plaque eduction Neutralisation Test (PRNT) but in less time, and with higher throughput. Using Micro-NT, we quantified NAbs from sera following COVID-19 vaccination and/or infection. We found a strong correlation between NT50 and antibody titres against the SARS-CoV-2 Spike protein, specifically the Receptor Binding Domain (RBD). An IgG titre of 456BAU/ml predicted neutralisation capacity against WT SARS-CoV-2 and Omicron BA.5 in in two diverse cohorts, providing a discrete threshold for identifying individuals at risk of developing severe COVID-19. NT50 serves as a correlate of protection against SARS-CoV-2 infection and severe disease, useful in COVID-19 vaccine trials. COVACC is a European Phase 3 clinical trial assessing reduced COVID-19 mRNA vaccination regimens in paediatric subjects with prior infection. Evaluating NT50s against WT SARS-CoV-2, Omicron BA.5 and Omicron JN.1, we concluded that a one-dose regimen was non-inferior to a two dose regimen in developing functional antibodies against these variants
Ionic Liquids as Enabling Formulations for Poorly Bioavailable Drugs
No full textOral delivery of active pharmaceutical ingredients (APIs) is the most predominant route of drug administration. The bioavailability of orally administered drugs is mainly dependent on their aqueous solubility and membrane permeability properties. Ionic liquid forms of drugs, known as API-ILs, have emerged as a promising solution to address challenges posed by poorly bioavailable drugs and solid-state stability. These organic salts, typically liquid at room temperature, have demonstrated the ability to enhance both aqueous solubility and membrane permeability of APIs. To further optimize their properties, lipidic excipients were successfully incorporated into API-ILs in this study. However, for the routine integration of liquid API-ILs into oral solid dosage forms, challenges related to ease of handling and manufacturing need to be addressed. Therefore, a comprehensive framework has been developed for transforming API-ILs and their lipidic multi-component solutions into solid presentations using spray encapsulation with various polymers. Multiple APIs spanning all BCS Classes were successfully transformed into ionic liquids and solidified, with subsequent evaluation of the solid API-IL products for dissolution, membrane permeability, stability, and powder flow properties, gauging their suitability for incorporation into oral solid dosage forms. Finally, two distinct isolation-free manufacturing processes were devised for the synthesis, purification, and solidification of API-ILs, with the first method focusing on hydrophilic API-ILs using ion exchange resins and the second method targeting lipophilic, self-emulsifying API-ILs through liquid-liquid extraction via a concentric annular separator
"Barely English"? Richard Stanihurst, Edmund Spenser, and the Remaking of the "Aeneid" in Early Modern Ireland
No full textThe phrase “barely English” was a criticism levelled by C. S. Lewis at Richard Stanihurst’s 1582 translation of the first four books of the Aeneid. Yet the text itself, when examined alongside other works by Stanihurst, also invites us to consider what it means to criticise a text for a lack of “English-ness”. The paratextual poetry and dedications situate his Aeneid translation very clearly within the Old English community in Ireland. My thesis is a comparison of this volume with Spenser’s The Faerie Queene, which similarly is an interpretation of Virgil’s Aeneid whose paratexts reflect an investment in the English Protestant ruling classes. My work will analyse these two epic poems, alongside the polemical works of both men, using an interdisciplinary methodology which considers both historical and literary perspectives. Through this comparison, I reveal the way in which both men used the Virgilian epic narrative of imperial conquest to explore their own relationship to the colonisation of Ireland and the English forces who enacted this process. I then use this as the basis for further examination of the poetics of these two texts, and demonstrate that in both works form and meaning and historical context are inseparable elements that build upon each other. Furthermore, I demonstrate that both texts, in their formal and semantic elements, are highly invested in the concept of community: they reflect the ways in which their authors identified as belonging to a variety of social and political communities, whether that be Stanihurst’s Old English, the poets who come together to write commendatory verses for The Faerie Queene, or the nation that each epic seeks to immortalise and define
Reading the Global City: New York, London and the Capitalist World-System in the Late Neoliberal Novel
No full textThis thesis examines works of fiction written in the wake of the 2008/11 financial crash which take the global city as a setting from which to interrogate capitalist relations of combined and uneven development and the cultural, ideological and spatial means through which these relations are obscured. These novels mediate critical responses to Fredric Jameson’s concept of “cognitive mapping,” which calls for a pedagogical aesthetic that would “enable a situational representation on the part of the individual subject to… the ensemble of society’s structures as a whole” (1991: 51). I contend that this preoccupation represents a characteristic current of critique in the “late neoliberal novel,” in which crisis precipitates the (re-) emergence of the horizon of totality in cultural productions. The thesis is divided into four chapters. The first analyses Tom McCarthy’s Satin Island (2015) as a work thematising the ideological, mediatory role played by particular forms of urban and global space in the (re-) production of “false consciousness” in post-Fordist cores, while the second examines Ben Lerner’s 10:04 (2014) in relation to its pursuit of an immanent form of cognitive mapping that seeks to overcome these epistemological and ideological conditions. In Chapter Four, Teju Cole’s Open City (2011) is analysed in relation to its counterhegemonic readings of urban space, revealing the repressed violence – past and present, local and global – in which the global city is implicated. Finally, Rachel Kushner’s The Flamethrowers (2014) is analysed as an engagement with the ascent of neoliberalism and its attendant cultural logic in 1970s New York, addressing the structural role played by artists in the resolution of Fordist crisis in both concrete urban and broad cultural terms in order to address the dialectical entanglements of subjectivity, art, space and totality
Enantioselective Synthesis of Sterically Hindered α-Aryl Stereocentres in N-Heterocycles
No full textPd-mediated decarboxylative catalysis has become a mild, but powerful tool for the asymmetric synthesis of stereocentres adjacent to a carbonyl group. In 2004, Both Tunge and Stoltz reported the first decarboxylative asymmetric allylic alkylation (DAAA), generating quaternary stereocentres in high enantioselectivities. Generally, the identity of the α-substituent in the formed stereocenter remained a sterically small group, such as a methyl or a benzyl substituent. Our group has focused on generating quaternary stereocentres bearing highly sterically hindered α-aryl substituents, where, in previous reports, we have been successful in obtaining exceptionally high enantioselectivities of up to > 99 % ee for a range of heterocyclic and non-heterocyclic substrates. Another form of decarboxylative catalysis that has been of interest to our group is the Pd-catalysed decarboxylative asymmetric protonation (DAP), which has been employed to generate tertiary stereocentres in high enantioselectivities. First reported by Muzart in 1992 via a chiral alcohol-mediated variant, it was further developed by Stoltz in 2006 as an extension to their previous DAAA work. Similar to our own DAAA work, we have been successful in extending DAP methodology to substrates containing bulky α-aryl substituents. Our group has reported both chiral amino alcohol-mediated DAP and chiral P,N ligand DAP methodology for the synthesis of α-aryl tertiary stereocentres from a range of heterocyclic and non-heterocyclic substrates, obtaining up to 95 % ee. The aim of this PhD project has been to further extend the scope of both DAAA and DAP methodology to two more N-heterocyclic substrates: α-aryl lactams and α-aryl 4-piperidones. The initial work in this project involved the synthesis a range of α-aryl substrates, the key step being a Pb-mediated α-arylation. We successfully synthesised 14 novel α-aryl lactam substrates, 11 α-aryl variation and 3 N-protecting group variations. We also successfully synthesised 13 novel α-aryl 4-piperidone substrates, all which are α-aryl variations. We next applied these novel substrates in DAAA and DAP catalysis. A substrate scope of 11 examples of DAAA with 6-membered lactam substrates demonstrated enantioselectivities of up to 82 % ee. Optimisation of DAAA with a 5-membered lactam substrate resulted in lowered enantioselectivity, with ees up to only 20 %. With the α-aryl 4-piperidone substrates, a substrate scope of 13 examples obtained excellent enantioselectivities of up to 99.9 % ee, with products bearing di- and mono-ortho substitution patterns showing the highest levels of enantioselectivity. We next applied these novel substrates to chiral amino alcohol-mediated DAP methodology, where it was found that (1R, 2S)-(-)-ephedrine, in the absence of a chiral ligand, afforded high enantioselectivities of up to 95 % ee with lactam derived substrates and up to 90 % ee with 4-piperidone derived substrates. A substrate scope of 20 examples showed that products containing di-ortho-methoxy-substituted phenyls and naphthyl groups showed the highest ees, whereas products not bearing this substitution pattern gave lower levels of enantioselectivity. Finally, Chapter 6 describes the work undertaken in a 2 month placement in the University of Nottingham in collaboration with Prof. Simon Woodward, where we applied Machine Learning (ML) to the DAAA data that our group has collected throughout the years. We successfully expanded upon the system the Woodward group previously reported for Rh-catalysed 1,4 additions, generating a simple quantitative structure-property relationship between the enantioselectivity of the Pd-catalysed DAAA and Trost-type ligands/substrate structure. Using easily interpretable chemical features, ML models were developed with RMSEs as low as 8 %, through previously optimised algorithms and a small number of DAAA examples
Computational Modelling and Experimental Development of Novel Liquid Air Energy Storage Systems
No full textAs the planet shifts towards sustainable energy, the need for efficient, scalable, and geographically flexible energy storage solutions is paramount. LAES systems, characterized by their geographical independence, long lifespan, and potential for leveraging existing industrial infrastructure, are emerging as a viable solution to this challenge. The research presented in this thesis encompasses the development and analysis of innovative approaches to enhance the efficiency and integration capabilities of LAES systems. A significant focus is placed on the novel concept of using packed beds for the direct liquefaction and regasification of air, aiming to improve the energy performance of the system. A comprehensive model, formulated and refined using data from various sources, is introduced to evaluate this concept. Experimental investigations, including the development of a packed bed experimental pilot rig, demonstrate the conceptual viability of this approach. The performance of the packed bed system, particularly in terms of energy efficiency, is critically assessed. Additionally, the thesis explores the integration of cryogenic CO2 capture in packed beds within LAES systems. A new model for cryogenic CO2 capture is developed. A parametric study using this model investigates the impact of a number of parameters on the performance of this cryogenic CO2 capture system. Building on these findings, the thesis finally proposes an innovative LAES system which integrates the packed bed model developed in this thesis into an LAES system. This packed bed LAES integrated system shows potential for high round-trip efficiency of up to 76%, and its modular nature makes it suitable for integration with external cold energy sources, such as LNG regasification terminals
Parrasio Micheli and Painting in Sixteenth-Century Venice: Reconsidering a Lost Reputation
No full textThis thesis is the first in-depth, scholarly study of the life and career of the Venetian renaissance painter Parrasio Micheli (c.1515-78) in over a century. It draws on new attributional, critical, documentary and archival evidence (including the present writer’s discovery of the artist’s criminal activity regarding Venetian convents) in representing this overlooked painter to modern scholarship. Parrasio is an unusual and fascinating subject for Venetian art historians: born the natural son of a Venetian aristocrat, yet at one time banished from the city (as this thesis can also reveal), he trained in the workshop of the leading painter of his time, Titian (this thesis posits Parrasio’s presence in the Titian’s Roman entourage in 1545-46), and received praise and his prestigious professional nickname from one of the foremost artistic literati of the period, Paolo Giovio. The thesis appraises this relationship and casts new light on correspondence concerning Parrasio on the part of other important early critical sources, including Pietro Aretino and Andrea Calmo. Parrasio decorated important state offices, including the epicentre of Venice’s international diplomacy – the Sala del Collegio in the Ducal Palace. On his death, he was buried, remarkably, beneath his own self-sponsored altarpiece (derived from a design he received from Paolo Veronese) and which featured his own prominent self-portrait. A few decades after his death, his reputation was besmirched in a biography by Carlo Ridolfi which has prejudiced his reputation and muddied his oeuvre. This thesis analyses this and other factors operative on his critical decline, and how the political events of mid-century Venice affected him and other painters of the time. In prioritising bespoke works for the Venetian ruling elite, it will be argued that Parrasio became excessively exposed to, and suffered from, the vicissitudes of his own clients’ fortunes. This thesis also clarifies and augments our knowledge of Parrasio’s serious, yet vainglorious attempt to succeed Titian as the favoured artist of the Spanish king Philip II
Unravelling the Biomolecular and Community Grammars of RNA Granule via Machine Learning
No full textNon-membrane organelles, recognized as biomolecular condensates, play a vital role in cellular compartmentation, maintaining stability, and executing cellular functions. RNA granules, specific biomolecular condensates enriched in RNAs and RNA binding proteins (RBPs), are pivotal in posttranscriptional regulation and are implicated in various human diseases. The dynamic and heterogeneous nature of RNA granule compositions poses challenges in understanding their formation and functionality. Despite advancements, a comprehensive exploration of RNA granule biomolecular (i.e., protein physico-chemical properties) and community grammars (i.e., protein-protein interactions) governing their formation and functionality remains challenging. In this study, we addressed these challenges by developing two machine learning models capable of accurately identifying RNA granule (i.e., processing body (PB) and stress granule (SG)) proteome from the overall human proteome. We developed two models that incorporate protein features and achieved high accuracy, surpassing traditional liquid-liquid phase separation (LLPS) models. Our classifiers accurately distinguished RNA granule proteins from the human proteome, demonstrating their reliability in proteome-wide identification. Intriguingly, the predicted RNA granule proteome reveals a significant enrichment in biological functions associated with RNA granule-related processes, mirroring findings from established high-confidence RNA granule protein datasets. This alignment underscores the potential of our approach to construct a comprehensive RNA granule proteome. The intricate nature of biosystems cannot be comprehended merely by examining their individual components. Recognizing the complexity of biosystems, we explored the roles of protein interactions in RNA granule formation and functionality. Our analysis revealed protein-protein interaction community grammars within the RNA granule proteome, emphasizing the importance of interactions in RNA granule formations and functionality. Key clusters with dense interactions were identified, showing commonality among diverse RNA granules and involvement in crucial biological functions, such as translation, mRNA decay, rRNA processing, and mRNA splicing. This analysis proposes a hypothesis: dense protein-protein interaction clusters serve as integral functional subunits, constituting relatively stable ‘cores’ within diverse RNA granules. In conclusion, combining machine learning with the RNA granule proteome protein-protein interaction network has allowed us to explore RNA granule protein compositions and functionality in a comprehensive way. This dual approach reveals the physico-chemical properties of individual proteins (i.e., hydrophobicity of each protein) and their collective roles (i.e., highly central proteins in predicted RNA granule proteome protein-protein interaction community) in cellular processes. The findings highlight the power of using machine learning and community analysis in molecular biology to understand complex non-membrane organelles, especially RNA granules, enhancing our knowledge of cell organization and regulation
Development of a feed to food chain risk assessment of mycotoxins in dairy produce under climate change influences
No full textClimate change is expected to result in a temperature increase of at least 1 – 1.8°C by the century's end, leading to an increase in extreme weather events like floods, droughts, and heatwaves. These changes pose significant concerns for agriculture and food safety, particularly regarding the prevalence of mycotoxins in food and feedstuffs. Mycotoxins are harmful secondary metabolites produced by fungi in infected crops such as maize, wheat, and barley that pose risks to human and animal health. While human exposure typically occurs through the consumption of mycotoxin-contaminated cereal products, exposure can occur through animal products such as milk when animals consume mycotoxin-contaminated feed. Mycotoxins in animal feed can thus carry-over, metabolise or bio-transfer into milk. Climate change may exacerbate mycotoxin production in bovine feed, thereby potentially increasing mycotoxin levels in milk and posing increased human health risks. This thesis aims to develop a feed-to-fork human health risk assessment model, incorporating climate change effects on mycotoxin presence in dairy produce intended for human consumption. Through a comprehensive literature review, the thesis establishes the impact of climate change on mycotoxins in crops and current methodologies for incorporating these effects into risk assessment models. Gaps in existing research are identified, including the lack of dynamic human health risk assessment models considering co-occurring mycotoxins in bovine milk and the lack of dynamic human health risk assessment models incorporating the effects of climate change for mycotoxins in bovine milk. This study addresses these gaps by developing a quantitative risk ranking model that helped identify priority mycotoxins that could be of risk to human health under various climatic regions. The human health risk assessment prioritised mycotoxins, aflatoxin, ochratoxin A, fumonisins, T-2/HT-2 toxin, zearalenone and deoxynivalenol under various climate scenarios. A meta-analysis was conducted to identify the prevalence and concentration of the priority mycotoxins in bovine feed components. Deoxynivalenol had the highest prevalence and concentration, followed by zearalenone, fumonisin, aflatoxin, T-2/HT-2 toxin, and ochratoxin A. A case study considering only concentration and prevalence for feed components originating from Europe is synthesised as an input for a human health risk assessment model for combinations of co-occurring priority mycotoxins. The findings of this study highlighted low risk from co-occurring priority mycotoxins to the population of Ireland, however, there was an increased risk from combinations of co-occurring mycotoxins consisting of aflatoxins. The study highlighted that aflatoxin needs to be studied further under climate scenarios and the importance of proper agricultural practices in mitigating mycotoxin contamination. A dynamic feed-to-fork human health risk assessment model was introduced, incorporating climate change variables and predictive crop-toxin models. The model, applied to France and Ireland under different climate change scenarios, indicates a relatively low risk of aflatoxin-contaminated milk consumption, albeit with increased risk under more severe climate change conditions. Sensitivity analyses highlights the significance of temperature and agricultural practices in influencing mycotoxin production. In conclusion, this thesis emphasises the importance of addressing climate change-induced food safety hazards like mycotoxins and advocates for proactive risk assessment and mitigation strategies. Continued research is essential to refine risk assessment models further and safeguard food safety amidst uncertain climate scenarios. The insights generated by this thesis can inform policymakers in setting guidelines and limits for mycotoxin contamination in dairy products, ensuring consumer well-being in a changing climate
The Synthesis and Application of P,N Ligands in Asymmetric Catalysis
No full textThe synthesis of enantiomerically pure compounds and the methods by which this can be achieved is an area of huge interest within modern organic chemistry. Asymmetric catalysis, whether it be transition metal catalysis or organocatalysis, is one of the most common ways of synthesising enantioenriched compounds, and some of these methods are discussed in detail within this thesis. Within the Guiry group much knowledge exists relating to the synthesis of chiral P,N ligands and their application in asymmetric catalysis. Based on the previously synthesised P,N ligand; (S,S,Ra)-UCD-Phim, a library of centrally chiral ligands with an imidazoline backbone are synthesised herein. These ligands were then applied in catalysis and results obtained using them could be used to analyse the benefits of different sterics and electronics on an asymmetric reaction. UCD-Phim had previously been shown to be an effect ligand in the A3 coupling reaction, so the library of ligands prepared in the present study was initially applied in this reaction affording excellent enantioselectivities of 67-94% ee. However, it was found that the yields were much more variable (4-94%) suggesting axial chirality may be key to obtaining good reactivity in this reaction as exemplified with UCD-Phim.One of the main drawbacks that exists to the use of axially chiral ligands is that above a certain temperature the barrier to rotation will be overcome and epimerisation will occur, and with UCD-Phim this happens at temperatures above 40 °C. To display the utility of the centrally chiral ligands they were therefore applied to a high temperature syn-arylnickelative cyclisation reaction. The current work describes the first enantioselective version of this reaction with ee’s of up to 66% and yields of up to iv 42%. The substrate scope of the racemic reaction was also expanded upon to include ketones and imines. Finally, the utility of UCD-Phim was expanded to show that it is an effective ligand in the asymmetric alkynylation of quinolones giving yields of up to 92% and enantioselectivities of up to 97% ee. The applicability of the reaction was proven through scale up and synthesis of the natural products (+)- cuspareine and (+)-galipinine