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Expanding the GenoChemetic toolbox : radical halogenases and aqueous alkyl halide cross-coupling
No full textNatural products are a very important class of bioactive and often medicinally relevant molecules, however strategies for their chemical diversification are often hindered by their complexity and high number of unactivated aliphatic carbons. The GenoChemetic strategy represents a powerful tool for natural product diversification, merging the biosynthetic production of reactive metabolites with mild aqueous chemistries to enable modification in biological conditions. The merger of biosynthetic production of aliphatically halogenated compounds by radical halogenases with aqueous alkyl halide coupling chemistries remains an unexploited but promising strategy for enabling functionalisation at C(sp³)-H centres in this way.
This PhD thesis focuses on the stepwise process to expand the GenoChemetic method of natural product diversification through biocatalytic halogenation from the sp² realm to the sp³ realm. To this end in silico techniques have been used to mine novel radical halogenase from genomic libraries to discover five novel radical halogenases from cyanobacteria, myxobacteria, and bacteroidetes. Furthermore, one vanadium dependent halogenase was discovered from algae which produce a distinct halo-metabolite signature when virally infected. These novel enzymes have been examined in a phylogenetic, structural, and genomic context, and recombinantly produced in Escherichia coli. Halogenation assays were designed, and a wide range of substrates used to probe these novel proteins for halogenation activity.
Methods for the aqueous coupling of sp³ alkyl halides have also been explored. By screening catalysts and ligands, it has been shown that that the water-soluble palladium source Na₂PdCl₄ can be used in conjunction with a tris(2,4-dimethyl-5-sulfophenyl)phosphine trisodium salt (TXPTS) ligand to enable the first fully aqueous, air tolerant, and mild Suzuki-Miyaura coupling. This aqueous coupling was able to derivatise a wide range of functionalised hydrophilic and hydrophobic primary alkyl halides. It was also used to tag two halogenated natural products with fluorescent and ionisable groups in a method for natural product analysis and analogue generation
Aphantasia, imagination and dreaming
Get PDFAphantasia is a recently discovered disorder characterised by the total incapacity to generate visual forms of mental imagery. This paper proposes that aphantasia raises important theoretical concerns for the ongoing debate in the philosophy and science of consciousness over the nature of dreams. Recent studies of aphantasia and its neurobehavioral correlates reveal that the majority of aphantasics, whilst unable to produce visual imagery while awake, nevertheless retain the capacity to experience rich visual dreams. This finding constitutes a novel explanandum for theories of dreaming. Specifically, I argue that the recent dream reports of aphantasics constitute an empirical challenge to the emerging family of views which claim that dreams are essentially imaginative experiences, constitutively involving the kinds of mental imagery which aphantasics, ex-hypothesi, lack. After presenting this challenge in the context of Jonathan Ichikawa’s recent arguments for this view, I argue that this empirical challenge may be overcome if the imagination theorist abandons Ichikawa’s account of dreaming in favour of a modified version. This involves the claim that dreams are essentially inactive and constitutively involve non voluntary forms of imagination. I conclude with a suggestion for further research which can test the viability of this alternative hypothesis, and move the debate forward.Peer reviewe
Slaying ideological dragons : the life and thought of Kenneth Minogue
Get PDFThis thesis analyses Kenneth Minogue's life and ideas, drawing from primary sources, especially his personal papers at the University of St Andrews’ Institute of Intellectual History. It traces Minogue’s intellectual development and assesses the three main themes in his work. Additionally, it examines the contemporary relevance of Minogue’s thought amid a globally polarised political landscape with radical ideological tendencies on both the Left and Right.
The thesis comprises two parts. The first provides a comprehensive intellectual biography of Minogue, beginning with his early years and the influence of figures like John Anderson and Michael Oakeshott on his intellectual development. The first chapter also delves into his early publications that critiqued inherent salvationist tendencies in modern ideologies. The second chapter focuses on Minogue's career as a public intellectual, particularly his engagement in debates on Higher Education at the London School of Economics and Political Science. It traces his involvement in the New Right movement and support for Thatcherism. The third chapter explores the later phase of Minogue’s career, examining his defence of Thatcherism, his Euroscepticism, opposition to identity politics, and concerns about ideology's adverse effects on authority and human conduct.
The second part of the thesis examines three central themes in Minogue's thought: his defence of conservative individualism, his critique of ideology, and his own brand of conservative realism. The fourth chapter explores Minogue’s view that conservative individualism embodies the essence of modernity, fostering the harmonious coexistence of freedom and authority in moral life. The fifth chapter evaluates Minogue’s critique of ideology as apolitical, emphasising his contribution to preserving its critical role in a non-Marxist context. The concluding chapter addresses the relevance of Minogue’s conservatism in contemporary politics, particularly amid the rise of the global reactionary Right
Liberating interdependence : the multivalent hermeneutics of Musa W. Dube
No full textThis thesis analyses and expounds upon the writings and methodology of Musa W. Dube, offering in effect a hermeneutics of Dube’s hermeneutics. It argues that Dube has created a unique methodology and style of argumentation: requiring a unique classification, multivalent—encompassing two or more types of criticism along with two or more layers of narrative. Through her use of diverse modes of critique e.g., post/colonial, feminist, and the active hybridity of African Independent Churches, Dube has formulated a dynamic heuristic tool for assessing past and contemporary patterns of colonization, while reading for decolonization and the revitalization of relationships as liberating interdependence. To adequately assess Dube’s work, the argument uses several layers of critical analysis, inclusive of European, British, American political and literary theory, interacting with African political and literary theory and theology. To that end, it uniquely argues (1) for the conceptualization of Dube’s work as multivalent narrativity; (2) a clarified understanding of her methodology for the sake of replicability; (3) for the value of this method in addressing decolonisation in local and international arenas; and (4) an original analysis of how Dube’s multivalent points of narration and argumentation interact at the literary and semiotic levels
Translingual creative writing in, and beyond, modern languages
Get PDFLeverhulme TrustWith a growing corpus of translingual literature embedded in Modern Language curricula and research, this article makes the case for the integration of translingual creative writing as a creative, (self-)reflexive and critical process. Through reflections from translingual writers and concrete writing prompts, it examines the role of creative writing in enhancing literary and linguistic competence, in affirming transnational trajectories, while discussing possible productive tensions between language accuracy, artistic ambition and personal expression. Translingual competence also opens up new critical perspectives, which are alert to cross-lingual and cultural dialogues: this article suggests that expertise developed in Modern Languages can provide stimulating frameworks for the practice and discipline of Creative Writing.Peer reviewe
Cetacean citations : rhythmic variability in the composition and recomposition of humpback whale song
Get PDFIn this interdisciplinary thesis I attend to the rhythmic variability of the phrases whose repetition is such a distinctive feature of humpback whale song, listening and responding as bioacoustician, musician, and zoömusicologist. I developed methods to visualize and measure individual distinctiveness and rhythmic precision in shared song phrases, and assessed thirteen hours of humpback song from ten singers, collected off Mo’orea, French Polynesia, September-November 2019. Using multiple regression and multivariate distance techniques, I found that individual singers sing shared phrases with their own individually distinctive rhythms but with equal levels of rhythmic precision, across a wide range of phrase variants. As a musician I recomposed with transcriptions and recordings of humpback song phrases, the ‘cetacean citations’ of my title, producing a portfolio of six works in collaboration with other musicians. In a reflective zoömusicological analysis of my compositional processes, I examined how composers might avoid both an ‘anthropodenial’ that fails to recognize the similarities between humans and other animals, and a ‘naïve anthropomorphism’ that fails to recognize the differences. Further, I challenged the presumption that there are no ethical questions involved in the musical use of other-than-human audio recordings via an analysis of their inevitable ‘objectification’ in contemporary composition. Drawing on Adorno’s critique of instrumental rationality and Plumwood’s critique of anthropocentrism, I elaborated the concept of an aesthetic rationality that treats other-than-human sounds with respect, through a set of strategies for composers to produce a non-anthropocentric multispecies music that neither enacts nor embodies human exceptionalism. Finally, I proposed the notion of ‘multispecies heterophony’ to describe the overlapping nonhierarchical sounding of difference. This compositional form was jointly inspired by the ‘asynchronous chorus’ of the collective singing of humpback whales, and the human dynamics of large group improvisation; I suggest that it offers a promising musical model for ecological thinking
Comparative analysis of ISGylation during the antiviral response against Paramyxovirus infection
No full textViral infection induces a significant antiviral response through the interferon response. This response leads to the production of hundreds of interferon stimulated genes (ISGs) including ISG15; a Ubl protein with multiple roles in the antiviral response. Within the antiviral response ISG15 plays a role as a negative regulator of the IFN response with loss of ISG15 generating an overactive response, plays a role in extracellular signalling and is capable of post-translationally modifying host and viral proteins through a process known as ISGylation. ISGylation is known to alter functions of proteins through aiding host defence and playing an antiviral role when modifying viral proteins. We have identified a novel modification of parainfluenza virus type-5 (PIV5) phosphoprotein (P protein) and through use of CRISPR/Cas9 and immunoblot analysis have confirmed that this modification is ISG15. Further to this we have shown that this appears to be the only modified protein of PIV5. As the P protein plays a critical role in viral replication we took a comparative approach through analysis of effects of ISGylation PIV5, PIV2 and PIV3. In order to comparatively analyse effects of ISGylation on plaque size we used a computationally-aided plaque assay approach to determine effects of ISGylation. Our initial dataset suggested that ISGylation had little to no effect on replication of these paramyxoviruses. However further investigation using IFIT1.ko cell lines yielded data suggesting that loss of ISGylation lead to an increase in plaque size in PIV2 and PIV5 suggesting ISGylation was antiviral to these viruses but noted no effect on PIV3. Importantly we noted that loss of ISG15 lead to a decrease in plaque size which is attributed to the role of ISG15 as a negative regulator of the antiviral response. These findings suggested that ISGylation plays a minor antiviral role with respect to PIV2 and PIV5 and potentially may impact other members of the Paramyxoviridae family, however this requires further investigation. As noted, we observed small plaque sizes present within ISG15.ko IFIT1.ko cells, particularly those infected with PIV3. We further investigated these plaques and observed a strange phenotype wherein immunostaining of viral plaques yielded only tiny viral plaques while counter staining for cell viability revealed large areas of cell death surrounding these small areas of viral activity. Further investigation into this suggested an IFN-alpha signalling dependent pathway causing cell death highlighting differences between the IFN-alpha and beta responses. Overall our data has shown that ISGylation is a minor antiviral factor for the Paramyxoviridae family, especially in comparison to the major antiviral role ISG15 plays within its negative regulation of the IFN response. This major role of ISG15 as a negative regulator is detracted from as cells lacking ISG15 undergo high levels of cell death in response to signalling from infected cells. Further investigations would be needed to identify the antiviral mechanism of ISGylation as well as whether other Paramyxoviridae are affected by this modification as well as the exact pathway that triggers cell death within ISG15.ko cells
Coral settlement and recruitment are negatively related to reef fish trait diversity
Get PDFFunding: Funding was provided by the Warman Foundation (to MD and JSM), the John Templeton Foundation (MD, JSM Grant #60501 'Putting the Extended Evolutionary Synthesis to the Test’), a Royal Society research Grant and a Leverhulme fellowship, the Leverhulme Trust Research Centre–the Leverhulme Centre for Anthropocene Biodiversity and a Leverhulme Research Grant (RPG-2019-402, MD), a National Science Foundation–Natural Environment Research Council Biological Oceanography Grant (1948946) (JSM, MD), two Ian Potter Doctoral Fellowships at Lizard Island Research Station (DTP and VB), and MASTS small Grant to VB.The process of coral recruitment is crucial to the functioning of coral reef ecosystems, as well as recovery of coral assemblages following disturbances. Fishes can be key mediators of this process by removing benthic competitors like algae, but their foraging impacts are capable of being facilitative or harmful to coral recruits depending on species traits. Reef fish assemblages are highly diverse in foraging strategies and the relationship between this diversity with coral settlement and recruitment success remains poorly understood. Here, we investigate how foraging trait diversity of reef fish assemblages covaries with coral settlement and recruitment success across multiple sites at Lizard Island, Great Barrier Reef. Using a multi-model inference approach incorporating six metrics of fish assemblage foraging diversity (foraging rates, trait richness, trait evenness, trait divergence, herbivore abundance, and sessile invertivore abundance), we found that herbivore abundance was positively related to both coral settlement and recruitment success. However, the correlation with herbivore abundance was not as strong in comparison with foraging trait diversity metrics. Coral settlement and recruitment exhibited a negative relationship with foraging trait diversity, especially with trait divergence and richness in settlement. Our findings provide further evidence that fish play a role in making benthic habitats more conducive for coral settlement and recruitment. Because of their ability to shape the reef benthos, the variation of fish biodiversity is likely to contribute to spatially uneven patterns of coral recruitment and reef recovery.Peer reviewe
“Chinese” studies for the twenty-first century
No full textThis is a slightly modified version of a presentation given to the Scottish Centre for China Research, University of Glasgow, 13 October 2022.Peer reviewe
Characterising the HLA-I Immunopeptidome of plasma-derived extracellular vesicles in patients with melanoma
Get PDFThis work was funded by grants from Breast Cancer Now UK (2018JulPR1086), and the Melville Trust for the Care and Cure of Cancer UK (XCT014). We also gratefully acknowledge funding from the EPSRC via EP/L017008/1 for TEM imaging infrastructure, and EP/R023751/1 and EP/T019298/1.Extracellular vesicles (EVs) frequently express human leukocyte antigen class I (HLA-I) molecules. The immunopeptidomes presented on EV HLA-I are being mapped to provide key information on both specific cancer-related peptides, and for larger immunopeptidomic signatures associated with disease. Utilizing HLA-I immunoisolation and mass spectrometry, we characterised the HLA-I immunopeptidome of EVs derived from the melanoma cancer cell line, ESTDAB-026, and the plasma of 12 patients diagnosed with advanced stage melanoma, alongside 11 healthy controls. The EV HLA-I immunopeptidome derived from melanoma cells features T cell epitopes with known immunogenicity and peptides derived from known tumour associated antigens (TAAs). Both T cell epitopes with known immunogenicity and peptides derived from known TAAs were also identifiable in the melanoma patient samples. Patient stratification into two distinct groups with varying immunological profiles was also observed. The data obtained in this study suggests for the first time that the HLA-I immunopeptidome of EVs derived from blood may aid in the detection of important diagnostic or prognostic biomarkers and also provide new immunotherapy targets.Peer reviewe
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