J.M. Synge, Modernism, and Political Protest

This thesis explores the works of the Irish writer J.M. Synge (1871-1909). By first seeking to define and examine the tenets of Synge’s artistic, spiritual and political value system, and by considering his works in a broadly chronological order, this research shows that Synge’s writings (and his trajectory into modernism) were a reaction to both literary and social modernity. Over the course of his career, Synge’s foundational value system, or ‘creed’, was subjected to a number of shocks by his encounters with the modernisation of rural Ireland and the political climate of the cultural Revival, which led him to a continuous literary experimentation. Ultimately, this thesis argues that Synge’s work, as it moves towards an increasingly modernist aesthetic, can be understood as an act of both literary and political protest. One of the main innovations of this thesis is its methodology. Throughout, archival materials are used in order to uncover the processes of authorial revision undertaken prior to the publication of Synge’s texts, showing how he edited, glossed, and subverted his previous work in line with his changing views on modernisation and on his earlier, more overt Romanticism. In addition to this, each chapter of this thesis explores Synge’s composition alongside his contemporary reading materials, showing the influence of various writers and broader discourses on the works discussed. In doing so, the thesis uncovers Synge’s interest in occultism, his engagement with various socialist works, his reading in evolutionary theory, and his later reaction against early eugenic nationalisms, and demonstrates the close relationship between his published and performed works and these discourses. Furthermore, in showing the importance of socialist politics to Synge’s literary development, this thesis demonstrates how several concerns typical of modernism (such as occult spirituality, degeneration, and eugenics) are approached by a leftist writer, and how left-wing politics manifest in early modernist literature. By tracing Synge’s ongoing reaction to modernisation, and his trajectory into literary modernism, this thesis explores in detail the contested relationship between Revivalism and modernism in the Irish context, and thus, through a study of one of Ireland’s major dramatists, lays the groundwork for further scholarly exploration of the interplay between these two movements. Finally, by exploring Synge’s afterlife in modernist writings, both as a modernising impulse and as a figure of modernist protest, this thesis suggests ways in which the work of later modernists might be reassessed in light of Synge’s work

Modulation of β-amyloid fibril formation in Alzheimer’s disease by microglia and infection

Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease

Macromolecular Crowding Enhances the Detection of DNA and Proteins by a Solid-State Nanopore

Nanopore analysis of nucleic acid is now routine, but detection of proteins remains challenging. Here, we report the systematic characterization of the effect of macromolecular crowding on the detection sensitivity of a solid-state nanopore for circular and linearized DNA plasmids, globular proteins (β-galactosidase), and filamentous proteins (α-synuclein amyloid fibrils). We observe a remarkable ca. 1000-fold increase in the molecule count for the globular protein β-galactosidase and a 6-fold increase in peak amplitude for plasmid DNA under crowded conditions. We also demonstrate that macromolecular crowding facilitates the study of the topology of DNA plasmids and the characterization of amyloid fibril preparations with different length distributions. A remarkable feature of this method is its ease of use; it simply requires the addition of a macromolecular crowding agent to the electrolyte. We therefore envision that macromolecular crowding can be applied to many applications in the analysis of biomolecules by solid-state nanopores

Design and Synthesis of Cysteine-Specific Labels for Photo-Crosslinking Studies

Chemical cross-linking mass-spectrometry (XL-MS) represents a powerful methodology to map ligand/biomacromolecule interactions, particularly where conventional methods such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy or cryo-electron microscopy (EM) are not feasible. In this manuscript, we describe the design and synthesis of two new photo-crosslinking reagents that can be used to specifically label free thiols through either maleimido or methanethiosulfonate groups and facilitate PXL-MS workflows. Both crosslinkers are based on light sensitive diazirines – precursors of highly reactive carbenes which offer additional advantages over alternative crosslinking groups such as benzophenones and aryl nitrenes given the controlled rapid and more indiscriminate reactivity

The changing nature of risk and risk management: the challenge of borders, uncertainty and resilience

No abstract available

Mechanistic Study of the Conductance and Enhanced Single-Molecule Detection in a Polymer–Electrolyte Nanopore

Solid-state nanopores have been widely employed in the detection of biomolecules, but low signal-to-noise ratios still represent a major obstacle in the discrimination of nucleic acid and protein sequences substantially smaller than the nanopore diameter. The addition of 50% poly(ethylene) glycol (PEG) to the external solution is a simple way to enhance the detection of such biomolecules. Here, we demonstrate with finite-element modeling and experiments that the addition of PEG to the external solution introduces a strong imbalance in the transport properties of cations and anions, drastically affecting the current response of the nanopore. We further show that the strong asymmetric current response is due to a polarity-dependent ion distribution and transport at the nanopipette tip region, leading to either ion depletion or enrichment for few tens of nanometers across its aperture. We provide evidence that a combination of the decreased/increased diffusion coefficients of cations/anions in the bath outside the nanopore and the interaction between a translocating molecule and the nanopore–bath interface is responsible for the increase in the translocation signals. We expect this new mechanism to contribute to further developments in nanopore sensing by suggesting that tuning the diffusion coefficients of ions could enhance the sensitivity of the system

A qualitative study of unmet needs and interactions with primary care among cancer survivors

INTRODUCTION: Despite increasing numbers, there is little research investigating the long-term needs of cancer survivors. The aim of this study is to explore the experiences of individuals who have survived at least 5 years following a cancer diagnosis, and to describe perceived unmet needs and interactions with primary care. METHODS: Forty long-term survivors of breast, colorectal and prostate cancer were purposively selected for an in-depth qualitative study. We aimed for a maximum variation sample according to cancer site, gender, time since diagnosis, cancer needs, anxiety and depression. Interviews were audio recorded and transcribed verbatim. Transcripts were coded thematically using a grounded theory approach. RESULTS: Analysis of the interview data is presented in four subthemes: the role they perceived for the general practitioner (GP), unmet needs, reasons for not using primary care for needs they perceived as cancer related, and ongoing care for cancer-related issues. The majority of cancer survivors did not see a role for their GP in their long-term care related to their cancer diagnosis as most considered that they did not need active follow-up, but some expressed a need for psychological services and information on possible long-term effects. Cancer survivors cited three main reasons for not using GP services in relation to their cancer diagnosis: GPs were seen as non-experts in cancer; they were perceived as too busy; and a lack of continuity within primary care made it difficult to talk about long-term issues. There was a wide variation in schedules and notification of PSA tests among the prostate cancer survivors. DISCUSSION: The results from this project suggest that some cancer survivors have specific emotional and physical needs that could benefit from input from their primary care team, but not all cancer survivors look to their GP for their long-term cancer-related care. Better information care planning is required from specialists in order to identify those who would benefit mos

Probing RNA Conformations Using a Polymer–Electrolyte Solid-State Nanopore

Nanopore systems have emerged as a leading platform for the analysis of biomolecular complexes with single-molecule resolution. The conformation of biomolecules, such as RNA, is highly dependent on the electrolyte composition, but solid-state nanopore systems often require high salt concentration to operate, precluding analysis of macromolecular conformations under physiologically relevant conditions. Here, we report the implementation of a polymer–electrolyte solid-state nanopore system based on alkali metal halide salts dissolved in 50% w/v poly(ethylene) glycol (PEG) to augment the performance of our system. We show that polymer–electrolyte bath governs the translocation dynamics of the analyte which correlates with the physical properties of the salt used in the bath. This allowed us to identify CsBr as the optimal salt to complement PEG to generate the largest signal enhancement. Harnessing the effects of the polymer–electrolyte, we probed the conformations of the Chikungunya virus (CHIKV) RNA genome fragments under physiologically relevant conditions. Our system was able to fingerprint CHIKV RNA fragments ranging from ∼300 to ∼2000 nt length and subsequently distinguish conformations between the co-transcriptionally folded and the natively refolded ∼2000 nt CHIKV RNA. We envision that the polymer–electrolyte solid-state nanopore system will further enable structural and conformational analyses of individual biomolecules under physiologically relevant conditions

pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers

Amyloid disorders cause debilitating illnesses through the formation of toxic protein aggregates. The mechanisms of amyloid toxicity and the nature of species responsible for mediating cellular dysfunction remain unclear. Here, using β2-microglobulin (β2m) as a model system, we show that the disruption of membranes by amyloid fibrils is caused by the molecular shedding of membrane-active oligomers in a process that is dependent on pH. Using thioflavin T (ThT) fluorescence, NMR, EM and fluorescence correlation spectroscopy (FCS), we show that fibril disassembly at pH 6.4 results in the formation of nonnative spherical oligomers that disrupt synthetic membranes. By contrast, fibril dissociation at pH 7.4 results in the formation of nontoxic, native monomers. Chemical cross-linking or interaction with hsp70 increases the kinetic stability of fibrils and decreases their capacity to cause membrane disruption and cellular dysfunction. The results demonstrate how pH can modulate the deleterious effects of preformed amyloid aggregates and suggest why endocytic trafficking through acidic compartments may be a key factor in amyloid disease