Literary forms of caricature in the early-nineteenth-century novel

This thesis examines the status of caricature in the literary culture of early-nineteenth- century Britain, with a focus on the novel. It shows how the early-nineteenth- century novel developed a variety of literary forms that negotiated and remade caricature for the bourgeois literary sphere. Case studies are drawn primarily from the published writings and manuscript drafts of Thomas Love Peacock, Jane Austen, Mary Shelley, and Walter Scott. The first chapter elucidates the various meanings and uses of ‘caricature’ in the eighteenth and early nineteenth centuries, when the term was more ambiguous and broadly applied than literary criticism and print history have acknowledged. I counter the assumption that the single-sheet satirical print was central to conceptions and practices of caricature in this period, giving examples of the textual, dramatic, and real-life ‘caricatures’ that were more often under discussion. The second and third chapters consider the unstable distinction between textual caricature and satirical characterisation in early-nineteenth-century literary culture. They explain how the literary construction of textual caricature developed from two sources: Augustan rulings against publishing satires on individuals, and caricature portraits as a pastime beloved of genteel British society. I argue that Peacock and Austen adapted forms of ‘caricaturistic writing’ that were conscious of the satirical literary work’s relation to caricature. Subsequent chapters turn to the thematic uses of caricature in the early-nineteenth- century novel. In the fourth chapter, I uncover the significance of caricature to deformity in Mary Shelley’s fiction, presenting evidence that her monsters’ disproportion was inherited from the ‘real-life’ caricatures diagnosed in philosophical and medical texts of the eighteenth century. The final chapter traces ideas about caricature through the writings of Walter Scott, and finds that Scott conceived of exemplary graphic and textual caricatures as artefacts of antiquarian interes

Discrete trajectories of resolving and persistent pain in people with rheumatoid arthritis despite undergoing treatment for inflammation: results from three UK cohorts

Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesised that discrete RA subgroups might display favourable or unfavourable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation.Growth Mixture Modelling was used to identify discrete trajectories of SF36-Bodily Pain scores during 3 years in 3 RA cohorts (Early RA Network (ERAN); n=683, British Society for Rheumatology Biologics Register Biologics (n=7090) and Non-Biologics (n=1720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years.Mean SF36-Bodily Pain scores in each cohort improved but remained throughout 3y follow up >1 SD worse than the UK general population average. Discrete Persistent Pain (59% to 79% of cohort participants) and Resolving Pain (19% to 27%) trajectories were identified in each cohort. In ERAN, a third trajectory displaying persistently Low Pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% of them were found to follow a Persistent Pain trajectory. When trajectories were compared, greater disability (aORs 2.3-2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (aORs 1.6-1.8) were risk factors for Persistent Pain trajectories in each cohort.In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during RA treatment. Inflammation does not fully explain the pain trajectories, and non-inflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long term burden of arthritis pain

Niche-Associated Activation of Rac Promotes the Asymmetric Division of <i>Drosophila</i> Female Germline Stem Cells

Background: Drosophila female germline stem cells (GSCs) reside adjacent to a cellular niche that secretes Bone Morphogenetic Protein (BMP) ligands and anchors the GSCs through adherens junctions. The GSCs divide asymmetrically such that one daughter remains in the niche as a GSC, while the other is born away from the niche and differentiates. However, given that the BMP signal can be diffusible, it remains unclear how a local extracellular asymmetry is sufficient to result in a robust pattern of asymmetric division. Methods and Findings: Here we show that GSCs are polarized with respect to the cellular niche. We first use a modified biosensor to demonstrate that the small GTPase Rac is asymmetrically activated within the GSC at the niche-GSC interface. Experiments using loss-of-function and gain-of-function mutations in Rac indicate that asymmetric Rac activity both localizes the microtubule binding protein Apc2 to orient one GSC centrosome at the niche-GSC interface during interphase and activates the Jun N-terminal kinase pathway to increase the ability of the GSC to respond to BMP ligands. Other processes act in concert with each function of Rac. Specifically, we demonstrate that the GSC cell cycle arrests at prometaphase if centrosomes are misoriented. Conclusions: Thus, the GSCs, an adult stem cell present in a cellular niche, have a niche-associated polarity that couples control of the division plane with increased response to an extracellular maintenance signal. Other processes work in parallel with the Rac-mediated polarity to ensure a robust pattern of asymmetric division. We suggest that all adult stem cells likely employ multiple, independently acting mechanisms to ensure asymmetric division to maintain tissue homeostasis.</p

CTCF regulates hepatitis B virus cccDNA chromatin topology

Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcription, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessible Chromatin Sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation

CTCF regulates hepatitis B virus cccDNA chromatin topology

Hepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcripts, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessibility/sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation

Is a Two-Day Cardiopulmonary Exercise Test a Valid Tool for The Diagnosis of Post-Exertional Malaise in Long COVID?

A two-day cardiopulmonary exercise testing (CPET) protocol (maximal ramp-incremental cycle test repeated 24hr apart) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients has suggested that day-2 performance is decreased relative to day-1. This difference has been attributed to post-exertional malaise (PEM), suggesting the two-day CPET as a protocol to investigate PEM in Long COVID (LC) patients. PURPOSE: We aimed to investigate any effects of PEM on exercise performance and cardiorespiratory and perceptual responses to a two-day CPET in LC patients to determine whether the day-1 CPET would impair performance, cardiorespiratory responses or perceptions of exercise at day-2. METHODS: Fifteen LC patients with one or more symptoms persisting for more than three months after their initial infection [n=7 females; n=1 hospitalized; mean(SD); age 53(11) yrs; body mass index 32.2(8.5) kg/m2; time between COVID-19 onset and CPET 13(7) months; forced expiratory volume in 1 second 89(15) %pred; forced vital capacity 92(14) %pred; diffusing capacity of the lungs for carbon monoxide 92(15) %pred; total lung capacity 86(12) %pred] were studied. Prior to any exercise testing, PEM was assessed relative to the past six months using the modified DePaul Symptom Questionnaire (mDSQ) (0-4 symptoms frequency and severity scores). Each performed a two-day CPET protocol; ramp was 10-20 W/min, with the same ramp rate used for the day-1 and day-2 CPET. Peak oxygen uptake, peak work rate, and gas exchange threshold were measured using standard techniques. Ratings of perceived dyspnea and leg effort during cycling were recorded at peak exercise using the modified Borg’s Scale (0-10). One-sample t-tests were used to assess significance of test-retest mean difference. RESULTS: The mDSQ indicated the presence of PEM symptoms in 80% of participants. However, no significant differences between day-1 and day-2 CPET were found in any of the variables assessed. CONCLUSION: The absence of any difference in cardiorespiratory and perceptual responses in 2-day CPET testing, despite patient reported presence of PEM symptoms, suggests that the two-day CPET protocol may not be a valid tool for the diagnosis of PEM in LC patients

JWST MIRI and NIRCam Unveil Previously Unseen Infrared Stellar Populations in NGC 6822

NGC 6822 is a nearby (\sim490 kpc) non-interacting low-metallicity (0.2 Z_\odot) dwarf galaxy which hosts several prominent Hii regions, including sites of highly embedded active star formation. In this work, we present an imaging survey of NGC 6822 conducted with the NIRCam and MIRI instruments onboard JWST. We provide a description of the data reduction, source extraction, and stellar population identifications from combined near- and mid-infrared (IR) photometry. Our NIRCam observations reach seven magnitudes deeper than previous JHKs surveys of this galaxy, which were sensitive to just below the tip of the red giant branch (TRGB). These JWST observations thus reveal for the first time in the near-IR the red clump stellar population and extend nearly three magnitudes deeper. In the mid-IR, we observe roughly two magnitudes below the TRGB with the MIRI F770W and F1000W filters. With these improvements in sensitivity, we produce a catalogue of \sim900,000 point sources over an area of \sim 6.0 x 4.3 arcmin2. We present several NIRCam and MIRI colour-magnitude diagrams and discuss which colour combinations provide useful separations of various stellar populations to aid in future JWST observation planning. Finally, we find populations of carbon- and oxygen-rich asymptotic giant branch stars which will assist in improving our understanding of dust production in low-metallicity, early Universe analogue galaxies