Theorizing voice and perspective in the narratives of Eliza Haywood and her contemporaries

This thesis traces the career of the prolific eighteenth-century author Eliza Haywood through narratological analysis of some of her key works. It contributes to the new wave of Haywood criticism that is moving away from the thematic, gender based focus that has dominated discussion of her oeuvre since her critical rediscovery in the 1980s. My narratological method demonstrates how understanding at a formal and thematic level is enhanced by the employment of theoretical narrative paradigms. Narratology is interested in the relationship between the events of a narrative (story) and how these events are presented (text). I utilize the narratological terminology of Gérard Genette because it is narrative discourse, rather than the mere events of a story, that provides the basis for a meaningful discussion concerning matters of presentation. Making the topic of narrative discourse central to the study requires analysis of voice, point of view, speech, and temporality, as it covers the ways in which the story is told. Throughout her career, Haywood manipulates these narrative features so as to create inventive texts that adapt to the changing trends of the literary marketplace. Key topics of discussion include Haywood s continuous but developing use both of the embedded narrative and anachronies; the differing levels of intrusion created by her narrators employment of metanarrative commentary; and her progressive use of metalepsis: from her inclusion of simple scene changes in her earlier work, to her emphatic use of explicit diegetic interruptions in her later work that mirror those utilised by Henry Fielding. The thesis follows a chronological structure and is historically and bibliographically informed. This approach enables the thesis to provide extended comparison of Haywood s narrative choices with those of her main forebears and contemporaries, especially Aphra Behn, Delarivier Manley, Samuel Richardson, Tobias Smollett, and Henry Fielding

Potential Contribution of Aromatase Inhibition to the Effects of Nicotine and Related Compounds on the Brain

Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking and many effects of nicotine are sexually dimorphic (reviewed by Pogun and Yararbas, 2009). Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product). Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine, and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction

Cross-tier web programming for curated databases: a case study

Curated databases have become important sources of information across several scientific disciplines, and as the result of manual work of experts, often become important reference works. Features such as provenance tracking, archiving, and data citation are widely regarded as important features for the curated databases, but implementing such features is challenging, and small database projects often lack the resources to do so. A scientific database application is not just the relational database itself, but also an ecosystem of web applications to display the data, and applications which allow data curation. Supporting advanced curation features requires changing all of these components, and there is currently no way to provide such capabilities in a reusable way. Cross-tier programming languages have been proposed to simplify the creation of web applications, where developers can write an application in a single, uniform language. Consequently, database queries and updates can be written in the same language as the rest of the program, and at least in principle, it should be possible to provide curation features reusably via program transformations. As a first step towards this goal, it is important to establish that realistic curated databases can be implemented in a cross-tier programming language. In this paper, we describe such a case study: reimplementing the web front end of a real world scientific database, the IUPHAR/BPS Guide to Pharmacology (GtoPdb), in the Links cross-tier programming language. We show how programming language features such as language-integrated query simplify the development process, and rule out common errors. Through a comparative performance evaluation, we show that the Links implementation performs fewer database queries, while the time needed to handle the queries is comparable to the Java version. Furthermore, while there is some overhead to using Links because of its comparative immaturity compared to Java, the Links version is usable as a proof-of-concept case study of cross-tier programming for curated databases. [ This paper is a conference pre-print presented at IDCC 2020 after lightweight peer review. The most up-to-date version of the paper can be found on arXiv https://arxiv.org/abs/2003.03845

Intestinal activation of Notch signaling induces rapid onset hepatic steatosis and insulin resistance.

Here we investigate the effects of expressing an activated mutant of Notch (ICD-E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD-E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis

Modal Sequencing and Dynamic Emission Properties of an 8-hour GMRT Observation of Pulsar B1822-09

The research presented here examines an 8-hour observation of pulsar B1822-09,taken by the Giant Metrewave Radio Telescope. B1822-09 has been known to exhibit two stable emission modes, the B-mode, where the precursor (PC) `turns-on', and the Q-mode, which is defined by interpulse (IP) emission. The results of our analysis, of this extremely long observation, have shown that B1822-09 exhibits at least three other emission behaviors that have not been seen before in other similar pulsars or in other observations of B1822-09. These three behaviors can be described as: Q-mode emission with PC emission, B-mode emission with IP emission, and instances where both the PC and IP are `on' when transitioning from one mode to the other. The pulse structure has been found to be more complex than previously thought. The MP has an inner cone/core triple (T) configuration together with a central sightline traverse. The IP is a 15/degr-wide region, that along with the MP originate from an open dipolar field. The PC emission comes from a still unknown source. We argue that the PC emission arises within the same region as the MP, but likely comes from higher in the magnetosphere. Overall, our analyses strongly suggest that mode changes allow information transfer between the two magnetic polar regions and contribute to global magnetospheric changes.Comment: 15 pages, submitted to MNRA

Human keratinocytes have two interconvertible modes of proliferation.

Single stem cells, including those in human epidermis, have a remarkable ability to reconstitute tissues in vitro, but the cellular mechanisms that enable this are ill-defined. Here we used live imaging to track the outcome of thousands of divisions in clonal cultures of primary human epidermal keratinocytes. Two modes of proliferation were seen. In 'balanced' mode, similar proportions of proliferating and differentiating cells were generated, achieving the 'population asymmetry' that sustains epidermal homeostasis in vivo. In 'expanding' mode, an excess of cycling cells was produced, generating large expanding colonies. Cells in expanding mode switched their behaviour to balanced mode once local confluence was attained. However, when a confluent area was wounded in a scratch assay, cells near the scratch switched back to expanding mode until the defect was closed. We conclude that the ability of a single epidermal stem cell to reconstitute an epithelium is explained by two interconvertible modes of proliferation regulated by confluence.The initial association of holoclone and paraclone type behaviour in clonal cultures of NFSK with stem and balanced progenitor dynamics was due to BDS working in collaboration with PHJ, VN-N, David Doupé and Allon Klein, based on the quantitative analysis of published and unpublished colony size distributions6 . We thank Gözde Akdeniz & David Doupé for experimental work that led up to the project that was analysed by Allon Klein and Genneth Zhang, Patrick Lombard at the Wellcome TrustMedical Research Council Cambridge Stem Cell Institute for Bioinformatics analysis and Esther Choolun for technical assistance. We acknowledge the support of the Wellcome Trust, Cambridge Cancer Centre, Medical Research Council, the NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research) and Cancer Research UK (Programme grant C609/A17257).This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncb328

Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

The front-line tuberculosis (TB) chemotherapeutics isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) have been labeled with carbon-11 and the biodistribution of each labeled drug has been determined in baboons using positron emission tomography (PET). Each radiosynthesis and formulation has been accomplished in 1 h, using [11C]CH3I to label RIF and [11C]HCN to label INH and PZA. Following iv administration, INH, PZA, RIF, and/or their radiolabeled metabolites clear rapidly from many tissues; however, INH, PZA, and/or their radiolabeled metabolites accumulate in the bladder while RIF and/or its radiolabeled metabolites accumulates in the liver and gall bladder, consistent with the known routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood−brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the minimum inhibitory concentration (MIC) values for inhibiting bacterial growth of Mycobacterium tuberculosis (MTB). The pharmacokinetic (PK) and drug distribution data have important implications for treatment of disseminated TB in the brain and pave the way for imaging the distribution of the pathogen in vivo.Chemistry and Chemical Biolog

Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention

BACKGROUND:Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. METHODOLOGY/PRINCIPAL FINDINGS:For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11)C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. CONCLUSIONS/SIGNIFICANCE:These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN

Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) was recently developed as a HDAC substrate and shows moderate blood–brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [18F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.Chemistry and Chemical Biolog