Bewilderments of vision: hallucination and literature, 1880-1914

Hallucination was always the ghost story's elephant in the room. Even before the vogue for psychical research and spiritualism began to influence writers at the end of the nineteenth century, tales of horror and the supernatural, of ghosts and demons, had been haunted by the possibility of some grand deception by the senses. Edgar Allan Poe's stories were full of mad narrators, conscience-stricken criminals and sinners, and protagonists who doubted their very eyes and ears. Writers such as Dickens and Le Fanu continued this idea of the cheat of the senses. But what is certainly true is that, towards the end of the century, hallucination took on a new force and significance in ghostly and horror fiction. Now, its presence was not the dominion of a handful of experimental thinkers but the province of popular authors writing very different kinds of stories. The approaches had become many and diverse, from Arthur Machen's ambivalent interest in occultism to Vernon Lee's passion for art and antiquity. Henry James's The Turn of the Screw (1898) is the most famous text to pose a question that was, in fact, being asked by many writers of the time: reality or delusion? Other writers, too, were forcing their readers to assess whether the ghostly had its origins in some supernatural phenomenon from beyond the grave, or from some deception within our own minds. This thesis explores the many factors which contributed to this rise in the interest in hallucination and visionary experience, during the period 1880-1914. From the time when psychical research became hugely popular, up until the First World War often considered a watershed in the history of the ghost story and literature in general something happened to the ghost story and related fiction. Through a close analysis of stories and novels written by Robert Louis Stevenson, Vernon Lee, Henry James, Arthur Machen, and Oliver Onions, I attempt to find out what happened, and even more importantly why it happened at all

Living in the community : the psychological experiences of adults with intellectual disabilities

This thesis explores the experiences of adults with Intellectual Disabilities (ID), as they navigate complex community and wider social phenomena, including resettlement from secure settings and the psychological impact of marginalisation. Chapter one is a systematic literature review of the psychological experiences of community-based marginalisation in adults with ID. A systematic search of the literature identified 12 articles that met the eligibility criteria for Thematic Synthesis. Three themes emerged from the analysis relating to a lack of belonging, feeling like a burden, and a sense of not having a meaningful future. Clinical implications include the need for therapeutic intervention to mitigate the psychological consequences of marginalisation in people with ID. Study limitations and research recommendations are also discussed. Chapter two is an original piece of NHS-based empirical research exploring the lived transitional experiences of adults, with ID and histories of offending, who have resettled into the community from secure settings. Eight men with mild ID participated in semi-structured interviews. Three superordinate themes emerged from an Interpretative Phenomenological Analysis, highlighting transitional experiences of how participants’ hopefulness about living freer community lives was undermined by experiences of loss and a sense of living with a restricted identity. Clinical implications relate to the need for specialist ID forensic provision that offers trauma-informed and compassion-focused support. Study limitations and research recommendations are considered. Chapter three is a first-person reflective narrative piece summarising the author’s experiences of conducting the research. Motivations and inspirations for the project are discussed, as is the value of reflexivity during the process of navigating and overcoming challenges; these are explored in the context of learning and personal and professional development

Uncovering the Mechanisms Underpinning Melanoma Invasiveness at Single Cell Resolution

Metastatic cancer is responsible for 90% of cancer-related deaths, and a lack of effective therapies has seen survival rates remain bleak. Solid cancer cells escape the primary tumour mass and acquire invasive potential through an epithelial to mesenchymal transition (EMT), regulated by a set of master transcription factors (TFs) known as EMT-TFs. EMT-TF activity is in turn controlled by interacting signalling pathways, including the TGFß, Wnt and NF- κB pathways, which become dysregulated in cancer. Once escaped, metastatic cancer cells employ interchangeable modes of migration, transitioning between fibroblast-like mesenchymal migration and amoeboid migration, where cells display a rounded morphology and navigate the extracellular matrix in a protease independent manner. However, the key molecules that orchestrate the switch between mesenchymal and amoeboid migratory modes remain incompletely understood. This thesis describes a novel 3D spheroid invasion assay and single cell isolation technique that provides detailed 3D data on growth and invasion, and allows for the specific isolation of cells of a given phenotype. Via the expression of a photoconvertible fluorescent protein, compact epithelial cells at the edge of a tumour mass, elongated cells in the process of leaving the mass, and rounded amoeboid cells migrating away from the mass were tagged for isolation. Photoconverted cells were then single-cell sorted by flow cytometry and subjected to paired-end Illumina single cell RNA sequencing. 463 differentially expressed genes were identified via DESeq2 and enriched pathways determined by GSEA analysis. Delta opioid receptor and folate transporter SLC19A1 expression were upregulated in amoeboid migration and their functions investigated via pharmacological perturbation, while INKA1 expression was downregulated in amoeboid cells and its function investigated via inducible overexpression. This work describes a novel, adaptable and readily implementable method for the analysis of the earliest phases of cancer cell invasion, and its application to the identification of genes underpinning the invasiveness of malignant melanoma

In vivo passage of Salmonella Typhimurium results in minor mutations in the bacterial genome and increases in vitro invasiveness

International audienceAbstractEggs and raw or undercooked egg-containing food items are frequently identified as the bacterial source during epidemiolocal investigation of Salmonella outbreaks. Multi-locus variable number of tandem repeats analysis (MLVA) is a widely used Salmonella typing method enabling the study of diversity within populations of the same serotype. In vivo passage, however, has been linked with changes in MLVA type and more broadly the Salmonella genome. We sought to investigate whether in vivo passage through layer hens had an effect on MLVA type as well as the bacterial genome and whether any mutations affected bacterial virulence. Layer hens were infected with either Salmonella Typhimurium DT9 (03-24-11-11-523) as part of a single infection or were co-infected with an equal amount of Salmonella Mbandaka. Salmonella shedding in both single and co-infected birds was variable over the course of the 16-week experiment. Salmonella Typhimurium and Salmonella Mbandaka were identified in feces of co-infected birds. Salmonella colonies isolated from fecal samples were subtyped using MLVA. A single change in SSTR-6 was observed in Salmonella Typhimurium strains isolated from co-infected birds. Isolates of Salmonella Typhimurium of both the parent (03-24-11-11-523) and modified (03-24-12-11-523) MLVA type were sequenced and compared with the genome of the parent strain. Sequence analysis revealed that in vivo passaging resulted in minor mutation events. Passaged isolates exhibited significantly higher invasiveness in cultured human intestinal epithelial cells than the parent strain. The microevolution observed in this study suggests that changes in MLVA may arise more commonly and may have clinical significance

A predictive safety filter for learning-based racing control

The growing need for high-performance controllers in safety-critical applications like autonomous driving has been motivating the development of formal safety verification techniques. In this paper, we design and implement a predictive safety filter that is able to maintain vehicle safety with respect to track boundaries when paired alongside any potentially unsafe control signal, such as those found in learning-based methods. A model predictive control (MPC) framework is used to create a minimally invasive algorithm that certifies whether a desired control input is safe and can be applied to the vehicle, or that provides an alternate input to keep the vehicle in bounds. To this end, we provide a principled procedure to compute a safe and invariant set for nonlinear dynamic bicycle models using efficient convex approximation techniques. To fully support an aggressive racing performance without conservative safety interventions, the safe set is extended in real-time through predictive control backup trajectories. Applications for assisted manual driving and deep imitation learning on a miniature remote-controlled vehicle demonstrate the safety filter's ability to ensure vehicle safety during aggressive maneuvers

Evaluation of fatty acid metabolism and innate immunity interactions between commercial broiler, F1 layer × broiler cross and commercial layer strains selected for different growth potentials

Background: The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid (FA) metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as well as genes involved with FA metabolism, immunity and cellular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil: lymphocyte ratios, relative organ weights and bodyweight data were also compared. Results: Broiler bodyweight (n = 12) was four times that of layers (n = 12) by d 14 and had significantly higher carcass fat percentage compared to the cross (n = 6; P = 0.002) and layers (P = 0.017) which were not significantly different from each other (P = 0.523). The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite all being raised on the same diet. Genes associated with FA synthesis and β-oxidation were upregulated in the broilers compared to the layers indicating a net overall increase in FA metabolism, which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as well as organelle stress indicators ERN1 and XBP1 were found to be non-significant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additionally there was no difference in heterophil: lymphocytes between any of the birds. Conclusions: The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cellular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.Nicky-Lee Willson, Rebecca E.A. Forder, Rick G. Tearle, Greg S. Nattrass, Robert J. Hughes, and Philip I. Hyn

Whole genome sequencing increases molecular diagnostic yield compared with current diagnostic testing for inherited retinal disease

Abstract not availableJamie M. Ellingford, Stephanie Barton, Sanjeev Bhaskar, Simon G. Williams, Panagiotis I. Sergouniotis, James O, Sullivan, Janine A. Lamb, Rahat Perveen, Georgina Hall, William G. Newman, Paul N. Bishop, Stephen A. Roberts, Rick Leach, Rick Tearle, Stuart Bayliss, Simon C. Ramsden, Andrea H. Nemeth, Graeme C.M. Blac

Mapping an atlas of tissue-specific drosophila melanogaster metabolomes by high resolution mass spectrometry

Metabolomics can provide exciting insights into organismal function, but most work on simple models has focussed on the whole organism metabolome, so missing the contributions of individual tissues. Comprehensive metabolite profiles for ten tissues from adult Drosophila melanogaster were obtained here by two chromatographic methods, a hydrophilic interaction (HILIC) method for polar metabolites and a lipid profiling method also based on HILIC, in combination with an Orbitrap Exactive instrument. Two hundred and forty two polar metabolites were putatively identified in the various tissues, and 251 lipids were observed in positive ion mode and 61 in negative ion mode. Although many metabolites were detected in all tissues, every tissue showed characteristically abundant metabolites which could be rationalised against specific tissue functions. For example, the cuticle contained high levels of glutathione, reflecting a role in oxidative defence; the alimentary canal (like vertebrate gut) had high levels of acylcarnitines for fatty acid metabolism, and the head contained high levels of ether lipids. The male accessory gland uniquely contained decarboxylated S-adenosylmethionine. These data thus both provide valuable insights into tissue function, and a reference baseline, compatible with the FlyAtlas.org transcriptomic resource, for further metabolomic analysis of this important model organism, for example in the modelling of human inborn errors of metabolism, aging or metabolic imbalances such as diabetes