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As part of the design of future coupled forecasting systems, operational centres such as the Met Office are starting to include interactions between the atmosphere and the ocean within the data assimilation system. This requires an improved understanding and representation of the correlations between short-range forecast errors in different variables. To understand the potential benefit of further coupling in the data assimilation scheme it is important to understand the significance of any cross-correlations between atmosphere and ocean short-range forecast errors as well as their temporal and spatial variability. In this work we examine atmosphere-ocean cross-covariances from an ensemble of the Met Office coupled NWP system for December 2019, with particular focus on short-range forecast errors that evolve at lead times up to 6 hours.We find that significant correlations exist between atmosphere and ocean forecast errors on these timescales, and that these vary diurnally, from day to day, spatially and synoptically. Negative correlations between errors in sea-surface temperature (SST) and 10m wind correlations strengthen as the solar radiation varies from zero at night (local time) to a maximum insolation around midday (local time). In addition, there are significant variations in correlation intensities and structures in response to synoptic-timescale forcing. Significant positive correlations between SST and 10m wind errors appear in the western North Atlantic in early December and are associated with variations in low surface pressures and their associated high wind speeds, that advect cold, dry continental air eastward over the warmer Atlantic ocean. Negative correlations across the Indo-Pacific Warm Pool are instead associated with light wind conditions on these short timescales.When we consider the spatial extent of cross-correlations, we find that in the Gulf Stream region positive correlations between wind speed and sub-surface ocean temperatures are generally vertically coherent down to a depth of about 100m, consistent with the mixing depth; however, in the tropical Indian and West Pacific oceans, negative correlations break down just below the surface layer. This is likely due to the presence of surface freshwater layers that form from heavy precipitation on the tropical oceans, manifested by the presence of salinity-stratified barrier layers within deeper isothermal layers that can effectively limit turbulent mixing of heat between the ocean surface and the deeper thermocline.

The most common malignant brain tumour in children, medulloblastoma (MB), is subdivided into four clinically relevant molecular subgroups, although targeted therapy options informed by understanding of different cellular features are lacking. Here, by comparing the most aggressive subgroup (Group 3) with the intermediate (SHH) subgroup, we identify crucial differences in tumour heterogeneity, including unique metabolism-driven subpopulations in Group 3 and matrix-producing subpopulations in SHH. To analyse tumour heterogeneity, we profiled individual tumour nodules at the cellular level in 3D MB hydrogel models, which recapitulate subgroup specific phenotypes, by single cell RNA sequencing (scRNAseq) and 3D OrbiTrap Secondary Ion Mass Spectrometry (3D OrbiSIMS) imaging. In addition to identifying known metabolites characteristic of MB, we observed intra- and internodular heterogeneity and identified subgroup-specific tumour subpopulations. We showed that extracellular matrix factors and adhesion pathways defined unique SHH subpopulations, and made up a distinct shell-like structure of sulphur-containing species, comprising a combination of small leucine-rich proteoglycans (SLRPs) including the collagen organiser lumican. In contrast, the Group 3 tumour model was characterized by multiple subpopulations with greatly enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity. Extensive TCA cycle metabolite measurements revealed very high levels of succinate and fumarate with malate levels almost undetectable particularly in Group 3 tumour models. In patients, high fumarate levels (NMR spectroscopy) alongside activated stress response pathways and high Nuclear Factor Erythroid 2-Related Factor 2 (NRF2; gene expression analyses) were associated with poorer survival. Based on these findings we predicted and confirmed that NRF2 inhibition increased sensitivity to vincristine in a long-term 3D drug treatment assay of Group 3 MB. Thus, by combining scRNAseq and 3D OrbiSIMS in a relevant model system we were able to define MB subgroup heterogeneity at the single cell level and elucidate new druggable biomarkers for aggressive Group 3 and low-risk SHH MB.

Background COVID-19 data have been generated across the United Kingdom as a by-product of clinical care and public health provision, as well as numerous bespoke and repurposed research endeavors. Analysis of these data has underpinned the United Kingdom’s response to the pandemic, and informed public health policies and clinical guidelines. However, these data are held by different organizations, and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find relevant data to access and interrogate the data they need to inform the pandemic response at pace. Objective We aimed to transform UK COVID-19 diagnostic data sets to be findable, accessible, interoperable, and reusable (FAIR). Methods A federated infrastructure model (COVID - Curated and Open Analysis and Research Platform [CO-CONNECT]) was rapidly built to enable the automated and reproducible mapping of health data partners’ pseudonymized data to the Observational Medical Outcomes Partnership Common Data Model without the need for any data to leave the data controllers’ secure environments, and to support federated cohort discovery queries and meta-analysis. Results A total of 56 data sets from 19 organizations are being connected to the federated network. The data include research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal health care records and demographics. The infrastructure is live, supporting aggregate-level querying of data across the United Kingdom. Conclusions CO-CONNECT was developed by a multidisciplinary team. It enables rapid COVID-19 data discovery and instantaneous meta-analysis across data sources, and it is researching streamlined data extraction for use in a Trusted Research Environment for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions while maintaining patient confidentiality and local governance procedures.

BACKGROUND COVID-19 data have been generated across the UK as a by-product of clinical care and public health provision, and numerous bespoke and repurposed research endeavours. Analysis of these data has underpinned the UK’s response to the pandemic and informed public health policies and clinical guidelines. However, these data are held by different organisations and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find, navigate permissions to access and interrogate the data they need to inform the pandemic response at pace. OBJECTIVE To transform UK COVID-19 diagnostic datasets to be Findable, Accessible, Interoperable and Reusable (FAIR). METHODS A federated infrastructure model was rapidly built to enable the automated and reproducible mapping of health Data Partners’ pseudonymised data to the OMOP common data model without the need for any data to leave the data controllers’ secure environments and to support federated cohort discovery queries and meta-analysis. RESULTS 56 datasets from 19 organisations are being connected to the federated network. The data includes research cohorts and COVID-19 data collected through routine health care provision linked to longitudinal healthcare records and demographics. The infrastructure is live, supporting aggregate level querying of data across the UK. CONCLUSIONS CO-CONNECT was developed by a multidisciplinary team enabling rapid COVID-19 data discovery, instantaneous meta-analysis across data sources, and is researching streamlined data extraction for egress into a Trusted Research Environment (TRE) for research and public health analysis. CO-CONNECT has the potential to make UK health data more interconnected and better able to answer national-level research questions whilst maintaining patient confidentiality and local governance procedures. CLINICALTRIAL

Ein zentrales Ergebnis der Studie ���100 Radical innovation breakthroughs for the future��� (RIBRI) (2019) ist die Annahme, dass zahlreiche Innovationen im Bereich ���K��nstlicher Intelligenz��� starke Auswirkungen auf die Weltwirtschaft und Gesellschaft haben werden. Diese Arbeit umfasst eine qualitative Untersuchung, bei der einer der Datens��tze der RIBRI-Studie auf denk- und handlungsleitende, geteilte Orientierungsmuster hinsichtlich einer Zukunft mit ���Ku��nstlicher Intelligenz��� untersucht wird. Der f��r die Analyse genutzte Leitbildansatz der Forschungsgruppe Umweltbildung fand aufgrund zahlreicher Anforderungen an die ben��tigte Datengrundlage bisher nur bedingt Anwendung. In der Arbeit wird eine Modifizierung vorgeschlagen, die eine transparente, nachvollziehbare Erstellung von Leitbildern fu��r Datengrundlagen erm��glicht, die keine Faktoren- und Clusteranalysen hergeben. Diese Arbeit versteht sich daher nicht nur als Analyse von vorliegenden ���KI-Leitbildern��� im oben genannten Projekt ���Radical Innovation Breakthrough Inquirer���, sondern vor allem als Beitrag zur Weiterentwicklung der Methoden der Zukunftsforschung.

Streptococcus uberis is one of the leading pathogens causing mastitis worldwide. Identification of S. uberis strains that fail to respond to treatment with antibiotics is essential for better decision making and treatment selection. We demonstrate that the combination of supervised machine learning and matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry can discriminate strains of S. uberis causing clinical mastitis that are likely to be responsive or unresponsive to treatment. Diagnostics prediction systems trained on 90 individuals from 26 different farms achieved up to 86.2% and 71.5% in terms of accuracy and Cohen’s kappa. The performance was further increased by adding metadata (parity, somatic cell count of previous lactation and count of positive mastitis cases) to encoded MALDI-TOF spectra, which increased accuracy and Cohen’s kappa to 92.2% and 84.1% respectively. A computational framework integrating protein–protein networks and structural protein information to the machine learning results unveiled the molecular determinants underlying the responsive and unresponsive phenotypes.

Iris neural stem/progenitor cells from mature porcine eyes were investigated using a new protocol for tissue culture, which consists of dispase treatment and Matrigel embedding. We used a number of culture conditions and found an intense differentiation of neuronal cells from both the iris pigmented epithelial (IPE) cells and the stroma tissue cells. Rod photoreceptor-like cells were also observed but mostly in a later stage of culture. Neuronal differentiation does not require any additives such as fetal bovine serum or FGF2, although FGF2 and IGF2 appeared to promote neural differentiation in the IPE cultures. Furthermore, the stroma-derived cells were able to be maintained in vitro indefinitely. The evolutionary similarity between humans and domestic pigs highlight the potential for this methodology in the modeling of human diseases and characterizing human ocular stem cells.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.

This essay examines the discursive interpenetration of trauma and celebrity culture, and, through an examination of the multiple killer in recent British writing and culture, locates the interest in both in the alienating otherness of the Real. Reading the work of Gordon Burn, David Peace and Rupert Thomson, the essay explores the semiotic crossover between the celebrity and the murderer as contemporary icons and situates both as symptoms of a pathological rewriting of subjectivity. The dynamics of trauma as a means of asserting a wounded and therefore meaningful self are addressed, and the narrative potential of repetition is highlighted. Underpinning the discussion is the figure of Myra Hindley whose image has proven a potent resource for artists and writers seeking to explore the uncomfortable attraction-in-repulsion of the ‘celebrity’ murderer.

Contemporary culture is caught in a representational bind: fascinated by—and yet tired of—its tendency towards artifice and involution, whilst simultaneously attracted to—and yet sceptical of—the idea of the authentic. The hermeneutical confusion brought about by this self-identity crisis has given rise to a semiotic indistinction around artificiality and authenticity, leaving the observer trapped not by their bipolarity, but caught within their layers as they interleave. This essay explores the ramifications of this through an examination of the relationship between Oscar Wilde's The Picture of Dorian Gray (1891) and Will Self's Dorian: An Imitation (2002). Identifying the imitative intent of Self's rewrite as problematic, the essay situates the twentieth-century's shift towards an ethic of private authenticity over sincerity as indicative of a significant change in self and social understanding. However, the demands and desires of late capitalism have made it increasingly difficult to isolate what that ...

This chapter explores the writing of Ali Smith from the late 1990s to the publication of How to be Both (2014). It concentrates primarily on her novels and short stories, though some attention is paid to her occasional writings. The chapter is broken into two broad generic sections, the first addressing her short stories together, the second her novels in chronological order. Each text is given close analytical study through formal, stylistic, and thematic critique, building to an overview of an author whose moral sense of duty for the care of the other is paradoxically set against her confusion at the impenetrability of that other’s being.

This chapter traces the development of Jon McGregor’s writing up to the publication of his collection of short stories This Isn’t the Sort of Thing that Happens to Someone Like You (2012). It establishes McGregor’s deep interest in the resonance of the everyday and the overlooked, and examines the ethical importance of mutual recognition and the import of the other in his writing. McGregor’s fiction always demands the gaze of an often disinterested world both as an act of charity, and as a statement of human connectedness.

This introduction outlines the critical aims of the study, identifying the authors covered and placing them within the context of post-millennial writing in Britain. It also centrally addresses the problems involved in practising literary criticism on very contemporary material, and contextualises debates around the end of the postmodern and its aftermath. It seeks to establish (and justify) a critical methodology that eschews broad synopticism in favour of close attentiveness to the reflections and refractions of one author beside another. It also introduces the themes of Materiality, Connectivity, and Authenticity that emerge repeatedly in the analyses that follow.

This study explores the landscape of contemporary British fiction through detailed analysis of five authors that have emerged to critical prominence in the 21st century. The authors addressed - Ali Smith, Andrew O’Hagan, Tom McCarthy, Sarah Hall, and Jon McGregor – have all established themselves through popular and critical success, but have received significantly less attention than some of their peers. This book does not seek to thrust these authors into a putative canon of 21st century literary writing, but rather to explore through close attention to the resonances, continuities, elisions, and frictions across their works the temper of the contemporary moment as it is expressed by a group of writers. Each is devoted a chapter that analyses their creative output to-date within the frame of their stylistic and thematic development, as well as drawing comparisons across their writing and that of their peers. The intention is never to provide the kind of synoptical overview that a period-study might suggest, instead Twenty-First Century Fiction: Contemporary British Voices seeks to juxtapose critical readings within a constellation of contemporary literary concerns to examine what cultural energies and flows are emerging in the new century. In doing so, it identifies three recurrent areas of concern that might be said to infiltrate our times; these are Materiality, Connectivity, and Authenticity. In many forms and through many articulations, these issues emerge as insistent – if inchoate – questions about how current literary practice is responding to the challenge of the post-millennial world.

This chapter focuses on the writing of the Cumbrian novelist Sarah Hall, and explores her work’s close engagement with place and landscape as constitutive of social identity. By examining her fiction up to and including The Wolf Border (2015), the chapter explores her insistent concern with the material heft of the physical world in an increasingly weightless, digitised realm. Material stuff matters in Hall’s work, and manifests a ineradicable relationship between the human being and the beauty, pain, and violence of the world.

This chapter explores the writing of Tom McCarthy and situates him as one of the exciting experimental voices of contemporary British writing that is seeking to explore the limits and tolerances of the realistic. The chapter situates McCarthy within the notion of the contemporary avant-garde novel and contextualises his fictional writing alongside his non-fiction and his work as a conceptual artist. This is followed by close analysis of his fiction up to Satin Island (2015). McCarthy’s writing absorbs the cultural novelty of digital convergence, channelling the technological sublime of the 21st century back into the shell of the realist novel to examine the extent to which it any longer has representational credibility.

This essay argues that the issue of what it means to live an authentic life in the twenty-first century has been a significant trope in recent British fiction. Negotiating between universalizing humanist perspectives and the radically individualizing politics of late-capitalist philosophy, Tom McCarthy’s Remainder and Steven Hall’s The Raw Shark Texts pose the question of whether any authenticity of the self can be imagined in an increasingly globalized, mediated, and digitalized world. Contextualizing these novels within contemporary British writing, this essay locates a profound psychological anxiety as the dominant mode for engaging with authentic subjectification.

This essay explores the intertextual debt to Hamlet in Graham Swift's Ever After. Employing Jacques Lacan's reading of desire in "Desire and the Interpretation of Desire in Hamlet," the author argues that Bill Unwin's paralysis of subjective agency encourages his identification with Hamlet so as to fix himself within the symbolic order. Unlike Hamlet, however, Unwin faces not only the crisis of the father's law, but postmodernity's collapse of symbolic authority.

Money: a Suicide Note (1984) and London Fields (1989) are Amis’ most political novels, vituperative castigations of the materialistic attitudes promoted by Thatcherite capitalism. Unlike the formalistic experimentalism of some of his later work (notably Time’s Arrow [1991]) and the characteristic emotional detachment that appears elsewhere in his fiction, these are committed and angry novels. Amis derides the conspicuousness of the Thatcherite yuppie generation, the consumerism that shamelessly affirms its self-perpetuation whilst disavowing any broader social responsibility. A devotee of free market economics, Money’s John Self lives out a fantasy of capitalist exorbitance protected from the reflections of conscience by the seductive reassurance of money.1 He can know himself only through his possessions, his material and psychic parameters irreducibly entwined, their substance determined only by his affluence in comparison with others. Self is a grotesque parody of superfluous consumption, shorn of morality and self-restraint. But Amis’ political engagement, his insistence on the interdependencies and responsibilities that permeate even this attenuated cultural framework, point towards a broader remit of social satire. Despite their metafictional flourishes these novels belong to the tradition of the ‘condition-of-England’ novel, the tradition beginning with such novels as Benjamin Disraeli’s Sybil (1845) and Elizabeth Gaskell’s North and South (1855).2

Daniel LEA and Berthold SCHOENE: Masculinity in Transition: An Introduction Susan BROOK: Engendering Rebellion: The Angry Young Man, Class and Masculinity Richard HORNSEY: Of Public Libraries and Paperbacks: "Deviant" Masculinity and the Spatial Practices of Reading in Post-War London Gill PLAIN: Hard Nuts to Crack: Devolving Masculinities in Contemporary Scottish Fiction Neil McMILLAN: Heroes and Zeroes: Monologism and Masculinism in Scottish Men's Writing of the 1970s and Beyond Emma PARKER: No Man's Land: Masculinity and Englishness in Graham Swift's Last Orders Rhiannon DAVIES: Enduring McEwan Antony ROWLAND: Patriarchy, Male Power and the Psychopath in the Poetry of Carol Ann Duffy Irene ROSE: Heralding New Possibilities: Female Masculinity in Jackie Kay's Trumpet Emma LIGGINS: Alan Hollinghurst and Metropolitan Gay Identities Notes on Contributors