Don Juan, 2012

A long poem in ottava rima, based on Byron's Don Juan, concerning the Eurocrisis and the social consequences of an economic policy of austerity, particularly as it has impacted on Greece.

Dipping Wings:for flute (alto fl), clarinet (bass cot), tpt, vla, vcl, perc and live electronics

commissioned by Ballet Rambert for 60th Anniversary season, choreographer Mary Evelyn, designer Liz Emmanuel. World premiere: Theatre Royal York 03/06/86

Generation of replication-proficient influenza virus NS1 point mutants with interferon-hyperinducer phenotype

The NS1 protein of influenza A viruses is the dedicated viral interferon (IFN)-antagonist. Viruses lacking NS1 protein expression cannot multiply in normal cells but are viable in cells deficient in their ability to produce or respond to IFN. Here we report an unbiased mutagenesis approach to identify positions in the influenza A NS1 protein that modulate the IFN response upon infection. A random library of virus ribonucleoproteins containing circa 40 000 point mutants in NS1 were transferred to infectious virus and amplified in MDCK cells unable to respond to interferon. Viruses that activated the interferon (IFN) response were subsequently selected by their ability to induce expression of green-fluorescent protein (GFP) following infection of A549 cells bearing an IFN promoter-dependent GFP gene. Using this approach we isolated individual mutant viruses that replicate to high titers in IFN-compromised cells but, compared to wild type viruses, induced higher levels of IFN in IFN-competent cells and had a reduced capacity to counteract exogenous IFN. Most of these viruses contained not previously reported NS1 mutations within either the RNA-binding domain, the effector domain or the linker region between them. These results indicate that subtle alterations in NS1 can reduce its effectiveness as an IFN antagonist without affecting the intrinsic capacity of the virus to multiply. The general approach reported here may facilitate the generation of replication-proficient, IFN-inducing virus mutants, that potentially could be developed as attenuated vaccines against a variety of viruses.

An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response

UNLABELLED: Influenza A viruses counteract the cellular innate immune response at several steps, including blocking RIG I-dependent activation of interferon (IFN) transcription, interferon (IFN)-dependent upregulation of IFN-stimulated genes (ISGs), and the activity of various ISG products; the multifunctional NS1 protein is responsible for most of these activities. To determine the importance of other viral genes in the interplay between the virus and the host IFN response, we characterized populations and selected mutants of wild-type viruses selected by passage through non-IFN-responsive cells. We reasoned that, by allowing replication to occur in the absence of the selection pressure exerted by IFN, the virus could mutate at positions that would normally be restricted and could thus find new optimal sequence solutions. Deep sequencing of selected virus populations and individual virus mutants indicated that nonsynonymous mutations occurred at many phylogenetically conserved positions in nearly all virus genes. Most individual mutants selected for further characterization induced IFN and ISGs and were unable to counteract the effects of exogenous IFN, yet only one contained a mutation in NS1. The relevance of these mutations for the virus phenotype was verified by reverse genetics. Of note, several virus mutants expressing intact NS1 proteins exhibited alterations in the M1/M2 proteins and accumulated large amounts of deleted genomic RNAs but nonetheless replicated to high titers. This suggests that the overproduction of IFN inducers by these viruses can override NS1-mediated IFN modulation. Altogether, the results suggest that influenza viruses replicating in IFN-competent cells have tuned their complete genomes to evade the cellular innate immune system and that serial replication in non-IFN-responsive cells allows the virus to relax from these constraints and find a new genome consensus within its sequence space.

IMPORTANCE: In natural virus infections, the production of interferons leads to an antiviral state in cells that effectively limits virus replication. The interferon response places considerable selection pressure on viruses, and they have evolved a variety of ways to evade it. Although the influenza virus NS1 protein is a powerful interferon antagonist, the contributions of other viral genes to interferon evasion have not been well characterized. Here, we examined the effects of alleviating the selection pressure exerted by interferon by serially passaging influenza viruses in cells unable to respond to interferon. Viruses that grew to high titers had mutations at many normally conserved positions in nearly all genes and were not restricted to the NS1 gene. Our results demonstrate that influenza viruses have fine-tuned their entire genomes to evade the interferon response, and by removing interferon-mediated constraints, viruses can mutate at genome positions normally restricted by the interferon response.

‘The Problem of the Future in Nineteenth-Century Spain’

This article examines the problems and paradoxes in the representation of the future in three nineteenth-century Spanish works: El futuro Madrid (1868) by Fernández de los Ríos, ‘Madrid en el siglo xxi’ (1847) by Neira de Mosquera, and Ni en la vida ni en la muerte by Juan Bautista Amorós (Silverio Lanza). While these texts demonstrate Spain’s participation in the general movement towards using the future as a setting for literary works, they do not corroborate the theory that the nineteenth century was a time of optimism and belief in the doctrine of Progress. Concepts derived from discussions of the future in the history of ideas, such as historia magistra vitae, are shown to be relevant to discussion of these futuristic fictions, in sometimes unexpected ways.

Es teatro vuestra oración: Santa Teresa’s performed confession in Juan Mayorga’s La lengua en pedazos

Juan Mayorga’s La Lengua en Pedazos (2010) strikes at the heart of the compositional circumstances of St Teresa's Libro de la Vida– staging, and arguably heightening the origins of her rhetorical strategies, the sense of awareness of readership and potential censure we encounter within the Libro de la Vida. His inquisitor refuses to be complicit in the tacit agreement that the word spoken in the theatrical space can conjure new realities –insistent on underscoring the textual origin of the visions painfully and partially offered up for his and our scrutiny. I will suggest that the persistent undertow towards a meta-commentary on the unmaking and remaking of the autobiographical text creates an unresolved tension between Teresa’s eloquent ability to take the spectator to a place beyond language, and our awareness that we are in the presence of a consummate performer, the textual source for the script itself produced with a supreme awareness of audience scrutiny. The play reflects ongoing lines of inquiry in our evolving understanding of the cultural production of Teresa and other holy women of the Early Modern period.