Inhibiting influenza virus replication using novel and established antiviral compounds

Circulating influenza viruses have the potential to cause pandemics, as seen in 2009 with the emergence of a novel H1N1 virus that rapidly disseminated worldwide. In such an event, huge reliance is placed upon antiviral drugs for the prophylaxis and treatment of influenza infections. To date, only two different classes of antiviral drug are licensed for the treatment of influenza and only one of these, oseltamivir, has been stockpiled by major world governments in preparation for an influenza pandemic. However, widespread resistance to this drug has been documented in seasonal circulating strains, which emerged in the absence of intense drug use and predominated over drug-sensitive phenotypes. Furthermore, examples of oseltamivir resistant viruses have been found sporadically in pandemic A/H1N1 2009 influenza strains. The need for novel antivirals is therefore essential for effective infection control of influenza viruses in future years. A potential source of novel therapies are licensed compound libraries. We begin with the screening of two compound libraries, resulting in the identification of several compounds which inhibited influenza virus replication in vitro. After completing a traditional library screen, a novel approach to high-throughput compound screening using reporter plasmids expressed in a stable cell line was attempted. Although these cell-lines did not prove maintainable in the long-term, this work resulted in the generation of a reporter plasmid that is directly initiated by influenza infection in vitro and is thus a useful tool for assaying polymerase fitness of different influenza strains. The investigation then focused on one of the newly discovered hits and attempted to identify the spectrum of activity of this compound, a glycosylation inhibiting molecule, which was shown to be efficacious against influenza A strains only. The drug was shown to have low toxicity and proved active against the recently emerged pandemic influenza virus. The thesis then documents the effects of a common oseltamivir-resistant mutation, H275Y, on the neuraminidase protein of a representative 2009 pandemic influenza virus. This mutation was well tolerated in vitro by the virus and did not handicap replication in a human airway epithelial model. However, subtle impediments to the neuraminidase activity of the mutant were observed biochemically which may suggest why this mutation has not emerged more readily in the field

Twitter as a flexible tool: how the job role of the journalist influences tweeting habits

This study focuses on the tweeting habits of journalists with different job roles at a UK city newspaper. The Twitter profiles of 16 journalists working at The Star in Sheffield were captured in 2014 and a content analysis was conducted to examine the types of information each individual was reporting. The data revealed Twitter was being utilised as a versatile tool for gathering, reporting and disseminating news, and there was correlation between types of tweets and the job role of the profile account holder. Those in managerial positions tended to include more hyperlinks to their own news website and use Twitter as a promotional tool whereas sports journalists tended to use the social media platform as a live reporting tool. News reporters at the newspaper did not regularly link back to their legacy platform, preferring to use Twitter to build relationships and interactions with users. The authors conclude that these data together with similar comparative studies are useful for identifying patterns in changing journalistic roles within a local, national and international context. The emerging trends challenge the notion of the redefinition of the journalist as a universal role and instead point towards multiple redefinitions of the varying roles of journalists

Lazy Evaluation and Delimited Control

The call-by-need lambda calculus provides an equational framework for reasoning syntactically about lazy evaluation. This paper examines its operational characteristics. By a series of reasoning steps, we systematically unpack the standard-order reduction relation of the calculus and discover a novel abstract machine definition which, like the calculus, goes "under lambdas." We prove that machine evaluation is equivalent to standard-order evaluation. Unlike traditional abstract machines, delimited control plays a significant role in the machine's behavior. In particular, the machine replaces the manipulation of a heap using store-based effects with disciplined management of the evaluation stack using control-based effects. In short, state is replaced with control. To further articulate this observation, we present a simulation of call-by-need in a call-by-value language using delimited control operations

Thinking the ontological politics of managerial and critical performativities: an examination of project failure

Recent contributions within Critical Management Studies have argued for critical engagements with performativity to acknowledge and advance the plurality of performance calculi within organizations. However, even critically minded authors persist in deploying managerial calculi of performance when criticizing the failure of management on its own terms. Equally, interpretive analyses of performance narratives as discursive power games have thus far offered little substantive challenge to managerial understandings of performativity, as orientated around maxims of efficiency, control and profit. Positioned against these managerialist and conservative tendencies in extant understandings of performativity, we draw together the ANT- derived notions of ontological performativity and politics, alongside empirical research on projects, and specifically project failure, to propose that if ontologies are performative, multiple, and political, then performativities are ontological, multiple and political, and are thus capable of being realized otherwise; but crucially, we can advance this thesis only if we better understand how managerial performativity simultaneously others and depends on that which is outside it: an absent hinterland of different performative realities. This theoretical move challenges how we might not only understand but assemble multiple performed realities — demanding new methodological, analytical and political resources and responses to engage with performativities

Who reads the project file? Exploring the power effects of knowledge tools in construction project management

Various critical authors have questioned the salience, efficacy and power effects of formal project management bodies of knowledge (PMBoKs). As a result project management knowledge tools are increasingly being conceptualized along more flexible, adaptable, reflexive, democratic and informal terms. A central driver for this shift is that PM knowledge will be more relevant and useful for practitioners if it can be reflexively tailored to fit local project scenarios, emergent problems and different communities of practice, rather than projects being structured to fit generic ‘best practice’ ideals. Hence new knowledge tools increasingly would appear critical to alleviate various detrimental power effects associated with bureaucratic knowledge practices within project‐based industries, not least construction. This assumption is examined through a study of a formal and codified project management knowledge tool—a project file—within a small team of project practitioners in a large civil engineering consultancy. Various concepts of power related to actor‐network theory (ANT) are mobilized to understand how non‐human artefacts can enact power and knowledge in nuanced ways within organizations. This theoretically informed study will aid both researchers and practitioners interested in the consequences of developing prescriptive or reflexive project management knowledge within construction contexts and beyond

Discovery of a 500 pc shell in the nucleus of Centaurus A

Spitzer Space Telescope mid-infrared images of the radio galaxy Centaurus A reveal a shell-like, bipolar, structure 500 pc to the north and south of the nucleus. This shell is seen in 5.8, 8.0 and 24 micron broad-band images. Such a remarkable shell has not been previously detected in a radio galaxy and is the first extragalactic nuclear shell detected at mid-infrared wavelengths. We estimate that the shell is a few million years old and has a mass of order million solar masses. A conservative estimate for the mechanical energy in the wind driven bubble is 10^53 erg. The shell could have created by a small few thousand solar mass nuclear burst of star formation. Alternatively, the bolometric luminosity of the active nucleus is sufficiently large that it could power the shell. Constraints on the shell's velocity are lacking. However, if the shell is moving at 1000 km/s then the required mechanical energy would be 100 times larger.Comment: submitted to ApJ Letter

Antigenic and genetic characterization of a divergent African virus, Ikoma lyssavirus

In 2009, a novel lyssavirus (subsequently named Ikoma lyssavirus, IKOV) was detected in the brain of an African civet (Civettictis civetta) with clinical rabies in the Serengeti National Park of Tanzania. The degree of nucleotide divergence between the genome of IKOV and those of other lyssaviruses predicted antigenic distinction from, and lack of protection provided by, available rabies vaccines. In addition, the index case was considered likely to be an incidental spillover event, and therefore the true reservoir of IKOV remained to be identified. The advent of sensitive molecular techniques has led to a rapid increase in the discovery of novel viruses. Detecting viral sequence alone, however, only allows for prediction of phenotypic characteristics and not their measurement. In the present study we describe the in vitro and in vivo characterization of IKOV, demonstrating that it is (1) pathogenic by peripheral inoculation in an animal model, (2) antigenically distinct from current rabies vaccine strains and (3) poorly neutralized by sera from humans and animals immunized against rabies. In a laboratory mouse model, no protection was elicited by a licensed rabies vaccine. We also investigated the role of bats as reservoirs of IKOV. We found no evidence for infection among 483 individuals of at least 13 bat species sampled across sites in the Serengeti and Southern Kenya

System among the corticosteroids: specificity and molecular dynamics.

Fil: Brookes, Jennifer C.. University College London; Estados UnidosFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Harker, Anthony H.. University College London; Estados UnidosFil: Stoneham, A. Marshall. University College London; Estados UnidosFil: Vinson, Gavin P.. Queen Mary University of London; Reino Unid