Strategies for influenza vaccines

The high mutation rate of influenza virus results in antigenic drift, meaning that each of the three components in the trivalent influenza vaccine are updated regularly so that the vaccine antigen closely matches the predominant or emerging strain. The production of influenza vaccines from the chosen seed has relied on embryonated chickens eggs for more than 40 years. Recent technological advances have resulted in the evaluation of several cell lines as alternative substrates for influenza vaccine production. Reverse genetics of influenza viruses allows the creation of viruses at will from cDNA. However, licensed cell lines have so far proved unpermissive for virus rescue and permissive lines remain largely unlicensed. A reverse genetics system for the production of influenza vaccines in PER.C6 cells has been developed and optimised. Many recent clinical isolates do not grow in eggs and hence require reassortment with a high growth, egg permissive backbone. Adventitious agents aside, cell lines able to support growth of clinical isolates could be used directly included in the vaccine, without the need for reassortment. However, this could lead to year on year variation in the quality and characteristics of the vaccine. Particularly pertinent, is the variation in the amount of IFN a clinical isolate can induce, which could severely limit yields. Yields and effects of IFN for a panel of high and low inducing viruses are investigated in a number of potential vaccine cell lines. The mechanisms behind virus IFN induction have been investigated. Using a panel of high and low inducing viruses the differences in growth and viral protein expressions, and activation of PRR has been analysed. The IFN response in PER.C6 cells has been characterised. Through an improved understanding of the mechanisms of IFN induction and inhibition, antagonists could be introduced into the vaccine cell line to improve yields

Sustaining the environment and visitor economy in Cornwall

This is the final version.The tourism industry, particularly in rural and coastal areas, is often heavily reliant on thriving ecosystems. Healthy ecosystems bring a range of benefits, not least the provision of food, water, and natural beauty for the visitor and local community alike. However, tourists can threaten the quality of the local environment, and the ‘burden’ of over-tourism is a growing concern in many parts of the world (Wood et al., 2019). The COVID-19 pandemic has heightened concern about the potential for over-tourism in Cornwall, as increasing numbers of people have taken their holidays ‘at home’ in the UK rather than abroad. At the time of writing, summer 2021 looks set to place further pressure on Cornwall’s local environment. However, the impacts of the pandemic also present an opportunity to explore ways of rebuilding the economy and society, to put nature’s recovery centre-stage. Funding from Research England’s Strategic Priorities Fund, administered through the University of Exeter, allowed partners and researchers to conduct a short project (running between January and March 2021) to explore potential policy ideas that could be further developed in the future. Our task was to identify, evaluate, and test the acceptance of locally-relevant evidence based ideas to: (1) Reduce any negative impact of tourism on nature in Cornwall; and (2) Generate understanding, funds, and volunteer time to protect and restore nature in Cornwall. Following a review of potential policy innovations, the partners and additional stakeholders agreed to focus on the development of nature-based activities, funding mechanisms, and appropriate organisational infrastructures to support nature and a sustainable visitor economy. This report outlines findings from investigations into these ideas, including recordings from a workshop, interviews with key stakeholders, and surveys conducted with nature-based activity providers, residents and visitors. Participation in nature-based activities is widely seen as a core attraction of Cornwall’s visitor economy. Ideas for their development initially focused on certification and standards as methods to ensure appropriate visitor engagement with nature, and to generate revenue for nature-focused organisations that would provide the expertise to train activity businesses, in return for qualified promotion. Given the diversity of activity provision and practical difficulty of standards enforcement, the support for such measures was not universal. However, opportunities were identified for training hospitality staff to effectively become front-line marketers for nature-based activities, and in developing nature recovery projects as a new type of attraction to which visitor contributions could produce tangible, shared benefits. Funding mechanisms to support the protection and restoration of nature aroused strong opinions in relation to the recurring topic of a tourism tax. Industry participants made clear their opposition to such a measure. Survey respondents, both residents and visitors, indicated a preference for visitors to contribute in comparison to locals, although the exact mechanism was generally unspecified. Best practice local examples of visitor gifting schemes point towards a solution to suit all parties, and this approach could be developed on a wider scale. Examples of networks at the local, regional, and sectoral scales were discussed, generating a variety of viewpoints about the best model for developing and delivering locally-led nature-based activities and visitor giving. Institutional support was advocated to encourage collaborative local endeavours, with the potential to benefit nature, communities, businesses, and visitors. Development of the rural visitor economy and the emergence of technological infrastructure were also raised as potential routes to mitigate the impact of overtourism and seasonality effects. These approaches have the potential to be further developed.UKRI Strategic Priorities Fun

Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice.

The highly pathogenic avian influenza (HPAI) H5N1 influenza virus has been a public health concern for more than a decade because of its frequent zoonoses and the high case fatality rate associated with human infections. Severe disease following H5N1 influenza infection is often associated with dysregulated host innate immune response also known as cytokine storm but the virological and cellular basis of these responses has not been clearly described. We rescued a series of 6:2 reassortant viruses that combined a PR8 HA/NA pairing with the internal gene segments from human adapted H1N1, H3N2, or avian H5N1 viruses and found that mice infected with the virus with H5N1 internal genes suffered severe weight loss associated with increased lung cytokines but not high viral load. This phenotype did not map to the NS gene segment, and NS1 protein of H5N1 virus functioned as a type I IFN antagonist as efficient as NS1 of H1N1 or H3N2 viruses. Instead we discovered that the internal genes of H5N1 virus supported a much higher level of replication of viral RNAs in myeloid cells in vitro but not in epithelial cells and that this was associated with high induction of type I IFN in myeloid cells. We also found that in vivo during H5N1 recombinant virus infection cells of haematopoetic origin were infected and produced type I IFN and proinflammatory cytokines. Taken together our data infer that human and avian influenza viruses are differently controlled by host factors in alternative cell types; internal gene segments of avian H5N1 virus uniquely drove high viral replication in myeloid cells, which triggered an excessive cytokine production, resulting in severe immunopathology

The conservation value of abandoned pits and quarries in Cornwall: a report of the conference held at County Hall, Truro on 22nd March 1999

Copyright © Cornwall County Counci

On the beach: new discoveries at Harlyn Bay, Cornwall

Following severe winter storms in February, 1990, Philip Steele reported the discovery of a stone covered pit containing a Trevisker Ware vessel eroding from the cliffs at Harlyn Bay. Historic Environment Service archaeologist Steve Hartgroves visited the site, recorded the section, and took samples of the pit fill and the soil layers identified. The pit was then excavated and the urn and its contents removed. The vessel contained a mixed fill of soil, cremated bone from several individuals and quartz stones, and a small bronze 'pendant'. The vessel, made from gabbroic clay with a burnished surface, is of slightly biconical shape, with an everted, bevelled rim and a band of shallow incised chevrons close to the top. Analyses of lipids from the vessel revealed that it probably been used to store ruminant dairy fats. Traces of fibre on the loop of the pendant suggest that it had been suspended from a cord. A radiocarbon date from the cremation deposit fell between 2120-1880 cal BC. This date is important as it provides an early date for incised Trevisker Ware and makes a major contribution to the debate on the Ware's decorative sequence. The date also makes this one of the few securely dated Early Bronze Age burials in Cornwall with a metalwork association

Synergistic assembly of linker for activation of T cells signaling protein complexes in T cell plasma membrane domains.

Transmembrane adaptor molecule LAT (linker for activation of T cells) forms a central scaffold for signaling protein complexes that accumulate in the vicinity of activated T cell antigen receptors (TCR). Here we used biochemical analysis of immunoisolated plasma membrane domains and fluorescence imaging of green fluorescence protein-tagged signaling proteins to investigate the contributions of different tyrosine-based signaling protein docking sites of LAT to the formation of LAT signaling protein assemblies in TCR membrane domains. We found that the phospholipase C gamma docking site of LAT and different Grb2/Gads docking sites function in an interdependent fashion and synergize to accumulate LAT, Grb2, and phospholipase C gamma in TCR signaling assemblies. Two-dimensional gels showed that Grb2 is a predominant cytoplasmic adaptor in the isolated LAT signaling complexes, whereas Gads, Crk-1, and Grap are present in lower amounts. Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains

NS1 proteins of avian influenza A viruses can act as antagonists of the human alpha/beta interferon response

Many viruses, including human influenza A virus, have developed strategies for counteracting the host type I interferon (IFN) response. We have explored whether avian influenza viruses were less capable of combating the type I IFN response in mammalian cells, as this might be a determinant of host range restriction. A panel of avian influenza viruses isolated between 1927 and 1997 was assembled. The selected viruses showed variation in their ability to activate the expression of a reporter gene under the control of the IFN-beta promoter and in the levels of IFN induced in mammalian cells. Surprisingly, the avian NS1 proteins expressed alone or in the genetic background of a human influenza virus controlled IFN-beta induction in a manner similar to the NS1 protein of human strains. There was no direct correlation between the IFN-beta induction and replication of avian influenza viruses in human A549 cells. Nevertheless, human cells deficient in the type I IFN system showed enhanced replication of the avian viruses studied, implying that the human type I IFN response limits avian influenza viruses and can contribute to host range restriction