Binding of Herpes Simplex Virus Type-1 Virions Leads to the Induction of Intracellular Signalling in the Absence of Virus Entry

The envelope of HSV-1 contains a number of glycoproteins, four of which are essential for virus entry. Virus particles lacking gB, gD, gH or gL are entry-defective, although these viruses retain the ability to bind to the plasma membrane via the remaining glycoproteins. Soluble forms of gD have been shown to trigger the nuclear translocation of the NF-κB transcriptional complex in addition to stimulating the production of Type I interferon. By taking advantage of the entry-defective phenotype of glycoprotein-deficient HSV-1 virus particles, the results presented here show that binding of virions to cellular receptors on the plasma membrane is sufficient to stimulate a change in cellular gene expression. Preliminary microarray studies, validated by quantitative real-time PCR, identified the differential expression of cellular genes associated with the NF-κB, PI3K/Akt, Jak/Stat and related Jak/Src pathways by virions lacking gB or gH but not gD. Gene induction occurred at a few particles per cell, corresponding to physiological conditions during primary infection. Reporter assay studies determined that NF-κB transcriptional activity is stimulated within an hour of HSV-1 binding, peaks between two and three hours post-binding and declines to background levels by five hours after induction. The immediate, transient nature of these signalling events suggests that HSV-1 glycoproteins, particularly gD, may alter the cellular environment pre-entry so as to condition the cell for viral replication

CumbraeCraft:a virtual environment for teaching cultural heritage to primary schoolchildren

Game-based learning is a research area that has grown within the past two decades, with evidence of tailoring commercial-off-the-shelf gaming, developing bespoke educational games, and using gamification-based learning tools in a variety of educational settings. However, the Covid-19 pandemic has accelerated the need to focus on virtual learning experiences that are engaging and motivating for schoolchildren to participate in as they face learning from home. Games are one such method of virtual learning experiences that aim to provide a stimulating experience for young people to continue their compulsory education. This paper introduces a project developed between Millport Conservation Area Regeneration Scheme (CARS) and a small team of game development students and academics from Abertay University. The purpose of the project was to develop a Minecraft Education world that could be used by teachers to engage primary schoolchildren in the history and heritage of the Isle of Cumbrae, an island in North Ayrshire, western Scotland. The project also set out to achieve aims of promoting local heritage and heritage tourism, enhancing national educational standards, serving as an electronic record of local heritage, and introducing potential career options in gaming to young people. The result - CumbraeCraft - is a suite of eight lessons that support teachers to use the game within the classroom as a way of teaching young people about local heritage and culture. The world focused on recreating locations and events from the Isle of Cumbrae to present interesting facts and knowledge to pupils in an interactive and enjoyable manner, focusing on interactions of exploration and discovery, narrative and communication, fellowship and teamwork, expression and creativity, and challenge-based learning. The aim of this paper is to present a case study on the design and development of CumbraeCraft as an educational environment to teach the heritage and history of island communities in western Scotland. Additionally, the paper spotlights a gap for games to be used to teach young people about local heritage and the historical significance of their communities and culture, with a particular emphasis on Scottish culture, language, and tradition.</p

Home-Time Is a Feasible and Valid Stroke Outcome Measure in National Datasets

Background and Purpose— Home-time (HT) is a stroke outcome measure based on time spent at home after stroke. We hypothesized that HT assessment would be feasible and valid using national data. Methods— We linked the Scottish Stroke Care Audit to routine healthcare data and calculated 90-day HT for all strokes, 2005 to 2017. We described prognostic validity (Spearman rank correlation) of HT to baseline factors. Results— We were able to calculate HT for 101 969 strokes (99.3% of total Scottish strokes). Mean HT was 46 days (95% CI, 45.8–46.2; range, 0–90). HT showed consistent correlation with our prespecified prognostic factors: age: ρ, −0.35 (95% CI, −0.35 to −0.36); National Institutes of Health Stroke Scale score, −0.54 (95% CI, −0.52 to −0.55); and 6 simple variables (ordinal), −0.61 (95% CI, −0.61 to −0.62). Conclusions— HT can be derived at scale using routine clinical data and appears to be a valid proxy measure of functional recovery. Other national databases could use HT as a time and cost efficient measure of medium and longer-term outcomes

THE SPRING MIGRATION OF ADULT NORTH AMERICAN OSPREYS

Most North American Ospreys (Pandion haliaetus) are migratory, breeding in northern latitudes and migrating long distances to and from their wintering grounds in the tropics. Although fall migration patterns of North American Ospreys have been described and studied, very little has been published about the spring migration of these birds. We used satellite telemetry to: (1) determine the characteristics (timing, duration, migratory routes) of spring migrations of Ospreys; (2) determine if differences in spring migration patterns existed between sexes and among three breeding populations (east coast, midwestern, and western); and (3) compare consecutive fall and spring migrations of individual Ospreys. The median dates for departure from the wintering grounds and arrival on the breeding grounds did not differ significantly between adult male and female Ospreys. Compared to their fall migrations, all male and all east coast Ospreys spent fewer days on migration, fewer days in stopover periods along the migration route, traveled shorter distances overall, and traveled farther (on average) each day during spring. In contrast, fall and spring migration characteristics of all female and western Ospreys were similar. Our findings suggest that, although sex and breeding location might influence the spring migration strategy used by individual Ospreys, both males and females minimize the time spent on migration to ensure a timely arrival on the breeding grounds to establish or defend a nesting territory

Trace element systematics and ore-forming processes in mafic VMS deposits: Evidence from the Troodos ophiolite, Cyprus

The volcanogenic massive sulfide (VMS) deposits in the Troodos ophiolite (Cyprus) are ancient analogues for modern day seafloor massive sulfide mineralisation formed in a supra-subduction zone environment. In this study we present the first detailed in situ study of trace elements in sulfides from twenty VMS deposits hosted in the Troodos ophiolite to better understand factors that influence the distribution, enrichment and incorporation of trace elements in different sulfide minerals. On a mineral scale, trace elements exhibit systematic variations between pyrite, chalcopyrite and sphalerite. Pyrite preferentially incorporates As, Sb, Au and Te, whilst chalcopyrite is enriched in Co and Se. Sphalerite is trace element poor with the exception of Ag and Cd. Selenium averages 278 ppm (n = 150) in chalcopyrite but only 42 ppm (n = 1322) in pyrite. Bismuth and Te in pyrite show a weak positive correlation (R2 = 0.35) in some VMS deposits possibly linked with the occurrence of Bi-telluride inclusions. Trace element concentrations also vary between colloform and euhedral pyrite, with an enrichment of Au, As, Sb, Cu and Zn in colloform compared to euhedral pyrite. Time resolved laser ablation profiles reveal that the trace element distribution on a mineral scale is not uniform and varies with crystallographic effects, fluctuating physicochemical fluid conditions such as temperature, pH, fS2, fO2 and ligand availability during sulfide precipitation. Incorporation mechanisms in sulfides differ between elements in pyrite, Ag, As, Se and Pb are hosted in solid solution or as nanoscale inclusions, whilst Au, Sb and Te may form micro-scale inclusions. On a regional scale (20 km) the distribution of trace elements exhibits systematic variations between three major structural domains; namely the Solea, Mitsero and Larnaca grabens. The VMS deposits of the magmatic-tectonic Solea graben are enriched in Se, Co, Te, Au and Cu relative to Mitsero, which is a purely extensional feature. Therefore, we hypothesise that a variable magmatic volatile influx related to a) ‘magma’ volume, b) migration of the magmatic-hydrothermal crack front and associated brine liberation or c) a variation in protolith metal concentration are responsible for regional scale variations in VMS geochemistry. This is suggested to be intrinsically linked to the spreading architecture of Troodos

Effects of magmatic volatile influx in mafic VMS hydrothermal systems: Evidence from the Troodos ophiolite, Cyprus

The Troodos ophiolite, Cyprus is the principal on- land analogue for mafic-hosted volcanogenic massive sulfide (VMS) deposits. This study, for the first time, presents sulfur isotope (δ34S) data on a regional scale from VMS deposits and other mineralised zones across the Troodos ophiolite. In combination δ34S, Se/S ratios and trace element chemistry (e.g., Se, Cu and Au) of different hydrothermal sulfides are used to assess variations in magmatic volatile influx and the source of metals and sulfur in ancient hydrothermal systems. Sulfur isotope analyses (n = 180) across 19 mineral deposits indicate a variable source of sulfur in the Troodos VMS hydrothermal system, this in turn allows a variable source of metals to be inferred. Pyrite δ34S range from −5.5‰ to +13.2‰ with an average of +4.6‰ (n = 160) for all deposits investigated. These δ34S variations cannot only be explained by variable proportions of thermochemical seawater sulfate reduction (δ34S +18 to +19‰) and leaching of primary magmatic sulfur from igneous rocks (δ34S 0-1‰). Consequently, two processes are proposed, explaining the trace metal and δ34S variation across the Troodos ore-forming systems including, i) a variable source of metals in the sheeted dyke complex and ii) the addition of a magmatic volatile-rich phase to the VMS hydrothermal systems. Two distinct lava units exist in the Troodos stratigraphy, namely the upper and lower pillow lavas (UPL and LPL). The more primitive UPL are enriched in Au, Se and Cu relative to As, Sb and Zn that are concentrated in the LPL. Some VMS deposits pre-date the formation of the UPL (e.g., Agrokipia A) suggesting Se, Cu and Au depleted source rocks. Hence, the stratigraphic position of VMS deposits and the ratio of UPL:LPL affinity elements (e.g., As + Zn + Sb vs. Cu + Se + Au) imply a systematic relationship between trace element distribution and stratigraphic depth; this relates to the relative proportion of UPL and LPL affinity lavas within the metal source region. δ34S values &lt;0‰ recorded in some VMS deposits that are less than the Troodos magmatic mean of 0- 1‰ may be related to anhydrite buffering during fluid ascent, microbial sulfate reduction or the direct contribution of magmatically derived sulfur, to the hydrothermal system from an underlying magma chamber via volatile exsolution. We propose that negative δ34S values combined with Se/S 106 ratios &gt;500 in pyrite suggest the contribution of a magmatic volatile component (e.g., Apliki and Skouriotissa). We demonstrate that the source of metals and sulfur in the Troodos VMS hydrothermal system is affected by regional scale processes related to i) variable source lithologies and, ii) the contribution of a magmatic volatile phase to some Troodos VMS hydrothermal systems

Mineral-scale variation in the trace metal and sulfur isotope composition of pyrite: implications for metal and sulfur sources in mafic VMS deposits

The link between metal enrichment and the addition of a magmatic volatile phase in volcanogenic massive sulfide deposits and actively forming seafloor massive sulfide deposits remains poorly characterized. This is especially true when considering how metal, sulfur and fluid flux change with time. In this study, we combine in situ sulfur isotope (δ34S; n = 31) measurements with trace metal chemistry of pyrite (n = 143) from the Mala VMS deposit, Troodos, Cyprus. The aim of our study is to assess the links between volatile influx and metal enrichment and establish how, or indeed if, this is preserved at the scale of individual mineral grains. We classify pyrite based on texture into colloform, granular, disseminated and massive varieties. The trace metal content of different pyrite textures is highly variable and relates to fluid temperature and secondary reworking that are influenced by the location of the sample within the mound. The sulfur isotope composition of pyrite at Mala ranges from − 17.1 to 7.5‰ (n = 31), with a range of − 10.9 to 2.5‰ within a single pyrite crystal. This variation is attributed to changes in the relative proportion of sulfur sourced from (i) SO2 disproportionation, (ii) thermochemical sulfate reduction, (iii) the leaching of igneous sulfur/sulfide and (iv) bacterial sulfate reduction. Our data shows that there is no correlation between δ34S values and the concentration of volatile elements (Te, Se) and Au in pyrite at Mala indicating that remobilization of trace metals occurred within the mound

Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample

Background: While ovarian cancer is recognised as having identifiable early symptoms, understanding of the key determinants of symptom awareness and early presentation is limited. A population-based survey of ovarian cancer awareness and anticipated delayed presentation with symptoms was conducted as part of the International Cancer Benchmarking Partnership (ICBP). Methods: Women aged over 50 years were recruited using random probability sampling (n = 1043). Computer-assisted telephone interviews were used to administer measures including ovarian cancer symptom recognition, anticipated time to presentation with ovarian symptoms, health beliefs (perceived risk, perceived benefits/barriers to early presentation, confidence in symptom detection, ovarian cancer worry), and demographic variables. Logistic regression analysis was used to identify the contribution of independent variables to anticipated presentation (categorised as < 3 weeks or ≥ 3 weeks). Results: The most well-recognised symptoms of ovarian cancer were post-menopausal bleeding (87.4%), and persistent pelvic (79.0%) and abdominal (85.0%) pain. Symptoms associated with eating difficulties and changes in bladder/bowel habits were recognised by less than half the sample. Lower symptom awareness was significantly associated with older age (p ≤ 0.001), being single (p ≤ 0.001), lower education (p ≤ 0.01), and lack of personal experience of ovarian cancer (p ≤ 0.01). The odds of anticipating a delay in time to presentation of ≥ 3 weeks were significantly increased in women educated to degree level (OR = 2.64, 95% CI 1.61 – 4.33, p ≤ 0.001), women who reported more practical barriers (OR = 1.60, 95% CI 1.34 – 1.91, p ≤ 0.001) and more emotional barriers (OR = 1.21, 95% CI 1.06 – 1.40, p ≤ 0.01), and those less confident in symptom detection (OR = 0.56, 95% CI 0.42 – 0.73, p ≤ 0.001), but not in those who reported lower symptom awareness (OR = 0.99, 95% CI 0.91 – 1.07, p = 0.74). Conclusions: Many symptoms of ovarian cancer are not well-recognised by women in the general population. Evidence-based interventions are needed not only to improve public awareness but also to overcome the barriers to recognising and acting on ovarian symptoms, if delays in presentation are to be minimised

Regionalisation and Civil Society in a Time of Austerity: The Cases of Manchester and Sheffield

Within the UK and as well as further afield, the spatial delineation of the ’city region’ has seen a renaissance as the de-facto spatial political unit of governance for economic development (Clarke & Cochrane, 2013).  This spatial realignment has been central to the construction of state projects such as the Northern Powerhouse, charged with taking forward the combined agendas of devolution, localism and austerity. The chapter deploys case study research from two city regions (Manchester and Sheffield) to look at the ways in which the city region is being constructed and the different ways in which ‘civil society’ is negotiating its way through this changing governance landscape. It is in this context that the chapter considers how city regions are being built and the ways in which this process is being limited or undermined through austerity

Impact of vaccination on the association of COVID-19 with cardiovascular diseases:An OpenSAFELY cohort study

Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a 'pre-vaccination' cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.</p