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Porcine reproductive and respiratory syndrome virus (PRRSV) remains a leading cause of economic loss in pig farming worldwide. Existing commercial vaccines, all based on modified live or inactivated PRRSV, fail to provide effective immunity against the highly diverse circulating strains of both PRRSV-1 and PRRSV-2. Therefore, there is an urgent need to develop more effective and broadly active PRRSV vaccines. In the absence of neutralizing antibodies, T cells are thought to play a central role in controlling PRRSV infection. Herpesvirus-based vectors are novel vaccine platforms capable of inducing high levels of T cells against encoded heterologous antigens. Therefore, the aim of this study was to assess the immunogenicity and efficacy of an attenuated herpesvirus-based vector (bovine herpesvirus-4; BoHV-4) expressing a fusion protein comprising two well-characterized PRRSV-1 T-cell antigens (M and NSP5). Prime-boost immunization of pigs with BoHV-4 expressing the M and NSP5 fusion protein (vector designated BoHV-4-M-NSP5) induced strong IFN-γ responses, as assessed by ELISpot assays of peripheral blood mononuclear cells (PBMC) stimulated with a pool of peptides representing PRRSV-1 M and NSP5. The responses were closely mirrored by spontaneous IFN-γ release from unstimulated cells, albeit at lower levels. A lower frequency of M and NSP5 specific IFN-γ responding cells was induced following a single dose of BoHV-4-M-NSP5 vector. Restimulation using M and NSP5 peptides from PRRSV-2 demonstrated a high level of cross-reactivity. Vaccination with BoHV-4-M-NSP5 did not affect viral loads in either the blood or lungs following challenge with the two heterologous PRRSV-1 strains. However, the BoHV-4-M-NSP5 prime-boost vaccination showed a marked trend toward reduced lung pathology following PRRSV-1 challenge. The limited effect of T cells on PRRSV-1 viral load was further examined by analyzing local and circulating T-cell responses using intracellular cytokine staining and proliferation assays. The results from this study suggest that vaccine-primed T-cell responses may have helped in the control of PRRSV-1 associated tissue damage, but had a minimal, if any, effect on controlling PRRSV-1 viral loads. Together, these results indicate that future efforts to develop effective PRRSV vaccines should focus on achieving a balanced T-cell and antibody response.

Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40–70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0–7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32–0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.

Climate change is rapidly altering the distributions of species and the composition of communities that have evolved over evolutionary time scales. Quantifying changes in species distributions and abundance in response to warming is critical to understanding how these changes modify structure, function and services provided by recipient communities. Changes in size structure of warm- and cool-affiliated species is an important indicator for climate-driven species redistributions over time, and has received relatively little attention. We quantified changes in length and biomass distributions of 25 species of Labridae fishes from 112 sites spanning 2000 km across a warm–cool temperate transition zone in south Western Australia. Length and biomass data were collected in 2005–2006 and 2014–2015 using diver operated stereo-video. In the decade between sampling events, south Western Australia experienced an extreme marine heatwave followed by repeated summers of anomalously warm ocean temperatures. Biomass of tropical and subtropical species increased 10-fold and 3-fold, respectively, between 2006 and 2015, whereas temperate species biomass remained relatively stable. In 2014–2015, the abundance and biomass of tropical species (e.g. Scarus ghobban) increased in the warmest regions and established multiple size classes poleward of their recorded 2005–2006 distributions, suggesting successful overwintering and recruitment where viable populations were not recorded in 2005–2006. Large, slow-growing temperate species such as Achoerodus gouldii and Bodianus frenchii decreased in small and medium size classes in warm regions. Our findings report a substantial change in the size structure and composition of labrid assemblages over a decade of climatic variability.

This paper provides an introduction to a new tool that is designed to provide operationally useful vulnerability information to National Weather Service (NWS) Weather Forecasting Offices (WFOs). The Brief Vulnerability Overview Tool (BVOT) is a shapefile containing local known , spatially specific , and weather-hazard-related vulnerabilities in a format that is easily integrated into the existing forecasting, warning, and decision support responsibilities and tasks of NWS WFO meteorologists. The methods for gathering vulnerability data and then building a BVOT for a WFO leverage and strengthen the relationships that NWS WFOs already have with their local emergency managers (EMs) and core partners to work together to identify operationally useful, local vulnerability knowledge. The BVOT is populated with discrete, known vulnerabilities to provide NWS meteorologists spatial situational awareness of those people, places, and things of greatest concern to their core partners. Crucially, the BVOT is a subsample of all potential vulnerabilities; its primary purpose is to make meteorologists aware of those weather-hazard-specific vulnerabilities that, as we posed to them, “keep them awake at night.” Here, we describe the development of the BVOT as a social science–informed operational tool; how the BVOT methods have evolved and how it can be integrated into the culture of the NWS as a tool for building and maintaining relationships with partners; and how the BVOT is designed to be used and its impact on operational decision-making as observed in NOAA’s Hazardous Weather Testbed.

Merkel cell carcinoma (MCC) is a rare and deadly neuroendocrine skin tumor frequently associated with clonal integration of a polyomavirus, Merkel cell polyomavirus (MCPyV), and MCC tumor cells express putative polyomavirus oncoprotein small T antigen (sTAg) and truncated large T antigen. Here, we show robust transforming activity of sTAg in vivo in a panel of transgenic mouse models. Epithelia of preterm sTAg-expressing embryos exhibited hyperplasia, impaired differentiation, increased proliferation, and apoptosis, and activation of a DNA damage response. Epithelial transformation did not require sTAg interaction with the protein phosphatase 2A protein complex, a tumor suppressor in some other polyomavirus transformation models, but was strictly dependent on a recently described sTAg domain that binds Fbxw7, the substrate-binding component of the Skp1/Cullin1/F-box protein ubiquitin ligase complex. Postnatal induction of sTAg using a Cre-inducible transgene also led to epithelial transformation with development of lesions resembling squamous cell carcinoma in situ and elevated expression of Fbxw7 target proteins. Our data establish that expression of MCPyV sTAg alone is sufficient for rapid neoplastic transformation in vivo, implicating sTAg as an oncogenic driver in MCC and perhaps other human malignancies. Moreover, the loss of transforming activity following mutation of the sTAg Fbxw7 binding domain identifies this domain as crucial for in vivo transformation.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria ( n  = 59 for molnupiravir and n  = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.

Bioregional categorisation of the Australian marine environment is essential to conserve and manage entire ecosystems, including the biota and associated habitats. It is important that these regions are optimally positioned to effectively plan for the protection of distinct assemblages. Recent climatic variation and changes to the marine environment in Southwest Australia (SWA) have resulted in shifts in species ranges and changes to the composition of marine assemblages. The goal of this study was to determine if the current bioregionalisation of SWA accurately represents the present distribution of shallow-water reef fishes across 2000 km of its subtropical and temperate coastline. Data was collected in 2015 using diver-operated underwater stereovideo surveys from 7 regions between Port Gregory (north of Geraldton) to the east of Esperance. This study indicated that (1) the shallow-water reef fish of SWA formed 4 distinct assemblages along the coast: one Midwestern, one Central and 2 Southern Assemblages; (2) differences between these fish assemblages were primarily driven by sea surface temperature, Ecklonia radiata cover, non-E. radiata (canopy) cover, understorey algae cover, reef type and reef height; and (3) each of the 4 assemblages were characterised by a high number of short-range Australian and Western Australian endemic species. The findings from this study suggest that 4, rather than the existing 3 bioregions would more effectively capture the shallow-water reef fish assemblage patterns, with boundaries having shifted southwards likely associated with ocean warming.

Climate change and associated increased water temperatures pose a substantial threat for the future of marine ecosystems. Temperate Australia is a global biodiversity hotspot which has experienced ocean warming rates 2 to 4 times faster than the global average. To better understand the effects of these temperature changes on marine fish distributions and densities, we surveyed territorial damselfishes across 2000 km of temperate coastline in south-western Australia. Diver-operated stereo-video was used to determine if the distribution and density of 4 pomacentrids (Parma occidentalis, P. mccullochi, P. victoriae and Pomacentrus milleri) and their biotic habitat changed between 2006 and 2015, a time period characterised by gradual warming trends and an extreme marine heatwave. Surveys showed that the density of the warm-water pomacentrids P. milleri and P. occidentalis increased, while cool-water P. victoriae and intermediate species P. mccullochi showed no changes in density. In northern, warmer waters, the density of habitat-forming algal species such as Ecklonia radiata decreased, while turf algae species increased. In general, 2015 was characterised by a shift toward non-canopy algae habitats when compared to 2006. The observed changes in fish assemblages were likely caused by a combination of increased temperatures and changes in habitat-forming algal species. These changes along the Western Australian coast provide insights into the different nature of cool- and warm-water affiliated species’ responses to ocean warming and biogenic habitat changes associated with climate change.

Background The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms. Methods One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators. Results Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. Conclusions Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant.

Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment. Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro . However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort ( n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.