Conservation of a crystallographic interface suggests a role for β-sheet augmentation in influenza virus NS1 multifunctionality

The structure of a monomeric effector domain from influenza A virus NS1 is presented from diffraction data extending to 1.8 Å resolution. Comparison of this and other NS1 effector-domain structures shows conformational changes at a strand–strand packing interface, hinting at a role for β-strand augmentation in NS1 function

Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

This work was supported by the Medical Research Council and the Scottish Funding Council.Influenza virus sialidase has an essential role in the virus’ life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the ‘150-loop’, providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.Publisher PDFPeer reviewe

Evidence for a unitary structure of spatial cognition beyond general intelligence

Performance in everyday spatial orientation tasks (e.g. map reading and navigation) has been considered functionally separate from performance on more abstract object-based spatial abilities (e.g. mental rotation and visualization). However, evidence remains scarce and unsystematic. With a novel gamified battery, we assessed six tests of spatial orientation in a virtual environment and examined their association with ten object-based spatial tests, as well as their links to general cognitive ability (g). We further estimated the role of genetic and environmental factors in underlying variation and covariation in these spatial tests. Participants (N = 2,660) were part of the Twins Early Development Study, aged 19 to 22. The 6 tests of spatial orientation clustered into a single ‘Navigation’ factor that was 64% heritable. Examining the structure of spatial ability across all 16 tests, three factors emerged: Navigation, Object Manipulation and Visualization. These, in turn, loaded strongly onto a general factor of Spatial Ability, which was highly heritable (84%). A large portion (45%) of this high heritability was independent of g. The results from this most comprehensive investigation of spatial abilities to date point towards the existence of a common genetic network that supports all spatial abilities

The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study

Aims/hypothesis Circulating fibroblast growth factor 21 (FGF21) levels are often elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. This study investigated the relationship of plasma FGF21 levels with cardiovascular events in patients with type 2 diabetes. Methods Plasma FGF21 levels were measured at baseline in 9,697 study participants with type 2 diabetes from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study by enzyme-linked immunosorbent assay. We assessed the association of FGF21 levels with incidence of different cardiovascular outcomes over 5-years. The primary outcome was total cardiovascular disease (CVD) events, and the secondary outcomes were the four individual components: coronary heart disease (CHD) events, total stroke, CVD mortality, coronary and carotid revascularization. Tertiary outcome was hospitalisation for angina pectoris. Results Higher baseline FGF21 levels were associated with higher risks of all cardiovascular outcome events after adjusting for the study treatment allocation (all p<0.01). The associations remained significant for total CVD events, and coronary and carotid revascularisation after further adjusting for confounding factors with HR (95% CI) being 1.28 (1.10, 1.50) and 1.26 (1.01, 1.56) respectively, for the highest tertile compared to the lowest tertile (overall effect p=0.002 and 0.007 respectively). The addition of FGF21 levels to a model including established CVD risk factors predicting total CVD led to a non-significant increase in the C-statistic, but resulted in significant integrated discrimination improvement and net reclassification improvement. Conclusions/interpretation Higher baseline plasma FGF21 levels were associated with higher risk of cardiovascular events in patients with type 2 diabetes

Impacts of Climate Change on indirect human exposure to pathogens and chemicals from agriculture

Objective: Climate change is likely to affect the nature of pathogens and chemicals in the environment and their fate and transport. Future risks of pathogens and chemicals could therefore be very different from those of today. In this review, we assess the implications of climate change for changes in human exposures to pathogens and chemicals in agricultural systems in the United Kingdom and discuss the subsequent effects on health impacts. Data sources: In this review, we used expert input and considered literature on climate change ; health effects resulting from exposure to pathogens and chemicals arising from agriculture ; inputs of chemicals and pathogens to agricultural systems ; and human exposure pathways for pathogens and chemicals in agricultural systems. Data synthesis: We established the current evidence base for health effects of chemicals and pathogens in the agricultural environment ; determined the potential implications of climate change on chemical and pathogen inputs in agricultural systems ; and explored the effects of climate change on environmental transport and fate of different contaminant types. We combined these data to assess the implications of climate change in terms of indirect human exposure to pathogens and chemicals in agricultural systems. We then developed recommendations on future research and policy changes to manage any adverse increases in risks. Conclusions: Overall, climate change is likely to increase human exposures to agricultural contaminants. The magnitude of the increases will be highly dependent on the contaminant type. Risks from many pathogens and particulate and particle-associated contaminants could increase significantly. These increases in exposure can, however, be managed for the most part through targeted research and policy changes

Correction: Alcohol advertising in sport and non-sport TV in Australia during children's viewing times

[This corrects the article DOI: 10.1371/journal.pone.0134889.]

Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study

Author version made available following 12 month embargo from date of publication (27 March 2015) in accordance with publisher copyright policy.Purpose Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. Methods Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. Results Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. Conclusions This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted

Phenotypic and genetic evidence for a unifactorial structure of spatial abilities

Spatial abilities encompass several skills differentiable from general cognitive ability (g). Importantly, spatial abilities have been shown to be significant predictors of many life outcomes, even after controlling for g. To date, no studies have analyzed the genetic architecture of diverse spatial abilities using a multivariate approach. We developed “gamified” measures of diverse putative spatial abilities. The battery of 10 tests was administered online to 1,367 twin pairs (age 19–21) from the UK-representative Twins Early Development Study (TEDS). We show that spatial abilities constitute a single factor, both phenotypically and genetically, even after controlling for g. This spatial ability factor is highly heritable (69%). We draw three conclusions: (i) The high heritability of spatial ability makes it a good target for gene-hunting research; (ii) some genes will be specific to spatial ability, independent of g; and (iii) these genes will be associated with all components of spatial ability

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

Multi-Messenger Astronomy with Extremely Large Telescopes

The field of time-domain astrophysics has entered the era of Multi-messenger Astronomy (MMA). One key science goal for the next decade (and beyond) will be to characterize gravitational wave (GW) and neutrino sources using the next generation of Extremely Large Telescopes (ELTs). These studies will have a broad impact across astrophysics, informing our knowledge of the production and enrichment history of the heaviest chemical elements, constrain the dense matter equation of state, provide independent constraints on cosmology, increase our understanding of particle acceleration in shocks and jets, and study the lives of black holes in the universe. Future GW detectors will greatly improve their sensitivity during the coming decade, as will near-infrared telescopes capable of independently finding kilonovae from neutron star mergers. However, the electromagnetic counterparts to high-frequency (LIGO/Virgo band) GW sources will be distant and faint and thus demand ELT capabilities for characterization. ELTs will be important and necessary contributors to an advanced and complete multi-messenger network.Comment: White paper submitted to the Astro2020 Decadal Surve