A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis

The structural flexibility or 'breathing' of the envelope (E) protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F) of the West Nile virus (WNV) E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV), but not Zika virus (ZIKV), E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing

Cathodoluminescence as a method of extracting detailed information from nanophotonics systems: a study of silicon nanocrystals

We investigated Si nanocaystal samples produced by high dose 600 keV Si+ implantation of fused silica and annealing using cathodoluminescence (CL). CL spectra collected under 5-25 keV electron irradiation show similar features to reported photoluminescenc

HOW CAN A VIRTUAL REALITY ENVIRONMENT ALLOW FOR TRANSFERABLE LEARNING IN SCIENCE?

Virtual reality (VR) is already providing the ability for students to have direct interactions with content in its ability to convert conceptual knowledge into reality. A VR environment can serve as a platform to further extend students understanding by allowing for exchangeable content that is co-created by students and their lecturers. We discuss how to achieve this using a modular VR platform which can be modified without needing VR programming expertise, containing customised content to create interactive learning experiences to serve various STEM subjects. For example, for students to study electromagnetism, a physics concept known to be difficult and counter-intuitive for students to understand, designing an environment where students can create and experience their own understanding is key. Here lecturers will provide a library of fields/operations and students draw from the library to see the phenomena in action, thus solving, testing and resolving interactions as a way to tacitly understand concepts. Having an environment that can be built to accommodate not only physics, but through scaffolded design allows students from chemistry, biochemistry or mathematics to be similarly engaged in the disciplinary content, creates transference not only between subjects but also into the real world

A preliminary assessment into the utility of social networks for engaging local communities in climate adaptation policy: working paper prepared for NSW Office of Environment & Heritage, Sydney, Australia.

There has been a growing recognition regarding the use of social networks to engage the community in government actions. However, despite increasing awareness about the potential importance of social networks, there is very limited evidence for their application in relation to climate policy. This study addresses this gap by assessing the potential of social networks for engaging local communities in climate adaptation policy, drawing on a case study of the Shoalhaven region in Australia. View/download https://www.uts.edu.au/sites/default/files/Cunninghametal2014utilityofsocialnetworks.pd

Sharing Longevity Risk: Why Governments Should Issue Longevity Bonds

Government-issued longevity bonds would allow longevity risk to be shared efficiently and fairly between generations. In exchange for paying a longevity risk premium, the current generation of retirees can look to future generations to hedge their systematic longevity risk. Longevity bonds will lead to a more secure pension savings market, together with a more efficient annuity market. By issuing longevity bonds, governments can aid the establishment of reliable longevity indices and key price points on the longevity risk term structure and help the emerging capital market in longevity-linked instruments to build on this term structure with liquid longevity derivatives

Deconvolution of conformational exchange from Raman spectra of aqueous RNA nucleosides

Ribonucleic acids (RNAs) are key to the central dogma of molecular biology. While Raman spectroscopy holds great potential for studying RNA conformational dynamics, current computational Raman prediction and assignment methods are limited in terms of system size and inclusion of conformational exchange. Here, a framework is presented that predicts Raman spectra using mixtures of sub-spectra corresponding to major conformers calculated using classical and ab initio molecular dynamics. Experimental optimization allowed purines and pyrimidines to be characterized as predominantly syn and anti, respectively, and ribose into exchange between equivalent south and north populations. These measurements are in excellent agreement with Raman spectroscopy of ribonucleosides, and previous experimental and computational results. This framework provides a measure of ribonucleoside solution populations and conformational exchange in RNA subunits. It complements other experimental techniques and could be extended to other molecules, such as proteins and carbohydrates, enabling biological insights and providing a new analytical tool

Comparing trends in mid-life ‘deaths of despair’ in the USA, Canada and UK, 2001–2019: is the USA an anomaly?

Objectives In recent years, ‘deaths of despair’ due to drugs, alcohol and suicide have contributed to rising mid-life mortality in the USA. We examine whether despair-related deaths and mid-life mortality trends are also changing in peer countries, the UK and Canada. Design Descriptive analysis of population mortality rates. Setting The USA, UK (and constituent nations England and Wales, Northern Ireland and Scotland) and Canada, 2001–2019. Participants Full population aged 35–64 years. Outcome measures We compared all-cause and ‘despair’-related mortality trends at mid-life across countries using publicly available mortality data, stratified by three age groups (35–44, 45–54 and 55–64 years) and by sex. We examined trends in all-cause mortality and mortality by causes categorised as (1) suicides, (2) alcohol-specific deaths and (3) drug-related deaths. We employ several descriptive approaches to visually inspect age, period and cohort trends in these causes of death. Results The USA and Scotland both saw large relative increases and high absolute levels of drug-related deaths. The rest of the UK and Canada saw relative increases but much lower absolute levels in comparison. Alcohol-specific deaths showed less consistent trends that did not track other ‘despair’ causes, with older groups in Scotland seeing steep declines over time. Suicide deaths trended slowly upward in most countries. Conclusions In the UK, Scotland has suffered increases in drug-related mortality comparable with the USA, while Canada and other UK constituent nations did not see dramatic increases. Alcohol-specific and suicide mortalities generally follow different patterns to drug-related deaths across countries and over time, questioning the utility of a cohesive ‘deaths of despair’ narrative

Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope

We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development

Excavations at Knowth Volume 6: The Passage Tomb Archaeology of the Great Mound at Knowth

The Brú na Bóinne complex in County Meath, Ireland, is one of the greatest Neolithic landscapes in northern Europe. Anyone who has ever had the chance to see these sites will know that these are truly monumental feats of engineering and it is only through experiencing these sites first hand that one is able to appreciate the size and scale of the monuments in this landscape. Rightly so, these sites have featured heavily in narratives of the Irish Neolithic where they are often described as the pinnacle of megalithic design and construction. These sites, however, cannot be considered ‘typical’. While there are other, large passage tombs, and other complexes of sites such as Loughcrew and Carrowkeel, Brú na Bóinne stands apart in terms of the sheer scale of the megalithic endeavour. These monuments have also been subjected to extensive amounts of research and fieldwork over the years, much still ongoing. Indeed, despite this landscape having been the focus for research for decades, new discoveries are being made all the time, as we saw in the summer of 2018 when drought conditions revealed previously unknown sites through parch marks seen from above