A phylogenetic method for detecting positive epistasis in gene sequences and its application to RNA virus evolution

RNA virus genomes are compact, often containing multiple overlapping reading frames and functional secondary structure. Consequently, it is thought that evolutionary interactions between nucleotide sites are commonplace in the genomes of these infectious agents. However, the role of epistasis in natural populations of RNA viruses remains unclear. To investigate the pervasiveness of epistasis in RNA viruses, we used a parsimony-based computational method to identify pairs of co-occurring mutations along phylogenies of 177 RNA virus genes. This analysis revealed widespread evidence for positive epistatic interactions at both synonymous and nonsynonymous nucleotide sites and in both clonal and recombining viruses, with the majority of these interactions spanning very short sequence regions. These findings have important implications for understanding the key aspects of RNA virus evolution, including the dynamics of adaptation. Additionally, many comparative analyses that utilize the phylogenetic relationships among gene sequences assume that mutations represent independent, uncorrelated events. Our results show that this assumption may often be invalid.</p

Nonprimate hepaciviruses in domestic horses, United kingdom

Although the origin of hepatitis C virus infections in humans remains undetermined, a close homolog of this virus, termed canine hepacivirus (CHV) and found in respiratory secretions of dogs, provides evidence for a wider distribution of hepaciviruses in mammals. We determined frequencies of active infection among dogs and other mammals in the United Kingdom. Samples from dogs (46 respiratory, 99 plasma, 45 autopsy samples) were CHV negative by PCR. Screening of 362 samples from cats, horses, donkeys, rodents, and pigs identified 3 (2%) positive samples from 142 horses. These samples were genetically divergent from CHV and nonprimate hepaciviruses that horses were infected with during 2012 in New York state, USA. Investigation of infected horses demonstrated nonprimate hepacivirus persistence, high viral loads in plasma (105–107 RNA copies/mL), and liver function test results usually within reference ranges, although several values ranged from high normal to mildly elevated. Disease associations and host range of nonprimate hepaciviruses warrant further investigation

Are skyline plot-based demographic estimates overly dependent on smoothing prior assumptions?

In Bayesian phylogenetics, the coalescent process provides an informative framework for inferring changes in the effective size of a population from a phylogeny (or tree) of sequences sampled from that population. Popular coalescent inference approaches such as the Bayesian Skyline Plot, Skyride and Skygrid all model these population size changes with a discontinuous, piecewise-constant function but then apply a smoothing prior to ensure that their posterior population size estimates transition gradually with time. These prior distributions implicitly encode extra population size information that is not available from the observed coalescent data i.e., the tree. Here we present a novel statistic, Ω, to quantify and disaggregate the relative contributions of the coalescent data and prior assumptions to the resulting posterior estimate precision. Our statistic also measures the additional mutual information introduced by such priors. Using Ω we show that, because it is surprisingly easy to over-parametrise piecewise-constant population models, common smoothing priors can lead to overconfident and potentially misleading inference, even under robust experimental designs. We propose Ω as a useful tool for detecting when effective population size estimates are overly reliant on prior assumptions and for improving quantification of the uncertainty in those estimates

NEW TOOLS FOR CULTURAL HERITAGE TOURISM: ACCESSIBLE VIRTUAL REALITY FOR MILAN’S BASILICA SANT’AMBROGIO

Although virtual reality provides much new unexplored territory for presenting and disseminating cultural heritage, operating VR headsets and controllers remains challenging for new users. By taking advantage of the tools available within the Unreal Engine game engine, the ergonomics of the Oculus Rift motion controllers, and certain principles of storytelling; one can develop a set of strategies for making the use of virtual reality more accessible and intuitive, allowing for new possibilities in the dissemination of built cultural heritage to a general audience. Therefore his paper aims to provide concrete examples of how to produce more effective VR tools for cultural heritage dissemination

CYP450 phenotyping and metabolite identification of quinine by accurate mass UPLC-MS analysis: a possible metabolic link to blackwater fever

BACKGROUND: The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug. METHODS: Incubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MS(E) analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes. RESULTS: The metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes. CONCLUSIONS: Taken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion