Advances in high‑throughput methods for the identification of virus receptors

Viruses have evolved many mechanisms to invade host cells and establish successful infections. The interaction between viral attachment proteins and host cell receptors is the first and decisive step in establishing such infections, initiating virus entry into the host cells. Therefore, the identification of host receptors is fundamental in understanding pathogenesis and tissue tropism. Furthermore, receptor identification can inform the development of antivirals, vaccines, and diagnostic technologies, which have a substantial impact on human health. Nevertheless, due to the complex nature of virus entry, the redundancy in receptor usage, and the limitations in current identification methods, many host receptors remain elusive. Recent advances in targeted gene perturbation, high-throughput screening, and mass spectrometry have facilitated the discovery of virus receptors in recent years. In this review, we compare the current methods used within the field to identify virus receptors, focussing on genomic- and interactome-based approaches.Peer reviewe

Adenovirus flow in host cell networks

Viruses are obligatory parasites that take advantage of intracellular niches to replicate. During infection, their genomes are carried in capsids across the membranes of host cells to sites of virion production by exploiting cellular behaviour and resources to guide and achieve all aspects of delivery and the downstream virus manufacturing process. Successful entry hinges on execution of a precisely tuned viral uncoating program where incoming capsids disassemble in consecutive steps to ensure that genomes are released at the right time, and in the right place for replication to occur. Each step of disassembly is cell-assisted, involving individual pathways that transmit signals to regulate discrete functions, but at the same time, these signalling pathways are organized into larger networks, which communicate back and forth in complex ways in response to the presence of virus. In this review, we consider the elegant strategy by which adenoviruses (AdVs) target and navigate cellular networks to initiate the production of progeny virions. There are many remarkable aspects about the AdV entry program; for example, the virus gains targeted control of a large well-defined local network neighbourhood by coupling several interacting processes (including endocytosis, autophagy and microtubule trafficking) around a collective reference state centred on the interactional topology and multifunctional nature of protein VI. Understanding the network targeting activity of protein VI, as well as other built-in mechanisms that allow AdV particles to be efficient at navigating the subsystems of the cell, can be used to improve viral vectors, but also has potential to be incorporated for use in entirely novel delivery systems.Peer reviewe

Comparative Analysis of the Saccharomyces cerevisiae and Caenorhabditis elegans Protein Interaction Network

Protein interaction networks aim to summarize the complex interplay of proteins in an organism. Early studies suggested that the position of a protein in the network determines its evolutionary rate but there has been considerable disagreement as to what extent other factors, such as protein abundance, modify this reported dependence. We compare the genomes of Saccharomyces cerevisiae and Caenorhabditis elegans with those of closely related species to elucidate the recent evolutionary history of their respective protein interaction networks. Interaction and expression data are studied in the light of a detailed phylogenetic analysis. The underlying network structure is incorporated explicitly into the statistical analysis. The increased phylogenetic resolution, paired with high-quality interaction data, allows us to resolve the way in which protein interaction network structure and abundance of proteins affect the evolutionary rate. We find that expression levels are better predictors of the evolutionary rate than a protein's connectivity. Detailed analysis of the two organisms also shows that the evolutionary rates of interacting proteins are not sufficiently similar to be mutually predictive. It appears that meaningful inferences about the evolution of protein interaction networks require comparative analysis of reasonably closely related species. The signature of protein evolution is shaped by a protein's abundance in the organism and its function and the biological process it is involved in. Its position in the interaction networks and its connectivity may modulate this but they appear to have only minor influence on a protein's evolutionary rate.Comment: Accepted for publication in BMC Evolutionary Biolog

A comparative analysis of parechovirus protein structures with other picornaviruses

Parechoviruses belong to the genus Parechovirus within the family Picornaviridae and are non-enveloped icosahedral viruses with a single-stranded RNA genome. Parechoviruses include human and animal pathogens classified into six species. Those that infect humans belong to the Parechovirus A species and can cause infections ranging from mild gastrointestinal or respiratory illness to severe neonatal sepsis. There are no approved antivirals available to treat parechovirus (nor any other picornavirus) infections. In this parechovirus review, we focus on the cleaved protein products resulting from the polyprotein processing after translation comparing and contrasting their known or predicted structures and functions to those of other picornaviruses. The review also includes our original analysis from sequence and structure prediction. This review highlights significant structural differences between parechoviral and other picornaviral proteins, suggesting that parechovirus drug development should specifically be directed to parechoviral targets.Peer reviewe

Nanomaterial structure determination using XUV diffraction

Diffraction using coherent XUV radiation is used to study the structure of nanophotonic materials, in this case an ordered array of 196nm spheres. Crystal structure and defects are visible, and the nanomaterial dielectric constant determined

Explanatory Journeys: Visualising to Understand and Explain Administrative Justice Paths of Redress

Administrative justice concerns the relationships between individuals and the state. It includes redress and complaints on decisions of a child's education, social care, licensing, planning, environment, housing and homelessness. However, if someone has a complaint or an issue, it is challenging for people to understand different possible redress paths and explore what path is suitable for their situation. Explanatory visualisation has the potential to display these paths of redress in a clear way, such that people can see, understand and explore their options. The visualisation challenge is further complicated because information is spread across many documents, laws, guidance and policies and requires judicial interpretation. Consequently, there is not a single database of paths of redress. In this work we present how we have co-designed a system to visualise administrative justice paths of redress. Simultaneously, we classify, collate and organise the underpinning data, from expert workshops, heuristic evaluation and expert critical reflection. We make four contributions: (i) an application design study of the explanatory visualisation tool (Artemus), (ii) coordinated and co-design approach to aggregating the data, (iii) two in-depth case studies in housing and education demonstrating explanatory paths of redress in administrative law, and (iv) reflections on the expert co-design process and expert data gathering and explanatory visualisation for administrative justice and law.Comment: 11 pages with 10 figures, accepted for publication in IEEE Transactions on Visualization and Computer Graphic

Promoting the independent mobility of young people with SEND: The lived experience of young people with autism, ADHD, and learning disabilities

Introduction: Young people with special educational needs and disabilities (SEND) are at heightened risk of road traffic injury and their caregivers are often concerned about independent mobility and the safety risks it poses. This qualitative research aimed to increase understanding of the facilitators and barriers to independent mobility for 7–10 and 11-13 year-olds with SEND. / Method: Thirteen young people (11 male and two female, six children 7-10 years-old and seven children 11-13 years-old) diagnosed with autism, attention deficit hyperactivity disorder (ADHD), or learning disabilities video recorded three journeys they regularly undertook and then participated in a semi-structured interview with their caregiver. A thematic analysis of travel films and interview transcripts was conducted. / Results: Younger children were typically not travelling independently, but both older and younger children were anxious about independent mobility. Younger and older children with SEND demonstrated unsafe behaviours in the road, had limited awareness at times of road safety, could become overwhelmed, and required longer to process information. / Conclusions: The findings informed recommendations for how to effectively support the independent mobility of young people with SEND. Children are often diagnosed with multiple conditions, and it is the profile rather than the specific diagnosis that impacts their road safety. Targeting specific behaviours rather than specific disorders may therefore be a more effective approach. Road safety was a central concern for caregivers, but it was one aspect of independent mobility and a broad focus on teaching independent mobility was preferable. Support with independent mobility and road safety should be provided by a range of people who come into contact with the young person and education may need repeating at key transition points

Combined approaches to flexible fitting and assessment in virus capsids undergoing conformational change

Peer reviewe

Adenosine triphosphatases of thermophilic archaeal double-stranded DNA viruses

Peer reviewe

Bioinformatic analysis of Entamoeba histolytica SINE1 elements

BACKGROUND: Invasive amoebiasis, caused by infection with the human parasite Entamoeba histolytica remains a major cause of morbidity and mortality in some less-developed countries. Genetically E. histolytica exhibits a number of unusual features including having approximately 20% of its genome comprised of repetitive elements. These include a number of families of SINEs - non-autonomous elements which can, however, move with the help of partner LINEs. In many eukaryotes SINE mobility has had a profound effect on gene expression; in this study we concentrated on one such element - EhSINE1, looking in particular for evidence of recent transposition. RESULTS: EhSINE1s were detected in the newly reassembled E. histolytica genome by searching with a Hidden Markov Model developed to encapsulate the key features of this element; 393 were detected. Examination of their sequences revealed that some had an internal structure showing one to four 26-27 nt repeats. Members of the different classes differ in a number of ways and in particular those with two internal repeats show the properties expected of fairly recently transposed SINEs - they are the most homogeneous in length and sequence, they have the longest (i.e. the least decayed) target site duplications and are the most likely to show evidence (in a cDNA library) of active transcription. Furthermore we were able to identify 15 EhSINE1s (6 pairs and one triplet) which appeared to be identical or very nearly so but inserted into different sites in the genome; these provide good evidence that if mobility has now ceased it has only done so very recently. CONCLUSIONS: Of the many families of repetitive elements present in the genome of E. histolytica we have examined in detail just one - EhSINE1. We have shown that there is evidence for waves of transposition at different points in the past and no evidence that mobility has entirely ceased. There are many aspects of the biology of this parasite which are not understood, in particular why it is pathogenic while the closely related species E. dispar is not, the great genetic diversity found amongst patient isolates and the fact, which may be related, that only a small proportion of those infected develop clinical invasive amoebiasis. Mobile genetic elements, with their ability to alter gene expression may well be important in unravelling these puzzles