Biophysical characterisation of the involvement of influenza A virus glycoproteins in receptor binding

Influenza A viruses (IAV) cause human infections in both seasonal and pandemic forms, which are responsible for significant levels of human infections. A major factor underlying IAV viral fitness and transmissibility, and therefore pandemic potential, is the interaction of the virus with the cell surface, which is mediated by the two surface glycoproteins haemagglutinin (HA) and neuraminidase (NA). These two glycoproteins have antagonistic activities with the HA responsible for receptor binding and the NA for receptor destroying activities. It has long been hypothesised that the balance between these antagonistic functions is important in altering virus fitness and transmissibility. This thesis presents a new biophysical approach, based on biolayer interferometry, for determining the relative importance of the HA and NA in altering virus binding to a receptor coated surface. These experiments identified a number of fundamental characteristics of virus attachment and interaction with surfaces. This new technique has also been used to examine two other lineages of viruses that are at different stages of becoming transmissible in humans. H7N9 viruses first infected humans in 2013 and have caused a large number of zoonotic infections. The receptor binding characteristics of these H7N9 viruses are characterised with a particular focus on the NA, as N9 NAs have been previously shown to have receptor binding properties. In 2009 a new H1N1 pandemic emerged, which was formed from a reassortment of two swine viruses. These new viruses had acquired a number of substitutions in the HA, which could affect receptor binding, also the combination of HA and NA was also novel. A number of HA mutants and combinations of HA and NA were examined in terms of receptor binding in an attempt to understand what changes in swine viruses might make them transmissible in humans

A functional role for small-conductance calcium-activated potassium channels in sensory pathways including nociceptive processes

We investigated the role of small-conductance calcium-activated potassium (SK) and intermediate-conductance calcium-activated potassium channels in modulating sensory transmission from peripheral afferents into the rat spinal cord. Subunit-specific antibodies reveal high levels of SK3 immunoreactivity in laminas I, II, and III of the spinal cord. Among dorsal root ganglion neurons, both peripherin-positive (C-type) and peripherin-negative (A-type) cells show intense SK3 immunoreactivity. Furthermore, dorsal root-stimulated sensory responses recorded in vitro are inhibited when SK channel activity is increased with 1-ethyl-2-benzimidazolinone (1-EBIO). In vivo electrophysiological recordings show that neuronal responses to naturally evoked nociceptive and nonnociceptive stimuli increase after application of the selective SK channel blocker 8,14-diaza-1,7( 1,4)-diquinolinacyclotetradecaphanedium ditrifluoroacetate (UCL 1848), indicating that SK channels are normally active in moderating afferent input. Conversely, neuronal responses evoked by mechanical stimuli are inhibited when SK channel activity is increased with 1-EBIO. These effects are reversed by the subsequent application of UCL 1848. Our data demonstrate that SK channels have an important role in controlling sensory input into the spinal cord

Layer by layer - Combining Monads

We develop a method to incrementally construct programming languages. Our approach is categorical: each layer of the language is described as a monad. Our method either (i) concretely builds a distributive law between two monads, i.e. layers of the language, which then provides a monad structure to the composition of layers, or (ii) identifies precisely the algebraic obstacles to the existence of a distributive law and gives a best approximant language. The running example will involve three layers: a basic imperative language enriched first by adding non-determinism and then probabilistic choice. The first extension works seamlessly, but the second encounters an obstacle, which results in a best approximant language structurally very similar to the probabilistic network specification language ProbNetKAT

Multi-locus homozygosity promotes actuarial senescence in a wild mammal.

This is the final version. Available from Wiley via the DOI in this record. DATA AVAILABILITY STATEMENT: Data available from the Dryad Digital Repository https://doi. org/10.5061/dryad.bk3j9kdg6 (Hudson, 2023)Genome-wide homozygosity, caused for example by inbreeding, is expected to have deleterious effects on survival and/or reproduction. Evolutionary theory predicts that any fitness costs are likely to be detected in late life because natural selection will filter out negative impacts on younger individuals with greater reproductive value. Here we infer associations between multi-locus homozygosity (MLH), sex, disease and age-dependent mortality risks using Bayesian analysis of the life histories of wild European badgers Meles meles in a population naturally infected with Mycobacterium bovis (the causative agent of bovine tuberculosis [bTB]). We find important effects of MLH on all parameters of the Gompertz-Makeham mortality hazard function, but particularly in later life. Our findings confirm the predicted association between genomic homozygosity and actuarial senescence. Increased homozygosity is particularly associated with an earlier onset, and greater rates of actuarial senescence, regardless of sex. The association between homozygosity and actuarial senescence is further amplified among badgers putatively infected with bTB. These results recommend further investigation into the ecological and behavioural processes that result in genome-wide homozygosity, and focused work on whether homozygosity is harmful or beneficial during early life-stages.Natural Environment Research Council (NERC)Natural Environment Research Council (NERC)Animal and Plant Health AgencyExpanding Excellence in EnglandUniversity of Exete

Dynamics of dental evolution in ornithopod dinosaurs.

Ornithopods were key herbivorous dinosaurs in Mesozoic terrestrial ecosystems, with a variety of tooth morphologies. Several clades, especially the 'duck-billed' hadrosaurids, became hugely diverse and abundant almost worldwide. Yet their evolutionary dynamics have been disputed, particularly whether they diversified in response to events in plant evolution. Here we focus on their remarkable dietary adaptations, using tooth and jaw characters to examine changes in dental disparity and evolutionary rate. Ornithopods explored different areas of dental morphospace throughout their evolution, showing a long-term expansion. There were four major evolutionary rate increases, the first among basal iguanodontians in the Middle-Late Jurassic, and the three others among the Hadrosauridae, above and below the split of their two major clades, in the middle of the Late Cretaceous. These evolutionary bursts do not correspond to times of plant diversification, including the radiation of the flowering plants, and suggest that dental innovation rather than coevolution with major plant clades was a major driver in ornithopod evolution

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Anthropogenically-mediated density dependence in a declining farmland bird

Land management intrinsically influences the distribution of animals and can consequently alter the potential for density-dependent processes to act within populations. For declining species, high densities of breeding territories are typically considered to represent productive populations. However, as density-dependent effects of food limitation or predator pressure may occur (especially when species are dependent upon separate nesting and foraging habitats), high territory density may limit per-capita productivity. Here, we use a declining but widespread European farmland bird, the yellowhammer Emberiza citrinella L., as a model system to test whether higher territory densities result in lower fledging success, parental provisioning rates or nestling growth rates compared to lower densities. Organic landscapes held higher territory densities, but nests on organic farms fledged fewer nestlings, translating to a 5 times higher rate of population shrinkage on organic farms compared to conventional. In addition, when parental provisioning behaviour was not restricted by predation risk (i.e. at times of low corvid activity), nestling provisioning rates were higher at lower territory densities, resulting in a much greater increase in nestling mass in low density areas, suggesting that food limitation occurred at high densities. These findings in turn suggest an ecological trap, whereby preferred nesting habitat does not provide sufficient food for rearing nestlings at high population density, creating a population sink. Habitat management for farmland birds should focus not simply on creating a high nesting density, but also on ensuring heterogeneous habitats to provide food resources in close proximity to nesting birds, even if this occurs through potentially restricting overall nest density but increasing population-level breeding success

Weekend admission to hospital has a higher risk of death in the elective setting than in the emergency setting: a retrospective database study of national health service hospitals in England

<p>Abstract</p> <p>Background</p> <p>Although acute hospitals offer a twenty-four hour seven day a week service levels of staffing are lower over the weekends and some health care processes may be less readily available over the weekend. Whilst it is thought that emergency admission to hospital on the weekend is associated with an increased risk of death, the extent to which this applies to elective admissions is less well known. We investigated the risk of death in elective and elective patients admitted over the weekend versus the weekdays.</p> <p>Methods</p> <p>Retrospective statistical analysis of routinely collected acute hospital admissions in England, involving all patient discharges from all acute hospitals in England over a year (April 2008-March 2009), using a logistic regression model which adjusted for a range of patient case-mix variables, seasonality and admission over a weekend separately for elective and emergency (but excluding zero day stay emergency admissions discharged alive) admissions.</p> <p>Results</p> <p>Of the 1,535,267 elective admissions, 91.7% (1,407,705) were admitted on the weekday and 8.3% (127,562) were admitted on the weekend. The mortality following weekday admission was 0.52% (7,276/1,407,705) compared with 0.77% (986/127,562) following weekend admission. Of the 3,105,249 emergency admissions, 76.3% (2,369,316) were admitted on the weekday and 23.7% (735,933) were admitted on the weekend. The mortality following emergency weekday admission was 6.53% (154,761/2,369,316) compared to 7.06% (51,922/735,933) following weekend admission. After case-mix adjustment, weekend admissions were associated with an increased risk of death, especially in the elective setting (elective Odds Ratio: 1.32, 95% Confidence Interval 1.23 to 1.41); vs emergency Odds Ratio: 1.09, 95% Confidence Interval 1.05 to 1.13).</p> <p>Conclusions</p> <p>Weekend admission appears to be an independent risk factor for dying in hospital and this risk is more pronounced in the elective setting. Given the planned nature of elective admissions, as opposed to the unplanned nature of emergency admissions, it would seem less likely that this increased risk in the elective setting is attributable to unobserved patient risk factors. Further work to understand the relationship between weekend processes of care and mortality, especially in the elective setting, is required.</p

Immune Escape Variants of H9N2 Influenza Viruses Containing Deletions at the Hemagglutinin Receptor Binding Site Retain Fitness In Vivo and Display Enhanced Zoonotic Characteristics

H9N2 avian influenza viruses are enzootic in poultry across Asia and North Africa, where they pose a threat to human health as both zoonotic agents and potential pandemic candidates. Poultry vaccination against H9N2 viruses has been employed in many regions; however, vaccine effectiveness is frequently compromised due to antigenic drift arising from amino acid substitutions in the major influenza virus antigen hemagglutinin (HA). Using selection with HA-specific monoclonal antibodies, we previously identified H9N2 antibody escape mutants that contained deletions of amino acids in the 220 loop of the HA receptor binding sites (RBSs). Here we analyzed the impact of these deletions on virus zoonotic infection characteristics and fitness. We demonstrated that mutant viruses with RBS deletions are able to escape polyclonal antiserum binding and are able to infect and be transmitted between chickens. We showed that the deletion mutants have increased binding to human-like receptors and greater replication in primary human airway cells; however, the mutant HAs also displayed reduced pH and thermal stability. In summary, we infer that variant influenza viruses with deletions in the 220 loop could arise in the field due to immune selection pressure; however, due to reduced HA stability, we conclude that these viruses are unlikely to be transmitted from human to human by the airborne route, a prerequisite for pandemic emergence. Our findings underscore the complex interplay between antigenic drift and viral fitness for avian influenza viruses as well as the challenges of predicting which viral variants may pose the greatest threats for zoonotic and pandemic emergence

What People Believe about How Memory Works: A Representative Survey of the U.S. Population

Incorrect beliefs about the properties of memory have broad implications: The media conflate normal forgetting and inadvertent memory distortion with intentional deceit, juries issue verdicts based on flawed intuitions about the accuracy and confidence of testimony, and students misunderstand the role of memory in learning. We conducted a large representative telephone survey of the U.S. population to assess common beliefs about the properties of memory. Substantial numbers of respondents agreed with propositions that conflict with expert consensus: Amnesia results in the inability to remember one's own identity (83% of respondents agreed), unexpected objects generally grab attention (78%), memory works like a video camera (63%), memory can be enhanced through hypnosis (55%), memory is permanent (48%), and the testimony of a single confident eyewitness should be enough to convict a criminal defendant (37%). This discrepancy between popular belief and scientific consensus has implications from the classroom to the courtroom