Selection of neutralizing antibody escape mutants with type A influenza virus HA-specific polyclonal antisera: possible significance for antigenic drift

Ten antisera were produced in rabbits by two or three intravenous injections of inactivated whole influenza type A virions. All contained haemagglutination-inhibition (HI) antibody directed predominantly to an epitope in antigenic site B and, in addition, various amounts of antibodies to an epitope in site A and in site D. The ability of untreated antisera to select neutralization escape mutants was investigated by incubating virus possessing the homologous haemagglutinin with antiserum adjusted to contain anti-B epitope HI titres of 100, 1000 and 10000 HIU/ml. Virus-antiserum mixtures were inoculated into embryonated hen's eggs, and progeny virus examined without further selection. Forty percent of the antisera at a titre of 1000 HIU/ml selected neutralizing antibody escape mutants as defined by their lack of reactivity to Mab HC10 (site B), and unchanged reactivity to other Mabs to site A and site D epitopes. All escape mutant-selecting antisera had a ratio of anti-site B (HC10)-epitope antibody[ratio]other antibodies of [gt-or-equal, slanted]2·0[ratio]1. The antiserum with the highest ratio (7·4[ratio]1) selected escape mutants in all eggs tested in four different experiments. No antiserum used at a titre of 10000 HIU/ml allowed multiplication of any virus. All antisera used at a titre of 100 HIU/ml permitted virus growth, but this was wild-type (wt) virus. We conclude that a predominant epitope-specific antibody response, a titre of [gt-or-equal, slanted]1000 HIU/ml, and a low absolute titre of other antibodies ([less-than-or-eq, slant]500 HIU/ml) are three requirements for the selection of escape mutants. None of the antisera in this study could have selected escape mutants without an appropriate dilution factor, so the occurrence of an escape mutant-selecting antiserum in nature is likely to be a rare event

Exploring efficacy in personal constraint negotiation: an ethnography of mountaineering tourists

Limited work has explored the relationship between efficacy and personal constraint negotiation for adventure tourists, yet efficacy is pivotal to successful activity participation as it influences people’s perceived ability to cope with constraints, and their decision to use negotiation strategies. This paper explores these themes with participants of a commercially organised mountaineering expedition. Phenomenology-based ethnography was adopted to appreciate the social and cultural mountaineering setting from an emic perspective. Ethnography is already being used to understand adventure participation, yet there is considerable scope to employ it further through researchers immersing themselves into the experience. The findings capture the interaction between the ethnographer and the group members, and provide an embodied account using their lived experiences. Findings reveal that personal mountaineering skills, personal fitness, altitude sickness and fatigue were the four key types of personal constraint. Self-efficacy, negotiation-efficacy and other factors, such as hardiness and motivation, influenced the effectiveness of negotiation strategies. Training, rest days, personal health, and positive self-talk were negotiation strategies. A conceptual model illustrates these results and demonstrates the interplay between efficacy and the personal constraint negotiation journey for led mountaineers

Low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir

Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 106 plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 102 pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 104 pfu gave an infection that was intermediate between those of the 106 pfu and 102 pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (106 pfu) and low (102 pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Automatic evaluation stimuli - the most frequently used words to describe physical activity and the pleasantness of physical activity

Physical activity is partially regulated by non-conscious processes including automatic evaluations - the spontaneous affective reactions we have to physical activity that lead us to approach or avoid physical activity opportunities. A sound understanding of which words best represent the concepts of physical activity and pleasantness (as associated with physical activity) is needed to improve the measurement of automatic evaluations and related constructs (e.g., automatic self-schemas, attentional biases). The first aim of this study was to establish population-level evidence of the most common word stimuli for physical activity and pleasantness. Given that response latency measures have been applied to assess automatic evaluations of physical activity and exercise, the second aim was to determine whether people use the same behavior and pleasant descriptors for physical activity and exercise. Australian adults (N = 1,318; 54.3% women; 48.9% aged 55 years or older) were randomly assigned to one of two groups, through a computer-generated 1:1 ratio allocation, to be asked to list either five behaviors and pleasant descriptors of physical activity (n = 686) or of exercise (n = 632). The words were independently coded twice as to whether they were novel words or the same as another (i.e., same stem or same meaning). Intercoder reliability varied between moderate and strong (agreement = 50.1 to 97.8%; κ = 0.48 to 0.82). A list of the 20 most common behavior and pleasantness words were established based on how many people reported them, weighted by the ranking (1-5) people gave them. The words people described as physical activity were mostly the same as those people used to describe exercise. The most common behavior words were 'walking,' 'running,' 'swimming,' 'bike riding,' and 'gardening'; and the most common pleasant descriptor words were 'relaxing,' 'happiness,' 'enjoyment,' 'exhilarating,' 'exhausting,' and 'good.' These sets of stimuli can be utilized as resources for response latency measurement tasks of automatic evaluations and for tools to enhance automatic evaluations of physical activity in evaluative conditioning tasks.Amanda L. Rebar, Stephanie Schoeppe, Stephanie J. Alley, Camille E. Short, James A. Dimmock, Ben Jackson, David E. Conroy, Ryan E. Rhodes and Corneel Vandelanott

Spontaneous emission from large quantum dots in nanostructures: exciton-photon interaction beyond the dipole approximation

We derive a rigorous theory of the interaction between photons and spatially extended excitons confined in quantum dots in inhomogeneous photonic materials. We show that, beyond the dipole approximation, the radiative decay rate is proportional to a non-local interaction function, which describes the interaction between light and spatially extended excitons. In this regime, light and matter degrees of freedom cannot be separated and a complex interplay between the nanostructured optical environment and the exciton envelope function emerges. We illustrate this by specific examples and derive a series of important analytical relations, which are useful for applying the formalism to practical problems. In the dipole limit, the decay rate is proportional to the projected local density of optical states and we obtain the strong and weak confinement regimes as special cases.Comment: 14 pages, 4 figure

Synthesis and evaluation of novel antifungal agents targeted to the plasma membrane H[+]-ATPase

A library of dienones were synthesized as candidate antifungal agents. These compounds were screened against Saccharomyces cerevisiae and Candida albicans using macro-broth susceptibility assay. The dienones exhibited a broad range of inhibition against S. cerevisiae (0.2-99%) and C. albicans (0-99%). 3,5-bis(p- trifluoromethylbenzylidene)-1-methyl-piperidine-4-one was identified as the most potent inhibitor of S. cerevisiae. Whereas, the most promising inhibitor of C. albicans was 2,6-bis(pyridine-3ylmethylene)cyclohexan-1-one

Electron correlation effects and magnetic ordering at the Gd(0001) surface

Effects of electron correlation on the electronic structure and magnetic properties of the Gd(0001) surface are investigated using of the full-potential linearized augmented plane wave implementation of correlated band theory ("LDA+U"). The use of LDA+U instead of LDA (local density approximation) total energy calculations produces the correct ferromagnetic ground state for both bulk Gd and the Gd surface. Surface strain relaxation leads to an 90 % enhancement of the interlayer surface-to-bulk effective exchange coupling. Application of a Landau-Ginzburg type theory yields a 30 % enhancement of the Curie temperature at the surface, in very good agreement with the experiment.Comment: revised version: minor typos correcte

Topological crystalline insulator states in Pb(1-x)Sn(x)Se

Topological insulators are a novel class of quantum materials in which time-reversal symmetry, relativistic (spin-orbit) effects and an inverted band structure result in electronic metallic states on the surfaces of bulk crystals. These helical states exhibit a Dirac-like energy dispersion across the bulk bandgap, and they are topologically protected. Recent theoretical proposals have suggested the existence of topological crystalline insulators, a novel class of topological insulators in which crystalline symmetry replaces the role of time-reversal symmetry in topological protection [1,2]. In this study, we show that the narrow-gap semiconductor Pb(1-x)Sn(x)Se is a topological crystalline insulator for x=0.23. Temperature-dependent magnetotransport measurements and angle-resolved photoelectron spectroscopy demonstrate that the material undergoes a temperature-driven topological phase transition from a trivial insulator to a topological crystalline insulator. These experimental findings add a new class to the family of topological insulators. We expect these results to be the beginning of both a considerable body of additional research on topological crystalline insulators as well as detailed studies of topological phase transitions.Comment: v2: published revised manuscript (6 pages, 3 figures) and supplementary information (5 pages, 8 figures

Panspermia, Past and Present: Astrophysical and Biophysical Conditions for the Dissemination of Life in Space

Astronomically, there are viable mechanisms for distributing organic material throughout the Milky Way. Biologically, the destructive effects of ultraviolet light and cosmic rays means that the majority of organisms arrive broken and dead on a new world. The likelihood of conventional forms of panspermia must therefore be considered low. However, the information content of dam-aged biological molecules might serve to seed new life (necropanspermia).Comment: Accepted for publication in Space Science Review