Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein

Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcRI and FcRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection

An optimized TOPS+ comparison method for enhanced TOPS models

This article has been made available through the Brunel Open Access Publishing Fund.Background Although methods based on highly abstract descriptions of protein structures, such as VAST and TOPS, can perform very fast protein structure comparison, the results can lack a high degree of biological significance. Previously we have discussed the basic mechanisms of our novel method for structure comparison based on our TOPS+ model (Topological descriptions of Protein Structures Enhanced with Ligand Information). In this paper we show how these results can be significantly improved using parameter optimization, and we call the resulting optimised TOPS+ method as advanced TOPS+ comparison method i.e. advTOPS+. Results We have developed a TOPS+ string model as an improvement to the TOPS [1-3] graph model by considering loops as secondary structure elements (SSEs) in addition to helices and strands, representing ligands as first class objects, and describing interactions between SSEs, and SSEs and ligands, by incoming and outgoing arcs, annotating SSEs with the interaction direction and type. Benchmarking results of an all-against-all pairwise comparison using a large dataset of 2,620 non-redundant structures from the PDB40 dataset [4] demonstrate the biological significance, in terms of SCOP classification at the superfamily level, of our TOPS+ comparison method. Conclusions Our advanced TOPS+ comparison shows better performance on the PDB40 dataset [4] compared to our basic TOPS+ method, giving 90 percent accuracy for SCOP alpha+beta; a 6 percent increase in accuracy compared to the TOPS and basic TOPS+ methods. It also outperforms the TOPS, basic TOPS+ and SSAP comparison methods on the Chew-Kedem dataset [5], achieving 98 percent accuracy. Software Availability: The TOPS+ comparison server is available at http://balabio.dcs.gla.ac.uk/mallika/WebTOPS/.This article is available through the Brunel Open Access Publishing Fun

Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam

While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods-wavelet analysis, economic analysis, statistical and disease transmission modelling-we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens

Assessing early memories of threat and subordination: Confirmatory factor analyisis of the early life experiences scale for adolescents.

The Early Life Experiences Scale (ELES) is a self-report questionnaire that assesses personal feelings of perceived threat and submissiveness in interactions within family. This paper presents the adaptation and validation of the ELES in Portuguese language for adolescents. The sample was composed of 771 adolescents from community schools with ages between 13 and 18 years old. Along with ELES, participants also answered the Early Memories of Warmth and Safeness Scale and the Positive and Negative Affect Schedule for Children and Adolescents. Confirmatory factor analysis (CFA) was performed to test the factor structure of the ELES and results confirm a three-factor structure, composed by Threat, Submissiveness and Unvalued dimensions. These emotional memories focused on perceived threat, submissiveness and unvalued seem to have a distinct nature. The scale also showed adequate internal consistency, good test-retest reliability and convergent validity with measures of positive emotional memories, positive and negative affect. There were sex differences for threat subscale and age differences for submissiveness subscale. Overall, these findings suggest that the ELES in its Portuguese version for adolescents may be a useful tool for research, educational and clinical contexts with school-aged adolescents

Quality science from quality measurement: The role of measurement type with respect to replication and effect size magnitude in psychological research

Copyright: © 2018 Kornbrot et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The quality of psychological studies is currently a major concern. The Many Labs Project (MLP) and the Open-Science-Collaboration (OSC) have collected key data on replicability and statistical effect sizes. We build on this work by investigating the role played by three measurement types: ratings, proportions and unbounded (measures without conceptual upper limits, e.g. time). Both replicability and effect sizes are dependent on the amount of variability due to extraneous factors. We predicted that the role of such extraneous factors might depend on measurement type, and would be greatest for ratings, intermediate for proportions and least for unbounded. Our results support this conjecture. OSC replication rates for unbounded, 43% and proportion 40% combined are reliably higher than those for ratings at 20% (effect size, w = .20). MLP replication rates for the original studies are: pro- portion = .74, ratings = .40 (effect size w = .33). Original effect sizes (Cohen’s d) are highest for: unbounded OSC cognitive = 1.45, OSC social = .90); next for proportions (OSC cogni- tive = 1.01, OSC social = .84, MLP = .82); and lowest for ratings (OSC social = .64, MLP = .31). These findings are of key importance to scientific methodology and design, even if the reasons for their occurrence are still at the level of conjecture.Peer reviewe

Stability Constraints on Classical de Sitter Vacua

We present further no-go theorems for classical de Sitter vacua in Type II string theory, i.e., de Sitter constructions that do not invoke non-perturbative effects or explicit supersymmetry breaking localized sources. By analyzing the stability of the 4D potential arising from compactification on manfiolds with curvature, fluxes, and orientifold planes, we found that additional ingredients, beyond the minimal ones presented so far, are necessary to avoid the presence of unstable modes. We enumerate the minimal setups for (meta)stable de Sitter vacua to arise in this context.Comment: 18 pages; v2: argument improved, references adde

How does it really feel to act together? : Shared emotions and the phenomenology of we-agency

Research on the phenomenology of agency for joint action has so far focused on the sense of agency and control in joint action, leaving aside questions on how it feels to act together. This paper tries to fill this gap in a way consistent with the existing theories of joint action and shared emotion. We first reconstruct Pacherie’s (Phenomenology and the Cognitive Sciences, 13, 25–46, 2014) account on the phenomenology of agency for joint action, pointing out its two problems, namely (1) the necessary trade-off between the sense of self- and we-agency; and (2) the lack of affective phenomenology of joint action in general. After elaborating on these criticisms based on our theory of shared emotion, we substantiate the second criticism by discussing different mechanisms of shared affect—feelings and emotions—that are present in typical joint actions. We show that our account improves on Pacherie’s, first by introducing our agentive model of we-agency to overcome her unnecessary dichotomy between a sense of self- and we-agency, and then by suggesting that the mechanisms of shared affect enhance not only the predictability of other agents’ actions as Pacherie highlights, but also an agentive sense of we-agency that emerges from shared emotions experienced in the course and consequence of joint action.Peer reviewe

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Inclusive search for same-sign dilepton signatures in pp collisions at root s=7 TeV with the ATLAS detector

An inclusive search is presented for new physics in events with two isolated leptons (e or mu) having the same electric charge. The data are selected from events collected from p p collisions at root s = 7 TeV by the ATLAS detector and correspond to an integrated luminosity of 34 pb(-1). The spectra in dilepton invariant mass, missing transverse momentum and jet multiplicity are presented and compared to Standard Model predictions. In this event sample, no evidence is found for contributions beyond those of the Standard Model. Limits are set on the cross-section in a fiducial region for new sources of same-sign high-mass dilepton events in the ee, e mu and mu mu channels. Four models predicting same-sign dilepton signals are constrained: two descriptions of Majorana neutrinos, a cascade topology similar to supersymmetry or universal extra dimensions, and fourth generation d-type quarks. Assuming a new physics scale of 1 TeV, Majorana neutrinos produced by an effective operator V with masses below 460 GeV are excluded at 95% confidence level. A lower limit of 290 GeV is set at 95% confidence level on the mass of fourth generation d-type quarks