Cross-protection against European swine influenza viruses in the context of infection immunity against the 2009 pandemic H1N1 virus : studies in the pig model of influenza

Pigs are natural hosts for the same influenza virus subtypes as humans and are a valuable model for cross-protection studies with influenza. In this study, we have used the pig model to examine the extent of virological protection between a) the 2009 pandemic H1N1 (pH1N1) virus and three different European H1 swine influenza virus (SIV) lineages, and b) these H1 viruses and a European H3N2 SIV. Pigs were inoculated intranasally with representative strains of each virus lineage with 6- and 17-week intervals between H1 inoculations and between H1 and H3 inoculations, respectively. Virus titers in nasal swabs and/or tissues of the respiratory tract were determined after each inoculation. There was substantial though differing cross-protection between pH1N1 and other H1 viruses, which was directly correlated with the relatedness in the viral hemagglutinin (HA) and neuraminidase (NA) proteins. Cross-protection against H3N2 was almost complete in pigs with immunity against H1N2, but was weak in H1N1/pH1N1-immune pigs. In conclusion, infection with a live, wild type influenza virus may offer substantial cross-lineage protection against viruses of the same HA and/or NA subtype. True heterosubtypic protection, in contrast, appears to be minimal in natural influenza virus hosts. We discuss our findings in the light of the zoonotic and pandemic risks of SIVs

Ant-based Neural Topology Search (ANTS) for Optimizing Recurrent Networks

Hand-crafting effective and efficient structures for recurrent neural networks (RNNs) is a difficult, expensive, and time-consuming process. To address this challenge, we propose a novel neuro-evolution algorithm based on ant colony optimization (ACO), called Ant-based Neural Topology Search (ANTS), for directly optimizing RNN topologies. The procedure selects from multiple modern recurrent cell types such as ∆-RNN, GRU, LSTM, MGU and UGRNN cells, as well as recurrent connections which may span multiple layers and/or steps of time. In order to introduce an inductive bias that encourages the formation of sparser synaptic connectivity patterns, we investigate several variations of the core algorithm. We do so primarily by formulating different functions that drive the underlying pheromone simulation process (which mimic L1 and L2 regularization in standard machine learning) as well as by introducing ant agents with specialized roles (inspired by how real ant colonies operate), i.e., explorer ants that construct the initial feed forward structure and social ants which select nodes from the feed forward connections to subsequently craft recurrent memory structures. We also incorporate communal intelligence, where best weights are shared by the ant colony for weight initialization, reducing the number of backpropagation epochs required to locally train candidate RNNs, speeding up the neuro-evolution process. Our results demonstrate that the sparser RNNs evolved by ANTS significantly outperform traditional one and two layer architectures consisting of modern memory cells, as well as the well-known NEAT algorithm. Furthermore, we improve upon prior state-of-the-art results on the time series dataset utilized in our experiments

Rapidly rotating second-generation progenitors for the blue hook stars of {\omega} Cen

Horizontal Branch stars belong to an advanced stage in the evolution of the oldest stellar galactic population, occurring either as field halo stars or grouped in globular clusters. The discovery of multiple populations in these clusters, that were previously believed to have single populations gave rise to the currently accepted theory that the hottest horizontal branch members (the blue hook stars, which had late helium-core flash ignition, followed by deep mixing) are the progeny of a helium-rich "second generation" of stars. It is not known why such a supposedly rare event (a late flash followed by mixing) is so common that the blue hook of {\omega} Cen contains \sim 30% of horizontal branch stars 10 , or why the blue hook luminosity range in this massive cluster cannot be reproduced by models. Here we report that the presence of helium core masses up to \sim 0.04 solar masses larger than the core mass resulting from evolution is required to solve the luminosity range problem. We model this by taking into account the dispersion in rotation rates achieved by the progenitors, whose premain sequence accretion disc suffered an early disruption in the dense environment of the cluster's central regions where second-generation stars form. Rotation may also account for frequent late-flash-mixing events in massive globular clusters.Comment: 44 pages, 8 figures, 2 tables in Nature, online june 22, 201

The role of healthcare professionals in encouraging parents to see and hold their stillborn baby: a meta-synthesis of qualitative studies.

Background: Globally, during 2013 there were three million recorded stillbirths. Where clinical guidelines exist some recommend that professionals do not encourage parental contact. The guidance is based on quantitative evidence that seeing and holding the baby is not beneficial for everyone, but has been challenged by bereaved parents' organisations. We aim to inform future guideline development through a synthesis of qualitative studies reporting data relevant to the research question; how does the approach of healthcare professionals to seeing and holding the baby following stillbirth impact parents views and experiences? Methods/Findings: Using a predetermined search strategy of PubMed and PsychINFO we identified robust qualitative studies reporting bereaved parental views and/or experiences relating to seeing and holding their stillborn baby (final search 24 February, 2014). Eligible studies were English language, reporting parental views, with gestational loss >20weeks. Quality was independently assessed by three authors using a validated tool. We used meta-ethnographic techniques to identify key themes and a line of argument synthesis. We included 12 papers, representing the views of 333 parents (156 mothers, 150 fathers, and 27 couples) from six countries. The final themes were: "[Still]birth: Nature of care is paramount", "Real babies: Perfect beauties, monsters and spectres", and "Opportunity of a lifetime lost." Our line-of-argument synthesis highlights the contrast between all parents need to know their baby, with the time around birth being the only time memories can be made, and the variable ability that parents have to articulate their preferences at that time. Thus, we hypothesised that how health professionals approach contact between parents and their stillborn baby demands a degree of active management. An important limitation of this paper is all included studies originated from high income, westernised countries raising questions about the findings transferability to other cultural contexts. We do not offer new evidence to answer the question "Should parents see and hold their stillborn baby?", instead our findings advance understanding of how professionals can support parents to make appropriate decisions in a novel, highly charged and dynamic situation. Conclusions: Guidelines could be more specific in their recommendations regarding parental contact. The role of healthcare professionals in encouraging parents to see and hold their stillborn baby is paramount. Parental choice not to see their baby, apprehension, or uncertainty should be continuously revisited in the hours after birth as the opportunity for contact is fleeting and final

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

Informing the design of a national screening and treatment programme for chronic viral hepatitis in primary care: qualitative study of at-risk immigrant communities and healthcare professionals

n Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedThis paper presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP-PG-1209-10038).

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Mild Transient Hypercapnia as a Novel Fear Conditioning Stimulus Allowing Re-Exposure during Sleep

Introduction:Studies suggest that sleep plays a role in traumatic memories and that treatment of sleep disorders may help alleviate symptoms of posttraumatic stress disorder. Fear-conditioning paradigms in rodents are used to investigate causal mechanisms of fear acquisition and the relationship between sleep and posttraumatic behaviors. We developed a novel conditioning stimulus (CS) that evoked fear and was subsequently used to study re-exposure to the CS during sleep.Methods:Experiment 1 assessed physiological responses to a conditioned stimulus (mild transient hypercapnia, mtHC; 3.0% CO2; n = 17)+footshock for the purpose of establishing a novel CS in male FVB/J mice. Responses to the novel CS were compared to tone+footshock (n = 18) and control groups of tone alone (n = 17) and mild transient hypercapnia alone (n = 10). A second proof of principle experiment re-exposed animals during sleep to mild transient hypercapnia or air (control) to study sleep processes related to the CS.Results:Footshock elicited a response of acute tachycardia (30-40 bpm) and increased plasma epinephrine. When tone predicted footshock it elicited mild hypertension (1-2 mmHg) and a three-fold increase in plasma epinephrine. When mtHC predicted footshock it also induced mild hypertension, but additionally elicited a conditioned bradycardia and a smaller increase in plasma epinephrine. The overall mean 24 hour sleep-wake profile was unaffected immediately after fear conditioning.Discussion:Our study demonstrates the efficacy of mtHC as a conditioning stimulus that is perceptible but innocuous (relative to tone) and applicable during sleep. This novel model will allow future studies to explore sleep-dependent mechanisms underlying maladaptive fear responses, as well as elucidate the moderators of the relationship between fear responses and sleep. © 2013 McDowell et al

Malaria parasites regulate the duration of the intra-erythrocytic cycle via serpentine receptor 10 and coordinate development with host daily rhythms

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 h suggesting a circadian basis, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches utilizing rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit daily rhythms in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 6% of Plasmodium falciparum genes show 24 h rhythms in expression under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a 24 h transcriptional rhythm and disrupting it in rodent malaria parasites shortens the IDC by 2-3 h; (v) Multiple processes including DNA replication, and the ubiquitin and proteasome pathways, are affected by loss of coordination with host rhythms and by disruption of SR10. Our results reveal malaria parasites are at least partly responsible for scheduling the IDC and coordinating their development with host daily rhythms

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.