Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor

<div><p>Macrophages are a diverse group of phagocytic cells acting in host protection against stress, injury, and pathogens. Here, we show that the scavenger receptor SR-A6 is an entry receptor for human adenoviruses in murine alveolar macrophage-like MPI cells, and important for production of type I interferon. Scavenger receptors contribute to the clearance of endogenous proteins, lipoproteins and pathogens. Knockout of SR-A6 in MPI cells, anti-SR-A6 antibody or the soluble extracellular SR-A6 domain reduced adenovirus type-C5 (HAdV-C5) binding and transduction. Expression of murine SR-A6, and to a lower extent human SR-A6 boosted virion binding to human cells and transduction. Virion clustering by soluble SR-A6 and proximity localization with SR-A6 on MPI cells suggested direct adenovirus interaction with SR-A6. Deletion of the negatively charged hypervariable region 1 (HVR1) of hexon reduced HAdV-C5 binding and transduction, implying that the viral ligand for SR-A6 is hexon. SR-A6 facilitated macrophage entry of HAdV-B35 and HAdV-D26, two important vectors for transduction of hematopoietic cells and human vaccination. The study highlights the importance of scavenger receptors in innate immunity against human viruses.</p></div

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Alternative Mechanisms for Tn5 Transposition

Bacterial transposons are known to move to new genomic sites using either a replicative or a conservative mechanism. The behavior of transposon Tn5 is anomalous. In vitro studies indicate that it uses a conservative mechanism while in vivo results point to a replicative mechanism. To explain this anomaly, a model is presented in which the two mechanisms are not independent—as widely believed—but could represent alternate outcomes of a common transpositional pathway

Human Wavelength Discrimination of Monochromatic Light Explained by Optimal Wavelength Decoding of Light of Unknown Intensity

We show that human ability to discriminate the wavelength of monochromatic light can be understood as maximum likelihood decoding of the cone absorptions, with a signal processing efficiency that is independent of the wavelength. This work is built on the framework of ideal observer analysis of visual discrimination used in many previous works. A distinctive aspect of our work is that we highlight a perceptual confound that observers should confuse a change in input light wavelength with a change in input intensity. Hence a simple ideal observer model which assumes that an observer has a full knowledge of input intensity should over-estimate human ability in discriminating wavelengths of two inputs of unequal intensity. This confound also makes it difficult to consistently measure human ability in wavelength discrimination by asking observers to distinguish two input colors while matching their brightness. We argue that the best experimental method for reliable measurement of discrimination thresholds is the one of Pokorny and Smith, in which observers only need to distinguish two inputs, regardless of whether they differ in hue or brightness. We mathematically formulate wavelength discrimination under this wavelength-intensity confound and show a good agreement between our theoretical prediction and the behavioral data. Our analysis explains why the discrimination threshold varies with the input wavelength, and shows how sensitively the threshold depends on the relative densities of the three types of cones in the retina (and in particular predict discriminations in dichromats). Our mathematical formulation and solution can be applied to general problems of sensory discrimination when there is a perceptual confound from other sensory feature dimensions

Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine

<p>Abstract</p> <p>Background</p> <p>A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons.</p> <p>Methods</p> <p>To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis.</p> <p>Results</p> <p>A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect.</p> <p>Conclusions</p> <p>While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations.</p

Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients

Preclinical and clinical studies demonstrate the feasibility of treating β-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human β-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients

Murine Gammaherpesvirus-68 Inhibits Antigen Presentation by Dendritic Cells

Dendritic cells (DCs) play a central role in initiating adaptive immunity. Murine gammaherpesvirus-68 (MHV-68), like many persistent viruses, infects DCs during normal host colonization. It therefore provides a means to understanding what host and viral genes contribute to this aspect of pathogenesis. The infected DC phenotype is likely to depend on whether viral gene expression is lytic or latent and whether antigen presentation is maintained. For MHV-68, neither parameter has been well defined. Here we show that MHV-68 infects immature but not mature bone marrow-derived DCs. Infection was predominantly latent and these DCs showed no obvious defect in antigen presentation. Lytically infected DCs were very different. These down-regulated CD86 and MHC class I expression and presented a viral epitope poorly to CD8+ T cells. Antigen presentation improved markedly when the MHV-68 K3 gene was disrupted, indicating that K3 fulfils an important function in infected DCs. MHV-68 infects only a small fraction of the DCs present in lymphoid tissue, so K3 expression is unlikely to compromise significantly global CD8+ T cell priming. Instead it probably helps to maintain lytic gene expression in DCs once CD8+ T cell priming has occurred