Limited antigenic diversity of Plasmodium falciparum apical membrane antigen 1 supports the development of effective multi-allele vaccines

BackgroundPolymorphism in antigens is a common mechanism for immune evasion used by many important pathogens, and presents major challenges in vaccine development. In malaria, many key immune targets and vaccine candidates show substantial polymorphism. However, knowledge on antigenic diversity of key antigens, the impact of polymorphism on potential vaccine escape, and how sequence polymorphism relates to antigenic differences is very limited, yet crucial for vaccine development. Plasmodium falciparum apical membrane antigen 1 (AMA1) is an important target of naturally-acquired antibodies in malaria immunity and a leading vaccine candidate. However, AMA1 has extensive allelic diversity with more than 60 polymorphic amino acid residues and more than 200 haplotypes in a single population. Therefore, AMA1 serves as an excellent model to assess antigenic diversity in malaria vaccine antigens and the feasibility of multi-allele vaccine approaches. While most previous research has focused on sequence diversity and antibody responses in laboratory animals, little has been done on the cross-reactivity of human antibodies.MethodsWe aimed to determine the extent of antigenic diversity of AMA1, defined by reactivity with human antibodies, and to aid the identification of specific alleles for potential inclusion in a multi-allele vaccine. We developed an approach using a multiple-antigen-competition enzyme-linked immunosorbent assay (ELISA) to examine cross-reactivity of naturally-acquired antibodies in Papua New Guinea and Kenya, and related this to differences in AMA1 sequence.ResultsWe found that adults had greater cross-reactivity of antibodies than children, although the patterns of cross-reactivity to alleles were the same. Patterns of antibody cross-reactivity were very similar between populations (Papua New Guinea and Kenya), and over time. Further, our results show that antigenic diversity of AMA1 alleles is surprisingly restricted, despite extensive sequence polymorphism. Our findings suggest that a combination of three different alleles, if selected appropriately, may be sufficient to cover the majority of antigenic diversity in polymorphic AMA1 antigens. Antigenic properties were not strongly related to existing haplotype groupings based on sequence analysis.ConclusionsAntigenic diversity of AMA1 is limited and a vaccine including a small number of alleles might be sufficient for coverage against naturally-circulating strains, supporting a multi-allele approach for developing polymorphic antigens as malaria vaccines

Correction: Structure of the Malaria Antigen AMA1 in Complex with a Growth-Inhibitory Antibody

Identifying functionally critical regions of the malaria antigen AMA1 (apical membrane antigen 1) is necessary to understand the significance of the polymorphisms within this antigen for vaccine development. The crystal structure of AMA1 in complex with the Fab fragment of inhibitory monoclonal antibody 1F9 reveals that 1F9 binds to the AMA1 solvent-exposed hydrophobic trough, confirming its importance. 1F9 uses the heavy and light chain complementarity-determining regions (CDRs) to wrap around the polymorphic loops adjacent to the trough, but uses a ridge of framework residues to bind to the hydrophobic trough. The resulting 1F9-AMA1–combined buried surface of 2,470 Å2 is considerably larger than previously reported Fab–antigen interfaces. Mutations of polymorphic AMA1 residues within the 1F9 epitope disrupt 1F9 binding and dramatically reduce the binding of affinity-purified human antibodies. Moreover, 1F9 binding to AMA1 is competed by naturally acquired human antibodies, confirming that the 1F9 epitope is a frequent target of immunological attack

Deciphering the evolution of the Milky Way discs: Gaia APOGEE Kepler giant stars and the Besançon Galaxy Model

[Context] Thanks to ongoing efforts to compute accurate stellar ages, we are able to characterise stars in different regions of the Milky Way. The Gaia and Kepler space-missions, along with ground-based spectroscopic surveys such as APOGEE, provide a unique way to study the chemo-kinematics relations as a function of age through the Galactic stellar populations and provide new constraints to Galactic evolution models. [Aims] We investigate the properties of the double sequences of the Milky Way discs visible in the [α/Fe] versus [Fe/H] diagram, which are usually associated to the chemical thin and thick discs at the solar circle. In the framework of Galactic formation and evolution, we discuss the complex relationships between age, metallicity, [α/Fe], and the radial, azimuthal, and vertical components of the space velocities. [Methods] We study stars with measured chemical and seismic properties from the APOGEE spectroscopic survey and the Kepler satellite, respectively. In addition, astrometry from the Gaia satellite is available for the majority of the sample. We separate the [α/Fe]-[Fe/H] diagram into three stellar populations: the thin disc, the high-α metal-poor thick disc, and the high-α metal-rich thick disc and characterise each of these in the age-chemo-kinematics parameter space. Because of the model-dependent nature of the ages inferred from asteroseismology, and because they depend on the quality of the input spectroscopic information, we compare results obtained from different APOGEE data releases (DR14 and DR16). We also use age determinations from two recent works in the literature. In addition, we use the Besançon stellar populations synthesis model to highlight selection biases and mechanisms (such as mergers and secular evolution) not included in the model. [Results] The thin disc exhibits a flat age-metallicity relation while [α/Fe] increases with stellar age. We confirm no correlation between radial and vertical velocities with [Fe/H], [α/Fe], and age for each stellar population. Considering both samples, Vφ decreases with age for the thin disc, while Vφ increases with age for the high-α metal-poor thick disc. We show that this difference is not due to sample selection. Although the age distribution of the high-α metal-rich thick disc is very close to that of the high-α metal-poor thick disc between 7 and 14 Gyr, its kinematics seems to follow that of the thin disc. This feature, not predicted by the hypotheses included in the Besançon Galaxy Model, suggests a different origin and history for this population. Finally, we show that there is a maximum dispersion of the vertical velocity, σZ, with age for the high-α metal-poor thick disc around 8 Gyr. The comparisons with the Besançon Galaxy Model simulations suggest a more complex chemo-dynamical scheme to explain this feature, most likely including mergers and radial migration effects.F.F., A.F., R.M., M.R., T.A. acknowledge support by the Spanish Ministry of Science, Innovation and University (MICIU/FEDER, UE) through grant RTI2018-095076-B-C21, the Institute of Cosmos Sciences University of Barcelona (ICCUB, Unidad de Excelencia “María de Maeztu”) through grant CEX2019-000918-M, the Ramon y Cajal Fellowship RYC2018-025968-I. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 800502. AM acknowledges funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 772293 – project ASTEROCHRONOMETRY, https://www.asterochronometry.eu

The Relationship Between Mono-Abundance and Mono-Age Stellar Populations in the Milky Way Disk

Studying the Milky Way disk structure using stars in narrow bins of [Fe/H] and [α/Fe] has recently been proposed as a powerful method to understand the Galactic thick and thin disk formation. It has been assumed so far that these mono-abundance populations (MAPs) are also coeval, or mono-age, populations. Here we study this relationship for a Milky Way chemodynamical model and show that equivalence between MAPs and mono-age populations exists only for the high-[α/Fe] tail, where the chemical evolution curves of different Galactic radii are far apart. At lower [α/Fe]-values an MAP is composed of stars with a range in ages, even for small observational uncertainties and a small MAP bin size. Due to the disk inside-out formation, for these MAPs younger stars are typically located at larger radii, which results in negative radial age gradients that can be as large as 2 Gyr kpc−1. Positive radial age gradients can result for MAPs at the lowest [α/Fe] and highest [Fe/H] end. Such variations with age prevent the simple interpretation of observations for which accurate ages are not available. Studying the variation with radius of the stellar surface density and scale height in our model, we find good agreement to recent analyses of the APOGEE red-clump (RC) sample when 1–4 Gyr old stars dominate (as expected for the RC). Our results suggest that the APOGEE data are consistent with a Milky Way model for which mono-age populations flare for all ages. We propose observational tests for the validity of our predictions and argue that using accurate age measurements, such as from asteroseismology, is crucial for putting constraints on Galactic formation and evolution

A Recombinant Blood-Stage Malaria Vaccine Reduces Plasmodium falciparum Density and Exerts Selective Pressure on Parasite Populations in a Phase 1-2b Trial in Papua New Guinea

The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic type

Tracing chemical evolution over the extent of the Milky Way's Disk with APOGEE Red Clump Stars

We employ the first two years of data from the near-infrared, high-resolution SDSS-III/APOGEE spectroscopic survey to investigate the distribution of metallicity and alpha-element abundances of stars over a large part of the Milky Way disk. Using a sample of ~10,000 kinematically-unbiased red-clump stars with ~5% distance accuracy as tracers, the [alpha/Fe] vs. [Fe/H] distribution of this sample exhibits a bimodality in [alpha/Fe] at intermediate metallicities, -0.9<[Fe/H]<-0.2, but at higher metallicities ([Fe/H]=+0.2) the two sequences smoothly merge. We investigate the effects of the APOGEE selection function and volume filling fraction and find that these have little qualitative impact on the alpha-element abundance patterns. The described abundance pattern is found throughout the range 5<R<11 kpc and 0<|Z|<2 kpc across the Galaxy. The [alpha/Fe] trend of the high-alpha sequence is surprisingly constant throughout the Galaxy, with little variation from region to region (~10%). Using simple galactic chemical evolution models we derive an average star formation efficiency (SFE) in the high-alpha sequence of ~4.5E-10 1/yr, which is quite close to the nearly-constant value found in molecular-gas-dominated regions of nearby spirals. This result suggests that the early evolution of the Milky Way disk was characterized by stars that shared a similar star formation history and were formed in a well-mixed, turbulent, and molecular-dominated ISM with a gas consumption timescale (1/SFE) of ~2 Gyr. Finally, while the two alpha-element sequences in the inner Galaxy can be explained by a single chemical evolutionary track this cannot hold in the outer Galaxy, requiring instead a mix of two or more populations with distinct enrichment histories.Comment: 18 pages, 17 figures. Accepted for publication in Ap

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13