Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the ...most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.
We present deep photometry in the B, V and I filters from CTIO/MOSAIC for about 270 000 stars in the Fornax dwarf spheroidal galaxy, out to a radius of rell ≈ 0.8 degrees. By combining the accurately ...calibrated photometry with the spectroscopic metallicity distributions of individual red giant branch stars we obtain the detailed star formation and chemical evolution history of Fornax. Fornax is dominated by intermediate age (1−10 Gyr) stellar populations, but also includes ancient (10−14 Gyr), and young (≤1 Gyr) stars. We show that Fornax displays a radial age gradient, with younger, more metal-rich populations dominating the central region. This confirms results from previous works. Within an elliptical radius of 0.8 degrees, or 1.9 kpc from the centre, a total mass in stars of 4.3 × 107 M⊙ was formed, from the earliest times until 250 Myr ago. Using the detailed star formation history, age estimates are determined for individual stars on the upper RGB, for which spectroscopic abundances are available, giving an age-metallicity relation of the Fornax dSph from individual stars. This shows that the average metallicity of Fornax went up rapidly from Fe/H ≤ −2.5 dex to Fe/H = −1.5 dex between 8−12 Gyr ago, after which a more gradual enrichment resulted in a narrow, well-defined sequence which reaches Fe/H ≈ −0.8 dex, ≈3 Gyr ago. These ages also allow us to measure the build-up of chemical elements as a function of time, and thus determine detailed timescales for the evolution of individual chemical elements. A rapid decrease in Mg/Fe is seen for the stars with Fe/H ≥ −1.5 dex, with a clear trend in age.
We present our analysis of the FLAMES dataset targeting the central 25′ region of the Sextans dwarf spheroidal galaxy (dSph). This dataset is the third major part of the high-resolution spectroscopic ...section of the ESO large program 171.B-0588(A) obtained by the Dwarf galaxy Abundances and Radial-velocities Team. Our sample is composed of red giant branch stars down to
V
∼ 20.5 mag, the level of the horizontal branch in Sextans, and allows users to address questions related to both stellar nucleosynthesis and galaxy evolution. We provide metallicities for 81 stars, which cover the wide Fe/H = −3.2 to −1.5 dex range. The abundances of ten other elements are derived: Mg, Ca, Ti, Sc, Cr, Mn, Co, Ni, Ba, and Eu. Despite its small mass, Sextans is a chemically evolved system, showing evidence of a contribution from core-collapse and Type Ia supernovae as well as low-metallicity asymptotic giant branch stars (AGBs). This new FLAMES sample offers a sufficiently large number of stars with chemical abundances derived with high accuracy to firmly establish the existence of a plateau in
α
/Fe at ∼0.4 dex followed by a decrease above Fe/H ∼ −2 dex. These features reveal a close similarity with the Fornax and Sculptor dSphs despite their very different masses and star formation histories, suggesting that these three galaxies had very similar star formation efficiencies in their early formation phases, probably driven by the early accretion of smaller galactic fragments, until the UV-background heating impacted them in different ways. The parallel between the Sculptor and Sextans dSph is also striking when considering Ba and Eu. The same chemical trends can be seen in the metallicity region common to both galaxies, implying similar fractions of SNeIa and low-metallicity AGBs. Finally, as to the iron-peak elements, the decline of Co/Fe and Ni/Fe above Fe/H ∼ −2 implies that the production yields of Ni and Co in SNeIa are lower than that of Fe. The decrease in Ni/Fe favours models of SNeIa based on the explosion of double-degenerate sub-Chandrasekhar mass white dwarfs.
A prominent hydrogen-related infrared absorption peak seen in many types of diamonds at 3107 cm(-1) has been the subject of investigation for many years. It is present in natural type-Ia material and ...can be introduced by heat-treating synthetic or CVD diamond. Based upon the most recent experimental data, it is thought that the defect giving rise to this vibrational mode is vacancy-related and is likely to contain nitrogen. Using first-principles simulations we present a VN3H model for the originating centre that simultaneously satisfies the different experimental observations including the strain response.
We have combined deep photometry in the B, V and I bands from CTIO/MOSAIC of the Sculptor dwarf spheroidal galaxy, going down to the oldest main sequence turn-offs, with spectroscopic metallicity ...distributions of red giant branch stars. This allows us to obtain the most detailed and complete star formation history to date, as well as an accurate timescale for chemical enrichment. The star formation history shows that Sculptor is dominated by old (>10 Gyr), metal-poor stars, but that younger, more metal-rich populations are also present. Using star formation histories determined at different radii from the centre we show that Sculptor formed stars with an increasing central concentration with time. The old, metal-poor populations are present at all radii, while more metal-rich, younger stars are more centrally concentrated. We find that within an elliptical radius of 1 degree, or 1.5 kpc from the centre, a total mass in stars of 7.8 × 106 M⊙ was formed, between 14 and 7 Gyr ago, with a peak at 13−14 Gyr ago. We use the detailed star formation history to determine age estimates for individual red giant branch stars with high resolution spectroscopic abundances. Thus, for the first time, we can directly determine detailed timescales for the evolution of individual chemical elements. We find that the trends in alpha-elements match what is expected from an extended, relatively uninterrupted period of star formation continuing for 6−7 Gyr. The knee in the alpha-element distribution occurs at an age of 10.9 ± 1Gyr, suggesting that SNe Ia enrichment began ≈2 ± 1 Gyr after the start of star formation in Sculptor.
Aims. The nature of the thick disc and its relation to the thin disc is presently an important subject of debate. In fact, the structural and chemo-dynamical transition between disc populations can ...be used as a test of the proposed models of Galactic disc formation and evolution. Methods. We used the atmospheric parameters, α/Fe abundances, and radial velocities, which were determined from the Gaia-ESO Survey GIRAFFE spectra of FGK-type stars (first nine months of observations) to provide a chemo-kinematical characterisation of the disc stellar populations. We focussed on a subsample of 1016 stars with high-quality parameters, covering the volume | Z | < 4.5 kpc and R in the range 2–13 kpc. Results. We have identified a thin to thick disc separation in the α/Fe vs. M/H plane, thanks to the presence of a low-density region in the number density distribution. The thick disc stars seem to lie in progressively thinner layers above the Galactic plane, as metallicity increases and α/Fe decreases. In contrast, the thin disc population presents a constant value of the mean distance to the Galactic plane at all metallicities. In addition, our data confirm the already known correlations between Vφ and M/H for the two discs. For the thick disc sequence, a study of the possible contamination by thin disc stars suggests a gradient up to 64 ± 9 km s-1 dex-1. The distributions of azimuthal velocity, vertical velocity, and orbital parameters are also analysed for the chemically separated samples. Concerning the gradients with galactocentric radius, we find, for the thin disc, a flat behaviour of the azimuthal velocity, a metallicity gradient equal to −0.058 ± 0.008 dex kpc-1 and a very small positive α/Fe gradient. For the thick disc, flat gradients in M/H and α/Fe are derived. Conclusions. Our chemo-kinematical analysis suggests a picture where the thick disc seems to have experienced a settling process, during which its rotation increased progressively and, possibly, the azimuthal velocity dispersion decreased. At M/H ≈ −0.25 dex and α/Fe≈ 0.1 dex, the mean characteristics of the thick disc in vertical distance to the Galactic plane, rotation, rotational dispersion, and stellar orbits’ eccentricity agree with that of the thin disc stars of the same metallicity, suggesting a possible connection between these two populations at a certain epoch of the disc evolution. Finally, the results presented here, based only on the first months of the Gaia ESO Survey observations, confirm how crucial large high-resolution spectroscopic surveys outside the solar neighbourhood are today for our understanding of the Milky Way history.
Abstract Ex vivo functional immunoassays such as ELISpot and intracellular cytokine staining (ICS) by flow cytometry are crucial tools in vaccine development both in the identification of novel ...immunogenic targets and in the immunological assessment of samples from clinical trials. Cryopreservation and subsequent thawing of PBMCs via validated processes has become a mainstay of clinical trials due to processing restrictions inherent in the disparate location and capacity of trial centres, and also in the need to standardize biological assays at central testing facilities. Logistical and financial requirement to batch process samples from multiple study timepoints are also key. We used ELISpot and ICS assays to assess antigen-specific immunogenicity in blood samples taken from subjects enrolled in a phase II malaria heterologous prime-boost vaccine trial and showed that the freeze thaw process can result in a 3–5-fold reduction of malaria antigen-specific IFNγ-producing CD3+ CD4+ effector populations from PBMC samples taken post vaccination. We have also demonstrated that peptide responsive CD8+ T cells are relatively unaffected, as well as CD4+ T cell populations that do not produce IFNγ. These findings contribute to a growing body of data that could be consolidated and synthesised as guidelines for clinical trials with the aim of increasing the efficiency of vaccine development pipelines.
ABSTRACT
Detailed chemical abundances of very metal-poor (VMP; Fe/H < −2) stars are important for better understanding the first stars, early star formation, and chemical enrichment of galaxies. Big ...on-going and coming high-resolution spectroscopic surveys provide a wealth of material that needs to be carefully analysed. For VMP stars, their elemental abundances should be derived based on the non-local thermodynamic equilibrium (non-LTE = NLTE) line formation because low metal abundances and low electron number density in the atmosphere produce the physical conditions favourable for the departures from LTE. The galactic archaeology research requires homogeneous determinations of chemical abundances. For this purpose, we present grids of the 1D-NLTE abundance corrections for lines of Na i, Mg i, Ca i, Ca ii, Ti ii, Fe i, Zn i, Zn ii, Sr ii, and Ba ii in the range of atmospheric parameters that represent VMP stars on various evolutionary stages and cover effective temperatures from 4000 to 6500 K, surface gravities from $\rm log g$ = 0.5 to 5.0, and metallicities −5.0 ≤ Fe/H ≤ −2.0. The data is publicly available, and we provide the tools for interpolating in the grids online.
•Viral vectored malaria vaccines adjuvanted with Matrix-M were well tolerated.•Addition of Matrix-M did not result in a reduction in cellular or humoral immunogenicity.•These vaccines adjuvanted with ...Matrix-M can be used safely in combination regimes with vaccines requiring an adjuvant.
The use of viral vectors in heterologous prime-boost regimens to induce potent T cell responses in addition to humoral immunity is a promising vaccination strategy in the fight against malaria. We conducted an open-label, first-in-human, controlled Phase I study evaluating the safety and immunogenicity of Matrix-M adjuvanted vaccination with a chimpanzee adenovirus serotype 63 (ChAd63) prime followed by a modified vaccinia Ankara (MVA) boost eight weeks later, both encoding the malaria ME-TRAP antigenic sequence (a multiple epitope string fused to thrombospondin-related adhesion protein). Twenty-two healthy adults were vaccinated intramuscularly with either ChAd63-MVA ME-TRAP alone (n=6) or adjuvanted with 25μg (n=8) or 50μg (n=8) Matrix-M. Vaccinations appeared to be safe and generally well tolerated, with the majority of local and systemic adverse events being mild in nature. The addition of Matrix-M to the vaccine did not increase local reactogenicity; however, systemic adverse events were reported more frequently by volunteers who received adjuvanted vaccine in comparison to the control group. T cell ELISpot responses peaked at 7-days post boost vaccination with MVA ME-TRAP in all three groups. TRAP-specific IgG responses were highest at 28-days post boost with MVA ME-TRAP in all three groups. There were no differences in cellular and humoral immunogenicity at any of the time points between the control group and the adjuvanted groups. We demonstrate that Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity.
Clinical Trials Registration NCT01669512.
To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in ...establishment of hepatocyte infection. For preclinical evaluation of immunogenicity of these proteins in mice, chimeric P. berghei sporozoites were created that express the P. falciparum proteins in sporozoites as an additional copy gene under control of the uis4 gene promoter. All fourteen chimeric parasites produced sporozoites but sporozoites of eight lines failed to establish a liver infection, indicating a negative impact of these P. falciparum proteins on sporozoite infectivity. Immunogenicity of the other six proteins (SPELD, ETRAMP10.3, SIAP2, SPATR, HT, RPL3) was analyzed by immunization of inbred BALB/c and outbred CD-1 mice with viral-vectored (ChAd63 or ChAdOx1, MVA) vaccines, followed by challenge with chimeric sporozoites. Protective immunogenicity was determined by analyzing parasite liver load and prepatent period of blood stage infection after challenge. Of the six proteins only SPELD immunized mice showed partial protection. We discuss both the low protective immunogenicity of these proteins in the chimeric rodent malaria challenge model and the negative effect on P. berghei sporozoite infectivity of several P. falciparum proteins expressed in the chimeric sporozoites.