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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context. The pattern of chemical abundance ratios in stellar populations of the Milky Way is a fingerprint of the Galactic chemical history. In order to interpret such chemical fossils of Galactic ...archaeology, chemical evolution models have to be developed. However, despite the complex physics included in the most recent models, significant discrepancies between models and observations are widely encountered. Aims. The aim of this paper is to characterise the abundance patterns of five iron-peak elements (Mn, Fe, Ni, Cu, and Zn) for which the stellar origin and chemical evolution are still debated. Methods. We automatically derived iron peak (Mn, Fe, Ni, Cu, and Zn) and α element (Mg) chemical abundances for 4666 stars, adopting classical LTE spectral synthesis and 1D atmospheric models. Our observational data collection is composed of high-resolution, high signal-to-noise ratios HARPS and FEROS spectra, which were previously parametrised by the AMBRE project. Results. We used the bimodal distribution of the magnesium-to-iron abundance ratios to chemically classify our sample stars into different Galactic substructures: thin disc, metal-poor and high-α metal rich, high-α, and low-α metal-poor populations. Both high-α and low-α metal-poor populations are fully distinct in Mg, Cu, and Zn, but these substructures are statistically indistinguishable in Mn and Ni. Thin disc trends of Ni/Fe and Cu/Fe are very similar and show a small increase at supersolar metallicities. Also, both thin and thick disc trends of Ni and Cu are very similar and indistinguishable. Yet, Mn looks very different from Ni and Cu. Mn/Fe trends of thin and thick discs actually have noticeable differences: the thin disc is slightly Mn richer than the thick disc. The Zn/Fe trends look very similar to those of α/Fe trends. The typical dispersion of results in both discs is low (≈0.05 dex for Mg, Mn, and Cu/Fe) and is even much lower for Ni/Fe (≈0.035 dex). Conclusions. It is clearly demonstrated that Zn is an α-like element and could be used to separate thin and thick disc stars. Moreover, we show that the Mn/Mg ratio could also be a very good tool for tagging Galactic substructures. From the comparison with Galactic chemical evolutionary models, we conclude that some recent models can partially reproduce the observed Mg, Zn, and, Cu behaviours in thin and thick discs and metal-poor sequences. Models mostly fail to reproduce Mn and Ni in all metallicity domains, however, models adopting yields normalised from solar chemical properties reproduce Mn and Ni better, suggesting that there is still a lack of realistic theoretical yields of some iron-peak elements. The very low scatter (≈0.05 dex) in thin and thick disc sequences could provide an observational constrain for Galactic evolutionary models that study the efficiency of stellar radial migration.
We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on ...chromosome 18q11.2, was associated with disease (combined P = 6.8 × 10−9, odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Context. Fornax is one of the most massive dwarf spheroidal galaxies in the Local Group. The Fornax field star population is dominated by intermediate age stars but star formation was going on over ...almost its entire history. It has been proposed that Fornax experienced a minor merger event. Aims. Despite recent progress, only the high metallicity end of Fornax field stars (Fe/H > –1.2 dex) has been sampled in larger number via high resolution spectroscopy. We want to better understand the full chemical evolution of this galaxy by better sampling the whole metallicity range, including more metal poor stars. Methods. We use the VLT-FLAMES multi-fibre spectrograph in high-resolution mode to determine the abundances of several α, iron-peak and neutron-capture elements in a sample of 47 individual red giant branch stars in the Fornax dwarf spheroidal galaxy. We combine these abundances with accurate age estimates derived from the age probability distribution from the colour-magnitude diagram of Fornax. Results. Similar to other dwarf spheroidal galaxies, the old, metal-poor stars of Fornax are typically α-rich while the young metal-rich stars are α-poor. In the classical scenario of the time delay between Type II (SNe II) and Type Ia Supernovae (SNe Ia), we confirm that SNe Ia started to contribute to the chemical enrichment at Fe/H between –2.0 and –1.8 dex. We find that the onset of SNe Ia took place between 12–10 Gyr ago. The high values of Ba/Fe, La/Fe reflect the influence of SNe Ia and AGB stars in the abundance pattern of the younger stellar population of Fornax. Conclusions. Our findings of low α/Fe and enhanced Eu/Mg are compatible with an initial mass function that lacks the most massive stars and with star formation that kept going on throughout the whole history of Fornax. We find that massive stars kept enriching the interstellar medium in α-elements, although they were not the main contributor to the iron enrichment.
The complex life cycle of the malaria parasite Plasmodium falciparum provides many options for vaccine design. Several new types of vaccine are now being evaluated in clinical trials. Recently, two ...vaccine candidates that target the pre-erythrocytic stages of the malaria life cycle - a protein particle vaccine with a powerful adjuvant and a prime-boost viral-vector vaccine - have entered Phase II clinical trials in the field and the first has shown partial efficacy in preventing malarial disease in African children. This Review focuses on the potential immunological basis for the encouraging partial protection induced by these vaccines, and it considers ways for developing more effective malaria vaccines.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We use Very Large Telescope (VLT)/Fibre Large Array Multi Element Spectrograph (FLAMES) intermediate-resolution (R 6500) spectra of individual red giant branch stars in the near-infrared Caii triplet ...(CaT) region to investigate the wide-area metallicity properties and internal kinematics of the Sextans dwarf spheroidal galaxy (dSph). Our final sample consists of 174 probable members of Sextans with accurate line-of-sight velocities (±2kms-1) and CaT Fe/H measurements (±0.2dex). We use the Mgi line at 8806.8Å as an empirical discriminator for distinguishing between probable members of the dSph (giant stars) and probable Galactic contaminants (dwarf stars). Sextans shows a similar chemodynamical behaviour to other Milky Way dSphs, with its central regions being more metal rich than the outer parts and with the more metal-rich stars displaying colder kinematics than the more metal-poor stars. Hints of a velocity gradient are found along the projected major axis and along an axis at position angle (PA) = 191°, however, a larger and more spatially extended sample may be necessary to pin down the amplitude and direction of this gradient. We detect a cold kinematic substructure at the centre of Sextans, consistent with being the remnant of a disrupted very metal poor stellar cluster. We derive the most extended line-of-sight velocity dispersion profile for Sextans, out to a projected radius of 1 6. From Jeans modelling of the observed line-of-sight velocity dispersion profile we find that this is consistent with both a cored dark matter halo with large core radius and cuspy halo with low concentration. The mass within the last measured point is in the range 2-4 × 108M, giving very large mass-to-light ratios, from 460 to 920(M/L)V, . PUBLICATION ABSTRACT
Traditional chemical adjuvants remain a practical means of enhancing the immunogenicity of vaccines. Nevertheless, it is recognized that increasing the immunogenicity of viral vectors is challenging. ...Recently, STING ligands have been shown to enhance the efficacy of different vaccine platforms, but their affectivity on viral-vectored vaccination has not been fully assessed. In this study we used a multi-pronged approach to shed light on the immunological properties and potential mechanisms of action of this type of adjuvant and focused our study on replication-deficient human adenovirus serotype 5 (AdHu5). When the STING ligand 2'3'-cGAMP was mixed with AdHu5, the adjuvant enhanced anti-vector immune responses while decreasing the transgene-specific CD8
T cell response. Studies employing STING-knockout mice and a 2'3'-cGAMP inactive analogue confirmed the aforementioned effects were STING dependent. In vitro assays demonstrated 2'3'-cGAMP induced the production of IFN-β which in turn negatively affected AdHu5 transgene expression and CD8
T cell immunogenicity. In an effort to overcome the negative impact of early 2'3'-cGAMP signaling on AdHu5 transgene immunogenicity, we generated a bicistronic vector encoding the 2'3'-cGAMP together with a model antigen. Intracellular production of 2'3'-cGAMP after AdHu5 infection was able to enhance transgene-specific CD8
T cell immunogenicity, although not to a level that would warrant progression of this adjuvant to clinical assessment. This work highlights the importance of timing of 2'3'-cGAMP administration when assessing its adjuvant capacity with different vaccine modalities.
IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4
T cells are being elucidated, ...with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Rα inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet
cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4.
We report an abundance analysis for the highly r-process-enhanced (r-II) star CS 29497-004, a very metal-poor giant with solar system Teff = 5013 K and Fe/H = −2.85, whose nature was initially ...discovered in the course of the HERES project. Our analysis is based on high signal-to-noise ratio, high-resolution (R ~ 75 000) VLT/UVES spectra and MARCS model atmospheres under the assumption of local thermodynamic equilibrium, and obtains abundance measurements for a total of 46 elements, 31 of which are neutron-capture elements. As is the case for the other ~25 r-II stars currently known, the heavy-element abundance pattern of CS 29497-004 well-matches a scaled solar system second peak r-process-element abundance pattern. We confirm our previous detection of Th, and demonstrate that this star does not exhibit an “actinide boost”. Uranium is also detected (log ϵ(U) = −2.20 ± 0.30), albeit with a large measurement error that hampers its use as a precision cosmo-chronometer. Combining the various elemental chronometer pairs that are available for this star, we derive a mean age of 12.2 ± 3.7 Gyr using the theoretical production ratios from published waiting-point approximation models. We further explore the high-entropy wind model (Farouqi et al. 2010, ApJ, 712, 1359) production ratios arising from different neutron richness of the ejecta (Ye), and derive an age of 13.7 ± 4.4 Gyr for a best-fitting Ye = 0.447. The U/Th nuclei-chronometer is confirmed to be the most resilient to theoretical production ratios and yields an age of 16.5 ± 6.6 Gyr. Lead (Pb) is also tentatively detected in CS 29497-004, at a level compatible with a scaled solar r-process, or with the theoretical expectations for a pure r-process in this star.
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