We present VLT FLAMES spectroscopic observations (R similar to 6500 ) in the Ca II triplet region for 470 probable kinematic members of the Sculptor (Scl) dwarf spheroidal galaxy. The accurate ...velocities ( plus or minus 2 km/s) and large area coverage of Scl allow us to measure a velocity gradient of 7.6 super(+3.0) km s-1 deg-1 along the projected major axis of Scl, likely a signature of intrinsic rotation. We also use our kinematic data to measure the mass distribution within this system. By considering independently the kinematics of the two distinct stellar components known to be present in Scl, we are able to relieve known degeneracies and find that the observed velocity dispersion profiles are best fitted by a cored dark matter halo with core radius rc = 0.5 kpc and mass enclosed within the last measured point M(<1.8 kpc) = (3.4 plus or minus 0.7) x 10 super(8) M <1.8, assuming an increasingly radially anisotropic velocity ellipsoid. This results in a mass-to-light ratio of 158 plus or minus 33 (M/L)solar inside 1.8 kpc. An NFW profile with concentration C = 20 and mass M(<1.8 kpc) = 2.2 super(+2) x 10 super(8) M sub(solar) statistically consistent with the observations, but it tends to yield poorer fits for the metal-rich stars.
Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune ...systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4(+) T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3(+) and FoxP3(-) T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically.
Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. ...Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.
ABSTRACT
The Pristine survey uses narrow-band photometry to derive precise metallicities down to the extremely metal-poor regime ($ \rm Fe/H \lt -3$), and currently consists of over 4 million ...FGK-type stars over a sky area of $\sim 2500\, \mathrm{deg}^2$. We focus our analysis on a subsample of ∼80 000 main-sequence turn-off stars with heliocentric distances between 6 and 20 kpc, which we take to be a representative sample of the inner halo. The resulting metallicity distribution function (MDF) has a peak at $ \rm Fe/H =-1.6$, and a slope of Δ(LogN)/$\Delta \rm Fe/H = 1.0 \pm 0.1$ in the metallicity range of $-3.4\; \lt\; \rm Fe/H\; \lt -2.5$. This agrees well with a simple closed-box chemical enrichment model in this range, but is shallower than previous spectroscopic MDFs presented in the literature, suggesting that there may be a larger proportion of metal-poor stars in the inner halo than previously reported. We identify the Monoceros/TriAnd/ACS/EBS/A13 structure in metallicity space in a low-latitude field in the anticentre direction, and also discuss the possibility that the inner halo is dominated by a single, large merger event, but cannot strongly support or refute this idea with the current data. Finally, based on the MDF of field stars, we estimate the number of expected metal-poor globular clusters in the Milky Way halo to be 5.4 for $ \rm Fe/H\; \lt\; -2.5$ and 1.5 for $ \rm Fe/H\; \lt\; -3$, suggesting that the lack of low-metallicity globular clusters in the Milky Way is not due simply to statistical undersampling.
Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin ...(BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.
This study aims to assess the decline in telomere length (TL) with age and evaluate effect modification by gender, chronic stress, and comorbidity in a representative sample of the US population.
...Cross-sectional data on 7826 adults with a TL measurement, were included from the National Health and Nutrition Examination Survey, years 1999-2002. The population rate of decline in TL across 10-year age categories was estimated using crude and adjusted regression.
In an adjusted model, the population rate of decline in TL with age was consistent and linear for only three age categories: 20-29 (β = -0.0172, 95% CI: -0.0342, -0.0002), 50-59 (β = -0.0182, 95% CI: -0.0311, -0.0054) and 70-79 (β = -0.0170, 95% CI: -0.0329, -0.0011) years. The population rate of decline in TL with age was significantly greater for males and those with high allostatic load and a history of comorbidities. When the population rate of decline in TL was analyzed by gender in 10-year age bins, a fairly consistent yet statistically non-significant decline for males was observed; however, a trough in the rate was observed for females in the age categories 20-29 years (β = -0.0284, 95% CI: -0.0464, -0.0103) and 50-59 years (β = -0.0211, 95% CI: -0.0391, -0.0032). To further elucidate the gender difference observed in the primary analyses, secondary analyses were conducted with reproductive and hormonal status; a significant inverse association was found between TL and parity, menopause, and age at menopause.
TL was shorter with increasing age and this decline was modified by gender, chronic stress and comorbidities; individuals with chronic morbidity and/or chronic stress and females in their twenties and fifties experienced greater decline. Female reproductive factors, i.e., parity and menopause, were associated with TL.
The origin of carbon-enhanced metal-poor (CEMP) stars and their possible connection with the chemical elements produced by the first stellar generation is still highly debated. In contrast to the ...Galactic halo, not many CEMP stars have been found in the dwarf spheroidal galaxies around the Milky Way. Here we present detailed abundances from ESO VLT/UVES high-resolution spectroscopy for ET0097, the first CEMP star found in the Sculptor dwarf spheroidal, which is one of the best studied dwarf galaxies in the Local Group. This star has Fe/H = −2.03 ± 0.10, C/Fe = 0.51 ± 0.10 and N/Fe = 1.18 ± 0.20, which is the first nitrogen measurement in this galaxy. The traditional definition of CEMP stars is C/Fe ≥ 0.70, but taking into account that this luminous red giant branch star has undergone mixing, it was intrinsically less nitrogen enhanced and more carbon-rich when it was formed, and so it falls under the definition of CEMP stars, as proposed by Aoki et al. (2007, ApJ, 655, 492) to account for this effect. By making corrections for this mixing, we conclude that the star had C/Fe ≈ 0.8 during its earlier evolutionary stages. Apart from the enhanced C and N abundances, ET0097 shows no peculiarities in other elements lighter than Zn, and no enhancement of the heavier neutron-capture elements (Ba, La, Ce, Nd, Sm, Eu, Dy), making this a CEMP-no star. However, the star does show signs of the weak r-process, with an overabundance of the lighter neutron-capture elements (Sr, Y, Zr). To explain the abundance pattern observed in ET0097, we explore the possibility that this star was enriched by primordial stars. In addition to the detailed abundances for ET0097, we present estimates and upper limits for C abundances in 85 other stars in Sculptor derived from CN molecular lines, including 11 stars with Fe/H ≤ −2. Combining these limits with observations from the literature, the fraction of CEMP-no stars in Sculptor seems to be significantly lower than in the Galactic halo.
Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual ...variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity.
We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL).
We discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 41% patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3–4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5–5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis that occurs in sepsis, including HIF1α and mTOR, and mediators of endotoxin tolerance, T-cell activation, and viral defence.
Our integrated genomics approach advances understanding of heterogeneity in sepsis by defining subgroups of patients with different immune response states and prognoses, as well as revealing the role of underlying genetic variation. Our findings provide new insights into the pathogenesis of sepsis and create opportunities for a precision medicine approach to enable targeted therapeutic intervention to improve sepsis outcomes.
European Commission, Medical Research Council (UK), and the Wellcome Trust.
Intracellular pathogens contribute to a significant proportion of infectious disease morbidity and mortality worldwide. Increasing evidence points to a major role for host genetics in explaining ...inter-individual variation in susceptibility to infectious diseases. A number of monogenic disorders predisposing to infectious disease have been reported, including susceptibility to intracellular pathogens in association with mutations in genes of the interleukin-12/interleukin-23/interferon-γ axis. Common genetic variants have also been demonstrated to regulate susceptibility to intracellular infection, for example the CCR5Δ32 polymorphism that modulates human immunodeficiency virus-1 (HIV-1) disease progression. Genome-wide association study approaches are being increasingly utilized to define genetic variants underlying susceptibility to major infectious diseases. This review focuses on the current state-of-the-art in genetics and genomics as pertains to understanding the genetic contribution to human susceptibility to infectious diseases caused by intracellular pathogens such as tuberculosis, leprosy, HIV-1, hepatitis, and malaria, with a particular emphasis on insights from recent genome-wide approaches. The results from these studies implicate common genetic variants in novel molecular pathways involved in human immunity to specific pathogens.
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