The Oxidation State of Sulfur in Lunar Apatite

Lunar apatites contain hundreds to thousands of parts per million of sulfur. This is puzzling because lunar basalts are thought to form in low oxygen fugacity (f(sub O2)) conditions where sulfur can only exist in its reduced form (S2()), a substitution not previously observed in natural apatite. We present measurements of the oxidation state of S in lunar apatites and associated mesostasis glass that show that lunar apatites and glass contain dominantly S2(), whereas natural apatites from Earth are only known to contain S6+. It is likely that many terrestrial and martian igneous rocks contain apatites with mixed sulfur oxidation states. The S6(+)/S2() ratios of such apatites could be used to quantify the f(sub O2) values at which they crystallized, given information on the portioning of S6(+) and S2() between apatite and melt and on the S6(+)/S2() ratios of melts as functions of f(sub O2) and melt composition. Such a well-calibrated oxybarometer based on this the oxidation state of S in apatite would have wide application

Alpha-1 antitrypsin deficiency impairs lung antibacterial immunity in mice

Alpha-1 antitrypsin (AAT) is a major inhibitor of serine proteases in mammals. Therefore, its deficiency leads to protease-antiprotease imbalance and a risk for developing lung emphysema. Although therapy with human plasma-purified AAT attenuates AAT deficiency-related emphysema, its impact on lung antibacterial immunity is poorly defined. Here, we examined the effect of AAT therapy on lung protective immunity in AAT-deficient (KO) mice challenged with Streptococcus pneumoniae. AAT-KO mice were highly susceptible to S. pneumoniae, as determined by severe lobar pneumonia and early mortality. Mechanistically, we found that neutrophil-derived elastase (NE) degraded the opsonophagocytically important collectins, surfactant protein A (SP-A) and D (SP-D), which was accompanied by significantly impaired lung bacterial clearance in S. pneumoniae-infected AAT-KO mice. Treatment of S. pneumoniae-infected AAT-KO mice with human AAT protected SP-A and SP-D from NE-mediated degradation and corrected the pulmonary pathology observed in these mice. Likewise, treatment with Sivelestat, a specific inhibitor of NE, also protected collectins from degradation and significantly decreased bacterial loads in S. pneumoniae-infected AAT-KO mice. Our findings show that NE is responsible for the degradation of lung SP-A and SP-D in AAT-KO mice affecting lung protective immunity in AAT deficiency

Country Concepts and the Rational Actor Trap: Limitations to Strategic Management of International NGOs

Growing criticism of inefficient development aid demanded new planning instruments of donors, including international NGOs (INGOs). A reorientation from isolated project-planning towards holistic country concepts and the increasing rationality of a result-orientated planning process were seen as answer. However, whether these country concepts - newly introduced by major INGOs too - have increased the efficiency of development cooperation is open to question. Firstly, there have been counteracting external factors, like the globalization of the aid business, that demanded structural changes in the composition of INGO portfolios towards growing short-term humanitarian aid; this was hardly compatible with the requirements of medium-term country planning. Secondly, the underlying vision of rationality as a remedy for the major ills of development aid was in itself a fallacy. A major change in the methodology of planning, closely connected with a shift of emphasis in the approach to development cooperation, away from project planning and service delivery, towards supporting the socio-cultural and political environment of the recipient communities, demands a reorientation of aid management: The most urgent change needed is by donors, away from the blinkers of result-orientated planning towards participative organizational cultures of learning.Des critiques croissantes de l'aide au développement inefficace exigent de nouveaux instruments de planification des bailleurs de fonds, y compris les ONG internationales (ONGI). Une réorientation de la planification des projets isolés vers des concepts holistiques de la planification de l’aide par pays ainsi que la rationalité croissante d'un processus de planification orientée vers les résultats ont été considérés comme réponse. Toutefois, si ces concepts de pays - nouvellement introduites par les grandes OING eux aussi - ont augmenté l'efficacité de la coopération au développement est ouvert à la question. Tout d'abord, il y a eu l’impact des facteurs externes, comme la mondialisation de l'entreprise de l'aide, qui a exigé des changements structurels dans la composition des portefeuilles des OING vers la croissance de l'aide humanitaire à court terme. Cela était difficilement compatible avec les exigences de l'aménagement du territoire à moyen terme. Deuxièmement, la vision sous-jacente de la rationalité accrue de la planification, concentré sur les resultats, comme un remède pour les grands maux de l'aide au développement était en soi une erreur. Un changement majeur dans la méthodologie de la planification, étroitement liée à un changement d'orientation dans l'approche de la coopération au développement, qui n’est pas concentrer sur planification du projet et la prestation de services, mais qui soutienne l'environnement socio-culturel et politique des communautés bénéficiaires, exige une réorientation de la gestion de l’aide: Le changement le plus urgent est un changement par les donateurs eux-mêmes, qui devrait implanter des cultures de collaboration étroit avec les partenaires et la population locale

The oxidation state of sulfur in lunar apatite

Lunar apatites contain hundreds to thousands of parts per million of sulfur. This is puzzling because lunar basalts are thought to form in low oxygen fugacity (f_(O_2)) conditions where sulfur can only exist in its reduced form (S^(2–)), a substitution not previously observed in natural apatite. We present measurements of the oxidation state of S in lunar apatites and associated mesostasis glass that show that lunar apatites and glass contain dominantly S^(2–), whereas natural apatites from Earth are only known to contain S^(6+). It is likely that many terrestrial and martian igneous rocks contain apatites with mixed sulfur oxidation states. The S^(6+)/S^(2–) ratios of such apatites could be used to quantify the f_(O_2) values at which they crystallized, given information on the portioning of S^(6+) and S^(2–) between apatite and melt and on the S^(6+)/S^(2–) ratios of melts as functions of f_(O_2) and melt composition. Such a well-calibrated oxybarometer based on this the oxidation state of S in apatite would have wide application

The oxidation state of sulfur in lunar apatite

Lunar apatites contain hundreds to thousands of parts per million of sulfur. This is puzzling because lunar basalts are thought to form in low oxygen fugacity (f_(O_2)) conditions where sulfur can only exist in its reduced form (S^(2–)), a substitution not previously observed in natural apatite. We present measurements of the oxidation state of S in lunar apatites and associated mesostasis glass that show that lunar apatites and glass contain dominantly S^(2–), whereas natural apatites from Earth are only known to contain S^(6+). It is likely that many terrestrial and martian igneous rocks contain apatites with mixed sulfur oxidation states. The S^(6+)/S^(2–) ratios of such apatites could be used to quantify the f_(O_2) values at which they crystallized, given information on the portioning of S^(6+) and S^(2–) between apatite and melt and on the S^(6+)/S^(2–) ratios of melts as functions of f_(O_2) and melt composition. Such a well-calibrated oxybarometer based on this the oxidation state of S in apatite would have wide application

Adenoviral vector-mediated GM-CSF gene transfer improves anti-mycobacterial immunity in mice - role of regulatory T cells.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in differentiation, survival and activation of myeloid and non-myeloid cells with important implications for lung antibacterial immunity. Here we examined the effect of pulmonary adenoviral vector-mediated delivery of GM-CSF (AdGM-CSF) on anti-mycobacterial immunity in M. bovis BCG infected mice. Exposure of M. bovis BCG infected mice to AdGM-CSF either applied on 6h, or 6h and 7days post-infection substantially increased alveolar recruitment of iNOS and IL-12 expressing macrophages, and significantly increased accumulation of IFNγpos T cells and particularly regulatory T cells (Tregs). This was accompanied by significantly reduced mycobacterial loads in the lungs of mice. Importantly, diphtheria toxin-induced depletion of Tregs did not influence mycobacterial loads, but accentuated immunopathology in AdGM-CSF-exposed mice infected with M. bovis BCG. Together, the data demonstrate that AdGM-CSF therapy improves lung protective immunity against M. bovis BCG infection in mice independent of co-recruited Tregs, which however critically contribute to limit lung immunopathology in BCG-infected mice. These data may be relevant to the development of immunomodulatory strategies to limit immunopathology-based lung injury in tuberculosis in humans

Lung anti-pneumococcal immunity is restored in chimeric Mincle KO mice reconstituted with the hematopoietic system of WT mice.

<p>Mincle KO mice received whole body irradiation (8 Gy), followed by transplantation with bone marrow cells (10⁷ cells/mouse i.v.) from either WT mice (WT onto KO, white bars), or Mincle KO mice (KO onto KO, transplantation controls, black bars). Seven weeks later, mice were infected orotracheally with 10⁷ CFU/mouse of type 19F <i>S</i>. <i>pneumoniae</i>. (A-C) Determination of BAL fluid cellular constituents (A, alveolar macrophages; B, alveolar exudate macrophages; C, alveolar recruited neutrophils) under baseline conditions (CL), or in response to infection, as indicated. (D) Analysis of Mincle expression on the cell surface of alveolar recruited neutrophils in bronchoalveolar lavage from <i>S</i>. <i>pneumoniae</i>-infected (24 h) Mincle KO mice reconstituted with WT (solid lines) or Mincle KO bone marrow cells (dashed lines). Grey histogram, isotype-stained negative control. (E,F) Determination of CFU counts in BAL fluids (E) or lung tissue (F), as indicated. (G-K) BAL fluid levels of proinflammatory cytokines TNFα (G), KC (H), IL-1β (I), or anti-inflammatory cytokines IL1ra (J), and IL-10 (K) in WT onto KO mice, or KO onto KO mice, as indicated. The data are shown as mean ± SD of n = 5 mice (A-F) or n = 4 mice (G-K) per time point and treatment group, and are representative of two experiments (Mann-Whitney U test).</p

Characterization of glycolipid Glc-DAG purified from <i>S</i>. <i>pneumoniae</i>.

<p>(A) NFAT-GFP reporter cells (4 x 10⁴ cells/well) were incubated with live <i>S</i>. <i>pneumoniae</i> at MOI 0.2, 2, 20 and 200 for 18 h followed by determination of the percentage of GFP-expressing reporter cells by flow cytometry. (B) FcRγ or Mincle+FcRγ expressing NFAT-GFP reporter cells (4 x 10⁴ cells/well) were incubated with aqueous or C:M fraction of <i>S</i>. <i>pneumoniae</i> lysates for 18 h, followed by determination of GFP-expressing reporter cells by flow cytometry. (C) HPTLC result of HPLC fractionated C:M portion of pneumococcal lysates with putative ligand indicated by an arrow head (copper acetate stain). (D) FcRγ (white bars) or Mincle + FcRγ (black bars) NFAT-GFP reporter cell assay of HPLC fractions obtained from scratched and purified HPTLC bands of <i>S</i>. <i>pneumoniae</i> lysates shown in (C). Experiments were repeated three times with similar results. See also <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006038#ppat.1006038.s002" target="_blank">S2 Fig</a>. (E-H) Effect of TDM (E), or <i>S</i>. <i>pneumoniae</i>-derived Glc-DAG (F), or synthetic Glc-DAG (C14:0/C14:0, (G), or C18:0/C18:0, (H)) to trigger GFP reporter activation in Mincle/FcRγ (black dots), or FcRγ only (white dots) expressing NFAT-GFP reporter cells.</p

Expression of Mincle in the lungs of mice after infection with <i>S</i>. <i>pneumoniae</i>.

<p>(A) WT mice were infected with <i>S</i>. <i>pneumoniae</i> (1 x 10⁷ CFU/mouse) or were mock-infected (PBS), and lungs were harvested at the given time points and Mincle mRNA levels were analyzed. Values are shown as mean ± SD (n = 3 mice per time point and treatment group). CL (control): Mock-infection relative to untreated control, all other values in (A), relative to mock-infection. * p<0.05, relative to mock-infection. (B) Flow sorted alveolar macrophages and neutrophils purified from lung tissue of mock- versus <i>S</i>. <i>pneumoniae</i>-infected WT mice were subjected to Mincle mRNA analysis by real-time RT-PCR. Data are shown as mean ± SD (n = 4–6 mice for mock-infected and n = 5 mice for <i>S</i>. <i>pneumoniae</i>-infected mice). * p<0.05 relative to neutrophils. (C) Mincle mRNA levels in neutrophils collected by bronchoalveolar lavage from the lungs of patients with pneumococcal pneumonia, relative to peripheral blood neutrophils collected from the same patients. Data are shown as mean ± SD (n = 3 patients). * p<0.05 relative to PB neutrophils. (D-J) WT mice were left untreated (D, and CL in H-J), or were infected with <i>S</i>. <i>pneumoniae</i> (10⁶ CFU/mouse). At 0 h, 24 h, 48 h, and 72 h post-infection, expression of Mincle was analyzed on BAL AM (D (0 h), E (24 h), and H), and BAL ExMacs (F (48 h), and I), and BAL neutrophils (G (48 h), and J) (see also <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006038#ppat.1006038.s001" target="_blank">S1 Fig</a>). Note that CL in (I,J) represents Mincle expression on resident alveolar macrophages (I) and neutrophils (J) purified from lung tissue of mock-infected WT mice. Horizontal bars: median values (n = 5–8 mice). Experiments were repeated two times with similar results. ** p<0.01, *** p<0.001, relative to mock-infection ((Mann-Whitney U test). ExMacs, exudate macrophages.</p

Impact of Mincle deficiency on lung proinflammatory cytokine release and macrophage necrosis in mice infected with <i>S</i>. <i>pneumoniae</i>.

<p>WT and Mincle KO mice were mock-infected or infected with <i>S</i>. <i>pneumoniae</i> (10⁷ CFU/mouse), and at indicated time points post-infection, BAL fluid TNF-α (A), KC (B), IL-1β (C), IL-10 (D), and IL-1ra (E) cytokine levels were measured. Data are shown as mean ± SD of n = 5–8 mice per time point and treatment group (12 h, n = 4 mice). Data are representative of two independent experiments with similar results. (F) WT and Mincle KO mice were mock-infected or low-dose infected with <i>S</i>. <i>pneumoniae</i> (5 x 10⁵ CFU/mouse). At the indicated time points, the percentage of necrotic macrophages (propidium iodide^pos/annexin V^neg) in BAL fluid was determined by flow cytometry. Values are shown as mean ± SD with n = 3 (0 h values) or 8 mice (12 and 24 h values) per time point and treatment group and are representative of two experiments. *p<0.05, **p<0.01, ***p<0.001 relative to WT mice. (Mann-Whitney U test).</p