Macrophage metalloelastase (MMP-12) deficiency does not alter bleomycin-induced pulmonary fibrosis in mice

BACKGROUND: Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium resulting in respiratory failure. The role of remodeling mediators such as metalloproteinases (MMPs) and their inhibitors (TIMPs) in the fibrogenic process remains misunderstood. In particular, macrophage metalloelastase, also identified as MMP-12, is known to be involved in remodeling processes under pathological conditions. However, MMP-12 involvement in pulmonary fibrosis is unknown. Here we investigated fibrotic response to bleomycin in MMP-12 deficient mice. MATERIALS AND METHODS: C57BL/6 mice, Balb/c mice and MMP-12 -/- mice with a C57BL/6 background received 0.3 mg bleomycin by intranasal administration. 14 days after, mice were anesthetized and underwent either bronchoalveolear lavage (BAL) or lung removal. Collagen deposition in lung tissue was determined by Sircol™ collagen assay, MMP activity in BAL fluid was analyzed by zymography, and other mediators were quantified in BAL fluid by ELISA. Real time PCR was performed to assess gene expression in lung removed one or 14 days after bleomycin administration. Student t test or Mann & Whitney tests were used when appropriate for statistical analysis. RESULTS: The development of pulmonary fibrosis in "fibrosis prone" (C57BL/6) mice was associated with prominent MMP-12 expression in lung, whereas MMP-12 expression was weak in lung tissue of "fibrosis resistant" (Balb/c) mice. MMP-12 mRNA was not detected in MMP-12 -/- mice, in conformity with their genotype. Bleomycin elicited macrophage accumulation in BAL of MMP-12 -/- and wild type (WT) mice, and MMP-12 deficiency had no significant effect on BAL cells composition. Collagen content of lung was increased similarly in MMP-12 -/- and WT mice 14 days after bleomycin administration. Bleomycin elicit a raise of TGF-β protein, MMP-2 and TIMP-1 protein and mRNA in BAL fluids and lung respectively, and no significant difference was observed between MMP-12 -/- and WT mice considering those parameters. CONCLUSION: The present study shows that MMP-12 deficiency has no significant effect on bleomycin-induced fibrosis

The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis

BACKGROUND: Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs) and their inhibitors (TIMPs), are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47(phox )-/- (KO) mice, deficient for ROS production through the NADPH-oxidase pathway. METHODS: Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL) or lung removal. RESULTS: BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47(phox )-/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid) was strikingly greater in KO than wild-type (WT) mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. CONCLUSIONS: These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis

The Io UV footprint: Location, inter-spot distances and tail vertical extent

The Io footprint (IFP) consists of one or several spots observed in both jovian hemispheres and is related to the electromagnetic interaction between Io and the magnetosphere. These spots are followed by an auroral curtain, called the tail, extending more than 90° longitude in the direction of planetary rotation. We use recent Hubble Space Telescope images of Jupiter to analyze the location of the footprint spots and tail as a function of Io's location in the jovian magnetic field. We present here a new IFP reference contour---the locus of all possible IFP positions---with an unprecedented accuracy, especially in previously poorly covered sectors. We also demonstrate that the lead angle - the longitudinal shift between Io and the actual IFP position - is not a reliable quantity for validation of the interaction models. Instead, the evolution of the inter-spot distances appears to be a better diagnosis of the Io-Jupiter interaction. Moreover, we present observations of the tail vertical profiles as seen above the limb. The emission peak altitude is ~900 km and remains relatively constant with the distance from the main spot. The altitudinal extent of the vertical emission profiles is not compatible with precipitation of a mono-energetic electron population. The best fit is obtained for a kappa distribution with a characteristic energy of ~70 eV and a spectral index of 2.3. The broadness of the inferred electron energy spectrum gives insight into the physics of the electron acceleration mechanism at play above the IFP tail

Rapport de sondages et d'analyses, Le Kilian et les carrières anciennes de trachyte dans la Chaîne des Puys (Puy-de-Dôme)

En 2008, l'existence de carrières souterraines médiévales avait été mise en évidence dans la pente ouest du Bois de Manson qui domine la dépression du Cratère Kilian, au pied sud du puy de Dôme. En 2009-2010, des sondages et prospections ont été étendus à tout l'ensemble du Kilian de façon à préciser l'étendue et, si possible, la chronologie de son exploitation dans le passé. Ces travaux ont permis d'observer, dans le fond du cratère et sur son flanc interne ouest, des amoncellements de déblais d'un volume considérable, témoignant d'une extraction de roche à grande échelle durant le haut Moyen Âge et très probablement aussi à l'époque gallo-romaine. Une nouvelle carrière souterraine a été découverte dans la pente interne ouest du cratère. La base du remplissage de cette carrière a livré des charbons datés entre la fin du IV e siècle et le début du VI e siècle par le radiocarbone, tandis que le sommet du remplissage contenait des tessons de céramique datables, par leur typologie, de la fin du V e siècle au début du VIII e siècle. L'état actuel des investigations conduit à faire l'hypothèse que les gallo-romains ont exploité, au fond du cratère, un trachyte compact dont on ne trouve aujourd'hui que les déchets de taille, et dont les affleurements sont masqués par les déblais, tandis que les artisans du Moyen Âge ont recherché un trachyte plus tendre dans les pentes hautes du cratère. Le Kilian doit donc s'ajouter aux trois sources actuellement connues de trachyte d'oeuvre dans le passé, à savoir les volcans Sarcoui, Aumône (ou petit Suchet) et Cliersou. Dès cette découverte, en 2008, s'est posée la question de savoir quelle part éventuelle le trachyte du Kilian avait pu prendre dans la construction du temple de Mercure au sommet du puy de Dôme et dans l'agglomération gallo-romaine située au col de Ceyssat. Pour y répondre, une campagne d'analyses géochimiques et pétrographiques été engagée pour caractériser, aux fins de comparaison, non seulement les trachytes du Kilian et ceux des ruines gallo-romaines, mais, de plus, les trachytes du Cliersou, de l'Aumône et du Sarcoui. Ces analyses ont finalement montré qu'il est possible de faire une discrimination statistiquement significative entre les différents trachytes étudiés, à l'exception de ceux du couple Cliersou-Aumône dont les laves sont très peu différentes les unes des autres. Le résultat le plus remarquable est que tous les trachytes gallo-romains échantillonnés (dont 10 échantillons distincts au temple de Mercure et 10 au col de Ceyssat) se rattachent sans ambiguïté au Kilian. En toute rigueur, ces nouvelles données ne permettent pas d'exclure sans appel la possibilité d'utilisation à l'époque gallo-romaine, au temple de Mercure et au col de Ceyssat, de trachytes provenant d'autres sources que le Kilian (cas des chaperons de mur du col de Ceyssat, provenant du puy de Dôme). Cependant, il faut ajouter qu'un examen visuel des trachytes d'oeuvre dans ces deux sites, portant sur un nombre de moellons et d'éléments architecturaux bien supérieur au nombre de ceux qui ont été analysés, conduit à conclure que leur source est probablement commune. Cette conclusion est basée sur un faciès minéralogique particulier, observable à l'oeil nu ou à la loupe

The complex behavior of the satellite footprints at Jupiter: the result of universal processes?

At Jupiter, some auroral emissions are directly related to the electromagnetic interaction between the moons Io, Europa and Ganymede on one hand and the rapidly rotating magnetospheric plasma on the other hand. Out of the three, the Io footprint is the brightest and the most studied. Present in each hemisphere, it is made of at least three different spots and an extended trailing tail. The variability of the brightness of the spots as well as their relative location has been tentatively explained with a combination of Alfvén waves’ partial reflections on density gradients and bi-directional electron acceleration at high latitude. Should this scenario be correct, then the other footprints should also show the same behavior. Here we show that all footprints are, at least occasionally, made of several spots and they all display a tail. We also show that these spots share many characteristics with those of the Io footprint (i.e. some significant variability on timescales of 2-3 minutes). Additionally, we present some Monte-Carlo simulations indicating that the tails are also due to Alfvén waves electron acceleration rather than quasi-static electron acceleration. Even if some details still need clarification, these observations strengthen the scenario proposed for the Io footprint and thus indicate that these processes are universal. In addition, we will present some early results from Juno-UVS concerning the location and morphology of the footprints during the first low-altitude observations of the polar aurorae. These observations, carried out in previously unexplored longitude ranges, should either confirm or contradict our understanding of the footprints

Possible Transient Luminous Events observed in Jupiter's upper atmosphere

11 transient bright flashes were detected in Jupiter's atmosphere using the UVS instrument on the Juno spacecraft. These bright flashes are only observed in a single spin of the spacecraft and their brightness decays exponentially with time, with a duration of ~1.4 ms. The spectra are dominated by H2 Lyman band emission and based on the level of atmospheric absorption, we estimate a source altitude of 260 km above the 1-bar level. Based on these characteristics, we suggest that these are observations of Transient Luminous Events (TLEs) in Jupiter's upper atmosphere. In particular, we suggest that these are elves, sprites or sprite halos, three types of TLEs that occur in the Earth's upper atmosphere in response to tropospheric lightning strikes. This is supported by visible light imaging, which shows cloud features typical of lightning source regions at the locations of several of the bright flashes. TLEs have previously only been observed on Earth, although theoretical and experimental work has predicted that they should also be present on Jupiter.Comment: Accepted in JGR: Planets. 28 pages, 8 figure

Repurposing Metformin in Nondiabetic People With HIV:Influence on Weight and Gut Microbiota

Background. People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio. Methods. In the Lilac pilot trial, we recruited 23 nondiabetic PWI I receiving ART for more than 2 years with a low CD4/CD8 ratio ( Results. Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. Conclusions. Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH

Appointing Women to Boards: Is There a Cultural Bias?

Companies that are serious about corporate governance and business ethics are turning their attention to gender diversity at the most senior levels of business (Institute of Business Ethics, Business Ethics Briefing 21:1, 2011). Board gender diversity has been the subject of several studies carried out by international organizations such as Catalyst (Increasing gender diversity on boards: Current index of formal approaches, 2012), the World Economic Forum (Hausmann et al., The global gender gap report, 2010), and the European Board Diversity Analysis (Is it getting easier to find women on European boards? 2010). They all lead to reports confirming the overall relatively low proportion of women on boards and the slow pace at which more women are being appointed. Furthermore, the proportion of women on corporate boards varies much across countries. Based on institutional theory, this study hypothesizes and tests whether this variation can be attributed to differences in cultural settings across countries. Our analysis of the representation of women on boards for 32 countries during 2010 reveals that two cultural characteristics are indeed associated with the observed differences. We use the cultural dimensions proposed by Hofstede (Culture’s consequences: International differences in work-related values, 1980) to measure this construct. Results show that countries which have the greatest tolerance for inequalities in the distribution of power and those that tend to value the role of men generally exhibit lower representations of women on boards

The Io, Europa and Ganymede auroral footprints at Jupiter in the ultraviolet: positions and equatorial lead angles

Jupiter's satellite auroral footprints are a consequence of the interaction between the Jovian magnetic field with co-rotating iogenic plasma and the Galilean moons. The disturbances created near the moons propagate as Alfv\'en waves along the magnetic field lines. The position of the moons is therefore "Alfv\'enically" connected to their respective auroral footprint. The angular separation from the instantaneous magnetic footprint can be estimated by the so-called lead angle. That lead angle varies periodically as a function of orbital longitude, since the time for the Alfv\'en waves to reach the Jovian ionosphere varies accordingly. Using spectral images of the Main Alfv\'en Wing auroral spots collected by Juno-UVS during the first forty-three orbits, this work provides the first empirical model of the Io, Europa and Ganymede equatorial lead angles for the northern and southern hemispheres. Alfv\'en travel times between the three innermost Galilean moons to Jupiter's northern and southern hemispheres are estimated from the lead angle measurements. We also demonstrate the accuracy of the mapping from the Juno magnetic field reference model (JRM33) at the completion of the prime mission for M-shells extending to at least 15RJ . Finally, we shows how the added knowledge of the lead angle can improve the interpretation of the moon-induced decametric emissions.Comment: 20 pages, 8 figures, Accepted for publication in Journal of Geophysical Research: Space Physics on 20 April 202