Petrography, mineralogy and geochemistry of a primitive pumice from Stromboli: implications for the deep feeding system

We describe the field relations, petrographic, mineralogical and geochemical characteristics of an exceptional “golden” pumice belonging to a tephra layer exposed on the summit area of Stromboli volcano, Italy. Pumice sample PST-9 comes from a fallout deposit older than a spatter agglutinate sequence emplaced during the twentieth century. The eruption that produced it had a size exceeding that of intermediate paroxysms but was smaller than large-scale, spatter-forming, paroxysms from the sixteenth century and 1930 A.D. Lapilli are strongly vesicular and crystal-poor, similar to other “golden” pumices. Modal proportions include 89 vol% glass, 8 vol% clinopyroxene, 1–2 vol% olivine and 1–2 vol% plagioclase. Plagioclase is represented by reacted crystals coming from the shallow resident magma and incorporated in the pumice during eruption. A total of 74 and 44 crystals of olivine and clinopyroxene, respectively, were examined and 187 and 99 electron microprobe analyses obtained. Fo in olivine ranges between 70 and 92 mol% and Fs in clinopyroxene between 3 and 13 mol%. PST-9 hosts a higher proportion of Fo-rich olivine and Fs-poor clinopyroxene than the other “golden” pumices. Groundmass glasses are basaltic (Mg# = 66–69), as are most rim glasses around olivine and clinopyroxene, and glass inclusions in clinopyroxene. They are more primitive than in the other “golden” pumices. A few rim glasses and glass inclusions are shoshonitic (Mg# = 45–50). Most glass inclusions in olivine have CaO/Al2O3 higher than the other glasses and the whole-rock. PST-9 has the highest bulk MgO, CaO, Mg# and CaO/Al2O3 and the lowest FeOt of all “golden” pumices analysed to date. Analysis of Fe-Mg partitioning between olivine, clinopyroxene and melt allows three crystallization stages to be recognized. The first involves primitive mantle-derived melts (Mg# = 74–80), the second basaltic melts represented by groundmass glasses and the third is associated with more evolved melts represented by the shoshonitic glasses. The population of crystals in “golden” pumices is heterogeneous not only because of crystal incorporation from the shallow resident magma, but also because of pre-eruptive recharge of the deep reservoir with primitive melts. Differences between PST-9 and the other “golden” pumices in terms of groundmass glass composition and distribution of olivine and clinopyroxene compositions reflect contrasted replenishment rates of the deep reservoir with primitive liquids. Gabbroic inclusions in a clinopyroxene crystal provide a direct illustration of melt wall-rock interaction and stress the variability of the deep reservoir in terms of temperature, crystallinity and phase assemblages. Deep crystallization of plagioclase should be considered as a possibility at Stromboli. PST-9 is exceptionally well representative of the early magmatic evolution of “golden” pumices

Melt inclusions track changes in chemistry and oxidation state of Etnean magmas

Mount Etna (Italy) is a stratovolcano, located near the convergent boundary between African and European plates. Since its appearance, it was characterized by continuous variability of eruptive style and magma composition, though more subtle. Currently, its volcanic activity consists of effusive and explosive eruptions marked by high gas fluxes. Olivine hosted melt inclusions (MIs), belonging to products of the last 15 ky, were analysed for their chemical composition, volatiles contents and Fe speciation, in order to interpret the chemical variability and to evaluate the oxidation state of Etnean magmas and its eventual evolution. Olivine phenocrysts were selected from the most primitive Fall Stratified (FS) eruption of picritic composition (Fo91), from the oldest Mt. Spagnolo and from more recent eruptions: 2002-2003, 2006, 2008-2009, and 2013; the MIs of some of these eruptions (Mt Spagnolo, 2008-2009 and 2013) are here investigated for the first time. The variability of the major elements contents in the MIs designates a continuous differentiation trend, marked by the decrease of MgO and CaO/Al2O3 ratio and the increase of alkalis. The volatiles content in etnean magmas is extremely variable. The highest H2O (5-6 wt.%) and CO2 (~0.5 wt.%) contents are found in FS magma entrapped at depth of 16-18 km (below crater level). S content achieves 4150 ppm in the older Mt. Spagnolo inclusions, completely H2O and CO2\u2013free. Fe3+/\u3a3Fe ratios obtained from XANES spectra for some melt inclusions, generally decrease from the most primitive and volatile-rich FS to the most evolved and degassed melts, suggesting changing in the oxidation state of etnean magmas. Petrological arguments coupled to modelling of fractional crystallization and degassing processes concur to suggest that the magmas of Mt. Spagnolo and of the recent eruptions may be produced by differentiation from the most oxidized and hydrous pristine FS magma along highly variable P-T paths, occasionally accompanied by mixing processes

The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype

We previously demonstrated inhibition of ovalbumin (OVA)-induced allergic airway hyper-responsiveness in the mouse using ES-62, a phosphorylcholine-containing glycoprotein secreted by the filarial nematode, Acanthocheilonema viteae. This inhibition correlated with ES-62-induced mast cell desensitisation, although the degree to which this reflected direct targeting of mast cells remained unclear as suppression of the Th2 phenotype of the inflammatory response, as measured by eosinophilia and IL-4 levels in the lungs, was also observed. We now show that inhibition of the lung Th2 phenotype is reflected in ex vivo analyses of draining lymph node recall cultures and accompanied by a decrease in the serum levels of total and OVA-specific IgE. Moreover, ES-62 also suppresses the lung infiltration by neutrophils that is associated with severe asthma and is generally refractory to conventional anti-inflammatory therapies, including steroids. Protection against Th2-associated airway inflammation does not reflect induction of regulatory T cell (Treg) responses (there is no increased IL-10 or Foxp3 expression) but rather a switch in polarisation towards increased T-bet expression and IFNγ production. This ES-62-driven switch in the Th1/Th2 balance is accompanied by decreased IL-17 responses, a finding in line with reports that IFNγ and IL-17 are counter-regulatory. Consistent with ES-62 mediating its effects via IFNγ-mediated suppression of pathogenic Th2/Th17 responses, we found that neutralising anti-IFNγ antibodies blocked protection against airway inflammation in terms of pro-inflammatory cell infiltration, particularly by neutrophils and lung pathology. Collectively, these studies indicate that ES-62, or more likely small molecule analogues, could have therapeutic potential in asthma, in particular for those subtypes of patients (e.g. smokers, steroid-resistant) who are refractory to current treatments

The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.

Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma

<p>Abstract</p> <p>Background</p> <p>Exposure to chlorine (Cl₂) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl₂-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury.</p> <p>Methods</p> <p>Balb/C mice were exposed to Cl₂gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl₂, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl₂exposure.</p> <p>Results</p> <p>Mice exposed to Cl₂had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl₂exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl₂-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl₂prevented lipid peroxidation in the lung. Following Cl₂exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl₂exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU.</p> <p>Conclusion</p> <p>Our data show that the anti-oxidant DMTU is effective in attenuating Cl₂induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.</p

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Upward migration of Vesuvius magma chamber over the past 20 thousand years

International audienceForecasting future eruptions of Vesuvius is an important challenge for volcanologists, as its reawakening could threaten the lives of 700,000 people living near the volcano1,2. Critical to the evaluation of hazards associated with the next eruption is the estimation of the depth of the magma reservoir, one of the main parameters controlling magma properties and eruptive style. Petrological studies have indicated that during past activity, magma chambers were at depths between 3 and 16km (refs 3– 7). Geophysical surveys have imaged some levels of seismic attenuation, the shallowest of which lies at 8–9km depth8, and these have been tentatively interpreted as levels of preferential magma accumulation. By using experimental phase equilibria, carried out on material from four main explosive events at Vesuvius, we show here that the reservoirs that fed the eruptive activity migrated from 7–8km to 3–4km depth between the AD 79 (Pompeii) and AD 472 (Pollena) events. If data from the Pomici di Base event 18.5 kyr ago9 and the 1944 Vesuvius eruption7 are included, the total upward migration of the reservoir amounts to 9–11 km. The change of preferential magma ponding levels in the upper crust can be attributed to differences in the volatile content and buoyancy of ascending magmas, as well as to changes in local stress field following either caldera formation10 or volcano spreading11. Reservoir migration, and the possible influence on feeding rates12, should be integrated into the parameters used for defining expected eruptive scenarios at Vesuvius

Mouse Protocadherin-1 gene expression is regulated by cigarette smoke exposure in vivo

Protocadherin-1 (PCDH1) is a novel susceptibility gene for airway hyperresponsiveness, first identified in families exposed to cigarette smoke and is expressed in bronchial epithelial cells. Here, we asked how mouse Pcdh1 expression is regulated in lung structural cells in vivo under physiological conditions, and in both short-term cigarette smoke exposure models characterized by airway inflammation and hyperresponsiveness and chronic cigarette smoke exposure models. Pcdh1 gene-structure was investigated by Rapid Amplification of cDNA Ends. Pcdh1 mRNA and protein expression was investigated by qRT-PCR, western blotting using isoform-specific antibodies. We observed 87% conservation of the Pcdh1 nucleotide sequence, and 96% conservation of the Pcdh1 protein sequence between men and mice. We identified a novel Pcdh1 isoform encoding only the intracellular signalling motifs. Cigarette smoke exposure for 4 consecutive days markedly reduced Pcdh1 mRNA expression in lung tissue (3 to 4-fold), while neutrophilia and airway hyperresponsiveness was induced. Moreover, Pcdh1 mRNA expression in lung tissue was reduced already 6 hours after an acute cigarette-smoke exposure in mice. Chronic exposure to cigarette smoke induced loss of Pcdh1 protein in lung tissue after 2 months, while Pcdh1 protein levels were no longer reduced after 9 months of cigarette smoke exposure. We conclude that Pcdh1 is highly homologous to human PCDH1, encodes two transmembrane proteins and one intracellular protein, and is regulated by cigarette smoke exposure in vivo

In Silico Screening Based on Predictive Algorithms as a Design Tool for Exon Skipping Oligonucleotides in Duchenne Muscular Dystrophy

The use of antisense 'splice-switching' oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2'O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R² 0.89) and 53 (R² 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of a target exon

Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia

Background Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD. Methods Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity. Results We confirm a two-phase postnatal growth pattern in WT muscle: first, increase in myonuclear number over weeks 1 to 3, then expansion of myonuclear domain. Mdx muscle growth lags behind that of WT prior to overt signs of pathology. Fibres are smaller, with fewer myonuclei and smaller myonuclear domains. Moreover, satellite cells are more readily detached from mdx than WT muscle fibres. At 3 weeks, mdx muscles enter a phase of florid myonecrosis, accompanied by concurrent regeneration of an intensity that results in complete replacement of pre-existing muscle over the succeeding 3 to 4 weeks. Both WT and mdx muscles attain maximum size by 12 to 14 weeks, mdx muscle fibres being up to 50% larger than those of WT as they become increasingly branched. Mdx muscle fibres also become hypernucleated, containing twice as many myonuclei per sarcoplasmic volume, as those of WT, the excess corresponding to the number of centrally placed myonuclei. Conclusions The best-known consequence of lack of dystrophin that is common to DMD and the mdx mouse is the conspicuous necrosis and regeneration of muscle fibres. We present protocols for measuring this in terms both of loss of muscle nuclei previously labelled with BrdU and of the intensity of myonuclear labelling with BrdU administered during the regeneration period. Both measurements can be used to assess the efficacy of putative antinecrotic agents. We also show that lack of dystrophin is associated with a number of previously unsuspected abnormalities of muscle fibre structure and function that do not appear to be directly associated with myonecrosis