ACID SPHINGOMYELINASE AS A NEW PHARMACOLOGICAL TARGET IN THE ACUTE AND CHRONIC MUSCLE DAMAGE: AN ALTERNATIVE STRATEGY FOR MUSCULAR DYSTROPHIES THERAPY

Skeletal muscle inflammation plays a critical role in bridging early muscle injury responses and timely muscle injury recovery (Yang and Hu, 2018). In this study, we investigated the functional role of the sphingolipid-metabolizing enzyme Acid Sphingomyelinase (A-SMase) in the pathophysiology of acute and chronic muscle damage in order to elucidate its role in the establishment of inflammation and in the subsequent muscle regeneration process so that this protein may be proposed as possible therapeutic target. A-SMase is a critical mediator of cell signaling since it is able to generate ceramide from the membrane lipid sphingomyelin thus modulating membrane fluidity, which is determinant in triggering many cellular processes. Several recent studies report the strong relation between high levels of A-SMase expression and inflammatory-associated disorders (Schissel et al., 1998; Devlin et al., 2008; Garcia-Ruiz et al., 2015). In this study, we found that A-SMase expression increases upon induced-acute muscle damage suggesting its involvement in skeletal muscle inflammation. We also demonstrated the importance of A-SMase in regulating the muscle regeneration process following acute muscle damage. Our results showed that A-SMase deficiency leads to an increase of muscle satellite cells, essential for skeletal muscle regeneration, soon after injury, accompanied by a higher number of regenerating myofibers within the injured site. Moreover, two important muscle transcription factors, MyoD and Myogenin, responsible for a correct regeneration were much higher in the absence of A-SMase suggesting that muscle regeneration is accelerated without the hydrolase. In addition, IGF-1, a potent enhancer of tissue regeneration, showed much higher expression levels in absence of A-SMase, consistently with our finding that A-SMase deficiency accelerates the regeneration process. Furthermore, we provide the first evidence of a novel role of A-SMase in regulating macrophage subsets during muscle regeneration demonstrating that A-SMase is able to regulate the polarization of macrophages towards an inflammatory M1 phenotype since its absence leads to an impairment in the expression of M1 macrophage markers. Noteworthy, investigating the role of A-SMase in mdx mice, a mouse model of Duchenne Muscular Dystrophy (DMD), we found an up-regulation of A-SMase in expression and activity in muscles of these mice, that implies its involvement in the pathogenesis of DMD with a particular effect on inflammation. Several studies demonstrated a predominant role of inflammation in the pathogenesis of DMD (Villalta et al., 2009; Radley et al., 2008). Of notice, we observed that the increase of A- SMase in mdx mice paralleled with the increase of muscle inflammatory state. This finding has been further corroborated by the use of the anti-inflammatory drug Naproxcinod that reduced inflammation in mdx muscle and at the same time significantly decreased A-SMase expression and activity. Altogether, our findings open new vistas in the identification of a new potential pharmacological target, A-SMase, in the development and regulation of skeletal muscle inflammation and regeneration process by raising the possibility that the modulation of A-SMase expression levels could bring therapeutic benefits not only in DMD pathology but also in various muscle-wasting diseases

Perturbative expansions from Monte Carlo simulations at weak coupling: Wilson loops and the static-quark self-energy

Perturbative coefficients for Wilson loops and the static-quark self-energy are extracted from Monte Carlo simulations at weak coupling. The lattice volumes and couplings are chosen to ensure that the lattice momenta are all perturbative. Twisted boundary conditions are used to eliminate the effects of lattice zero modes and to suppress nonperturbative finite-volume effects due to Z(3) phases. Simulations of the Wilson gluon action are done with both periodic and twisted boundary conditions, and over a wide range of lattice volumes (from $3^4$ to $16^4$) and couplings (from $\beta \approx 9$ to $\beta \approx 60$). A high precision comparison is made between the simulation data and results from finite-volume lattice perturbation theory. The Monte Carlo results are shown to be in excellent agreement with perturbation theory through second order. New results for third-order coefficients for a number of Wilson loops and the static-quark self-energy are reported.Comment: 36 pages, 15 figures, REVTEX documen

GREENET - An Early Stage Training Network in Enabling Technologies for Green Radio

International audienceIn this paper, we describe GREENET (an early stage training network in enabling technologies for green radio), which is a new project recently funded by the European Commission under the auspices of the 2010 Marie Curie People Programme. Through the recruitment and personalized training of 17 Early Stage Researchers (ESRs), in GREENET we are committed to the development of new disruptive technologies to address all aspects of energy efficiency in wireless networks, from the user devices to the core network infrastructure, along with the ways the devices and equipment interact with one another. Novel techniques at the physical, link, and network layers to reduce the energy consumption and carbon footprint of 4G devices will be investigated, such as Spatial Modulation (SM) for Multiple-Input-Multiple-Output (MIMO) systems, Cooperative Automatic Repeat reQuest (C-ARQ) protocols, and Network Coding (NC) for lossy networks. Furthermore, cooperation and cognition paradigms will be exploited as additional assets to improve the energy efficiency of wireless networks with the challenging but indispensable constraint of optimizing the system capacity without degrading the user's Quality-of-Service (QoS)

Lipid-soluble Vitamins A, D, and E in HIV-Infected Pregnant women in Tanzania.

There is limited published research examining lipid-soluble vitamins in human immunodeficiency virus (HIV)-infected pregnant women, particularly in resource-limited settings. This is an observational analysis of 1078 HIV-infected pregnant women enrolled in a trial of vitamin supplementation in Tanzania. Baseline data on sociodemographic and anthropometric characteristics, clinical signs and symptoms, and laboratory parameters were used to identify correlates of low plasma vitamin A (<0.7 micromol/l), vitamin D (<80 nmol/l) and vitamin E (<9.7 micromol/l) status. Binomial regression was used to estimate risk ratios and 95% confidence intervals. Approximately 35, 39 and 51% of the women had low levels of vitamins A, D and E, respectively. Severe anemia (hemoglobin <85 g/l; P<0.01), plasma vitamin E (P=0.02), selenium (P=0.01) and vitamin D (P=0.02) concentrations were significant correlates of low vitamin A status in multivariate models. Erythrocyte Sedimentation Rate (ESR) was independently related to low vitamin A status in a nonlinear manner (P=0.01). The correlates of low vitamin D status were CD8 cell count (P=0.01), high ESR (ESR >81 mm/h; P<0.01), gestational age at enrollment (nonlinear; P=0.03) and plasma vitamins A (P=0.02) and E (P=0.01). For low vitamin E status, the correlates were money spent on food per household per day (P<0.01), plasma vitamin A concentration (nonlinear; P<0.01) and a gestational age <16 weeks at enrollment (P<0.01). Low concentrations of lipid-soluble vitamins are widely prevalent among HIV-infected women in Tanzania and are correlated with other nutritional insufficiencies. Identifying HIV-infected persons at greater risk of poor nutritional status and infections may help inform design and implementation of appropriate interventions

Development of an adverse outcome pathway for cranio-facial malformations: A contribution from in silico simulations and in vitro data

Mixtures of substances sharing the same molecular initiating event (MIE) are supposed to induce additive effects. The proposed MIE for azole fungicides is CYP26 inhibition with retinoic acid (RA) local increase, triggering key events leading to craniofacial defects. Valproic acid (VPA) is supposed to imbalance RA-regulated gene expression trough histone deacetylases (HDACs) inhibition. The aim was to evaluate effects of molecules sharing the same MIE (azoles) and of such having (hypothetically) different MIEs but which are eventually involved in the same adverse outcome pathway (AOP). An in silico approach (molecular docking) investigated the suggested MIEs. Teratogenicity was evaluated in vitro (WEC). Abnormalities were modelled by PROAST software. The common target was the branchial apparatus. In silico results confirmed azole-related CYP26 inhibition and a weak general VPA inhibition on the tested HDACs. Unexpectedly, VPA showed also a weak, but not marginal, capability to enter the CYP 26A1 and CYP 26C1 catalytic sites, suggesting a possible role of VPA in decreasing RA catabolism, acting as an additional MIE. Our findings suggest a new more complex picture. Consequently two different AOPs, leading to the same AO, can be described. VPA MIEs (HDAC and CYP26 inhibition) impinge on the two converging AOPs

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Autophagy-mediated neuroprotection induced by octreotide in an ex vivo model of early diabetic retinopathy

Neuronal injury plays a major role in diabetic retinopathy (DR). Our hypothesis was that the balance between neuronal death and survival may depend on a similar equilibrium between apoptosis and autophagy and that a neuroprotectant may act by influencing this equilibrium. Ex vivo mouse retinal explants were treated with high glucose (HG) for 10days and the somatostatin analog octreotide (OCT) was used as a neuroprotectant. Chloroquine (CQ) was used as an autophagy inhibitor. Apoptotic and autophagic markers were evaluated using western blot and immunohistochemistry. HG-treated explants displayed a significant increase of apoptosis paralleled by a significant decrease of the autophagic flux, which was likely to be due to increased activity of the autophagy regulator mTOR (mammalian target of rapamycin). Treatment with OCT rescued HG-treated retinal explants from apoptosis and determined an increase of autophagic activity with concomitant mTOR inhibition. Blocking the autophagic flux with CQ completely abolished the anti-apoptotic effect of OCT. Immunohistochemical observations showed that OCT-induced autophagy is localized to populations of bipolar and amacrine cells and to ganglion cells. These observations revealed the antithetic role of apoptosis and autophagy, highlighting their equilibrium from which neuronal survival is likely to depend. These data suggest the crucial role covered by autophagy, which could be considered as a molecular target for DR neuroprotective treatment strategies

Lacto-fermented garlic handcrafted in the Lower Silesia Region (Poland): Microbial diversity, morpho-textural traits, and volatile compounds

The aim of the present study was to provide a first characterization of lacto-fermented garlic manufactured by local small-scale artisanal producers in the Lower Silesia Region (Poland). The lacto-fermented garlic samples showed high nutritional features in terms of antioxidant activity. A total of 86 compounds, belonging to various chemical classes, were identified by headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC/MS). Most of these compounds belonged to six main classes, being sulfur compounds, esters and acetates, oxygenated monoterpenes, monoterpene hydrocarbons, and alcohols. Aldehydes, acids, ketones, furans, and phenols were also identified. In the analyzed samples, counts up to 8 log cfu g-1 were observed for lactic acid bacteria. Metataxonomic analysis revealed the presence of Levilactobacillus, Lactiplantibacillus, Latilactobacillus, Secundilactobacillus, Weissella, Leuconostoc, Lactococcus, Pediococcus, and Lacticaseibacillus among the major taxa. These results were confirmed by the isolation and characterization of viable lactic acid bacteria. Indeed, the presence of the closest relatives to Lacticaseibacillus casei group, Pediococcus parvulus, Levilactobacillus brevis, Levilactobacillus parabrevis, and Lactiplantibacillus plantarum group was observed. A good acidification performance in salty garlic-based medium was observed for all the isolates that, between 8 and 15 days of fermentation, reached pH values comprised between 4 and 3.5, depending on the tested species. Of note, 15 out of the 37 lactic acid bacteria isolates (Levilactobacillus parabrevis, Pediococcus parvulus, Lactiplantibacillus plantarum group, and Lacticaseibacillus casei group) showed the presence of the hdcA gene of Gram-positive bacteria encoding for histidine decarboxylase. Furthermore, for 8 out of the 37 isolates the in-vitro exopolysaccharides production was observed. No isolate showed inhibitory activity against the three Listeria innocua strains used as surrogate for Listeria monocytogenes