Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a ‘combination therapy’ currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration. DOI: http://dx.doi.org/10.7554/eLife.04631.00

Measurements of geopolymers conductivity as binder for encapsulation of metallic nuclear waste by impedance spectroscopy

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Influence of Activating Solution and the addition of NaF on Metakaolin-Based Geopolymer Physico-Chemical Properties

International audienceThe technology of geo-polymerisation is attracting a lot of interest due to the wide variety of potential applications. Recently emerging and alternative cementitious systems based on geo-polymers have been reported in literature. Geo-polymer materials have been proposed as new binders for safe radioactive waste containment. Moreover, their good fluidity and fire resistance make them compatible with industrial processes for embedding wastes. The purpose of this work was to investigate the physico-chemical properties of meta-kaolin-based geo-polymer which could be used as mineral binder for encapsulation of metallic nuclear wastes. To improve the knowledge of this binder, its microstructure and its interstitial solution have been characterized during hydration (up to 28 days). Interstitial solutions were extracted at different hydration time and subsequent analyses allow us to determine their chemical composition. pH measurements confirm the high alkalinity of the interstitial pore solution. The influence of the activating solution (NaOH or KOH) and the addition of NaF as corrosion inhibitor in the geo-polymer composition were also studied. The nature of different crystalline phases was identified by X-ray diffraction. Water accessible porosity for these materials was estimated around 59%. The pore size distribution was determined by mercury intrusion porosity. Alkaline cations have proved to induce changes in the pore size distribution, these ones coming from whether the activating solution or the NaF addition

Corrosion of Mg and Mg alloys in a Na-geopolymer and in its Synthetic Pore Solution

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Study of general and galvanic corrosion of Mg alloys in Na-geopolymer / NaF and its synthetic pore solution

International audienceGeopolymers are currently studied at CEA as new binders for the conditioning of Mg alloys cladding wastes, generated from the reprocessing of UNGG spent fuels (Uranium Natural Graphite Gas). This alumino-silicate matrix is activated with NaOH solution in the presence of sodium fluoride (Na-Geopolymer/NaF). Galvanic corrosion of Mg wastes may occur in the geopolymer matrix due to the contact with residual graphite materials or steel from the container. The aim of this work was to study the general corrosion of Mg alloys, and their galvanic corrosion when coupled to Steel S235JR. Corrosion rates of Mg-0.5%Zr on synthetic Na-geopolymer/NaF pore solution were obtained from impedance diagrams. The obtained values indicate a decrease of the instantaneous corrosion rates with time. Corrosion rates calculated for the galvanic coupling Mg-0.5%Zr with Steel S235JR were obtained by ZRA measurements. Higher corrosion rates are observed when Mg-0.5%Zr is coupled to Steel S235JR. XPS analysis showed Mg(OH)2, MgF2, Na- ions and silicates to be the main constituents of the surface. It was showed that the thickness and composition of the surface layer evolve with time. After 3 days the surface composition obtained for the sample under general corrosion test was similar to that obtained after galvanic corrosion. Nevertheless, after 28 days there is a decrease on the silicates composition and in the amount MgF2, which completely disappears for the general corrosion

Olfactory function in children assessed with psychophysical and electrophysiological techniques

International audienceThe olfactory information processing abilities of children undergo changes during early life. The aims of the present study were to describe these changes and to probe for their electrophysiological correlates. These aims were investigated in two experiments. In Experiment 1, responses of 146 subjects (3-12 years) were tested with psychophysical tools. Approximately 2/3 of the subjects completed the olfactory tests ("Sniffin' Sticks"). In Experiment 2, 12 additional subjects (3-10 years) were tested with electrophysiological tools. Event-related potentials (ERPs) were recorded in response to olfactory stimulation with H(2)S. Results from Experiment 1 indicated that data from the group of 3-5-year olds were very unreliable, with 44% of incomplete measures rendering the tests unsuitable for routine use with 3-5-year olds. From an age of 6 years on the results suggested that the development of olfactory function was well advanced with a significant increase found only for odor identification, but not for odor thresholds, or odor discrimination. Results from Experiment 2 indicated an increase of the P2 latency with age, although the small sample size has to be considered in the interpretation of these data. While more research is needed, these results may be interpreted such that children attach more meaning to odorous stimuli with age

Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a 'combination therapy' currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration

Relationships between asbestos exposure and pleural plaques: dose and time effects using fractional polynomials

International audienceObjective: The aim of this study was to confirm the relationship between several parameters of exposure to asbestos and pleural plaques (PP) using data from a large cohort of retired workers occupationally exposed to asbestos in France.Method: A large screening programme, including high-resolution CT (HRCT) examinations at inclusion and two other HRCT campaigns, was organised from 2003 to 2016 in four regions of France for voluntary, formerly asbestos-exposed workers. Exposure to asbestos has been evaluated by industrial hygienists based on the complete work history. The time since first exposure, the time since last exposure, Cumulative Exposure Index and maximum level of exposure to asbestos, were used in logistic regression using fractional polynomials to model the relationship with PP.Results: The study included 5392 subjects with at least one HRCT available. There was a significant non-linear effect of time since first exposure, time since last exposure and Cumulative Exposure Index to asbestos on the presence of PP. The risk of PP increased with increasing Cumulative Exposure Index to asbestos adjusted for time since first exposure, age and smoking status. Models also show that PP odds rise with increasing time since first exposure adjusted for cumulative index exposure, age and smoking status. PP odds decrease when time since last exposure increases.Conclusion: The study provides new data on the link between asbestos exposure and the presence of PP using fractional polynomials with non-linear relationships for time exposure parameters and asbestos exposure parameters