Etude de l'induction de stress cellulaire par les nouveaux signaux de communication issus de la téléphonie mobile sur la peau et le système nerveux central

Le téléphone mobile est actuellement le moyen de communication le plus courant et il émet des ondes électromagnétiques radiofréquences (RF). Lors d’une communication, l’absorption de l'énergie RF dans les tissus se fait au niveau de la peau et des tissus cérébraux. Elle diminue en fonction de la distance par rapport au téléphone. Notre travail porte sur l'évaluation déffets biologiques des RF de la téléphonie mobile sur la peau, organe représentant la première barrière de protection de l’organisme et sur le cerveau absorbant chacun environ 25% de l'énergie émise par un téléphone. Nous avons cherché à caractériser une réponse de stress cellulaire au niveau de la peau et du cerveau après exposition aux RF de type GSM-900, GSM-1800 et UMTS. Nous avons utilisé des modèles cellulaires et animaux de la peau (kératinocytes et fibroblastes primaires humains, épidermes reconstruits (ER), rats Hairless) et du cerveau (lignées humaines SH-SY5Y et CHME-5, rats Sprague-Dawley). Le stress cellulaire a été caractérisé par la recherche de léxpression de certaines protéines de choc thermique HSP (Hsc70, Hsp25 ou Hsp27 et Hsp70), de lésions de l’ADN, de surprolifération et d’apoptose cellulaires. Différents temps et niveaux déxposition ont été étudiés. Nos travaux ne montrent aucun effet du GSM-1800 et de l'UMTS sur les modèles de peau et de cerveau. Les seuls effets détectés sont une diminution d’Hsc70 dans les fibroblastes et une augmentation d’Hsp70 dans les ER après exposition au GSM-900. En l'absence déffets sur les autres paramètres cellulaires et chez l'animal, ces données suggèrent une adaptation cellulaire non délétère.Mobile telephony is currently the most common way of wireless communication. It uses Radiofrequency Fields (RFR). During a mobile phone call, absorption of RFR energy occurs in skin and cerebral tissues. It decreases according to the distance with regard to the phone. This PhD work dealt with investigations of biologic effects of various mobile phone RFR signals on the skin and brain. Each organ absorbs approximately 25 % of the total energy emitted by a phone. We investigated the cellular stress response after exposure to GSM-900, GSM-1800 and UMTS signals. We used cellular and animal models for the skin (primary human keratinocytes and fibroblasts, reconstructed epidermis ER, Hairless rats) and for the brain (human cell lines SH-SY5Y and CHME- 5, and Sprague-Dawley rats). Cellular stress was characterized by heat shock proteins (HSPs) expression (Hsc70, Hsp25 or Hsp27 and Hsp70), and DNA damage, cellular over-proliferation and apoptosis. Various exposure durations and levels (up to 13 W/kg) were used. There was no effect of GSM-1800 and UMTS exposure on the skin and brain models. The only effects reported were a decreased expression of Hsc70 in fibroblasts and an increased expression of Hsp70 in ER after exposure to GSM-900. As no other effects on cellular biological parameters and on animals were detected, these data suggest cell adaptation without deleterious effects

Antioxidant peroxiredoxin 6 protein rescues toxicity due to oxidative stress and cellular hypoxia in vitro, and attenuates prion-related pathology in vivo

Protein misfolding, mitochondrial dysfunction and oxidative stress are common pathomechanisms that underlie neurodegenerative diseases. In prion disease, central to these processes is the post-translational transformation of cellular prion protein (PrPc) to the aberrant conformationally altered isoform; PrPSc. This can trigger oxidative reactions and impair mitochondrial function by increasing levels of peroxynitrite, causing damage through formation of hydroxyl radicals or via nitration of tyrosine residues on proteins. The 6 member Peroxiredoxin (Prdx) family of redox proteins are thought to be critical protectors against oxidative stress via reduction of H2O2, hydroperoxides and peroxynitrite. In our in vitro studies cellular metabolism of SK-N-SH human neuroblastoma cells was significantly decreased in the presence of H2O2 (oxidative stressor) or CoCl2 (cellular hypoxia), but was rescued by treatment with exogenous Prdx6, suggesting that its protective action is in part mediated through a direct action. We also show that CoCl2-induced apoptosis was significantly decreased by treatment with exogenous Prdx6. We proposed a redox regulator role for Prdx6 in regulating and maintaining cellular homeostasis via its ability to control ROS levels that could otherwise accelerate the emergence of prion-related neuropathology. To confirm this, we established prion disease in mice with and without astrocyte-specific antioxidant protein Prdx6, and demonstrated that expression of Prdx6 protein in Prdx6 Tg ME7-animals reduced severity of the behavioural deficit, decreased neuropathology and increased survival time compared to Prdx6 KO ME7-animals. We conclude that antioxidant Prdx6 attenuates prion-related neuropathology, and propose that augmentation of endogenous Prdx6 protein represents an attractive adjunct therapeutic approach for neurodegenerative diseases

Impact and compression after impact experimental study of a composite laminate with a cork thermal shield

The aim of this paper is to present an experimental study of impact and compression after impact (CAI) tests performed on composite laminate covered with a cork thermal shield (TS) intended for launchers fairing. Drop weight impact tests have been performed on composite laminate sheets with and without TS in order to study its effect on the impact damage. The results show the TS is a good mechanical protection towards impact as well as a good impact revealing material. Nevertheless, totally different damage morphology is obtained during the impact test with or without TS, and in particular at high impact energy, the delaminated area is larger with TS. Afterwards, CAI tests have been performed in order to evaluate the TS effect on the residual strength. The TS appears to increase the residual strength for a same impact energy, but at the same time, it presents a decrease in residual strength before observing delamination. In fact, during the impact tests with TS, invisible fibres’ breakages appear before delamination damage contrary to the impacts on the unshielded sheets

Enamel susceptibility to red wine staining after 35% hydrogen peroxide bleaching

Concern has been expressed regarding the staining of enamel surface by different beverages after bleaching. This study investigated the influence of 35% hydrogen peroxide bleaching agents on enamel surface stained with wine after whitening treatments. Flat and polished bovine enamel surfaces were submitted to two commercially available 35% hydrogen peroxide bleaching agents or kept in 100% humidity, as a control group (n = 10). Specimens of all groups were immersed in red wine for 48 h at 37°C, immediately, 24 h or 1 week after treatments. All specimens were ground into powder and prepared for the spectrophotometric analysis. Data were subjected to two-way analysis of variance and Fisher's PLSD test at 5% significance level. The amount of wine pigments uptake by enamel submitted to bleaching treatments was statistically higher than that of control group, independently of the evaluation time. Results suggested that wine staining susceptibility was increased by bleaching treatments

A study on the inclusion of forest canopy morphology data in numerical simulations for the purpose of wind resource assessment

A series of numerical simulations of the flow over a forest stand have been conducted using two different turbulence closure models along with various levels of canopy morphology data. Simulations have been validated against Stereoscopic Particle Image Velocimetry measurements from a wind tunnel study using one hundred architectural model trees, the porosities of which have been assessed using a photographic technique. It has been found that an accurate assessment of the porosity of the canopy, and specifically the variability with height, improves simulation quality regardless of the turbulence closure model used or the level of canopy geometry included. The observed flow field and recovery of the wake is in line with characteristic canopy flows published in the literature and it was found that the shear stress transport turbulence model was best able to capture this detail numerically

Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice

Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer’s disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced brain Aβ deposition. In contrast, APOE ε2 allele carries show reduced AD risk, later age of disease onset, and lesser Aβ accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Aβ pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APP(SW)/PS1(dE9)/APOE ε2-TR (APP/E2) and APP(SW)/PS1(dE9)/APOE ε4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ε2 or ε4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Aβ interaction on Aβ deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Aβ pathology with APP/E4 mice showing a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Aβ12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Aβ sequence, which competitively blocks the apoE/Aβ interaction. In both lines, the treatment significantly reduced brain Aβ accumulation, co-accumulation of apoE within Aβ plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Aβ deposition and future therapies targeting the apoE/Aβ interaction could produce favorable outcome in APOE ε2 and ε4 allele carriers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-014-0075-0) contains supplementary material, which is available to authorized users

APOE genotype differentially modulates effects of anti-Aβ, passive immunization in APP transgenic mice

BACKGROUND: APOE genotype is the foremost genetic factor modulating β-amyloid (Aβ) deposition and risk of sporadic Alzheimer’s disease (AD). Here we investigated how APOE genotype influences response to anti-Aβ immunotherapy. METHODS: APP(SW)/PS1(dE9) (APP) transgenic mice with targeted replacement of the murine Apoe gene for human APOE alleles received 10D5 anti-Aβ or TY11-15 isotype control antibodies between the ages of 12 and 15 months. RESULTS: Anti-Aβ immunization decreased both the load of fibrillar plaques and the load of Aβ immunopositive plaques in mice of all APOE backgrounds. Although the relative reduction in parenchymal Aβ plaque load was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute Aβ plaque load values, given their highest baseline. The immunization stimulated phagocytic activation of microglia, which magnitude adjusted for the post-treatment plaque load was the greatest in APP/ε4 mice implying association between the ε4 allele and impaired Aβ phagocytosis. Perivascular hemosiderin deposits reflecting ensued microhemorrhages were associated with vascular Aβ (VAβ) and ubiquitously present in control mice of all APOE genotypes, although in APP/ε3 mice their incidence was the lowest. Anti-Aβ immunization significantly reduced VAβ burden but increased the number of hemosiderin deposits across all APOE genotypes with the strongest and the weakest effect in APP/ε2 and APP/ε3 mice, respectively. CONCLUSIONS: Our studies indicate that APOE genotype differentially modulates microglia activation and Aβ plaque load reduction during anti-Aβ immunotherapy. The APOE ε3 allele shows strong protective effect against immunotherapy associated microhemorrhages; while, conversely, the APOE ε2 allele increases risk thereof. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0156-1) contains supplementary material, which is available to authorized users

Injury activates transient olfactory stem cell states with diverse lineage capacities

Tissue homeostasis and regeneration are mediated by programs of adult stem cell renewal and differentiation. However, the mechanisms that regulate stem cell fates under such widely varying conditions are not fully understood. Using single-cell techniques, we assessed the transcriptional changes associated with stem cell self-renewal and differentiation and followed the maturation of stem cell-derived clones using sparse lineage tracing in the regenerating mouse olfactory epithelium. Following injury, quiescent olfactory stem cells rapidly shift to activated, transient states unique to regeneration and tailored to meet the demands of injury-induced repair, including barrier formation and proliferation. Multiple cell fates, including renewed stem cells and committed differentiating progenitors, are specified during this early window of activation. We further show that Sox2 is essential for cells to transition from the activated to neuronal progenitor states. Our study highlights strategies for stem cell-mediated regeneration that may be conserved in other adult stem cell niches

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Frontotemporal Dementia-Like Disease Progression Elicited by Seeded Aggregation and Spread of FUS

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression