APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.This research was supported by grants from Alzheimer’s Research UK and the Wellcome Trust (to F.J.L.) and core funding to the Gurdon Trust from the Wellcome Trust and Cancer Research UK. N.S. was supported by a Woolf-Fisher Trust (NZ) PhD studentship. H.Z. was supported by the Wolfson Centre at UCL, and the UCLH Dementia BRU provided financial support for the collection of patient materials. F.J.L. is a Wellcome Trust Senior Investigator, K.B. is a Torsten So¨ derberg Academy Professor, and H.Z. is a Wallenberg Academy Fellow.This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S2211124715003599

Nose-only inhalations of high-dose alumina nanoparticles/hydrogen chloride gas mixtures induce strong pulmonary pro-inflammatory response: a pilot study

Objective Solid composite propellants combustion, in aerospace and defense fields, can lead to complex aerosols emission containing high concentrations of alumina nanoparticles (Al2O3 NPs) and hydrogen chloride gas (HClg). Exposure to these mixtures by inhalation is thus possible but literature data toward their pulmonary toxicity are missing. To specify hazards resulting from these combustion aerosols, a pilot study was implemented. Materials and methods Male Wistar rats were nose-only exposed to Al2O3 NPs (primary size 13 nm, 10 g/L suspension leading to 20.0–22.1 mg/m3 aerosol) and/or to HClg aerosols (5 ppm target concentration) following two exposure scenarios (single exposures (SE) or repeated exposures (RE)). Bronchoalveolar lavage fluids (BALF) content and lungs histopathology were analyzed 24 h after exposures. Results Repeated co-exposures increased total proteins and LDH concentrations in BALF indicating alveolar–capillary barrier permeabilization and cytolysis. Early pulmonary inflammation was induced after RE to Al2O3 NPs ± HClg resulting in PMN, TNF-α, IL-1β, and GRO/KC increases in BALF. Both exposure scenarios resulted in pulmonary histopathological lesions (vascular congestions, bronchial pre-exfoliations, vascular and interalveolar septum edemas). Lung oxidative damages were observed in situ following SE. Conclusion Observed biological effects are dependent on both aerosol content and exposure scenario. Results showed an important pro-inflammatory effect of Al2O3 NPs/HClg mixtures on the lungs of rat 24 h after exposure. This pilot study raises concerns toward potential long-term pulmonary toxicity of combustion aerosols and highlights the importance for further studies to be led in order to define dose limitations and exposure thresholds for risk management at the work place

First Report of Phytophthora ramorum on Ornamental Plants in France

In April 2002, Phytophthora ramorum was associated with twig blight and brown spots on Rhododendron spp. leaves from a nursery in France. The isolate was identified by its morphological characters on V8 agar: slow growth, deciduous and semipapillate sporangia, and abundant production of large chlamydospores (3). The identification was confirmed by ITS rDNA sequencing. During 2002, P. ramorum was also isolated from diseased Viburnum tinus and V. × bodnantense plants exhibiting symptoms of wilting and stem base discoloration. Subsequently, repeated surveys for P. ramorum were carried out in nurseries and areas surrounding nurseries throughout France

The Major Cicatricial Pemphigoid Antigen Is a 180-kD Protein that Shows Immunologic Cross-Reactivities with the Bullous Pemphigoid Antigen

Recent studies have shown that sera from patients with cicatricial pemphigoid (CP) contained autoantibodies against epidermal antigens of molecular weight 230 kD and/or 180 kD by immunoblotting, similar to those recognized by bullous pemphigoid (BP) sera. Previous immunoprecipitation studies have shown that BP sera only precipitated the 230-kD antigen. To characterize the CP antigen(s) we tested 10 CP sera, 10BP sera, and four controls by both immunoprecipitation of radiolabeled cells and immunoblotting of epidermal extracts. For immunoprecipitation, we used 0.5% NP-40 extracts of both normal human keratinocytes and Pam cells. All CP sera precipitated a 180-kD protein that co-migrated with the BP180 antigen precipitated by some individual BP sera. Two of these CP sera also faintly bound a 230-kD protein of similar molecular weight as the major BP230 antigen. CP and BP sera with an immunoblotting pattern of 180 kD immunoprecipitated a co-migrating 180-kD protein. CP sera reacting by immunoblotting with the 230-kD antigen precipitated the 180-kD and/or the 230-kD antigen. In contrast, BP sera reacting with the 230-kD antigen only precipitated this antigen. In further experiments, labeled 0.5% NP-40 extracts from Pam cells were first preabsorbed with a reference BP serum and then immunoprecipitated with CP sera. Under these conditions, CP sera that immunoprecipitated both 180-kD and 230-kD proteins with the standard procedure no longer precipitated these proteins. Our results suggest that a 180-kD protein is the major CP target-antigen that demonstrated immunologic cross-reactivities with the BP180 and the BP230 antigens

Determination of glyphosate and AMPA in indoor settled dust by hydrophilic interaction liquid chromatography with tandem mass spectrometry and implications for human exposure

In Press, Journal Pre-proofInternational audienceThe widespread application of glyphosate leads to significant contamination of outdoor environmental compartments, notably air and soil, which can contaminate indoor air and dust. This study assessed the contamination of indoor household dust for the first time in France and potential exposure to glyphosate through the inadvertent ingestion of dust. A specific and new analytical method was developed using HILIC MS/MS (hydrophilic interaction liquid chromatography with tandem mass spectrometry) to measure polar pesticides, such as glyphosate, aminomethylphosphonic acid, and glufosinate, in indoor dust, with a low quantification limit (25 ng/g). The dust from vacuum cleaner bags of 60 rural and urban households (Brittany, France) was analyzed. All samples contained glyphosate (median 1,675 ng/g for rural dwellings (n = 29), 457 ng/g for urban dwellings (n = 31)), more than 90% contained aminomethylphosphonic acid, and none contained glufosinate. Concentrations were influenced by the rural or urban setting, the proximity of crops, and the use of weed killers on driveways or lawns. Glyphosate exposure via indoor dust ingestion was < 1% of both acceptable daily intake and dietary intake. However, the high quantification limit of the glyphosate concentration in the food analysis method probably leads to overestimation of the dose from food

Lipid Droplet Proteins in Acne Skin: A Sound Target for the Maintenance of Low Comedogenic Sebum and Acne-Prone Skin Health

In adipocytes and sebocytes, lipid droplet proteins control the storage of lipids in organized droplets and their release on demand. The contribution of lipid droplet proteins to the pathogenesis of acne is plausible because they control the levels of comedogenic free fatty acids. The expression of two lipid droplet proteins, CIDEA and PLIN2, was analyzed in the skin of patients with acne by immunohistochemistry and western blotting. The design of clinical protocols allowed correlating the expression of CIDEA and PLIN2 with both comedogenesis and the release of free fatty acids. Both proteins were detected by immunohistochemistry in the sebaceous glands of patients with acne, with a disturbed expression pattern of PLIN2 compared with that in the controls. Higher levels of PLIN2 and CIDEA, as detected by western blotting in the infundibulum, significantly correlated with lower ongoing comedogenesis over 48 weeks of Silybum marianum fruit extract application. Accordingly, free fatty acid release from sebum triglycerides was significantly decreased, as shown with two distinct methods. The data are consistent with the expected role of PLIN2 and CIDEA in the prevention of comedogenic free fatty acid release. Modulation of PLIN2 and CIDEA expression appears as a sound target for the maintenance of low comedogenic sebum and acne-prone skin health

APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons

Design, Synthesis and SAR in 2,4,7-Trisubstituted Pyrido[3,2-d]Pyrimidine Series as Novel PI3K/mTOR Inhibitors

International audienceThis work describes the synthesis, enzymatic activities on PI3K and mTOR, in silico docking and cellular activities of various uncommon 2,4,7 trisubstituted pyrido[3,2-d]pyrimidines. The series synthesized offers a chemical diversity in C-7 whereas C-2 (3-hydroxyphenyl) and C-4 groups (morpholine) remain unchanged, in order to provide a better understanding of the molecular determinants of PI3K selectivity or dual activity on PI3K and mTOR. Some C-7 substituents were shown to improve the efficiency on kinases compared to the 2,4-di-substituted pyrimidopyrimidine derivatives used as references. Six novel derivatives possess IC50 values on PI3Kα between 3 and 10 nM. The compounds with the best efficiencies on PI3K and mTOR induced micromolar cytotoxicity on cancer cell lines possessing an overactivated PI3K pathway

Expertise en vue de la fixation de valeurs limites d’exposition à des agents chimiques en milieu professionnel - Évaluation des effets sur la santé et des méthodes de mesure des niveaux d’exposition sur le lieu de travail pour le protoxyde d’azote (CAS n°10024-97-2)

Les VLEP telles que recommandées par le CES sont des niveaux de concentration en polluants dans l’atmosphère des lieux de travail à ne pas dépasser sur une période de référence déterminée et en deçà desquels le risque d’altération de la santé est négligeable. Même si des modifications physiologiques réversibles sont parfois tolérées, aucune atteinte organique ou fonctionnelle de caractère irréversible ou prolongée n’est admise à ce niveau d’exposition pour la grande majorité des travailleurs. Ces niveaux de concentration sont déterminés en considérant que la population exposée (les travailleurs) est une population qui ne comprend ni enfants ni personnes âgées.Ces niveaux de concentrations sont déterminés par les experts du CES à partir des informations disponibles dans des études épidémiologiques, cliniques, de toxicologie animale, etc. L’identification de ces concentrations sécuritaires pour la santé humaine nécessite généralement d’appliquer des facteurs d’ajustement aux valeurs identifiées directement par les études. Ces facteurs permettent de prendre en compte un certain nombre d’éléments d’incertitude inhérents à la démarche d’extrapolation conduite dans le cadre d’une évaluation des effets sanitaires des substances chimiques sur l’Homme.Trois types de valeurs sont recommandées par le CES :- valeur limite d’exposition 8 heures (VLEP-8h) : il s’agit de la limite de la moyenne pondérée en fonction du temps de la concentration atmosphérique d’un agent chimique dans la zone de respiration d’un travailleur au cours d’un poste de 8 heures. Dans l’état actuel des connaissances scientifiques (en toxicologie, médecine, épidémiologie, etc.), la VLEP-8h est censée protéger d’effets sur la santé à moyen et long termes, les travailleurs exposés régulièrement et pendant la durée d’une vie de travail à l’agent chimique considéré ;- valeur limite d’exposition à court terme (VLCT-15min) : il s’agit de la limite de la moyenne pondérée en fonction du temps de la concentration atmosphérique d’un agent chimique dans la zone de respiration d’un travailleur sur une période de référence de 15 minutes pendant le pic d’exposition quelle que soit sa durée. Elle vise à protéger les travailleurs des effets néfastes sur la santé (effets toxiques immédiats ou à court terme, tels que des phénomènes d’irritation), dus à des pics d’exposition ;- valeur plafond : il s’agit de la limite de la concentration atmosphérique d’un agent chimique dans la zone de respiration d’un travailleur, qui ne doit être dépassée à aucun moment de la période de travail. Cette valeur est appliquée aux substances reconnues comme irritant fort ou corrosif ou pouvant causer un effet grave potentiellement irréversible, à très court terme.Ces trois types de valeurs sont exprimés :- soit en mg.m-3, c'est-à-dire en milligrammes d’agent chimique par mètre cube d’air et en ppm (parties par million), c'est-à-dire en centimètres cube d’agent chimique par mètre cube d’air, pour les gaz et les vapeurs ;- soit en mg.m-3 uniquement, pour les aérosols liquides et solides ; soit en f.cm-3, c'est-à-dire en fibres par cm3 pour les matériaux fibreux.La valeur de la VLEP-8h peut être dépassée sur de courtes périodes pendant la journée de travail à condition toutefois :- que la moyenne pondérée des valeurs sur l’ensemble de la journée de travail ne soit pas dépassée ;- de ne pas dépasser la valeur de la VLCT si elle existe.En plus des VLEP, le CES évalue la nécessité d’attribuer ou non une mention « peau », lorsqu’une pénétration cutanée significative a été identifiée (Anses,à paraître). Cette mention indique la nécessité de prendre en compte la voie d’exposition cutanée dans l’évaluation de l’exposition et, le cas échéant, de mettre en œuvre des mesures de prévention appropriées (telles que le port de gants de protection). En effet, la pénétration cutanée des substances n’est pas prise en compte pour la détermination des niveaux de valeurs limites atmosphériques et peut donc potentiellement entraîner des effets sanitaires indépendamment du respect de ces dernières.Le CES évalue également la nécessité d’attribuer ou non une mention « bruit » signalant un risque d’atteinte auditive en cas de co-exposition au bruit et à la substance en dessous des limites d’exposition recommandées afin que les préventeurs mettent en place des mesures appropriées (collectives, individuelles et médicales).Le CES évalue également les méthodes de référence applicables pour la mesure des niveaux d’exposition sur le lieu de travail. La qualité de ces méthodes et leur applicabilité à la mesure des expositions aux fins de comparaison à une VLEP ont été évaluées notamment sur leur conformité aux exigences de performance de la NF EN 482 et de leur niveau de validation

Development of genomic resources for <em>Medicago truncatula</em> and related legume crops

National audienc