Flagellin concentrations in expectorations from cystic fibrosis patients.

International audienceBACKGROUND: The aim was to measure flagellin concentrations in the expectorations of CF patients and to examine whether there are correlations with the level of respiratory insufficiency and inflammation. METHODS: Sputum samples from 31 adult patients chronically colonized with P. aeruginosa were collected and analysed for their content of flagellin and IL-8. Clinical data were extracted from patient files. RESULTS: Regardless of whether patients are colonized with mucoid strains or not, they carry clones of P. aeruginosa that express flagellin. While flagellin was present in airways of all of our CF patients, it is difficult to ascertain its contribution to inflammation (IL-8) and lung function deterioration. CONCLUSIONS: This is the first demonstration that flagellin is present in the sputum of patients. Thus, attempts to down regulate inflammation by the use of TLR5 (flagellin receptor) antagonists remain a possibility. However, this result needs to be extended to a larger number of patients to validate it for future research on this subject

USING HYDROGEOPHYSICS & XRF TO PRODUCE A HIGH-RESOLUTION 3-DIMENSIONAL SOIL CADMIUM MAP FOR EVALUATING HYBRID WHEAT TRIALS

Cadmium (Cd) accumulation in wheat decreases germination, growth, grain yield, and in higher concentration leads to adverse effects on human health (Liu et al, 2018). Due to wheat cultivars variation in Cd accumulation, wheat breeders aim to select those at low Cd concentration lines in a field. Hence the need to quantify the concentration of Cd at different parts of a field and visually represent on a high resolution Cd distribution map. Various ways to quantify the concentration of soil Cd exist. However, the cost of equipment required make the process quite expensive and labor intensive. This work studied the feasibility of predicting the concentration of Cd and other soil chemical elements based on readily available environmental covariates collected at the site. These are electrical conductivity in shallow and deep zones (ECaS, ECaD), total gamma counts and elevation. Soil samples were collected from Havelock farm, analyzed in the lab and then results were used to train and test different statistical models to predict the occurrence of chemical elements in the soil. Showed statistical correlation between Geo-covariates and some soil element data (i.e. Zn & Fe) providing proof-of-concept for technique and warranting further investigation • At Havelock Cd was below level of detection • Adding VNIR to Geo-covariates improves prediction accuracy in nonlinear statistical model

Determination of the pressure in micrometric bubbles in irradiated nuclear fuels

In oxide nuclear fuels, at high burn-up or during high temperature periods such as ramp tests, out-of- pile heating tests, or any irradiations at high linear heat rates, fission gases can form micrometric or quasi-micrometric bubbles. During nominal operations, these bubbles participate to the pellet swelling, to the decrease of the fuel thermal conductivity and are involved in the mechanisms leading to fission gas release. During events involving a temperature increase, the resulting increase in the internal pres- sure of the bubbles might play a role in fuel fragmentation and in the opening of grain boundaries. The gas densities inside these bubbles are therefore one of the useful experimental information for the un- derstanding of the fuel behaviour, and for the fuel behaviour code progress and validation. Two methods were developed to evaluate the gas density in the quasi-micrometric bubbles, using electron probe micro analyser, secondary ion mass spectrometry and focused ion beam scanning electron microscope together. The first method provides a mean gas density for all quasi-micrometric bubbles in a given area. The sec- ond method provides a gas density in a single selected bubble. In addition to the gas density, the 3D size and shape of the selected bubble is measured and can be related to the gas density result. In this work, these methods were applied to the bubbles formed in the centre of a PWR Cr doped UO 2 at 38.8 GWd/t U after a ramp test in the Osiris reactor, with a 12 h plateau at 470 W/cm, and to the bubbles formed in a PWR Cr doped UO 2 at 62.8 GWd/t U in the centre of the pellet and on the bubbles of the high burn-up structure on the rim. Both show the high pressures reached in these bubbles.CEA-DES, EDF and Framatom

Complete Ascertainment of Intragenic Copy Number Mutations (CNMs) in the CFTR Gene and its Implications for CNM Formation at Other Autosomal Loci

Over the last 20 years since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than 1,600 different putatively pathological CFTR mutations have been identified. Until now, however, copy number mutations (CNMs) involving the CFTR gene have not been methodically analyzed, resulting almost certainly in the under-ascertainment of CFTR gene duplications compared with deletions. Here, high-resolution array comparative genomic hybridization (averaging one interrogating probe every 95 bp) was used to analyze the entire length of the CFTR gene (189 kb) in 233 cystic fibrosis chromosomes lacking conventional mutations. We succeeded in identifying five duplication CNMs that would otherwise have been refractory to analysis. Based upon findings from this and other studies, we propose that deletion and duplication CNMs in the human autosomal genome are likely to be generated in the proportion of approximately 2-3:1. We further postulate that intragenic gene duplication CNMs in other disease loci may have been routinely underascertained. Finally, our analysis of +/-20 bp flanking each of the 40 CFTR breakpoints characterized at the DNA sequence level provide support for the emerging concept that non-B DNA conformations in combination with specific sequence motifs predispose to both recurring and nonrecurring genomic rearrangements. Hum Mutat 31:421-428, 2010. (C) 2010 Wiley-Liss, Inc

Synaptic Maturation at Cortical Projections to the Lateral Amygdala in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a neuro-developmental disorder caused by loss of function of Mecp2 - methyl-CpG-binding protein 2 - an epigenetic factor controlling DNA transcription. In mice, removal of Mecp2 in the forebrain recapitulates most of behavioral deficits found in global Mecp2 deficient mice, including amygdala-related hyper-anxiety and lack of social interaction, pointing a role of Mecp2 in emotional learning. Yet very little is known about the establishment and maintenance of synaptic function in the adult amygdala and the role of Mecp2 in these processes. Here, we performed a longitudinal examination of synaptic properties at excitatory projections to principal cells of the lateral nucleus of the amygdala (LA) in Mecp2 mutant mice and their wild-type littermates. We first show that during animal life, Cortico-LA projections switch from a tonic to a phasic mode, whereas Thalamo-LA synapses are phasic at all ages. In parallel, we observed a specific elimination of Cortico-LA synapses and a decrease in their ability of generating presynaptic long term potentiation. In absence of Mecp2, both synaptic maturation and synaptic elimination were exaggerated albeit still specific to cortical projections. Surprisingly, associative LTP was unaffected at Mecp2 deficient synapses suggesting that synaptic maintenance rather than activity-dependent synaptic learning may be causal in RTT physiopathology. Finally, because the timing of synaptic evolution was preserved, we propose that some of the developmental effects of Mecp2 may be exerted within an endogenous program and restricted to synapses which maturate during animal life

Effect of seasonal malaria chemoprevention plus azithromycin on Plasmodium falciparum transmission: gametocyte infectivity and mosquito fitness.

BACKGROUND: Seasonal malaria chemoprevention (SMC) consists of administration of sulfadoxine-pyrimethamine (SP) + amodiaquine (AQ) at monthly intervals to children during the malaria transmission period. Whether the addition of azithromycin (AZ) to SMC could potentiate the benefit of the intervention was tested through a double-blind, randomized, placebo-controlled trial. The effect of SMC and the addition of AZ, on malaria transmission and on the life history traits of Anopheles gambiae mosquitoes have been investigated. METHODS: The study included 438 children randomly selected from among participants in the SMC + AZ trial and 198 children from the same area who did not receive chemoprevention. For each participant in the SMC + AZ trial, blood was collected 14 to 21 days post treatment, examined for the presence of malaria sexual and asexual stages and provided as a blood meal to An. gambiae females using a direct membrane-feeding assay. RESULTS: The SMC treatment, with or without AZ, significantly reduced the prevalence of asexual Plasmodium falciparum (LRT X22 = 69, P < 0.0001) and the gametocyte prevalence (LRT X22 = 54, P < 0.0001). In addition, the proportion of infectious feeds (LRT X22 = 61, P < 0.0001) and the prevalence of oocysts among exposed mosquitoes (LRT X22 = 22.8, P < 0.001) was reduced when mosquitoes were fed on blood from treated children compared to untreated controls. The addition of AZ to SPAQ was associated with an increased proportion of infectious feeds (LRT X21 = 5.2, P = 0.02), suggesting a significant effect of AZ on gametocyte infectivity. There was a slight negative effect of SPAQ and SPAQ + AZ on mosquito survival compared to mosquitoes fed with blood from control children (LRTX22 = 330, P < 0.0001). CONCLUSION: This study demonstrates that SMC may contribute to a reduction in human to mosquito transmission of P. falciparum, and the reduced mosquito longevity observed for females fed on treated blood may increase the benefit of this intervention in control of malaria. The addition of AZ to SPAQ in SMC appeared to enhance the infectivity of gametocytes providing further evidence that this combination is not an appropriate intervention

Virtualia 2016. La réalité virtuelle au service de la recherche: Actes du séminaire organisé par le CIREVE à Caen (19 octobre 2016),

International audienceLe séminaire Virtualia est né en 2006 en même temps que le Centre Interdisciplinaire de Réalité Virtuelle (CIREVE) de l’Université de Caen Normandie. Son objectif est de permettre aux équipes associées au CIREVE d’exposer leurs méthodologies et les résultats de leurs travaux dans le domaine de la Réalité Virtuelle, tout en s’ouvrant à des communications extérieures. Il a connu quatre éditions de 2006 à 2009.2016 fut l’occasion de relancer VIRTUALIA et de concrétiser le partenariat avec les Universités de Rouen et du Havre dans le cadre de la COMUE. Une Structure Fédérative de Recherche « CIREVE » est en effet en cours de labellisation au sein de Normandie Université. 2016 est également une année importante car elle marque à la fois le dixième anniversaire du CIREVE et la finalisation d’une plate-forme de réalité virtuelle normande, unique en son genre sur le territoire français. Elle est composée d’une salle immersive quatre faces de 45 m2, équipée d’un tapis roulant particulièrement adapté pour l’analyse de la marche en temps réel (GRAIL de Motek Medical). Les calculateurs de cette salle immersive sont mutualisés avec un amphithéâtre attenant de 150 places, de manière que les expérimentations effectuées avec un sujet unique dans la salle immersive puissent être suivies par un auditoire nombreux (besoins de formation notamment). Les équipes utilisent le matériel au fur et à mesure des développements informatiques et de nouveaux protocoles d’expérimentation germent dans l’esprit des chercheurs qui voient dans la réalité virtuelle des possibilités de tests jamais atteintes.Une centaine de chercheurs utilise régulièrement le plateau technique CIREVE, dans des visées de recherche qui leur sont propres. Il est toutefois apparu qu’un certain nombre de problématiques concernaient toutes les disciplines et qu’une partie de la réflexion sur les mondes virtuels pouvait être mutualisée. Le séminaire VIRTUALIA permet d’offrir un espace de rencontre à ces chercheurs, issus d’horizons différents, pour discuter de l’utilisation de l’outil d’un point de vue épistémologique. Il est par exemple capital de s’interroger sur la notion de présence. Le sujet se comporte-il de la même façon dans l’environnement virtuel et dans le monde réel ? Les chemins de circulation choisis dans le modèle virtuel sont-ils les mêmes que ceux qui seraient empruntés en réalité ? Les conclusions établies dans le modèle virtuel sont-elles directement transposables à la réalité ? Un des enjeux du travail est d’évaluer la pertinence subjective des modèles virtuels, ce qui est capital avant de généraliser leur utilisation dans des actions de formation par exemple. L’utilisation d’une technologie n’est jamais complètement neutre. Dans le cadre des mondes virtuels, l’interaction de l’homme avec le monde de synthèse n’est possible qu’au travers de logiciels et d’interfaces matérielles. Il faut s’assurer que les processus cognitifs soient adéquats avant de s’interroger sur le résultat des simulations. Naturellement, le séminaire permet également à chaque discipline d’exposer les résultats des dernières recherches réalisées grâce à la réalité virtuelle.Les domaines scientifiques concernés par la réalité virtuelle sont multiples : les civilisations et les patrimoines culturels, la médecine, les neurosciences, la psychologie, les sciences du mouvement et du sport, l’ingénierie, l’informatique. L’Université de Caen Normandie étant pluridisciplinaire, le spectre des utilisations est très large. Elles se répartissent en trois axes principaux et un axe en émergence :LA REPRÉSENTATION : la réalité virtuelle permet de représenter et de visualiser, interactivement et en trois dimensions, des environnements disparus, dégradés, inaccessibles, ou des environnements futurs.Domaines concernés : civilisations, patrimoine, linguistique...L'EXPÉRIMENTATION : en permettant d'interagir en temps réel avec un monde numérique 3D, la réalité virtuelle offre de nouvelles perspectives d'expérimentations dans des environnements de plus en plus proches du réel et en même temps parfaitement contrôlables.Domaines concernés : santé, neuropsychologie, psychologie, activités physiques et sportives...LA CREATION ET LE DEVELOPPEMENT D’OUTILS : les informaticiens créent et testent des applications concernant les méthodes de navigation en monde virtuel, de restitution de la réalité.Domaine concerné : informatique.LA FORMATION (axe en émergence) : par la représentation de la connaissance, par les diverses possibilités d'expérimentation, la réalité virtuelle est un formidable outil de formation.Domaines concernés : sciences du langage, médecine, informatique (serious game, simulation...).Une partie importante de la réflexion développée lors du séminaire Virtualia 2016 a été consacrée aux enjeux sociétaux liés à la réalité virtuelle : notions de mémoire, d’apprentissage des gestes techniques, d’être humain « augmenté » etc. Les articles publiés attestent du savoir-faire, bien réel cette fois, que le CIREVE a acquis en termes de création de mondes virtuels pour représenter, expérimenter et former. La publication des actes du séminaire Virtualia vise à mettre en lumière des recherches particulièrement innovantes qui s’effectuent dans un cadre technologique exceptionnel.- S. Madeleine, Virtualia 2016. Introduction (et direction de l'édition)- J. Grieu, F. Lecroq, Th. Galinho, H. Boukachour, Environnements industriels virtualisés et processus d’apprentissage- Ph. Brunet, J. Dehut, Images 3D et humanités numériques : modélisation et restitution du geste théâtral- G. Lecouvey, J. Gonneaud, N. Legrand, G. Rauchs, F. Eustache, B. Desgranges, Réalité virtuelle et mémoire- N. Benguigui, C. Mandil, M. Mallek, L. Lejeune, R. Thouvarecq, Étude des liens entre perception et action dans des environnements virtuels- E.-G. Dupuy, A. Maneuvrier, E. Vlamynck, S. Besnard, B. Bienvenu, L.-M. Decker, Le syndrome d’Ehlers-Danlos type hypermobile : évolution des stratégies posturales en réponse à un programme de rééducation à visée somesthésique- C. Weismann-Arcache, Réalité virtuelle et humain augmenté : subjectivation, désubjectivation ?- L. Haddouk, Réalité psychique en visioconsultatio

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called episignatures ). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands