Diet-Related Metabolites Associated with Cognitive Decline Revealed by Untargeted Metabolomics in a Prospective Cohort

Scope: Untargeted metabolomics may reveal preventive targets in cognitive aging, including within the food metabolome. Methods and results: A case-control study nested in the prospective Three-City study includes participants aged &65 years and initially free of dementia. A total of 209 cases of cognitive decline and 209 controls (matched for age, gen- der, education) with slower cognitive decline over up to 12 years are contrasted. Using untargeted metabolomics and bootstrap-enhanced penalized regression, a baseline serum signature of 22 metabolites associated with subsequent cognitive decline is identified. The signature includes three coffee metabolites, a biomarker of citrus intake, a cocoa metabolite, two metabolites putatively derived from fish and wine, three medium-chain acylcarnitines, glycodeoxycholic acid, lysoPC(18:3), trimethyllysine, glucose, cortisol, creatinine, and arginine. Adding the 22 metabolites to a reference predictive model for cognitive decline (conditioned on age, gender, education and including ApoE-ε4, diabetes, BMI, and number of medications) substantially increases the predictive performance: cross-validated Area Under the Receiver Operating Curve = 75% [95% CI 70-80%] compared to 62% [95% CI 56-67%]. Conclusions: The untargeted metabolomics study supports a protective role of specific foods (e.g., coffee, cocoa, fish) and various alterations in the endogenous metabolism responsive to diet in cognitive aging

Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

Transgenic SOD1 mice as a model for developing amyotrophic lateral sclerosis therapies

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a loss of motor neurons in the brain (brainstem and cortex) and the spinal cord that leads to a motor neurological symptomatology. Approximately 10% of ALS cases have a familial form of ALS. Among the familial cases, 20% are caused by dominantly inherited mutations (around 100 different mutations) in the protein Cu/Zn superoxide dismutase (SOD1). To date, genetic ALS models on mutated SOD1 (SOD1G93A, SOD1G85R and SOD1G37R) transgenesis in rodents have been successful in recapitulating the main features of the human pathology, especially the loss of spinal or facial motoneurons, the increased astrogliosis, the activation of microglia and the cellular and molecular disruptions in motoneurons. The therapies toward a treatment or cure for ALS have been met with limited success. In the present study, SOD1G93A transgenic mice have been used to test new gene therapies to slow disease progression and pharmacological approach to obtain a better comprehension of the pathological process, more precisely, to define the involvement of microglial activation in the spread of the disease. For the approach by gene therapy, injection of viral vectors in a localized region of central nervous system (CNS) constitutes an excellent tool for the development of new therapies. In the present study, the viral-mediated expression of potential neuroprotective factors was explored in the lumbar spinal cord or facial nucleus of SOD1G93A transgenic mice. As HIV-1-derived lentiviral vectors can efficiently transduce neurons in CNS, these retroviral vectors were used to over-express the neurotrophic factor GDNF (glial cell line-derived neurotrophic factor) to supply a trophic support to lumbar and facial motoneurons, or RNAi molecules specifically targeting the SOD1G93A gene to inhibit the mutant SOD1 expression, the cause of the disease, in the lumbar spinal cord of SOD1G93A transgenic mice. For the study of the level of microglial involvement in the pathology, SOD1G93A transgenic mice had a daily pharmacological treatment with an inhibitor of microglial activation, the minocycline. The present thesis demonstrates that, on the one hand, at the difference of laboratories that delayed the disease progression by intramuscular injection of adenoviral vectors or adenoassociated vectors encoding for GDNF, the intraspinal injection of lentivirus encoding for GDNF did not lead to a protection of lumbar motoneurons and a delay of the disease. But this study showed a significantly rescue of facial motoneurons by the injection of lentivirus encoding for GDNF directly in facial nucleus. A selective vulnerability between motoneurons in facial nucleus and these in lumbar spinal cord has been therefore underlined. On the other hand, we showed that the therapeutic approach to inhibit the mutant SOD1 expression look as the most effective to delay the progression of the ALS pathology. Both studies of gene therapy, compared to others studies using the same therapeutic factors, demonstrated clearly that to optimize a therapeutic treatment, it seems better to act at muscular junction level with a retrograde transport form muscle to motoneuronal bodies of the therapeutic molecule or viral vector. Nevertheless, motoneuron-restricted silencing of mutant SOD1 would be useful for better understanding of neuronal and glial cellular mechanism mediating ALS-linked mutated SOD1 toxicity. Regarding the involvement of microglia in the pathological process, the inhibition of microglial activation by the minocycline treatment, suggests, on the one hand, that microglial activation do not initiate the pathological process and that this microgliosis might be a consequence and triggered by multiple disruptions. On the other hand, that minocycline could protect completely facial motoneurons and partially spinal motoneurons by its anti-apoptotic property. Therapeutic approaches aiming to act directly on the cause of the disease as well as a better comprehension of the role of non-neuronal cells in the pathological process may therefore open new perspectives for the treatment of ALS pathology

DERMATOLOGIE DU LAPIN DE COMPAGNIE

Le lapin, nouvel animal de compagnie (NAC), est de plus en plus représenté en consultation. De nombreuses variétés existent notamment les lapins nains. Après avoir rappelé les particularités anatomiques et biologiques du lapin domestique, les modalités de son examen clinique sont exposées. Puis l'étude se limite à la présentation des affections cutanées, motifs fréquents de consultation, avec, successivement, une approche sémiologique et étiologique. L'accent est porté sur les dermatoses parasitaires et bactériennes fréquemment observées en clinique et pour lesquelles le praticien dispose d'un arsenal thérapeutique plus vaste. Les molécules contre-indiqués sont citées et quelques protocoles de traitements sont proposés.MAISONS-ALFORT-Ecole Vétérin (940462302) / SudocSudocFranceF

Les dossiers de pensions des troupes coloniales et indigènes. La sous-série GR 13 Yf

En avril 2011, le Service historique de la Défense (SHD) a débuté le classement des dossiers de pensions des troupes coloniales et des troupes indigènes pour la période 1850-1950. 14 000 premiers dossiers ont été inventoriés, sur un total de 24 000, l’objectif étant d’achevé le classement pour le centenaire de la Grande Guerre. L’opération comporte également une phase importante de reconditionnement permettant une communication immédiate et idéale aux lecteurs au gré des mises à jour régulièr..

Effect of hemp on cement hydration: experimental characterization of the Interfacial Transition Zone

Hempcrete is low carbon footprint building material, which consists in a mix of a cement and/or lime binder and vegetal particles (shiv). Its high porosity and low density give it good insulation, hygrothermal and acoustic properties. On the other hand, the mechanical strength of hempcrete is very poor, which limited its used like a filling material in a load bearing structure. Its limits mechanical properties are due, among other things, to an Interfacial Transition Zone (ITZ) around the shiv, which is not hydrated like the rest of the matrix. The identification of the size and the characteristics of this ITZ is a key parameter to improve the mechanical properties of these kind of bio-based material. A new experimental test protocol, based on image analysis, was developed to achieve repetitive and robust visual observations of the formation of the ITZ. The high-water absorption and the leaching of shiv are the main parameters, which drive the shape and strength of the ITZ. A microstructural characterization was also conducted to understand the nature and origin of this less hydrated zone around the hemp. This experimental protocol will allow to determine the mix parameters that impact ITZ development and select the most appropriate binder/vegetal fiber couple to use

Influence of density and release properties of UCx_x targets on the fission product yields at ALTO

International audienceTo study the influence of the structural properties of UC$_x$ targets on their release properties, several types of targets using different precursors (carbon and uranium) were synthesized, characterized, irradiated and heated leading to the determination of the released fractions of eight elements. In this article, the production rates of these targets are estimated under the use conditions at ALTO, i.e. with targets bombarded by an electron beam (10 μA, 50 MeV). We have simulated the fission number produced using the FLUKA code. Then, we have determined the release efficiency as a function of the half-life of the isotopes using average diffusion coefficients deduced for the elements studied previously. Finally, we compare the production rates obtained from the various targets and conclude that the target must be adapted to the element studied. It is crucial to find in each case the best compromise between the target density and the release efficiency

Development of radioactive beams at ALTO: Part 1. Physicochemical comparison of different types of UCx_x targets using a multivariate statistical approach

International audienceThe optimization of the microstructure of the UCx target is a key point since many years in the field of ISOL method. The ultimate goal is to facilitate the release of the fission products, especially those with short half-lives. Fourteen UCx samples were synthetized from different uranium and carbon sources using three mixing protocols. All carburized samples were systematically characterized in terms of nature and proportion phases, grain and aggregate size, open and close porosity proportion and open pore size distribution. Our results were analysed using a multivariate statistical approach in order to remove any subjective bias. Strong correlations between the physicochemical characteristics of the samples as well as the impact of the synthesis process have been highlighted. In particular, using carbon nanotubes as carbon source combined with a new method of mixing is the key parameter to limit the sintering and to obtain samples with small grains and a high porosity well distributed over small pores. Moreover the microstructure obtained proved to be stable at high temperature