Integration of beta-Catenin, Sirtuin, and FOXO Signaling Protects from Mutant Huntingtin Toxicity

One of the current challenges of neurodegenerative disease research is to determine whether signaling pathways that are essential to cellular homeostasis might contribute to neuronal survival and modulate the pathogenic process in human disease. In Caenorhabditis elegans, sir-2.1/SIRT1 overexpression protects neurons from the early phases of expanded polyglutamine (polyQ) toxicity, and this protection requires the longevity-promoting factor daf-16/FOXO. Here, we show that this neuroprotective effect also requires the DAF-16/FOXO partner bar-1/beta-catenin and putative DAF-16-regulated gene ucp-4, the sole mitochondrial uncoupling protein (UCP) in nematodes. These results fit with a previously proposed mechanism in which the beta-catenin FOXO and SIRT1 proteins may together regulate gene expression and cell survival. Knockdown of beta-catenin enhanced the vulnerability to cell death of mutant-huntingtin striatal cells derived from the HdhQ111 knock-in mice. In addition, this effect was compensated by SIRT1 overexpression and accompanied by the modulation of neuronal UCP expression levels, further highlighting a cross-talk between beta-catenin and SIRT1 in the modulation of mutant polyQ cytoxicity. Taken together, these results suggest that integration of beta-catenin, sirtuin and FOXO signaling protects from the early phases of mutant huntingtin toxicity

Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma : Long-Term Results of the PRIMA Study

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high-tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m(2), once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P <.001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.Peer reviewe

Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination

Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

Modélisation systémique de la digestion dans le rumen : comparaison des modèles existants, modélisation des flux d'amidon, approche thermodynamique des fermentations

Nutritional and zootechnical responses of ruminants to diets largely depend on responses at the rumen level. The objective of this study was to bring new prospects to progress in rumen modeling, pioneered in the early seventies. To tackle this work, we decided to favor a systemic modeling approach based on various organizational levels: from organs to nutrients flows and down to mechanisms of cellular regulation. The first part of this study was devoted to compare current rumen models. Indeed, few comparative validations had been undertaken until now. The results pointed out that models share common principles but have also their own characteristics. Their main weakness was their inability to predict the end-products of fermentation (volatile fatty acids, gas, microbial matter) in a satisfactory way. We investigated two directions to progress in this area. The first one deals with the representation of starch digestion; this carbohydrate substrate explains the most variation in ruminal digestion rates of a diet. We developed a model predicting starch flows to better quantify and explain observed variation. This study was conducted from quantitative databases related to in situ and in vivo flows. Results for variation within experiments were entirely satisfactory. However, variation among experiments remained large and was difficult to explain. The second direction was based on the application of thermodynamic laws to microbial metabolism. The objective was to improve the prediction of end-products of fermentation. This original approach of fermentation includes both modeling and experimental work. Results allowed some properties resulting from thermodynamic principles to be identified and strengthened interest in the subject. This work has contributed to some progress on rumen modeling, especially on the modeling of starch flows. It also opens a promising new field of knowledge that deserves further attention.Les réponses nutritionnelles et zootechniques des ruminants aux variations de régime sont largement conditionnées par leurs effets au niveau du rumen. L'objectif de ce travail était d'apporter de nouvelles perspectives pour progresser dans la démarche de modélisation de cet organe, qui a débuté dans les années 1970. Pour l'aborder, nous avons privilégié une approche par modélisation systémique à différents niveaux organisationnels: de l'organe, aux flux de nutriments et jusqu'aux mécanismes de régulation cellulaire. La première partie du travail était consacrée à une étude comparative des modèles actuels. Peu de validations comparées des modèles avaient été entreprises jusqu'à présent. Les résultats rendent compte des principes communs appliqués mais aussi des spécificités de chacun des modèles. Leur plus grande faiblesse réside dans leur incapacité à prédire de façon satisfaisante les équilibres des produits terminaux des fermentations (acides gras volatils, gaz et matières microbiennes). Pour progresser dans ce domaine, nous avons exploré deux voies. La première concerne la représentation de la digestion de l'amidon, substrat glucidique expliquant la majeure partie des variations de la vitesse de digestibilité ruminale des rations. Nous avons développé un modèle de prédiction des flux d'amidon pour mieux quantifier et expliquer les variations observées. Cette étude a été réalisée à partir de bases de données quantitatives portant sur ces flux mesurés in sacco et in vivo. Les résultats obtenus expliquent assez précisément les variations observées intra-essai. Par contre, les variations inter-essais demeurent importantes et difficiles à apprécier. La seconde voie est basée sur l'application des lois de la thermodynamique au métabolisme microbien. L'objectif est d'améliorer la prédiction des produits terminaux des fermentations. Cette approche originale des aspects fermentaires a comporté un volet modélisation et un volet expérimental. Les résultats permettent de dégager certaines propriétés comme résultant des principes de la thermodynamique et nous confortent dans l'intérêt de cette approche. Ce travail de thèse contribue aux avancées en matière de modélisation du rumen, notamment pour la modélisation des flux d'amidon. Il propose aussi de nouveaux champs de recherche encore peu explorés

Thermodynamic modeling of ruminal fermentations

The main weakness of current rumen models is their inability to explain the end-products of fermentation (volatile fatty acids, gas, and microbial matter) in a satisfactory way. The objective of this study was to improve this prediction based on the application of thermodynamic laws to microbial metabolism. Therefore, a dynamic model of rumen fermentation was developed. In this original approach, the reactions evolved with a decrease in Gibbs energy according to thermodynamic laws. Some simulated results obtained with this model were similar to experimental observations. The predicted post-prandial evolution of the volatile fatty acid profile was satisfactory. However, simulations of some other parameters (pH, redox potential) were less reliable and further studies should be conducted to represent these better. The results allowed some properties resulting from thermodynamic principles to be identified and strengthened the importance of this subject.Modélisation thermodynamique des fermentations ruminales. La principale limite des modèles du rumen actuellement développés est leur incapacité à prédire de façon satisfaisante les produits terminaux des fermentations (acides gras volatils, gaz et biomasse microbienne). Cette étude visait à améliorer cette prédiction en se basant sur l'application des lois de la thermodynamique au métabolisme microbien. Un modèle dynamique des fermentations ruminales a ainsi été développé. Dans cette approche originale, les réactions évoluent selon les lois de la thermodynamique, avec une diminution de l'énergie de Gibbs. Certains résultats des simulations, obtenues avec le modèle, concordent bien avec des observations expérimentales. Ainsi, l'évolution post-prandiale du profil des acides gras volatils était satisfaisante. Cependant, les simulations obtenues pour d'autres paramètres (pH, potentiel d'oxydo-réduction) ont été moins pertinentes et d'autres études doivent être menées pour mieux représenter ces facteurs. Les résultats ont permis d'identifier des propriétés résultant des principes de la thermodynamique et de souligner la pertinence et l'intérêt de cette démarche

Thermodynamic modeling of ruminal fermentations

The main weakness of current rumen models is their inability to explain the end-products of fermentation (volatile fatty acids, gas, and microbial matter) in a satisfactory way. The objective of this study was to improve this prediction based on the application of thermodynamic laws to microbial metabolism. Therefore, a dynamic model of rumen fermentation was developed. In this original approach, the reactions evolved with a decrease in Gibbs energy according to thermodynamic laws. Some simulated results obtained with this model were similar to experimental observations. The predicted post-prandial evolution of the volatile fatty acid profile was satisfactory. However, simulations of some other parameters (pH, redox potential) were less reliable and further studies should be conducted to represent these better. The results allowed some properties resulting from thermodynamic principles to be identified and strengthened the importance of this subject.Modélisation thermodynamique des fermentations ruminales. La principale limite des modèles du rumen actuellement développés est leur incapacité à prédire de façon satisfaisante les produits terminaux des fermentations (acides gras volatils, gaz et biomasse microbienne). Cette étude visait à améliorer cette prédiction en se basant sur l'application des lois de la thermodynamique au métabolisme microbien. Un modèle dynamique des fermentations ruminales a ainsi été développé. Dans cette approche originale, les réactions évoluent selon les lois de la thermodynamique, avec une diminution de l'énergie de Gibbs. Certains résultats des simulations, obtenues avec le modèle, concordent bien avec des observations expérimentales. Ainsi, l'évolution post-prandiale du profil des acides gras volatils était satisfaisante. Cependant, les simulations obtenues pour d'autres paramètres (pH, potentiel d'oxydo-réduction) ont été moins pertinentes et d'autres études doivent être menées pour mieux représenter ces facteurs. Les résultats ont permis d'identifier des propriétés résultant des principes de la thermodynamique et de souligner la pertinence et l'intérêt de cette démarche

Modélisation systémique de la digestion dans le rumen (comparaison des modèles existants, modélisation des flux d'amidon, approche thermodynamique des fermentations)

PARIS-AgroParisTech Centre Paris (751052302) / SudocSudocFranceF

An Evaluation of Two Systems for the Management of the Microbiological Quality of Water in Dental Unit Waterlines: Hygowater® and IGN Calbénium®

International audienceWater in dental unit waterlines (DUWL) represents a risk for vulnerable patients if its microbiological quality is not controlled. The aim of this prospective study was to evaluate two systems for its management under real conditions: Hygowater® and IGN Calbenium®. Samples of the output water of DUWL were obtained for 5 previously contaminated units connected to Hygowater®, and 5 non-contaminated units connected to IGN Calbenium®, which was already effective for more than 1 year, as a control group. Samples were regularly collected up to 6 months after the implementation of Hygowater®, and were then cultured and analyzed. With IGN Calbenium®, except for a technical problem and a sample result in one unit at 6 months (Heterotrophic Plate Count (HPC) at 37 °C of 66 colony forming units (cfu)/mL), the results showed an absence of contamination. Hygowater® took a couple of weeks to be effective on initially contaminated DUWL (over 200 cfu/mL for all the units), then showed its efficacy for 2 months (HPC at 37 °C with a mean of 40.2 ufc/mL, and HPC at 22 °C with a mean of 0.2 ufc/mL). At 6 months, results were satisfactory for HPC at 22 °C (mean of 12 ufc/mL), but HPC at 37 °C gave non-satisfactory results for 4 of the 5 units (mean of 92.2 ufc/mL). Both systems have an effect on the microbiological quality of DUWL. IGN Calbenium® appears to be more reliable on a long-term basis