Transcriptional Effects of Glucocorticoid Receptors in the Dentate Gyrus Increase Anxiety-Related Behaviors

The Glucocorticoid Receptor (GR) is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC) hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown. To address this issue, we generated a mutated form of the GR called ΔGR. ΔGR is a constitutively transcriptionally active form of the GR that is localized in the nuclei and activates transcription without binding to glucocorticoids. Using the tetracycline-regulated system (Tet-OFF), we developed an inducible transgenic approach that allows the expression of the ΔGR in specific brain areas. We focused our study on a mouse line that expressed ΔGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG) of the hippocampus. This restricted expression of the ΔGR increased anxiety-related behaviors without affecting other behaviors that could indirectly influence performance in anxiety-related tests. This behavioral phenotype was also associated with an up-regulation of the MAPK signaling pathway and Egr-1 protein in the DG. These findings identify glutamatergic neurons in the DG as one of the cellular substrate of stress-related pathologies

La coccidiose chez les poulets domestiques : revue sur les stratégies de prévention et de contrôle

La coccidiose aviaire est l'un des défis les plus importants et les plus persistants auxquels est confrontée l'industrie avicole mondiale, entraînant une baisse de productivité due aux dommages intestinaux causés par le protozoaire apicomplexe intracellulaire Eimeria. Le cycle de vie d'Eimeria est complexe, caractérisé par des stades intra- et extracellulaires. Le stade intracellulaire induit une réponse inflammatoire en partie responsable de la formation de lésions tissulaires, des hémorragies diarrhéiques, une mauvaise croissance, une sensibilité accrue à d'autres agents pathogènes et, dans certains cas sévères (E. tenella et E. necatrix), une forte mortalité. Une bonne gestion sanitaire est indispensable pour prévenir la coccidiose chez les poulets. L'administration d'anticoccidiens dans les aliments peut également réduire efficacement l’intensité de l’infection par Eimeria. Cependant, leur utilisation à grande échelle et sur une longue durée a entraîné le développement de résistances à ces additifs dans le monde entier. Des vaccins vivants non atténués et atténués ont été développés mais ils présentent certaines limites. En plus des méthodes conventionnelles de prévention et de contrôle, les produits phytogéniques émergent comme alternative pour contrôler la coccidiose aviaire. Les recherches en cours sur la sélection génétique et des vaccins recombinants et sous-unitaires sont prometteuses pour la prévention, mais leur efficacité et leur adoption dans l'industrie avicole restent à démontrer. De plus, comme alternatives aux coccidiostatiques, des stratégies utilisant des extraits naturels sont plus acceptées par les consommateurs et sont de plus en plus étudiées. Cet article présente donc une vue d'ensemble de l'impact économique de la coccidiose chez les poulets sur la production et aborde les stratégies intégrées de la santé pour contrôler la coccidiose chez les poulets

Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration

Disease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy

Molecular epidemiology of DFNB1 deafness in France

BACKGROUND: Mutations in the GJB2 gene have been established as a major cause of inherited non syndromic deafness in different populations. A high number of sequence variations have been described in the GJB2 gene and the associated pathogenic effects are not always clearly established. The prevalence of a number of mutations is known to be population specific, and therefore population specific testing should be a prerequisite step when molecular diagnosis is offered. Moreover, population studies are needed to determine the contribution of GJB2 variants to deafness. We present our findings from the molecular diagnostic screening of the GJB2 and GJB6 genes over a three year period, together with a population-based study of GJB2 variants. METHODS AND RESULTS: Molecular studies were performed using denaturing High Performance Liquid Chromatograghy (DHPLC) and sequencing of the GJB2 gene. Over the last 3 years we have studied 159 families presenting sensorineural hearing loss, including 84 with non syndromic, stable, bilateral deafness. Thirty families were genotyped with causative mutations. In parallel, we have performed a molecular epidemiology study on more than 3000 dried blood spots and established the frequency of the GJB2 variants in our population. Finally, we have compared the prevalence of the variants in the hearing impaired population with the general population. CONCLUSION: Although a high heterogeneity of sequence variation was observed in patients and controls, the 35delG mutation remains the most common pathogenic mutation in our population. Genetic counseling is dependent on the knowledge of the pathogenicity of the mutations and remains difficult in a number of cases. By comparing the sequence variations observed in hearing impaired patients with those sequence variants observed in general population, from the same ethnic background, we show that the M34T, V37I and R127H variants can not be responsible for profound or severe deafness

Rencontres Henri-Jean Martin : vingt ans de patrimoine

Enregistrements vidéos des Rencontres Henri-Jean Martin qui se sont tenues les 8 et 9 octobre 2012 à l\u27enssib

Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia

65Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.openopenPatrizia Noris; Nicole Schlegel; Catherine Klersy; Paula G. Heller; Elisa Civaschi; Nuria Pujol-Moix; Fabrizio Fabris; Remi Favier; Paolo Gresele; Véronique Latger-Cannard; Adam Cuker; Paquita Nurden; Andreas Greinacher; Marco Cattaneo; Erica De Candia; Alessandro Pecci; Marie-Françoise Hurtaud-Roux; Ana C. Glembotsky; Eduardo Muñiz-Diaz; Maria Luigia Randi; Nathalie Trillot; Loredana Bury; Thomas Lecompte; Caterina Marconi; Anna Savoia; Carlo L. Balduini; Sophie Bayart; Anne Bauters; Schéhérazade Benabdallah-Guedira; Françoise Boehlen; Jeanne-Yvonne Borg; Roberta Bottega; James Bussel; Daniela De Rocco; Emmanuel de Maistre; Michela Faleschini; Emanuela Falcinelli; Silvia Ferrari; Alina Ferster; Tiziana Fierro; Dominique Fleury; Pierre Fontana; Chloé James; Francois Lanza; Véronique Le Cam Duchez; Giuseppe Loffredo; Pamela Magini; Dominique Martin-Coignard; Fanny Menard; Sandra Mercier; Annamaria Mezzasoma; Pietro Minuz; Ilaria Nichele; Lucia D. Notarangelo; Tommaso Pippucci; Gian Marco Podda; Catherine Pouymayou; Agnes Rigouzzo; Bruno Royer; Pierre Sie; Virginie Siguret; Catherine Trichet; Alessandra Tucci; Béatrice Saposnik; Dino VeneriPatrizia, Noris; Nicole, Schlegel; Catherine, Klersy; Paula G., Heller; Elisa, Civaschi; Nuria Pujol, Moix; Fabrizio, Fabris; Remi, Favier; Paolo, Gresele; Véronique Latger, Cannard; Adam, Cuker; Paquita, Nurden; Andreas, Greinacher; Marco, Cattaneo; Erica De, Candia; Alessandro, Pecci; Marie Françoise Hurtaud, Roux; Ana C., Glembotsky; Eduardo Muñiz, Diaz; Maria Luigia, Randi; Nathalie, Trillot; Loredana, Bury; Thomas, Lecompte; Caterina, Marconi; Savoia, Anna; Carlo L., Balduini; Sophie, Bayart; Anne, Bauters; Schéhérazade Benabdallah, Guedira; Françoise, Boehlen; Jeanne Yvonne, Borg; Bottega, Roberta; James, Bussel; DE ROCCO, Daniela; Emmanuel de, Maistre; Faleschini, Michela; Emanuela, Falcinelli; Silvia, Ferrari; Alina, Ferster; Tiziana, Fierro; Dominique, Fleury; Pierre, Fontana; Chloé, James; Francois, Lanza; Véronique Le Cam, Duchez; Giuseppe, Loffredo; Pamela, Magini; Dominique Martin, Coignard; Fanny, Menard; Sandra, Mercier; Annamaria, Mezzasoma; Pietro, Minuz; Ilaria, Nichele; Lucia D., Notarangelo; Tommaso, Pippucci; Gian Marco, Podda; Catherine, Pouymayou; Agnes, Rigouzzo; Bruno, Royer; Pierre, Sie; Virginie, Siguret; Catherine, Trichet; Alessandra, Tucci; Béatrice, Saposnik; Dino, Vener

Excessive Food Intake, Obesity and Inflammation Process in Zucker fa/fa Rat Pancreatic Islets

Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced β-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to ß-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro-inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and β-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1β, IL-6 and TNFα expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning β-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35) and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1β and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of β-cell function by IL-1β. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an inflammatory process. That the latter could contribute to β-cell hyperactivity/proliferation and possibly lead to progressive β-cell failure in these animals, deserves further investigations

Toll-Like Receptor 3 (TLR3) Plays a Major Role in the Formation of Rabies Virus Negri Bodies

Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3−/− mice—in which brain tissue was less severely infected—had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV–induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit