IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity

Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9–deficient mice fail to develop experimental oral antigen–induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9–mediated mast cell responses have an important role in food allergy

Functioning of the dimeric GABA(B) receptor extracellular domain revealed by glycan wedge scanning

The G-protein-coupled receptor (GPCR) activated by the neurotransmitter GABA is made up of two subunits, GABA(B1) and GABA(B2). GABA(B1) binds agonists, whereas GABA(B2) is required for trafficking GABA(B1) to the cell surface, increasing agonist affinity to GABA(B1), and activating associated G proteins. These subunits each comprise two domains, a Venus flytrap domain (VFT) and a heptahelical transmembrane domain (7TM). How agonist binding to the GABA(B1) VFT leads to GABA(B2) 7TM activation remains unknown. Here, we used a glycan wedge scanning approach to investigate how the GABA(B) VFT dimer controls receptor activity. We first identified the dimerization interface using a bioinformatics approach and then showed that introducing an N-glycan at this interface prevents the association of the two subunits and abolishes all activities of GABA(B2), including agonist activation of the G protein. We also identified a second region in the VFT where insertion of an N-glycan does not prevent dimerization, but blocks agonist activation of the receptor. These data provide new insight into the function of this prototypical GPCR and demonstrate that a change in the dimerization interface is required for receptor activation

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS)

BACKGROUND End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis

Genetic and molecular mechanisms leading to eosinophilic esophagitis

From the epidemiologic studies, to the first genome wide association study in 2010, the understanding of the molecular pathogenesis of EoE has been both inspiring and puzzling. Epidemiologic studies have highlighted the contribution of the genetic in the EoE disease by emphasizing the presence of familial type of EoE, but has also revealed the complexity of its transmission that does not follow a Mendelian inheritance. The molecular pathogenesis advances have helped in the understanding of the mechanisms underlying this esophageal inflammation but has also allow the identification of candidate genes for which single nucleotide polymorphisms (SNP) are associated with the disease. Recently, the genome wide analysis of more than half a million single nucleotide polymorphism has allowed the identification of gene variations associated with the EoE disease and has led to substantial advance in the understanding of the molecular mechanisms leading to EoE. Undeniably, EoE is a complex polygenic disease and we certainly are only at the ground level of its detailed comprehension

Mécanismes moléculaires de régulation de l'expression du peptide en feuille de trèfle 3 (TFF3) et de l'éotaxine 3 lors d'un processus inflammatoire intestinale impliquant les cytokines de types 2.

Nous étudions les mécanismes contrôlant, en situation inflammatoire l'expression de TFF3, peptide protecteur et réparateur de l'épithélium intestinal, et de l'éotaxine-3, une chémokine assurant le recrutement de leucocytes. Nous démontrons dans des lignées mucoïdes que l'IL-4 et 13 stimulent l'expression de TFF3. L'établissement de lignées exprimant un dominant négatif du facteur de transcription STAT6 a permis de révéler le rôle clé de STAT6 dans l'induction de TFF3. Dans ce même contexte, l'éotaxine-3 est clairement sur-exprimée dans les entérocytes. La liaison de STAT6 au promoteur du gène codant l'eotaxine-3 est responsable de cette activation. Ces résultats sont confortés dans un modèle d'allergie alimentaire chez la souris.En conclusion, les cytokines de type 2 stimulent, via STAT6, l'activité transcriptionnelle des cellules épithéliales.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Identifiability and estimation of aircraft parameters and delays by using optimal input design

International audienc

Identifiability of a Nonlinear Delayed-Differential Aerospace Model

International audienc

An optimal input design procedure

International audienceThis technical communique presents a method which aims at improving input design searching in some dynamical systems. The original idea of the proposed method is the combination of a dynamic programming method working on square wave inputs followed by a Quasi-Newton algorithm working on infinite differential switching mode inputs. These infinite differential functions approximate square wave inputs in order to enlarge the set of admissible inputs while ensuring a reasonable computation requirement which is not the case of classical methods based on dynamic programming only. Moreover, they correspond to practical inputs. The precise description of the approach is followed by an application in aerospace sciences