Speech production in aging

The manner and extent to which normal aging affects the ability to speak are not fully understood. While age-related changes in voice fundamental frequency and intensity have been documented, changes affecting the planning and articulation of speech are less well understood. In the present study, 76 healthy, cognitively normal participants aged between 18 and 93 years old were asked to produce auditorily and visually triggered sequences of finely controlled movements (speech, oro-facial, and manual movement). These sequences of movements were either (1) simple, in which at least two of the three movements were the same, or (2) complex, in which three different movements were produced. For each of the resulting experimental condition, accuracy was calculated. The results show that, for speech and oro-facial movements, accuracy declined as a function of age and complexity. For these movements, the negative effect of complexity on performance accuracy increased with age. No aging or complexity effects were found for the manual movements on accuracy, but a significant slowing of movement was found, particularly for the complex sequences. These results demonstrate that there is a significant deterioration of fine motor control in normal aging across different response modalities

IL-1 and IL-23 Mediate Early IL-17A Production in Pulmonary Inflammation Leading to Late Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice. METHODS: The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice. RESULTS: We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis. CONCLUSIONS: Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology

Structural and functional characterization of the Mycobacterium tuberculosis uridine monophosphate kinase: insights into the allosteric regulation†

Nucleoside Monophosphate Kinases (NMPKs) family are key enzymes in nucleotide metabolism. Bacterial UMPKs depart from the main superfamily of NMPKs. Having no eukaryotic counterparts they represent attractive therapeutic targets. They are regulated by GTP and UTP, while showing different mechanisms in Gram(+), Gram(–) and archaeal bacteria. In this work, we have characterized the mycobacterial UMPK (UMPKmt) combining enzymatic and structural investigations with site-directed mutagenesis. UMPKmt exhibits cooperativity toward ATP and an allosteric regulation by GTP and UTP. The crystal structure of the complex of UMPKmt with GTP solved at 2.5 Å, was merely identical to the modelled apo-form, in agreement with SAXS experiments. Only a small stretch of residues was affected upon nucleotide binding, pointing out the role of macromolecular dynamics rather than major structural changes in the allosteric regulation of bacterial UMPKs. We further probe allosteric regulation by site-directed mutagenesis. In particular, a key residue involved in the allosteric regulation of this enzyme was identified

Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

Amelogenesis imperfecta (AI) designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20) produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues), pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI

A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement.

BACKGROUND: Orodental diseases include several clinically and genetically heterogeneous disorders that can present in isolation or as part of a genetic syndrome. Due to the vast number of genes implicated in these disorders, establishing a molecular diagnosis can be challenging. We aimed to develop a targeted next-generation sequencing (NGS) assay to diagnose mutations and potentially identify novel genes mutated in this group of disorders. METHODS: We designed an NGS gene panel that targets 585 known and candidate genes in orodental disease. We screened a cohort of 101 unrelated patients without a molecular diagnosis referred to the Reference Centre for Oro-Dental Manifestations of Rare Diseases, Strasbourg, France, for a variety of orodental disorders including isolated and syndromic amelogenesis imperfecta (AI), isolated and syndromic selective tooth agenesis (STHAG), isolated and syndromic dentinogenesis imperfecta, isolated dentin dysplasia, otodental dysplasia and primary failure of tooth eruption. RESULTS: We discovered 21 novel pathogenic variants and identified the causative mutation in 39 unrelated patients in known genes (overall diagnostic rate: 39%). Among the largest subcohorts of patients with isolated AI (50 unrelated patients) and isolated STHAG (21 unrelated patients), we had a definitive diagnosis in 14 (27%) and 15 cases (71%), respectively. Surprisingly, COL17A1 mutations accounted for the majority of autosomal-dominant AI cases. CONCLUSIONS: We have developed a novel targeted NGS assay for the efficient molecular diagnosis of a wide variety of orodental diseases. Furthermore, our panel will contribute to better understanding the contribution of these genes to orodental disease. TRIAL REGISTRATION NUMBERS: NCT01746121 and NCT02397824.journal articleresearch support, non-u.s. gov't2016 Feb2015 10 26importe

La Thèbes des morts: La dynamique thébaine dans les idées égyptiennes de l’au-delà

International audienceLe 24 février 2015 s’est tenue à Montpellier une table ronde rassemblant les membres du projet « La Thèbes des morts » inscrit dans le cadre du LabEx Archimède. Les participants ont exposé le bilan d’un an de travail et, chacun dans son domaine a montré comment, au cours du Ier millénaire avant J.-C., s’est manifestée la dynamique de la pensée thébaine dans le domaine funéraire. On trouvera ici un résumé des communications

Contribution of IL-17 to the pulmonary inflammatory response

Airway exposure to endotoxin and other microbial Toll-like receptor (TLR) agonists induces a rapid production of mediators including IL-1, neutrophil recruitment and bronchoconstriction, which are abrogated in mice deficient for distinct TLRs or the common adaptor molecule myeloid differentiation factor 88 (MyD88). Intranasal IL-17 administration causes acute neutrophilic lung inflammation in a proinflammatory environment. Recent investigations revealed that IL-17 is up-regulated upon endotoxin aerosol exposure and neutralization of IL-17 diminished endotoxininduced inflammation, suggesting a role of endogenous IL-17 in endotoxin-induced lung inflammation. Furthermore, administration of IL-1β mobilizes neutrophils and induces IL-17 production in the lung. Therefore, IL-17 might participates in IL-1β-induced lung inflammation. Importantly, lung injury leads to NALP3 inflammasome activation, leading to IL-1β-dependent acute inflammation. The participation of IL-17 in this response is discussed. In conclusion, TLR-agonist and injury-induced lung inflammation depend in part on IL-1β and IL-17. The role of inflammasome activation cleaving pro-IL-1β leading to mature IL-1ß and IL-1β-dependent IL-17 production and inflammation need to be explored further