Otitis Media in a New Mouse Model for CHARGE Syndrome with a Deletion in the Chd7 Gene

Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-β1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome

Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl+/− Mouse, a Model of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS

Gene Therapy Restores Auditory and Vestibular Function in a Mouse Model of Usher Syndrome Type 1c

Because there are currently no biological treatments for deafness, we sought to advance gene therapy approaches to treat genetic deafness. We reasoned that gene delivery systems that target auditory and vestibular sensory cells with high efficiency would be required to restore complex auditory and balance function. We focused on Usher Syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and used a knock-in mouse model, Ush1c c.216G>A, which carries a cryptic splice site mutation found in French-Acadian patients with Usher Syndrome type IC (USH1C). Following delivery of wild-type Ush1c into the inner ears of neonatal Ush1c c.216G>A mice, we find recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders

Les pouvoirs locaux dans la France du centre et de l'ouest (VIIIe-XIe siècles)

Cet ouvrage est le fruit d'une réflexion commune lancée par ses deux directeurs qui, au fil de leurs travaux de leurs discussions et de leurs entretiens, ont à de nombreuses reprises eu envie d'établir des ponts et des passerelles entre la société féodale chère à l'un et le monde carolingien qui retenait l'attention de l'autre. À de nombreuses reprises, ils se sont retrouvés sur des interrogations communes qui touchaient aux aspects les plus pragmatiques de ces mondes, où les enjeux de pouvoir, le contrôle de la terre et de la société, la transmission de son rang et de son importance continuaient à puiser leur origine et leurs méthodes dans un passé magnifié. Aussi leur a-t-il paru utile d'associer à leur démarche d'autres chercheurs des universités de l'Ouest pour tenter une synthèse au niveau des pouvoirs locaux, car c'est à ce niveau d'encadrement, où les soucis d'une mutation politique due à l'effacement des souverains carolingiens est le moins sensible, qu'on est le mieux à même de percevoir les continuités, les mutations graduelles, les nouvelles stratégies visant à permettre à ceux qui se veulent quelqu'un de tenir le rang auquel ils prétendent. Volontairement chaque auteur s'est circonscrit dans une espace étroit pour permettre d'établir des comparaisons et saisir ainsi les principes communs comme les diversités qui président à l'action des pouvoirs locaux dans la France du centre et de l'ouest du VIIIe au XIe siècle

First contribution of the excavation and chronostratigraphic study of the Ruways 1 Neolithic shell midden (Oman) in terms of Neolithisation, palaeoeconomy, social‐environmental interactions and site formation processes

The NeoArabia project tries to understand how environmental, social, economic and technological factors work in concert to influence settlement and abandonment along a latitudinal transect of 1200 km from UAE to southern Oman. This region was affected by wide north–south variations in the Indo‐Arabian monsoon, marine upwelling activity and eustatic variations in the Mid‐Holocene. On the local settlement scale, this transect is based on fine stratigraphic excavations and permits the reconstruction of the site formation processes and site catchment analysis. A large number of studies have been conducted on the Ruways‐1 site, focusing on a deep stratified sequence corresponding to three millennia of occupation. These studies include on‐site climate‐environmental signal analysis, local palaeogeography and environmental reconstruction, reservoir effect studies, typo‐technological studies, palaeoeconomic strategies, anthropological studies, sclerochronological studies and, finally, site formation processes, the understanding of which makes it possible to explain the potential and limits of the archaeological excavation. The first results confirm the richness of these archaeological archives for documenting the socio‐environmental dynamics, but also the richness of its complex sedimentary structure and the importance of conducting fine and multidisciplinary excavations to answer questions about the rhythms and functions of occupations and the causalities of socio‐environmental changes.Agence Nationale de la Recherche, Grant/Award Number: ANR‐16‐CE03‐00007; French National Research Agency; Ministère de la Culture et de la CommunicationPeer reviewe

First contribution of the excavation and chronostratigraphic study of the Ruways 1 Neolithic shell midden (Oman) in terms of Neolithisation, palaeoeconomy, social‐environmental interactions and site formation processes

International audienceThe NeoArabia project tries to understand how environmental, social, economic and technological factors work in concert to influence settlement and abandonment along a latitudinal transect of 1200 km from UAE to southern Oman. This region was affected by wide north–south variations in the Indo‐Arabian monsoon, marine upwelling activity and eustatic variations in the Mid‐Holocene. On the local settlement scale, this transect is based on fine stratigraphic excavations and permits the reconstruction of the site formation processes and site catchment analysis. A large number of studies have been conducted on the Ruways‐1 site, focusing on a deep stratified sequence corresponding to three millennia of occupation. These studies include on‐site climate‐environmental signal analysis, local palaeogeography and environmental reconstruction, reservoir effect studies, typo‐technological studies, palaeoeconomic strategies, anthropological studies, sclerochronological studies and, finally, site formation processes, the understanding of which makes it possible to explain the potential and limits of the archaeological excavation. The first results confirm the richness of these archaeological archives for documenting the socio‐environmental dynamics, but also the richness of its complex sedimentary structure and the importance of conducting fine and multidisciplinary excavations to answer questions about the rhythms and functions of occupations and the causalities of socio‐environmental changes

Studies on the vasoconstrictor action of melatonin and putative melatonin receptor ligands in the tail artery of juvenile Wistar rats

1. In this study we compared the vasoconstrictor activity of melatonin in rat isolated tail artery using two different recording systems, the Halpern pressure myograph and the Halpern-Mulvany wire myograph, with the view to determining a reliable method for obtaining pharmacological data on vascular melatonin receptors. In addition, we characterized the melatonin receptor in this preparation, using analogues of melatonin, and examined the activity of various naphthalenic derivatives with biological activity in non-vascular models of melatonin receptors. 2. Using the Halpern pressure myograph, cumulative addition of melatonin (0.1 nM to 1 μM) produced direct vasoconstriction (19.3±6.4% reduction in lumen diameter, n=5) in five of 11 pressurized segments, with pEC(50) of 9.14±0.17. Similarly, non-cumulative application of melatonin caused vasoconstriction (19.7±4.6% reduction in lumen diameter, n=7) in seven of 20 preparations examined with pEC(50) of 8.74±0.26. The selective alpha(2)-adrenoceptor agonist, UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate), produced vasoconstriction in all ‘melatonin-insensitive' preparations. 3. Melatonin (0.1 nM to 1 μM) failed to elicit isometric contractions of tail artery segments in the Halpern wire myograph, but produced concentration-dependent potentiation of electrically-evoked, isometric contractions (maximum effect of 150–200% enhancement) when applied either non-cumulatively (seven of seven preparations) or cumulatively (four of seven preparations). The pEC(50) value of melatonin (non-cumulative) was 8.50±0.10 (n=7) which was not different from that obtained in the pressure myograph. All further experiments were conducted using a non-cumulative protocol against electrically-evoked, isometric contractions. 4. Based on the pEC(50) values for the melatonin analogues examined, the pharmacological profile for the enhancement of electrically-evoked contractions was 2-iodomelatonin>6-chloromelatonin⩾(−)-AMMTC□thinsp;5 S21634⩾melatonin⩾S20098>S20242⩾S20304>6- hydroxymelatonin>S20932> (+) -AMMTC>N-acetyl-5-HT. Our data suggests the vascular receptor belongs to the MEL(1)-like subtype. All the indole-based analogues of melatonin, 2-iodomelatonin, (−)-AMMTC, (+)-AMMTC, S20932, 6-chloromelatonin, 6-hydroxymelatonin and N-acetyl-5-HT, behaved as full agonists. All the naphthalenic derivatives examined, S21634, S20098, S20242 and S20304 behaved as partial agonists relative to melatonin. 5. The naphthalenic-based antagonists, S20928 and S20929, did not modify electrically-evoked, isometric contractions of the tail artery, but produced a parallel, rightward displacement of the melatonin concentration-response curve. Based upon the effect of 1 μM S20928 and S20929, the estimated pK(B) values for these antagonists were 7.18±0.25 (n=4) and 7.17±0.25 (n=5), respectively. 6. We demonstrated that enhancement of electrically-evoked, isometric contractions of the rat isolated tail artery (using the Halpern-Mulvany wire myograph) is a simple and reproducible model for assessing the activity of putative agonists, partial agonists and antagonists at vascular melatonin receptors. Pharmacological characterization of the receptor suggests the presence of a MEL(1)-like subtype