An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen’s Metaphyseal Chondrodysplasia

Jansen’s metaphyseal chondrodysplasia (JMC) is a rare disease of bone and mineral ion physiology that is caused by activating mutations in PTHR1. Ligand‐independent signaling by the mutant receptors in cells of bone and kidney results in abnormal skeletal growth, excessive bone turnover, and chronic hypercalcemia and hyperphosphaturia. Clinical features further include short stature, limb deformities, nephrocalcinosis, and progressive losses in kidney function. There is no effective treatment option available for JMC. In previous cell‐based assays, we found that certain N‐terminally truncated PTH and PTHrP antagonist peptides function as inverse agonists and thus can reduce the high rates of basal cAMP signaling exhibited by the mutant PTHR1s of JMC in vitro. Here we explored whether one such inverse agonist ligand, [Leu11,dTrp12,Trp23,Tyr36]‐PTHrP(7‐36)NH2 (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1‐H223R allele of JMC in osteoblastic cells via the collagen‐1α1 promoter (C1HR mice). We observed that after 2 weeks of twice‐daily injection and relative to vehicle controls, the IA analog resulted in significant improvements in key skeletal parameters that characterize the C1HR mice, because it reduced the excess trabecular bone mass, bone marrow fibrosis, and levels of bone turnover markers in blood and urine. The overall findings provide proof‐of‐concept support for the notion that inverse agonist ligands targeted to the mutant PTHR1 variants of JMC can have efficacy in vivo. Further studies of such PTHR1 ligand analogs could help open paths toward the first treatment option for this debilitating skeletal disorder. © 2019 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/1/jbmr3913-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/2/jbmr3913.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154322/3/jbmr3913_am.pd

Resistance to First-Line Anti-TB Drugs Is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known. Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment. Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions

Classement des bois guyanais de structure. Comparaison de trois techniques non-destructives : visuelle, ultrasonore et analyse modale

L'objectif de l'étude est de comparer trois méthodes de classement non-deà.tructives des avivés en dimension d'emploi. Ces méthodes sont : le classement visuel, la mesure de la vitesse de propagation des ondes ultrasonores (système SYLVATEST), l'analyse modale (système du Cirad-forêt : BING). Les avivés (3 x 0,15 x 0,055 m3 proviennent de deux espèces de la forêt guyanaise les plus utilisées pour la construction : l'Angélique (#Dicorynia guianensis# Amsh., 77 pièces testées) et le Gonfolo (#Qualea# Spp., 86 pièces testées). Sur la base du classement visuel, tous les choix sont représentés. Les propriétéà. de réjërence sont le module d'élasticité et la résistance obtenus par un essai destructif de flexion statique quatre points. La confrontation des valeurs et des classements obtenus par les différentes techniques révèle que : - le classement visuel n'est pas une technique eficace de classement pour les bois guyanais de construction, - l'analyse modale présente un grandpotentiel pour devenir un outil de classement eficient, - la technique ultrasonore n'est pas aussi eficace que l'analyse modale. Néanmoins, c'est une méthode de terrain très pratique, - en fonction de l'espèce la qualité de la prédiction des techniques non-destructives est sensiblement diffiérente, - pour des pièces de structure le " coup de vent " fracture transversale provoquant une très faible résistance à la rupture) est un défaut d'autant plus grave qu'il est très peu dôétectabl aussi bien visuellement que par les méthodes non-destructives. (Résumé d'auteur

Caractérisation de l'Évolution des communautés d'Oiseaux sur les causses méridionaux du Massif central

International audienceOpen habitat bird species of Southern Massif Central (France) are highly dependent of traditional land uses such as extensive livestock farming. These practices have however largely declined other the last decades. Despite the high conservation value of these species at the national level, little is known about their recent trends in this region. In this study, we aimed to monitor changes in the occurrence of bird species of southern Massif Central. Our study relied on 167 point-counts repeated exactly at the same locations in 1995 and 2017. We specifically focused on four target species related to open habitat: the Tawny Pipit, the Ortolan Bunting, the Woodlark, and the Dartford Warbler. We observed a strong negative trend for species strongly associated with open habitat, while forest and generalist species showed stable or positive trends. This study is the first to quantify trends in bird occurrence in this study area based on repeatable and standardized methods. Alarming trends observed for open habitat specialist species call for the urgent need to implement conservation actions for thèse species and their habitats throughout the study are