Hearing loss in a mouse model of Muenke syndrome

The heterozygous Pro250Arg substitution mutation in fibroblast growth factor receptor 3 (FGFR3), which increases ligand-dependent signalling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signalling plays dosage-sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3P244R). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3P244R mice showed dominant, fully penetrant hearing loss that was more severe than that in Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters'-to-pillar cells) along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. In addition, there was excess outer hair cell development in the apical region. We conclude that low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome and that the genetically equivalent mouse provides an excellent model that could be useful in testing hearing loss therapies aimed at manipulating the levels of FGF signalling in the inner ear

Hot deformation behaviour and recrystallization mechanisms in a niobium stabilized austenitic stainless steel

International audience316Nb austenitic stainless steels are used in nuclear industry for their excellent corrosion resistance and high temperature mechanical properties. In thick-walled components, work hardening, dynamic recovery and recrystallization govern hot workability. Static recovery and static or post-dynamic recrystallization can induce further metallurgical evolution during cooling. In addition, solute atoms and niobium-rich precipitates may significantly affect recrystallization mechanisms. Obtaining a homogeneous microstructure requires deep understanding of the hot deformation behaviour and mechanisms of this material. The influence of hot deformation conditions on recrystallization was determined from torsion tests. Metallographic and electron backscatter diffraction examinations showed extended dynamic recovery, which delays dynamic recrystallization. A particular dynamic recrystallization mechanism explains progressive elimination of annealing twin boundaries. Coarse initial grain size, solute drag, and pinning of grain boundaries and dislocations by fine Nb(C,N) particles hinder dynamic recrystallization which is not the dominant microstructural evolution mechanism in the studied conditions

In-depth comparison of powder and ingot metallurgical M50 Bearing Steels

Powder metallurgy (PM) for bearing steel manufacturing was introduced several decades ago and mainly aimed at limiting segregation effects in high-alloy grades. Despite the significant potential of this relatively new process for producing high-performance bearing steels, its use in commercial applications is still very limited today. It is thought that the slow acceptance of this promising technology is partially due to a lack of understanding of how modern PM steels compare to conventional ingot metallurgical steels. Most of the comparative studies published on this topic have only focused on a few key mechanical properties, which are rarely related to the microstructure. For this study, several variants of M50 were produced using ingot metallurgical and PM processes. This grade was chosen as its performance is well known to be limited by segregation, and it could therefore benefit from a PM process route. The evolution of the microstructure during manufacturing, from solidification to tempering, was carefully investigated. After heat treatment, toughness, hardness, and rolling contact fatigue (RCF) life were measured. RCF tests were performed using a ball-on-rod configuration to compare the performance of the alloys as well as to evaluate the microstructural changes during testing. Differences in the populations of stress raisers (primary carbides and nonmetallic inclusions) were also assessed and used to explain the variations in RCF fatigue lives

Thermokinetic Modelling of High-Temperature Evolution of Primary Nb(C,N) in Austenite Applied to Recrystallization of 316Nb Austenitic Stainless Steel

International audienceThe size evolution of niobium carbonitrides Nb(C,N) and the evolution of the composition of an austenitic matrix in 316Nb stainless steel were simulated using DICTRA software. For the first time, the complete nine-element composition of steel was taken into account during isothermal and even anisothermal heat treatments. A reduced model was then proposed to optimize the calculation time for complex heat treatments. The change in the mean Nb content in austenite due to Nb(C,N) evolution during different heat treatments was studied. It qualitatively agrees with experimental data as obtained by electron probe microanalysis. Furthermore, the model was successfully applied to explain the effect of heat treatments on the recrystallization behavior of 316Nb steel during hot torsion tests. Moreover, the effect of the thermodynamic database and the number of alloying elements chosen was discussed. We showed that taking into account seven or even nine elements greatly improves the accuracy compared to usual simplified compositions. The proposed method can be useful in designing heat treatments promoting or conversely hindering recrystallization for a wide variety of Nb-bearing steels

Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation

Accumulating in vitro evidence suggests that the p38 mitogen-activated protein kinase (MAPK) pathway is involved in endochondral ossification. To investigate the role of this pathway in endochondral ossification, we generated transgenic mice with expression in chondrocytes of a constitutively active mutant of MKK6, a MAPK kinase that specifically activates p38. These mice had a dwarf phenotype characterized by reduced chondrocyte proliferation, inhibition of hypertrophic chondrocyte differentiation, and a delay in the formation of primary and secondary ossification centers. Histological analysis with in situ hybridization showed reduced expression of Indian hedgehog, PTH/PTH-related peptide receptor (PTH, parathyroid hormone), cyclin D1, and increased expression of p21 in chondrocytes. In addition, both in vivo and in transfected cells, p38 signaling increased the transcriptional activity of Sox9, a transcription factor essential for chondrocyte differentiation. In agreement with this observation, transgenic mice that express a constitutively active mutant of MKK6 in chondrocytes showed phenotypes similar to those of mice that overexpress SOX9 in chondrocytes. These observations are consistent with the notion that increased activity of Sox9 accounts at least in part for the phenotype caused by constitutive activation of MKK6 in chondrocytes. Therefore, our study provides in vivo evidence for the role of p38 in endochondral ossification and suggests that Sox9 is a likely downstream target of the p38 MAPK pathway