A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

The Potential of N-Rich Plasma-Polymerized Ethylene (PPE:N) Films for Regulating the Phenotype of the Nucleus Pulposus

We recently developed a nitrogen-rich plasma-polymerized biomaterial, designated “PPE:N” (N-doped plasma-polymerized ethylene) that is capable of suppressing cellular hypertrophy while promoting type I collagen and aggrecan expression in mesenchymal stem cells from osteoarthritis patients. We then hypothesized that these surfaces would form an ideal substrate on which the nucleus pulposus (NP) phenotype would be maintained. Recent evidence using microarrays showed that in young rats, the relative mRNA levels of glypican-3 (GPC3) and pleiotrophin binding factor (PTN) were significantly higher in nucleus pulposus (NP) compared to annulus fibrosus (AF) and articular cartilage. Furthermore, vimentin (VIM) mRNA levels were higher in NP versus articular cartilage. In contrast, the levels of expression of cartilage oligomeric matrix protein (COMP) and matrix gla protein precursor (MGP) were lower in NP compared to articular cartilage. The objective of this study was to compare the expression profiles of these genes in NP cells from fetal bovine lumbar discs when cultured on either commercial polystyrene (PS) tissue culture dishes or on PPE:N with time. We found that the expression of these genes varies with the concentration of N ([N]). More specifically, the expression of several genes of NP was sensitive to [N], with a decrease of GPC3, VIM, PTN, and MGP in function of decreasing [N]. The expression of aggrecan, collagen type I, and collagen type II was also studied: no significant differences were observed in the cells on different surfaces with different culture time. The results support the concept that PPE:N may be a suitable scaffold for the culture of NP cells. Further studies are however necessary to better understand their effects on cellular phenotypes

Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice.

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key elements from the ECG waveform (RR-, PR-, ST-, QT-interval, QT corrected, and QRS complex) demonstrate minimal sexual dimorphism. As expected, anesthesia induces a decrease in heart rate and was shown for both inhalation (isoflurane) and injectable (tribromoethanol) anesthesia. In the absence of pharmacological, environmental, or genetic challenges, we did not observe major age-related ECG changes in C57BL/6N-inbred mice as the differences in the reference ranges of 12-week-old compared to 62-week-old mice were negligible. The generalizability of the C57BL/6N substrain reference ranges was demonstrated by comparison with ECG data from a wide range of non-IMPC studies. The close overlap in data from a wide range of mouse strains suggests that the C57BL/6N-based reference ranges can be used as a robust and comprehensive indicator of normality. We report a unique ECG reference resource of fundamental importance for any experimental study of cardiac function in mice

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.</p

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Social dominance orientation, prejudice, and discrimination: A new computer-based method for studying discriminatory behaviors

International audienc

Influence of Drying on the Stiffness and Strength of Cement-Stabilized Soils

Nowadays, improving the strength and deformation properties of soft soils by deep soil mixing is a commonly used technique. There is also an increasing interest in the use of this technique forfoundation/structural elements and excavation retaining walls applications. The compressive strength and elastic modulus of the soil mix material are key parameters in the design of these structures. However, there is very limited information available on the impact of exposure to air drying (in the case of retaining wall) on he strength and stiffness of cement stabilized soils. The aim of this study is to investigate the effects of different curing conditions (immersionin water, cycles of wetting and drying, continuous air drying) on the mechanical properties of soils treated with cement in the laboratory. Free-free resonance tests and unconfined compression tests were performed on specimens of silt and sand treated with blastfurnace slag cement. Strength increases more rapidly than stiffness between 7 and 30 days. The strength of stabilized soils submitted to cyclic wetting and drying before the cement hydration process is complete continues to increase. As long as the periods of drying do not induce microcracks, the stiffness ofthe treated soil specimens also increases with time. However, the stiffness is lower than for the specimens cured in water indicating a disruptive effect of the imposed wetting-drying cycles on stiffness. Continuous exposure to air drying inhibits strength development due to insufficient water for hydration. Significant stiffness decreases were observed on specimens of stabilized silt and are attributed to microcracking

Predominant intracellular localization of the type I transforming growth factor-beta receptor and increased nuclear accumulation after growth arrest

NRC publication: Ye

Rheological properties of cement-stabilised kaolin

International audienceDeep soil mixing is a process used to improve the mechanical properties of soft soils by mixing dry or wet binders with the existing soil. The strength and deformation properties of the treated soils depend on the initial soil conditions, the type and amount of binder used and the curing conditions. The homogeneity and strength of soils stabilised by deep mixing also depend on the mixing mechanisms that occur during construction. These mixing mechanisms are directly related to the rheological properties of the materials being mixed. Therefore, rheology is the starting point in understanding the processes involved in deep soil mixing although knowledge of the rheological characteristics of stabilised clays is very limited. The aim of the research presented in this paper is to investigate the effects of cement stabilisation on the rheological properties of kaolin clay. The flow properties of kaolin, cement slurries and kaolin–cement mixtures at various moisture contents were measured using a rheometer with two different geometries:parallel plates and the ball measuring system. For all mixtures tested, the shear stresses increase as the moisture content decreases. A good agreement was found between the stresses measured using the parallel plates and the ball measuring system for kaolin suspensions, validating the use of this shear geometry for subsequent studies on coarse grained soils. The results are discussed with respect to in situ soil mixing processes. It is proposed that observations made in the field on the relation between blade rotation speed and strength and homogeneity of treated soils can be explained by the shear-thinning behaviour of clays. The yield stress may be a relevant tool to study the workability of soil-cement mixtures