An Analytical Fiber ODF Reconstruction in 3D Polarized Light Imaging

International audienceThree dimensional polarized light imaging (3D-PLI) utilizes the birefringence in postmortem tissue to map its spatial fiber structure at a submillimeter resolution. We propose an analytical method to compute the fiber orientation distribution function (ODF) from high-resolution vector data provided by 3D-PLI. This strategy enables the bridging of high resolution 3D-PLI to diffusion magnetic resonance imaging with relatively low spatial resolution. First, the fiber ODF is modeled as a sum of K orientations on the unit sphere and expanded with a high order spherical harmonics series. Then, the coefficients of the spherical harmonics are derived directly with the spherical Fourier transform. We quantitatively validate the accuracy of the reconstruction against synthetic data and show that we can recover complex fiber configurations in the human heart at different scales

Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella.

International audienceTen to fifteen percent of couples are confronted with infertility and a male factor is involved in approximately half the cases. A genetic etiology is likely in most cases yet only few genes have been formally correlated with male infertility. Homozygosity mapping was carried out on a cohort of 20 North African individuals, including 18 index cases, presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF) including absent, short, coiled, bent, and irregular flagella. Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1, which encodes an inner dynein heavy chain and is expressed in testis. RT-PCR, immunostaining, and electronic microscopy were carried out on samples from one of the subjects with a mutation located on a donor splice site. Neither the transcript nor the protein was observed in this individual, confirming the pathogenicity of this variant. A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects, suggesting that DNAH1 function in cilium is not as critical as in sperm flagellum

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

The Myosin Myocardial Mesh Interpreted as a Biological Analogous of Nematic Chiral Liquid Crystals

International audienceThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution .There are still grey areas in the understanding of the myoarchitecture of the ventricularmass. This is despite the progress of investigation methods since the beginning of the 21st century(diffusion tensor magnetic resonance imaging, microcomputed tomography, and polarised lightimaging). The objective of this article is to highlight the specificities and the limitations of polarisedlight imaging (PLI) of the unstained myocardium embedded in methyl methacrylate (MMA). Thus,to better differentiate our method from other PLI modes, we will refer to it by the acronym PLI-MMA.PLI-MMA shows that the myosin mesh of the compact left ventricular wall behaves like a biologicalanalogous of a nematic chiral liquid crystal. Results obtained by PLI-MMA are: the main directionof the myosin molecules contained in an imaged voxel, the crystal liquid director n, and a regionalisotropy index RI that is an orientation tensor, the equivalent of the crystal liquid order parameter.The vector n is collinear with the first eigenvector of diffusion tensor imaging (DTI-MRI). The RIhas not been confounded with the diffusion tensor of DTI that gives information about the threeeigenvectors of the ellipsoid of diffusion. PLI-MMA gives no information about the collagen network.The physics of soft matter has allowed the revisiting of Streeter’s conjecture on the myoarchitectureof the compact left ventricular wall: “geodesics on a nested set of toroidal surfaces”. Once thetorus topology is understood, this characterisation of the myoarchitecture is more accurate andparsimonious than former descriptions. Finally, this article aims to be an enthusiastic invitationto a transdisciplinary approach between physicists of liquid crystals, anatomists, and specialistsof imaging

Exploration du polymorphisme d'inversion de la région 7q11.23 dans le syndrome de Williams-Beuren (mise au point technique et discussion des applications)

GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The Nematic Chiral Liquid Crystal Structure of the Cardiac Myoarchitecture: Disclinations and Topological Singularities

International audienceThis is our second article devoted to the cardiac myoarchitecture considered as a nematic chiral liquid crystal (NCLC). While the first article focused on the myoarchitecture of the left ventricle (LV), this new article extends to the whole ventricular mass and introduces the concept of disclinations and topological singularities, which characterize the differences and relationships between the left and right ventricles (RV). At the level of the ventricular apices, we constantly observed a vortex shape at the LV apex, corresponding, in the terminology of liquid crystals, to a "+1 disclination"; we never observed this at the RV apex. At the level of the interventricular septum (IVS), we identified "−1/2 disclinations" at the anterior and posterior parts. During the perinatal period, there was a significant difference in their distribution, with more "−1/2 disclinations" in the posterior part of the IVS. After birth, concomitant to major physiological changes, the number of "−1/2 disclinations" significantly decreased, both in the anterior and posterior parts of the IVS. Finally, the description of the disclinations must be considered in any attempt to segment the whole ventricular mass, in biomechanical studies, and, more generally, for the characterization of myocardial remodeling

Interactions entre profil cognitif et fonctions motrices chez le jeune adulte porteur de trisomie 21

Les conséquences de la trisomie 21 (T21) sur les capacités cognitives et motrices sont diverses et variables. Notre objectif était d'identifier les caractéristiques fonctionnelles associées à ce syndrome. Nous avons d'abord établi le profil cognitif d'adultes T21 à un niveau d'analyse global du comportement. Pour cela, nous avons utilisé une batterie italienne d'évaluation neuropsychologique (Progetto Senior) pour les personnes déficientes intellectuelles (DI). Après traduction, nous avons vérifié sa cohérence interne. Le profil cognitif des participants T21 établi ensuite en référence à des individus DI ou non révèle une hétérogénéité de l'altération des fonctions cognitives. Parallèlement, nous avons testé l'impact de l'allocation de l'attention sur le traitement de l'information au moyen des techniques de chronométrie mentale et de recueil des potentiels évoqués tardifs. Nous avons montré que les individus T21 sont capables d'orienter leur attention vers les stimuli pertinents, traités toutefois d'autant plus lentement que la composante motrice de la tâche est faible. Nous attribuons ce déficit à un défaut d'allocation d'attention vers les étapes motrices du traitement. En conclusion, notre travail suggère que : 1) les difficultés motrices des individus T21 sont en partie dues à un déficit d'allocation de l'attention étroitement lié aux caractéristiques de la tâche ; 2) les approches neurophysiologiques sont pertinentes pour affiner les endophénotypes associés à la trisomie 21 que sont les déficits sensori-moteurs ; 3) l'outil Progetto Senior, plus global, semble mieux adapté pour une aide à la prise en charge.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Fibre Orientation in Human Fetal Heart and Ventricular Mechanics : A Small Perturbation Analysis.

The study of the topological organisation of myocardial cells is a basic requirement for understanding the mechanical design of the normal and pathological heart. Anatomical observations show that cardiac muscle tissue has a highly specialized architecture. We have made new quantitative measurements of fibre orientation through the heart wall by means of polarized light analysis on some thick sections of human fetal heart embedded in a resin and polymerized. A small perturbation method to find an equilibrium solution in a cylindrical left ventricular (LV) geometry with fibres running on toroidal shells of revolution is used to investigate the mechanical behaviour of three human fetal hearts (FH) of 14, 20 and 33 weeks of gestational age. The results of fibre strains and stresses presented for end-systolic state show significant differences when compared to results of the cylindrical geometry with regular helicoidal fibres running on cylindrical surfaces. Moreover, the toroidal shells of revolution explain shear stresses and strains in the transverse plane which also exist in the adult heart

Three-dimensional cartography of the pattern of the myofibres in the second trimester fetal human heart.

The aim of the present study was to describe the fibre architecture of the fetal heart at mid gestation, and to clarify some persistent controversies concerning the architecture of the myofibres in the right ventricular wall and the muscular ventricular septum. We used quantitative polarized light microscopy to obtain information about the orientation of myocardial cells in the ventricular mass. These cells, joined into a network by anastomoses, have at any point in the ventricular mass a principal direction--the fibre direction. We have quantitated this information in the form of maps of the azimuth and elevation angles, in 18 midgestation fetal hearts. Our findings show that the fibre architecture of the heart can be conceptualised as myocardial fibres running like geodesics on a nested set of warped "pretzels". This model is an extension to the whole ventricular mass of Krehl's Triebwerk, and Streeter's model which was restricted to the left ventricle. A "pretzel" itself can be considered as two doughnuts joined side-by-side, with the tunnel at the center of each doughnut corresponding to the ventricular cavity. Over and above the excellence of the fit between the data and the geodesic representation, three strong arguments support this model. First, it is the only existing model that explains the observed rolling over of fibres around the atrioventricular valvar orifices. Second, it explains the trajectory of the fibres from the epicardium to the endocardium at the basal parts of both ventricles and at the apical part of the left ventricle. Third, the predicted topological singularities of the model are systematically observed in each of the 18 hearts studied

Postnatal myocardium remodelling generates inhomogeneity in the architecture of the ventricular mass

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