Le dernier roman d'Aragon, dans lequel les commentateurs ont parfois cru discerner un affaiblissement de la veine littéraire, préfigure le nouveau millénaire en cours, marqué par les effondrements ...multiples et la révision des cadres de pensée qui avaient paru s’imposer jusqu’alors. Théâtre/Roman traite du théâtre au propre et au figuré, dans un jeu de miroir entre les protagonistes de la représentation – acteur, metteur en scène – et le théâtre intérieur de l’écriture romanesque. La voix tragique de l’Écrivain et de ses doubles, confrontés à la faillite d’un idéal révolutionnaire néanmoins réaffirmé, trouve des échos dans d’autres œuvres du passé et d’autres époques qui l’universalisent. Le face-à-face vertigineux entre roman et théâtre, par l’orchestration poétique de la composition d’ensemble, ouvre pour le lecteur un espace inédit d’exploration, nommé ici, avec l’assentiment tacite d’Aragon, arrière-texte. Un passage de relais est suggéré: « Dans ce que je vois, il y a toujours ce que je ne vois pas ».
The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native ...domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.
RTK KIT regulates a variety of crucial cellular processes via its cytoplasmic domain (CD), which is composed of the tyrosine kinase domain, crowned by the highly flexible domains-the juxtamembrane ...region, kinase insertion domain, and C-tail, which are key recruitment regions for downstream signalling proteins. To prepare a structural basis for the characterization of the interactions of KIT with its signalling proteins (KIT INTERACTOME), we generated the 3D model of the full-length CD attached to the transmembrane helix. This generic model of KIT in inactive state was studied by molecular dynamics simulation under conditions mimicking the natural environment of KIT. With the accurate atomistic description of the multidomain KIT dynamics, we explained its intrinsic (intra-domain) and extrinsic (inter-domain) disorder and represented the conformational assemble of KIT through free energy landscapes. Strongly coupled movements within each domain and between distant domains of KIT prove the functional interdependence of these regions, described as allosteric regulation, a phenomenon widely observed in many proteins. We suggested that KIT, in its inactive state, encodes all properties of the active protein and its post-transduction events.
We propose a generic method for the statistical analysis of collections of anatomical shape complexes, namely sets of surfaces that were previously segmented and labeled in a group of subjects. The ...method estimates an anatomical model, the template complex, that is representative of the population under study. Its shape reflects anatomical invariants within the dataset. In addition, the method automatically places control points near the most variable parts of the template complex. Vectors attached to these points are parameters of deformations of the ambient 3D space. These deformations warp the template to each subject's complex in a way that preserves the organization of the anatomical structures. Multivariate statistical analysis is applied to these deformation parameters to test for group differences. Results of the statistical analysis are then expressed in terms of deformation patterns of the template complex, and can be visualized and interpreted. The user needs only to specify the topology of the template complex and the number of control points. The method then automatically estimates the shape of the template complex, the optimal position of control points and deformation parameters. The proposed approach is completely generic with respect to any type of application and well adapted to efficient use in clinical studies, in that it does not require point correspondence across surfaces and is robust to mesh imperfections such as holes, spikes, inconsistent orientation or irregular meshing.
The approach is illustrated with a neuroimaging study of Down syndrome (DS). The results demonstrate that the complex of deep brain structures shows a statistically significant shape difference between control and DS subjects. The deformation-based modelingis able to classify subjects with very high specificity and sensitivity, thus showing important generalization capability even given a low sample size. We show that the results remain significant even if the number of control points, and hence the dimension of variables in the statistical model, are drastically reduced. The analysis may even suggest that parsimonious models have an increased statistical performance.
The method has been implemented in the software Deformetrica, which is publicly available at www.deformetrica.org.
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•Construction of anatomical models from surface data segmented in a series of images•Models reflect the anatomical organization of complexes of brain structures.•Space deformations measure shape differences between different subjects' complexes.•Multivariate statistics are computed on few adapted deformation parameters.•Shape statistics are displayed as interpretable deformation patterns.
This paper proposes an original approach for the statistical analysis of longitudinal shape data. The proposed method allows the characterization of typical growth patterns and subject-specific shape ...changes in repeated time-series observations of several subjects. This can be seen as the extension of usual longitudinal statistics of scalar measurements to high-dimensional shape or image data. The method is based on the estimation of continuous subject-specific growth trajectories and the comparison of such temporal shape changes across subjects. Differences between growth trajectories are decomposed into morphological deformations, which account for shape changes independent of the time, and time warps, which account for different rates of shape changes over time. Given a longitudinal shape data set, we estimate a mean growth scenario representative of the population, and the variations of this scenario both in terms of shape changes and in terms of change in growth speed. Then, intrinsic statistics are derived in the space of spatiotemporal deformations, which characterize the typical variations in shape and in growth speed within the studied population. They can be used to detect systematic developmental delays across subjects. In the context of neuroscience, we apply this method to analyze the differences in the growth of the hippocampus in children diagnosed with autism, developmental delays and in controls. Result suggest that group differences may be better characterized by a different speed of maturation rather than shape differences at a given age. In the context of anthropology, we assess the differences in the typical growth of the endocranium between chimpanzees and bonobos. We take advantage of this study to show the robustness of the method with respect to change of parameters and perturbation of the age estimates.
The Computational Anatomy project is the morphome-scale study of shape and form, which we model as an orbit under diffeomorphic group action. Metric comparison calculates the geodesic length of the ...diffeomorphic flow connecting one form to another. Geodesic connection provides a positioning system for coordinatizing the forms and positioning their associated functional information. This article reviews progress since the Euler-Lagrange characterization of the geodesics a decade ago. Geodesic positioning is posed as a series of problems in Hamiltonian control, which emphasize the key reduction from the Eulerian momentum with dimension of the flow of the group, to the parametric coordinates appropriate to the dimension of the submanifolds being positioned. The Hamiltonian viewpoint provides important extensions of the core setting to new, object-informed positioning systems. Several submanifold mapping problems are discussed as they apply to metamorphosis, multiple shape spaces, and longitudinal time series studies of growth and atrophy via shape splines.
This paper examine the Euler-Lagrange equations for the solution of the large deformation diffeomorphic metric mapping problem studied in Dupuis et al. (1998) and Trouvé (1995) in which two images I ...^sub 0^, I ^sub 1^ are given and connected via the diffeomorphic change of coordinates I ^sub 0^^sup -1^=I ^sub 1^ where =Φ^sub 1^ is the end point at t= 1 of curve Φ^sub t^, t0, 1 satisfying ^sup .^Φ^sub t^=v ^sub t^ (Φ^sub t^), t 0,1 with Φ^sub 0^=id. The variational problem takes the form ... where v ^sub t^^sub V^ is an appropriate Sobolev norm on the velocity field v ^sub t^(·), and the second term enforces matching of the images with ·^sub L^ ^sup 2^ representing the squared-error norm. In this paper we derive the Euler-Lagrange equations characterizing the minimizing vector fields v ^sub t^, t0, 1 assuming sufficient smoothness of the norm to guarantee existence of solutions in the space of diffeomorphisms. We describe the implementation of the Euler equations using semi-lagrangian method of computing particle flows and show the solutions for various examples. As well, we compute the metric distance on several anatomical configurations as measured by ∫^sub 0^ ^sup 1^v ^sub t^^sub V^dt on the geodesic shortest paths.PUBLICATION ABSTRACT
Advances in the development of largely automated microscopy methods such as MERFISH for imaging cellular structures in mouse brains are providing spatial detection of micron resolution gene ...expression. While there has been tremendous progress made in the field of Computational Anatomy (CA) to perform diffeomorphic mapping technologies at the tissue scales for advanced neuroinformatic studies in common coordinates, integration of molecular- and cellular-scale populations through statistical averaging via common coordinates remains yet unattained. This paper describes the first set of algorithms for calculating geodesics in the space of diffeomorphisms, what we term space-feature-measure LDDMM, extending the family of large deformation diffeomorphic metric mapping (LDDMM) algorithms to accommodate a space-feature action on marked particles which extends consistently to the tissue scales. It leads to the derivation of a cross-modality alignment algorithm of transcriptomic data to common coordinate systems attached to standard atlases.
We represent the brain data as geometric measures, termed as space-feature measures supported by a large number of unstructured points, each point representing a small volume in space and carrying a list of densities of features elements of a high-dimensional feature space. The shape of space-feature measure brain spaces is measured by transforming them by diffeomorphisms. The metric between these measures is obtained after embedding these objects in a linear space equipped with the norm, yielding a so-called “chordal metric”.
•Space-feature measures provide a flexible representation for the registration of recently developed molecular imaging modalities.•Their discretization on simplicial meshes induces a new variation on the large deformation diffeomorphic metric mapping family of algorithms.•This algorithm can be adapted to perform atlas-based registration.•They can be interpreted in terms of point process realizations.
Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric ...conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1's oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments.
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