Tomographic diffractive microscopy: towards highresolution 3-D real-time data acquisition, image reconstruction and display of unlabeled samples

Tomographic diffractive microscopy allows for imaging unlabeled specimens, with a better resolution than conventional microscopes, giving access to the index of refraction distribution within the specimen, and possibly at high speed. Principles of image formation and reconstruction are presented, and progresses towards realtime, three-dimensional acquisition, image reconstruction and final display, are discussed

Roadmap on Label-Free Super-resolution Imaging

Label-free super-resolution (LFSR) imaging relies on light-scattering processes in nanoscale objects without a need for fluorescent (FL) staining required in super-resolved FL microscopy. The objectives of this Roadmap are to present a comprehensive vision of the developments, the state-of-the-art in this field, and to discuss the resolution boundaries and hurdles that need to be overcome to break the classical diffraction limit of the label-free imaging. The scope of this Roadmap spans from the advanced interference detection techniques, where the diffraction-limited lateral resolution is combined with unsurpassed axial and temporal resolution, to techniques with true lateral super-resolution capability that are based on understanding resolution as an information science problem, on using novel structured illumination, near-field scanning, and nonlinear optics approaches, and on designing superlenses based on nanoplasmonics, metamaterials, transformation optics, and microsphere-assisted approaches. To this end, this Roadmap brings under the same umbrella researchers from the physics and biomedical optics communities in which such studies have often been developing separately. The ultimate intent of this paper is to create a vision for the current and future developments of LFSR imaging based on its physical mechanisms and to create a great opening for the series of articles in this field.Peer reviewe

Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission

Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Étude et réalisation d un système de transmission d images robuste pour canaux radiomobiles

Cette thèse traite de la problématique de la transmission d'images compressées sur les canaux radiomobiles. L'approche classique qui consiste à considérer séparement le codage de source et le codage de canal conduit souvent à des systèmes complexes et possédant des rendements de codage assez faibles (< 30%). Dans le but de concevoir un système robuste et peu complexe, l'approche suivie dans ce travail a été celle de l'optimisation conjointe des éléments du système de transmission et a consisté à adapter un codeur d'image propriétaire appelé WTSOM, initialement conçu pour des transmissions à fort TEB, aux contraintes des canaux radiomobiles. Pour ce faire, nous avons d'une part, fait le point sur les différents aspects du codage de canal, comme les modulations numériques et le codage correcteur d'erreurs, en développant la plupart des algorithmes qui nous ont ensuite permis d'évaluer les performances des différentes solutions. D'autre part, nous avons également fait le point sur les techniques de modélisation statistique des canaux radiomobiles ce qui nous a permis de disposer de modèles de canaux réalistes pour évaluer nos stratégies de transmission. Les solutions adoptées ont conduit au système WTSOM-Wireless qui tolère des TEB de plus de 5% avec un rendement de codage de 74%. Ce système ne nécessite pas d'estimation de canal et est de type BICM : il combine des Turbo Codes en Blocs à haut-rendement à une modulation différentielle à haute efficacité spectrale appelée 16DAPSK. Il intègre également un algorithme de restauration d'image très efficace basé sur les EDP et qui exploite l'information de fiabilité en sortie du Turbo décodeur. Nous comparons notre système à la norme JPWL et constatons que celui-ci tolère des TEB dix fois supérieurs et qu'il est également relativement insensible aux variations de la fréquence Doppler du canal. Enfin, dans une dernière partie, nous validons nos stratégies grâce à la conception et à la mise en oeuvre d'un système expérimental qui a nécessité l'implementation des fonctions de synchronisation indispensables à tout système de communication numérique pratique.This thesis deals with the transmission of compressed images over mobile fading channels. Most of the time, the classical approach, which consists in designing separately the source and charnel coding parts, yields complex and low code rate systems (<30%). In order to design a robust system and of low complexity, the approach followed in this work has been to jointly optimise the different parts which make up the transmission system and has consisted in adapting a proprietary image coder called WTSOM, initially designed for high BER transmissions, to the constraints of mobile fading channels. For that purpose, we have on the one hand, reviewed several aspects of channel coding like digital modulations and error correction coding by developing most of the algorithms needed. These have enabled us to assess the performance of different design solutions. On the other hand, we have also reviewed the statistical methods used to model mobile fading channels. This has enabled us to design realistic channel models which we have used to evaluate our transmission strategies. The solutions adopted have led to the design of the WTSOM-Wireless system which tolerates BER values of more than 5% together with an overall code rate of 74%. This system does not require any channel estimation and is of the BICM type: it combines high rate Block Turbo Codes and a high spectral efficiency differential modulation called 16DAPSK. It also integrates a very efficient PDE-based image restoration algorithm which takes advantage of the reliability information at the output of the Turbo decoder. We have compared this system to the JPWL standard and have noticed that it tolerates BER values ten times higher than JPWL and that it is also relatively insensitive to the Doppler frequency of the channel. Finally, in the last part of this thesis, our strategies have been validated thanks to the design and the implementation of an experimental testbed which required the implementation of all the synchronisation fonctions needed in a real digital communication system.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Modélisation et simulation informatique de la transmission nerveuse

Au cours des dernières années, la biologie et plus généralement la recherche médicale, a connu des avancées majeures grâce aux nombreux progrès de la microscopie, de la génétique, de la biologie moléculaire, de la protéomique, et du séquençage à haut débit. Il s agit maintenant d identifier à partir de toutes ces données gigantesques, les grandes lois de la biologie. Le principe de la biologie intégrative ou systémique est de poser les bases d'une véritable théorie de l'organisation fonctionnelle du vivant à partir des différents mécanismes découverts expérimentalement. De la même manière que l'on décrit la matière par les théories des mathématiques, de la physique, et de la chimie, on veut pouvoir comprendre, formaliser et modéliser le fonctionnement des mécanismes du vivant. Cette thèse a consisté à réaliser une bibliothèque de modèles fonctionnels des réactions chimiques qui prennent place dans les cellules nerveuses aussi appelés modèles élémentaires et de les assembler afin d obtenir un système mimant le plus finement possible les mécanismes de la propagation du signal électrique au sein d une synapse. Les travaux réalisés jusqu'alors ont permis de modéliser les mécanismes essentiels et de reconstituer le comportement d une synapse glutamatergique. En particulier, l utilisation de cette nouvelle méthode de recherche et de développement de médicaments a pour objectif de proposer des molécules innovantes, en optimisant leurs propriétés biochimiques. Cette technique permettra, dans un futur proche, l'avènement d'une nouvelle génération de pharmaceutiques, dit multi-cibles, c'est-à-dire permettant d'intervenir sur les différents mécanismes d'une pathologie.In recent years, biology and medical research more generally, has seen major advances in microscopy, genetics, molecular biology, proteomics, and high-throughput sequencing. We now identify from these huge data, the great laws of biology. The principle of integrative biology or systemic is to defined the basis of the foundations for a theory of the functional organization of living from different mechanisms discovered experimentally. In the same way that matter is described by the theories of mathematics, physics, and chemistry, we want to understand, formalize and model the functioning of living mechanisms. This thesis has been to achieve a library of functional models of chemical reactions that take place in nerve cells also called elementary models and assemble them to obtain a system mimicking the finest possible mechanisms of electrical signal propagation within of a synapse. The work done so far allow us to model the essential mechanisms and reconstruct the behavior of a glutamatergic synapse. In particular, the use of this new method of research and drug development aims to offer innovative molecules by optimizing their biochemical properties. This technique will, in the near future, the advent of a new generation of pharmaceuticals, said multi-target, able to intervene on the different mechanisms of disease.MULHOUSE-SCD Sciences (682242102) / SudocSudocFranceF

Robust image transmission strategies for fading channels

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Smith-Purcell Radiation from Electrons Moving Parallel to a Grating at Oblique Incidence to the Rulings.

Abstract not availableJRC.D-Institute for Reference Materials and Measurements (Geel