Robustness and Randomness

Robustness problems of computational geometry algorithms is a topic that has been subject to intensive research efforts from both computer science and mathematics communities. Robustness problems are caused by the lack of precision in computations involving floating-point instead of real numbers. This paper reviews methods dealing with robustness and inaccuracy problems. It discussed approaches based on exact arithmetic, interval arithmetic and probabilistic methods. The paper investigates the possibility to use randomness at certain levels of reasoning to make geometric constructions more robust

Biophysical and structural characterisation of the c-Myc/Mid2 complex – Elucidation of a molecular platform for new c-Myc inhibitors discovery

c-Myc est un facteur de transcription de type bHLH-LZ qui joue un rôle central dans la croissance et la prolifération cellulaire en contrôlant l’expression d’une pléthore de gènes impliqués dans la ribogénèse, le métabolisme, l’apoptose et le cycle cellulaire. Les niveaux d’expression de c-Myc sont dérégulés et surélevés suite à l’activation d’oncogène pilotes ou à la translocation de son gène. Elle devient alors oncogénique et contribue à la tumorigénèse d’un vaste éventail de cancer. De plus, les cellules tumorales surexprimant c-Myc deviennent dépendantes à son activité transcriptionnelle exacerbée et cette dépendance représente le talon d’Achille des cellules tumorales. En effet, son inhibition avec une protéine dominante négative (Omomyc) dans plusieurs modèle cellulaires et murins de cancer mène à un effondrement des tumeurs établies. Grâce à ces travaux, c-Myc est maintenant reconnue comme une cible thérapeutique importante et beaucoup d’efforts sont maintenant consacrés pour trouver des inhibiteurs de son activité transcriptionnelle. L’activité transcriptionnelle de c-Myc passe par son hétérodimérisation avec Max, un autre facteur de transcription de type bHLH-LZ, et sa liaison à des régions promotrices d’ADN. Plusieurs groupes de recherche ont tenté de développer des petites molécules capables de lier c-Myc spécifiquement afin d’empêcher cette étape préalable. De par la nature intrinsèquement désordonnée de c-Myc, l’approche classique n’a pu permettre, jusqu’à présent, le développement d’inhibiteurs spécifique avec une utilité clinique. Dans le cadre d’une précédente étude effectuée dans le laboratoire, nous avons montré qu’une région de Miz-1, un facteur de transcription de type BTB/POZ, pouvait lier spécifiquement c-Myc. Cette région de Miz-1, appelée Mid2, forme un complexe avec c-Myc et l’empêche d’héterodimériser avec Max. Ainsi, le complexe c-Myc/Mid2 offre une plateforme alternative pour développer une nouvelle génération d’inhibiteurs contre c-Myc. Ce mémoire rapporte une étude structurale et biophysique du complexe c-Myc/Mid2 ainsi que sa capacité en tant qu’inhibiteur prototypique. Le chapitre 1 présentera un état des connaissances sur c-Myc et Miz-1, exposera les inhibiteurs de c-Myc déjà existants ainsi que les particularités attribuées aux protéines intrinsèquement désordonnées. Le chapitre 2 explique les méthodes utilisées afin de mener à bien le projet. Le chapitre 3 expose l’étude des caractéristiques biochimiques du Mid2 sous forme de petits peptides, ainsi que leur capacité à complexer c-Myc et de compétitionner avec Max afin d’empêcher la liaison de l’hétérodimère à l’ADN. L’application des déterminants structuraux élucidés dans ce mémoire de maitrise permettront le développement d’une nouvelle génération d’inhibiteurs de l’oncoprotéine c-Myc, pouvant mener au final à de nouvelles thérapies pour vaincre le cancer.Abstract: The c-Myc oncoprotein, a bHLH-LZ type transcription factor, plays a central role in cellular growth and proliferation by activating and repressing a plethora of genes implicated in ribogenesis, metabolism, apoptosis and cell cycle. The importance of this role is highlighted when c-Myc expression levels are upscaled/deregulated by its translocation or the activation of pilot oncogenes. The protein then becomes oncogenic and contributes toward the tumorigenesis of a wide variety of cancers. Tumor cells overexpressing c-Myc are then addicted to its enhanced transcriptional activity. This addiction is the Achille’s heel of cancer cells. In fact, inhibition with a negative dominant protein (Omomyc) in a variety of cancer cell lines and mice models leads towards tumor regression. This work led to c-Myc being recognised as an important therapeutic target and considerable efforts are now being made to find inhibitors for its transcriptional activity. c-Myc’s transcriptional activity is done in heterodimer with Max, another bHLH-LZ transcription factor, and their binding to DNA promoter regions. Many research groups attempted to develop small molecule inhibitors capable of specifically binding c-Myc to prevent the heterodimerization step. By the intrinsically disordered nature of c-Myc, rational drug design couldn’t, to this day, develop specific inhibitors with a clinical utility. In previous experiments done in our laboratory, we showed that a region of Miz-1, a BTB/POZ transcription factor, could specifically bind c-Myc. This Miz-1 region, Mid2, forms a complex with c-Myc and prevents its heterodimerization with Max. Thusly, the c-Myc/Mid2 complex offers an alternative platform for the development of a prototypic c-Myc inhibitor. This Master’s thesis is a structural and biophysical study of the c- Myc/Mid2 complex and its potency as a prototypic inhibitor. The first chapter will feature knowledge about c-Myc and Miz-1, existing direct c-Myc inhibitors and the particularities about intrinsically disordered proteins. Chapter two explains the methods used to carry out the project. Chapter three exposes a thermodynamical and biophysical study of Mid2 born peptides, their characterization in complex or not with c-Myc and their competition with Max to form the complex in presence of DNA. The application of elucidated structural determinants in this Master’s thesis will permit the development of a new generation of direct inhibitors for the c-Myc oncoprotein, leading towards novel therapies to fight cancer

Les enjeux de l’hadronthérapie par ions carbone

National audienceL’ambition de doter la France d’un centre de traitement des tumeurs par faisceaux d’ions carbone est née, à la fin des années 1990, de la rencontre à l’Université Claude Bernard Lyon 1 de quelques médecins et physiciens, convaincus que la France avait toutes les capacités médicales et scientifiques pour initier un tel programme. Ce projet de « carbonethérapie » prit le nom de projet ETOILE (Espace de Traitement Oncologique par Ions Légers en Europe) au début des années 2000. Pour comprendre pourquoi il n’a pas été réalisé et évaluer les chances pour qu’il le soit un jour, il faut analyser les enjeux, les difficultés et les avantages de la carbonethérapie, comparée à la protonthérapie et aux formes les plus avancées de la radiothérapie

Biological systems: from water radiolysis to carbon ion radiotherapy

International audienceHadron therapy is an innovative cancer treatment method based on the acceleration of light ions at high energy. In addition to their interesting profile of dose deposition, which ensures accurate targeting of localized tumors, carbon ions offer biological properties that lead to an efficient treatment for radio-and chemo-resistant tumors and to provide a boost for tumors in hypoxia. This paper is a short review of the progress in theoretical, experimental, fundamental and applied research, aiming at understanding the origin of the biological benefits of light ions better. As a limit of such a vast and multidisciplinary domain, this review adopts the point of view of the physicists, leaning on results obtained in connection with CIMAP's IRRABAT platform. 1. Introduction Interaction of fast ions with biological systems constitutes one aspect of the interdisciplinary researches performed with ion-beam facilities. This domain is as rich as it is complex since it encompasses several orders of magnitude in both space and time. The shortest space and time scale corresponds to atomic collisions, which may be as short as 10 −18 s for the interaction of fast ions with individual atoms. At the opposite end of this domain, late effects – like cancer induction, chromosomal instability or organ dysfunctions – may appear or remain several years after irradiations. While irradiations may be limited to a very localized region, the whole behavior of an organ may be affected, possibly leading to human death, in particular when the irradiation dose and spatial extension are high. Between these two extreme scales, stands a great number of mechanisms, including for instance: the transport of the primary ejected electrons, the relaxation of the ionized and excited molecules, which may lead to direct damage in biological targets and to radical species and associated biochemical reactions. These early physical and chemical stages are followed by numerous and complex cell responses, such as the triggering of mechanisms to check DNA, to repair its damage, to manage the oxidative stress or to induce cell death. The numerous biological endpoints that have been studied reveal the complexity and the diversity of this biological response. These endpoints may involve particular structures of cells at the molecular scale (tracking of protein activities, damage in DNA, protein or lipid) or at the sub-cellular scale (chromosomes, nucleus, membranes, mitochondria.. .) and may concern cell organization (3D cell culture, tissues, organs, body). The domain of low dose

Dérivation d'une mesure vectorielle sur un intervalle

Article dans "Séminaire d'analyse convexe", Montpellier, exposé n°

Glacier flow monitoring by digital camera and space-borne SAR images

International audienceMost of the image processing techniques have been first proposed and developed on small size images and progressively applied to larger and larger data sets resulting from new sensors and application requirements. In geosciences, digital cameras and remote sensing images can be used to monitor glaciers and to measure their surface velocity by different techniques. However, the image size and the number of acquisitions to be processed to analyze time series become a critical issue to derive displacement fields by the conventional correlation technique. In this paper, an efficient correlation software is used to compute from optical images the motion of a serac fall and from Synthetic Aperture Radar (SAR) images the motion of Alpine glaciers. The optical images are acquired by a digital camera installed near the Argentière glacier (Chamonix, France) and the SAR images are acquired by the high resolution TerraSAR-X satellite over the Mont-Blanc area. The results illustrate the potential of this software to monitor the glacier flow with camera images acquired every 2 h and with the size of the TerraSAR-X scenes covering 30 × 50 km2

Magnetic Behavior Of Rare-earth Iron-rich Intermetallic Compounds

The thermal variation of lattice parameters of rare earth-transition metal intermetallic compounds rich in Fe, Co, or Ni in the temperature range of 25-900oK is studied. For the Fe compounds, negative thermal expansion is observed below their magnetic ordering temperatures regardless of the nature of substitutional ordering. For Co and Ni compounds, the thermal expansion behavior is normal. It is then concluded that for the Fe compounds, the magnetic properties are mainly determined by the Fe-Fe interatomic distances and the number of Fe nearest neighbors, whereas for Co and Ni compounds the magnetic properties are determined by the conduction electron transfer from the rare earth to the 3 d band of Co or Ni, The anomalous thermal expansion of Fe compounds and the metamagnetic transition of the Lu compound is explained in terms of the distance dependence. of the interaction energy as proposed by Neel. © 1971, IEEE. All rights reserved

A chest wall model based on rib kinematics

International audienceThe success of radiotherapy treatment could be compromised by motion. Lung tumours are particularly concerned by this problem because their positions are subject to breathing motion. To reduce the uncertainty on the position of pulmonary tumours during breathing cycle, we propose to develop a complete thoracic biomechanical model. This model will be monitored through the measurement of external parameters (thorax outer-surface motion, air flow...) and should predict in real-time the location of lung tumour. In this paper, we expose a biomechanical model of the lung environment, based on anatomical and physiological knowledge. The model includes the skin, the ribs, the pleura and the soft tissue between the skin and the ribcage. Motions and deformations are computed with the Finite Element Method. The ribcage direct kinematics model, permits to compute the skin position from the ribs motion. Conversely, the inverse kinematics provides rib motion and consequently lung motion. It can be computed from the outer-surface motion. With regards to available clinical data the results are promising. In particular, the average error is lower than the resolution of the CT-scan images used as input data.Le succès du traitement par radiothérapie pourrait être compromis par le mouvement. Les tumeurs pulmonaires sont particulièrement concernées par ce problème, parce que leurs positions sont soumises à la respiration. Pour réduire l'incertitude sur la position des tumeurs pulmonaires au cours de la respiration, nous proposons de développer un modèle biomécanique de la cage thoracique. Ce modèle sera suivi par la mesure des paramètres externes (mouvement de la surface du thorax extérieur, quantité d'air inspirée et expirée ...) et devrait prévoir en temps réel la localisation de la tumeur du poumon. Dans ce document, nous exposons un modèle biomécanique de l'appareil respiratoire, fondé sur les connaissances anatomiques et physiologiques. Le modèle comprend la peau, les côtes, la plèvre et les tissus mous entre la peau et la cage thoracique. Les mouvements et les déformations sont calculées avec la méthode des éléments finis. Le modèle cinématique direct de la cage thoracique permet de calculer la position de la peau à partir du mouvement des côtes. Inversement, la cinématique inverse permet de déduire le mouvement des côtes et des poumons à partir du mouvement externe de la peau. Les résultats obtenus par ce modèle sont satisfaisants surtout que l’erreur moyenne est inférieure à la résolution des images CT-scan utilisées comme données d’entrée

A Preliminary Study For A Biomechanical Model Of The Respiratory System

Engineering and Computational Sciences for Medical Imaging in Oncology - ECSMIO is the special session 1 of International Conference on Computer Vision Theory and Applications - VISAPP 2010International audienceTumour motion is an essential source of error for treatment planning in radiation therapy. This motion is mostly due to patient respiration. To account for tumour motion, we propose a solution that is based on the biomechanical modelling of the respiratory system. To compute deformations and displacements, we use continuous mechanics laws solved with the finite element method. In this paper, we propose a preliminary study of a complete model of the respiratory system including lungs, chest wall and a simple model of the diaphragm. This feasibility study is achieved by using the data of a "virtual patient". Results are in accordance with the anatomic reality, showing the feasibility of a complete model of the respiratory system