Дисертації з теми "Modélisation prédictive – Dissertation universitaire"
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Bremaud, Luc. "Contribution à la modélisation de l’endommagement sous sollicitations dynamiques de céramiques." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE092.
Ceramics play a crucial role in both the industrial and military sectors due to their unique thermomechanical properties. However, their behavior under dynamic loading is complex, with significantly lower tensile strength compared to compression, leading to cracking, damage, and multi-fragmentation. The pursuit of advanced technology necessitates continuous development of the ballistic properties of ceramics. The high cost and technical complexity of dynamic experiments have given rise to simulation programs that seek to digitally replicate the dynamic fracture behavior of these materials.This thesis explored the application of the Discrete Element Method (DEM) to enhance the reproduction of dynamic phenomena in brittle ceramics, with a focus on representing cracking and the evolution of stress at fracture with strain rate. Alumina was chosen as the study material due to the abundance of experimental data available in the literature.The third chapter dealt with the representation of the material in the elastic regime, while the fourth chapter examined the incorporation of different damage models within the discrete approach. Comparisons between experimental and numerical rear face velocity profiles from Gas Gun Projectile Impact (GEPI) tests showed that the use of the Denoual-Forquin-Hild (DFH) and Kachanov laws provided good correlation with experimental data.The fifth chapter presents various types of experimental dynamic fragmentation tests on AL23 alumina: Rockspall tests, edge-on impact tests (from the literature), and laser shock experiments. DEM numerical simulations, using the previously identified damage law as the one that best reproduces GEPI spall tests, were conducted to represent the damage mechanisms, simple and multiple fragmentation of AL23 alumina targets subjected to extreme loading conditions.Finally, to obtain experimental data on dynamic tests of a new ceramic with a more complex behavior, an experimental campaign was conducted on plasma-sprayed yttria-stabilized zirconia. Impact-on-edge and Rockspall tests were carried out to study simple and multi-fragmentation of this ceramic with a complex microstructure. This provided experimental data that will be used in future modeling efforts.In summary, this thesis contributes to improving the replication of the behavior of brittle ceramics subjected to dynamic loading such as impacts or shocks. It highlights the potential of the DEM method to represent multi-fragmentation phenomena and identifies relevant damage models for simulating dynamically observed effects. These results have significant implications for representing the dynamic fracture behavior of high-performance armor materials in various industrial and military applications
Amoretti, Thomas. "Développement d’un outil de modélisation et d’optimisation pour les éoliennes à double rotor : application à la comparaison avec l’éolien classique." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE079.
The production of energy with low greenhouse gas emissions is a major objective of global sustainabledevelopment. One of the promising technologies for achieving this is wind power. The work presented in this manuscript concerns the study of an innovative horizontal-axis wind turbine system with two successive rows of rotors. The main objective is to compare multi-rotor technology with "conventional" wind turbine technology, in order to establish the advantages and disadvantages of each in a given use case. Dual-rotor wind turbines can have the rotors turning in opposite directions (contra-rotating) or in the same direction (co-rotating), which influences the performance obtained.To make this comparison, modeling and optimization tools were developed to compare the technologies as broadly as possible, without any preconceived ideas about the parameters to be set. Following a literature review, the comparison criteria selected were AEP (Annual Energy Production) and turbine mass. The modeling is based on a faithful, fast-resolving aerodynamic model, based on BEM (Blade Element Momentum) theory adapted for two rotors. This aerodynamic model interacts with mechanical, electromechanical and component weight models to describe the behavior of each technology. The models are coupled with a control strategy to provide performance values for thewind turbines modeled in this way. To find instances of each wind turbine technology for comparison, single-objective optimization algorithms (PSO) or unweighted multi-objective optimization algorithms (NSGA-II) were used. The models were validated by comparison with data from the literature and specialized software (Qblade and HELICIEL), and the comparison between technologies was carried out on a case study including a specific statistical wind distribution
Mboup, Bassirou. "Validation de biomarqueurs prédictifs de la réponse au traitement : extension des courbes de prédictivités à un critère de jugement censuré On Evaluating How Well a Biomarker Can Predicttreatment Response With Survival Data Insights for Quantifying the Long-Term Benefit of Immunotherapy Using Quantile Regression." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASR011.
It is common in oncology to want to determine whether or not only a subgroup of patients will benefit from a treatment. This is one of the paradigms of personalized or stratified medicine. Predictive biomarkers are often used to select these patients and most of these biomarkers are continuous. For example genomic signatures such as Oncotype-Dx. A methodology for evaluating a biomarker with binary response has been proposed in the literature. The objective of this thesis is in first work to extend this methodology with right-censored data and to determine at different prediction horizons the optimal threshold of the biomarker beyond which treatment will be attributed or avoided. A model whose estimates of these parameters are based on inverse censored probability weights is proposed to provide consistent estimators. An extension of the predictiveness curves will be carried out. In a second work, a test of the calibration hypothesis with right-censored data has been proposed. This test will be valid beyond the 60% censoring rate contrary to those already existing in the literature and will allow us to study the influence of a bad calibration on the determination of the threshold. A third work focuses on the determination of the threshold of a new prognostic biomarker for ovarian cancer in order to classify patients at high or low risk of relapse. Finally, a fourth work consists in illustrating the relevance of the censored quantile regression for quantifying the long term benefit of immunotherapy in a reconstructed data set from a single randomized trial. The proposed methodology can be readilty employed for individual patients data meta-analysis to summarize evidence of immunotherapy as quantified by the upper quantile of the survival distribution
Loisel, François. "Analyse cinématique et biomécanique de la main et du poignet par modélisation personnalisée. Effet de lésions et d’instrumentations." Electronic Thesis or Diss., Paris, HESAM, 2023. http://www.theses.fr/2023HESAE097.
The architecture of the hand and wrist is a complex set of articulations enabling the efficient execution of all the gestures of daily life.Precision of movement and transmission of effector forces require optimal joint congruence and bone cohesion ensured by an organized ligament system.Any trauma resulting in articular step off (fracture) or loss of bone cohesion (ligament rupture) is likely to produce pathological kinematics within these joints. The result is pain, decrease range of motion and impaired overall function. Knowledge of the pathophysiological mechanisms leading to these disorders is essential on several levels: firstly, in a diagnostic context, to be able to identify and treat any injury, even a partial one. Secondly, to improve overall knowledge of the physiological and pathological kinematics of the hand and wrist. And lastly, as part of an innovation drive to propose new solutions (implants) to unresolved problems.The design of customized geometric and biomechanical models in the general context of the study of human joints provides answers to these types of questions. In preliminary work, linked to my Master's research and Stan Durand's thesis, biomechanical tests were carried out on anatomical parts to analyze the effect of a specific implant on the kinematic behavior of the wrist, and to design a method for personalized modeling of the hand and wrist using low-dose biplane X-rays.Following on from this project, this thesis has several objectives.The first objective is to validate our method of personalized hand and wrist modeling in living subjects, by comparing it with the reference technique of TDM segmentation.Secondly, we will apply this method to create a corridor of physiological displacement of certain carpal bones of interest (scaphoid, lunate, triquetrum), between two reference positions (wrist in neutral position or closed fist) among a population of volunteers free of ligament lesions. This corridor of normality is useful for comparing physiological and pathological displacements in clinical practice.Indeed, the third objective is to compare carpal kinematic data from patients with infra-radiological ligament lesions with this corridor of normality. The aim is to assess the diagnostic capabilities of the customized model. By analyzing pre- and post-operative data, a feasibility study will also investigate the field of objective follow-up of surgical restoration by suture or ligament re-anchoring.The aim of such a study is therefore to use geometric, kinematic and biomechanical models of the hand and wrist to assess normal and pathological kinematics (diagnosis), and to analyze current surgical implants in order to propose areas for improvement
Aussem, Alexandre. "Théorie et applications des réseaux de neurones récurrents et dynamiques à la prédiction, à la modélisation et au contrôle adaptif des processus dynamiques." Paris 5, 1995. http://www.theses.fr/1995PA05S002.
Bauvin, Pierre. "Modélisation de la stéatose hépatique (NAFLD) et de ses facteurs de risque par apprentissage sur des données de santé." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S028.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which is a combination of simple, slowly progressing steatosis, and non-alcoholic steatohepatitis (NASH), an inflammatory form which accelerates its progression. It is estimated that one in four people in the world is affected by NAFLD, and its prevalence is increasing rapidly, in parallel with the prevalence of its main risk factors: overweight, obesity and type 2 diabetes.This pathology is asymptomatic up to the complications, cirrhosis and liver cancer (hepatocellular carcinoma, HCC), which leads to late diagnosis and a negative impact on the associated morbidity and mortality. Furthermore, the reference diagnosis requires a liver biopsy, an invasive examination that cannot be performed routinely. As a result, the progression of the disease is poorly known and its estimation may suffer from a selection bias, towards patients with significant risk factors, who require a biopsy in the first place. A better understanding would allow the implementation of strategies to reduce its burden.The modelling approach is appropriate to take into account all susceptible patients, without having to carry out a large-scale follow-up study using liver biopsies in patients who are mostly asymptomatic. The objectives of this thesis are to describe and quantify the progression of NAFLD, to predict the associated morbidity and mortality, and to identify the population at risk, using Markov models. To do this, it is necessary to fill in some of the progression parameters via a literature review, to characterise the initial states (population likely to develop NAFLD) and the final states (mortality due to NAFLD), in order to deduce the missing progression parameters between the onset of the disease and mortality, by back-calculation.To exhaustively characterise NAFLD mortality, we identified all patients with cirrhosis or HCC from national hospital databases, representing more than 380,000 patients. We then developed an identification algorithm to determine the etiology underlying the hepatic complication, based on all the stays of the identified patients. This algorithm requires the identification of patients with cirrhosis or HCC of alcoholic or viral origin, to obtain by elimination only NAFLD patients. Once the specific mortality data had been obtained, we estimated the population likely to develop NAFLD, defined as all individuals with overweight or type 2 diabetes, excluding the population of excessive drinkers. We estimated the prevalence and incidence of this population, and modelled its evolution with age and years, based on individual data from surveys representative of the French population.Finally, we quantified the progression of NAFLD, and the impact of risk factors, using two approaches: from the literature, and from biopsy data from more than 1,800 obese patients who were candidates for bariatric surgery, resulting in a tool for predicting the progression of NAFLD in this population. We chose to back-calculate the progression parameters corresponding to the asymptomatic states, which are the most susceptible to selection bias.We obtained a model of the progression of NAFLD, taking into account the dynamic distribution of the population among weight classes and diabetes status, and resulting in the observed statistics of NAFLD deaths. The model takes into account gender, age, year, BMI (body mass index) class, diabetes status and the presence of a genetic polymorphism (PNPLA3 rs738409, C→G) as covariates of progression. It is a tool for assessing the impact of a possible treatment or public health policy on morbidity and mortality
Vuillod, Bruno. "Stratégie de modélisation multi-fidélité via une approche système incluant des métamodèles basés sur les entités NURBS." Electronic Thesis or Diss., Paris, HESAM, 2024. http://www.theses.fr/2024HESAE003.
The more complex the problem, the greater the amount of computational resources needed to simulate it. On the other hand, the need for accuracy in the results of a system will not be the same depending on its design phase and the domain studied. The goal of this thesis is to propose a fast, low-cost multi-fidelity modeling strategy. To meet this need, a hybrid modeling approach is developed that combines Model-Based System Engineering (MBSE) and a metamodel based on Non-Uniform Rational Basis-Spline (NURBS) hypersurfaces. More specifically, the scientific challenge of this work is to develop a metamodel based on NURBS entities to simulate the behavior of highly nonlinear systems that require high fidelity modeling but are capable of providing results in real time to be compatible with the MBSE approach. In this context, the NURBS entity-based metamodel is obtained as a solution to an optimization problem solved with a gradient algorithm. In addition, a smoothing term is included in the problem formulation, not only to reduce the influence of any spurious nonlinearities in the training database, but also to limit the phenomenon of overfitting. The technical and scientific challenge of this work is to couple the general MBSE approach with the NURBS-based metamodel
Werbrouck, Coralie. "Modélisation in vitro & in vivo de la résistance à la radiothérapie dans les gliomes infiltrants du tronc cérébral (DIPG) TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL001.
Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumours. Though accepted as the main therapeutic, radiotherapy is only transiently efficient and not even in every patient. We previously identified a heterogeneous response to radiotherapy at diagnosis (Castel et al., 2015). The aim of the project was to define the mechanisms of radioresistance.First, we assessed in vitro response to ionizing radiations in a collection of DIPG cellular models derived from treatment-naïve biopsies and we uncovered TP53 mutation as the main driver of increased radioresistance. We validated this finding in 4 isogenic pairs of DIPG cells with TP53WT and TP53KD. Then, we demonstrated with an extended cohort of 73 DIPG patients that mutated TP53 patients had a poor response to radiotherapy. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize TP53MUT DIPG to ionizing radiations. CHK1 inhibition increases response to radiation specifically in TP53MUT cells and could be considered as a new therapeutic approach in this setting. Finally, we established in vitro radioresistant DIPG cells to study tumour relapse and we developed tools to model post-radiotherapy relapse through the study of clonal dynamics using single cell RGB marking.In all, this results go further in the understanding of the DIPG radioresistance. We demonstrated that a TP53 alteration is a theranostic marker to predict radioresistance and we opened new therapeutic opportunities in combination with radiotherapy for the treatment of this pediatric disease, which remains incurable
Tounsi, Latifa. "Microalgue rouge du genre porphyridium : modélisation de la production de métabolites et application dans la production d'emballages actifs." Electronic Thesis or Diss., Université Clermont Auvergne (2021-...), 2023. http://www.theses.fr/2023UCFA0144.
A microalga was isolated from the Tunisian coast in the Mahdia governorate and subsequently identified using morphological criteria as well as molecular biology techniques. The isolate was identified as belonging to the genus Porphyridium. In the 1st part, Porphyridium sp. and Porphyridium cruentum UTEX 161 were grown in 3 culture media to identify the optimal growth medium and enhance the production of metabolites. Results showed that Porphyridium could thrive in a wide range of media. The highest biomass production was achieved with the Pm medium (2 × 107 cells/mL) for Porphyridium sp. The highest pigment content (chlorophyll a = 0.678 ± 0.005 pg/cell, total carotenoids = 0.18 ± 0.003 pg/cell, B-phycoerythrin = 3.88 ± 0.003 pg/cell) and soluble proteins (14.58 ± 0.35 pg/cell) were observed with F/2 medium. Porphyridium sp. accumulated a higher amount of starch in the F/2 medium (0.69 ± 0.016%) and was on par with the Hemerick medium (0.62 ± 0.050%). The Hemerick medium showed the most promise in terms of lipid (2.23%) and EPS (5.41 ± 0.56) production. For Porphyridium cruentum, the F/2 medium was the best medium for growth (4.65 × 106 cells/mL) and production of pigments (chlorophyll a = 1.76 ± 0.007 pg/cell, total carotenoids = 0.48 ± 0.0022 pg/cell, B-phycoerythrin = 15.77 ± 0.6 pg/cell), starch (3.97 ± 0.22%) and proteins (34.36 ± 1.035 pg/cell). However, the Pm and Hemerick media proved to be the best for supporting the production of lipid (4.51 ± 0.45%) and EPS (14.19 ± 0.19 pg/cell),. In the 2nd part, bioactive films based on gelatin and sodium alginate were developed by incorporating an aqueous extract of B-phycoerythrin from Porphyridium cruentum at different concentrations (45, 67.5, and 90 μg/mL). The optimization process yielded a maximum B-phycoerythrin content of 4.16 ± 0.24% under the following conditions: NaCl = 17 g/L, MgCl2.6H2O = 2.6 g/L and K2HPO4 = 0 g/L. The B-phycoerythrin extract demonstrated antibacterial and antioxidant properties. The incorporation of B-phycoerythrin led to a significant increase in water swelling index and solubility, as well as a notable decrease in moisture content. Furthermore, when added to gelatin and sodium alginate films, the B-phycoerythrin extract improved the L*, a*, and ΔE* values. X-ray diffraction analysis revealed that the addition of B-phycoerythrin extract had a positive influence on the crystallinity of the developed films. The films incorporating the B-phycoerythrin extract exhibited a homogeneous structure with a slightly rough surface. The new films demonstrated complete biodegradability and promising antioxidant potential
Sotty, Jules. "Toxicité in vitro des particules atmosphériques fines et ultrafines : focus sur les bronchopneumopathies chroniques et la fonction mitochondriale." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S024.
Epidemiological studies have highlighted an association between ambient particulate matter (PM) level and hospital admissions or even mortality related with exacerbation of asthma and chronic obstructive pulmonary disease (COPD). While the role of inhaled PM in exacerbating these pathologies has been reported, pathophysiological mechanisms initiating and maintaining airway inflammation are not yet well understood. Reported health issues seems to be mostly caused by finest particles, due to their ability to diffuse deeply in the lungs, where clearance is less effective. Although numerous experimental studies demonstrated the toxicity of fine particles (PM2.5), mainly through oxidative stress-induced airway inflammation, only few studies have paid close attention to the ultrafine fraction (PM0.1), which attains new properties at nanometric scale. Because of its high specific surface area, PM0.1 is likely to be more biologically reactive. In this study, in vitro assays were conducted, exposing differentiated models of human bronchial epithelial cells (HBEC), from healthy, asthmatic and COPD-diseased donors, to one or three low dose of PM0.18-2.5 and PM0.18. Cytotoxicity, extracellular secretion of proinflammatory mediators and gene expression were studied. Furthermore, mitochondrion is a major endogenous source of reactive oxygen species (ROS) through oxidative metabolism, and coordinate many cell survival signaling processes. In this context, alterations in mitochondrial dynamic and function might play a key role in maintaining PM-induced oxidative stress and inflammation within lung cells, especially in case of chronic lung diseases initiation and/or exacerbation. Human bronchial epithelial BEAS-2B cells were also acutely or repeatedly exposed to low doses of fine (PM0.18-2.5) or ultrafine (PM0.18) particles, in order to characterize mitochondrial dynamic and function without massive cell death. Results highlighted in this study should contribute to a better understanding of the mechanisms governing the initiation and/or exacerbation of chronic airway lung diseases induced by air pollution-derived fine and ultra-fine PM
Delacôte, Claire. "Vers une meilleure compréhension de la maladie du foie liée à l'alcool et des facteurs influençant sa progression : approche de modélisation." Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S029.
In France, excessive alcohol consumption is the leading cause of cirrhosis and hepatocellular carcinoma (HCC), ahead of viral hepatitis and metabolic syndrome. In 2016, there were nearly 10,500 deaths by cirrhosis or HCC, despite a significant decrease in per capita alcohol consumption since 1960 (26L in 1960, 11.7L in 2017).Alcohol drinkers are at risk of developing alcohol-related liver disease (ALD). It progresses from the initial stage of steatosis to more advanced stages of fibrosis and cirrhosis, which may lead to complications: decompensation and HCC. ALD is an asymptomatic disease prior to the onset of complications, and many patients are diagnosed late with life-threatening consequences.Implementing early actions targeting excessive alcohol drinkers could help to reduce liver morbidity and mortality through the avoidance or earlier diagnosis of complications. The evaluation of the possible benefit of such public health actions requires, on the one hand, knowledge of the different stages leading to the development of complications and, on the other hand, knowledge of the impact of risk factors on progression, in order to be able to determine the populations to target. Among the risk factors identified, the metabolic syndrome plays an important role. Thus, in order to understand the mechanisms of evolution of ALD, it is necessary to study in parallel those leading to non-alcoholic fatty liver disease (NAFLD).The natural history of ALD is still poorly described, especially for the stages preceding cirrhosis. Mathematical modeling provides a conceptual framework to overcome the ethical issues that would arise from a cohort study of the evolution of ALD.The main objective of this work is to mathematically reconstruct the natural history of ALD and to predict the associated morbidity and mortality. The secondary objectives are to estimate the incidence of this pathology and to identify the at-risk population. For this purpose, we developed a Markov model that simulates the trajectory of cohorts of individuals from the moment they start at-risk alcohol consumption until their death. It integrates the main risk factors described as associated with the progression of ALD in the literature (sex, age, overweight and obesity, amount of alcohol, genetic polymorphism). Unknown parameters of progression are estimated by a back-calculation method.Three steps were necessary to supply and calibrate this model : 1) characterize mortality by decompensated cirrhosis and HCC related to alcohol consumption or metabolic syndrome from data provided by the French National Hospital Discharge database; 2) set up a Markov model on hospitalization data of excessive consumers to estimate the progression of fibrosis; 3) implement a Markov model on survey data from the general French population to estimate the process of entry into at-risk alcohol consumption or the onset of overweight and obesity.In conclusion, this work is the first to characterize the progression of ALD in the general French population. It is based on robust epidemiological data to which new insights are provided. The developed tools could be used to test the impact of public health policies that could be implemented in populations most likely to develop liver damage
Gay, Marion. "Conception, synthèse et évaluation de composes interagissant avec la dégradation des protéines pour le traitement de maladies neurodégénératives." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S056.
Two physiopathological processes are involved in Alzheimer’s disease: the senile plaques (amyloid pathology) consisting of Aβ peptide aggregates and neurofibrillary tangles (Tau pathology) caused by the accumulation of hyper and abnormal phosphorylated Tau protein. Currently, only symptomatic treatments are available. Therefore, the development of curative drugs is a very active research field. Previous work in the laboratory led to the discovery of a family of compounds (MSBD) which lead-compounds are active on both pathologies of the Alzheimer’s disease. A drug candidate, AZP2006, emerged from that research and is currently in phase 1 clinical trials. Investigations on the identification of the biological target of AZP2006 led to p97/VCP protein, a target that has attracted considerable attention over the last few years for the treatment of neurodegenerative diseases (NDD).This PhD thesis deals with three main aspects:1) Study of the interactions between p97/VCP and developed compounds. STD-NMR studies have confirmed the interaction between AZP2006 and p97/VCP, though these preliminary results have to be confirmed by complementary techniques. AZP2006-based chemical probes were designed and synthesized to develop a FRET-based binding assay in order to get a more quantitative characterization of the binding.2) Development of new p97/VCP ligands. Based on previous ligands developed in the laboratory, a pharmacophore model was built. Subsequent, virtual screening and de novo design led to the identification of several chemical structures. Four families were synthesized and tested in vitro showing a good effect on Aβ peptides secretion and APP metabolism. These compounds are being tested on Tau hyperphosphorylation. The binding to p97/VCP was confirmed by STD-NMR.3) Development of multi target compounds acting on both the two pathology of Alzheimer disease and acetylcholinesterase (AChE). Activities of these compounds were validated in vitro (inhibition of AChE, Aβ peptides secretion, APP metabolism and Tau). In vivo, one of the compounds increased cognitive performance in two mice transgenic models.The results obtained during this PhD confirmed the therapeutic potential of p97/VCP in NDD and proposed new structures for their treatment
Deltreil, Guillaume. "Matrices emplois expositions biomécaniques et troubles musculosquelettiques : comment modéliser au mieux les contraintes physiques par matrice dans la prédictivité des troubles musculosquelettiques." Electronic Thesis or Diss., Angers, 2023. https://dune.univ-angers.fr/documents/dune17781.
Musculoskeletal disorders (MSDs) represent a major occupational health issue. The growth in the number of workers affected by these pathologies is a marker of the worsening of working conditions. Job-exposure matrices area tool for assessing the impact on the relationship between these conditions and these disorders. The objective of this thesis was to study, from a lifetime perspective,musculoskeletal disorders based on data from job-exposure matrices and using statistical tools.The CONSTANCES job-exposure matrix was used as a source of exposure across this work. It is based on the cohort of the same name and gathers personal and work-related data concerning the general population. Through the development of a tool, it was possible to select a logistic regression model linking the interaction between the duration of exposure and the level of exposure with the appearance of the pathology within the framework of the study of knee pain. It was showed that the level of exposure was the most strongly impacting factor (1.34-2.81) on the onset of disorders, although the duration also increased (0.83-1.10) the risks. Secondly, it was possible to found that this same model should also be selected for the study of low back pain and severe hand pain, with similar results. Finally, using a machine learning tool, it was possible to adapt our model within the framework of the study of the imbalance data. Tor the carpal tunnel surgery, the impact of the duration (1.29) was more important than in the other studies but it is the level of intensity (1.31) which remained the most determining.In conclusion, the job-exposure matrices made it possible to obtain an assessment of the impact of different factors on the occurrence of several disorders, even in a context of data imbalance, although many more studies are needed before it can be applied by practitioners
Guyot, Pauline. "Modélisation et analyse du signal électrocardiographique pour l'étude du système cardio-respiratoire. Application au syndrome d'apnées du sommeil." Electronic Thesis or Diss., Université de Lorraine, 2019. http://www.theses.fr/2019LORR0134.
The heart is at the center of the cardiorespiratory system and the electrocardiogram is one of the most standard medical exam to monitor it along with echocardiography. Electrocardiogram analysis is complex due to the various cardiac pathologies and the emergence of new measurement technologies allows the acquisition of longer but also noisier signals taken in a daily life context. Noise and the huge amount of processed data impose the development of more accurate and robust analytical methods. This thesis aims at developing a new modeling method of cardiac waves using a dictionary composed of skew normal distribution. It fully characterizes each wave (P, Q, R, S and T) through a small number of parameters. This modeling also permits the precise computation of the different classical intervals used in electrocardiography but also the classification of each beat to provide an accelerated reading of long signals and a diagnostic assistance. Finally, those analytical tools are used on two different subjects: the creation of an electrocardiogram simulator as part of the Hopital Virtuel de Lorraine project ; and the detection of sleep apnea syndrom on electrocardiogram signals and more particularly the Cheyne-Stokes respiration, a nocturnal respiratory pathology still not understood, primarily impacting patients with severe heart failure. The method is based on the extraction of signals correlated to respiration from the electrocardiogram signal and allows to graduate different levels of the Cheyne-Stokes respiration
Champon, Isabelle. "Compréhension et modélisation des mécanismes de désactivation d’un catalyseur de méthanation de CO2 au sein d’un réacteur-échangeur milli-structuré à lit fixe." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAF045.
Power-to-SNG aims at storing the renewable electric surplus as SNG (Substitute Natural Gas) via the CO2 methanation reaction with a solid catalyst. For the purpose of the SNG direct injection into the gas network, high conversion rates are needed. Nevertheless, over time, the catalyst deactivates and the SNG may no longer meet the gas network injection specifications. In this work, a methodology is developed to understand the main deactivation mechanisms of a commercial catalyst (Ni/Al2O3) in a milli-structured fixed-bed reactor-heat exchanger in order to model them. Deactivation is dealt with at different experimental scales. A kinetic model and deactivation laws are identified and subsequently implemented in an already existing multi-scale reactor model. Finally, the simulation results are compared with experimental deactivation results obtained at the scale of the milli-structured reactor
Briki, Amani. "Production de succinate par Corynebacterium glutamicum en microaérobiose : approches expérimentales et numériques, de l’échelle métabolique au bioréacteur." Electronic Thesis or Diss., Université de Lorraine, 2021. http://www.theses.fr/2021LORR0082.
Succinate is a diacid used nowadays as a building block in the synthesis of various molecules of interest. It is mostly produced by chemical synthesis. A part of succinate is industrially produced using a microbiological process. Corynebacterium glutamicum, a well-known industrial producer of amino acids, is able to produce organic acids, in particular succinate, under micro-aerobic and anaerobic conditions. The aim of this work was thus to understand the physiological response of C. glutamicum 2262 to change in oxygen supply conditions. Both experimental and numerical tools have been implemented. The first step was to identify, experimentally, the parameters influencing the physiological response of C. glutamicum 2262 during batch and continuous cultures. This approach allowed to identify oxygenation level and residual glucose concentration as key parameters for organic acids production. The ratio OUR/GUR was also defined as a relevant indicator of the physiological state of C. glutamicum 2262. It was observed that organic acids were simultaneously produced during micro-aerobic phase corresponding to ratio below 1, whereas, above this value, a maximal growth was obtained. The maximal succinate production was obtained at the lower oxygenation level. Moreover, a re-consumption of the produced succinate was also observed when a threshold residual concentration of glucose was reached. Considering the influence of these two key parameters, a highly performant fed-batch process for the succinate production using a wild-type strain of C. glutamicum was defined. Then, a kinetic model was developed. This primary model was then generalized by integrating a correlation between kinetic parameters of model and oxygenation level. The results of both primary and generalized model simulation, showed an excellent agreement with the experimental data. The generalized model was then successfully transposed to a C. glutamicum mutant strain. In addition, a simplified metabolic model for C. glutamicum 2262 was constructed to understand the metabolic response of this bacterium in micro-aerobiosis. Both predicted production fluxes of lactate in microaerobiosis and of biomass synthesis during aerobiosis phase, under stationary conditions, agreed with the experimental data. This metabolic model was also able to predict, under dynamic conditions, the concentration profiles of the succinate during highly limited oxygen supply conditions
Pérez, lanzón María. "Modeling Hormone Receptor Positive Breast Cancer in Immunocompetent Mice Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression Organoids for Modeling Genetic Diseases. In: International Review of Cell and Molecular Biology A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells Failure of immunosurveillance accelerates aging The metabolomic signature of extreme longevity: Naked mole rats versus mice Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL019.
Progress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer
Missiaen, Lise. "Quantification des changements de la circulation océanique profonde de l'Atlantique au cours des changements climatiques rapides des derniers 40 ka." Electronic Thesis or Diss., Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV004.
The last 40 ky, have been characterized by abrupt and high amplitude temperature changes (8 to 15 °C in less than 300 years) in Greenland and in the North Atlantic region, associated with drastic ocean and atmospheric circulation changes. The mechanisms behind these abrupt climate changes are still debated. The objective of this thesis is to quantify the ocean circulation changes associated with these abrupt climate changes. In the first part of this thesis, I combined the information of three geochemical proxies in order to overcome the limitations of each proxy taken separately. The carbon isotopic ratios of the benthic foraminifers (δ13C and Δ14C), as well as the sedimentary Pa/Th ratio, have been measured in the North Atlantic sediment core SU90-08 (43°N, 30°W, 3080m). The proxies depict an apparently inconsistent situation over the last glacial maximum: the carbon isotopes indicate that the deep water mass was poorly ventilated while the Pa/Th evidence an active overturning cell. These observations question the type of signal recorded by each proxy. Besides, in order to quantify the circulation changes, a modeling approach is required. In the second part of this thesis, I have implemented the calculation of the Pa/Th in the climate model of intermediate complexity iLOVECLIM. The model is able to simulate the simultaneous evolution of the three proxies and has been used to decipher the multi-proxy response to abrupt circulation changes. The results show that the proxy response varies in the three main Atlantic water masses. In the deep (>2000m) western North Atlantic, the carbon isotopes response lags the Pa/Th response by a few hundreds of years, exemplifying/illustrating a possible decoupling between the different proxies
Apra, Caroline. "Etude du développement des méninges & modélisation de tumeurs fibreuses solitaires chez la souris par introduction du gène de fusion NAB2-STAT6 dans les cellules PGDS-positives." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL052.
Meningeal solitary fibrous tumors (SFT), like somatic SFT, are characterized by the NAB2-STAT6 fusion gene. This fusion induces the nuclear relocation of the STAT6 transcription factor and the activation of EGR transcription, increasing proliferation. Meningeal SFT cells, like meningioma cells, are positive for prostaglandin-D2-Synthase (PGDS), a specific marker of meningeal, especially arachnoid, cells. In Part 1, we showed that benign SFT can transform into malignant TFS - formerly hemangiopericytomas - and we reported the therapeutic efficacy of pazopanib, an inhibitor of vascular endothelial growth factor. Part 2 is devoted to the molecular study of SFT: the comparison of the exome of pairs of SFT, a grade I primary and grade III recurrence, brought out the pathogenic variant of TP53 c.743G> T. The transcriptome of meningeal SFT showed the aggregation of SFT from all localizations, distinct from meningiomas. Part 3 presents the modeling of meningeal SFT in genetically modified mice by the introduction of two NAB2-STAT6 fusion genes (exons 2-16 and 6-17). The RCAS-NAB2-STAT6 retroviruses, injected at birth into the subdural space of PGDS-tva mice, specifically infect arachnoid cells. After more than a year of follow-up, the animals did not develop any SFT. It is likely that, as in many other tumor models, fusion is not sufficient to induce tumor development. In Part 4, we adapted the iDisco method, which usually allows three-dimensional visualization of brain samples, for mouse embryos and whole skulls, and described the expression of PGDS in mice in situ, between the 11th post-conception day and the 7th post-natal day. It is located in the meninges at the skull base in the early stages and at the convexity after birth, and also in the radial glia
Mejlachowicz, Dan. "Développement de modèles in vitro et in vivo pour analyser la réponse aux radiations ionisantes du tissu thyroïdien normal humain." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL057.
The only demonstrated etiologic factor for thyroid cancer is an exposure to ionizing radiation (IR) during childhood. Epidemiological studies can measure a significant risk to develop a cancer following thyroid doses above 50 mGy. This risk is observed after external exposure to high doses/dose rates (radiotherapy) and after contamination of iodine radioisotopes at lower doses.As the risk decreases with the dose, if radiation-induced cancers (R) develop after thyroid doses <50mGy, an excess of cancers cannot be measured by conventional epidemiology, especially because the incidence of sporadic cancers (S) increases. Consequently, it is not possible to answer the societal debates concerning the risk associated to low doses exposure, such as the risk for patients during medical diagnosis by imagery technics in the "head and neck" area especially for children, following Chernobyl and Fukushima accidents fallout, and following contamination after the atmospheric nuclear tests in French Polynesia.To answer the questionnning about the risk of low doses IR on human thyroid, a better knowledge of the exposure according to doses and dose rates is necessary,. Thyroid carcinogenesis presents specificities among species. Indeed, in mice, S or R thyroid cancers incidence is low, and the few R tumors developping are mainly follicular cancers whereas there are mainly papillary cancers in humans (S and R).In order to analyze the normal human thyroid tissue response to IR, we have developed several approaches using biopsies of non-pathological tissues from patients who have undergone thyroidectomy: primary thyrocyte cultures, in vitro 3D models (thyrospheres and organotypic cultures) and xenografts in mice.For 3D models, maintenance of polarity, cell differentiation, tissue complexity and physiological activity of the cultures were controlled. We obtained thyrospheres (6 donors) organized in follicles delimiting a lumen composed of thyroglobulin. We used the matrigel-based protocol described by Toda et al. (2002) for organotypic cultures of porcin tissue, and showed an hypoxic stress in the human tissue (7 donors). An optimal oxygenation of the tissue was obtained by air-liquid interface culture (3 donors). In ALI organotypic cultures, a secretion of free thyoid hormone T4 was observed (1 donor, at 1 week), and this protocol allowed the tissue maintenance over 4 weeks. Mouse xenografts permitted human tissue maintenance over a period of at least one year, we already succeed in maintaining the thyroid tissue over 5 weeks in SCID/beige mice (3 donors).In parallel, we compared the proliferation, the survival and the kinetics of DNA strand breaks induction/repair after exposure of thyrocytes from patients exposed (radiotherapy) during childhood (2 donors) or unexposed (3 donors), in primary cultures. We reproducibly observed that exposed thyrocytes are more radioresistant than unexposed thyrocytes. These results strongly suggest the existence of a long-term phenotypic signature of exposure to IR in normal thyroid tissue, consistent with the identification of molecular signatures discriminating exposed and unexposed normal thyroid tissue by C Ory and N Ugolin in the laboratory. As suggested by C Dupuy's team, this imprinting could be due to the development of a chronic oxidative stress following IR exposure in the thyroid.The models developed during this thesis will be essential to understand low and high doses IR effects and risks on the human thyroid. They will also be usefull to asses the effects of endocrine disruptors (ED) on human thyroid, alone or in cocktail and estimate if this ED exposure may modify the radiosensitivity of the thyroid. These models will be used to analyse the first steps on radiation-induced thyroid carcinogenesis as well as the origin of this persistent long-term exposure imprinting
Missiaen, Lise. "Quantification des changements de la circulation océanique profonde de l'Atlantique au cours des changements climatiques rapides des derniers 40 ka." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV004/document.
The last 40 ky, have been characterized by abrupt and high amplitude temperature changes (8 to 15 °C in less than 300 years) in Greenland and in the North Atlantic region, associated with drastic ocean and atmospheric circulation changes. The mechanisms behind these abrupt climate changes are still debated. The objective of this thesis is to quantify the ocean circulation changes associated with these abrupt climate changes. In the first part of this thesis, I combined the information of three geochemical proxies in order to overcome the limitations of each proxy taken separately. The carbon isotopic ratios of the benthic foraminifers (δ13C and Δ14C), as well as the sedimentary Pa/Th ratio, have been measured in the North Atlantic sediment core SU90-08 (43°N, 30°W, 3080m). The proxies depict an apparently inconsistent situation over the last glacial maximum: the carbon isotopes indicate that the deep water mass was poorly ventilated while the Pa/Th evidence an active overturning cell. These observations question the type of signal recorded by each proxy. Besides, in order to quantify the circulation changes, a modeling approach is required. In the second part of this thesis, I have implemented the calculation of the Pa/Th in the climate model of intermediate complexity iLOVECLIM. The model is able to simulate the simultaneous evolution of the three proxies and has been used to decipher the multi-proxy response to abrupt circulation changes. The results show that the proxy response varies in the three main Atlantic water masses. In the deep (>2000m) western North Atlantic, the carbon isotopes response lags the Pa/Th response by a few hundreds of years, exemplifying/illustrating a possible decoupling between the different proxies
Deyawe, Kongmeneck Audrey. "Investigation des mécanismes d’activation et de couplage du canal potassique voltage-dépendant KV7.1 dans les cardiomyocytes à l’aide de méthodes computationnelles." Electronic Thesis or Diss., Université de Lorraine, 2020. http://www.theses.fr/2020LORR0175.
KV7.1 is a voltage-gated ion channel that open to selectively diffuse K+ ions across the plasma membrane upon membrane depolarization. In the myocardium tissue, KV7.1 channel is co-expressed with the ancillary subunit KCNE1 to generate the IKS current during cardiac action potential. The mutations of KV7.1 and KCNE1that are linked to severe cardiac arrhythmias make KV7.1 channel a major therapeutic target. Each α-subunit of KV7.1 tetramer counts six transmembrane helices (S1 to S6), the first four ones forming the voltage-sensor domain (VSD), and the last two ones forming the pore domain (PD). This channel has a 2-step activation mechanism involving three stable states: resting, intermediate and activated. These conformations can induce pore opening or closure by a process called VSD-PD coupling. Accordingly, the states for KV7.1 channel are Resting/Closed (RC), Intermediate/Open (IO) and Activated/Open (AO). In the presence of KCNE1, the coupling is inhibited in the intermediate state, thus the states for IKS channel are RC, Intermediate/Closed (IC) and AO. Furthermore, the lipid PIP2 (phosphatidylinositol-4,5-bisphosphate) plays a crucial role in the VSD-PD coupling of KV7 channels. Despite the information drawn from both functional and structural studies of KV7.1, the modulation mechanisms of its VSD-PD coupling by KCNE1 and PIP2 remain unclear at an atomistic level. With the help of powerful computational tools, we designed molecular models of Kv7.1 in order to have a better understanding of its function. The study of these models, conducted in collaboration with Pr. Jianmin Cui’s research team (Washington University of Saint-Louis, USA) allowed us to obtain four novel results about the way Kv7.1 opens. Indeed, this joint study revealed a novel VSD-PD coupling mechanism that we conceptualized by a “hand-and-elbow” model likely to occur in all domain swapped (KV1- KV7) channels. The analyses of IKS MD trajectories suggest that KCNE1 disrupts the “hand-and-elbow” model. In addition, the interactions between KCNE1 and PIP2 form a tourniquet around the cytoplasmic region of S6, leading to pore closure in both RC and IC models. Finally, the S6 helix of KV7.1 has a motif SFF (338-340), highly conserved in KV7 family, which forms an unidentified hydrophobic gate in KV7.1 pore. Two of these results were confirmed by in vitro experiments conducted by our collaborators on this channel, which validates the quality of our models for innovative therapeutic research