Monoclonal antibodies (MAbs) have an expanding market for use in diagnostic and therapeutic applications. Industrial production of these biopharmaceuticals is usually achieved based on fed-batch cultures of mammalian cells in bioreactors (Chinese hamster ovary (CHO) and Hybridoma cells), which can express different kinds of recombinant proteins. In order to reach high cell densities in these bioreactors, it is necessary to carry out an optimization of their production processes. Hence, macroscopic model equations must be developed to describe cell growth, nutrient consumption and product generation. These models will be very useful for designing the bioprocess, for developing robust controllers and for optimizing its productivity.<p>This thesis presents a new kinetic model of hybridoma cell metabolism in fed batch culture and typical illustration of a systematic methodology for mathematical modelling, parameter estimation and model-based optimization and state estimation of bioprocesses. <p>In the first part, a macroscopic model that takes into account phenomena of overflow metabolism within glycolysis and glutaminolysis is proposed to simulate hybridoma HB-58 cell cultures. The model of central carbon metabolism is reduced to a set of macroscopic reactions. The macroscopic model describes three metabolism states: respiratory metabolism, overflow metabolism and critical metabolism. The model parameters and confidence intervals are obtained via a nonlinear least squares identification. It is validated with experimental data of fed-batch hybridoma cultures and successfully predicts the dynamics of cell growth and death, substrate consumption (glutamine and glucose) and metabolites production (lactate and ammonia). Based on a sensitivity analysis of the model outputs with respect to the parameters, a model reduction is proposed. <p>In the next step, the effort is directed to the maximization of biomass productivity in fed-batch cultures of hybridoma cells based on the overflow metabolism model. Optimal feeding rate, on the one hand, for a single feed stream containing both glucose and glutamine and, on the other hand, for two separate feed streams of glucose and glutamine are determined using a Nelder-Mead simplex optimization algorithm. Two different objective functions (performance criteria) are considered for optimization; the first criterion to be maximized is the biomass productivity obtained at the end of the fed-batch culture, the second criterion to be minimized is the difference between global substrate consumption and the maximum respiratory capacity.<p>The optimal multi exponential feed rate trajectory improves the biomass productivity by 10% as compared to the optimal single exponential feed rate. Moreover, this result is validated by the one obtained with the analytical approach in which glucose and glutamine are fed to the culture so as to control the hybridoma cells at the critical metabolism state, which allows maximizing the biomass productivity. The robustness analysis of optimal feeding profiles obtained with different optimization strategies is considered, first, with respect to parameter uncertainties and, finally, with respect to model structure errors.<p>Finally, the overflow metabolism model is used to develop an extended Kalman filter for online estimation of glucose and glutamine in hybridoma cell fed-batch cultures based on the considered available measurements (biomasses (on-line), lactate and ammonia (on-line or off-line)). The observability conditions are examined, and the performances are analysed with simulations of hybridoma cell fed-batch cultures. Glutamine estimation sensitivity is enforced by minimizing a cost function combining a usual least-squares criterion with a state estimation sensitivity criterion. <p> / Doctorat en Sciences de l'ingénieur / info:eu-repo/semantics/nonPublished

Nous considérons deux modèles EDP-EDO couplés: un pour modéliser des goulots d’étranglementmobiles et l’autre pour décrire la distribution du trafic sur une bretelle d’accès. Le premier modèle a étéintroduit pour décrire le mouvement d’un bus, qui roule à une vitesse inférieure à celle des autresvoitures, en réduisant la capacité de la route et générant ainsi un goulot d’étranglement. Une loi deconservation scalaire avec une contrainte mobile sur le flux décrit le trafic et une EDO décrit latrajectoire du bus. Nous présentons un résultat d’existence des solutions du modèle et nous proposonsune méthode numérique “front/capturing" et une méthode basée sur une technique de reconstructiondes ondes de chocs. Dans la deuxième partie, nous introduisons un nouveau modèle macroscopique dejonction pour les bretelles d’autoroute. Nous considérons le modèle de trafic de Lighthill-Whitham-Richards sur une jonction composée d’une voie principale, une bretelle d’accès et une bretelle de sortie,toutes reliées par un nœud. Une loi de conservation scalaire décrit l’évolution de la densité des véhiculessur la voie principale et une EDO décrit l’évolution de la longueur de la file d’attente sur la bretelled’accès. La définition de la solution du problème de Riemann à la jonction est basée sur la résolutiond’un problème d’optimisation linéaire et sur l’utilisation d’un paramètre de priorité. Ensuite, ce modèleest étendu aux réseaux et discrétisé en utilisant un schéma de Godunov qui prend en compte les effetsde la bretelle d’accès. Enfin, nous présentons un modèle d’optimisation de la circulation sur les ronds points. / In this thesis we consider two coupled PDE-ODE models. One to model moving bottlenecks and theother one to describe traffic flow at junctions. First, we consider a strongly coupled PDE-ODE systemthat describes the influence of a slow and large vehicle on road traffic. The model consists of a scalarconservation law accounting for the main traffic evolution, while the trajectory of the slower vehicle isgiven by an ODE depending on the downstream traffic density. The moving constraint is expressed byan inequality on the flux, which models the bottleneck created in the road by the presence of the slowerDépôt de thèse – Donnéescomplémentairesvehicle. We prove the existence of solutions to the Cauchy problem for initial data of bounded variation.Moreover, two numerical schemes are proposed. The first one is a finite volume algorithm that uses alocally nonuniform moving mesh. The second one uses a reconstruction technique to display thebehavior of the vehicle. Next, we consider the Lighthill-Whitham-Richards traffic flow model on ajunction composed by one mainline, an onramp and an offramp, which are connected by a node. Theonramp dynamics is modeled using an ordinary differential equation describing the evolution of thequeue length. The definition of the solution of the Riemann problem at the junction is based on anoptimization problem and the use of a right of way parameter. The numerical approximation is carriedout using a Godunov scheme, modified to take into account the effects of the onramp buffer. Aftersuitable modification, the model is used to solve an optimal control problem on roundabouts. Two costfunctionals are numerically optimized with respect to the right of way parameter.

La congestion des autoroutes est un problème qui apparait de façon récurrente et qui a un large impact économique, environnemental et social. Ce problème peut être résolu en augmentant la capacité des autoroutes ou en diminuant la demande de trafic. Ces solutions sont longues à mettre en oeuvre et sont très coûteuses. Une solution accessible à plus court terme consiste à mettre en oeuvre un système de gestion du trafic. Dans cette optique, plusieurs actions et mesures de contrôle ont été développées pour améliorer l’efficacité des autoroutes. Parmi ces actions, on peut citer le contrôle d’accès et la limitation dynamique de la vitesse. Le contrôle d’accès consiste en une régulation du flux de véhicules désirant entrer sur une autoroute à partir d’une rampe. Nous avons développé la stratégie DFC (Différence de Flux Caractérisée par une densité désirée). Elle vise à maintenir sur la chaussée principale, au niveau de la rampe d’entrée,une densité inférieure à une cible déterminée au préalable à l’aide de simulations. Cette nouvelle stratégie a été comparée aux stratégies existantes telles que ALINEA et PI-ALINEA. La stratégie DFC présente l’intérêt de ne pas générer de phénomènes oscillatoires dans les trajectoires du flux et de ne pas nécessiter de paramètres à régler. La limitation dynamique de la vitesse impose sur plusieurs tronçons de la chaussée principale une limitation de vitesse qui dépend des conditions de circulation. L’objectif est d’éviter la congestion au niveau d’un goulot d’étranglement qui se trouve en aval. Nous avons proposé plusieurs stratégies de limitation dynamique de la vitesse. Elles utilisent toutes le modèle de trafic METANET. Deux des méthodes proposées exploitent le terme d’anticipation du modèle METANET et la troisième est basée sur le flux. Enfin, les différentes stratégies de limitation dynamique de la vitesse ont été utilisées en coordinationavec le contrôle d’accès DFC. La coordination permet d’obtenir des résultats meilleurs qu’un contrôle d’accès utilisé seul ou une limitation dynamique de la vitesse utilisée seule. / The highways congestion is a problem which appears in a recurring way and which has a wide economic, environmental and social impact. This problem can be resolved by increasing the highways capacity or by decreasing the traffic demand. These solutions are long to operate and are very expensive. An accessible solution in the shorter run consists in implementing a traffic management system.In this optics, several actions and control measures were developed to improve the efficiency of highways. Among these actions, we can quote the ramp metering control and the dynamic speed limits.The ramp metering consists of a regulation of the vehicles flow wishing to enter on a highway from an on-ramp. We developed the DFC strategy (Différence de Flux Characterisée par une densité désirée). It aims at maintaining on the main road, at the vicinity of the on-ramp, a density lower than a target beforehand determined by means of simulations. This new strategy was compared with the existing strategies such as ALINEA and PI-ALINEA. The DFC strategy presents the interest not to generate oscillatory phenomena in the trajectories of flow and not to require parameters to be adjusted. The dynamic speed limits imposes on several sections of the main road a speed limit which depends on traffic conditions. The objective is to avoid the congestion at a downstream bottleneck. We proposed several strategies of dynamic speed limits. They use quite the METANET model of traffic. Two of the proposed methods exploit the model METANET anticipation term and the third is based on the flow. Finally, the various strategies of dynamic speed limits were used in coordination with the DFC ramp metering. The coordination allows to obtain the results better than ramp metering used only or dynamic speed limits used only.

This Master thesis was created as research for project GA 102/09/1897 Security in car traffic - BAD, which is i.a. considers testing of continuousness of traffic with dynamically updated navigation. Main goal of project is simulator of traffic infrastructure creation. Simulators are two. One of them evaluate trafiic flow on bigger network of roads and crossroads. Second one simulate behaviour of cars during passage of crossroads. In this project is as well parsed theory of traffic activity and mentioned theoretical principles on which are built both simulators.

Les nids d'abeille d’aluminium combinent légèreté et grande capacité d’absorption d'énergie. Ils sont alors de plus en plus utilisés dans les secteurs du transport (automobile, aéronautique …) pour contribuer conjointement à l’allègement structural et à la sécurité. Dans cette thèse, le comportement à l’écrasement des nids d'abeille est étudié en tenant compte de l'effet combiné de l'angle d'orientation dans le plan des cellules, de l’angle de chargement et de la vitesse de sollicitation, que la littérature ne relate pas. Un dispositif de chargement mixte compression/cisaillement est conçu pour mener l’étude expérimentale. L’analyse des résultats porte sur le pic initial d’effort, le plateau d’effort, ainsi que sur les modes de déformation. Les résultats montrent une augmentation de la résistance sous sollicitation dynamique dépendante de l’angle de chargement Ψ. Elle devient moins significative quand l’angle de chargement augmente jusqu’à atteindre un angle critique. Pour Ψ > Ψcritique, les réponses quasi-statiques sont même plus élevées que les réponses dynamiques. Une étude numérique est alors entreprise. Elle permet de comprendre ce phénomène qui est imputé aux mécanismes de déformation locaux des cellules. Les résultats numériques montrent également que l’effet de l’angle d’orientation □ dans le plan est plus prononcé sur la force tangentielle que sur la force normale, que cela influence également les modes d’effondrement et donc la réponse mécanique. Ces simulations numériques, couplées aux résultats expérimentaux, permettent alors de dissocier les composantes normale et tangentielle de la réponse des nids d’abeille et d’identifier les paramètres d'un critère macroscopique de résistance exprimé en fonction de la vitesse d'impact, de l'angle de chargement et de l'angle d'orientation dans le plan. Finalement, dans le but de réduire le coût des simulations numériques, un modèle élément fini (EF) réduit basé sur un critère de périodicité tenant compte de l'angle d'orientation dans le plan est proposé et son domaine de validité est évalué. / Aluminium honeycombs combine lightweight with an efficient energy absorption capability (specific energy). They are widely used as crash energy absorbing and protective structures in a wide range of transport applications (automotive, aircraft …) to reduce energy consumption and greenhouse gas emission. Reducing vehicle mass has however to be done while at least maintaining the same safety levels. In this thesis, the honeycomb behaviour is investigated under mixed shear-compression loadings taking into account the combined effect of the in-plane orientation angle and the impact velocity, which has not been deeply investigated in the literature. Experimental study based on an improvement of a mixed shear-compression loading device is realised. Experimental analysis focuses on the initial peak and average crushing forces as well as the deforming pattern modes. Comparing quasi-static and dynamic results, a dynamic enhancement depending of the loading angle Ψ is observed under mixed shear-compression loading until a critical loading angle (Ψcritical). Beyond, a negative enhancement is observed. Thus, a numerical study is carried out. The negative enhancement phenomenon is attributed to the collapse mechanisms which are affected by the loading angle Ψ. Numerical results also highlight that the in-plane orientation angle has an effect on the collapse mechanisms and consequently on the mechanical response. This effect is more pronounced on the tangential force than the normal force. The combined effect of the in-plane orientation angle and the loading angle is analysed on the three identified deforming pattern modes. Combining numerical and experimental results, the average crushing normal and shear forces are dissociated. Therefore, the parameters of a macroscopic yield criterion for the mixed shear-compression honeycomb behaviour depending of the impact velocity, the loading angle and the in-plane orientation angle are identified. Finally, in order to optimise the cost in CPU-time of the numerical simulation, a reduced FE model based on the periodicity procedure taking into account the in-plane orientation angle is proposed and its validity range is evaluated.

Cette thèse porte sur l’analyse et l’homogénéisation d’équations aux dérivées partielles (EDP) posées sur des réseaux avec des applications en trafic routier. Deux types de travaux ont été réalisés : le premier axe de travail consiste à considérer des modèles microscopiques de trafic routier et d’établir une connexion entre ces modèles et des modèles macroscopiques du genre de ceux introduit par Imbert et Monneau [1]. Une telle connexion va permettre de justifier rigoureusement les modèles macroscopiques du trafic routier. En effet, les modèles microscopiques décrivent la dynamique de chaque véhicule individuellement et sont donc plus faciles à justifier du point de vue modélisation. Par contre, ces modèles ne sont pas utilisables pour décrire le trafic à grande échelle (des villes par exemple). Les modèles macroscopiques font le jeu inverse : ils sont fort pour décrire le trafic à grande échelle mais du point de vue modélisation, ils sont compliqués à mettre en œuvre pour prédire toutes les situations du trafic (par exemple trafic libre ou congestionné). Le passage du microscopique au macroscopique est fait en s’appuyant sur la théorie des solutions de viscosité et en particulier les techniques d’homogénéisation. Le second axe consiste à considérer une équation d’Hamilton-Jacobi avec une jonction qui bouge en temps. Cette équation peut décrire la circulation des voitures sur une route avec la présence d’un véhicule particulier (plus lent que les voitures par exemple). On prouve l’existence et l’unicité (par un principe de comparaison) d’une solution de viscosité pour cette EDP. [1] Cyril Imbert and Régis Monneau. Flux-limited solutions for quasi-convex hamilton-jacobi equations on networks. Annales Scientifiques de l’ENS, 50(2) :357–448, 2013. / This thesis deals with the analysis and homogenization of partial differential equations (PDE) posed on networks with application to traffic. Two types of work are done : the first line of work consists to consider microscopic traffic models in order to establish a connection between these models and macroscopic models like the one introduced by Imbert and Monneau [1]. Such connection allows to justify rigorously the macroscopic models of traffic. In fact, microscopic models describe the dynamic of each vehicle individually and so they are easy to justify from the modelization point of view. On the other hand, these models are complicated to implement in order to describe the traffic at large scales (cities for example). Macroscopic models do the opposite : they are effective for describing the traffic at large scales but from the modelization point of view, they are incapable to predict all traffic situations (for example free or congested flow). The passage from microscopic to macroscopic is done using the viscosity solutions theory and in particular homogenization technics. The second line of work consists to consider a Hamilton-Jacobi equation coupled by a junction condition which moves in time. This equation can describe the circulation of cars on a road with the presence of a particular vehicle (slower than the cars for example). We prove existence and uniqueness (by a comparison principle) of viscosity solution of this PDE. [1] Cyril Imbert and Régis Monneau. Flux-limited solutions for quasi-convex hamilton-jacobi equations on networks. Annales Scientifiques de l’ENS, 50(2) :357–448, 2013.

A new theoretical formalism is developed for the study of the mechanical behaviour of magneto-sensitive elastomers (MSEs) under a uniform external magnetic field. This formalism allows us to combine macroscopic continuum-mechanics and microscopic approaches for complex analysis of MSEs with different shapes and with different particle distributions. It is shown that starting from a model based on an explicit discrete particle distribution one can separate the magnetic field inside the MSE into two contributions: one which depends on the shape of the sample with finite size and the other, which depends on the local spatial particle distribution. The magneto-induced deformation and the change of elastic modulus are found to be either positive or negative, their dependences on the magnetic field being determined by a non-trivial interplay between these two contributions. Mechanical properties are studied for two opposite types of coupling between the particle distribution and the magneto-induced deformation: absence of elastic coupling and presence of strong affine coupling. Predictions of a new formalism are in a qualitative agreement with existing experimental data.

The Macroscopic Fundamental Diagram (MFD) describes the relation of average network flow, density and speed in urban networks. It can be estimated based on empirical or simulation data, or approximated analytically. Two main analytical approximation methods to derive the MFD for arterial roads and urban networks exist at the moment. These are the method of cuts (MoC) and related approaches, as well as the stochastic approximation (SA). This paper systematically evaluates these methods including their most recent advancements for the case of an urban arterial MFD. Both approaches are evaluated based on a traffic data set for a segment of an arterial in the city of Munich, Germany. This data set includes loop detector and signal data for a typical working day. It is found that the deterministic MoC finds a more accurate upper bound for the MFD for the studied case. The estimation error of the stochastic method is about three times higher than the one of the deterministic method. However, the SA outperforms the MoC in approximating the free-flow branch of the MFD. The analysis of the discrepancies between the empirical and the analytical MFDs includes an investigation of the measurement bias and an in-depth sensitivity study of signal control and public transport operation related input parameters. This study is conducted as a Monte-Carlo-Simulation based on a Latin Hypercube sampling. Interestingly, it is found that applying the MoC for a high number of feasible green-to-cycle ratios predicts the empirical MFD well. Overall, it is concluded that the availability of signal data can improve the analytical approximation of the MFD even for a highly inhomogeneous arterial.

I den här uppsatsen beskrivs på vilket sätt kemins tre perspektiv(makroskopiskt, submikroskopiskt, symboliskt) förekommer i lärareskemiundervisning.Datainsamlingen gjordes genom semistrukturerade intervjuer med 13 läraresom spelades in och transkriberades. Några av lärarna undervisar i kemi igrundskolans senare år och några i gymnasieskolan. Därefter gjordes entematisk analys av intervjuerna.I analysresultatet framgick följande teman: • Lämplig substans • Elevens (förståelse) inre bild • Omedveten medvetenhet • Två perspektiv i taget I temat lämplig substans framgick att lärare i sin undervisning oftaanvänder substanser som elever känner till sedan tidigare.I temat elevens (förståelse) inre bild framgick att lärare i första handförsöker hjälpa eleven att föreställa sig hur kemin fungerar.I temat omedveten medvetenhet framgick att de tre perspektiven förekomi lärares kemiundervisning även om endast en tillämpade detta medvetet ochsystematiskt. I de andras undervisning fanns begreppen med även om lärarnainte tänkte på det.I temat två perspektiv i taget framgick att lärarna oftast arbetade med tvåperspektiv och sällan med alla tre samtidigt.De tre perspektiven (begreppen) förekommer i samtliga lärares undervisningmen de flesta lärare använder andra termer för detta. Begreppen används oftatillsammans och ostrukturerat vilket kan bidra till missuppfattningar hoseleverna. Endast en lärare undervisar systematiskt utifrån terminologinmakroskopiskt, submikroskopiskt och symboliskt. / In this essay it is described in what way three perspectives (macroscopic,submicroscopic, symbolic) of chemistry occur in teachers’ chemistryeducation.Data was collected using semi structured interviews with 13 teachers. Theinterviews were recorded and transcribed. Some of the teachers work withchemistry education in the upper stage of the primary school and some workin upper secondary education (high school). Then thematic analysis wasapplied on the transcribed interviews.The following themes were found in the resulting analysis: • Appropriate substance • The student’s mental picture • Unaware awareness • Two perspectives at a time In the theme appropriate substance it was found that teachers often usesubstances in their education that are already known to the student.In the theme the student’s mental picture it was found that teachersgenerally try to help the student imagine how chemistry works.In the theme unaware awareness it was found that the three perspectivesoccurred in the teachers’ education, but the words were only applied by one ofthe teachers systematically. In the other teachers’ teaching the concepts werepart of the education even if the teachers weren’t aware of the terminology.In the theme two perspectives at a time it was found that the teachersusually applied two perspectives but seldom all three at the same time.The three perspectives (the concepts) exist in all teacher’s education but mostof the teachers use other expressions. The concepts are used together andunstructured which may contribute students’ misconceptions. Only oneteacher educates systematically using the terminology macroscopic,submicrosopic and symbolic.

This paper describes a general approach to the specification the stable regime speed-flow function, for motorways, as a part of the stable regime Stochastic Fundamental Diagram consistent with main assumptions of Transportation Systems Theory. Main original elements are: • Specification of speed-flow functions consistent with travel time function, such as BPR-like functions; • Calibration from disaggregate data, say data from single vehicle trajectories; • Specification of the speed r. v. distribution consistent with those used in RUT for route choice behavior modelling, such as Gamma, Inv-Gamma.