Monitoring Infection Risk for Air and Soil Borne Fungal Plant Pathogens using Antibody and DNA Techniques and Mathematical Models describing Environmental Parameters

Economic losses resulting from disease development can be reduced by accurate and early detection of plant pathogens. Early detection can provide the grower with useful information on optimal crop rotation patterns, varietal selections, appropriate control measures, harvest date and post harvest handling. Classical methods for the isolation of pathogens are commonly used only after disease symptoms. This frequently results in a delay in application of control measures at potentially important periods in crop production. This paper describes the application of both antibody and DNA based systems to monitor infection risk of air and soil borne fungal pathogens and the use of this information with mathematical models describing risk of disease associated with environmental parameters.

Recherche sur les modèles, conceptions et attentes des enseignants en supervision pédagogique

[…] À l'aide de ce travail, je désire produire ou identifier dans une recherche, les attentes ou les besoins des enseignants en supervision, de façon à développer un vrai contexte adéquat de relation d'aide, c'est-à-dire d'expression et de satisfaction de besoins mutuels. Dans une époque où tous les intervenants du monde de l'éducation (lire ici États Généraux) ont manifesté un besoin éminent de superviser dans le but d'améliorer la qualité de l'enseignement à l'école primaire et secondaire, il deviendrait très avantageux de connaître les besoins et les réticences de chacun en matière de supervision pédagogique, afin d'en tirer des lignes de force permettant de rendre cette supervision dite essentielle, efficace et désirée de tous.

A Haptic System for Depicting Mathematical Graphics for Students with Visual Impairments

When teaching students with visual impairments educators generally rely on tactile tools to depict visual mathematical topics. Tactile media, such as embossed paper and simple manipulable materials, are typically used to convey graphical information. Although these tools are easy to use and relatively inexpensive, they are solely tactile and are not modifiable. Dynamic and interactive technologies such as pin matrices and haptic pens are also commercially available, but tend to be more expensive and less intuitive. This study aims to bridge the gap between easy-to-use tactile tools and dynamic, interactive technologies in order to facilitate the haptic learning of mathematical concepts. We developed an haptic assistive device using a Tanvas electrostatic touchscreen that provides the user with multimodal (haptic, auditory, and visual) output. Three methodological steps comprise this research: 1) a systematic literature review of the state of the art in the design and testing of tactile and haptic assistive devices, 2) a user-centered system design, and 3) testing of the system’s effectiveness via a usability study. The electrostatic touchscreen exhibits promise as an assistive device for displaying visual mathematical elements via the haptic modality.

Análisis didáctico fenomenológico como instrumento para la planificación currícular por parte de los docentes de matemáticas de la educación básica primaria

La planificación curricular (PC) constituye una de las actividades y competencias más importantes de los docentes en los distintos niveles de la educación escolar en general. Por esta razón en el trabajo de maestría que presentamos nos proponemos reflexionar con los participantes sobre los aportes que puede hacer el Análisis Didáctico Matemático (ADM) en general, y el Análisis Didáctico Fenomenológico (ADF) en particular, al desarrollo de los procesos de PC y de formación profesional relativa a la PC por parte de los docentes de matemáticas de EBP. Para esto nos enmarcamos en la propuesta teórica de los organizadores del currículo (Rico, 1998; Castro, 2001; Rico y Segovia, 2001; Bedoya, 2002) y sobre el ADF (Freudenthal, 1983; Puig, 1997). Desde el punto de vista metodológico se trabajó mediante estrategias de investigación y sistematización de experiencias educativas, que articulan en el diseño procesos de investigación acción y estudio de casos. Se llevaron a cabo talleres de formación docente en los que se propuso la planificación de una unidad didáctica (UD) sobre el CME (Conocimiento Matemático Escolar) de estadística descriptiva para grado quinto, a fin de analizarlas a la luz de las nociones conceptuales y concepciones de los maestros sobre el proceso de PC.

The Control of a Mathematical Analog of a Tentacle

A 2-dimensional dynamic analog of squid tentacles was presented. The tentacle analog consists of a multi-cell structure, which can be easily replicated to a large scale. Each cell of the model is a quadrilateral with unit masses at the corners. Each side of the quadrilateral is a spring-damper system in parallel. The spring constants are the controls for the system. The dynamics are subject to the constraint that the area of each quadrilateral must remain constant. The system dynamics was analyzed, and various equilibrium points were found with different controls. Then these equilibrium points were further determined experimentally, demonstrated to be asymptotically stable. A simulation built in MATLAB was used to find the convergence rates under different controls and damping coefficients. Finally, a control scheme was developed and used to drive the system to several configurations observed in real tentacle.

Hybrid mathematical and informational modeling of beam-to-column connections

The analysis of steel and composite frames has traditionally been carried out by idealizing beam-to-column connections as either rigid or pinned. Although some advanced analysis methods have been proposed to account for semi-rigid connections, the performance of these methods strongly depends on the proper modeling of connection behavior. The primary challenge of modeling beam-to-column connections is their inelastic response and continuously varying stiffness, strength, and ductility. In this dissertation, two distinct approaches—mathematical models and informational models—are proposed to account for the complex hysteretic behavior of beam-to-column connections. The performance of the two approaches is examined and is then followed by a discussion of their merits and deficiencies. To capitalize on the merits of both mathematical and informational representations, a new approach, a hybrid modeling framework, is developed and demonstrated through modeling beam-to-column connections. Component-based modeling is a compromise spanning two extremes in the field of mathematical modeling: simplified global models and finite element models. In the component-based modeling of angle connections, the five critical components of excessive deformation are identified. Constitutive relationships of angles, column panel zones, and contact between angles and column flanges, are derived by using only material and geometric properties and theoretical mechanics considerations. Those of slip and bolt hole ovalization are simplified by empirically-suggested mathematical representation and expert opinions. A mathematical model is then assembled as a macro-element by combining rigid bars and springs that represent the constitutive relationship of components. Lastly, the moment-rotation curves of the mathematical models are compared with those of experimental tests. In the case of a top-and-seat angle connection with double web angles, a pinched hysteretic response is predicted quite well by complete mechanical models, which take advantage of only material and geometric properties. On the other hand, to exhibit the highly pinched behavior of a top-and-seat angle connection without web angles, a mathematical model requires components of slip and bolt hole ovalization, which are more amenable to informational modeling. An alternative method is informational modeling, which constitutes a fundamental shift from mathematical equations to data that contain the required information about underlying mechanics. The information is extracted from observed data and stored in neural networks. Two different training data sets, analytically-generated and experimental data, are tested to examine the performance of informational models. Both informational models show acceptable agreement with the moment-rotation curves of the experiments. Adding a degradation parameter improves the informational models when modeling highly pinched hysteretic behavior. However, informational models cannot represent the contribution of individual components and therefore do not provide an insight into the underlying mechanics of components. In this study, a new hybrid modeling framework is proposed. In the hybrid framework, a conventional mathematical model is complemented by the informational methods. The basic premise of the proposed hybrid methodology is that not all features of system response are amenable to mathematical modeling, hence considering informational alternatives. This may be because (i) the underlying theory is not available or not sufficiently developed, or (ii) the existing theory is too complex and therefore not suitable for modeling within building frame analysis. The role of informational methods is to model aspects that the mathematical model leaves out. Autoprogressive algorithm and self-learning simulation extract the missing aspects from a system response. In a hybrid framework, experimental data is an integral part of modeling, rather than being used strictly for validation processes. The potential of the hybrid methodology is illustrated through modeling complex hysteretic behavior of beam-to-column connections. Mechanics-based components of deformation such as angles, flange-plates, and column panel zone, are idealized to a mathematical model by using a complete mechanical approach. Although the mathematical model represents envelope curves in terms of initial stiffness and yielding strength, it is not capable of capturing the pinching effects. Pinching is caused mainly by separation between angles and column flanges as well as slip between angles/flange-plates and beam flanges. These components of deformation are suitable for informational modeling. Finally, the moment-rotation curves of the hybrid models are validated with those of the experimental tests. The comparison shows that the hybrid models are capable of representing the highly pinched hysteretic behavior of beam-to-column connections. In addition, the developed hybrid model is successfully used to predict the behavior of a newly-designed connection.

Applying Mathematical Models to Study the Role of the Immune System in Chronic Myelogenous Leukemia

Although tyrosine kinase inhibitors (TKIs) such as imatinib have transformed chronic myelogenous leukemia (CML) into a chronic condition, these therapies are not curative in the majority of cases. Most patients must continue TKI therapy indefinitely, a requirement that is both expensive and that compromises a patient's quality of life. While TKIs are known to reduce leukemic cells' proliferative capacity and to induce apoptosis, their effects on leukemic stem cells, the immune system, and the microenvironment are not fully understood. A more complete understanding of their global therapeutic effects would help us to identify any limitations of TKI monotherapy and to address these issues through novel combination therapies. Mathematical models are a complementary tool to experimental and clinical data that can provide valuable insights into the underlying mechanisms of TKI therapy. Previous modeling efforts have focused on CML patients who show biphasic and triphasic exponential declines in BCR-ABL ratio during therapy. However, our patient data indicates that many patients treated with TKIs show fluctuations in BCR-ABL ratio yet are able to achieve durable remissions. To investigate these fluctuations, we construct a mathematical model that integrates CML with a patient's autologous immune response to the disease. In our model, we define an immune window, which is an intermediate range of leukemic concentrations that lead to an effective immune response against CML. While small leukemic concentrations provide insufficient stimulus, large leukemic concentrations actively suppress a patient's immune system, thus limiting it's ability to respond. Our patient data and modeling results suggest that at diagnosis, a patient's high leukemic concentration is able to suppress their immune system. TKI therapy drives the leukemic population into the immune window, allowing the patient's immune cells to expand and eventually mount an efficient response against the residual CML. This response drives the leukemic population below the immune window, causing the immune population to contract and allowing the leukemia to partially recover. The leukemia eventually reenters the immune window, thus stimulating a sequence of weaker immune responses as the two populations approach equilibrium. We hypothesize that a patient's autologous immune response to CML may explain the fluctuations in BCR-ABL ratio that are regularly seen during TKI therapy. These fluctuations may serve as a signature of a patient's individual immune response to CML. By applying our modeling framework to patient data, we are able to construct an immune profile that can then be used to propose patient-specific combination therapies aimed at further reducing a patient's leukemic burden. Our characterization of a patient's anti-leukemia immune response may be especially valuable in the study of drug resistance, treatment cessation, and combination therapy.

Consumerism in urban Russia in the 1880s and 90s: Exploring conceptions of time, space, and modernity through bicycle and watch advertisements

This paper discusses the urban consumer culture in Moscow and Petersburg during the 1880s and 1890s and uses the consumption of bicycles and watches as a lens through which to explore changing perceptions of time and space within the experience of modernity at the end of the nineteenth century. Specifically, I argue that the way in which consumers and merchants constructed a dialogue of meaning around particular objects; the way in which objects are consumed by a culture gives insight into the values, morals, and tenure of that culture. The paper preferences newspaper ads and photographs as the mouthpieces of merchants and consumers respectively as they constructed a dialogue in the language of consumerism, and explores the ways in which both parties sought to assign meaning to objects during the experience of modernity. I am particularly interested in the way consumers perform elements of cultural modernity in photographs and how these instances of performance relate to their negotiation of modernity. The paper takes as its focus large section of the urban Russian population, much of whom can traditionally be called “middle class” but whose diversity has led me to the adoption of the term “consumer community,” and whose makeup is described in detail. The paper contributes to the continuing scholarly discourse on the makeup of the middle class in Russia and the social boundaries of late tsarist society. It speaks to the the developing sensibilities and values of a generation struggling to define itself in a rapidly changing world, to the ways in which conceptualizations of public and private space, as well as feminine and masculine space were redefined, and to the developing visual culture of the Russian consumer society, largely predicated on the display of objects to signify socially desirable traits. Whereas other explorations of consumer culture and advertisements have portrayed the relationship between merchants and consumers as a one-sided monologue in which merchants convince consumers that certain objects have cultural value, I emphasis the dialogue between merchants and consumers, and their mutual negotiation of cultural meaning through objects.

Hydrometallurgical process modeling using advanced mathematical tools

Hydrometallurgical process modeling is the main objective of this Master’s thesis work. Three different leaching processes namely, high pressure pyrite oxidation, direct oxidation zinc concentrate (sphalerite) leaching and gold chloride leaching using rotating disc electrode (RDE) are modeled and simulated using gPROMS process simulation program in order to evaluate its model building capabilities. The leaching mechanism in each case is described in terms of a shrinking core model. The mathematical modeling carried out included process model development based on available literature, estimation of reaction kinetic parameters and assessment of the model reliability by checking the goodness fit and checking the cross correlation between the estimated parameters through the use of correlation matrices. The estimated parameter values in each case were compared with those obtained using the Modest simulation program. Further, based on the estimated reaction kinetic parameters, reactor simulation and modeling for direct oxidation zinc concentrate (sphalerite) leaching is carried out in Aspen Plus V8.6. The zinc leaching autoclave is based on Cominco reactor configuration and is modeled as a series of continuous stirred reactors (CSTRs). The sphalerite conversion is calculated and a sensitivity analysis is carried out so to determine the optimum reactor operation temperature and optimum oxygen mass flow rate. In this way, the implementation of reaction kinetic models into the process flowsheet simulation environment has been demonstrated.

Application of mathematical models to mycotoxins children risk assessment: a case study of Portuguese children exposure to co-occurring mycotoxins in processed cereal-based foods

People, animals and the environment can be exposed to multiple chemicals at once from a variety of sources, but current risk assessment is usually carried out based on one chemical substance at a time. In human health risk assessment, ingestion of food is considered a major route of exposure to many contaminants, namely mycotoxins, a wide group of fungal secondary metabolites that are known to potentially cause toxicity and carcinogenic outcomes. Mycotoxins are commonly found in a variety of foods including those intended for consumption by infants and young children and have been found in processed cereal-based foods available in the Portuguese market. The use of mathematical models, including probabilistic approaches using Monte Carlo simulations, constitutes a prominent issue in human health risk assessment in general and in mycotoxins exposure assessment in particular. The present study aims to characterize, for the first time, the risk associated with the exposure of Portuguese children to single and multiple mycotoxins present in processed cereal-based foods (CBF). Portuguese children (0-3 years old) food consumption data (n=103) were collected using a 3 days food diary. Contamination data concerned the quantification of 12 mycotoxins (aflatoxins, ochratoxin A, fumonisins and trichothecenes) were evaluated in 20 CBF samples marketed in 2014 and 2015 in Lisbon; samples were analyzed by HPLC-FLD, LC-MS/MS and GC-MS. Daily exposure of children to mycotoxins was performed using deterministic and probabilistic approaches. Different strategies were used to treat the left censored data. For aflatoxins, as carcinogenic compounds, the margin of exposure (MoE) was calculated as a ratio of BMDL (benchmark dose lower confidence limit) to the aflatoxin exposure. The magnitude of the MoE gives an indication of the risk level. For the remaining mycotoxins, the output of exposure was compared to the dose reference values (TDI) in order to calculate the hazard quotients (ratio between exposure and a reference dose, HQ). For the cumulative risk assessment of multiple mycotoxins, the concentration addition (CA) concept was used. The combined margin of exposure (MoET) and the hazard index (HI) were calculated for aflatoxins and the remaining mycotoxins, respectively. 71% of CBF analyzed samples were contaminated with mycotoxins (with values below the legal limits) and approximately 56% of the studied children consumed CBF at least once in these 3 days. Preliminary results showed that children exposure to single mycotoxins present in CBF were below the TDI. Aflatoxins MoE and MoET revealed a reduced potential risk by exposure through consumption of CBF (with values around 10000 or more). HQ and HI values for the remaining mycotoxins were below 1. Children are a particularly vulnerable population group to food contaminants and the present results point out an urgent need to establish legal limits and control strategies regarding the presence of multiple mycotoxins in children foods in order to protect their health. The development of packaging materials with antifungal properties is a possible solution to control the growth of moulds and consequently to reduce mycotoxin production, contributing to guarantee the quality and safety of foods intended for children consumption.

Oil spill environmental risk assessment of stationary sources in offshore zones (Innovating a mathematical model)

Nowadays, risks arising from the rapid development of oil and gas industries are significantly increasing. As a result, one of the main concerns of either industrial or environmental managers is the identification and assessment of such risks in order to develop and maintain appropriate proactive measures. Oil spill from stationary sources in offshore zones is one of the accidents resulting in several adverse impacts on marine ecosystems. Considering a site's current situation and relevant requirements and standards, risk assessment process is not only capable of recognizing the probable causes of accidents but also of estimating the probability of occurrence and the severity of consequences. In this way, results of risk assessment would help managers and decision makers create and employ proper control methods. Most of the represented models for risk assessment of oil spills are achieved on the basis of accurate data bases and analysis of historical data, but unfortunately such data bases are not accessible in most of the zones, especially in developing countries, or else they are newly established and not applicable yet. This issue reveals the necessity of using Expert Systems and Fuzzy Set Theory. By using such systems it will be possible to formulize the specialty and experience of several experts and specialists who have been working in petroliferous areas for several years. On the other hand, in developing countries often the damages to environment and environmental resources are not considered as risk assessment priorities and they are approximately under-estimated. For this reason, the proposed model in this research is specially addressing the environmental risk of oil spills from stationary sources in offshore zones.

Exploration des pratiques et des conceptions éthiques des enseignantes et des enseignants du collégial en lien avec la compétence éthique

L’actualité est dominée par les questions d’éthique, dans le secteur économique entre autres où les actions des investisseurs comme celles des dirigeants d’organisations doivent répondre aux normes éthiques de leur domaine. C’est le cas aussi en éducation où l’attention est portée sur la professionnalisation de l’enseignement. Celle-ci est axée sur la formation et le travail des enseignantes et des enseignants. Elle vise à les former à des normes éthiques élevées et aux compétences professionnelles spécifiques au travail. L’une des composantes de la professionnalisation est l’éthique. L’éthique de la profession enseignante sous-tend les actions de l’enseignante et de l’enseignant dans sa pratique en ce qui a trait au contenu enseigné, aux étudiantes et aux étudiants, aux collègues et à soi. Or, la formation en éthique et en pédagogie n’est pas une condition à l’embauche des enseignantes et des enseignants des secteurs pré-universitaires et techniques du collégial qui sont recrutés comme des professionnels ou des spécialistes disciplinaires. Cette recherche vise à explorer sur le terrain les pratiques et les conceptions éthiques des enseignantes et des enseignants au collégial. Il s’agit de répertorier les pratiques éthiques en vue de connaître les raisons sur lesquelles ces derniers se basent pour les justifier. Pour situer le contexte de la problématique à l’origine de cette recherche, les facteurs suivants ont été pris en considération : les réductions des ressources financières qui caractérisent le milieu professionnel collégial depuis plus d’une décennie, les changements organisationnels et pédagogiques importants tels que l’approche-programme, la finalité de l’éducation, la nature de la tâche enseignante, le manque de formation en éthique et en pédagogie, l’insuffisance de l’encadrement des nouveaux enseignantes et enseignants qui arrivent en grand nombre, session après session, au collégial. Pour rendre compte des pratiques et des conceptions éthiques des enseignantes et des enseignants, il a été nécessaire de considérer et de préciser les éléments qui constituent le cadre de référence. Il s’agit de l’éthique, de la compétence éthique (MEQ, 2001), de l’éthique appliquée, de l’éthique réflexive, de la finalité de l’éducation, de la complexité de la tâche d’enseignement, de la compétence professionnelle au collégial (Dorais, Laliberté, 1999), des principales préoccupations éthiques au collégial (Desautels, Gohier, Jutras, 2009) et du cycle de vie de la carrière enseignante. Étant donné que la recherche porte sur les pratiques et les conceptions éthiques des enseignantes et des enseignants en lien avec la compétence éthique, une méthodologie qualitative a été utilisée. Un questionnaire de renseignements sociodémographiques et une entrevue semi-dirigée ont permis d’obtenir des données qualitatives à partir desquelles les récits des enseignantes et des enseignants ont été analysés afin de dresser un répertoire de leurs pratiques éthiques. Cette méthodologie a été privilégiée puisqu’elle permet de comprendre la signification que donnent les enseignantes et les enseignants à leurs pratiques et à leurs conceptions éthiques. L’interprétation des résultats comprend une analyse descriptive et une analyse compréhensive des données. Le travail a d’abord consisté à regrouper les données selon les principaux enjeux éthiques qui sont en fait des thèmes relevant de la compétence éthique. Par exemple, la préparation des cours, l’évaluation des apprentissages des étudiantes et des étudiants, les préoccupations éthiques des enseignantes et des enseignants en rapport aux collègues, etc. Une fois le portrait d’un thème fait, une analyse compréhensive est réalisée pour en trouver le sens à partir de l’explication des pratiques professionnelles des enseignantes et des enseignants. Les résultats de la recherche ont permis de constater la présence constante chez les enseignantes et les enseignants du souci d’amener les étudiantes et les étudiants à la réussite scolaire. Cela se traduit par la recherche de l’amélioration des moyens d’enseignement, les mises à jour des contenus enseignés, la recherche d’activités d’apprentissage qui ont un sens pour les étudiantes et les étudiants et le courage professionnel (essayer de nouvelles pratiques professionnelles). Les résultats montrent aussi que, malgré l’absence d’une structure permanente pour développer la compétence éthique, c’est-à-dire l’absence de balises administratives en matière d’éthique, les enseignantes et enseignantes développent bien la compétence éthique. Parmi les moyens qu’ils se donnent pour améliorer le développement de l’éthique, ils privilégient la sensibilisation à travers des groupes de discussion avec les pairs.

Improving the use of G-CSF during chemotherapy using physiological mathematical modelling : a quantitative systems pharmacology approach

La diminution des doses administrées ou même la cessation complète d'un traitement chimiothérapeutique est souvent la conséquence de la réduction du nombre de neutrophiles, qui sont les globules blancs les plus fréquents dans le sang. Cette réduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de myélosuppression, est précipitée par les effets létaux non spécifiques des médicaments anti-cancéreux, qui, parallèlement à leur effet thérapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'atténuer cet impact myélosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogène du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libération dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothérapie soient bien établis, les protocoles d'administration demeurent mal définis et sont fréquemment déterminés ad libitum par les cliniciens. Avec l'optique d'améliorer le dosage thérapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothérapeutique, nous avons développé un modèle physiologique du processus de granulopoïèse, qui incorpore les connaissances actuelles de pointe relatives à la production des neutrophiles des cellules souches hématopoïétiques dans la moelle osseuse. À ce modèle physiologique, nous avons intégré des modèles pharmacocinétiques/pharmacodynamiques (PK/PD) de deux médicaments: le PM00104 (Zalypsis®), un médicament anti-cancéreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents à la physiologie, nous avons estimé les paramètres de manière exhaustive sans devoir recourir à l'ajustement des données, ce qui nous a permis de prédire des données cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothérapie avec une période de 14 jours où l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothérapie). En utilisant ce modèle physio-PK/PD, nous avons démontré que le nombre d'administrations du rhG-CSF pourrait être réduit de dix (pratique actuelle) à quatre ou même trois administrations, à condition de retarder le début du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilité clinique de notre approche de modélisation, nous avons investigué l'impact de la variabilité PK présente dans une population de patients, sur les prédictions du modèle, en intégrant des modèles PK de population (Pop-PK) des deux médicaments. En considérant des cohortes de 500 patients in silico pour chacun des cinq scénarios de variabilité plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons établi qu'il n'y avait aucune différence significative dans les prédictions du modèle entre le patient-type et la population. Ceci démontre la robustesse de l'approche que nous avons développée et qui s'apparente à une approche de pharmacologie quantitative des systèmes (QSP). Motivés par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies périodiques telles que la neutropénie cyclique, nous avons ensuite soumis l'étude du modèle au contexte des maladies dynamiques. En mettant en évidence la non validité du paradigme de la rétroaction des cytokines pour l'administration exogène des mimétiques du G-CSF, nous avons développé un modèle physiologique PK/PD novateur comprenant les concentrations libres et liées du G-CSF. Ce nouveau modèle PK a aussi nécessité des changements dans le modèle PD puisqu’il nous a permis de retracer les concentrations du G-CSF lié aux neutrophiles. Nous avons démontré que l'hypothèse sous-jacente de l'équilibre entre la concentration libre et liée, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endogènes et mènerait en fait à la surestimation de la clairance rénale du médicament. En procédant ainsi, nous avons réussi à reproduire des données cliniques obtenues dans diverses conditions (l'administration exogène du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mécanismes responsables de la réponse physiologique aux deux médicaments. Finalement, afin de mettre en exergue l’approche intégrative en pharmacologie adoptée dans cette thèse, nous avons démontré sa valeur inestimable pour la mise en lumière et la reconstruction des systèmes vivants complexes, en faisant le parallèle avec d’autres disciplines scientifiques telles que la paléontologie et la forensique, où une approche semblable a largement fait ses preuves. Nous avons aussi discuté du potentiel de la pharmacologie quantitative des systèmes appliquées au développement du médicament et à la médecine translationnelle, en se servant du modèle physio-PK/PD que nous avons mis au point.