Estudos recentes demonstraram que as armadilhas extracelulares de neutrófilos (NETs) formam uma estrutura capaz de anular fatores de virulência e destruir microrganismos. Pacientes portadores da síndrome de Hiper-IgM ligada ao X (X-HIGM), imunodeficiência causada por mutações no gene do CD40 ligante (CD40L), são altamente suscetíveis a infecções oportunistas causadas por fungos. Uma vez que a resposta de neutrófilos apresenta grande importância para o controle de infecções fúngicas e estudos que apontam influencia da interação CD40-CD40L na granulopoiese, propusemos investigar se a suscetibilidade a infecções em pacientes com X-HIGM estariam relacionadas à falha na formação de NETs. Os resultados obtidos indicam que pacientes X-HIGM apresentam falha na geração de NETs de maneira estímulo-dependente, possivelmente relacionada a maturação incompleta dos neutrófilos. O estudo contribui para o avanço no conhecimento sobre a imunopatologia da deficiência de CD40L e para elucidação dos mecanismos envolvidos na suscetibilidade a infecções em pacientes com X-HIGM. / Recent studies have shown that neutrophil extracellular traps (NETs) release an structure able to annul virulence factors and destroying microorganisms. Patients with X-linked Hyper-IgM syndrome (X-HIGM), a rare immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene, are highly susceptible to opportunistic infections caused by fungi. Since neutrophil responses are important to control fungal infection and studies that indicate the influence of CD40-CD40L interaction on granulopoiesis, we propose to investigate whether the susceptibility to infections in X-HIGM patients could be related to the failure in NET formation. The results indicate that X-HIGM patients present a failure in NET generation in a stimulus-dependent manner, likely related to incomplete neutrophil maturation. The study contributes to the advancement of knowledge on the immunopathology of CD40L deficiency and contributes to elucidate the mechanisms involved in the susceptibility to infections in X-HIGM patients.

La mucoviscidose est une maladie génétique caractérisée par une obstruction des voies respiratoires, des infections et une inflammation pulmonaire résultant du recrutement massif de neutrophiles qui sécrètent des protéases : l’élastase, la protéase 3 et la cathepsine G. Ces protéases peuvent être sécrétées selon deux voies, la dégranulation ou la sécrétion de NETs (Neutrophil Extracellular Traps), qui sont des fibres de chromatine auxquelles elles sont associées et décrites comme des structures antimicrobiennes. Dans le milieu extracellulaire, la dérégulation du contrôle de l’activité des protéases par leurs inhibiteurs conduit à la dégradation progressive du tissu pulmonaire. Nous avons montré que cette dérégulation était modulée par l’interaction des protéases avec l’ADN présent dans les sécrétions bronchiques des patients et que le ciblage de ces protéases par des inhibiteurs exogènes pouvait être amélioré in vitro par de la DNase ou de la polylysine qui compacte l’ADN. Ce polypeptide est également bactéricide vis-à-vis des pathogènes majeurs de la mucoviscidose, S. aureus et P. aeruginosa. Nos travaux montrent également que les NETs sont sécrétés dans les poumons des patients où ils constituent un réservoir de protéases actives potentiellement délétère et n’ont pas d’effet bactéricide vis-à-vis de S. aureus et P. aeruginosa. Nos travaux montrent que les voies de signalisation conduisant à la sécrétion des NETs varient selon le stimulus, générant des structures aux propriétés différentes. / Cystic fibrosis (CF) is a hereditary disease characterized by the obstruction of the airways, infections and a chronic lung inflammation due to a massive recruitment of neutrophils that secrete proteases: the elastase, the proteinase 3 and the cathepsin G. These proteases can be secreted by two mechanisms, namely degranulation and the secretion of NETs (Neutrophil Extracellular Traps), which are chromatin fibers to which they are bound and that have been described as antimicrobial structures. In the extracellular environment, the dysregulation of these proteases control by their inhibitors leads to progressive lung tissue degradation. We have shown that this dysregulation was influenced by the interaction of the proteases with the DNA found in the lung secretions of CF patients and that targeting these proteases with exogenous inhibitors could be improved in vitro by DNase or polylysine, which compacts DNA. This polypeptide also presents a bactericidal effect towards the major CF-associated pathogens, S. aureus and P. aeruginosa. Our work also shows that NETs are secreted in the lungs of CF patients, where they are a potentially deleterious reservoir of active proteases, and that they do not display any bactericidal effect towards S. aureus and P. aeruginosa. Our work shows that the signalization pathways leading to NETs secretion vary depending on the stimulus, generating structures that present different properties.

Coloured Petri nets (CPN) are an extension of a standard place-transition Petri nets (P/T PN). Every token and place have its type (and eventually a value) and various inscriptions can be inserted into the net. CPN excel with great readibility and expresivity. At the same time, they carry a well-defined formal basis, which eases its computer simulation and allows limited verification of certain attributes to be performed. Motivation for doing this project is the simple fact that currently only one public software tool is available for CPN creation and simulation - CPNTools developed on the Aarhus university. The program, however, is quite complicated and hard to handle for an unexperienced user. The goal is to research capabilities and properties of both CPNs and CPNTools and on this basis design and implement a didactic application with swift and intuitive interface that helps users without deeper theoretical insight to get a grasp of the problematics.

Malaria is a vector-borne disease that presents the most persistent and serious public health burden in Liberia. Numerous studies have examined the relationship between ITN use and malaria prevalence. However, little research has explored the effectiveness of ITNs in controlling malaria among children in postwar Liberia. The aim of this study was to examine the association between ITN ownership, parental economic status, ITN installation support, and malaria prevalence among children. This was a quantitative cross-sectional study guided by the health belief model. The study used secondary data from the 2011 Liberia Malaria Indicator Survey. Chi-square for association and Logistic regression were used to analyze the data. The results revealed a significant association between parental education and malaria prevalence. There was also a significant association between parental economic status and malaria prevalence. However, there was no significant association between ITN ownership and malaria prevalence after controlling for parental education and ownership of structure. These findings may foster social change by helping public health authorities in Liberia integrate ITN use with other strategies like mosquito larvae elimination and indoor/outdoor insecticide spraying as part of a comprehensive approach to malaria control. Additionally, massive awareness and economic capacity building should be undertaken to empower malaria endemic communities with the understanding that malaria can be rapidly reduced with other robust strategies in combination with ITN use. These strategies, if implemented, may effectively control malaria prevalence among children and the emotional and financial burdens endure by their families.

Indiana University-Purdue University Indianapolis (IUPUI) / In the healthcare industry, several modern patient identification and patient matching systems have been introduced. Most of these implement patient identification by their first, middle and last names. They also use Social Security Number and other similar national identifiers. These methods may not work for many developing and underdeveloped countries where identifying a patient is a challenge with highly redundant and interchangeable first and last names of the patient, this is aggravated by the absence of a national identification system. In order to make the patient identification more efficient, Muzima, an interface of OpenMRS (Open source medical records system) introduced an additional identifier, fingerprint, through a module to the system. Ordinary and Time Petri nets are used to analyze this module. Chapter 1 introduces Muzima fingerprint module and describes the workflow of this interface followed by the related work, importance and applications of Petri nets. Chapter 2 introduces Ordinary and Time Petri nets using examples. Chapter 3 discusses about the mathematical modeling of the Muzima Fingerprint module using Petri nets. Chapter 4 explains the qualitative and quantitative analysis done on the Muzima fingerprint module. Chapter 5 discusses about the programming and simulation done to prove the theoretical results obtained. Chapter 6 provides the conclusion and future work for the thesis.

Le test d’identification d’état d’un système à événement discret (SED) a pour but d’en identifier l’état final, lorsque son état initial est inconnu. Une solution classique à ce problème, en supposant que le SED n’ait pas de sorties observables, consiste à déterminer une séquences de synchronisation, c.à-d., une séquence d’événements d’entrée qui conduit le SED sur un état connu. Ce problème a été résolu dans les années 60’ à l’aide des automates. L’objectif principal de cette thèse est d’utiliser les réseaux de Petri (RdP) pour obtenir une résolution plus optimal de ce problème et pour une plus large classe de systèmes.Initialement, nous montrons que la méthode classique peut être aisément étendue aux RdP synchronisés. Pour cette classe de réseaux non-autonomes, toute transition est associée à un événement d’entrée.L’approche proposée est générale, dans la mesure où elle s’applique à des RdP bornés arbitraires. Cependant, elle engendre le problème d’explosion combinatoire du nombre d’états. Pour obtenir des meilleures solutions, nous considérons une classe spéciale de RdP : les graphes d’état (GdE). Pour ces réseaux, nous considérons d’abord les GdE fortement connexes et proposons des approches pour la construction de SS, qui exploitent les propriétés structurelles du réseau en évitant ainsi une énumération exhaustive de l’espace d’état. Ces résultats s’étendent aux GdE non fortement connexes et à tout RdP synchronisé composé de GdE. Enfin, nous considérons la classe des RdP non bornés et proposons des séquences qui synchronisent le marquage des places non bornées. Une boîte à outils fournit toutes les approches décrites et est appliquée à des différents bancs d’essai. / State-identification experiments are designed to identify the final state of a discrete event system (DES) when its initial state is unknown. A classical solution, assuming the DES has no observable outputs, consists in determining a synchronizing sequence (SS), i.e., a sequence of input events that drives the system to a known state. This problem was essentially solved in the 60’ using automata. The main objective of this thesis is to use Petri nets (PNs) for solving the state-identification problem more efficiently and for a wider class of systems.We start showing that the classical SS construction method based on automata can be easily applied to synchronized PNs, a class of non-autonomous nets where each transition is associated with an input event. The proposed approach is fairly general and it works for arbitrary bounded nets with a complexity that is polynomial with the size of the state space. However, it incurs in the state-space explosion problem.Looking for more efficient solutions, we begin by considering a subclass of PNs called state machines (SMs). We first consider strongly connected SMs and propose a framework for SS construction that exploits structural criteria, not requiring an exhaustive enumeration of the state space of the net. Results are further extended to larger classes of nets, namely non strongly connected SMs and nets containing SM subnets. Finally we consider the class of unbounded nets that describe infinite state systems: even in this case we are able to compute sequences to synchronize the marking of bounded places. A Matlab toolbox implementing all approaches previously described has been designed and applied to a series of benchmarks.

Un environnement spatial naturel hostile, les systèmes spatiaux de télédétection traditionnels,monolithiques et téléopérés depuis le sol, demeurent vulnérables face à un nombre croissant de menaces émergentes issues de l’environnement spatial artificiel (armes antisatellites,débris). Plutôt que de chercher à protéger physiquement les satellites, nous proposons d’adopter une stratégie fondée sur le concept de résilience, qui traduit la capacité d’un système à poursuivre sa mission face à des aléas imprévisibles, fût-ce en mode dégradé. En nous appuyant sur de récentes innovations dans les technologies spatiales, nous nous sommes intéressés à la conception et à l’évaluation d’architectures système fondées sur la mise en réseau de constellations de microsatellites hétérogènes, autonomes et communicants.Afin d’étudier de telles architectures, appelées réseaux de constellations autonomes (RCA),nous proposons une approche de modélisation ainsi qu’un outil de simulation à base de réseaux de Petri imbriqués. Grâce à des métriques issues des réseaux de télécommunication ainsi que des systèmes multiagents, nous avons évalué les RCA au travers de leurs performances opérationnelles et de leurs capacités de communication, nominales puis dans divers modes dégradés. Du point de vue de la résilience, les résultats présentés mettent en évidence l’intérêt de disposer de réseaux de communication denses et de modules de reconfiguration autonomes embarqués au sein même des satellites. / Although Earth observation space systems are designed with strong safety requirements due to an hostile natural space environment, they remain vulnerable to an increasing range of emerging space threats such as antisatellite weapons or orbital debris. Instead of a physical protection of these monolithic and remote-controlled assets, we propose a design strategy based on the concept of resilience which is the ability of a system to maintain an acceptable level of performance in the presence of unforeseeable disturbance.Thanks to the latest space technology innovations, we devised new system architectures composed of networked constellations of heterogeneous and autonomous interacting microsatellites. We decided to model these architectures, called autonomous networked constellations (RCA in French), thanks to Petri nets, and more specifically their nets-within-nets variant. Using telecommunication and multiagent metrics, we assessed different RCA configurations through their operational performance and communicability, for nominal as wellas degraded modes. From the resilience point of view, we present quantitative results that point out the benefits of dense space networks and embedded autonomous reconfiguration modules.

Background: Challenges persist in ensuring access to and optimal use of long-lasting, insecticidal bed nets (LLINs). Factors associated with ownership and use may differ depending on the history of malaria and prevention control efforts in a specific region. Understanding how the cultural and social-environmental context of bed net use may differ between high- and low-risk regions is important when identifying solutions to improve uptake and appropriate use. Methods: Community forums and a household, cross-sectional survey were used to collect information on factors related to bed net ownership and use in western Kenya. Sites with disparate levels of transmission were selected, including an endemic lowland area, Miwani, and a highland epidemic-prone area, Kapkangani. Analysis of ownership was stratified by site. A combined site analysis was conducted to examine factors associated with use of all available bed nets. Logistic regression modelling was used to determine factors associated with ownership and use of owned bed nets. Results: Access to bed nets as the leading barrier to their use was identified in community forums and cross-sectional surveys. While disuse of available bed nets was discussed in the forums, it was a relatively rare occurrence in both sites. Factors associated with ownership varied by site. Education, perceived risk of malaria and knowledge of individuals who had died of malaria were associated with higher bed net ownership in the highlands, while in the lowlands individuals reporting it was easy to get a bed net were more likely to own one. A combined site analysis indicated that not using an available bed net was associated with the attitudes that taking malaria drugs is easier than using a bed net and that use of a bed net will not prevent malaria. In addition, individuals with an unused bed net in the household were more likely to indicate that bed nets are difficult to use, that purchased bed nets are better than freely distributed ones, and that bed nets should only be used during the rainy season. Conclusion: Variations in factors associated with ownership should be acknowledged when constructing messaging and distribution campaigns. Despite reports of bed nets being used for other purposes, those in the home were rarely unused in these communities. Disuse seemed to be related to beliefs that can be addressed through education programmes. As mass distributions continue to take place, additional research is needed to determine if factors associated with LLIN ownership and use change with increasing availability of LLIN.

Platelets play a crucial role for blood hemostasis, the process that prevents bleeding. In addition, platelets have been demonstrated to promote cancer progression and cancer related complications like metastasis and thrombosis. Platelets can affect cancer related diseases either directly or by interacting with other blood cells or molecules in the circulation of individuals with cancer. The current thesis addresses the role of platelets in tumor progression and tumor-induced systemic effects of cancer, with a special focus on the effects on the vasculature. In the first paper, the role of platelets in tumor progression in histidine-rich glycoprotein (HRG)-deficient mice was addressed. We report that HRG-deficient mice show enhanced tumor growth, epithelial to mesenchymal transition (EMT) and metastasis. The enhanced platelet activity in the absence of HRG is responsible for the accelerated tumor progression. In the second paper, we demonstrate that platelet-derived PDGFB is a central player to keep the tumor vessels functional. Moreover, in a pancreatic neuroendocrine carcinoma model with PDGFB-deficient platelets, spontaneous liver metastasis was enhanced. With this finding we identify a previously unknown role of platelet derived PDGFB. In the third paper, we found that TBK1 mediates platelet-induced EMT by activation of NF-kB signaling, which suggest that TBK1 contributes to tumor invasiveness in mammary epithelial tumors. In the last paper, we report that the vascular function in organs that are neither affected by the primary tumor, nor represent metastatic sites, is impaired in mice with cancer. We show that tumor-induced formation of intravascular neutrophil extracellular traps (NETs), a fibril matrix consisting of neutrophils with externalized DNA and histones, granule proteases and platelets, are responsible for the impaired peripheral vessel function.

We propose a method to deal simultaneously with model uncertainty and correlated regressors in linear regression models by combining elastic net specifications with a spike and slab prior. The estimation method nests ridge regression and the LASSO estimator and thus allows for a more flexible modelling framework than existing model averaging procedures. In particular, the proposed technique has clear advantages when dealing with datasets of (potentially highly) correlated regressors, a pervasive characteristic of the model averaging datasets used hitherto in the econometric literature. We apply our method to the dataset of economic growth determinants by Sala-i-Martin et al. (Sala-i-Martin, X., Doppelhofer, G., and Miller, R. I. (2004). Determinants of Long-Term Growth: A Bayesian Averaging of Classical Estimates (BACE) Approach. American Economic Review, 94: 813-835) and show that our procedure has superior out-of-sample predictive abilities as compared to the standard Bayesian model averaging methods currently used in the literature. (authors' abstract) / Series: Research Report Series / Department of Statistics and Mathematics