Sequential PDEVS Architecture

International audienceParallel Discrete Event System Specification (PDEVS) is a well-known formalism used to model and simulate Discrete Event Systems. This formalism uses an abstract simulator that defines a set of abstract algorithms that are parallel by nature. To implement simulators using these abstract algorithms , several architectures were proposed. Most of these architectures follow distributed approaches that may not be appropriate for single core processors or microcontrollers. In order to reuse efficiently PDEVS models in this type of systems, we define a new architecture that provides a single threaded execution by passing messages in a call/return fashion to simplify the execution time analysis

The DEVStone Metric: Performance Analysis of DEVS Simulation Engines

The DEVStone benchmark allows us to evaluate the performance of discrete-event simulators based on the DEVS formalism. It provides model sets with different characteristics, enabling the analysis of specific issues of simulation engines. However, this heterogeneity hinders the comparison of the results among studies, as the results obtained on each research work depend on the chosen subset of DEVStone models. We define the DEVStone metric based on the DEVStone synthetic benchmark and provide a mechanism for specifying objective ratings for DEVS-based simulators. This metric corresponds to the average number of times that a simulator can execute a selection of 12 DEVStone models in one minute. The variety of the chosen models ensures we measure different particularities provided by DEVStone. The proposed metric allows us to compare various simulators and to assess the impact of new features on their performance. We use the DEVStone metric to compare some popular DEVS-based simulators

Isolation and Characterization of Extracellular Vesicles from Various Biological Matrices using Capillary-Channeled Polymer (C-CP) Fiber Solid-Phase Extraction Spin-Down Tips

A number of recent works have emphasized the need to isolate nanometer-scale analytes, like extracellular vesicles (EVs), from various biologically-relevant fluids. Exosomes are a subset of small EVs that range from 30-200 nm in diameter that serve as biomolecular snapshots of their cell of origin containing mother cell-specific DNA, miRNA, mRNA, and proteins. As critical components of intercellular communication, exosomes and other EVs play significant roles in many physiological and pathological processes. Diverse populations of these vesicles can be collected from biofluids, including blood, saliva, and urine, from cell culture conditioned media and primary cells, and even from plant fluid stocks. With their characteristic vector-like activities and accessible collection from renewable sources, the large-scale processing of EVs from patient biofluids for clinical diagnostics and from plant fluids or high-yield bioreactors for use as therapeutic vectors has been previously proposed. However, these applications are limited by extremely impure, low-yield exosome recoveries, despite the large availability of exosome sources. Hence, an isolation method that provides high concentrations of pure, bioactive EVs from diverse sources on reasonable scales of time and cost is of much interest. Employed in this work is a rapid EV isolation method using a hydrophobic interaction chromatography (HIC) workflow on a capillary-channeled polymer (C-CP) fiber spin-down tip. Here, EVs are isolated from several biofluid sources, including mock biofluid matrices, clinical patient biofluid samples, cellular milieu from mammalian and amoeba cell lines, and over 20 fruit and vegetable sample stocks. Representative populations of EVs are obtained using the C-CP tip method, where up to 12 samples are simultaneously processed in a standard tabletop centrifuge in less than 15 minutes. This batch solid-phase extraction technique allows up to 1 x 1012 EVs to be obtained from each μL-scale aliquot of the original biofluid. The tip-isolated EVs were characterized using transmission electron microscopy (TEM), multi-angle light scattering (MALS), nanoparticle tracking analysis (NTA), absorbance quantification, protein purity assay, and immunoassays to EV and source-specific proteins. The efficient HIC C-CP tip isolation method produces the required integrity and purity of recovered EVs to enable fundamental research to be performed and their therapeutic vector and clinical diagnostic potentials to be better explored

A Continuous-Time Microsimulation and First Steps Towards a Multi-Level Approach in Demography

Microsimulation is a methodology that closely mimics life-course dynamics. In this thesis, we describe the development of the demographic microsimulation with a continuous time scale that we have realized in the context of the project MicMac - Bridging the micro-macro gap in population forecasting. Furthermore, we detail extensions that we have added to the initial version of the MicMac microsimulation.Mikrosimulation ist eine Prognosetechnik, die sich hervorragend eignet, um Bevölkerungsdynamik realitätsnah abzubilden. In dieser Dissertation beschreiben wir die Entwicklung einer demografischen Mikrosimulation, die wir im Rahmen des Projektes MicMac - Bridging the micro-macro gap in population forecasting erstellt haben. Zudem erläutern wir Erweiterungen, die wir an der ursprünglichen MicMac- Mikrosimulation vorgenommen haben

Therapeutic potential and pharmacological significance of extracellular vesicles derived from traditional medicinal plants

Medicinal plants are the primary sources for the discovery of novel medicines and the basis of ethnopharmacological research. While existing studies mainly focus on the chemical compounds, there is little research about the functions of other contents in medicinal plants. Extracellular vesicles (EVs) are functionally active, nanoscale, membrane-bound vesicles secreted by almost all eukaryotic cells. Intriguingly, plant-derived extracellular vesicles (PDEVs) also have been implicated to play an important role in therapeutic application. PDEVs were reported to have physical and chemical properties similar to mammalian EVs, which are rich in lipids, proteins, nucleic acids, and pharmacologically active compounds. Besides these properties, PDEVs also exhibit unique advantages, especially intrinsic bioactivity, high stability, and easy absorption. PDEVs were found to be transferred into recipient cells and significantly affect their biological process involved in many diseases, such as inflammation and tumors. PDEVs also could offer unique morphological and compositional characteristics as natural nanocarriers by innately shuttling bioactive lipids, RNA, proteins, and other pharmacologically active substances. In addition, PDEVs could effectively encapsulate hydrophobic and hydrophilic chemicals, remain stable, and cross stringent biological barriers. Thus, this study focuses on the pharmacological action and mechanisms of PDEVs in therapeutic applications. We also systemically deal with facets of PDEVs, ranging from their isolation to composition, biological functions, and biotherapeutic roles. Efforts are also made to elucidate recent advances in re-engineering PDEVs applied as stable, effective, and non-immunogenic therapeutic applications to meet the ever-stringent demands. Considering its unique advantages, these studies not only provide relevant scientific evidence on therapeutic applications but could also replenish and inherit precious cultural heritage

Isolation of extracellular vesicles from citrus limon fruit through membrane-based techniques.

The project is aimed at the development of a membrane-based protocol for the isolation of plant-derived extracellular vesicles. In particular, citrus limon fruit is selected as source material, due to its beneficial phyto-properties, availability and cheapness. In the chosen strategy the focus is placed upon the development of a protocol potentially suitable for large-scale operations, conversely to differential ultracentrifugation method, the benchmark in extracellular vesicles production, whose applicability is limited to lab-scale operations. In this context dead-end and crossflow MF/UF units are compared, both as concentration and purification steps. Followingly, the isolated vesicles ware analysed and characterized with SEC liquid chromatography and both physical and biochemical methods. Finally, passive cargo loading techniques are applied to the isolated vesicles to test their encapsulation capability with bioactive phytocomponents, as curcumin

Aufgabenorientierte Multi-Robotersteuerungen auf Basis des SBC-Frameworks und DEVS: vorgelegt von Birger Freymann

In der Industrie sind Roboter bereits seit Jahrzehnten als leistungsfähige und flexible Werkzeuge etabliert. Mit neuen Anwendungsbereichen und Anforderungen, wie sie zum Beispiel im Rahmen der Industrie 4.0 Initiative definiert werden, kommt der effizienten Entwicklung von Robotersteuerungen eine immer größere Bedeutung zu. Diese Tendenz erfordert die Entwicklung neuer Methoden zur herstellerunabhängigen und applikationsübergreifenden Programmierung von Roboteranwendungen. Entscheidend sind hierbei systematische Vorgehensmodelle, theoriekonforme und modellbasierte Entwicklungsmethoden sowie moderne Programmiersysteme als Entwicklungswerkzeuge. Die Vielzahl der herstellerspezifischen Entwicklungsumgebungen auf dem Markt zeigt, dass sich existierende Standards im Bereich der Steuerungsentwicklung für Roboter bisher kaum durchsetzen konnten. Die methodische und softwaretechnische Diversität erschwert es, unterschiedliche Robotertypen und Roboter unterschiedlicher Hersteller in Teams zu gruppieren, um leistungsfähige, flexible und kostengünstige Multi-Robotersysteme (MRS) umzusetzen. Durchgängige Toolketten sowie Methoden der Modellbildung und Simulation spielen dabei eine wichtige Rolle. In der Literatur wird in diesem Zusammenhang vom Rapid-Control-Prototyping (RCP) gesprochen. Gegenwärtig sind RCP-basierte Techniken in der industriellen Robotik fast immer herstellerspezifisch. In dieser Arbeit wird ein Ansatz zur durchgängigen, modellbasierten und herstellerunabhängigen Steuerungsentwicklung für Roboterteams mit industriellen Knickarmrobotern entwickelt. Aufbauend auf dem Simulation-Based-Control (SBC)-Ansatz und dem Task-Oriented-Control (TOC)-Ansatz werden Entwicklungsmethoden aus dem Bereich von Single-Robotersystemen (SRS) auf MRS übertragen. Es werden mögliche Interaktionen zwischen Robotern untersucht und hierauf aufbauend Interaktionsklassen definiert. Zur Umsetzung einer durchgängigen Steuerungsentwicklung wird der Discrete-Event-System-Specification (DEVS)-Formalismus diskutiert und es werden Erweiterungen zur Echtzeit- und Prozessanbindung untersucht. Hieraus abgeleitet wird ein modifizierter Formalismus entwickelt und dessen Eignung zur durchgängigen, modellbasierten Steuerungsentwicklung anhand eines Fallbeispiels demonstriert. Zur Spezifikation der entwickelten Modelle wird die DEVS-Diagramm-Notation verwendet und um zusätzliche Beschreibungsmittel erweitert. Basierend auf den zuvor definierten Interaktionsklassen werden Lösungsansätze zur TOC-basierten Umsetzung von Interaktionen mittels modularer und wiederverwendbarer Aufgaben erarbeitet. Anschließend wird deren prototypische Umsetzung anhand von Fallbeispielen mittels des neu entwickelten DEVS-Formalismus gezeigt. Die Komplexität der Interaktionen steigt mit jedem Fallbeispiel an. Zur besseren Handhabung der Komplexität wird mit dem Erweiterten System-Entity-Structure/Model-Base (SES/MB)-Ansatz eine zusätzliche modellbasierte Technik eingeführt, mit dem SBC- sowie dem TOC-Ansatz integriert und anhand eines Fallbeispiels der bisherigen Vorgehensweise gegenübergestellt.Robots have been established in industry for decades as powerful and flexible tools. With new application areas and requirements, such as those defined in the context of the Industry 4.0 initiative, the efficient development of robot controllers is becoming increasingly important. This trend requires the development of new methods for the manufacturer-independent and application-independent programming of robot applications. The decisive factors here are systematic procedural models, theory-compliant and model-based development methods, and modern programming systems as development tools. The large number of manufacturer-specific development environments on the market shows that existing standards in the area of control development for robots have hardly been able to establish themselves. The methodological and software diversity makes it difficult to group different robot types and robots from different manufacturers in teams in order to implement powerful, flexible and cost-effective multi-robot systems (MRS). Continuous tool chains as well as methods of modeling and simulation play an important role in this context. In the literature, rapid control prototyping (RCP) is spoken of in this context. Currently, RCP-based techniques in industrial robotics are almost always manufacturer-specific. In this thesis, an approach for end-to-end, model-based and vendor-independent control development for robot teams with industrial jointed-arm robots is developed. Based on the Simulation-Based-Control (SBC) approach and the Task-Oriented-Control (TOC) approach, development methods from the field of single robot systems (SRS) are transferred to MRS. Possible interactions between robots are investigated and, based on this, interaction classes are defined. For the implementation of an integrated control development the Discrete-Event-System-Specification (DEVS) formalism is discussed and extensions for real-time and process integration are investigated. Derived from this, a modified formalism is developed and its suitability for integrated, model-based control development is demonstrated by means of a case study. For the specification of the developed models the DEVS diagram notation is used and extended by additional descriptive means. Based on the previously defined interaction classes, approaches for the TOC-based implementation of interactions are developed using modular and reusable tasks. Subsequently, their prototypical implementation is shown on the basis of case studies using the newly developed DEVS formalism. The complexity of the interactions increases with each case study. For a better handling of the complexity, the Extended System-Entity-Structure/Model-Base (SES/MB) approach is introduced as an additional model-based technique, integrated with the SBC and TOC approaches, and compared with the previous approach using a case study

Simulator adaptation at runtime for component-based simulation software

Component-based simulation software can provide many opportunities to compose and configure simulators, resulting in an algorithm selection problem for the user of this software. This thesis aims to automate the selection and adaptation of simulators at runtime in an application-independent manner. Further, it explores the potential of tailored and approximate simulators - in this thesis concretely developed for the modeling language ML-Rules - supporting the effectiveness of the adaptation scheme.Komponenten-basierte Simulationssoftware kann viele Möglichkeiten zur Komposition und Konfiguration von Simulatoren bieten und damit zu einem Konfigurationsproblem für Nutzer dieser Software führen. Das Ziel dieser Arbeit ist die Entwicklung einer generischen und automatisierten Auswahl- und Adaptionsmethode für Simulatoren. Darüber hinaus wird das Potential von spezifischen und approximativen Simulatoren anhand der Modellierungssprache ML-Rules untersucht, welche die Effektivität des entwickelten Adaptionsmechanismus erhöhen können

Assessment and modulation of the lymphatic function throughout the onset and progression of atherosclerosis

L'athérosclérose est la principale cause de maladies coronariennes, affectant les artères de grand et moyen calibre. C'est une maladie inflammatoire chronique caractérisée par des plaques situées dans la couche de l’intima, composées de cellules inflammatoires, de cellules musculaires lisses, de composants fibreux et de lipides. Qu'il provienne de source alimentaire ou hépatique, le cholestérol qui s'accumule dans les macrophages des tissus périphériques, comme la paroi artérielle, engendre une réaction inflammatoire et doit être conséquemment mobilisé à l'aide d’accepteurs de cholestérol comme les lipoprotéines de haute densité (HDL). Ce processus spécifique est appelé transport inverse du cholestérol (mRCT). Des études ont démontré que l'apolipoprotéine A-I (apoA-I) pourrait être un acteur clé dans la régulation du mRCT, exerçant des effets différents de ceux du HDL. Plus important encore, le système lymphatique a récemment été identifié comme un nouvel acteur essentiel dans l'élimination du cholestérol de la lésion athérosclérotique (Martel et al., JCI 2013). Il a été démontré que sans vaisseaux lymphatiques fonctionnels, la mobilisation du cholestérol hors de la plaque ne peut pas être réalisée correctement et aggrave la maladie. Le réseau lymphatique est parallèle au système sanguin et il est présent dans presque tous les tissus du corps. C'est un acteur essentiel dans le maintien de l'homéostase des fluides, dans le transport des cellules immunitaires de la périphérie vers les ganglions lymphatiques correspondants, ainsi que dans l’absorption des lipides alimentaires de l'intestin vers la circulation sanguine. Le système lymphatique comprend les vaisseaux lymphatiques (LVs) initiaux et collecteurs, ainsi que les ganglions lymphatiques, qui ont une anatomie spécifique et des rôles distincts. La lymphe, le liquide clair qui circule dans les LVs, se jette dans la circulation sanguine au niveau de la veine sous-clavière. Les plaquettes sont responsables de la régulation de cette séparation des vaisseaux sanguins et lymphatiques via la formation d’un thrombus formé lors de l’interaction de leur récepteur CLEC-2 avec la podoplanine présente sur les cellules endothéliales lymphatiques. Il a également été démontré que l’activité plaquettaire était nécessaire tout au long de la vie pour maintenir l’intégrité des jonctions des LVs. L'athérosclérose est également caractérisée par une activation cellulaire et une apoptose accrue. Par conséquent, ces activités cellulaires peuvent entraîner la formation de particules submicroniques appelées vésicules extracellulaires qui ont des effets variables, mais souvent néfastes, sur l'endothélium sanguin et l'évolution de la plaque. La maladie cardiovasculaire a été associée à une augmentation du nombre des vésicules extracellulaires (EVs) en circulation, et nous croyons que ces véhicules pourraient être impliqués dans le dysfonctionnement lymphatique lié à l'athérosclérose. D'après des données récentes publiées au cours de ma maîtrise, l'amélioration du transport lymphatique pourrait limiter la progression de l'athérosclérose et favoriser la régression de la plaque. Nous avons montré que le transport lymphatique est altéré chez les jeunes souris prédisposés à développer l'athérosclérose, même avant l'apparition de la plaque. Nous avons prouvé que cet effet est d’abord associé à un défaut au niveau des vaisseaux collecteurs et nous suggérons que l'amélioration de la liaison du VEGF-C/ VEGFR3 puisse supprimer ce défaut spécifique. L'objectif global de cette thèse était de poursuivre dans cette voie et de mieux définir le rôle de l’important facteur de croissance lymphatique, VEGF-C, et de la lipoprotéine apoA-I dans la maintenance de l’intégrité et la fonction des vaisseaux lymphatiques. En outre, une meilleure description des composants de la lymphe, en particulier des agents libérés par les cellules, a été jugée nécessaire. La première publication nous a permis de montrer que, lorsqu'elles étaient injectées avec un mutant du facteur de croissance VEGF-C ciblant spécifiquement le récepteur VEGFR-3 (VEGF-C 152s), avant l'administration d'une diète pro-athérogène, les souris Ldlr-/- étaient protégées contre l’accumulation excessive dans la plaque et celle-ci était plus stable à long terme. La capacité de contraction soutenue des vaisseaux lymphatiques collecteurs et l'expression accrue de VEGFR-3 et de FOXC2 observée chez ces souris traitées avec VEGF-C-152s ont contribué à la clairance des composants nocifs contenus dans les tissus périphériques tels que les macrophages et le cholestérol. La deuxième publication a montré que des souris Ldlr-/- athérosclérotiques traitées à faible dose avec de l’apoA-I, présentaient un transport lymphatique accru et une hyperperméabilité des vaisseaux lymphatiques collecteurs abrogée, possiblement par une modulation de l’activité plaquettaire. La troisième publication est la première à démontrer la présence de vésicules extracellulaires d'origines hétérogènes dans la lymphe des souris et que le nombre de différents sous-types augmente chez les souris athérosclérotiques. Collectivement, ces études confirment la présence d'un dysfonctionnement lymphatique chez la souris avant même l'apparition de la plaque, et il est intéressant de noter que ce dysfonctionnement est principalement associé à un défaut des vaisseaux lymphatiques collecteurs, limitant ainsi le transport de la lymphe des tissus périphériques vers le sang. Différents traitements avec des facteurs de croissance et des lipoprotéines peuvent potentiellement moduler l’apparition et la progression de la lésion en améliorant la fonction lymphatique à différents stades de la maladie athérosclérotique. Nos découvertes concernant la présence de EVs dans la lymphe représentent leur potentiel en tant que biomarqueurs, mais également une nouvelle cible pour mieux comprendre la dysfonction lymphatique.Atherosclerosis is the principal cause of coronary artery disease (CAD), affecting large- and medium-sized arteries. It is a chronic inflammatory disease characterized by intimal plaques composed of inflammatory cells, smooth muscle cells, fibrous components and lipids. Cholesterol that accumulates within macrophages in peripheral tissues, like the arterial wall, whether from dietary or synthetic sources, promotes inflammatory responses and needs to be excreted with the help of the cholesterol acceptor high density lipoprotein (HDL). This specific process is termed macrophage reverse cholesterol transport (mRCT) and studies have demonstrated that lipid free apolipoprotein A-I (apoA-I) could be a key player in mRCT regulation, exuding different effects than HDL. More importantly, recently, the lymphatic system has been identified as a novel prerequisite player in the removal of cholesterol out of the atherosclerotic lesion (Martel et al., JCI 2013). It has been demonstrated that without functioning lymphatic vessels cholesterol mobilization from the plaque cannot be properly achieved and aggravates the disease. The lymphatic network runs in parallel to the blood vasculature and is present in almost all the tissues of the body. It is a crucial player in maintaining fluid homeostasis, trafficking immune cells from the periphery to corresponding lymph nodes, as well as transporting lipids from the intestine to the circulation. The lymphatic system comprises the initial and collecting lymphatic vessels (LVs), as well as lymph nodes, all with a specific anatomy and distinctive roles. Lymph, the clear fluid that circulates within LVs drains towards the bloodstream at the level of the subclavian vein. Platelets are responsible to regulate this blood/lymphatic vessel separation by forming a clog, upon the interaction of their C-type lectin-like receptor 2 (CLEC-2) with podoplanin, present on lymphatic endothelial cells. Platelet activity has also been shown to be required throughout life in order to maintain LV junction integrity. Atherosclerosis is also characterized by increased cellular activation and apoptosis. Consequently, these cellular activities may result in the formation of submicron particles called extracellular vesicles (EVs) that have variable effects on the blood endothelium and subsequent plaque evolution. CAD has been associated with increased circulating EVs, and we suspect that these EVs might be involved in atherosclerosis-related lymphatic dysfunction. Based on recent data collected during my master’s degree, there is evidence that enhancing lymphatic transport could limit atherosclerosis progression and favour plaque regression. We showed that lymphatic transport is impaired in young, atherosclerosis-prone mice, even before atherosclerosis onset. We believe it to be potentially associated with a defect in the lymphatic pumping capacity, and we suggest that enhancing VEGF-C/VEGFR-3 binding can abolish this specific defect. The global objective of this thesis was to pursue along this path and better delineate the role of the important lymphatic-specific growth factor, VEGF-C and the lipoprotein apoA-I, on collecting LVs function. Furthermore, a better understanding of lymph components, especially cellular releasants was deemed necessary. The first publication allowed us to show that when injected with VEGF-C 152s, before the administration of a pro-atherogenic regimen, Ldlr-/- mice were protected from excessive plaque formation and long-term, had a more stable plaque. The sustained contraction capacity of the collecting lymphatic vessels and the enhanced expression of VEGFR-3 and FOXC2 observed in these VEGF-C-152s treated mice contributed to the clearance of harmful components contained in peripheral tissues such as the macrophages and cholesterol. The second publication showed that atherosclerotic Ldlr-/- mice treated with low-dose lipid-free apoA-I had enhanced lymphatic transport and abrogated collecting LV permeability possibly through modulation of platelet activity. The third publication is the first ever to demonstrate the presence of extracellular vesicles of heterogeneous origins in the lymph of mice, and that their levels differ in atherosclerosis. Collectively, these studies confirm that lymphatic dysfunction is present before the onset of atherosclerosis, and particularly of interest, that this dysfunction is primarily associated with a defect in the collecting vessels, thereby limiting the lymph transport from peripheral tissues to the blood. Different treatments with growth factors and lipoproteins have the potential to modulate the lesion onset and progression through the enhancement of lymphatic function, while our findings regarding the presence of EVs in lymph represents their potential as biomarkers, but also a new venue to better understand lymphatic dysfunction