Using Indexed and Synchronous Events to Model and Validate Cyber-Physical Systems

Timed Transition Models (TTMs) are event-based descriptions for modelling, specifying, and verifying discrete real-time systems. An event can be spontaneous, fair, or timed with specified bounds. TTMs have a textual syntax, an operational semantics, and an automated tool supporting linear-time temporal logic. We extend TTMs and its tool with two novel modelling features for writing high-level specifications: indexed events and synchronous events. Indexed events allow for concise description of behaviour common to a set of actors. The indexing construct allows us to select a specific actor and to specify a temporal property for that actor. We use indexed events to validate the requirements of a train control system. Synchronous events allow developers to decompose simultaneous state updates into actions of separate events. To specify the intended data flow among synchronized actions, we use primed variables to reference the post-state (i.e., one resulted from taking the synchronized actions). The TTM tool automatically infers the data flow from synchronous events, and reports errors on inconsistencies due to circular data flow. We use synchronous events to validate part of the requirements of a nuclear shutdown system. In both case studies, we show how the new notation facilitates the formal validation of system requirements, and use the TTM tool to verify safety, liveness, and real-time properties.Comment: In Proceedings ESSS 2015, arXiv:1506.0325

L’hypothèque légale de la construction — Un outil de protection des créances des sous-traitants toujours efficace?

L’hypothèque légale de la construction est le principal mécanisme de protection des créances des intervenants de l’industrie de la construction. Par l’adoption de ce régime, le législateur a voulu protéger l’intégrité économique de cette industrie. Par contre, l’utilisation de notions mécaniques plus ou moins efficaces dans la mise en œuvre de l’hypothèque légale, la prolifération d’outils de contournement contractuels et les mécanismes de protection des propriétaires nuisent à l’efficacité du régime légal à protéger les créances des sous-traitants. Des correctifs pourraient néanmoins être apportés pour restaurer l’équité du régime légal. Par ailleurs, lorsqu’un immeuble appartient à l’État ou l’un de ses mandataires, il devient pratiquement impossible pour un sous-traitant d’exercer ses recours hypothécaires compte tenu des privilèges et immunités dont jouissent l’État et de ses mandataires. Les biens affectés à l’utilité publique des personnes morales de droit public non-mandataires de l’État jouissent également d’une grande protection, surtout dans le domaine municipal. Ceci rend bien illusoire tout recours hypothécaire intenté par un sous-traitant malgré le fait le législateur cherchait justement, par le maintien d’un régime légal, à protéger leurs créances.The construction hypothec is the main mechanism for the protection of the claims of every participant in the construction industry. With the adoption of this legal regime, the Quebec legislator tried to protect the economic integrity of this industry. However, the use of notions more or less efficient for the execution of this legal regime, the increase of contractual mechanisms which avoid the application of the legal regime and legal dispositions which protect the owners harm the efficiency of the legal regime to correctly protect subcontractor's claims. Nevertheless, some correctives can be found to restore the legal regime's equity. Moreover, when a immoveable is owned by the State or any of its agents, it is practically impossible for a subcontractor to exercise his hypothecary rights because of the State's privileges and immunities. The property appropriated to public utility of the legal persons established in the public interest which are not agents of the State enjoy also a strong protection, particularly in the municipal sector. In any case, it is rendering illusory the exercise by a subcontractors of any of his hypothecary rights despite the fact that the legislator's goal, by maintaining this legal regime, was precisely to protect their claims

Muscle satellite cells adopt divergent fates: a mechanism for self-renewal?

Growth, repair, and regeneration of adult skeletal muscle depends on the persistence of satellite cells: muscle stem cells resident beneath the basal lamina that surrounds each myofiber. However, how the satellite cell compartment is maintained is unclear. Here, we use cultured myofibers to model muscle regeneration and show that satellite cells adopt divergent fates. Quiescent satellite cells are synchronously activated to coexpress the transcription factors Pax7 and MyoD. Most then proliferate, down-regulate Pax7, and differentiate. In contrast, other proliferating cells maintain Pax7 but lose MyoD and withdraw from immediate differentiation. These cells are typically located in clusters, together with Pax7-ve progeny destined for differentiation. Some of the Pax7+ve/MyoD-ve cells then leave the cell cycle, thus regaining the quiescent satellite cell phenotype. Significantly, noncycling cells contained within a cluster can be stimulated to proliferate again. These observations suggest that satellite cells either differentiate or switch from terminal myogenesis to maintain the satellite cell pool

Methodologies in organic chemistry and their applications to the synthesis of bio-active small molecules

This thesis is separated into two parts. In part A, a novel 5-alkyl-2-silyloxy cyclopentadiene is presented. Racemic and enantioselective syntheses of the new cyclopentadiene have been developed. This new cyclopentadiene is significantly more stable towards 1,5-H shifts than most cyclopentadienes. Through the use of computational modeling, it was determined that the added stability comes from the electron donation of the 2-silyloxy group into the LUMO of the diene. The novel diene was used for Diels-Alder cycloadditions at room temperature with a variety of dienophiles. An europium Lewis acid was found to be compatible with the diene while activating dienophiles for cycloaddition. It was also determined that an enantioenriched diene will generate a cycloaddition product with no erosion in enantiomeric excess. Stabilization by a silyloxy group was also used to generate a stable 1-alkyl-3-silyloxy cyclopentadiene that underwent smooth Diels-Alder reaction. The 5-alkyl-2-silyloxy cyclopentadiene was used as a cycloaddition partner in the synthesis of part of the natural product palau'amine. Through a Diels-Alder/oxidative cleavage sequence, the E-ring stereoarray of the originally proposed structure of Palau'amine was obtained.In part B, the synthesis and purification of a novel multi-action drug, triciferol, are presented. Triciferol was designed to combine a vitamin D3 framework and a metal binding group with histone deacetylase inhibition properties. The secosteroidal core of triciferol is obtained from degradation of vitamin D2. The vitamin D A-ring is obtained from (-)-quinic acid and is appended to the core by a Horner reaction. The unsaturated side chain is built by sequential Wittig reactions and terminated by a metal-binding hydroxamic acid. This conjugated hydroxamic acid group was found to be susceptible to exposition to trace metals. The final purification of triciferol could only be accomplished using reverse phase silica chromatography. Triciferol was found to be an effective bifunctional agent, acting both as an agonist of the vitamin D receptor and an inhibitor of histone deacetylase. Moreover, it proved to be a potent anti-cancer drug in vitro.Cette thèse comprend deux parties. Dans la partie A, un nouveau 5-alkyl-2-silyloxy cyclopentadiène est présenté. Deux synthèses de ce nouveau cyclopentadiène ont été développées : l'une racémique et l'autre énantiosélective. Le nouveau cyclopentadiène est significativement plus stable vis-à-vis de la migration 1,5 d'hydrogène que la plupart des cyclopentadiènes connus. À l'aide de la modélisation par ordinateur, la stabilité du nouveau cyclopentadiène a été attribuée à une donation électronique du groupe 2-silyloxy au LUMO du diène. Le nouveau cyclopentadiène a été utilisé lors de cycloadditions Diels-Alder à température ambiante avec une sélection de diénophiles. Un acide de Lewis à base d'europium, permettant d'activer les diénophiles sans décomposer le diène, a été trouvé. Il fut aussi déterminé qu'une version énantioenrichie du cyclopentadiène génère un produit de cycloaddition sans aucune détérioration de l'excès énantiomérique initial. La stabilisation par un groupe silyloxy a aussi été appliquée avec succès à un cyclopentadiène 1-alkyle-3-silyloxy, lui permettant d'encourir un Diels-Alder sans problème. Le 5-alkyle-2-silyloxy cyclopentadiene a été utilisé lors d'une cycloaddition menant à la synthèse d'une partie de la palau'amine, un produit naturel. La stéréochimie de l'anneau E de la structure originale de la palau'amine a été atteinte grâce à une séquence de Diels-Alder / clivage oxydatif.Dans la partie B, la synthèse et la purification d'un nouveau médicament bi-fonctionnel, le triciferol, sont présentées. Le triciferol a été conçu afin de combiner la structure de la vitamine D3 à un groupe chélateur de métaux, ayant la capacité d'inhiber les HDAC. Le centre sécostéroïde du triciferol est obtenu par dégradation de la vitamine D2. L'anneau A est synthétisé à partir d'acide quinique et est attaché au centre sécostéroïde grâce à une réaction de Horner. La chaine insaturée est construite par réactions de Wittig et est terminée par un acide hydroxamique chélateur. Cet acide hydroxamique insaturé se décompose facilement en présence de métaux ; la purification finale du triciférol doit être effectuée par une chromatographie en phase inverse. Le triciférol a les capacité d'un médicament bi-fonctionnel : c'est un agoniste du récepteur de la vitamine D et un inhibiteur des enzymes HDAC. f

Synthetic Antigens Reveal Dynamics of BCR Endocytosis during Inhibitory Signaling

B cells detect foreign antigens through their B cell antigen receptor (BCR). The BCR, when engaged by antigen, initiates a signaling cascade. Concurrent with signaling is endocytosis of the BCR complex, which acts to downregulate signaling and facilitate uptake of antigen for processing and display on the cell surface. The relationship between signaling and BCR endocytosis is poorly defined. Here, we explore the interplay between BCR endocytosis and antigens that either promote or inhibit B cell activation. Specifically, synthetic antigens were generated that engage the BCR alone or both the BCR and the inhibitory co-receptor CD22. The lectin CD22, a member of the Siglec family, binds sialic acid-containing glycoconjugates found on host tissues, inhibiting BCR signaling to prevent erroneous B cell activation. At low concentrations, antigens that can cocluster the BCR and CD22 promote rapid BCR endocytosis; whereas, slower endocytosis occurs with antigens that bind only the BCR. At higher antigen concentrations, rapid BCR endocytosis occurs upon treatment with either stimulatory or inhibitory antigens. Endocytosis of the BCR, in response to synthetic antigens, results in its entry into early endocytic compartments. Although the CD22-binding antigens fail to activate key regulators of antigen presentation (e.g., Syk), they also promote BCR endocytosis, indicating that inhibitory antigens can be internalized. Together, our observations support a functional role for BCR endocytosis in downregulating BCR signaling. The reduction of cell surface BCR levels in the absence of B cell activation should raise the threshold for BCR subsequent activation. The ability of the activating synthetic antigens to trigger both signaling and entry of the BCR into early endosomes suggests strategies for targeted antigen delivery