Rich Counter-Examples for Temporal-Epistemic Logic Model Checking

Model checking verifies that a model of a system satisfies a given property, and otherwise produces a counter-example explaining the violation. The verified properties are formally expressed in temporal logics. Some temporal logics, such as CTL, are branching: they allow to express facts about the whole computation tree of the model, rather than on each single linear computation. This branching aspect is even more critical when dealing with multi-modal logics, i.e. logics expressing facts about systems with several transition relations. A prominent example is CTLK, a logic that reasons about temporal and epistemic properties of multi-agent systems. In general, model checkers produce linear counter-examples for failed properties, composed of a single computation path of the model. But some branching properties are only poorly and partially explained by a linear counter-example. This paper proposes richer counter-example structures called tree-like annotated counter-examples (TLACEs), for properties in Action-Restricted CTL (ARCTL), an extension of CTL quantifying paths restricted in terms of actions labeling transitions of the model. These counter-examples have a branching structure that supports more complete description of property violations. Elements of these counter-examples are annotated with parts of the property to give a better understanding of their structure. Visualization and browsing of these richer counter-examples become a critical issue, as the number of branches and states can grow exponentially for deeply-nested properties. This paper formally defines the structure of TLACEs, characterizes adequate counter-examples w.r.t. models and failed properties, and gives a generation algorithm for ARCTL properties. It also illustrates the approach with examples in CTLK, using a reduction of CTLK to ARCTL. The proposed approach has been implemented, first by extending the NuSMV model checker to generate and export branching counter-examples, secondly by providing an interactive graphical interface to visualize and browse them.Comment: In Proceedings IWIGP 2012, arXiv:1202.422

Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone

INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several β3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific αvβ3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of αvβ3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of αvβ3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. αvβ3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, αvβ3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, αvβ3 increased 66cl4 tumor cell adhesion and αvβ3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific αvβ3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors

Differential In Vitro Effects of Intravenous versus Oral Formulations of Silibinin on the HCV Life Cycle and Inflammation

Silymarin prevents liver disease in many experimental rodent models, and is the most popular botanical medicine consumed by patients with hepatitis C. Silibinin is a major component of silymarin, consisting of the flavonolignans silybin A and silybin B, which are insoluble in aqueous solution. A chemically modified and soluble version of silibinin, SIL, has been shown to potently reduce hepatitis C virus (HCV) RNA levels in vivo when administered intravenously. Silymarin and silibinin inhibit HCV infection in cell culture by targeting multiple steps in the virus lifecycle. We tested the hepatoprotective profiles of SIL and silibinin in assays that measure antiviral and anti-inflammatory functions. Both mixtures inhibited fusion of HCV pseudoparticles (HCVpp) with fluorescent liposomes in a dose-dependent fashion. SIL inhibited 5 clinical genotype 1b isolates of NS5B RNA dependent RNA polymerase (RdRp) activity better than silibinin, with IC50 values of 40–85 µM. The enhanced activity of SIL may have been in part due to inhibition of NS5B binding to RNA templates. However, inhibition of the RdRps by both mixtures plateaued at 43–73%, suggesting that the products are poor overall inhibitors of RdRp. Silibinin did not inhibit HCV replication in subgenomic genotype 1b or 2a replicon cell lines, but it did inhibit JFH-1 infection. In contrast, SIL inhibited 1b but not 2a subgenomic replicons and also inhibited JFH-1 infection. Both mixtures inhibited production of progeny virus particles. Silibinin but not SIL inhibited NF-κB- and IFN-B-dependent transcription in Huh7 cells. However, both mixtures inhibited T cell proliferation to similar degrees. These data underscore the differences and similarities between the intravenous and oral formulations of silibinin, which could influence the clinical effects of this mixture on patients with chronic liver diseases

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

Tight-binding calculation of orbital relaxations and hopping integral modifications around vacancies and antisite defects in GaAs

We study the influence of changes in the tight-binding parameters around point defects in semiconductors and we apply our method to study the various charge states of the vacancies and anti-site defects in GaAs. We take into account the changes in the hopping integrals between two nearest neighbours of a vacancy which arise from the lifting of the orthogonality condition between the orbitals of the removed atom and the orbitals of the neighbouring atoms. We take into account the changes in the hopping integrals between a substitutional defect and its nearest neighbours which arise from the differences between the orbitals of the substitutional defect and the orbitals of the substituted atom. Lastly, we take into account the changes in the energy levels of the nearest neighbours of a defect which arise from the electronic rearrangement around the defect We propose a systematic method to calculate these changes and we investigate their consequences on the electronic structure of the various charge states of the vacancies and anti-site defects in GaAs. We compare our results with other tight-binding calculations where these changes have not been taken into account.Nous étudions l'importance des modifications des paramètres de liaisons fortes autour de défauts ponctuels dans les semi-conducteurs sur la structure électronique de ceux-ci et nous appliquons notre méthode à l'étude des divers états de charge des lacunes et des défauts d'anti-structure dans GaAs. Nous prenons en considération les modifications des intégrales de transfert entre deux atomes premiers voisins d'une lacune, modifications qui proviennent d'une levée de la condition d'orthogonalité entre les orbitales de l'atome qui a été enlevé et les orbitales de ses voisins. Nous prenons également en considération les modifications des intégrales de transfert entre un défaut substitutionnel et ses premiers voisins, modifications qui proviennent des différences entre les orbitales du défaut substitutionnel et les orbitales de l'atome substitué. Enfin, nous prenons en considération les modifications des niveaux d' énergie des premiers voisins d'un défaut, modifications qui proviennent du réarrangement électronique autour du défaut Nous proposons une méthode systématique pour calculer ces modifications et nous étudions leurs effets sur la structure électronique des divers états de charges des lacunes et des défauts d'anti-structure dans GaAs. Nous comparons nos résultats avec d'autres calculs de liaisons fortes dans lesquelles ces modifications ont été négligées

Real-time estimation of projectile roll angle using magnetometers: in-lab experimental validation

The knowledge of the roll angle of a projectile is decisive to apply guidance and control law. For example, the goal of ISL's project GSP (Guided Supersonic Projectile) is to change the flight path of an airdefence projectile in order to correct the aim error due to the target manoeuvres. The originality of the concept is based on pyrotechnical actuators and onboard sensors which control the angular motion of the projectile. First of all, the control of the actuators requires the precise control of the roll angle of the projectile. To estimate the roll angle of the projectile, two magnetometers are embedded in the projectile to measure the projection of the Earth magnetic field along radial axes of the projectiles. Then, an extended Kalman filter (EKF) is used to compute the roll angle estimation. As the rolling frequency of the GSP is about 22 Hz, it was easy to test the navigation algorithm in laboratory. In a previous paper [1], the In-Lab demonstration of this concept showed that the roll angle estimation was possible with an accuracy of about 1◦ . In this paper, the demonstration is extended to high-speed roll rate, up to 1000 Hz. Thus, two magnetometers, a DSP (Digital Signal Processor) and a LED (Light Eminent Diode), are rotated using a pneumatic motor; the DSP runs an EKF and a guidance algorithm to compute the trigger times of the LED. By using a high-speed camera, the accuracy of the method can be observed and improved