Model checking probabilistic and stochastic extensions of the pi-calculus

We present an implementation of model checking for probabilistic and stochastic extensions of the pi-calculus, a process algebra which supports modelling of concurrency and mobility. Formal verification techniques for such extensions have clear applications in several domains, including mobile ad-hoc network protocols, probabilistic security protocols and biological pathways. Despite this, no implementation of automated verification exists. Building upon the pi-calculus model checker MMC, we first show an automated procedure for constructing the underlying semantic model of a probabilistic or stochastic pi-calculus process. This can then be verified using existing probabilistic model checkers such as PRISM. Secondly, we demonstrate how for processes of a specific structure a more efficient, compositional approach is applicable, which uses our extension of MMC on each parallel component of the system and then translates the results into a high-level modular description for the PRISM tool. The feasibility of our techniques is demonstrated through a number of case studies from the pi-calculus literature

Critical behavior at Mott-Anderson transition: a TMT-DMFT perspective

We present a detailed analysis of the critical behavior close to the Mott-Anderson transition. Our findings are based on a combination of numerical and analytical results obtained within the framework of Typical-Medium Theory (TMT-DMFT) - the simplest extension of dynamical mean field theory (DMFT) capable of incorporating Anderson localization effects. By making use of previous scaling studies of Anderson impurity models close to the metal-insulator transition, we solve this problem analytically and reveal the dependence of the critical behavior on the particle-hole symmetry. Our main result is that, for sufficiently strong disorder, the Mott-Anderson transition is characterized by a precisely defined two-fluid behavior, in which only a fraction of the electrons undergo a "site selective" Mott localization; the rest become Anderson-localized quasiparticles.Comment: 4+ pages, 4 figures, v2: minor changes, accepted for publication in Phys. Rev. Let

On the relative expressiveness of higher-order session processes

By integrating constructs from the λ-calculus and the π-calculus, in higher-order process calculi exchanged values may contain processes. This paper studies the relative expressiveness of HOπ, the higher-order π-calculus in which communications are governed by session types. Our main discovery is that HO, a subcalculus of HOπ which lacks name-passing and recursion, can serve as a new core calculus for session-typed higher-order concurrency. By exploring a new bisimulation for HO, we show that HO can encode HOπ fully abstractly (up to typed contextual equivalence) more precisely and efficiently than the first-order session π-calculus (π). Overall, under session types, HOπ, HO, and π are equally expressive; however, HOπ and HO are more tightly related than HOπ and π

A Model-Theoretic Reconstruction of the Operational Semantics of Logic Programs

AbstractIn this paper we define a new notion or truth on Herbrand interpretations extended with variables which allows us to capture, by means of suitable models, various observable properties, such as the ground success set, the set of atomic consequences, and the computed answer substitutions. The notion of truth extends the classical one to account for non-ground formulas in the interpretations. The various operational semantics are all models. An ordering on interpretations is defined to overcome the problem that the intersection of a set of models is not necessarily a model. The set of interpretations with this partial order is shown to be a complete lattice, and the greatest lower bound of any set of models is shown to be a model. Thus there exists a least model, which is the least Herbrand model and therefore the ground success set semantics. Richer operational semantics are non-least models, which can, however, be effectively defined by fixpoint constructions. The model corresponding to the computed answer substitutions operational semantics is the most primitive one (the others can easily be obtained from it)

Collagen prolyl hydroxylation-dependent metabolic perturbation governs epigenetic remodeling and mesenchymal transition in pluripotent and cancer cells

Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires Vitamin C (VitC). Here we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic Budesonide, blocked metastatic dissemination of breast cancer cells in vivo by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control cell state transition and paves the way for the development of novel antimetastatic strategies. Significance: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer

The GTPase-activating protein RN-tre controls focal adhesion turnover and cell migration.

SummaryBackgroundIntegrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive.ResultsHere, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of β1, but not β3, integrins and delays the turnover of FAs, ultimately impairing β1-dependent, but not β3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5.ConclusionsOur findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chemotactic cell migration

Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1

Cell-cell junctions are an integral part of epithelia and are often disrupted in cancer cells during epithelial-to-mesenchymal transition (EMT), which is a main driver of metastatic spread. We show here that Metastasis suppressor-1 (Mtss1; Missing in Metastasis, MIM), a member of the IMD-family of proteins, inhibits cell-cell junction disassembly in wound healing or HGF-induced scatter assays by enhancing cell-cell junction strength. Mtss1 not only makes cells more resistant to cell-cell junction disassembly, but also accelerates the kinetics of adherens junction assembly. Mtss1 drives enhanced junction formation specifically by elevating Rac-GTP. Lastly, we show that Mtss1 depletion reduces recruitment of F-actin at cell-cell junctions. We thus propose that Mtss1 promotes Rac1 activation and actin recruitment driving junction maintenance. We suggest that the observed loss of Mtss1 in cancers may compromise junction stability and thus promote EMT and metastasis

Chronic Replication Problems Impact Cell Morphology and Adhesion of DNA Ligase I Defective Cells

Moderate DNA damage resulting from metabolic activities or sub-lethal doses of exogenous insults may eventually lead to cancer onset. Human 46BR.1G1 cells bear a mutation in replicative DNA ligase I (LigI) which results in low levels of replication-dependent DNA damage. This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM) checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence. Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation. Here we show that parental 46BR.1G1 and 7A3 cells differ in important features such as cell morphology, adhesion and migration. Comparison of gene expression profiles in the two cell lines detects Bio-Functional categories consistent with the morphological and migration properties of LigI deficient cells. Interestingly, ATM inhibition makes 46BR.1G1 more similar to 7A3 cells for what concerns morphology, adhesion and expression of cell-cell adhesion receptors. These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression

Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma

During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition, known as unjamming. The biomolecular machinery behind unjamming and its pathophysiological relevance remain, however, unclear. Here, we study unjamming in a variety of normal and tumorigenic epithelial two-dimensional (2D) and 3D collectives. Biologically, the increased level of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyperactivation of the kinase ERK1/2 and phosphorylation of the actin nucleator WAVE2. This cascade triggers collective motility effects with striking biophysical consequences. Specifically, unjamming in tumour spheroids is accompanied by persistent and coordinated rotations that progressively remodel the extracellular matrix, while simultaneously fluidizing cells at the periphery. This concurrent action results in collective invasion, supporting the concept that the endo-ERK1/2 pathway is a physicochemical switch to initiate collective invasion and dissemination of otherwise jammed carcinoma