A mass action model of a fibroblast growth factor signaling pathway and its simplification

We consider a kinetic law of mass action model for Fibroblast Growth Factor (FGF) signaling, focusing on the induction of the RAS-MAP kinase pathway via GRB2 binding. Our biologically simple model suffers a combinatorial explosion in the number of differential equations required to simulate the system. In addition to numerically solving the full model, we show that it can be accurately simplified. This requires combining matched asymptotics, the quasi-steady state hypothesis, and the fact subsets of the equations decouple asymptotically. Both the full and simplified models reproduce the qualitative dynamics observed experimentally and in previous stochastic models. The simplified model also elucidates both the qualitative features of GRB2 binding and the complex relationship between SHP2 levels, the rate SHP2 induces dephosphorylation and levels of bound GRB2. In addition to providing insight into the important and redundant features of FGF signaling, such work further highlights the usefulness of numerous simplification techniques in the study of mass action models of signal transduction, as also illustrated recently by Borisov and co-workers (Borisov et al. in Biophys. J. 89, 951–66, 2005, Biosystems 83, 152–66, 2006; Kiyatkin et al. in J. Biol. Chem. 281, 19925–9938, 2006). These developments will facilitate the construction of tractable models of FGF signaling, incorporating further biological realism, such as spatial effects or realistic binding stoichiometries, despite a more severe combinatorial explosion associated with the latter

A Study of the PDGF Signaling Pathway with PRISM

In this paper, we apply the probabilistic model checker PRISM to the analysis of a biological system -- the Platelet-Derived Growth Factor (PDGF) signaling pathway, demonstrating in detail how this pathway can be analyzed in PRISM. We show that quantitative verification can yield a better understanding of the PDGF signaling pathway.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Towards the Automated Verification of Weibull Distributions for System Failure Rates

Weibull distributions can be used to accurately model failure behaviours of a wide range of critical systems such as on-orbit satellite subsystems. Markov chains have been used extensively to model reliability and performance of engineering systems or applications. However, the exponentially distributed sojourn time of Continuous-Time Markov Chains (CTMCs) can sometimes be unrealistic for satellite systems that exhibit Weibull failures. In this paper, we develop novel semi-Markov models that characterise failure behaviours, based on Weibull failure modes inferred from realistic data sources. We approximate and encode these new models with CTMCs and use the PRISM probabilistic model checker. The key bene t of this integration is that CTMC-based model checking tools allow us to automatically and e ciently verify reliability properties relevant to industrial critical systems

Algorithmic Analysis of Qualitative and Quantitative Termination Problems for Affine Probabilistic Programs

In this paper, we consider termination of probabilistic programs with real-valued variables. The questions concerned are: 1. qualitative ones that ask (i) whether the program terminates with probability 1 (almost-sure termination) and (ii) whether the expected termination time is finite (finite termination); 2. quantitative ones that ask (i) to approximate the expected termination time (expectation problem) and (ii) to compute a bound B such that the probability to terminate after B steps decreases exponentially (concentration problem). To solve these questions, we utilize the notion of ranking supermartingales which is a powerful approach for proving termination of probabilistic programs. In detail, we focus on algorithmic synthesis of linear ranking-supermartingales over affine probabilistic programs (APP's) with both angelic and demonic non-determinism. An important subclass of APP's is LRAPP which is defined as the class of all APP's over which a linear ranking-supermartingale exists. Our main contributions are as follows. Firstly, we show that the membership problem of LRAPP (i) can be decided in polynomial time for APP's with at most demonic non-determinism, and (ii) is NP-hard and in PSPACE for APP's with angelic non-determinism; moreover, the NP-hardness result holds already for APP's without probability and demonic non-determinism. Secondly, we show that the concentration problem over LRAPP can be solved in the same complexity as for the membership problem of LRAPP. Finally, we show that the expectation problem over LRAPP can be solved in 2EXPTIME and is PSPACE-hard even for APP's without probability and non-determinism (i.e., deterministic programs). Our experimental results demonstrate the effectiveness of our approach to answer the qualitative and quantitative questions over APP's with at most demonic non-determinism.Comment: 24 pages, full version to the conference paper on POPL 201

Stochastic Invariants for Probabilistic Termination

Termination is one of the basic liveness properties, and we study the termination problem for probabilistic programs with real-valued variables. Previous works focused on the qualitative problem that asks whether an input program terminates with probability~1 (almost-sure termination). A powerful approach for this qualitative problem is the notion of ranking supermartingales with respect to a given set of invariants. The quantitative problem (probabilistic termination) asks for bounds on the termination probability. A fundamental and conceptual drawback of the existing approaches to address probabilistic termination is that even though the supermartingales consider the probabilistic behavior of the programs, the invariants are obtained completely ignoring the probabilistic aspect. In this work we address the probabilistic termination problem for linear-arithmetic probabilistic programs with nondeterminism. We define the notion of {\em stochastic invariants}, which are constraints along with a probability bound that the constraints hold. We introduce a concept of {\em repulsing supermartingales}. First, we show that repulsing supermartingales can be used to obtain bounds on the probability of the stochastic invariants. Second, we show the effectiveness of repulsing supermartingales in the following three ways: (1)~With a combination of ranking and repulsing supermartingales we can compute lower bounds on the probability of termination; (2)~repulsing supermartingales provide witnesses for refutation of almost-sure termination; and (3)~with a combination of ranking and repulsing supermartingales we can establish persistence properties of probabilistic programs. We also present results on related computational problems and an experimental evaluation of our approach on academic examples.Comment: Full version of a paper published at POPL 2017. 20 page

Automated Security Analysis of IoT Software Updates

IoT devices often operate unsupervised in ever-changing environments for several years. Therefore, they need to be updated on a regular basis. Current approaches for software updates on IoT, like the recent SUIT proposal, focus on granting integrity and confidentiality but do not analyze the content of the software update, especially the IoT application which is deployed to IoT devices. To this aim, in this paper, we present IoTAV, an automated software analysis framework for systematically verifying the security of the applications contained in software updates w.r.t. a given security policy. Our proposal can be adopted transparently by current IoT software updates workflows. We prove the viability of IoTAV by testing our methodology on a set of actual RIOT OS applications. Experimental results indicate that the approach is viable in terms of both reliability and performance, leading to the identification of 26 security policy violations in 31 real-world RIOT applications

More Scalable LTL Model Checking via Discovering Design-Space Dependencies (D3)

Modern system design often requires comparing several models over a large design space. Different models arise out of a need to weigh different design choices, to check core capabilities of versions with varying features, or to analyze a future version against previous ones. Model checking can compare different models; however, applying model checking off-the-shelf may not scale due to the large size of the design space for today’s complex systems. We exploit relationships between different models of the same (or related) systems to optimize the model-checking search. Our algorithm, D3 , preprocesses the design space and checks fewer model-checking instances, e.g., using nuXmv. It automatically prunes the search space by reducing both the number of models to check, and the number of LTL properties that need to be checked for each model in order to provide the complete model-checking verdict for every individual model-property pair. We formalize heuristics that improve the performance of D3 . We demonstrate the scalability of D3 by extensive experimental evaluation, e.g., by checking 1,620 real-life models for NASA’s NextGen air traffic control system. Compared to checking each model-property pair individually, D3 is up to 9.4 × faster

Syntactic Markovian Bisimulation for Chemical Reaction Networks

In chemical reaction networks (CRNs) with stochastic semantics based on continuous-time Markov chains (CTMCs), the typically large populations of species cause combinatorially large state spaces. This makes the analysis very difficult in practice and represents the major bottleneck for the applicability of minimization techniques based, for instance, on lumpability. In this paper we present syntactic Markovian bisimulation (SMB), a notion of bisimulation developed in the Larsen-Skou style of probabilistic bisimulation, defined over the structure of a CRN rather than over its underlying CTMC. SMB identifies a lumpable partition of the CTMC state space a priori, in the sense that it is an equivalence relation over species implying that two CTMC states are lumpable when they are invariant with respect to the total population of species within the same equivalence class. We develop an efficient partition-refinement algorithm which computes the largest SMB of a CRN in polynomial time in the number of species and reactions. We also provide an algorithm for obtaining a quotient network from an SMB that induces the lumped CTMC directly, thus avoiding the generation of the state space of the original CRN altogether. In practice, we show that SMB allows significant reductions in a number of models from the literature. Finally, we study SMB with respect to the deterministic semantics of CRNs based on ordinary differential equations (ODEs), where each equation gives the time-course evolution of the concentration of a species. SMB implies forward CRN bisimulation, a recently developed behavioral notion of equivalence for the ODE semantics, in an analogous sense: it yields a smaller ODE system that keeps track of the sums of the solutions for equivalent species.Comment: Extended version (with proofs), of the corresponding paper published at KimFest 2017 (http://kimfest.cs.aau.dk/