Modelling the Dynamics of an Aedes albopictus Population

We present a methodology for modelling population dynamics with formal means of computer science. This allows unambiguous description of systems and application of analysis tools such as simulators and model checkers. In particular, the dynamics of a population of Aedes albopictus (a species of mosquito) and its modelling with the Stochastic Calculus of Looping Sequences (Stochastic CLS) are considered. The use of Stochastic CLS to model population dynamics requires an extension which allows environmental events (such as changes in the temperature and rainfalls) to be taken into account. A simulator for the constructed model is developed via translation into the specification language Maude, and used to compare the dynamics obtained from the model with real data.Comment: In Proceedings AMCA-POP 2010, arXiv:1008.314

Efficient negation using abstract interpretation

While negation has been a very active área of research in logic programming, comparatively few papers have been devoted to implementation issues. Furthermore, the negation-related capabilities of current Prolog systems are limited. We recently presented a novel method for incorporating negation in a Prolog compiler which takes a number of existing methods (some modified and improved by us) and uses them in a combined fashion. The method makes use of information provided by a global analysis of the source code. Our previous work focused on the systematic description of the techniques and the reasoning about correctness and completeness of the method, but provided no experimental evidence to evalúate the proposal. In this paper, we report on an implementation, using the Ciao Prolog system preprocessor, and provide experimental data which indicates that the method is not only feasible but also quite promising from the efficiency point of view. In addition, the tests have provided new insight as to how to improve the proposal further. Abstract interpretation techniques are shown to offer important improvements in this application

Process algebra modelling styles for biomolecular processes

We investigate how biomolecular processes are modelled in process algebras, focussing on chemical reactions. We consider various modelling styles and how design decisions made in the definition of the process algebra have an impact on how a modelling style can be applied. Our goal is to highlight the often implicit choices that modellers make in choosing a formalism, and illustrate, through the use of examples, how this can affect expressability as well as the type and complexity of the analysis that can be performed

Multiple verification in computational modeling of bone pathologies

We introduce a model checking approach to diagnose the emerging of bone pathologies. The implementation of a new model of bone remodeling in PRISM has led to an interesting characterization of osteoporosis as a defective bone remodeling dynamics with respect to other bone pathologies. Our approach allows to derive three types of model checking-based diagnostic estimators. The first diagnostic measure focuses on the level of bone mineral density, which is currently used in medical practice. In addition, we have introduced a novel diagnostic estimator which uses the full patient clinical record, here simulated using the modeling framework. This estimator detects rapid (months) negative changes in bone mineral density. Independently of the actual bone mineral density, when the decrease occurs rapidly it is important to alarm the patient and monitor him/her more closely to detect insurgence of other bone co-morbidities. A third estimator takes into account the variance of the bone density, which could address the investigation of metabolic syndromes, diabetes and cancer. Our implementation could make use of different logical combinations of these statistical estimators and could incorporate other biomarkers for other systemic co-morbidities (for example diabetes and thalassemia). We are delighted to report that the combination of stochastic modeling with formal methods motivate new diagnostic framework for complex pathologies. In particular our approach takes into consideration important properties of biosystems such as multiscale and self-adaptiveness. The multi-diagnosis could be further expanded, inching towards the complexity of human diseases. Finally, we briefly introduce self-adaptiveness in formal methods which is a key property in the regulative mechanisms of biological systems and well known in other mathematical and engineering areas.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Multiscale Bone Remodelling with Spatial P Systems

Many biological phenomena are inherently multiscale, i.e. they are characterized by interactions involving different spatial and temporal scales simultaneously. Though several approaches have been proposed to provide "multilayer" models, only Complex Automata, derived from Cellular Automata, naturally embed spatial information and realize multiscaling with well-established inter-scale integration schemas. Spatial P systems, a variant of P systems in which a more geometric concept of space has been added, have several characteristics in common with Cellular Automata. We propose such a formalism as a basis to rephrase the Complex Automata multiscaling approach and, in this perspective, provide a 2-scale Spatial P system describing bone remodelling. The proposed model not only results to be highly faithful and expressive in a multiscale scenario, but also highlights the need of a deep and formal expressiveness study involving Complex Automata, Spatial P systems and other promising multiscale approaches, such as our shape-based one already resulted to be highly faithful.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Parametric timed model checking for guaranteeing timed opacity

Information leakage can have dramatic consequences on systems security. Among harmful information leaks, the timing information leakage is the ability for an attacker to deduce internal information depending on the system execution time. We address the following problem: given a timed system, synthesize the execution times for which one cannot deduce whether the system performed some secret behavior. We solve this problem in the setting of timed automata (TAs). We first provide a general solution, and then extend the problem to parametric TAs, by synthesizing internal timings making the TA secure. We study decidability, devise algorithms, and show that our method can also apply to program analysis.Comment: This is the author (and extended) version of the manuscript of the same name published in the proceedings of ATVA 2019. This work is partially supported by the ANR national research program PACS (ANR-14-CE28-0002), the ANR-NRF research program (ProMiS) and by ERATO HASUO Metamathematics for Systems Design Project (No. JPMJER1603), JS

Embryonic stem cell-derived CD166+ precursors develop into fully functional sinoatrial-like cells

Rationale: A cell-based biological pacemaker is based on the differentiation of stem cells and the selection of a population displaying the molecular and functional properties of native sinoatrial node (SAN) cardiomyocytes. So far, such selection has been hampered by the lack of proper markers. CD166 is specifically but transiently expressed in the mouse heart tube and sinus venosus, the prospective SAN. Objective: We have explored the possibility of using CD166 expression for isolating SAN progenitors from differentiating embryonic stem cells. Methods and Results: We found that in embryonic day 10.5 mouse hearts, CD166 and HCN4, markers of the pacemaker tissue, are coexpressed. Sorting embryonic stem cells for CD166 expression at differentiation day 8 selects a population of pacemaker precursors. CD166(+) cells express high levels of genes involved in SAN development (Tbx18, Tbx3, Isl-1, Shox2) and function (Cx30.2, HCN4, HCN1, CaV1.3) and low levels of ventricular genes (Cx43, Kv4.2, HCN2, Nkx2.5). In culture, CD166(+) cells form an autorhythmic syncytium composed of cells morphologically similar to and with the electrophysiological properties of murine SAN myocytes. Isoproterenol increases (+57%) and acetylcholine decreases (-23%) the beating rate of CD166-selected cells, which express the -adrenergic and muscarinic receptors. In cocultures, CD166-selected cells are able to pace neonatal ventricular myocytes at a rate faster than their own. Furthermore, CD166(+) cells have lost pluripotency genes and do not form teratomas in vivo. Conclusions: We demonstrated for the first time the isolation of a nonteratogenic population of cardiac precursors able to mature and form a fully functional SAN-like tissue

Generation of human induced pluripotent stem cells (EURACi001-A, EURACi002-A, EURACi003-A) from peripheral blood mononuclear cells of three patients carrying mutations in the CAV3 gene

Caveolinopathies are a heterogeneous family of genetic pathologies arising from alterations of the caveolin-3 gene (CAV3), encoding for the isoform specifically constituting muscle caveolae. Here, by reprogramming peripheral blood mononuclear cells, we report the generation of induced pluripotent stem cells (iPSCs) from three patients carrying the ΔYTT deletion, T78K and W101C missense mutations in caveolin-3. iPSCs displayed normal karyotypes and all the features of pluripotent stem cells in terms of morphology, specific marker expression and ability to differentiate in vitro into the three germ layers. These lines thus represent a human cellular model to study the molecular basis of caveolinopathies