42 research outputs found
Model-based Investigation of the Coupling between the Cell Cycle and the Circadian Clock in Mouse Embryonic Fibroblasts
Experimental observations have put in evidence autonomous self-sustained cir-cadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the milieu is enriched in FBS, the absence of such acceleration in confluent cells, and the absence of any period doubling phenomena. In order to explain these observations, we study a possible entrainment of the circadian clock by the cell cycle through a regulation of clock genes around the mitosis phase. We develop a computational model and a formal specification of the observed behavior to investigate the conditions of entrainment in period and phase. We show that either the selective inhibition of Bmal1 transcription, or the selective activation of RevErb-α at the end of the mitosis phase, allow us to fit the experimental data, while a uniform inhibition of transcription during mitosis seems incompatible with the phase data. We conclude on some further $ This article is the extended revision of a preliminary communication published in [1]. Email addresses: [email protected] (Pauline Traynard), [email protected] (Céline Feillet), [email protected] (Sylvain Soliman), [email protected] (Franck Delaunay), [email protected] (François Fages) Preprint submitted to Elsevier December 19, 2015 predictions of the model
On Robustness Computation and Optimization in BIOCHAM-4
Long version with appendicesInternational audienceBIOCHAM-4 is a tool for modeling, analyzing and synthesizing biochemical reaction networks with respect to some formal, yet possibly imprecise, specification of their behavior. We focus here on one new capability of this tool to optimize the robustness of a parametric model with respect to a specification of its dynamics in quantitative temporal logic. More precisely, we present two complementary notions of robustness: the statistical notion of model robustness to parameter perturbations, defined as its mean functionality, and a metric notion of formula satisfaction robustness, defined as the penetration depth in the validity domain of the temporal logic constraints. We show how the formula robustness can be used in BIOCHAM-4 with no extra cost as an objective function in the parameter optimization procedure, to actually improve the model robustness. We illustrate these unique features with a classical example of the hybrid systems community and provide some performance figures on a model of MAPK signalling with 37 parameters
Formal computational framework for the study of molecular evolution
Over the past 10 years, multiple executable modelling formalisms for molecular
biology have been developed in order to address the growing need for a
system-level understanding of complex biological phenomena. An important class
of these formalisms are biology-inspired process algebras, which offer-among
other desirable properties - an almost complete separation of model specification
(syntax) from model dynamics (semantics). In this thesis, the similarity between
this separation and the genotype-phenotype duality in evolutionary biology is
exploited to develop a process-algebraic approach to the study of evolution of
biochemical systems.
The main technical contribution of this thesis is the continuous π-calculus (cπ),
a novel process algebra based on the classical π-calculus of Milner et. al. Its two
defining characteristics are: continuous, compositional, computationally inexpensive
semantics, and a
exible interaction structure of processes (molecules). Both
these features are conductive to evolutionary analysis of biochemical systems
by, respectively, enabling many variants of a given model to be evaluated, and
facilitating in silico evolution of new functional connections. A further major
contribution is a collection of variation operators, syntactic model transformation
schemes corresponding to common evolutionary events. When applied to a
cπ model of a biochemical system, variation operators produce its evolutionary
neighbours, yielding insights into the local fitness landscape and neutral neighbourhood.
Two well-known biochemical systems are modelled in this dissertation to validate
the developed theory. One is the KaiABC circadian clock in the cyanobacterium
S. elongatus, the other is a mitogen-activated protein kinase cascade. In each case
we study the system itself as well as its predicted evolutionary variants. Simpler
examples, particularly that of a generic enzymatic reaction, are used throughout
the thesis to illustrate important concepts as they are introduced
Continuous-time temporal logic specification and verification for nonlinear biological systems in uncertain contexts
In this thesis we introduce a complete framework for modelling and verification of biological systems in uncertain contexts based on the bond-calculus process algebra and
the LBUC spatio-temporal logic. The bond-calculus is a biological process algebra which
captures complex patterns of interaction based on affinity patterns, a novel communication
mechanism using pattern matching to express multiway interaction affinities and general
kinetic laws, whilst retaining an agent-centric modelling style for biomolecular species.
The bond-calculus is equipped with a novel continuous semantics which maps models to
systems of Ordinary Differential Equations (ODEs) in a compositional way.
We then extend the bond-calculus to handle uncertain models, featuring interval uncertainties in their species concentrations and reaction rate parameters. Our semantics is also
extended to handle uncertainty in every aspect of a model, producing non-deterministic
continuous systems whose behaviour depends either on time-independent uncertain parameters and initial conditions, corresponding to our partial knowledge of the system at
hand, or time-varying uncertain inputs, corresponding to genuine variability in a system’s
behaviour based on environmental factors.
This language is then coupled with the LBUC spatio-temporal logic which combines
Signal Temporal Logic (STL) temporal operators with an uncertain context operator
which quantifies over an uncertain context model describing the range of environments
over which a property must hold. We develop model-checking procedures for STL and
LBUC properties based on verified signal monitoring over flowpipes produced by the
Flow* verified integrator, including the technique of masking which directs monitoring for
atomic propositions to time regions relevant to the overall verification problem at hand.
This allows us to monitor many interesting nested contextual properties and frequently
reduces monitoring costs by an order of magnitude. Finally, we explore the technique
of contextual signal monitoring which can use a single Flow* flowpipe representing a
functional dependency to complete a whole tree of signals corresponding to different
uncertain contexts. This allows us to produce refined monitoring results over the whole
space and to explore the variation in system behaviour in different contexts
Recent advances in petri nets and concurrency
CEUR Workshop Proceeding
Natural smartness in hypothetical animals. Of paddlers and glowballs
To obtain a reasonably self-contained and complete simulation of navigational sensori-motor behaviour, a neuroethological model of a hypothetical animal, the paddler, has been developed