2023Activity reportProject-TeamLIFEWARE

3.1 Chemical Reaction Network (CRN) Theory

Originally, Feinberg's mathematical theory of Chemical Reaction Networks (CRN) and Thomas's influence networks, were created to provide sufficient and/or necessary structural conditions for the existence of multiple steady states and oscillations in complex gene networks. Those conditions can be verified by static analyzers without knowing kinetic parameter values, nor making any simulation. In this first approach, most of our work consists in considering the hypergraph structure of a CRN (Petri net invariants, species-reaction labelled hypergraph, influence graph, reductions by subgraph epimorphisms) and analysing their interplay with the dynamics of CRNs in their different interpretations (Boolean, CTMC, ODE, time scale separations) which can be related in the framework of abstract interpretation1. For example, our study of the influence graphs of reaction systems 7 lead recently to sufficient graphical conditions ensuring rate-independence of CRN 4, or some time ago to the non-trivial generalization to reaction systems of Thomas' conditions of multi-stationarity and Soulé's proof given for influence systems, with much greater efficiency by several orders of magnitude for testing them when compared to current symbolic computation methods 2.

However, we aim at development a computational theory of CRNs and biochemical programming. Our original method to infer CRNs from ODEs 5 showed the generality of CRNs, and lead us to prove the Turing-completeness of continuous CRNs over a finite set of molecular species, showing that any computable function over the real numbers (i.e. computable in arbitrary precision by a Turing machine) can be computed by a CRN over a finite set of molecular species 6. (Best paper award CMSB 2017, Prix La Recherche 2019). This result closed the last open problem on the computation power of CRNs in their different semantics and has opened a whole research avenue on CRN design by compilation of mathematical functions. This is illustrated by a series of publications since that date 10 (best paper award CMSB 2022), again this year 23 , and innovative applications in synthetic biology 3.

3.2 Logical Paradigm for Systems Biology

Our group was among the first ones in 2002 to apply model-checking methods to systems biology in order to reason on large molecular interaction networks, such as Kohn's map of the mammalian cell cycle (800 reactions over 500 molecules) 2. The logical paradigm for systems biology that we have subsequently developed for quantitative models can be summarized by the following identifications :

biological model = transition system $K$, initial state $s$

dynamical behavior specification = temporal logic formula $\varphi$

model validation = model-checking $K,s\vDash ?\varphi$

model reduction = sub-model-checking, $K^{\text{'}}\subset K$ s.t. $K^{\text{'}}?,s\vDash \varphi$

model prediction = formula enumeration, $\varphi$ s.t. $K,s\vDash \varphi ?$

static experiment design = symbolic model-checking, $K,s?\vDash \varphi$

model synthesis = constraint solving $K?,s\vDash \varphi$

model inference = constraint solving $K?,s?\vDash \varphi$

In particular, the definition of a continuous satisfaction degree for first-order temporal logic formulae with constraints over the reals, was the key to generalize this approach to quantitative models, opening up the field of model-checking to model optimization 34

This line of research continues with the development of temporal logic constraint patterns with efficient solvers, and their use for model building, in partnership with biologists to answer concrete questions in the biomedical domain5616, 15 and the pharmaceutical industry 9, 20, 14, 20.

3.3 Constraint Solving and Optimization

Constraint solving and optimization algorithms are important in our research. On the one hand, static analyses of CRNs often involve solving hard combinatorial optimization problems, for which we have shown that constraint logic programming techniques, including Answer Set Programming (ASP), are particularly successful, often beating dedicated algorithms on real-size instances from model repositories by orders of magnitude 12, 217.

On the other hand, parameter search problems involve solving hard continuous optimization problems, for which evolutionary algorithms, and especially the covariance matrix evolution strategy (CMA-ES) (EPI RANDOPT) have shown to provide best results in our context. Constraint-based models and efficient constraint solvers are thus instrumental in our approach for building quantitative models, gaining model-based insights, revisiting biological hypotheses, and contributing to biological knowledge.

4.1 Preamble

Our collaborative work on biological applications is expected to serve as a basis for groundbreaking advances in cell functioning understanding, cell monitoring and control, and novel therapy design and optimization. Our collaborations with biologists are focused on concrete biological questions, and on the building of mechanistic models of biological systems to answer them. Furthermore, one important application of our research is the development and distribution of a modeling software for computational systems biology and synthetic biology.

4.2 Modeling software for systems and synthetic biology at the cellular level

Since 2002, we develop an open-source software environment for modeling and analyzing biochemical reaction systems. This software, called the Biochemical Abstract Machine (BIOCHAM), is compatible with SBML for importing and exporting models from repositories such as BioModels. It can perform a variety of static analyses, specify behaviors in Boolean or quantitative temporal logics, search parameter values satisfying temporal constraints, and make various simulations. While the primary reason of this development effort is to be able to implement our ideas and experiment them quickly on a large scale, using rapid prototyping techniques based on constraint logic programming, BIOCHAM is distributed and used by other groups worldwide, for building CRN models, for comparing CRN analysis/synthesis techniques, and for teaching computational systems biology. A Jupyter BIOCHAM kernel has been developed to use BIOCHAM on our web server without any installation which is heavily used for teaching. We plan to continue developing BIOCHAM for these different purposes with the recruitment of a research engineer to improve the software quality and animation of the community of users.

Since 2018, the CaSQ software complements this effort by providing an interface to import large interaction maps written in SBML using the CellDesigner tool and translate them into Boolean influence models with various tools compatible with the SBML-qual standard.

Since 2020, we participate in the CoLoMoTo notebook platform, which provides an integrated collection of software tools for the analysis of qualitative models, including CaSQ. This platform encourages the reproducibility of analysis by combining Docker images (reproducible software environment) and Jupyter notebooks (reproducible and shareable workflows).

These two last efforts play a central role in the global Covid-19 Disease Maps project.

4.3 Biomedical applications

We plan to continue to tackle challenging concrete biomedical questions with academic and industrial partners in an opportunist way, according to both the scope of the question on the international scene, and the relevance of our theoretical approaches to the question.

As mentioned above, our long-standing collaboration with F. Molina's CNRS-ALCEN lab on the design, optimization and industrialization of biochemical diagnosis vesicles 3 continues on a design methodology of robust CRNs including analog functions and derivative estimation 23.

Our successful collaboration with Servier on knowledge graphs and CRN model parameterizations using quantitative temporal logic for drug screening 9 continues with a new CIFRE thesis with Servier started this fall on CRN model learning from experimental data.

Our similarly successful collaboration with Johnson& Johnson Santé Beauté France on multi-scale modeling of the epidermis and multifactorial aspects of atopic dermatitis 14, 20 has revealed complex metastability behaviors in our population dynamics models and further emerging properties when combined with a multi-agent model at the tissue level. This research continued with O. Radulescu in Montpellier on the tropical algebraic analysis of quasi-stability in our model has led to a generalization of this phenomenon in population dynamicas models 20.

We also keep ready to continue our long-standing collaborations on chronotherapies as specialists of coupled models of the cell cycle and the circadian clock 11, 16 and their systemic regulators8.

Last but not least, our group became very active in cooperative efforts at the European scale to design large molecular interaction maps for diseases such as Covid-19 13 or rheumatoid arthritis 19 and derive from them Boolean dynamical models using the CaSQ software as well as developing hybrid models 17.

5.1 Footprint of research activities

In synthetic biology, our approach based on analog computation target enzymatic reactions with proteins in artificial DNA-free RNA-free vesicles. This is an original approach to solving major safety issue for applications in medicine and the environment.

5.2 Impact of research results

Our multidisciplinary research rooted in fundamental computer science aims at contributing to biology and medicine by going quite far in the applications with partners from academia and industry, in particular with the pharma industry.

6.1 Trap spaces of Boolean networks are conflict-free siphons of their Petri net encoding

Participants: Sylvain Soliman.

Boolean network modeling of gene regulation but also of post-transcriptomic systems has proven over the years that it can bring powerful analyses and corresponding insight to the many cases where precise biological data is not sufficiently available to build a detailed quantitative model. Besides simulation, the analysis of such models is mostly based on attractor computation, since those correspond roughly to observable biological phenotypes. The recent use of trap spaces made a real breakthrough in that field allowing to consider medium-sized models that used to be out of reach. However, with the continuing increase in model size and complexity of Boolean update functions, the state-of-the-art computation of minimal trap spaces based on prime implicants shows its limits due to the difficulty of the prime-implicant computation.

In 21, we explore and prove for the first time a connection between trap spaces of a general Boolean network and siphons of its Petri net encoding. Besides important theoretical applications in studying properties of trap spaces, the connection enables us to propose an alternative approach to compute minimal trap spaces, and hence complex attractors, of a general Boolean network. It replaces the need for prime implicants by a completely different technique, namely the enumeration of maximal siphons in the Petri net encoding of the original model. We then demonstrate its efficiency and compare it to the state-of-the-art methods on a large collection of real-world and randomly generated models.

6.2 Stochastic chemical kinetics of cell fate decision systems: from single cells to populations and back

Participants: Guillaume Ballif, Jakob Ruess.

Stochastic chemical kinetics is a widely used formalism for studying stochasticity of chemical reactions inside single cells. Experimental studies of reaction networks are generally performed with cells that are part of a growing population, yet the population context is rarely taken into account when models are developed. Models that neglect the population context lose their validity whenever the studied system influences traits of cells that can be selected in the population, a property that naturally arises in the complex interplay between single-cell and population dynamics of cell fate decision systems.

In 18, we represent such systems as absorbing continuous-time Markov chains. We show that conditioning on non-absorption allows one to derive a modified master equation that tracks the time evolution of the expected population composition within a growing population. This allows us to derive consistent population dynamics models from a specification of the single-cell process. We use this approach to classify cell fate decision systems into two types that lead to different characteristic phases in emerging population dynamics. Subsequently, we deploy the gained insights to experimentally study a recurrent problem in biology: how to link plasmid copy number fluctuations and plasmid loss events inside single cells to growth of cell populations in dynamically changing environments.

6.3 A Skin Microbiome Model with AMP interactions and Analysis of Quasi-Stability vs Stability in Population Dynamics

Participants: François Fages, Elea Thibault-Greugny.

The skin microbiome plays an important role in the maintenance of a healthy skin. It is an ecosystem, composed of several species, competing for resources and interacting with the skin cells. Imbalance in the cutaneous microbiome, also called dysbiosis, has been correlated with several skin conditions, including acne and atopic dermatitis. Generally, dysbiosis is linked to colonization of the skin by a population of opportunistic pathogenic bacteria. Treatments consisting in non-specific elimination of cutaneous microflora have shown conflicting results.

In 20, we introduce a mathematical model based on ordinary differential equations, with 2 types of bacteria populations (skin commensals and opportunistic pathogens) and including the production of antimicrobial peptides to study the mechanisms driving the dominance of one population over the other. By using published experimental data, assumed to correspond to the observation of stable states in our model, we reduce the number of parameters of the model from 13 to 5. We then use a formal specification in quantitative temporal logic to calibrate our model by global parameter optimization and perform sensitivity analyses. On the time scale of 2 days of the experiments, the model predicts that certain changes of the environment, like the elevation of skin surface pH, create favorable conditions for the emergence and colonization of the skin by the opportunistic pathogen population, while the production of human AMPs has non-linear effect on the balance between pathogens and commensals. Surprisingly, simulations on longer time scales reveal that the equilibrium reached around 2 days can in fact be a quasi-stable state followed by the reaching of a reversed stable state after 12 days or more. We analyse the conditions of quasi-stability observed in this model using tropical algebraic methods, and show their non-generic character in contrast to slow-fast systems. These conditions are then generalized to a large class of population dynamics models over any number of species.

7.1 New software

8.1 Stochastic chemical kinetics of cell fate decision systems: from single cells to populations and back

Participants: Guillaume Ballif, Henri Mermoz Kouyé, Jakob Ruess.

Stochastic chemical kinetics is a widely used formalism for studying stochasticity of chemical reactions inside single cells. Experimental studies of reaction networks are generally performed with cells that are part of a growing population, yet the population context is rarely taken into account when models are developed. Models that neglect the population context lose their validity whenever the studied system influences traits of cells that can be selected in the population, a property that naturally arises in the complex interplay between single-cell and population dynamics of cell fate decision systems.

In 18, we represent such systems as absorbing continuous-time Markov chains. We show that conditioning on non-absorption allows one to derive a modified master equation that tracks the time evolution of the expected population composition within a growing population. This allows us to derive consistent population dynamics models from a specification of the single-cell process. We use this approach to classify cell fate decision systems into two types that lead to different characteristic phases in emerging population dynamics. Subsequently, we deploy the gained insights to experimentally study a recurrent problem in biology: how to link plasmid copy number fluctuations and plasmid loss events inside single cells to growth of cell populations in dynamically changing environments.

8.2 A Skin Microbiome Model with AMP interactions and Analysis of Quasi-Stability vs Stability in Population Dynamics

Participants: François Fages.

The skin microbiome plays an important role in the maintenance of a healthy skin. It is an ecosystem, composed of several species, competing for resources and interacting with the skin cells. Imbalance in the cutaneous microbiome, also called dysbiosis, has been correlated with several skin conditions, including acne and atopic dermatitis. Generally, dysbiosis is linked to colonization of the skin by a population of opportunistic pathogenic bacteria. Treatments consisting in non-specific elimination of cutaneous microflora have shown conflicting results.

In 20, we introduce a mathematical model based on ordinary differential equations, with 2 types of bacteria populations (skin commensals and opportunistic pathogens) and including the production of antimicrobial peptides to study the mechanisms driving the dominance of one population over the other. By using published experimental data, assumed to correspond to the observation of stable states in our model, we reduce the number of parameters of the model from 13 to 5. We then use a formal specification in quantitative temporal logic to calibrate our model by global parameter optimization and perform sensitivity analyses. On the time scale of 2 days of the experiments, the model predicts that certain changes of the environment, like the elevation of skin surface pH, create favorable conditions for the emergence and colonization of the skin by the opportunistic pathogen population, while the production of human AMPs has non-linear effect on the balance between pathogens and commensals. Surprisingly, simulations on longer time scales reveal that the equilibrium reached around 2 days can in fact be a quasi-stable state followed by the reaching of a reversed stable state after 12 days or more. We analyse the conditions of quasi-stability observed in this model using tropical algebraic methods, and show their non-generic character in contrast to slow-fast systems. These conditions are then generalized to a large class of population dynamics models over any number of species.

In 8, this is combined with a multi-agent model of the skin for further analyses of the multifactorial factors leading to atopic dermatitis.

8.3 On Estimating Derivatives of Input Signals in Biochemistry

Participants: François Fages, Mathieu Hemery.

The online estimation of the derivative of an input signal is widespread in control theory and engineering. In the realm of chemical reaction networks (CRN), this raises however a number of specific issues on the different ways to achieve it. A CRN pattern for implementing a derivative block has already been proposed for the PID control of biochemical processes, and proved correct using Tikhonov's limit theorem.

In 23, we give a detailed mathematical analysis of that CRN, thus clarifying the computed quantity and quantifying the error done as a function of the reaction kinetic parameters. In a synthetic biology perspective, we show how this can be used to design error correcting terms to compute online functions involving derivatives with CRNs. In the systems biology perspective, we give the list of models in BioModels containing (in the sense of subgraph epimorphisms) the core derivative CRN, most of which being models of oscillators and control systems in the cell, and discuss in detail two such examples: one model of the circadian clock and one model of a bistable switch.

This provides one more brick to our vision of the cell as an analog chemical computer, calculating with proteins, and changing of programs according to gene expression 25.

8.4 Trap spaces of Boolean networks are conflict-free siphons of their Petri net encoding

Participants: Sylvain Soliman.

Boolean network modeling of gene regulation but also of post-transcriptomic systems has proven over the years that it can bring powerful analyses and corresponding insight to the many cases where precise biological data is not sufficiently available to build a detailed quantitative model. Besides simulation, the analysis of such models is mostly based on attractor computation, since those correspond roughly to observable biological phenotypes. The recent use of trap spaces made a real breakthrough in that field allowing to consider medium-sized models that used to be out of reach. However, with the continuing increase in model size and complexity of Boolean update functions, the state-of-the-art computation of minimal trap spaces based on prime implicants shows its limits due to the difficulty of the prime-implicant computation.

In 21, we explore and prove for the first time a connection between trap spaces of a general Boolean network and siphons of its Petri net encoding. Besides important theoretical applications in studying properties of trap spaces, the connection enables us to propose an alternative approach to compute minimal trap spaces, and hence complex attractors, of a general Boolean network. It replaces the need for prime implicants by a completely different technique, namely the enumeration of maximal siphons in the Petri net encoding of the original model. We then demonstrate its efficiency and compare it to the state-of-the-art methods on a large collection of real-world and randomly generated models.

8.5 Efficient Enumeration of Fixed Points in Complex Boolean Networks Using Answer Set Programming

Participants: Sylvain Soliman.

Boolean Networks (BNs) are an efficient modeling formalism with applications in various research fields such as mathematics, computer science, and more recently systems biology. One crucial problem in the BN research is to enumerate all fixed points, which has been proven crucial in the analysis and control of biological systems. Indeed, in that field, BNs originated from the pioneering work of R. Thomas on gene regulation and from the start were characterized by their asymptotic behavior: complex attractors and fixed points. The former being notably more difficult to compute exactly, and specific to certain biological systems, the computation of stable states (fixed points) has been the standard way to analyze those BNs for years. However, with the increase in model size and complexity of Boolean update functions, the existing methods for this problem show their limitations. To our knowledge, the most efficient state-of-the-art methods for the fixed point enumeration problem rely on Answer Set Programming (ASP).

In 24, we propose two new efficient ASP-based methods to solve this problem. We evaluate them on both real-world and pseudo-random models, showing that they vastly outperform four state-of-the-art methods as well as can handle very large and complex models.

8.6 Hybrid computational modeling highlights reverse warburg effect in breast cancer-associated fibroblasts

Participants: Sahar Aghakhani, Anna Niarakis, Sylvain Soliman.

Cancer-associated fibroblasts (CAFs) are amongst the key players of the tumor microenvironment (TME) and are involved in cancer initiation, progression, and resistance to therapy. They exhibit aggressive phenotypes affecting extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved.

In 17, we present the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining a cell-and diseasespecific asynchronous Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, in light of our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.

In 27, this is generalized to computational modeling of metabolic reprogramming in both rheumatoid arthritis synovial fibroblasts and cancer associated fibroblasts.

8.7 A large-scale Boolean model of the rheumatoid arthritis fibroblast-like synoviocytes predicts drug synergies in the arthritic joint

Participants: Anna Niarakis, Sylvain Soliman.

Rheumatoid arthritis (RA) is a complex autoimmune disease with an unknown aetiology. However, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) play a significant role in initiating and perpetuating destructive joint inflammation by expressing immuno-modulating cytokines, adhesion molecules, and matrix remodelling enzymes. In addition, RA-FLS are primary drivers of inflammation, displaying high proliferative rates and an apoptosis-resistant phenotype. Thus, RA-FLS-directed therapies could become a complementary approach to immune-directed therapies by predicting the optimal conditions that would favour RA-FLS apoptosis, limit inflammation, slow the proliferation rate and minimise bone erosion and cartilage destruction.

In 19, we present a large-scale Boolean model for RA-FLS that consists of five submodels focusing on apoptosis, cell proliferation, matrix degradation, bone erosion and inflammation. The five-phenotype-specific submodels can be simulated independently or as a global model. In silico simulations and perturbations reproduced the expected biological behaviour of the system under defined initial conditions and input values. The model was then used to mimic the effect of mono or combined therapeutic treatments and predict novel targets and drug candidates through drug repurposing analysis.

8.8 Reactmine: a statistical search algorithm for inferring chemical reactions from time series data

Participants: François Fages, Julien Martinelli, Sylvain Soliman.

Inferring chemical reaction networks (CRN) from concentration time series is a challenge encouraged by the growing availability of quantitative temporal data at the cellular level. This motivates the design of algorithms to infer the preponderant reactions between the molecular species observed in a given biochemical process, and build CRN structure and kinetics models. Existing ODE-based inference methods such as SINDy resort to least square regression combined with sparsity-enforcing penalization, such as Lasso. However, we observe that these methods fail to learn sparse models when the input time series are only available in wild type conditions, i.e. without the possibility to play with combinations of zeroes in the initial conditions.

In 31, we present a CRN inference algorithm which enforces sparsity by inferring reactions in a sequential fashion within a search tree of bounded depth, ranking the inferred reaction candidates according to the variance of their kinetics on their supporting transitions, and re-optimizing the kinetic parameters of the CRN candidates on the whole trace in a final pass. We show that Reactmine succeeds both on simulation data by retrieving hidden CRNs where SINDy fails, and on two real datasets, one of fluorescence videomicroscopy of cell cycle and circadian clock markers, the other one of biomedical measurements of systemic circadian biomarkers possibly acting on clock gene expression in peripheral organs, by inferring preponderant regulations in agreement with previous model-based analyses. The code is available at together with introductory notebooks. , a statistical constraint-based search algorithm is introduced to learn chemical reaction networks from single time series data, and compared to state-of-the-art SINDy algorithm to learn differential equations from time series data.

8.9 Neural-based classification rule learning for sequential data

Participants: Marine Collery, François Fages.

Discovering interpretable patterns for classification of sequential data is of key importance for a variety of fields, ranging from genomics to fraud detection or more generally interpretable decision-making.

In 22, we propose a novel differentiable fully interpretable method to discover both local and global patterns (i.e. catching a relative or absolute temporal dependency) for rule-based binary classification. It consists of a convolutional binary neural network with an interpretable neural filter and a training strategy based on dynamically-enforced sparsity. We demonstrate the validity and usefulness of the approach on synthetic datasets and on an open-source peptides dataset. Key to this end-to-end differentiable method is that the expressive patterns used in the rules are learned alongside the rules themselves.

In 28, this approach is compared to other approaches to rule learning from sequential data.

9.1 Bilateral contracts with industry

10.1 International research visitors

10.2 European initiatives

10.3 National initiatives

11.1 Promoting scientific activities

11.2 Teaching - Supervision - Juries

11.3 Popularization

12.1 Major publications

• 1 articleS.Sahar Aghakhani, S.Sylvain Soliman and A.Anna Niarakis. Metabolic Reprogramming in Rheumatoid Arthritis Synovial Fibroblasts: a Hybrid Modeling Approach.PLoS Computational Biology1812December 2022, e1010408HALDOI
• 2 articleA.Adrien Baudier, F.François Fages and S.Sylvain Soliman. Graphical Requirements for Multistationarity in Reaction Networks and their Verification in BioModels.Journal of Theoretical Biology459December 2018, 79--89HALDOIback to text
• 3 articleA.Alexis Courbet, P.Patrick Amar, F.François Fages, E.Eric Renard and F.Franck Molina. Computer‐aided biochemical programming of synthetic microreactors as diagnostic devices.Molecular Systems Biology144April 2018HALDOIback to textback to text
• 4 inproceedingsE.Elisabeth Degrand, F.François Fages and S.Sylvain Soliman. Graphical Conditions for Rate Independence in Chemical Reaction Networks.Proceedings CMSB 2020: The 18th International Conference on Computational Methods in Systems BiologyCMSB 2020 - 18th International Conference on Computational Methods in Systems BiologyKonstanz / Online, GermanySeptember 2020HALback to text
• 5 articleF.François Fages, S.Steven Gay and S.Sylvain Soliman. Inferring reaction systems from ordinary differential equations.Theoretical Computer Science599September 2015, 64--78HALDOIback to text
• 6 inproceedingsF.François Fages, G.Guillaume Le Guludec, O.Olivier Bournez and A.Amaury Pouly. Strong Turing Completeness of Continuous Chemical Reaction Networks and Compilation of Mixed Analog-Digital Programs.CMSB 2017 - 15th International Conference on Computational Methods in Systems BiologyLecture Notes in Computer ScienceProceedings of the fiveteen international conference on Computational Methods in Systems Biology, CMSB 201710545Darmstadt, GermanySeptember 2017, 108-127HALback to text
• 7 articleF.François Fages, T.Thierry Martinez, D. A.David A Rosenblueth and S.Sylvain Soliman. Influence Networks compared with Reaction Networks: Semantics, Expressivity and Attractors.IEEE/ACM Transactions on Computational Biology and BioinformaticsPP992018, 1-14HALDOIback to text
• 8 thesisE.Eléa Greugny. Computational modeling approaches to multifactorial aspects of atopic dermatitis.Institut Polytechnique de ParisOctober 2022HALback to text
• 9 articleJ.Jeremy Grignard, V.Véronique Lamamy, E.Eva Vermersch, P.Philippe Delagrange, J.-P.Jean-Philippe Stephan, T.Thierry Dorval and F.François Fages. Mathematical modeling of the microtubule detyrosination/tyrosination cycle for cell-based drug screening design.PLoS Computational Biology186June 2022, e1010236HALDOIback to textback to text
• 10 inproceedingsM.Mathieu Hemery and F.François Fages. Algebraic Biochemistry: a Framework for Analog Online Computation in Cells.CMSB 2022 - International Conference on Computational Methods in Systems BiologyBucarest, RomaniaSeptember 2022HALback to text
• 11 thesisJ.Julien Martinelli. On learning mechanistic models from time series data with applications to personalised chronotherapies.Institut Polytechnique de ParisFebruary 2022HALback to text
• 12 articleF.Faten Nabli, T.Thierry Martinez, F.François Fages and S.Sylvain Soliman. On Enumerating Minimal Siphons in Petri nets using CLP and SAT solvers: Theoretical and Practical Complexity.Constraints212April 2016, 251--276HALDOIback to text
• 13 articleM.Marek Ostaszewski, A.Anna Niarakis, A.Alexander Mazein, I.Inna Kuperstein, R.Robert Phair, A.Aurelio Orta-Resendiz, V.Vidisha Singh, S. S.Sara Sadat Aghamiri, M. L.Marcio Luis Acencio, E.Enrico Glaab, A.Andreas Ruepp, G.Gisela Fobo, C.Corinna Montrone, B.Barbara Brauner, G.Goar Frishman, L. C.Luis Cristóbal Monraz Gómez, J.Julia Somers, M.Matti Hoch, S.Shailendra Kumar Gupta, J.Julia Scheel, H.Hanna Borlinghaus, T.Tobias Czauderna, F.Falk Schreiber, A.Arnau Montagud, M.Miguel Ponce de Leon, A.Akira Funahashi, Y.Yusuke Hiki, N.Noriko Hiroi, T. G.Takahiro G Yamada, A.Andreas Dräger, A.Alina Renz, M.Muhammad Naveez, Z.Zsolt Bocskei, F.Francesco Messina, D.Daniela Börnigen, L.Liam Fergusson, M.Marta Conti, M.Marius Rameil, V.Vanessa Nakonecnij, J.Jakob Vanhoefer, L.Leonard Schmiester, M.Muying Wang, E. E.Emily E Ackerman, J. E.Jason E Shoemaker, J.Jeremy Zucker, K.Kristie Oxford, J.Jeremy Teuton, E.Ebru Kocakaya, G.Gökçe Ya Gmur Summak, K.Kristina Hanspers, M.Martina Kutmon, S.Susan Coort, L.Lars Eijssen, F.Friederike Ehrhart, D.Devasahayam Arokia, B.Balaya Rex, D.Denise Slenter, M.Marvin Martens, N.Nhung Pham, R.Robin Haw, B.Bijay Jassal, L.Lisa Matthews, M.Marija Orlic-Milacic, A. S.Andrea Senff Ribeiro, K.Karen Rothfels, V.Veronica Shamovsky, R.Ralf Stephan, C.Cristoffer Sevilla, T.Thawfeek Varusai, J.-M.Jean-Marie Ravel, R.Rupsha Fraser, V.Vera Ortseifen, S.Silvia Marchesi, P.Piotr Gawron, E.Ewa Smula, L.Laurent Heirendt, V.Venkata Satagopam, G.Guanming Wu, A.Anders Riutta, M.Martin Golebiewski, S.Stuart Owen, C.Carole Goble, X.Xiaoming Hu, R. W.Rupert W Overall, D.Dieter Maier, A.Angela Bauch, B. M.Benjamin M Gyori, J. A.John A Bachman, C.Carlos Vega, V.Valentin Grouès, M.Miguel Vazquez, P.Pablo Porras, L.Luana Licata, M.Marta Iannuccelli, F.Francesca Sacco, A.Anastasia Nesterova, A.Anton Yuryev, A.Anita De Waard, D.Denes Turei, A.Augustin Luna, O.Ozgun Babur, S.Sylvain Soliman, A.Alberto Valdeolivas, M.Marina Esteban-Medina, M.Maria Peña-Chilet, K.Kinza Rian, T.Tomáš Helikar, B.Bhanwar Lal Puniya, D.Dezso Modos, A.Agatha Treveil, M.Marton Olbei, B.Bertrand De Meulder, S.Stephane Ballereau, A.Aurélien Dugourd, A.Aurélien Naldi, V.Vincent Noël, L.Laurence Calzone, C.Chris Sander, E.Emek Demir, T.Tamas Korcsmaros, T. C.Tom C Freeman, F.Franck Augé, J. S.Jacques S Beckmann, J.Jan Hasenauer, O.Olaf Wolkenhauer, E. L.Egon L Wilighagen, A. R.Alexander R Pico, C. T.Chris T Evelo, M. E.Marc E Gillespie, L. D.Lincoln D Stein, H.Henning Hermjakob, P.Peter D'eustachio, J.Julio Saez-Rodriguez, J.Joaquin Dopazo, A.Alfonso Valencia, H.Hiroaki Kitano, E.Emmanuel Barillot, C.Charles Auffray, R.Rudi Balling, R.Reinhard Schneider and C.-1.COVID-19 Disease Map Community. COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.Molecular Systems Biology1710October 2021, e10387HALDOIback to text
• 14 articleE.Eléa Thibault Greugny, J.Jalil Bensaci, F.François Fages and G.Georgios Stamatas. Computational modeling predicts impaired barrier function and higher sensitivity to skin inflammation following pH elevation.Experimental DermatologyNovember 2022HALDOIback to textback to text
• 15 articleP.Pauline Traynard, A.Adrien Fauré, F.François Fages and D.Denis Thieffry. Logical model specification aided by model- checking techniques: application to the mammalian cell cycle regulation.Bioinformatics32172016, i772-i780HALDOIback to text
• 16 articleP.Pauline Traynard, C.Céline Feillet, S.Sylvain Soliman, F.Franck Delaunay and F.François Fages. Model-based investigation of the circadian clock and cell cycle coupling in mouse embryonic fibroblasts: Prediction of RevErb-α up-regulation during mitosis.BioSystems149November 2016, 59--69HALDOIback to textback to text

12.2 Publications of the year