On 1st January 2014, the new team Lifeware has been created as a follow-up of the Contraintes project-team, which ended on 31st December 2013.

The web pages will be progressively updated.

## The Contraintes research team

Contraintes is a project-team of Inria, located in the Paris-Rocquencourt research center. Created in March 2001, Contraintes investigates the theoretical foundations, design, implementation and applications of formal methods for mastering the complexity of complex systems in two domains: real-life combinatorial optimization problems and cell biology.

In combinatorial optimization, Contraintes develops declarative modeling languages and hybrid discrete-continuous constraint propagation algorithms for solving search problems in high dimension. We apply these techniques to bin packing, scheduling and graph problems.

In computational biology, Contraintes investigates, in collaboration with biologists, the tight integration of *in silico* and *in vivo* approaches, including the use of micro-fluidic and synthetic biology techniques. We build computational models of cell signaling, gene expression and cell cycle control.

In synergy in both domains, we develop logic-based modeling languages, abstraction and model reduction techniques, and inference and search algorithms.

Contraintes is associated to the PhD programs Sciences Mathématiques de Paris Centre and Frontiers in Life Sciences in Paris. Contraintes and the Weiss's lab for synthetic biology at MIT, USA collaborate via the TisHom associated team.

## Highlights

### A paper accepted in Discrete Applied Mathematics

Steven Gay, François Fages, Thierry Martinez, Sylvain Soliman, Christine Solnon. On the subgraph Epimorphism Problem. *Discrete Applied Mathematics*, 162:214–228, 2014.

### An article in the Bulletin of Mathematical Biology

refining the 10 years old result of C. Soulé on feedback circuits and multistationaritySylvain Soliman. A stronger necessary condition for the multistationarity of chemical reaction networks. *Bulletin of Mathematical Biology*, 75(11):2289–2303, 2013.

### A paper accepted in PLoS Computational Biology

S. Stoma, A. Donzé, F. Bertaux, O. Maler and G. Batt. STL-based analysis of TRAIL-induced apoptosis challenges the notion of type I/type II cell line classification. *PLoS Computational Biology*, 9(5):e1003056, 2013.

### Release of Biocham-web in May 2013

Biocham-Web provides you access to the latest version of Biocham as a web service.

### A paper accepted at CP 2012

Faten Nabli, François Fages, Thierry Martinez, Sylvain Soliman. A Boolean Model for Enumerating Minimal Siphons and Traps in Petri-nets. In *Proceedings of CP'2012, 18th International Conference on Principles and Practice of Constraint Programming*, pages 798–814, volume 7514 of *Lecture Notes in Computer Science*. Springer-Verlag, 2012. [ slides ] [ poster ]

### A paper accepted in PNAS

Jannis Uhlendorf, Agnés Miermont, Thierry Delaveau, Gilles Charvin, François Fages and Samuel Bottani, Gregory Batt, Pascal Hersen. Long-term model predictive control of gene expression at the population and single-cell levels. *Proceedings of the National Academy of Sciences USA*, 109(35):14271–14276, 2012.

### A paper accepted in MolSysBiol, with Robert Lefkowitz, Nobel Prize in Chemistry 2012

Domitille Heitzler, Guillaume Durand, Nathalie Gallay, Aurélien Rizk, Seungkirl Ahn, Jihee Kim, Jonathan D. Violin, Laurence Dupuy and Christophe Gauthier, Vincent Piketty, Pascale Crépieux, Anne Poupon, Frédérique Clément, François Fages, Robert J. Lefkowitz, Eric Reiter. Competing G protein-coupled receptor kinases balance G protein and *β*-arrestin signaling. *Molecular Systems Biology*, 8(590), 2012.

### A paper accepted in Algorithms for Molecular Biology

Sylvain Soliman. Invariants and Other Structural Properties of Biochemical Models as a Constraint Satisfaction Problem. *Algorithms for Molecular Biology*, 7(15), 2012.

### Release of FO-CTL(ℝ_{lin}) in January 2012

FO-CTL(ℝ_{lin}) is a constraint solver for full First-Order Computation Tree Logic formulae with linear arithmetic over the reals in constrained transition systems (CTS). CTS are transition systems where both states and transitions are described with constraints.

### Two papers accepted in TCS

Aurélien Rizk, Grégory Batt, François Fages, Sylvain Soliman. Continuous Valuations of Temporal Logic Specifications with applications to Parameter Optimization and Robustness Measures. *Theoretical Computer Science*, 412(26):2827–2839, 2011.

Elisabetta De Maria, François Fages, Aurélien Rizk, Sylvain Soliman. Design, Optimization, and Predictions of a Coupled Model of the Cell Cycle, Circadian Clock, DNA Repair System, Irinotecan Metabolism and Exposure Control under Temporal Logic Constraints. *Theoretical Computer Science*, 412(21):2108–2127, 2011.

### A paper accepted at PPDP 2010

Thierry Martinez. Semantics-preserving translations between Linear Concurrent Constraint Programming and Constraint Handling Rules. In *Proceedings of PPDP'10, International Conference on Principles and Practice of Declarative Programming, Edinburgh, UK*, pages 57–66. ACM, 2010.

### Release of Biocham 3 in June 2010

Biocham 3 is now available including a new SBGN graphical editor, new methods for model reduction, parameter optimization and robustness analyses w.r.t. temporal logic specifications.

### A paper accepted at ECCB 2010 and in Bioinformatics

Steven Gay, Sylvain Soliman, François Fages. A Graphical Method for Reducing and Relating Models in Systems Biology. *Bioinformatics*, 26(18):i575–i581, 2010.

### A paper accepted at CP 2009

François Fages, Aurélien Rizk. From Model-Checking to Temporal Logic Constraint Solving. In *Proceedings of CP'2009, 15th International Conference on Principles and Practice of Constraint Programming*, pages 319–334, *Lecture Notes in Computer Science*. Springer-Verlag, 2009.

### A paper accepted in JTB

Sriram Krishnamachari, Sylvain Soliman, François Fages. Dynamics of the interlocked positive feedback loops explaining the robust epigenetic switching in Candida albicans. *Journal of Theoretical Biology*, 258(1):71–88, 2009.

### A paper accepted at ISMB 2009 and in Bioinformatics

Aurélien Rizk, Grégory Batt, François Fages, Sylvain Soliman. A general computational method for robustness analysis with applications to synthetic gene networks. *Bioinformatics*, 12(25):il69–il78, 2009.

### Release of Rules2CP and PKML in April 2009

Rules2CP is a general purpose rule-based modeling language for constraint programming. It aims at making constraint programming technology easier to use by non-programmers, by modeling combinatorial optimization problems with logical rules and elementary data structures. The Packing Knowledge Modeling Language (PKML) is a Rules2CP library dedicated to industrial bin packing problems.

### A paper accepted in TCS

François Fages, Aurélien Rizk. On Temporal Logic Constraint Solving for the Analysis of Numerical Data Time series. *Theoretical Computer Science*, 408(1):55–65, 2008.

### A paper in a book chapter

François Fages, Sylvain Soliman. Model Revision from Temporal Logic Properties in Systems Biology. In *Probabilistic Inductive Logic Programming*, pages 287–304, volume 4911 of *Lecture Notes in Computer Science*. Springer-Verlag, 2008.

### A paper accepted in TCS

François Fages, Sylvain Soliman. Abstract Interpretation and Types for Systems Biology. *Theoretical Computer Science*, 403(1):52–70, 2008.

### Release of CHRat in July 2008

The CHRat language is a modular version of the Constraint Handling Rules language CHR, called CHRat for modular CHR with ask and tell. Any constraint defined in a CHRat component can be reused both in rules and guards in another CHRat component to define new constraint solvers.

### Release of Biocham 2.7 in April 2008

Biocham 2.7 releases a powerful parameter search procedure with respect to temporal logic quantitative properties, a stochastic simulator and an inference system for conservation laws.

### A paper accepted at FMSB 2008

François Fages, Sylvain Soliman. From reaction models to influence graphs and back: a theorem. In *Proceedings of Formal Methods in Systems Biology FMSB'08*, *Lecture Notes in Computer Science*. Springer-Verlag, 2008.

### IGEM 2007 foundational research prize

For its first participation to the iGEM 2007 competition organised by the MIT on synthetic biology, the French team with Aurélien Rizk was finalist and won the first prize of foundational research using Biocham.