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      A Hybrid Hoare Logic for Gene Network Models

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          Abstract

          The main difficulty when modelling gene networks is the identification of the parameters that govern their dynamics. It is particularly difficult for models in which time is continuous: parameters have real values which cannot be enumerated. The widespread idea is to infer new constraints that reduce the range of possible values. Here we present a new work based on a particular class of Hybrid automata (inspired by Thomas discrete models) where discrete parameters are replaced by signed celerities. We propose a new approach involving Hoare logic and weakest precondition calculus (a la Dijkstra) that generates constraints on the parameter values. Indeed, once proper specifications are extracted from biological traces with duration information (found in the literature or biological experiments), they play a role similar to imperative programs in the classical Hoare logic. We illustrate our hybrid Hoare logic on a small model controlling the lacI repressor of the lactose operon.

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          Most cited references6

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          An axiomatic basis for computer programming

          C. Hoare (1969)
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            A comparative analysis of synthetic genetic oscillators.

            Synthetic biology is a rapidly expanding discipline at the interface between engineering and biology. Much research in this area has focused on gene regulatory networks that function as biological switches and oscillators. Here we review the state of the art in the design and construction of oscillators, comparing the features of each of the main networks published to date, the models used for in silico design and validation and, where available, relevant experimental data. Trends are apparent in the ways that network topology constrains oscillator characteristics and dynamics. Also, noise and time delay within the network can both have constructive and destructive roles in generating oscillations, and stochastic coherence is commonplace. This review can be used to inform future work to design and implement new types of synthetic oscillators or to incorporate existing oscillators into new designs.
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              Multistationarity, the basis of cell differentiation and memory. II. Logical analysis of regulatory networks in terms of feedback circuits.

              Circuits and their involvement in complex dynamics are described in differential terms in Part I of this work. Here, we first explain why it may be appropriate to use a logical description, either by itself or in symbiosis with the differential description. The major problem of a logical description is to find an adequate way to involve time. The procedure we adopted differs radically from the classical one by its fully asynchronous character. In Sec. II we describe our "naive" logical approach, and use it to illustrate the major laws of circuitry (namely, the involvement of positive circuits in multistationarity and of negative circuits in periodicity) and in a biological example. Already in the naive description, the major steps of the logical description are to: (i) describe a model as a set of logical equations, (ii) derive the state table from the equations, (iii) derive the graph of the sequences of states from the state table, and (iv) determine which of the possible pathways will be actually followed in terms of time delays. In the following sections we consider multivalued variables where required, the introduction of logical parameters and of logical values ascribed to the thresholds, and the concept of characteristic state of a circuit. This generalized logical description provides an image whose qualitative fit with the differential description is quite remarkable. A major interest of the generalized logical description is that it implies a limited and often quite small number of possible combinations of values of the logical parameters. The space of the logical parameters is thus cut into a limited number of boxes, each of which is characterized by a defined qualitative behavior of the system. Our analysis tells which constraints on the logical parameters must be fulfilled in order for any circuit (or combination of circuits) to be functional. Functionality of a circuit will result in multistationarity (in the case of a positive circuit) or in a cycle (in the case of a negative circuit). The last sections deal with "more about time delays" and "reverse logic," an approach that aims to proceed rationally from facts to models. (c) 2001 American Institute of Physics.
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                Author and article information

                Journal
                2016-10-21
                Article
                1610.06715
                0d24d353-6e9b-4316-b576-f2c261bd5267

                http://arxiv.org/licenses/nonexclusive-distrib/1.0/

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                cs.LO

                Theoretical computer science
                Theoretical computer science

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