SRI Pathway Logic

Category Cross-Omics>Pathway Analysis/Tools

Abstract Pathway Logic (PL) is a symbolic systems biology approach to the modeling and analysis of molecular and cellular processes based on 'rewriting logic'.

Such formal theories can include both specific facts and general principles relating and categorizing data elements and processes.

New data structures for representing biological entities and their relations and properties can easily be defined. Theories concerning different types of information can also be combined using well- understood operations for combining logical theories.

A wide range of analytical tools developed for the analysis of computer system specifications is being adapted to carry out new kinds of analysis of experimental data curated into formal theories.

In PL, biological molecules, their states, locations, and their roles in molecular or cellular processes can be modeled at very different levels of abstraction.

For example, a complex signaling protein can be modeled either according to an overall state, its post-translational modifications, or as a collection of protein functional domains and their internal or external interactions.

Similarly biological processes can be represented at different levels of granularity using 'rewrite rules'. Each rule represents a step (at the chosen level of granularity) in a biological process such as metabolism or intra-/intercellular signaling.

A rule may represent a family of reactions using variables to stand for families of molecular components. Rules express dependencies on biological context; for example, a scaffold needed to hold proteins in position to interact productively.

A collection of rules together with the underlying data type specifications forms a PL knowledge base (KB). Each biological molecule that is declared in a PL rewrite theory has associated metadata linking it to standard database entries, for example HUGO or UniProt/Swiss-Prot for proteins, along with other information such as category and synonyms.

This information is part of the KB. It is important to place the knowledge in a broader context and to be able to integrate it with other knowledge sources. Each rule has associated evidence used to justify the rule, which is also part of the KB.

A 'PL model' consists of a specification of an initial state (cell components and locations) interpreted in the context of a KB. Such models are executable and can be understood as specifying possible ways a system can evolve.

Logical inference and analysis techniques are used for simulation to study possible ways a system could evolve, to assemble pathways as answers to queries, and to reason about dynamic assembly of complexes, cascading transmission of signals, feedback-loops, cross talk between subsystems, and larger pathways.

Logical and computational reflections are used to transform and further analyze models.

Pathways are Not predefined. Instead they are assembled by applying the rules starting from an initial state, searching for a state meeting given conditions.

For example, a pathway leading to specific conditions, such as activation of a Ras protein can be generated as the result of a logical query. A subnet (subset of reactions) composed of all possible relevant pathways can also be generated.

A subnet consisting of connections to a given set of molecular components can be generated by graph exploration techniques.

PL knowledge is represented and analyzed using Maude, a rewriting- logic-based formalism. Maude is a high-performance reflective language and system supporting both equational and 'rewriting logic' specification and programming for a wide range of applications.

‘Rewriting logic’ is logic of concurrent change that can naturally deal with state and with concurrent computations.

The Pathway Logic Assistant (PLA) provides an interactive visual representation of 'PL models'. The PLA allows you to explore a Pathway logic KB and to query models derived from such a KB.

One interacts with PLA via two (2) main types of windows: the KB manager (KBManager, unique to a session) and graph viewer window(s) (zero or more per session).

A model can be derived using a predefined initial state (called a dish), or by interactively creating an initial state using the dish editor. The resulting model is represented as a 'Petri net' whose transitions are the KB rules reachable from the initial state.

The Petri net graph is displayed in the 'PLA viewer' which the user can use to browse the network and query the model for subnets and pathways.

Using PLA you can also incrementally explore the KB network by specifying a set of rules or occurrences from which to start and then selectively adding connected rules and occurrences.

In addition, graphs (i.e. the underlying networks) that have been constructed by 'querying models' or exploring can be compared.

A graph viewer has a mode determined by the interface provided by the underlying network: Pnet for networks generated from a dish (models) and subnets resulting from queries; Xnet for networks generated by exploring; and Cnet for comparison nets.

The reason for modes is that the meaningful operations/interactions depend on the mode (how the network was generated).

Using PLA a biologist can:

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G6G Abstract Number 20265

G6G Manufacturer Number 102509