Abstract
BackgroundIn this paper, we use: i) formalised anatomical knowledge of connectivity between body structures and ii) a formal theory of physiological transport between fluid compartments in order to define and make explicit the routes followed by proteins to a site of interaction. The underlying processes are the objects of mathematical models of physiology and, therefore, the motivation for the approach can be understood as using knowledge representation and reasoning methods to propose concrete candidate routes corresponding to correlations between variables in mathematical models of physiology. In so doing, the approach projects physiology models onto a representation of the anatomical and physiological reality which underpins them.ResultsThe paper presents a method based on knowledge representation and reasoning for eliciting physiological communication routes. In doing so, the paper presents the core knowledge representation and algorithms using it in the application of the method. These are illustrated through the description of a prototype implementation and the treatment of a simple endocrine scenario whereby a candidate route of communication between ANP and its receptors on the external membrane of smooth muscle cells in renal arterioles is elicited. The potential of further development of the approach is illustrated through the informal discussion of a more complex scenario.ConclusionsThe work presented in this paper supports research in intercellular communication by enabling knowledge‐based inference on physiologically‐related biomedical data and models.
Highlights
In this paper, we use: i) formalised anatomical knowledge of connectivity between body structures and ii) a formal theory of physiological transport between fluid compartments in order to define and make explicit the routes followed by proteins to a site of interaction
Triage: Ability to select the kind of interaction and the kind of candidate routes based on heuristics and a knowledge base, which includes the ability to: (a) represent kinds of physiological communication, (b) ascribe to proteins their capability to follow a route of a given kind, (c) carry inference—for the classification of an interaction and the selection of routes and fragments thereof—based on necessary and sufficient conditions for the occurrence of a given interaction; 3
We apply our algorithm to the construction of one possible route of communication between two specific locations as our implementation takes advantage of the Dijkstra algorithm searching for the shortest path between two discrete nodes in a graph. We focus on this base case; providing more or alternate routes consists in performing similar operations as in the base case and combining their results
Summary
We use: i) formalised anatomical knowledge of connectivity between body structures and ii) a formal theory of physiological transport between fluid compartments in order to define and make explicit the routes followed by proteins to a site of interaction. A considerable proportion of physiological, pharmacological and disease processes involves the interaction between proteins (i.e. peptides, polypeptides, or their complexes) across distinct subcellular, tissue and anatomical compartments. A simple example of a short communication route is that taken by a protein diffusing from the bloodstream in the capillaries of a given organ (e.g. coronary microcirculation) to the extracellular tissue fluid compartment of that organ (e.g. tissue fluid in the left ventricular wall) In this case, the anatomical route starts inside a capillary and ends in the extracellular tissue fluid with an intermediate step in the endothelial intercellular space during the crossing of the capillary wall by the protein as it is filtrated by the capillary. Even such a simple example shows the potential complexity of giving an account of such phenomena in that: 1) sites (i.e. portions of blood in the capillaries of an organ, as well as portions of tissue fluid of that same organ) need to be identified and 2) transport modalities need to be taken into account relative to the translocating objects and their physical and chemical characteristics
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