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    <article-meta>
      <title-group>
        <article-title>The Ontology of Physics for Biology - a companion to Basic Formal Ontology</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <string-name>Daniel L. Cook</string-name>
          <email>dcook@uw.edu</email>
          <xref ref-type="aff" rid="aff1">1</xref>
          <xref ref-type="aff" rid="aff2">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>John H. Gennari</string-name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Maxwell L. Neal</string-name>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <aff id="aff0">
          <label>0</label>
          <institution>Center for Global Infectious Disease Research, Seattle Children's Research Institute</institution>
          ,
          <addr-line>Seattle, Washington</addr-line>
          ,
          <country country="US">USA</country>
        </aff>
        <aff id="aff1">
          <label>1</label>
          <institution>Department of Biomedical Informatics and Medical Education, University of Washington</institution>
          ,
          <addr-line>Seattle, Washington</addr-line>
          ,
          <country country="US">USA</country>
        </aff>
        <aff id="aff2">
          <label>2</label>
          <institution>Department of Physiology and Biophysics, University of Washington</institution>
          ,
          <addr-line>Seattle, Washington</addr-line>
          ,
          <country country="US">USA</country>
        </aff>
      </contrib-group>
      <abstract>
        <p>The Ontology of Physics for Biology (OPB) has been developed to annotate and reason over the physical and system dynamical content of physiological simulation models and data sets. It has been built in the context of Open Biomedical Ontology (OBO) upon which we rely for annotating the biological content of biological simulation and analysis models. However, there is little ontological support for basic concepts, entities, and laws of classical physics that are the bases of our physics-based understanding of how and why biophysical processes occur as they do. To address this gap, we developed the Ontology of Physics for Biology as a formal representation of energy-bearing biophysical entities, their observable physical properties, and the quantitative dependencies (i.e., laws) amongst the values of those properties. In this paper, we review the OPB's representation of system dynamics and introduce extensions for representing entities, properties, and dependencies of thermodynamics. Based on these representations, we propose a thermodynamics-based definition of dynamical biological process as the flow of thermodynamical energy. It is yet to be determined how these essential aspects of classical physics lie within or relate to the ontological framework of the Basic Formal Ontology (BFO). We suggest that the OPB can function as a companion ontology to BFO in the domain of system dynamics and thermodynamics.</p>
      </abstract>
      <kwd-group>
        <kwd>physics ontology</kwd>
        <kwd>bioengineering</kwd>
        <kwd>thermodynamics</kwd>
        <kwd>biophysical modeling</kwd>
      </kwd-group>
    </article-meta>
  </front>
  <body>
    <sec id="sec-1">
      <title>Biophysical modeling and ontologies</title>
      <p>system</p>
      <p>
        dynamics,
Physics-based mathematical modeling and analysis of biological
processes can provide insight into understanding physiology and
pathophysiology. Early models (
        <xref ref-type="bibr" rid="ref1 ref2">1,2</xref>
        ) in the mid-20th century laid
the foundations for our understanding of the biophysics of
enzymatic reactions, neuronal ion channel gating, and the integrated
behavior of complex metabolic networks. Since these seminal
studies, physics-based computational modeling has expanded for
all biophysical domains and disciplines and across all
spatiotemporal scales.
      </p>
      <p>These models have been critical resources for a series of
multiscale physiological modeling projects such as DARPA's Virtual
Soldier Project (VSP, http://www.virtualsoldier.us/), the EU's
Virtual Physiological Human project (VPH;
https://www.vph-institute.org/), the NIH's Virtual Physiological Rat project (VPR;
http://virtualrat.org/), and the Center for Reproducible
Biomedical Modeling (https://reproduciblebiomodels.org/). Each of these
projects was a multicenter collaboration of mathematical
modelers of physics-based physiological and pathophysiological
systems across temporal and spatial scales. Each project addressed
major challenges in finding, accessing, and reusing the contents
of available model repositories and biomedical database
resources.</p>
      <p>
        The results and knowledge from these projects comprise what
physiological modelers have dubbed the "physiome" (
        <xref ref-type="bibr" rid="ref3 ref4">3,4</xref>
        ). The
multiscale, multidomain physiome has been the focus of
ambitious projects such as the EBI-sponsored VPH project (
        <xref ref-type="bibr" rid="ref5">5</xref>
        ). The
results of these and other efforts are a number of model
repositories such as BioModels (EBI; https://www.ebi.ac.uk/biomodels/)
and the Physiome Model Repository
(https://models.physiomeproject.org/welcome).
      </p>
      <p>These projects have faced major challenges of data access and
alignment and the more general problems of computer model
interoperability and reproducibility. Serious syntactic problems
stemmed from using different modeling languages and
computational platforms despite the availability of web-friendly languages
(e.g. the Web Ontology Language, OWL) and data exchange
standards. Such problems were, and are, symptomatic of
pervasive and intractable semantic problems that are the product of
socalled "silo" thinking, use of local jargons, and domain-specific
terminologies.</p>
      <p>
        In response, the biomedical community advocated the use of
semantically rich ontologies, as available in growing collections
such as the Open Biomedical Ontology collection (OBO;
http://www.obofoundry.org/) and BioPortal
(https://bioportal.bioontology.org/). Interoperability of these
ontologies has been greatly enhanced by the strong unifying
spatiotemporal, "realist" framework provided by the Basic Formal
Ontology (BFO) (
        <xref ref-type="bibr" rid="ref6">6</xref>
        ).
      </p>
      <p>
        However, the BFO framework only partially meets the needs of
biophysical investigators and modelers as it offers scant
representation of those physical properties, biophysical laws, and
thermodynamic constraints that are the foundations of biophysical
analysis, modeling, and data representation. Whereas BFO and OBO
ontologies are based on the philosophical perspective of
"realism", the Ontology of Physics for Biology (OPB) (
        <xref ref-type="bibr" rid="ref7 ref8">7,8</xref>
        ) is based
on biophysical theory and bioengineering practices as used by
generations of physical scientists for concise and predictive
means for representing, analyzing, and explaining biophysical
entities and processes.
      </p>
      <p>Copyright © 2019 for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0).
In this paper, we describe the OPB representational schema
focusing on four aspects of biophysics: 1) We define OPB
dynamical property classes based on "stock-and-flow" system dynamic
modeling; 2) we describe "physical dependency" classes that
represent physical laws such as Ohm's Law that apply across multiple
biodynamical domains; 3) we describe OPB representation of
thermodynamical energy and entropy; and 4) we propose to
define and classify biophysical processes as the flow of energy
and/or information. We focus on these four aspects of the OPB
that may present challenges to integrating and interoperating with
BFO realism-based ontologies.</p>
    </sec>
    <sec id="sec-2">
      <title>Challenges of representing biophysics</title>
      <p>Our representational challenge has been to define and represent
the physical attributes and the physical laws that are the basis for
biophysical analysis and modeling. Physical properties such as
flow rate, pressure, and flow resistance must be defined in a
manner that is useful for applying basic constitutive laws such as
Hooke’s law or Ohm’s law. Constraints, such as for conservation
of mass and charge, must govern the values of such properties.
Such laws and constraints are expressed as mathematical
abstractions that include differential and integral calculus.</p>
      <sec id="sec-2-1">
        <title>Available ontology resources</title>
        <p>Annotating computational, biophysical models benefits greatly
from access to existing repositories of structural
knowledge—ontologies—that span all spatial scales for annotating structural
participants in computational models. In particular, there exists a
wide range of ontologies of biological structures and processes
that are now available on the web, such as those hosted at the
European Bioinformatics Institute
(https://www.ebi.ac.uk/ols/ontologies). The following list
exemplifies the span of structural and temporal scales represented in
selected OBO ontologies:</p>
        <p>Foundational Model of Anatomy (FMA): organ systems,
organs, tissues, cells
•
•
•
•
•
•
physics to mediate the representation and exchange of biophysical
knowledge across physical, mathematical, and physiological
domain boundaries.</p>
        <p>
          Although there are excellent resources for these structural
elements, we find that there are scant resources for the representation
of biophysical laws (e.g. Ohm’s law) and the processes that they
govern. Borst, et al. developed the PhysSys Ontology (9; no
longer available) which foreshadowed key elements of the OPB
but was restricted to the domain of engineering system dynamics.
Gruber (
          <xref ref-type="bibr" rid="ref10">10</xref>
          ) developed an Ontology of Engineering Mathematics
(no longer available) which focused on the mathematical
abstractions without being tailored to biological systems analysis.
Our key representational goals for the OPB have been to: 1)
provide explicit physics-based definitions and classification of
observable physical properties such as mass, flow rate, and
temperature, 2) represent physical processes according to the system
dynamical architecture of stocks and flows, 3) represent the
mathematics of infinite and infinitesimal spans of time and space, 4)
extend the domain of continuants to include electrical charge and
thermodynamic energy, and 5) define and classify the laws and
axioms of physics for mapping onto the mathematics of analytical
models.
        </p>
      </sec>
      <sec id="sec-2-2">
        <title>OPB development, implementation, and use</title>
        <p>In developing a formal ontology of biophysics and systems
dynamics that could serve the large biophysical analysis and
modeling communities, we recognized the value of following the
representational guidelines of the BFO and OBO. This perspective was
inspired by our colleagues at the University of Washington who
developed and maintain the Foundational Model of Anatomy
(FMA). Some aspects of OPB development have been reported
{Cook, 2011 #522;Neal, 2013 #813;Neal, 2016 #1006}) and
presented to prior meetings of the International Conference on
Biomedical Ontology (ICBO).</p>
        <p>
          The OPB has a growing impact in the biomodeling domain as
evidenced by our participation in the Computational Modeling in
Biology Network (COMBINE, https://co.mbine.org) to develop
tools and standards that are responsive to that community’s user
base. Most recently, these collaborations have led to our
participation in the Center for Reproducible Biomedical Modeling
(http://reproduciblemodels.org/). As part of this center, and with
collaborators at the Auckland Bioengineering Institute, we have
recently established a pipeline with several peer-reviewed
journals whereby models associated with new publications would be
annotated and curated by staff in the Center prior to publication
and dissemination by the journal. These annotations use the
framework provided by the OPB as well as tools such as SemGen
(
          <xref ref-type="bibr" rid="ref12 ref13 ref14">12,13,14</xref>
          ) and others that rely on the semantics of the OPB for
representing the mathematical and biophysical properties of these
models.
        </p>
        <p>OBP domain content has been gleaned from physics and
biophysics textbooks, literature resources, online resources, and extensive
discussions with a broad range of biophysical and physiological
modelers. We have sought to represent the biophysical entities,
theories and computations used by physiologists, biophysicists,
and bioengineers to represent and analyze physical entities and
processes in biological systems. In doing so, the OPB adopts basic
BFO spatiotemporal classes such as for continuants and
occurrents but is expanded to represent immaterial aspects of
biophysical reality such as energy, electrical charge, and physical laws.</p>
        <sec id="sec-2-2-1">
          <title>Cell Ontology (CO): cells and cell parts</title>
        </sec>
        <sec id="sec-2-2-2">
          <title>Gene Ontology (GO): genomic components</title>
        </sec>
        <sec id="sec-2-2-3">
          <title>GO-Plus: processes and participants</title>
        </sec>
        <sec id="sec-2-2-4">
          <title>Protein Ontology (PO): proteins</title>
        </sec>
        <sec id="sec-2-2-5">
          <title>ChEBI: small molecules, ions</title>
          <p>To frame the content of these ontologies, the BFO offers two key
classes: BFO:continuant represents discrete, space-occupying,
temporally-persistent material things that are the participants in
BFO:process (subclass of BFO:occurrent) that represents what
happens to continuants that are participating in the process for an
interval of time. The OBO repository ensures conformance with
the Basic Formal Ontology (BFO) and with the Relations
Ontology (RO) that represents and defines spatial relations.</p>
        </sec>
      </sec>
      <sec id="sec-2-3">
        <title>Need for an ontology of biophysics</title>
        <p>
          A major challenge to quantitative biophysical modeling by
bioengineers is that, although they may adhere to a common
understanding of physics, they employ a variety of space-time
coordinate systems, mathematical formalisms, languages, data
structures, and computational platforms to encode and compute model
prediction and insights. The resulting "tower of Babel" is a major
impediment to knowledge sharing and hinders collaborative
work. We were thus motivated to develop an ontology of classical
We have strived to structure the OPB to map as well as possible
to the BFO and OBO ontologies. However, as others have noted
(
          <xref ref-type="bibr" rid="ref15">15</xref>
          ), there are key mathematical concepts such as temporal and
spatial differentiation and integration of property values that are
outside of the realist framework. Furthermore, key physical
entities that are immaterial (thermodynamic energy and entropy),
dynamical laws, and unbounded spatiotemporal entities
(gravitational fields) do not fit comfortably into the realist
representational framework.
        </p>
      </sec>
      <sec id="sec-2-4">
        <title>Physiological modeling</title>
        <p>Biophysicists, bioengineers, and physiologists aim to understand
the structural, thermodynamic, and system dynamic basis of
physiological function across structural and temporal scales. We are
inspired by important questions such as: how do the parts of the
cardiovascular system combine to finely regulate heart rate,
cardiac contractility, and vascular resistance to maintain blood
pressure? How do pancreatic beta-cells control insulin secretory rate
to regulate blood glucose? Answers to such clinically and
biologically important questions are described as physiological
hypotheses, subjected to laboratory evaluation, and formalized as
physics-based mathematical models based on the principles of
classical physics.</p>
        <p>Our goal has been to represent the biophysical aspects of
continuants and processes across biophysical domains
(electrophysiology, fluid dynamics, etc.) that span spatial scales from atomic to
organismal. The OPB represents biophysical reality as it is
perceived, measured, and analyzed by generations of clinicians,
physiologists, and bioengineers. Accordingly, our measure of
success is the degree to which we can annotate and reason over
the explanatory constructs that constitute the broad range of
biological system dynamical knowledge and analytical methods.
In the following, we describe key features of the OPB, focusing
on those aspects that include abstract models of mathematics and
biophysics. Recently, we have extended the OPB to include
definitions of thermodynamic entities (energy, entropy, etc.) and
representations of the laws by which they depend upon one another.
We also describe extensions to the OPB that formalize the
representation of spatiotemporal continua and of thermodynamics in
support of recent advances in energy bond-graph modeling
(1618).</p>
      </sec>
    </sec>
    <sec id="sec-3">
      <title>OPB overview</title>
      <p>The OPB represents those aspects of the real world that can be
and have been represented analytically using the theories,
mathematics, and procedures of classical physics. It represents the
quantitative aspects of biomedical reality by identifying physically
observable attributes of physical continuants and processes, and
offering classes that represent theorems, physical laws, and
analytical procedures for explaining prior events and for predicting
future events.</p>
      <p>Physics is a quantitative, computational science based on defining
and quantifying the observable properties of physical entities and
then specifying quantitative rules and laws by which such
quantities depend upon one another. Chemistry is the science
responsible for identifying and quantifying atomic and molecular species
and then discovering and specifying, for example, the quantitative
reaction laws that specify chemical reaction rates. Hydraulics is
the science of fluid quantities and fluid flows. Electricity is the
science of electrical charges and charge flow. Each of these
physical sciences are concerned with the amounts of “stuff” (e.g.,
material, charge, momentum) and the rules that determine rates of
flow or exchange during physical processes.</p>
      <p>The upper three OPB class levels are shown in Figure 1. The top
class OPB:Physics entity is defined as “A Thing that is a quality,
definition, abstraction, or law of classical physics as discovered
and applied to the explanation, analysis, and simulation of
biophysical entities and processes.” The next two subclasses
distinguish classes that represent real from analytical entities as: 1)
OPB:Physics real entity is defined as “A physics entity that is a
continuant or process in the real world and that occupies space
and time, and is composed of portions of matter, energy, or
information.” The second subclass, OPB:Physics analytical entity is
defined as “A physics entity that encodes or expresses a theory,
hypothesis, or explanation that relates instances of physics
continuants and processes for purposes of demonstration, calculation,
education, or simulation.”
Whether explicitly or implicitly, biophysical modeling adopts a
generalized "stock-and-flow" system dynamic modeling
paradigm based on stocks of "stuff" (i.e., continuants) coupled by
flows of "stuff" (i.e., processes) amongst the stocks. Bank
accounts work that way. Inventories work that way. Automobile gas
tanks and batteries work that way. Biophysical systems work that
way. The key modeling tasks are to: 1) define amounts of stuff in
each stock, 2) define flow rates of stuff amongst stocks, 3) apply
conservation constraints by which amounts depend on flow rates,
4) apply constitutive laws by which flow rates depend on
amounts.</p>
      <p>A key feature of computational system dynamics is that it is
concerned solely with the values of the physical properties (e.g.,
amounts of material, velocity of motion) of the modeled
continuants and occurrents. The continuants (e.g., heart, blood, cell) and
processes (beating, flowing, migrating) are implicit in the
mathematics and their identities are established only by annotations
against appropriate ontologies such as in the OBO collection.
Furthermore, some models may simply represent generalized,
hypothetical abstractions pertinent to broad classes of continuants and
processes.</p>
    </sec>
    <sec id="sec-4">
      <title>OPB:Physical properties</title>
      <p>
        Physical properties are the physically observable attributes
(phenotypes) of physical participants of physical processes across all
spatiotemporal scales and across all biophysical domains (see
Figure 2). We have defined (
        <xref ref-type="bibr" rid="ref7">7</xref>
        ) the OPB:Physical property class
as “A physics real entity that is a physically observable attribute
of a physics continuant or process that can be represented as a
scalar, vector or tensor, or as an aggregate of such measures, or as
can be computationally derived from such measures.” Key
subclasses are shown in Figure 2.
Dynamical property classes constitute a dual-inheritance
hierarchy whereby each property is a subclass of OPB:Dynamical
property and of OPB:Dynamical domain (Figure 3).
The OPB:Dynamical property class distinguishes two subclasses
OPB:Dynamical rate property and OPB:Dynamical state
property that apply to each of six OPB:Dynamical domains as shown
in Figure 3. For example, blood flowing across the boundary of a
vessel would have an instance of OPB:Fluid flow rate as a
physical property. Its quantitative value may be expressed in various
units (gal/hr, l/min, etc.) and may represent bulk flow rate fluid
though an entire conduit, or a vector flow rate at a point in a flow
field. The corresponding state property for the portion of fluid in
the vessel (OPB:Portion of fluid) is an instance of OPB:Amount
of fluid and would quantify the amount of a portion of fluid in,
say, pints or milliliters, or as fluid density (OPB:Volume density
of material).
      </p>
      <p>
        These properties are defined according to the stock-and-flow
kinetics as reciprocal relations whereby the amount of a stock is
equal to the temporal integral of the net flow rate of stuff into the
stock, and the net flow rate from the stock is the temporal
derivative of the amount in the stock:
amount = ∫ (flow rate) dt
flow rate = d/dt (amount)
The OPB represents subclasses of OPB:Amount property and of
OPB:Flow rate property for each of the six OPB:Dynamical
domains (Figure 3) as a dual inheritance hierarchy (
        <xref ref-type="bibr" rid="ref7">7</xref>
        ) based on
property kind (OPB:Dynamical property) and domain
(OPB:Dynamical domain). A less familiar but nonetheless
important, temporal relationship between is the one between
subclasses representing momentum (OPB:Dynamical momentum
property) and representing force (OPB:Dynamical force
property) that applies to material continuants analogously to that of
amount and flow rate. Hence, momentum = ∫ (force) dt, and force
= d/dt (momentum). These quantitative dependencies are
fundamental property value constraints of dynamical modeling
according to physical "laws".
      </p>
      <p>Figure 4 illustrates a representational choice that we have yet to
resolve as a "best practice". In the left hand panel, we show
OPB:Material density subclasses of OPB:Physical property
which include subclasses that scale material mass across lineal,
areal, and volumnal spatial spans. This representational strategy
"precoordinates" material amounts with spatial spans to represent
material spatial densities. The alternative representational
strategy is to annotate density properties by "postcoordinating" a
OPB:Material amount instance with an OPB:Property spatial
scope instance. The curatorial advantage of the latter strategy is
that it obviates explicitly representing every class that combines
property kind and a spatial scope. For annotating biophysical data
and model variables we adopted a post-coordination strategy to
solve the combinatoric explosion of attributing to every physical
entity class (e.g., FMA classes) each physical property class that
may apply. It remains to be determined whether pre- or
post-coordination best suits the representation of physical properties
variants in Figure 5.</p>
      <p>In effect, we have adopted a post-coordination strategy for
annotating data and variables, as needed, to declare their particular
attributes. Otherwise, the OPB would be burdened to a priori
represent all possible property instances rather than relying on
applications to annotate and interpret property attributes as are relevant
to a particular application. We welcome further discussion with
BFO community members to determine whether this approach
harmonizes with the representational logic underlying
BFO:Quality and its subclasses.</p>
      <sec id="sec-4-1">
        <title>Property expression variants</title>
        <p>All dynamical properties—masses, forces, flow rates, volumes,
etc.—exist and are quantifiable at every temporal instant for every
instance of a physical continuant or occurrence. In that sense,
such attributes are as real as the continuant or process property
that bears the value. A common problem is that an observed
property instance may be modeled differently by different modelers.
For example, different models could regard the same observed
force as a 3-dimensional vector quantity, as a scalar quantity, or
as a 2-dimensional array of surface-normal mechanical stresses.
Each representation readily transforms into the others, but they
must be distinguished by annotations.</p>
        <p>However, representing the specific physical meaning of a
physical property can be documented using subclasses of the
OPB:Physics property variant class (Figure 5).</p>
      </sec>
    </sec>
    <sec id="sec-5">
      <title>OPB:Dynamical dependencies</title>
      <p>
        Dynamical dependencies define and distinguish state and rate
properties across dynamical domains and do so in a widely
recognized network of properties and their dependencies (
        <xref ref-type="bibr" rid="ref17 ref20 ref9">9, 17, 20</xref>
        ).
The OPB network version is shown in Figure 6 where physical
property instances are represented as ovals and their physical
dependencies as arcs bearing rectangles. Dynamical dependencies
representing calculus functions (squares on left side of Figure 6)
are labeled "d/dt" for temporal derivatives (OPB:Temporal
derivative constraint) or "∫dt" for temporal integrals (OPB:Temporal
integral constraint).
OPB:Constraint dependency classes (see Figure 7) represent
conservation constraints as defined by the fundamental theorems of
calculus. For example, the net change in the value of a conserved
quantity within a spatial boundary, over a span of time, is a
temporal integral of the flow rate across that boundary. Thus,
OPB:Constraint dependency instances are purely mathematical
constraints on the value of a conserved quantity such as for a
volume change due to a fluid flow, a change in electrical charge due
to an electrical current, or the movement of an object for a certain
distance.
The OPB expresses these essential relations as flows
(OPB:Dynamical flow rate) and amounts (OPB:Dynamical
amount) as shown as ovals in Figure 6. The essential mathematics
of these relationships are that the temporal integral ("∫dt") of a
rate property value determines the resulting change in a
corresponding state property value (or, reciprocally, the temporal
differential ("d/dt") of a state property value to determine a rate
property).
      </p>
      <p>For example, the increment of fluid volume due to fluid inflow is
the flow rate times the interval of flow if the flow rate is constant.
If not constant, the change in volume is the (definite) temporal
integral of the flow rate as a function of time over the time
interval: ∆V = ∫F(t) dt. Or, by the mathematical inverse, the rate of
change of volume equals the fluid flow rate; dV/dt = F(t). By
analogy to the relationship of flow rates to amounts, there is a
corresponding, but less familiar dynamical relationship between forces
and momenta as diagrammed in the lower part of Figure 4. Such
analogies define state and rate dynamical properties across all
physical domains. These property/dependency relations are
mapped diagrammatically on the left side of Figure 4 as integrals
and derivatives.</p>
      <p>These figures represent all such domain-independent "stock and
flow" relationships between flow rates of stuff (OPB:Dynamical
flow rate) and the changes in the amount of stuff
(OPB:Dynamical amount). Some dependencies represent the
accumulation and depletion of stocks (e.g., material, charge,
momentum) due to inflows and outflows. These are represented by
subclasses of OPB:Temporal calculus constraint. OPB:Temporal
constraint (i.e., dx/dt) represents how the rate of change of the
amount of a stock equals the flow rate across the boundary of the
stock. And, inversely, OPB:Temporal integral (i.e., ∫xdt)
represents how much a the amount of a stock changes during a period
of time given the flow rate across its boundary. The
OPB:Temporal calculus constraint (Figure 5) also holds that any
material object (i.e., composed of matter) to which solid force or
fluid pressure is applied possesses momentum in proportion to its
mass, m, and velocity, v, such that their product, mv, is its
momentum (OPB:Translational momentum). Figure 4 shows that
such dependencies apply to the physical relationship between
forces and the momentum of a material object to which the force
is applied.</p>
      <p>
        These are examples of the fundamental importance of temporal
and spatial continua, and their continuous derivatives and
integrals to our understanding, representation, and analysis of
biodynamical systems. Yet, as we understand it, such temporal and
spatial derivatives and integrals have no representational support in
BFO (
        <xref ref-type="bibr" rid="ref15">15</xref>
        ).
      </p>
      <p>Issue 1: How to represent spatial and temporal
derivatives of the quantitative values of physical
properties?</p>
      <sec id="sec-5-1">
        <title>OPB:Constitutive dependency</title>
        <p>As opposed to OPB:Constraint dependency classes,
OPB:Constitutive dependency classes represent "constitutive
laws" that are known only by empirical observations and
descriptions. They may be simple linear relations as first described by
mid-nineteenth century scientists who identified the three
fundamental relations shown as arcs with rectangles in Figure 4. Such
constitutive laws may be characterized by linear coefficients such
as resistance (R) for Ohm's law, capacitance (C) for Faraday’s
law, and inductance (I) for Henry's law. These linear coefficients
are represented as subclasses of OPB:Constitutive proportionality
such as OPB:Fluid flow resistance. However, biophysical
phenomena and models are rife with non-proportional (i.e.,
nonlinear) constitutive dependencies such as for the Michaelis-Menten
enzyme kinetic model for which OPB includes classes such as
OPB:Property of non-proportional chemical rate law that
includes subclasses for “Km” and “Vmax”, the Michaelis-Menten
model parameters.</p>
      </sec>
      <sec id="sec-5-2">
        <title>Dependency network defines dynamical properties circularly</title>
        <p>The closed topology of the dependency network diagrammed in
Figure 4 has profound ontological implications for the
understanding of systems dynamics properties: 1) masses, flows, flow
resistances, etc. are defined in a manner that is entirely circular,
thus 2) no single property has primacy for defining and evaluation
other properties. Consequently, the calibration of physical
measurement devices depends on established standards such as those
of the Systeme Internationale (SI).</p>
      </sec>
    </sec>
    <sec id="sec-6">
      <title>Thermodynamical entities and dependencies</title>
      <p>Thermodynamics represents principles and constraints on
whether and how fast all biological processes occur. Yet the most
foundational thermodynamical quantity, energy, receives only
scant representation in available ontologies such as the BFO,
GFO, and other OBO ontologies. However, thermodynamics
principles are fundamental to all manner of biophysical processes
and physics-based analyses performed by bioengineers,
biophysicists, and physical biochemists.</p>
      <p>
        Thermodynamics is a facet of reality as expressed by its two key
thermodynamic quantities—energy and entropy—that are
defined and known solely by computations on observable physical
properties. Beyond such computations there are no other
definitions of these terms. As expressed by Nobel Prize-winning
physicist Richard Feynman (
        <xref ref-type="bibr" rid="ref19">19</xref>
        ):
"What we have discovered about energy is that we have
a scheme with a set of rules. From each set of rules we
can calculate a number for each kind of energy. When
we add all the numbers together, from all the different
kinds of energy, we always get the same total. But as far
as we know there are no real units, no little ball
bearings. It is abstract, purely mathematical that there is a
number such that when you calculate it, it does not
change. I cannot interpret it better than that."
      </p>
      <p>— Richard Feynman
Thus, energy, like other physical entities and properties, is an
entity with properties that exist and are discovered and defined as
entities and dependencies of classical physics. Despite their
ineffable natures, thermodynamic entities and their quantification are
inferred from values of dynamical properties according to the
values of observable amount and flow rates. Figures 8 and 9 show
some of these relationships, and some key definitions of
thermodynamical entities are as follows:
•
•
•</p>
      <p>OPB:Portion of kinetic energy — A portion of energy
proportional to velocity or rate of flow of a material or
electrical charge.</p>
      <p>OPB:Portion of potential energy — A portion of energy
proportional to the amount and displacement of a
dynamical entity in a potential energy field or potential
energy difference.</p>
      <sec id="sec-6-1">
        <title>OPB:Portion of entropy — A thermodynamic entity that is the extent that a process is thermodynamically reversible.</title>
        <p>—————</p>
        <p>
          Although thermodynamic quantities and terms are invoked
technically ("horsepower", "solar energy") and colloquially ("feel the
burn"), in fact thermodynamic quantities and flows are
themselves invisible and, per Feynman, are defined and quantified
solely as mathematical functions. Yet the "reality" of
thermodynamic energy is hardly debatable. First, thermodynamic energy is
a conserved quantity just as is matter. Second, thermodynamic
laws apply universally across all spatiotemporal scales from
subatomic particles, to biological organisms, to astrophysics.
The utility of thermodynamics-based dynamical analysis has long
been appreciated (
          <xref ref-type="bibr" rid="ref17 ref20 ref21">17, 20, 21</xref>
          ) and has recently received
computational support as multidomain biophysical modeling using
socalled "bond graph theory" (
          <xref ref-type="bibr" rid="ref16">16</xref>
          ). Thus, we have recently focused
on a thorough representation of the entities, properties, and
dependencies that represent the foundations of classical
thermodynamics.
        </p>
        <p>Building from Figure 4, Figure 9 shows a schematic view of how
thermodynamic entities are derived from the more basic ideas of
forces, flows, amounts and momenta. Also represented in Figure
9, is that a dynamical flow rate times an applied force is
partitioned between flow of heat energy (Q, as for frictional losses) or
power (P, useful work rate) depending on the specific
physiological mechanism.</p>
        <p>Issue 2: How "real" are energy and entropy given that
they are defined and evaluated only by physical
dependencies of the values of observable properties?</p>
      </sec>
    </sec>
    <sec id="sec-7">
      <title>OPB:Dynamical process as energy flow</title>
      <p>The mappings of Figure 9 suggest that a fundamental feature of
real biophysical systems is that nothing happens or occurs without
the flow and dissipation of energy. As a simple example, consider
an elastic basketball that is dropped from some height. As the ball
accelerates toward the ground, its gravitational potential energy
(proportional to its elevation) is converted to kinetic energy
(proportional to its momentum times velocity; as in Figure 9). On
impacting the pavement, the accumulated kinetic energy is
converted to elastic potential energy as the ball and the earth are
deformed by contact forces. Once deformation is complete, then the
elastic forces accelerate the ball upwards as the elastic potential
energy is converted to kinetic energy. The cycle of falling and
rebounding would be perpetual but for the friction of air flow
around the ball with consequent heat dissipation and entropy
production.</p>
      <p>These entities and relations are the basis for analyzing multiscale,
multidomain processes throughout biomedicine from molecular
biophysics to cardiovascular function to skeletal biomechanics.
The overriding principle is that nothing flows, moves, accelerates,
or changes shape without the flow and dissipation of energy. This
observation has suggested to us a biophysics-based definition of
OPB:Dynamical process as "A physics occurrent that is the flow
or exchange of matter and/or energy amongst dynamical entities
that are participants in the process."
The broad notion is that biological continuants are physical things
that change only by virtue of the flow and dissipation of energy.
Whether material entities are being synthesized, participating in
processes, or are being degraded, energy is flowing and being
dissipated (as entropy as in Figure 9). Even in a steady-state situation
during which there are no changes in, say, chemical
concentration, muscle length, or blood flow rate, energy is flowing and
being dissipated. This definition is inclusive because it applies to all
manner of physical participants in all physical domains and
scales. It also satisfies the notion that no real physical process can
occur without the flow and expenditure of energy (OPB:Portion
of energy) with an attendant increase of entropy (OPB:Portion of
entropy).</p>
      <p>
        Each dynamical process class specifies the structural class of each
process participant, the specific dynamical properties of each
process participant, the dependencies (e.g., physical law) amongst
those properties, and flow rates of energy that constitute the
process. This is a fine-grained, physics-based approach that we use
to identify, annotate, and reason over biophysical mechanisms as
computationally modeled in the Physiome and other projects (
        <xref ref-type="bibr" rid="ref11 ref12 ref13">11,
12, 13</xref>
        ). Key subclasses of OPB:Dynamical process are shown in
Figure 10.
Issue 3: Can the OPB's system dynamical perspective
rationalize and simplify the classification of biological
processes according to energy types and flows?
The OPB is an ontology of classical physics as applied to
problems in biomedical research, biophysical analysis, and
mathematical modeling. It represents foundational aspects of classical
physics, engineering system dynamics, and thermodynamics of
biological entities, systems and their processes. Whereas it takes
inspiration from the "realist" representational framework of the
BFO, it expresses and formalizes principles of system dynamics
and thermodynamics that are the bases of dynamical analysis of
biological processes.
      </p>
      <p>
        The OPB builds on and extends the "realist" ontological
foundations of BFO to represent classical physics as a computational
ontology. We routinely computationally integrate OPB and
BFObased OBO ontologies to annotate and compute across the
continuants, processes, and physical properties of biophysical models
(
        <xref ref-type="bibr" rid="ref12 ref13 ref14">12, 13, 14</xref>
        ). Thus, we can demonstrate computational
compatibility of BFO and OPB.
      </p>
      <p>
        However, we are concerned with ontological incompatibilities
that exist when representing physical entities, physical properties,
and the laws of classical physics in the context of BFO realism.
We have four concerns as raised in prior sections and relate them
to those raised by Lord and Stevens (
        <xref ref-type="bibr" rid="ref15">15</xref>
        ).
      </p>
      <sec id="sec-7-1">
        <title>OPB:Physical property classes include temporal, spatial, and spatiotemporal derivatives of physical property values.</title>
        <p>
          Such mathematical functions are absolutely critical to the
representation and analysis of dynamical physical systems, beginning
with the definition of "velocity" as the differential rate of change
of position per unit time at any instant in time. A central concept
from calculus, per Newton and Leibniz, is to reframe the
definition so that the velocity at a point in time (or place in space) is the
limit of the ratio of ∆x/∆t as ∆t approaches zero duration.
Conversely, the change of location (∆x) of an entity is the temporal
integral ∆x = ∫vdt over a span of time ∆t. Generalizations of such
calculus-based quantitative relationships pervade all manner of
analytical modeling systems, both as ordinary differential
equations (ODE) and, more generally, as partial differential equations
(PDE). OPB offers these classes not as actual computations on
the property values but simply as qualitative dependencies so that,
for example, a derivative computation in a mathematical model
(e.g., dx/dt) would have a positive value if the value x was
calculated to increase over a time interval. Lord and Stevens (
          <xref ref-type="bibr" rid="ref15">15</xref>
          ) offer
additional examples of differentials that have no representation in
realism.
        </p>
      </sec>
      <sec id="sec-7-2">
        <title>OPB:Dynamical dependency classes represent quantitative dependencies of physical property values upon each other according to constraint axioms and laws of physics.</title>
        <p>The OPB:Dynamical dependency classes represent all manner of
rules, observations, intuitions, or hard-and-fast physical laws. As
a simple example, a dynamical dependency instance can represent
an empirical finding that when a patient consumes more
carbohydrate their blood glucose level increases for a span of time. From
this observation, one might derive a mathematical model that
approximates the observed changes using an analytical model that
also represents an (empirical) dependency of blood glucose on the
rate of sugar uptake into the blood.</p>
        <p>Some dependencies are instances of OPB:Conservation
dependency that express fundamental axioms such as for conservation of
mass or energy. Others constraints are instances of
OPB:Constitutive dependencies that represent empirically
observed dependencies such as for "Ohm's Law" which is a
relationship between an electrical current (I) and the electrical voltage (V)
across an electrical conducting pathway (see Figure 4). In an
"ideal" case, Ohm's law represents I-V relations as linear, as for
electrical circuits elements. However, the I-V constitutive
dependency of cell membrane ion channel current flow is usually
quite nonlinear as well as time-dependent. In OPB such specific
cases are representable as subclasses of OPB: Dynamical
dependency.</p>
        <p>OPB:Thermodynamical entity and dependency classes
represent thermodynamic properties and property value
dependencies according to the laws of thermodynamics.
One key issue between classical physics and BFO realism is that
from the perspective of physics, thermodynamic energy appears
to be just as "real" as matter in that: 1) both are subject to a
universal law of conservation and can be neither created nor
destroyed, and 2) the amount of each is fully determined by
mathematical functions of the values of other dynamical
properties as mapped in Figure 9.</p>
        <p>
          Although the formal, quantitative definitions of thermodynamic
quantities (e.g., heat, work, entropy, kinetic energy) are less
familiar than dynamical quantities (velocity, amount, momentum,
etc.), thermodynamical analyses have profound power for
representing and constraining dynamical analyses. Thus,
important modeling approaches have included these concepts (
          <xref ref-type="bibr" rid="ref16 ref17 ref18 ref21">16,
17, 18, 21</xref>
          ).
        </p>
        <p>A major concern for representing thermodynamic energy in a
realist context is that because it can be neither created nor
destroyed (i.e., conserved) it would seem to be some kind of
BFO:Continuant and more specifically, an instance of
BFO:Immaterial entity such as a spatial region of 0, 1, 2, or
3dimensions. However, two issues arise when considering energy
entities with respect to the BFO stricture that all spatial entities
are spatially bound. First, potential energy fields such as for
gravitional potential or electrical potential fields can extend
spatially without limit. Second, it is not clear just where the
energy in a field resides as it exists only by virtue of a
displacement of charge or material within the field.</p>
        <p>Issue 4: How "real" are physical laws that consist
entirely of mathematical functions of the values of
observable physical properties?
OPB:Dynamical processes are defined as the flow energy or
information amongst participants in such processes.
Every biophysical process, whether a molecular reaction, a flow
of blood, or exocytosis of a hormone granule occurs because it is
energetically favorable to do so and will stop if the energy sources
are depleted. This simple notion is pervasive for all scales and
domains and applies as well to muscle flexion as to glucose
phosphorylation. We therefore define physical processes as the flow
of thermodynamic energy. This notion offers attractive features
by providing a means to: 1) calculate an energy expenditure for
each process according to, say, metabolic energy output and
contractile energy consumption, 2) trace causal pathways according
to how energy is exchanged amongst system components. We
have begun to implement this idea by defining OPB:Dynamical
process as "A physics occurrent that is the flow or exchange of
matter and/or energy amongst dynamical entities that are
participants in the process."
We have reviewed our implementation and use of the Ontology
of Physics for Biology with an eye to maintaining as much
consistency as possible with the realist orientation of the Basic
Formal Ontology (BFO). However, whereas the OPB has benefitted
greatly from the BFO formalism, there are concepts central to the
representation of classical physics that are difficult to fit into the
realist perspective. Consequently, we consider the OPB to be an
orthogonal companion ontology to BFO. Given wider use and
maturity of the evolving OPB, we seek to enhance BFO-OPB
interoperability in support of semantic annotation, logical
inference, and quantitative analysis of complex, multiscale,
multidomain biological systems.</p>
      </sec>
    </sec>
    <sec id="sec-8">
      <title>Acknowledgments</title>
      <p>We thank Cornelius Rosse, Onard Mejino, and Fred Bookstein for
early guidance and support, and Robert Hoehendorf and George
Gkoutos for collaborations and discussion. This research was
supported by NIH grants #P41EB023912 and #R01LM011969.</p>
    </sec>
    <sec id="sec-9">
      <title>Address for correspondence</title>
    </sec>
  </body>
  <back>
    <ref-list>
      <ref id="ref1">
        <mixed-citation>
          1.
          <string-name>
            <surname>Hodgkin</surname>
            ,
            <given-names>A.L.</given-names>
          </string-name>
          and
          <string-name>
            <given-names>A.F.</given-names>
            <surname>Huxley</surname>
          </string-name>
          ,
          <article-title>A quantitative description of membrane current and its application to conduction and excitation in nerve</article-title>
          .
          <source>J Physiol</source>
          ,
          <year>1952</year>
          .
          <volume>117</volume>
          (
          <issue>4</issue>
          ): p.
          <fpage>500</fpage>
          -
          <lpage>44</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref2">
        <mixed-citation>
          2.
          <string-name>
            <surname>Michaelis</surname>
            ,
            <given-names>L.</given-names>
          </string-name>
          , et al.,
          <article-title>The original Michaelis constant: translation of the 1913 Michaelis-Menten paper</article-title>
          .
          <source>Biochemistry</source>
          ,
          <year>2011</year>
          .
          <volume>50</volume>
          (
          <issue>39</issue>
          ): p.
          <fpage>8264</fpage>
          -
          <lpage>9</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref3">
        <mixed-citation>
          3.
          <string-name>
            <surname>Crampin</surname>
            ,
            <given-names>E.J.</given-names>
          </string-name>
          ,
          <string-name>
            <given-names>N.P.</given-names>
            <surname>Smith</surname>
          </string-name>
          ,
          <string-name>
            <given-names>and P.J.</given-names>
            <surname>Hunter</surname>
          </string-name>
          <article-title>, Multi-scale modelling and the IUPS physiome project</article-title>
          .
          <source>J Mol Histol</source>
          ,
          <year>2004</year>
          .
          <volume>35</volume>
          (
          <issue>7</issue>
          ): p.
          <fpage>707</fpage>
          -
          <lpage>14</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref4">
        <mixed-citation>
          4.
          <string-name>
            <surname>Hunter</surname>
            ,
            <given-names>P.</given-names>
          </string-name>
          , et al.,
          <article-title>Integration from proteins to organs: the IUPS Physiome Project</article-title>
          .
          <source>Mech Ageing Dev</source>
          ,
          <year>2005</year>
          .
          <volume>126</volume>
          (
          <issue>1</issue>
          ): p.
          <fpage>187</fpage>
          -
          <lpage>92</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref5">
        <mixed-citation>
          5.
          <string-name>
            <surname>Fenner</surname>
            ,
            <given-names>J.W.</given-names>
          </string-name>
          , et al.,
          <string-name>
            <surname>The</surname>
            <given-names>EuroPhysiome</given-names>
          </string-name>
          ,
          <article-title>STEP and a roadmap for the virtual physiological human</article-title>
          .
          <source>Phil. Trans. R. Soc. A</source>
          ,
          <year>2008</year>
          .
          <volume>366</volume>
          : p.
          <fpage>2979</fpage>
          -
          <lpage>2999</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref6">
        <mixed-citation>
          6.
          <string-name>
            <surname>Arp</surname>
            , R.,
            <given-names>B.</given-names>
          </string-name>
          <string-name>
            <surname>Smith</surname>
            , and
            <given-names>A.</given-names>
          </string-name>
          <string-name>
            <surname>Spear</surname>
          </string-name>
          ,
          <article-title>Building Ontologies with Basic Formal Ontology2015</article-title>
          , Cambridge, MA: The MIT Press.
        </mixed-citation>
      </ref>
      <ref id="ref7">
        <mixed-citation>
          7.
          <string-name>
            <surname>Cook</surname>
            ,
            <given-names>D.L.</given-names>
          </string-name>
          ,
          <string-name>
            <given-names>F.L.</given-names>
            <surname>Bookstein</surname>
          </string-name>
          , and
          <string-name>
            <given-names>J.H.</given-names>
            <surname>Gennari</surname>
          </string-name>
          ,
          <article-title>Physical Properties of Biological Entities: An Introduction to the Ontology of Physics for Biology</article-title>
          .
          <source>PLoS ONE</source>
          ,
          <year>2011</year>
          .
          <volume>6</volume>
          (
          <issue>12</issue>
          ): p.
          <fpage>e28708</fpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref8">
        <mixed-citation>
          8.
          <string-name>
            <surname>Cook</surname>
            ,
            <given-names>D.L.</given-names>
          </string-name>
          , et al.,
          <article-title>Ontology of physics for biology: representing physical dependencies as a basis for biological processes</article-title>
          .
          <source>Journal of Biomedical Semantics</source>
          ,
          <year>2013</year>
          .
          <volume>4</volume>
          (
          <issue>12</issue>
          ): p.
          <fpage>41</fpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref9">
        <mixed-citation>
          9.
          <string-name>
            <surname>Borst</surname>
            ,
            <given-names>P.</given-names>
          </string-name>
          , H. Akkermans, and
          <string-name>
            <given-names>J.</given-names>
            <surname>Top</surname>
          </string-name>
          , Engineering ontologies. Int. J.
          <string-name>
            <surname>Human-Computer Studies</surname>
          </string-name>
          ,
          <year>1997</year>
          .
          <volume>46</volume>
          : p.
          <fpage>365</fpage>
          -
          <lpage>406</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref10">
        <mixed-citation>
          10.
          <string-name>
            <surname>Gruber</surname>
            , T.R. and
            <given-names>G.R.</given-names>
          </string-name>
          <string-name>
            <surname>Olsen</surname>
          </string-name>
          .
          <article-title>An Ontology for Engineering Mathematics</article-title>
          . in
          <source>Fourth International Conference on Principles of Knowledge Representation and Reasoning</source>
          .
          <year>1994</year>
          . Gustav Stressman Institut, Bonn, Germany: Morgan Kaufmann.
        </mixed-citation>
      </ref>
      <ref id="ref11">
        <mixed-citation>
          11.
          <string-name>
            <surname>Cook</surname>
            ,
            <given-names>D.L.</given-names>
          </string-name>
          , et al.
          <article-title>HeartCyc, a cardiac cycle process ontology based in the Ontology of Physics for Biology</article-title>
          .
          <source>in 2nd International Conference on Biomedical Ontology (ICBO-2011)</source>
          .
          <year>2011</year>
          . Buffalo, NY.
        </mixed-citation>
      </ref>
      <ref id="ref12">
        <mixed-citation>
          12.
          <string-name>
            <surname>Neal</surname>
            ,
            <given-names>M.L.</given-names>
          </string-name>
          ,
          <string-name>
            <given-names>D.L.</given-names>
            <surname>Cook</surname>
          </string-name>
          , and
          <string-name>
            <given-names>J.H.</given-names>
            <surname>Gennari</surname>
          </string-name>
          .
          <article-title>An OWL knowledge base for classifying and querying collections of physiological models: A prototype human physiome</article-title>
          .
          <source>in International Conference on Biomedical Ontology</source>
          <year>2013</year>
          (
          <article-title>ICBO2013</article-title>
          ).
          <year>2013</year>
          . Montreal, Ont, CA: CEUR-WS:
          <fpage>24</fpage>
          -Nov-
          <year>2013</year>
          .
        </mixed-citation>
      </ref>
      <ref id="ref13">
        <mixed-citation>
          13.
          <string-name>
            <surname>Neal</surname>
            ,
            <given-names>M.L.</given-names>
          </string-name>
          ,
          <string-name>
            <given-names>J.H.</given-names>
            <surname>Gennari</surname>
          </string-name>
          , and
          <string-name>
            <given-names>D.L.</given-names>
            <surname>Cook</surname>
          </string-name>
          .
          <article-title>Qualitative causal analyses of biosimulation models</article-title>
          .
          <source>in International Conference on Biomedical Ontology and BioCreative</source>
          .
          <year>2016</year>
          . Corvallis,
          <string-name>
            <surname>OR</surname>
          </string-name>
          , USA: CEUR-ws.org Volume
          <volume>1747</volume>
          .
        </mixed-citation>
      </ref>
      <ref id="ref14">
        <mixed-citation>
          14.
          <string-name>
            <surname>Neal</surname>
            ,
            <given-names>M.L.</given-names>
          </string-name>
          , et al.,
          <article-title>Semantics-Based Composition of Integrated Cardiomyocyte Models Motivated by RealWorld Use Cases</article-title>
          .
          <source>PLoS One</source>
          ,
          <year>2015</year>
          .
          <volume>10</volume>
          (
          <issue>12</issue>
          ): p.
          <fpage>e0145621</fpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref15">
        <mixed-citation>
          15.
          <string-name>
            <surname>Lord</surname>
            ,
            <given-names>P.</given-names>
          </string-name>
          and
          <string-name>
            <given-names>R.</given-names>
            <surname>Stevens</surname>
          </string-name>
          ,
          <article-title>Adding a little reality to building ontologies for biology</article-title>
          .
          <source>PLoS One</source>
          ,
          <year>2010</year>
          .
          <volume>5</volume>
          (
          <issue>9</issue>
          ): p.
          <fpage>e12258</fpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref16">
        <mixed-citation>
          16.
          <string-name>
            <surname>Gawthrop</surname>
            ,
            <given-names>P.</given-names>
          </string-name>
          and
          <string-name>
            <given-names>E.J.</given-names>
            <surname>Crampin</surname>
          </string-name>
          ,
          <article-title>Bond Graph Representation of Chemical Reaction Networks</article-title>
          .
          <source>IEEE Trans Nanobioscience</source>
          ,
          <year>2018</year>
          .
          <volume>17</volume>
          (
          <issue>4</issue>
          ): p.
          <fpage>449</fpage>
          -
          <lpage>455</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref17">
        <mixed-citation>
          17.
          <string-name>
            <surname>Karnopp</surname>
            ,
            <given-names>D.</given-names>
          </string-name>
          ,
          <article-title>Bond graph techniques for dynamic systems in engineering</article-title>
          and biology,
          <year>1979</year>
          , New York: Pergamon Press.
        </mixed-citation>
      </ref>
      <ref id="ref18">
        <mixed-citation>
          18.
          <string-name>
            <surname>Le Rolle</surname>
            ,
            <given-names>V.</given-names>
          </string-name>
          , et al.,
          <article-title>A bond graph model of the cardiovascular system</article-title>
          .
          <source>Acta Biotheor</source>
          ,
          <year>2005</year>
          .
          <volume>53</volume>
          (
          <issue>4</issue>
          ): p.
          <fpage>295</fpage>
          -
          <lpage>312</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref19">
        <mixed-citation>
          19.
          <string-name>
            <surname>Feynman</surname>
            ,
            <given-names>R.</given-names>
          </string-name>
          ,
          <source>The Character of Physical Law1994: Modern Library.</source>
        </mixed-citation>
      </ref>
      <ref id="ref20">
        <mixed-citation>
          20.
          <string-name>
            <surname>Perelson</surname>
            ,
            <given-names>A.S.</given-names>
          </string-name>
          ,
          <article-title>Network thermodynamics. An overview</article-title>
          .
          <source>Biophys J</source>
          ,
          <year>1975</year>
          .
          <volume>15</volume>
          (
          <issue>7</issue>
          ): p.
          <fpage>667</fpage>
          -
          <lpage>685</lpage>
          .
        </mixed-citation>
      </ref>
      <ref id="ref21">
        <mixed-citation>
          21.
          <string-name>
            <surname>Beard</surname>
            ,
            <given-names>D.A.</given-names>
          </string-name>
          ,
          <article-title>A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation</article-title>
          .
          <source>PLOS Computational Biology</source>
          ,
          <year>2005</year>
          .
          <volume>2</volume>
          (
          <issue>1</issue>
          ).
        </mixed-citation>
      </ref>
    </ref-list>
  </back>
</article>