From c73d3c008acd591d67471c478366c584a2efd562 Mon Sep 17 00:00:00 2001
From: Abigail R Watson <awatson@mitre.org>
Date: Fri, 8 Dec 2023 11:10:14 -0500
Subject: [PATCH] valid SBML

---
 .../physiology/models/Cortisol_Depression.xml | 239 ++++++++++++++----
 1 file changed, 194 insertions(+), 45 deletions(-)

diff --git a/src/main/resources/physiology/models/Cortisol_Depression.xml b/src/main/resources/physiology/models/Cortisol_Depression.xml
index 2ca887080c..86471677a9 100644
--- a/src/main/resources/physiology/models/Cortisol_Depression.xml
+++ b/src/main/resources/physiology/models/Cortisol_Depression.xml
@@ -5,14 +5,127 @@
       <compartment id="CNS" name="Central Nervous System" constant="true"/>
       <compartment id="HPA_Axis" name="Hypothalamic-Pituitary-Adrenal Axis" constant="true"/>
     </listOfCompartments>
+    <listOfFunctionDefinitions>
+        <functionDefinition id="step_function">
+            <math xmlns="http://www.w3.org/1998/Math/MathML">
+                <lambda>
+                    <bvar><ci>x</ci></bvar>
+                    <bvar><ci>T</ci></bvar>
+                    <bvar><ci>a</ci></bvar>
+                    <bvar><ci>b</ci></bvar>
+                    <piecewise>
+                        <piece>
+                            <apply>
+                                <plus/>
+                                <ci>a</ci>
+                                <ci>b</ci>
+                            </apply>
+                            <apply>
+                                <geq/>
+                                <ci>x</ci>
+                                <ci>T</ci>
+                            </apply>
+                        </piece>
+                        <otherwise>
+                            <ci>a</ci>
+                        </otherwise>
+                    </piecewise>
+                </lambda>
+            </math>
+        </functionDefinition>
+        <functionDefinition id="MR_function">
+            <math xmlns="http://www.w3.org/1998/Math/MathML">
+                <lambda>
+                    <bvar><ci>a</ci></bvar>
+                    <ci>a</ci> <!-- The function returns the input as output -->
+                </lambda>
+            </math>
+        </functionDefinition>
+        <functionDefinition id="GR_function">
+            <math xmlns="http://www.w3.org/1998/Math/MathML">
+                <lambda>
+                    <bvar><ci>a</ci></bvar>
+                    <bvar><ci>kGR</ci></bvar>
+                    <apply>
+                        <plus/>
+                        <apply>
+                            <power/>
+                            <apply>
+                                <divide/>
+                                <ci>a</ci>
+                                <ci>kGR</ci>
+                            </apply>
+                            <cn type="integer"> 3 </cn>
+                        </apply>
+                        <cn type="integer"> 1 </cn>
+                    </apply>
+                </lambda>
+            </math>
+        </functionDefinition>
+    </listOfFunctionDefinitions>
+    <listOfParameters>
+        <!-- 0.016*60*24 -->
+        <parameter id="a1_ext" value="23.04" constant="true"/>
+
+        <!-- 0.17*60*24 -->
+        <parameter id="a1" value="244.8" constant="true"/>
+        
+        <!-- 0.035*60*24 -->
+        <parameter id="a2" value="50.4" constant="true"/>
+        
+        <!-- 0.0086*60*24 -->
+        <parameter id="a3" value="12.384" constant="true"/>
+
+        <parameter id="a5" value="0.099" constant="true"/>
+        <parameter id="a6" value="0.099" constant="true"/>
 
+        <!-- 1/21 -->
+        <parameter id="a7" value="0.047619047619048" constant="true"/>
+    </listOfParameters>
     <listOfSpecies>
-      <species id="Cortisol" compartment="HPA_Axis" initialAmount="1" constant="false"/>
-      <species id="HPA_Hormone_Glands" compartment="HPA_Axis" initialAmount="1" constant="false"/>
-      <species id="Neurotransmitters" compartment="CNS" initialAmount="1" constant="false"/>
-      <species id="Stress_Indicators" compartment="CNS" initialAmount="1" constant="false"/>
-    </listOfSpecies>
+        <species id="Cortisol" compartment="HPA_Axis" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="HPA_Hormone_Glands" compartment="HPA_Axis" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="Neurotransmitters" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true"  />
+        <species id="Stress_Indicators" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
 
+        <species id="A" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="P" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+        <species id="x2" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="x3" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+        <species id="h" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="D_t" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="u_t" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+        <!-- <species id="a1" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="a2" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="a3" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="a5" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="a6" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="a7" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" /> -->
+
+        <species id="x1_tot" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="x1_internal" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="x1_external" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="x1_dose" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+
+        <species id="dA_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="dP_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="dh_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="dx1_internal_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="dx2_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="dx3_dt" compartment="CNS" initialAmount="1" constant="false" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+        <species id="a" compartment="CNS" constant="true" initialAmount="1" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="b" compartment="CNS" constant="true" initialAmount="3" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="T" compartment="CNS" constant="true" initialAmount="1.5" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+        <species id="kGR" compartment="CNS" constant="true" initialAmount="4" hasOnlySubstanceUnits="false" boundaryCondition="true" />
+
+    </listOfSpecies>
+    
     <listOfReactions>
       <!-- Reactions would be defined here with kinetic laws. -->
       <!-- Example: -->
@@ -23,13 +136,14 @@
       <!-- Adrenal_Gland_Activity -->
       <!-- dA_dt = a5*A*(x2 - 1) -->
 
-      <reaction id="Adrenal_Gland_Activity">
+      <reaction id="Adrenal_Gland_Activity" reversible="false" fast="false">
         <listOfReactants>
-            <speciesReference species="A" stoichiometry="1"/>
-            <speciesReference species="x2" stoichiometry="1"/>
+            <speciesReference constant="false" species="A" stoichiometry="1"/>
+            <speciesReference constant="false" species="x2" stoichiometry="1"/>
+            <!-- <speciesReference constant="false" species="a5" stoichiometry="1"/> -->
         </listOfReactants>
         <listOfProducts>
-            <speciesReference species="A" stoichiometry="1"/>
+            <speciesReference constant="false" species="dA_dt" stoichiometry="1"/>
         </listOfProducts>
         <kineticLaw>
             <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -51,13 +165,14 @@
       <!-- Pituitary_Gland_Activity -->
       <!-- dP_dt = a6*P*(x1_tot - 1) -->
 
-        <reaction id="Pituitary_Gland_Activity">
+        <reaction id="Pituitary_Gland_Activity" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="P" stoichiometry="1"/>
-                <speciesReference species="x1_tot" stoichiometry="1"/>
+                <!-- <speciesReference constant="false" species="a6" stoichiometry="1"/> -->
+                <speciesReference constant="false" species="P" stoichiometry="1"/>
+                <speciesReference constant="false" species="x1_tot" stoichiometry="1"/>
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="P" stoichiometry="1"/>
+                <speciesReference constant="false" species="dP_dt" stoichiometry="1"/>
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -76,16 +191,26 @@
         </reaction>
 
 
-      <!-- Hippocampal_Activity -->
-      <!-- dh_dt = a7*(1*D_t/step(x3,T) - h) -->
 
-        <reaction id="Hippocampal_Activity">
+
+        <!-- Hippocampal_Activity -->
+        <!-- dh_dt = a7*(1*D_t/step(x3,T) - h) -->
+
+
+        <reaction id="Hippocampal_Activity" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="h" stoichiometry="1"/>
-                <speciesReference species="x3" stoichiometry="1"/>
+                <speciesReference constant="false" species="T" stoichiometry="1"/>
+                <!-- <speciesReference constant="false" species="a7" stoichiometry="1"/> -->
+                <speciesReference constant="false" species="D_t" stoichiometry="1"/>
+                <speciesReference constant="false" species="h" stoichiometry="1"/>
+                <speciesReference constant="false" species="x3" stoichiometry="1"/>
+
+                <speciesReference constant="false" species="a" stoichiometry="1"/>
+                <speciesReference constant="false" species="b" stoichiometry="1"/>
+
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="h" stoichiometry="1"/>
+                <speciesReference constant="false" species="dh_dt" stoichiometry="1"/>
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -101,6 +226,8 @@
                                     <ci> step_function </ci>
                                     <ci> x3 </ci>
                                     <ci> T </ci>
+                                    <ci> a </ci>
+                                    <ci> b </ci>
                                 </apply>
                             </apply>
                         </apply>
@@ -113,15 +240,19 @@
 
       <!-- dx1_internal_dt = a1*(u_t/(h*MR(x3)*GR(x3)) - x1_internal) -->
 
-        <reaction id="CRH_Internal_Dynamics">
+        <reaction id="CRH_Internal_Dynamics" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="x1_internal" stoichiometry="1"/>
-                <speciesReference species="u_t" stoichiometry="1"/> <!-- Assuming u_t is a species -->
-                <speciesReference species="h" stoichiometry="1"/>
-                <speciesReference species="x3" stoichiometry="1"/>
+                <!-- <speciesReference constant="false" species="a1" stoichiometry="1"/> -->
+                <speciesReference constant="false" species="x1_internal" stoichiometry="1"/>
+                <speciesReference constant="false" species="u_t" stoichiometry="1"/> <!-- Assuming u_t is a species -->
+                <speciesReference constant="false" species="h" stoichiometry="1"/>
+                <speciesReference constant="false" species="x3" stoichiometry="1"/>
+
+                <speciesReference constant="true" species="a"/>
+                <speciesReference constant="true" species="kGR"/>
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="x1_internal" stoichiometry="1"/>
+                <speciesReference constant="false" species="dx1_internal_dt" stoichiometry="1"/>
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -136,9 +267,16 @@
                                 <apply>
                                     <times/>
                                     <ci> h </ci>
-                                    <ci> MR_function </ci>
+                                    <apply>
+                                        <ci> MR_function </ci>
+                                        <ci> a </ci>
+                                    </apply>
                                     <ci> x3 </ci>
-                                    <ci> GR_function </ci>
+                                    <apply>
+                                        <ci> GR_function </ci>
+                                        <ci> a </ci>
+                                        <ci> kGR </ci>
+                                    </apply>
                                     <ci> x3 </ci>
                                 </apply>
                             </apply>
@@ -152,13 +290,16 @@
 
         <!-- dx1_internal_dt = a1*(u_t/(h*MR(x3)*GR(x3)) - x1_internal) -->
 
-        <reaction id="CRH_External_Dynamics">
+        <reaction id="CRH_External_Dynamics" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="x1_external" stoichiometry="1"/>
-                <speciesReference species="x1_dose" stoichiometry="1"/> <!-- Assuming x1_dose is a species or input function -->
+                <!-- <speciesReference constant="false" species="a1" stoichiometry="1"/> -->
+                <speciesReference constant="false" species="u_t" stoichiometry="1"/>
+                <speciesReference constant="false" species="x3" stoichiometry="1"/>
+                <speciesReference constant="false" species="x1_external" stoichiometry="1"/>
+                <speciesReference constant="false" species="x1_dose" stoichiometry="1"/> <!-- Assuming x1_dose is a species or input function -->
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="x1_external" stoichiometry="1"/>
+                <speciesReference constant="false" species="dx1_internal_dt" stoichiometry="1"/>
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -178,17 +319,21 @@
             </kineticLaw>
         </reaction>
 
-        <!-- dx2_dt = a2*(x1_tot*P/GR(x3) - x2) -->
+        <!-- dx2_dt = a2 * (x1_tot * P / GR(x3) - x2) -->
 
-        <reaction id="CRH_to_ACTH_Dynamics">
+        <reaction id="CRH_to_ACTH_Dynamics" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="x2" stoichiometry="1"/>
-                <speciesReference species="x1_tot" stoichiometry="1"/>
-                <speciesReference species="P" stoichiometry="1"/>
-                <speciesReference species="x3" stoichiometry="1"/> <!-- For GR function -->
+                <!-- <speciesReference constant="false" species="a2" stoichiometry="1"/> -->
+                <speciesReference constant="false" species="x2" stoichiometry="1"/>
+                <speciesReference constant="false" species="x1_tot" stoichiometry="1"/>
+                <speciesReference constant="false" species="P" stoichiometry="1"/>
+                <speciesReference constant="false" species="x3" stoichiometry="1"/> <!-- For GR function -->
+
+                <speciesReference constant="true" species="a"/>
+                <speciesReference constant="true" species="kGR"/>
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="x2" stoichiometry="1"/>
+                <speciesReference constant="false" species="dx2_dt" stoichiometry="1"/>
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">
@@ -204,8 +349,11 @@
                                     <ci> x1_tot </ci>
                                     <ci> P </ci>
                                 </apply>
-                                <ci> GR_function </ci>
-                                <ci> x3 </ci>
+                                <apply>
+                                    <ci> GR_function </ci>
+                                    <ci> x3 </ci>
+                                    <ci> kGR </ci>
+                                </apply>
                             </apply>
                         </apply>
                         <ci> x2 </ci>
@@ -216,14 +364,15 @@
 
         <!-- dx3_dt = a3*(x2*A - x3) -->
 
-        <reaction id="ACTH_to_Cortisol_Dynamics">
+        <reaction id="ACTH_to_Cortisol_Dynamics" reversible="false" fast="false">
             <listOfReactants>
-                <speciesReference species="x3" stoichiometry="1"/>
-                <speciesReference species="x2" stoichiometry="1"/>
-                <speciesReference species="A" stoichiometry="1"/>
+                <!-- <speciesReference constant="false" species="a3" stoichiometry="1" /> -->
+                <speciesReference constant="false" species="x3" stoichiometry="1" />
+                <speciesReference constant="false" species="x2" stoichiometry="1" />
+                <speciesReference constant="false" species="A" stoichiometry="1" />
             </listOfReactants>
             <listOfProducts>
-                <speciesReference species="x3" stoichiometry="1"/>
+                <speciesReference constant="false" species="dx3_dt" stoichiometry="1" />
             </listOfProducts>
             <kineticLaw>
                 <math xmlns="http://www.w3.org/1998/Math/MathML">