Updated model

data/boolean_network/cd8t_cell.cfg

@@ -4,7 +4,7 @@ discrete_time = 0;
 use_physrandgen = FALSE;
 seed_pseudorandom = 100;
 
-max_time = 1;
-time_tick = 0.1;
+max_time = 10;
+time_tick = 1;
 
 Active.is_internal = FALSE;

data/boolean_network/epithelial_cell.bnd

@@ -8,4 +8,228 @@ Node Virus_replication {
 
 Node Chemokin_secretion {
 	logic = Virus_inside;
-}
\ No newline at end of file
+}
+
+Node Virus_damage {
+	logic = Virus_damage;
+}
+
+Node TCell_attached {
+	logic = TCell_attached;
+}
+
+Node FAS_FASL_complex {
+
+	logic = (TCell_attached);
+	rate_up = @logic ? $u_FAS_FASL_complex : 0;
+	rate_down = @logic ? 0 : $d_FAS_FASL_complex;
+}
+Node BAD_BBC3_BCL2L11_complex {
+
+	logic = (BCL2_MCL1_BCL2L1_complex);
+	rate_up = @logic ? $u_BAD_BBC3_BCL2L11_complex : 0;
+	rate_down = @logic ? 0 : $d_BAD_BBC3_BCL2L11_complex;
+}
+
+Node Apoptosome_complex {
+
+	logic = (CYCS & APAF1 & !AKT1 & CASP9_Cytoplasm_input);
+	rate_up = @logic ? $u_Apoptosome_complex : 0;
+	rate_down = @logic ? 0 : $d_Apoptosome_complex;
+}
+
+Node TNF_TNFRSF1A_complex {
+
+	logic = (TNF_TNFRSF1A_complex);
+	rate_up = @logic ? $u_TNF_TNFRSF1A_complex : 0;
+	rate_down = @logic ? 0 : $d_TNF_TNFRSF1A_complex;
+}
+
+Node TRADD_FADD_complex {
+
+	logic = (TNF_TNFRSF1A_complex & FADD & TRADD);
+	rate_up = @logic ? $u_TRADD_FADD_complex : 0;
+	rate_down = @logic ? 0 : $d_TRADD_FADD_complex;
+}
+
+Node BCL2_MCL1_BCL2L1_complex {
+
+	logic = (!Orf7a & E & !BAD) | (Orf7a & !BAD);
+	rate_up = @logic ? $u_BCL2_MCL1_BCL2L1_complex : 0;
+	rate_down = @logic ? 0 : $d_BCL2_MCL1_BCL2L1_complex;
+}
+
+Node FADD {
+
+	logic = (FAS_FASL_complex);
+	rate_up = @logic ? $u_FADD : 0;
+	rate_down = @logic ? 0 : $d_FADD;
+}
+
+Node CASP8 {
+
+	logic = (!TRADD_FADD_complex & FADD) | (TRADD_FADD_complex);
+	rate_up = @logic ? $u_CASP8 : 0;
+	rate_down = @logic ? 0 : $d_CASP8;
+}
+
+Node CASP3 {
+
+	logic = ( CASP9_Cytoplasm | CASP8);
+	rate_up = @logic ? $u_CASP3 : 0;
+	rate_down = @logic ? 0 : $d_CASP3;
+}
+
+Node CASP9_Cytoplasm_input {
+
+	logic = (CASP9_Cytoplasm_input);
+	rate_up = @logic ? $u_CASP9_Cytoplasm_input : 0;
+	rate_down = @logic ? 0 : $d_CASP9_Cytoplasm_input;
+}
+
+Node CASP9_Cytoplasm {
+
+	logic = (Apoptosome_complex & !AKT1);
+	rate_up = @logic ? $u_CASP9_Cytoplasm : 0;
+	rate_down = @logic ? 0 : $d_CASP9_Cytoplasm;
+}
+
+Node BID {
+
+	logic = (CASP8);
+	rate_up = @logic ? $u_BID : 0;
+	rate_down = @logic ? 0 : $d_BID;
+}
+
+Node CYCS {
+
+	logic = (MAPK14);
+	rate_up = @logic ? $u_CYCS : 0;
+	rate_down = @logic ? 0 : $d_CYCS;
+}
+
+Node APAF1 {
+
+	logic = (BAX);
+	rate_up = @logic ? $u_APAF1 : 0;
+	rate_down = @logic ? 0 : $d_APAF1;
+}
+
+Node AKT1 {
+
+	logic = (!M);
+	rate_up = @logic ? $u_AKT1 : 0;
+	rate_down = @logic ? 0 : $d_AKT1;
+}
+
+Node BAX {
+
+	logic = (!BAD_BBC3_BCL2L11_complex & !BCL2_MCL1_BCL2L1_complex & BID) | (BAD_BBC3_BCL2L11_complex & !BCL2_MCL1_BCL2L1_complex);
+	rate_up = @logic ? $u_BAX : 0;
+	rate_down = @logic ? 0 : $d_BAX;
+}
+
+Node CASP7 {
+
+	logic = (!CASP8 & CASP9_Cytoplasm) | (CASP8);
+	rate_up = @logic ? $u_CASP7 : 0;
+	rate_down = @logic ? 0 : $d_CASP7;
+}
+
+Node Apoptosis_phenotype {
+
+	logic = (!CASP3 & !CASP7 & !Orf3b & !Orf8a & !N & !Orf6 & !S & Orf9b) | (!CASP3 & !CASP7 & !Orf3b & !Orf8a & !N & !Orf6 & S) | (!CASP3 & !CASP7 & !Orf3b & !Orf8a & !N & Orf6) | (!CASP3 & !CASP7 & !Orf3b & !Orf8a & N) | (!CASP3 & !CASP7 & !Orf3b & Orf8a) | (!CASP3 & !CASP7 & Orf3b) | (!CASP3 & CASP7) | (CASP3);
+	rate_up = @logic ? $u_Apoptosis_phenotype : 0;
+	rate_down = @logic ? 0 : $d_Apoptosis_phenotype;
+}
+
+Node M {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_M : 0;
+	rate_down = @logic ? 0 : $d_M;
+}
+
+Node Orf7a {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf7a : 0;
+	rate_down = @logic ? 0 : $d_Orf7a;
+}
+
+Node TRADD {
+
+	logic = (TRADD);
+	rate_up = @logic ? $u_TRADD : 0;
+	rate_down = @logic ? 0 : $d_TRADD;
+}
+
+Node Orf3a {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf3a : 0;
+	rate_down = @logic ? 0 : $d_Orf3a;
+}
+
+Node MAPK14 {
+
+	logic = (Orf3a);
+	rate_up = @logic ? $u_MAPK14 : 0;
+	rate_down = @logic ? 0 : $d_MAPK14;
+}
+
+Node E {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_E : 0;
+	rate_down = @logic ? 0 : $d_E;
+}
+
+Node Orf3b {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf3b : 0;
+	rate_down = @logic ? 0 : $d_Orf3b;
+}
+
+Node Orf8a {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf8a : 0;
+	rate_down = @logic ? 0 : $d_Orf8a;
+}
+
+Node N {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_N : 0;
+	rate_down = @logic ? 0 : $d_N;
+}
+
+Node Orf6 {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf6 : 0;
+	rate_down = @logic ? 0 : $d_Orf6;
+}
+
+Node S {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_S : 0;
+	rate_down = @logic ? 0 : $d_S;
+}
+
+Node Orf9b {
+
+	logic = (Virus_damage);
+	rate_up = @logic ? $u_Orf9b : 0;
+	rate_down = @logic ? 0 : $d_Orf9b;
+}
+
+Node BAD {
+
+	logic = (!AKT1);
+	rate_up = @logic ? $u_BAD : 0;
+	rate_down = @logic ? 0 : $d_BAD;
+}

data/boolean_network/epithelial_cell.cfg

 Virus_inside.istate = FALSE;
+Virus_damage.istate = FALSE;
 Virus_replication.istate = FALSE;
 Chemokin_secretion.istate = FALSE;
+TCell_attached.istate = FALSE;
+
+$nb_mutable = 0;
+$u_FAS_FASL_complex = 1;
+$d_FAS_FASL_complex = 1;
+$u_BAD_BBC3_BCL2L11_complex = 1;
+$d_BAD_BBC3_BCL2L11_complex = 1;
+$u_Apoptosome_complex = 1;
+$d_Apoptosome_complex = 1;
+$u_TNF_TNFRSF1A_complex = 1;
+$d_TNF_TNFRSF1A_complex = 1;
+$u_TRADD_FADD_complex = 1;
+$d_TRADD_FADD_complex = 1;
+$u_BCL2_MCL1_BCL2L1_complex = 1;
+$d_BCL2_MCL1_BCL2L1_complex = 1;
+$u_FADD = 1;
+$d_FADD = 1;
+$u_CASP8 = 1;
+$d_CASP8 = 1;
+$u_CASP3 = 1;
+$d_CASP3 = 1;
+$u_CASP9_Cytoplasm = 1;
+$d_CASP9_Cytoplasm = 1;
+$u_BID = 1;
+$d_BID = 1;
+$u_CYCS = 1;
+$d_CYCS = 1;
+$u_APAF1 = 1;
+$d_APAF1 = 1;
+$u_AKT1 = 1;
+$d_AKT1 = 1;
+$u_BAX = 1;
+$d_BAX = 1;
+$u_CASP7 = 1;
+$d_CASP7 = 1;
+$u_Apoptosis_phenotype = 1;
+$d_Apoptosis_phenotype = 1;
+$u_M = 1;
+$d_M = 1;
+$u_Orf7a = 1;
+$d_Orf7a = 1;
+$u_TRADD = 1;
+$d_TRADD = 1;
+$u_Orf3a = 1;
+$d_Orf3a = 1;
+$u_MAPK14 = 1;
+$d_MAPK14 = 1;
+$u_E = 1;
+$d_E = 1;
+$u_Orf3b = 1;
+$d_Orf3b = 1;
+$u_Orf8a = 1;
+$d_Orf8a = 1;
+$u_N = 1;
+$d_N = 1;
+$u_Orf6 = 1;
+$d_Orf6 = 1;
+$u_S = 1;
+$d_S = 1;
+$u_Orf9b = 1;
+$d_Orf9b = 1;
+$u_BAD = 1;
+$d_BAD = 1;
+FAS_FASL_complex.istate = FALSE;
+BAD_BBC3_BCL2L11_complex.istate = FALSE;
+Apoptosome_complex.istate = FALSE;
+TNF_TNFRSF1A_complex.istate = FALSE;
+TRADD_FADD_complex.istate = FALSE;
+BCL2_MCL1_BCL2L1_complex.istate = FALSE;
+FADD.istate = FALSE;
+CASP8.istate = FALSE;
+CASP3.istate = FALSE;
+CASP9_Cytoplasm.istate = FALSE;
+BID.istate = FALSE;
+CYCS.istate = FALSE;
+APAF1.istate = FALSE;
+AKT1.istate = FALSE;
+BAX.istate = FALSE;
+CASP7.istate = FALSE;
+Apoptosis_phenotype.istate = FALSE;
+M.istate = FALSE;
+Orf7a.istate = FALSE;
+TRADD.istate = FALSE;
+CASP9_Cytoplasm_input.istate = FALSE;
+Orf3a.istate = FALSE;
+MAPK14.istate = FALSE;
+E.istate = FALSE;
+Orf3b.istate = FALSE;
+Orf8a.istate = FALSE;
+N.istate = FALSE;
+Orf6.istate = FALSE;
+S.istate = FALSE;
+Orf9b.istate = FALSE;
+BAD.istate = FALSE;
 
 discrete_time = 0;
 use_physrandgen = FALSE;
 seed_pseudorandom = 100;
 
-max_time = 1;
-time_tick = 0.1;
+max_time = 10;
+time_tick = 1;
 
 Virus_inside.is_internal = FALSE;
+Virus_damage.is_internal = FALSE;
 Virus_replication.is_internal = FALSE;
-Chemokin_secretion.is_internal = FALSE;
\ No newline at end of file
+Chemokin_secretion.is_internal = FALSE;
+TCell_attached.is_internal = FALSE;
+
+FAS_FASL_complex.is_internal = False;
+BAD_BBC3_BCL2L11_complex.is_internal = False;
+Apoptosome_complex.is_internal = False;
+TNF_TNFRSF1A_complex.is_internal = False;
+TRADD_FADD_complex.is_internal = False;
+BCL2_MCL1_BCL2L1_complex.is_internal = False;
+FADD.is_internal = TRUE;
+CASP8.is_internal = TRUE;
+CASP3.is_internal = TRUE;
+CASP9_Cytoplasm.is_internal = False;
+BID.is_internal = TRUE;
+CYCS.is_internal = TRUE;
+APAF1.is_internal = TRUE;
+AKT1.is_internal = TRUE;
+BAX.is_internal = TRUE;
+CASP7.is_internal = TRUE;
+Apoptosis_phenotype.is_internal = False;
+M.is_internal = TRUE;
+Orf7a.is_internal = TRUE;
+TRADD.is_internal = TRUE;
+CASP9_Cytoplasm_input.is_internal = False;
+Orf3a.is_internal = TRUE;
+MAPK14.is_internal = TRUE;
+E.is_internal = TRUE;
+Orf3b.is_internal = TRUE;
+Orf8a.is_internal = TRUE;
+N.is_internal = TRUE;
+Orf6.is_internal = TRUE;
+S.is_internal = TRUE;
+Orf9b.is_internal = TRUE;
+BAD.is_internal = TRUE;
+

data/boolean_network/macrophage.cfg

@@ -4,7 +4,7 @@ discrete_time = 0;
 use_physrandgen = FALSE;
 seed_pseudorandom = 100;
 
-max_time = 1;
-time_tick = 0.1;
+max_time = 10;
+time_tick = 1;
 
 Active.is_internal = FALSE;

data/boolean_network/neutrophil.cfg

@@ -4,7 +4,7 @@ discrete_time = 0;
 use_physrandgen = FALSE;
 seed_pseudorandom = 100;
 
-max_time = 1;
-time_tick = 0.1;
+max_time = 10;
+time_tick = 1;
 
 Active.is_internal = FALSE;

data/initial.xml

@@ -11,9 +11,9 @@
 		</software>
 		<citation />
 		<current_time units="min">0.000000</current_time>
-		<current_runtime units="sec">0.123792</current_runtime>
-		<created>2020-10-26T18:40:36Z</created>
-		<last_modified>2020-10-26T18:40:36Z</last_modified>
+		<current_runtime units="sec">2.590947</current_runtime>
+		<created>2020-11-06T14:23:26Z</created>
+		<last_modified>2020-11-06T14:23:26Z</last_modified>
 	</metadata>
 	<microenvironment>
 		<domain name="microenvironment">

src/custom_modules/epithelium_submodel.cpp

@@ -16,6 +16,11 @@ void epithelium_contact_function( Cell* pC1, Phenotype& p1, Cell* pC2, Phenotype
 
 void epithelium_phenotype( Cell* pCell, Phenotype& phenotype, double dt )
 {
+	if (pCell->phenotype.intracellular->need_update())
+	{		
+		pCell->phenotype.intracellular->update();
+	}
+	
 	static int debris_index = microenvironment.find_density_index( "debris");
 	
 	// receptor dynamics 
@@ -163,7 +168,13 @@ void TCell_induced_apoptosis( Cell* pCell, Phenotype& phenotype, double dt )
 	static int debris_index = microenvironment.find_density_index( "debris" ); 
 	static int proinflammatory_cytokine_index = microenvironment.find_density_index("pro-inflammatory cytokine");
 	
-	if( pCell->custom_data["TCell_contact_time"] > pCell->custom_data["TCell_contact_death_threshold"] )
+	pCell->phenotype.intracellular->set_boolean_node_value(
+		"TCell_attached", 
+		pCell->custom_data["TCell_contact_time"] > pCell->custom_data["TCell_contact_death_threshold"]
+	);
+	
+	if ( pCell->phenotype.intracellular->get_boolean_node_value("Apoptosis_phenotype") && pCell->phenotype.intracellular->get_boolean_node_value("TCell_attached"))
+	// if( pCell->custom_data["TCell_contact_time"] > pCell->custom_data["TCell_contact_death_threshold"] )
 	{
 		// make sure to get rid of all adhesions! 
 		// detach all attached cells 

src/custom_modules/immune_submodels.cpp

@@ -378,6 +378,11 @@ void CD8_Tcell_contact_function( Cell* pC1, Phenotype& p1, Cell* pC2, Phenotype&
 
 void CD8_Tcell_phenotype( Cell* pCell, Phenotype& phenotype, double dt )
 {
+	if (pCell->phenotype.intracellular->need_update())
+	{	
+		pCell->phenotype.intracellular->update();
+	}
+
 	static int debris_index = microenvironment.find_density_index( "debris");
 	
 	if( phenotype.death.dead == true )
@@ -500,6 +505,11 @@ void immune_cell_motility_direction( Cell* pCell, Phenotype& phenotype , double
 
 void macrophage_phenotype( Cell* pCell, Phenotype& phenotype, double dt )
 {
+	if (pCell->phenotype.intracellular->need_update())
+	{	
+		pCell->phenotype.intracellular->update();
+	}
+	
 	static int apoptosis_index = phenotype.death.find_death_model_index( "Apoptosis" ); 
 	static Cell_Definition* pCD = find_cell_definition( "macrophage" ); 
 	static int proinflammatory_cytokine_index = microenvironment.find_density_index( "pro-inflammatory cytokine");
@@ -616,6 +626,11 @@ void macrophage_mechanics( Cell* pCell, Phenotype& phenotype, double dt )
 
 void neutrophil_phenotype( Cell* pCell, Phenotype& phenotype, double dt )
 {
+	if (pCell->phenotype.intracellular->need_update())
+	{	
+		pCell->phenotype.intracellular->update();
+	}
+	
 	//	std::cout << __FUNCTION__ << " " << __LINE__ << std::endl; 
 	static int apoptosis_index = phenotype.death.find_death_model_index( "apoptosis" ); 
 	static Cell_Definition* pCD = find_cell_definition( "neutrophil" ); 
@@ -654,8 +669,10 @@ void neutrophil_phenotype( Cell* pCell, Phenotype& phenotype, double dt )
 			UniformRandom() < probability_of_phagocytosis && 
 			pTestCell->phenotype.volume.total < max_phagocytosis_volume )
 		{
-			// #pragma omp critical(neutrophil_eat)
+			#pragma omp critical(neutrophil_eat)
 			{
+				std::cout << "Neutrophil is eating, and being activated" << std::endl;		
+			}{
 				// remove_all_adhesions( pTestCell ); // debug 
 				pCell->ingest_cell( pTestCell ); 
 			}

src/custom_modules/internal_viral_dynamics.cpp

@@ -124,15 +124,10 @@ void internal_virus_model( Cell* pCell, Phenotype& phenotype, double dt )
 	phenotype.molecular.internalized_total_substrates[nA_external] = 
 		pCell->custom_data[nA_internal];	
 	
-	if (pCell->phenotype.intracellular->need_update())
-	{	
-		pCell->phenotype.intracellular->set_boolean_node_value(
-			"Virus_inside",
-			pCell->custom_data[nV_internal] > 1
-		);
-		pCell->phenotype.intracellular->update();
-	}
-	
+	pCell->phenotype.intracellular->set_boolean_node_value(
+		"Virus_inside",
+		pCell->custom_data[nV_internal] > 1
+	);
 	
 	return; 
 }

src/custom_modules/internal_viral_response.cpp

@@ -34,6 +34,10 @@ void internal_virus_response_model_setup( void )
 	return; 
 }
 
+// bool fuzzy_heavyside_normal(double value, double average, double stddev) {
+// 	return value > PhysiCell::NormalRandom(average, stddev);
+// }
+
 void internal_virus_response_model( Cell* pCell, Phenotype& phenotype, double dt )
 {
 	static Cell_Definition* pCD = find_cell_definition( "lung epithelium" ); 
@@ -48,26 +52,40 @@ void internal_virus_response_model( Cell* pCell, Phenotype& phenotype, double dt
 	
 	// actual model goes here 
 
-	// now, set apoptosis rate 
+	// boolean-controlled apoptosis
 	
 	static int apoptosis_model_index = cell_defaults.phenotype.death.find_death_model_index( "apoptosis" );
-	// phenotype.death.rates[apoptosis_model_index] = 
+	pCell->phenotype.intracellular->set_boolean_node_value(
+		"Virus_damage", 
+		// fuzzy_heavyside_normal(pCell->custom_data[nA_internal], 50, 10)
+		pCell->custom_data[nA_internal] > 10.0
+	);
+	
+	if ( pCell->phenotype.intracellular->get_boolean_node_value("Apoptosis_phenotype") && !pCell->phenotype.intracellular->get_boolean_node_value("TCell_attached")) {
+		// std::cout << "Triggering apoptosis based on boolean model" << std::endl;
+		pCell->start_death(apoptosis_model_index);
+	}
+
+	// // now, set apoptosis rate 
+	
+	// static int apoptosis_model_index = cell_defaults.phenotype.death.find_death_model_index( "apoptosis" );
+	// // phenotype.death.rates[apoptosis_model_index] = 
 	
-	// base death rate (from cell line)
-	double base_death_rate = 
-		pCD->phenotype.death.rates[apoptosis_model_index]; 
+	// // base death rate (from cell line)
+	// double base_death_rate = 
+	// 	pCD->phenotype.death.rates[apoptosis_model_index]; 
 	
-	// additional death rate from infectoin  
-	double additional_death_rate = pCell->custom_data["max_infected_apoptosis_rate"] ; 
+	// // additional death rate from infectoin  
+	// double additional_death_rate = pCell->custom_data["max_infected_apoptosis_rate"] ; 
 	
 	
-	double v = pCell->custom_data[nA_internal] / 
-		pCell->custom_data["max_apoptosis_half_max"] ; 
-	v = pow( v, pCell->custom_data["apoptosis_hill_power"] ); 
+	// double v = pCell->custom_data[nA_internal] / 
+	// 	pCell->custom_data["max_apoptosis_half_max"] ; 
+	// v = pow( v, pCell->custom_data["apoptosis_hill_power"] ); 
 	
-	double effect = v / (1.0+v); 
-	additional_death_rate *= effect; 
-	phenotype.death.rates[apoptosis_model_index] = base_death_rate + additional_death_rate; 
+	// double effect = v / (1.0+v); 
+	// additional_death_rate *= effect; 
+	// phenotype.death.rates[apoptosis_model_index] = base_death_rate + additional_death_rate; 
 	
 	// if we're infected, secrete a chemokine for the immune model
 	static int nAV = pCell->custom_data.find_variable_index( "assembled_virion" );