/**
 * 
 */
package muscle;

import java.util.List;

import repast.simphony.context.Context;
import repast.simphony.engine.environment.RunEnvironment;
import repast.simphony.parameter.Parameters;
import repast.simphony.space.continuous.ContinuousSpace;
import repast.simphony.space.grid.Grid;
import repast.simphony.engine.schedule.ScheduledMethod;
import repast.simphony.util.ContextUtils;

/**
 * @author Kelley Virgilio
 * This class contains the growth factors for the model: getGF, setGF functions defined for all
 */
public class GrowthFactors {

	public static Grid<Object> grid; 
	public static ContinuousSpace<Object> space;
	public static int activeDelay = 96; // time delay from latent to active tgf, 96 normal
	
	// DISEASE STATE PARAMETERS
	public static double m1MacAdded = 0; // 0 at healthy 
	public static double m2MacAdded = 0; // 0 at healthy 
	public static double mdxTGF = 0; // 0 at healthy 
	//private static int activeDelay = 1; // void at healthy; add baseline active TGF 
	
	static final int numGrowthFactors = 31; // Number of growth factors in model
	public static double[] growthFactors = new double[numGrowthFactors]; // growth factors
	static final int simLength = 3000 + activeDelay + 1; 
	public static double[] activeTgf = new double[simLength]; // holds active TGF at each time step
	
	public GrowthFactors(Grid<Object> grid, ContinuousSpace<Object> space){
		this.grid = grid;
		this.space = space;
	}
	
	public static double[] getGrowthFactors(){
		return growthFactors;
	}
	
	// Growth factor solver
	public static double[] growthFactorSolver(double[] inflamCells, Context<Object> context){
		//inflammCells: 0 RM; 1 N; 2 Na; 3 M1; 4 M1ae; 5 M1de; 6 M2
		double[] growthFactorsTemp = new double[numGrowthFactors];
		List<Object> activeFibroblasts =  Fibroblast.getActiveFibroblasts(context);// active fibroblasts
		double numActiveFibrob = activeFibroblasts.size(); // number of active fibroblasts
		double inflamFibroblasts = 0; // fibroblasts only secrete certain factors in an inflammatory environment
		double inflamSSC = 0; // sscs only secrete certain factors in an inflammatory environment
		double numActiveSSC = SSC.getActiveSSCs(context).size(); // number of active sscs
		// exclude signals from fully differentiated SSCs
		double numActiveSecretingSSC = SSC.getNumActSecretingSSCs(context); // secreting sscs
		double numMyofbs = Fibroblast.getMyofibroblasts(context).size(); // number of myofibroblasts
		double rmNecr = 0.; // number of resident macrophages scaled to the amount of muscle damage
		double percentNecrotic = Necrosis.getPercentNecrotic(context); // percent of muscle that is necrotic
		// activation is a function of initial damage only
		int timestep = 1;
		if (percentNecrotic < 0.001){ // lower limit of damage for resident macrophages to detect
			rmNecr = 0; 
		}
		else{
			rmNecr = inflamCells[0]; // else all resident macrophages detect damage
		}
		// INFLAMMATION WEIGHTING FUNCTION:
		// weighting function to determine if it is a pro-inflammatory or anti-inflammatory environment 
		double inflamWeight = (growthFactors[1]- getActiveTgf(InflamCell.getTick()))/(40.*Fiber.origFiberNumber); 
		if (inflamWeight < 0) {
			inflamWeight = 0;
		}
		inflamFibroblasts = numActiveFibrob*inflamWeight; // number of fibroblasts weighted by inflammatory environment
		inflamSSC = numActiveSSC*inflamWeight; // number of sscs weighted by inflammatory environment
		
		double m1Mac = inflamCells[3]; // m1 macrophages
		double m2Mac = inflamCells[6]; // m2 macrophages
		
		// DISEASE STATE PARAMETERS
		// MACROPHAGE PHENOTYPE ANALYSIS:
		// M1: INFLAMMATORY-- add in a constant level of inflammatory M1s
		//m1Mac = m1Mac + m1MacAdded; // 0 added at healthy
		//
		// M2: anti-inflammatory- add in constant level of M2
		//m2Mac = m2Mac + m2MacAdded; // 0 added at healthy
		
		// LIT REPLICATION SCALING PARAMTERS: Murphy et al. 2011 
		numActiveFibrob = numActiveFibrob*(1/Fiber.tcf4Scale); // scale secretions --> less // tcf4scale = 1 at healthy = no change
		inflamFibroblasts = inflamFibroblasts*(1/Fiber.tcf4Scale); // scale secretions --> less // tcf4scale = 1 at healthy = no change
		numActiveSecretingSSC = numActiveSecretingSSC*(1/Fiber.pax7Scale); // scale secretions --> more // pax7scale = 1 at healthy = no change
		inflamSSC = inflamSSC*(1/Fiber.pax7Scale); // scale secretions --> more // pax7scale = 1 at healthy = no change
		numMyofbs = numMyofbs*(1/Fiber.tcf4Scale); // scale secretions --> less // tcf4scale = 1 at healthy = no change
		
		// INFLAMMATORY CELLS: 
		// 0 RM- resident macrophages
		// 1 N- neutrophils
		// 2 Na- apoptotic neutrophils
		// 3 M1- M1 macrophages 
		// 4 M1ae- M1 apoptotic eating 
		// 5 M1de- M1 debris eating
		// 6 M2- M2 macrophages
		
		// SECRETE GROWTH FACTORS AT EACH TIME STEP:
		double dtgfdt = (1*numActiveFibrob + 1*inflamCells[4] + 2*m2Mac); //tgf
		double dtnfdt = (1*rmNecr + 2*inflamCells[1] +2*m1Mac + 2*inflamCells[4] + 2*inflamCells[5] + .2*inflamSSC); //tnf
		double digf1dt = (2*numActiveFibrob + 1*m1Mac+1*inflamCells[4]+1*inflamCells[5]+1*m2Mac); //igf1
		double dpdgfdt = (1*numActiveFibrob); //pdgf
		double dmmpxdt = (1*numActiveFibrob + 1*numActiveSecretingSSC + 1*numMyofbs);// mmpX
		double dactiveTGFTempdt = (2*numMyofbs);//tgf myofibroblast release
		double decmprotdt = (2*numActiveFibrob + 1*numActiveSecretingSSC + 1*numMyofbs);//ecmprot
		double dil1dt = (2*rmNecr+1*inflamCells[1]+1*m1Mac+1*inflamCells[4]+1*inflamCells[5] + 1*inflamFibroblasts + 1*numActiveSecretingSSC);//il1
		double dil8dt = (1*rmNecr+1*inflamCells[1]+1*m1Mac+2*inflamCells[5] + 1*inflamFibroblasts + .2*inflamSSC);//il8
		double dcxcl2dt = (1*rmNecr);//cxcl2
		double dcxcl1dt = (1*rmNecr);//cxcl1
		double dccl3dt = (1*rmNecr+1*inflamCells[1]-1*inflamCells[2]);//ccl3
		double dccl4dt = (1*rmNecr+1*inflamCells[1]);//ccl4
		double dil6dt = (1*inflamCells[1]+3*m1Mac+3*inflamCells[5] + 1*numActiveFibrob + 1*inflamSSC);//il6
		double dmcpdt = (1.7*inflamCells[1] + 1*inflamFibroblasts + 1*inflamSSC);//mcp
		double difndt = (5*inflamCells[1]+1*inflamCells[5]);//ifn
		double dlactoferinsdt = (5*inflamCells[2]);//lactoferins
		double dhgfdt = percentNecrotic*100*5;//hgf - Released from ecm with damage // eliminated effect of apop neutrophils and released with % necrotic at damage
		double dvegfdt = (1*inflamCells[2]+1*m1Mac+inflamCells[4]+1*inflamCells[5]+.5*numActiveSecretingSSC);//vegf
		double dmmp12dt = (2*m1Mac+2*inflamCells[4]+2*inflamCells[5]+1*numActiveSecretingSSC);//mmp12
		double dgcsfdt = (1*m1Mac+1*inflamCells[4]+1*inflamCells[5]);//gcsf
		double dil10dt = (1*m1Mac+ 0.1*inflamCells[4]+ 0.5*inflamCells[5]+1.2*m2Mac);//il10
		double dlipoxinsdt = (1*inflamCells[4]+1*inflamCells[5]);//lipoxins
		double dresolvinsdt = (3*inflamCells[4]+2*inflamCells[5]);//resolvins
		double dccl17dt = (1*inflamCells[4]+2.8*m2Mac);//ccl17
		double dccl22dt = (1*inflamCells[4]+1*m2Mac+1*numActiveSecretingSSC);//ccl22
		double dcollagen4dt = (1*m2Mac);//collagen4
		double dpge2dt = (3*m2Mac);//	pge2
		double drosdt = (1*inflamCells[1] + 1*inflamCells[5]);//	ros
		double dfgfdt = numActiveFibrob; // fgf
		double dil4dt = 0; // il4
		// GROWTH FACTOR SOLVER 
		// add new growth factors and include half-life
		growthFactorsTemp[0] = (growthFactors[0] + dtgfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[1] = (growthFactors[1] + dtnfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[2] = (growthFactors[2] + digf1dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[3] = (growthFactors[3] + dpdgfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[4] = (growthFactors[4] + dmmpxdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[5] = (growthFactors[5] + dactiveTGFTempdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[6] = (growthFactors[6] + decmprotdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[7] = (growthFactors[7] + dil1dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[8] = (growthFactors[8] + dil8dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[9] = (growthFactors[9] + dcxcl2dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[10] = (growthFactors[10] + dcxcl1dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[11] = (growthFactors[11] + dccl3dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[12] = (growthFactors[12] + dccl4dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[13] = (growthFactors[13] + dil6dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[14] = (growthFactors[14] + dmcpdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[15] = (growthFactors[15] + difndt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[16] = (growthFactors[16] + dlactoferinsdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[17] = (growthFactors[17] + dhgfdt)*Math.pow(.5, timestep/8.); // slower half-life to account for ecm breakdown/release
		growthFactorsTemp[18] = (growthFactors[18] + dvegfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[19] = (growthFactors[19] + dmmp12dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[20] = (growthFactors[20] + dgcsfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[21] = (growthFactors[21] + dil10dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[22] = (growthFactors[22] + dlipoxinsdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[23] = (growthFactors[23] + dresolvinsdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[24] = (growthFactors[24] + dccl17dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[25] = (growthFactors[25] + dccl22dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[26] = (growthFactors[26] + dcollagen4dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[27] = (growthFactors[27] +	dpge2dt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[28] = drosdt; // does not build up- flushes every step
		growthFactorsTemp[29] = (growthFactors[29] +	dfgfdt)*Math.pow(.5, timestep/5.);
		growthFactorsTemp[30] = (growthFactors[30] +	dil4dt)*Math.pow(.5, timestep/5.);
		growthFactors = growthFactorsTemp;
		// if growth factor below threshold == 0
		if (growthFactors[0] < .0001){
			growthFactors[0] = 0.;
		}
		if (growthFactors[1] < .0001){
			growthFactors[1] = 0.;
		}
		// DISEASE STATE PARAMETERS
//		// LEMOS REPLICATION: ANTI-TNF at day 3,4,5,6
//		if (InflamCell.getTick() >= 60 && InflamCell.getTick() < 144){
//			growthFactors[1] = 0.;
//		}
//		// Full TNF block
		//growthFactors[1] = 0.;
//		// 
		if (growthFactors[2] < .0001){
			growthFactors[2] = 0.;
		}
		if (growthFactors[3] < .0001){
			growthFactors[3] = 0.;
		}
		if (growthFactors[4] < .0001){
			growthFactors[4] = 0.;
		}
		if (growthFactors[5] < .0001){
			growthFactors[5] = 0.;
		}
		if (growthFactors[6] < .0001){
			growthFactors[6] = 0.;
		}
		if (growthFactors[7] < .0001){
			growthFactors[7] = 0.;
		}
		if (growthFactors[8] < .0001){
			growthFactors[8] = 0.;
		}
		if (growthFactors[9] < .0001){
			growthFactors[9] = 0.;
		}
		if (growthFactors[10] < .0001){
			growthFactors[10] = 0.;
		}
		if (growthFactors[11] < .0001){
			growthFactors[11] = 0.;
		}
		if (growthFactors[12] < .0001){
			growthFactors[12] = 0.;
		}
		if (growthFactors[13] < .0001){
			growthFactors[13] = 0.;
		}
		if (growthFactors[14] < .0001){
			growthFactors[14] = 0.;
		}
		if (growthFactors[15] < .0001){
			growthFactors[15] = 0.;
		}
		if (growthFactors[16] < .0001){
			growthFactors[16] = 0.;
		}
		if (growthFactors[17] < .0001){
			growthFactors[17] = 0.;
		}
		if (growthFactors[18] < .0001){
			growthFactors[18] = 0.;
		}
		if (growthFactors[19] < .0001){
			growthFactors[19] = 0.;
		}
		if (growthFactors[20] < .0001){
			growthFactors[20] = 0.;
		}
		if (growthFactors[21] < .0001){
			growthFactors[21] = 0.;
		}
		if (growthFactors[22] < .0001){
			growthFactors[22] = 0.;
		}
		if (growthFactors[23] < .0001){
			growthFactors[23] = 0.;
		}
		if (growthFactors[24] < .0001){
			growthFactors[24] = 0.;
		}
		if (growthFactors[25] < .0001){
			growthFactors[25] = 0.;
		}
		if (growthFactors[26] < .0001){
			growthFactors[26] = 0.;
		}
		if (growthFactors[27] < .0001){
			growthFactors[27] = 0.;
		}
		if (growthFactors[28] < .0001){
			growthFactors[28] = 0.;
		}
		if (growthFactors[29] < .0001){
			growthFactors[29] = 0.;
		}
		if (growthFactors[30] < .0001){
			growthFactors[30] = 0.;
		}
		return growthFactors;
	}
	
	// Calculate active-TGFbeta
	public static void initializeActiveTgf(){
		for (int i = 0; i < activeDelay; i++){
			activeTgf[i] = 0 + mdxTGF;
		}
	}
	public static void setActiveTgf(int tick){
		// at each time step, store the amount of active tgf
		activeTgf[tick + activeDelay] = growthFactors[0] + mdxTGF;
		//activeTgf[tick + activeDelay] = 0; // TEST: block active tgf
	}
	public static double getActiveTgf(int tick){
		return activeTgf[tick] + growthFactors[5];
		//return 0; // TEST: block active tgf
	}
	
	// get growth factors:
	public double getTgf(){
		return growthFactors[0];
	}
	public double getTnf(){
		return growthFactors[1] + Fiber.mdxTnf;
	}
	public double getIgf1(){
		return growthFactors[2];
	}
	public double getPdgf(){
		return growthFactors[3];
	}
	public double getMmpx(){
		return growthFactors[4];
	}
	public double getCollagenX(){
		return growthFactors[5];
	}
	public double getEcmprot(){
		return growthFactors[6];
	}
	public double getIl1(){
		return growthFactors[7];
	}
	public double getIl8(){
		return growthFactors[8];
	}
	public double getCxcl2(){
		return growthFactors[9];
	}
	public double getCxcl1(){
		return growthFactors[10];
	}
	public double getCcl3(){
		return growthFactors[11];
	}
	public double getCcl4(){
		return growthFactors[12];
	}
	public double getIl6(){
		return growthFactors[13];
	}
	public double getMcp(){
		return growthFactors[14];
	}
	public double getIfn(){
		return growthFactors[15] + Fiber.mdxIfn;
	}
	public double getLactoferins(){
		return growthFactors[16];
	}
	public double getHgf(){
		return growthFactors[17];
	}
	public double getVegf(){
		return growthFactors[18];
	}
	public double getMmp12(){
		return growthFactors[19];
	}
	public double getGcsf(){
		return growthFactors[20];
	}
	public double getIl10(){
		return growthFactors[21];
	}
	public double getLipoxins(){
		return growthFactors[22];
	}
	public double getResolvins(){
		return growthFactors[23];
	}	
	public double getCcl17(){
		return growthFactors[24];
	}
	public double getCcl22(){
		return growthFactors[25];
	}
	public double getCollagen4(){
		return growthFactors[26];
	}
	public double getPge2(){
		return growthFactors[27];
	}
	public double getRos(){
		return growthFactors[28];
	}
	public double getFgf(){
		return growthFactors[29];
	}
}