SCZ-associated variant effects on L5 pyr cell NN activity and delta osc. (Maki-Marttunen et al 2018)

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Accession:237469
" … Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a decit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia."
Reference:
1 . Mäki-Marttunen T, Krull F, Bettella F, Hagen E, Næss S, Ness TV, Moberget T, Elvsåshagen T, Metzner C, Devor A, Edwards AG, Fyhn M, Djurovic S, Dale AM, Andreassen OA, Einevoll GT (2019) Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations. Cereb Cortex 29:875-891 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Neuron or other electrically excitable cell;
Brain Region(s)/Organism: Neocortex;
Cell Type(s): Neocortex L5/6 pyramidal GLU cell;
Channel(s): Ca pump; I A, slow; I h; I K; I K,Ca; I K,leak; I L high threshold; I M; I Na,p; I Na,t; I T low threshold;
Gap Junctions: Gap junctions;
Receptor(s): AMPA; NMDA; Gaba;
Gene(s): Cav1.2 CACNA1C; Cav1.3 CACNA1D; Cav3.3 CACNA1I; HCN1; Kv2.1 KCNB1; Nav1.1 SCN1A; PMCA ATP2B2;
Transmitter(s): Glutamate; Gaba;
Simulation Environment: NEURON; Python; LFPy;
Model Concept(s): Schizophrenia; Oscillations;
Implementer(s): Maki-Marttunen, Tuomo [tuomo.maki-marttunen at tut.fi];
Search NeuronDB for information about:  Neocortex L5/6 pyramidal GLU cell; AMPA; NMDA; Gaba; I Na,p; I Na,t; I L high threshold; I T low threshold; I K; I K,leak; I M; I h; I K,Ca; I A, slow; Ca pump; Gaba; Glutamate;
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scznet
haymod
models
morphologies
README.html
Ca_HVA.mod *
Ca_LVAst.mod *
CaDynamics_E2.mod *
epsp.mod *
Ih.mod *
Im.mod *
K_Pst.mod *
K_Tst.mod *
Nap_Et2.mod *
NaTa_t.mod *
SK_E2.mod *
SKv3_1.mod *
calcifcurves.py
calcifcurves_comb.py
collectppispthrcoeff300_relthr.py
collectscalings_cs.py
collectthresholddistalamps300.py
copydata.sh
drawppiranges.py
drawsubthppiamps_comb.py
findsubthppi300_relthr.py
findsubthppi300_relthr_comb_one.py
findthresholddistalamp300_control.py
findthresholddistalamps300.py
findthresholddistalamps300_comb.py
mutation_stuff.py *
mutation_stuff.pyc
mutindexlist.sav
mytools.py *
mytools.pyc
ppi300_relthr_comb_recordSK.py
presaved.tar.gz
runcontrol.py
savesynapselocations300.py
scalemutations_cs.py
testsubthppi300_comb_fixed.py
                            
from neuron import h
import matplotlib
matplotlib.use('Agg')
import numpy
from pylab import *
import mytools
import pickle
import sys
import os.path

import mutation_stuff
MT = mutation_stuff.getMT()
defVals = mutation_stuff.getdefvals()
keyList = defVals.keys()
for idefval in range(0,len(keyList)):
  if type(defVals[keyList[idefval]]) is not list:
    defVals[keyList[idefval]] = [defVals[keyList[idefval]], defVals[keyList[idefval]]] #make the dictionary values [somatic, apical]
updatedVars = ['somatic','apical','basal'] # the possible classes of segments that defVals may apply to
whichDefVal = [0,1,0]                      # use the defVal[0] for somatic and basal segments and defVal[1] for apical segments

unpicklefile = open('control_cs.sav', 'r')
unpickledlist = pickle.load(unpicklefile)
unpicklefile.close()
spikfreqs_control_All = unpickledlist[0]
timesc_control_All = unpickledlist[1]
Vsomac_control_All = unpickledlist[2]
VDerivc_control_All = unpickledlist[3]
VDcoeff_control_All = unpickledlist[4]
Is_control = unpickledlist[19]
Is = [0.2,0.4,0.6,0.8,1.0,1.2,1.4]

theseCoeffsAllAll = []

squareAmps = [[0.696,0,1.137],[0.872,0,0.993]]
epsp_gmaxs = [[0,0.0612,0.100],[0,0.455,0.518]]

for icell in range(0,2):
  spikfreqs_control = mytools.interpolate(Is_control,spikfreqs_control_All[icell],Is)
  Vsomac_control = Vsomac_control_All[icell]
  VDerivc_control = VDerivc_control_All[icell]
  VDcoeff_control = VDcoeff_control_All[icell]
  timesc_control = timesc_control_All[icell]
  print spikfreqs_control

  morphology_file = "morphologies/cell"+str(icell+1)+".asc"
  biophys_file = "models/L5PCbiophys3.hoc"
  template_file = "models/L5PCtemplate.hoc"
  v0 = -80
  ca0 = 0.0001
  proximalpoint = 400
  distalpoint = 620
  BACdt = 5.0

  h("""
load_file("stdlib.hoc")
load_file("stdrun.hoc")
objref cvode
cvode = new CVode()
cvode.active(1)
load_file("import3d.hoc")
objref L5PC
load_file(\""""+biophys_file+"""\")
load_file(\""""+template_file+"""\")
L5PC = new L5PCtemplate(\""""+morphology_file+"""\")
objref st1
st1 = new IClamp(0.5)
L5PC.soma st1
objref sl,st2,ns,syn1,con1,isyn, tvec
isyn = new Vector()
tvec = new Vector()
sl = new List()
double siteVec[2]
sl = L5PC.locateSites("apic","""+str(distalpoint)+""")
maxdiam = 0
for(i=0;i<sl.count();i+=1){
  dd1 = sl.o[i].x[1]
  dd = L5PC.apic[sl.o[i].x[0]].diam(dd1)
  if (dd > maxdiam) {
    j = i
    maxdiam = dd
  }
}
siteVec[0] = sl.o[j].x[0]
siteVec[1] = sl.o[j].x[1]
print "distalpoint gCa_HVA: ", L5PC.apic[siteVec[0]].gCa_HVAbar_Ca_HVA
print "distalpoint gCa_LVA: ", L5PC.apic[siteVec[0]].gCa_LVAstbar_Ca_LVAst
access L5PC.apic[siteVec[0]]
st2 = new IClamp(siteVec[1])
st2.amp = 0
L5PC.apic[siteVec[0]] {
  st2
  syn1 = new AlphaSynapse(siteVec[1])
  syn1.e = 0
  syn1.tau = 5
  syn1.onset = 200 + """+str(BACdt)+""" 
  cvode.record(&syn1.i,isyn,tvec)
}
objref vsoma, vdend, recSite, vdend2, isoma, cadend, cadend2, casoma
vsoma = new Vector()
casoma = new Vector()
vdend = new Vector()
cadend = new Vector()
vdend2 = new Vector()
cadend2 = new Vector()
access L5PC.soma
cvode.record(&v(0.5),vsoma,tvec)
cvode.record(&cai(0.5),casoma,tvec)
access L5PC.apic[siteVec[0]]
cvode.record(&v(siteVec[1]),vdend,tvec)
cvode.record(&cai(siteVec[1]),cadend,tvec)
sl = new List()
sl = L5PC.locateSites("apic","""+str(proximalpoint)+""")
maxdiam = 0
for(i=0;i<sl.count();i+=1){
  dd1 = sl.o[i].x[1]
  dd = L5PC.apic[sl.o[i].x[0]].diam(dd1)
  if (dd > maxdiam) {
    j = i
    maxdiam = dd
  }
}
siteVec[0] = sl.o[j].x[0]
siteVec[1] = sl.o[j].x[1]
access L5PC.apic[siteVec[0]]
recSite = new IClamp(siteVec[1])
recSite.amp = 0
L5PC.apic[siteVec[0]] {
        recSite
}
access L5PC.apic[siteVec[0]]
cvode.record(&v(siteVec[1]),vdend2,tvec)
cvode.record(&cai(siteVec[1]),cadend2,tvec)
access L5PC.soma
isoma = new Vector()
cvode.record(&st1.i,isoma,tvec)
""")

  ITERS = 20
  theseCoeffsAll = []
  theseMutValsAll = []
  theseMutVarsAll = []

  counter = -1
  for igene in range(0,len(MT)):
   theseCoeffsGene = []
   for imut in range(0,len(MT[igene])):
    theseCoeffsMut = []
    nVals = len(MT[igene][imut])*[0]
    thesemutvars = []
    for imutvar in range(0,len(MT[igene][imut])):
      thesemutvars.append(MT[igene][imut][imutvar][0])
      if type(MT[igene][imut][imutvar][1]) is int or type(MT[igene][imut][imutvar][1]) is float:
        MT[igene][imut][imutvar][1] = [MT[igene][imut][imutvar][1]]
      nVals[imutvar] = len(MT[igene][imut][imutvar][1])
    cumprodnVals = cumprod(nVals)
    allmutvars = cumprodnVals[len(MT[igene][imut])-1]*[thesemutvars[:]]
    allmutvals = []
    for iallmutval in range(0,cumprodnVals[len(MT[igene][imut])-1]):
      allmutvals.append([0]*len(thesemutvars))
    for iallmutval in range(0,cumprodnVals[len(MT[igene][imut])-1]):
      for imutvar in range(0,len(MT[igene][imut])):
        if imutvar==0:
          allmutvals[iallmutval][imutvar] = MT[igene][imut][imutvar][1][iallmutval%nVals[imutvar]]
        else:
          allmutvals[iallmutval][imutvar] = MT[igene][imut][imutvar][1][(iallmutval/cumprodnVals[imutvar-1])%nVals[imutvar]]
    theseMutValsAll.append(allmutvals[:])  
    theseMutVarsAll.append(allmutvars[:])  
    for iallmutval in range(0,cumprodnVals[len(MT[igene][imut])-1]):
      counter = counter + 1
      if len(sys.argv) > 1 and int(float(sys.argv[1])) != counter:
        continue
      nextCoeffs = [0.0,2.0,1.0]
      for iter in range(0,ITERS+2+3):
        thisCoeff = nextCoeffs[min(iter,2)]
   
        mutText = ""
        for imutvar in range(0,len(MT[igene][imut])):
          if imutvar > 0 and imutvar%2==0:
            mutText = mutText+"\n"
          mutvars = allmutvars[iallmutval][imutvar]
          if type(mutvars) is str:
            mutvars = [mutvars]
          mutText = mutText + str(mutvars) + ": "
          mutvals = allmutvals[iallmutval][imutvar]
          for kmutvar in range(0,len(mutvars)):
            if mutvars[kmutvar].find('offm') > -1 or mutvars[kmutvar].find('offh') > -1 or mutvars[kmutvar].find('ehcn') > -1:
              newVal = [x+thisCoeff*mutvals for x in defVals[mutvars[kmutvar]]]
              if mutvals >= 0 and kmutvar==0:
                mutText = mutText + "+" + str(mutvals*thisCoeff) +" mV"
              elif kmutvar==0:
                mutText = mutText  + str(mutvals*thisCoeff) +" mV"
            else:
              newVal = [x*(mutvals**thisCoeff) for x in defVals[mutvars[kmutvar]]]
              if kmutvar==0:
                mutText = mutText + "*" + str(mutvals**thisCoeff)
            if kmutvar < len(mutvars)-1:
              mutText = mutText + ", "
            if mutvars[kmutvar].find('_Ih') > -1:
              updateThese = [1,1,1]
            elif mutvars[kmutvar].find('_Ca_HVA') > -1 or mutvars[kmutvar].find('_Ca_LVAst') > -1 or mutvars[kmutvar].find('_SKv3.1') > -1 or mutvars[kmutvar].find('_Ca_HVA') > -1 or mutvars[kmutvar].find('_SK_E2') > -1 or mutvars[kmutvar].find('_NaTa_t') > -1 or mutvars[kmutvar].find('_CaDynamics_E2') > -1:
              updateThese = [1,1,0]
            elif mutvars[kmutvar].find('_K_Pst') > -1 or mutvars[kmutvar].find('_K_Tst') > -1 or mutvars[kmutvar].find('_Nap_Et2') > -1: 
              updateThese = [1,0,0]
            elif mutvars[kmutvar].find('_Im') > -1:
              updateThese = [0,1,0]
            else:
              print "Error: str=" + str(mutvars[kmutvar])
              updatedVars = [0,0,0]
            for iupdated in range(0,3):
              if updateThese[iupdated]:
                print """forsec L5PC."""+str(updatedVars[iupdated])+""" {
"""+mutvars[kmutvar]+""" = """+str(newVal[whichDefVal[iupdated]])+"""
}"""
                h("""forsec L5PC."""+str(updatedVars[iupdated])+""" {
"""+mutvars[kmutvar]+""" = """+str(newVal[whichDefVal[iupdated]])+"""
}""")
        print mutText
    
        ############################################# Condition 1: Short burst #############################################
        tstop = 500.0
        squareAmp = squareAmps[icell][0]
        squareDur = 150.0
        epsp_gmax = 0.0
        h("""
tstop = """+str(tstop)+"""
v_init = """+str(v0)+"""
cai0_ca_ion = """+str(ca0)+"""
st1.amp = """+str(squareAmp)+"""
st1.del = 200
st1.dur = """+str(squareDur)+"""
syn1.gmax = """+str(epsp_gmax)+"""
syn1.onset = 200 + """+str(BACdt)+""" 
""")
        h.init()
        h.run()

        times=np.array(h.tvec)
        Vsoma=np.array(h.vsoma)
        spikes = mytools.spike_times(times,Vsoma,-35,-45)
        nSpikes1 = len(spikes)

        close("all")

        f, axarr = plt.subplots(2, 3)
        axarr[0,0].plot(times, Vsoma)
        axarr[0,0].set_title("Perisomatic firing, nspikes="+str(nSpikes1))
        axarr[0,0].set_ylim([-100,40])
        for ix in range(0,3):
          for iy in range(0,2):
            axarr[iy,ix].set_position([0.05+0.3*ix, 0.05+0.4*(1-iy), 0.23, 0.3])

        ############################################# Condition 2: Distal EPSC #############################################
        squareAmp = 0.0
        epsp_gmax = epsp_gmaxs[icell][1]
        h("""
tstop = """+str(tstop)+"""
v_init = """+str(v0)+"""
cai0_ca_ion = """+str(ca0)+"""
st1.amp = """+str(squareAmp)+"""
st1.dur = """+str(squareDur)+"""
syn1.gmax = """+str(epsp_gmax)+"""
syn1.onset = 200 + """+str(BACdt)+""" 
""")
        h.init()
        h.run()
        times=np.array(h.tvec)
        Vdend=np.array(h.vdend)
        Vdend2=np.array(h.vdend2)
        Vsoma=np.array(h.vsoma)
        spikes = mytools.spike_times(times,Vsoma,-35,-45)
        nSpikes2 = len(spikes)
        axarr[1,0].plot(times, Vsoma)
        axarr[1,0].plot(times, Vdend2)
        axarr[1,0].plot(times, Vdend)
        axarr[1,0].set_ylim([-100,40])
        axarr[1,0].set_title("Strong distal EPSC, nspikes="+str(nSpikes2))

        ############################################# Condition 3: Somatic stim + EPSC #############################################
        squareAmp = squareAmps[icell][2]
        squareDur = 10
        epsp_gmax = epsp_gmaxs[icell][2]
        h("""
tstop = """+str(tstop)+"""
v_init = """+str(v0)+"""
cai0_ca_ion = """+str(ca0)+"""
st1.amp = """+str(squareAmp)+"""
st1.dur = """+str(squareDur)+"""
syn1.gmax = """+str(epsp_gmax)+"""
syn1.onset = 200 + """+str(BACdt)+""" 
""")
        h.init()
        h.run()
        times=np.array(h.tvec)
        Vdend=np.array(h.vdend)
        Vdend2=np.array(h.vdend2)
        Vsoma=np.array(h.vsoma)
        spikes = mytools.spike_times(times,Vsoma,-35,-45)
        nSpikes3 = len(spikes)
        axarr[1,1].plot(times, Vsoma)
        axarr[1,1].plot(times, Vdend2)
        axarr[1,1].plot(times, Vdend)
        axarr[1,1].set_ylim([-100,40])
        axarr[1,1].set_title("Short stimulus at soma + weak EPSC, nspikes="+str(nSpikes3))

        ############################################# Condition 4: IF curve #############################################
        spikfreqs = len(Is)*[0]
        for iI in range(0,len(Is)):
          tstop = 4000.0
          squareAmp = Is[iI]
          squareDur = 3800.0
          epsp_gmax = 0.0
          h("""
tstop = """+str(tstop)+"""
v_init = """+str(v0)+"""
cai0_ca_ion = """+str(ca0)+"""
st1.amp = """+str(squareAmp)+"""
st1.del = 200
st1.dur = """+str(squareDur)+"""
syn1.gmax = """+str(epsp_gmax)+"""
syn1.onset = 200 + """+str(BACdt)+""" 
""")
          h.init()
          h.run()

          times=np.array(h.tvec)
          Vsoma=np.array(h.vsoma)
          spikes = mytools.spike_times(times,Vsoma,-35,100)
          spikfreqs[iI] = sum([1 for x in spikes if x >= 500.0])/3.5
          if iI==4: # use the memb. pot. time course of 1.0nA for the limit cycle
            times_lc = times[:]
            Vsoma_lc = Vsoma[:]
            spikes_lc = spikes[:]

        axarr[0,2].plot(Is, spikfreqs)
        axarr[0,2].set_xlim([0,1.25])
        axarr[0,2].set_ylim([0,20])
        spikfreqdiffsum = sum([abs(x-y) for x,y in zip(spikfreqs,spikfreqs_control)])
        spikfreqdiffrel = spikfreqdiffsum/sum(spikfreqs_control)
        axarr[0,2].set_title("IF curve, diff="+str(spikfreqdiffrel))
        print "IF curve, diff="+str(spikfreqdiffrel)

        ############################################# Condition 5: Limit cycle #############################################
        if len(spikes_lc) < 3:
          lcdiff = 1e6
        else:
          spts = spikes_lc[len(spikes_lc)-3:len(spikes_lc)]
          istart = next((i for i,x in enumerate(times_lc) if x > spts[0]))
          iend = next((i for i,x in enumerate(times_lc) if x > spts[1]))+4
          nsteps = iend-istart-1
          Vsomac = Vsoma_lc[istart:iend]
          timesc = times_lc[istart:iend]
          VDerivc = mytools.membpotderivs(timesc,Vsomac)
          VDcoeff =  mytools.limitcyclescaledv(Vsomac,VDerivc,Vsomac,VDerivc)
          lcdiff1 = mytools.limitcyclediff(Vsomac[1:nsteps-1],VDerivc,Vsomac_control,VDerivc_control,VDcoeff_control)
          lcdiff2 = mytools.limitcyclediff(Vsomac_control,VDerivc_control,Vsomac[1:nsteps-1],VDerivc,VDcoeff_control)
          lcdiff = 0.5*(lcdiff1+lcdiff2)
          axarr[1,2].plot(Vsomac[1:nsteps-1],VDerivc)
          axarr[1,2].set_title("Limit cycle")
          axarr[1,2].set_xlim([-70,30])
          axarr[1,2].set_ylim([-200,600])

        f.suptitle(mutText)
        if iter < ITERS+2:
          f.savefig("vrecs_cs"+str(icell)+"_mut"+str(igene)+"_"+str(imut)+"_"+str(iallmutval)+"_ITER"+str(iter)+".png")
        else:
          f.savefig("vrecs_cs"+str(icell)+"_mut"+str(igene)+"_"+str(imut)+"_"+str(iallmutval)+"_TEST"+str(iter-ITERS-2)+".png")

        #Print the parameters and their default values:
        for idefval in range(0,len(defVals.keys())):
          thisdefval = defVals.keys()[idefval]
          if thisdefval.find('_Im') > -1:
            h('print "L5PC.apic[0].'+thisdefval+' = ", L5PC.apic[0].'+thisdefval+', "Default = ", '+str(defVals[thisdefval][1]))
            #) #+" (def="+str(defVals[thisdefval])+")"
          else:
            h('print "L5PC.soma[0].'+thisdefval+' = ", L5PC.soma[0].'+thisdefval+', "Default = ", '+str(defVals[thisdefval][0]))
            #h('print L5PC.soma[0]."+thisdefval) #+" (def="+str(defVals[thisdefval])+")"

        isChanged = nSpikes1 != 4 or nSpikes2 != 1 or nSpikes3 != 2 or spikfreqdiffrel > 0.15 or lcdiff > 600.0
        print isChanged
        if iter==0 and isChanged:
          print "Even null mutation causes different spiking!! igene="+str(igene)+", imut="+str(imut)+", iallmutval="+str(iallmutval)
          continue
        if iter==1 and not isChanged:
          print "This mutation effect does not alter spiking even when doubled!! igene="+str(igene)+", imut="+str(imut)+", iallmutval="+str(iallmutval)
          continue
        if iter>=2 and iter < ITERS+2:
          if isChanged:
            nextCoeffs = [nextCoeffs[0],nextCoeffs[2],0.5*nextCoeffs[0]+0.5*nextCoeffs[2]]
          else:
            nextCoeffs = [nextCoeffs[2],nextCoeffs[1],0.5*nextCoeffs[1]+0.5*nextCoeffs[2]]
        if iter == ITERS+1:
          nextCoeffs = [nextCoeffs[2],nextCoeffs[2],nextCoeffs[2]*0.99]
        if iter == ITERS+2:
          nextCoeffs = [nextCoeffs[0],nextCoeffs[0],nextCoeffs[0]*1.0]
        if iter == ITERS+3:
          nextCoeffs = [nextCoeffs[0],nextCoeffs[0],nextCoeffs[0]*1.01]
      

      #Restore default values:
      for imutvar in range(0,len(MT[igene][imut])):
        mutvars = allmutvars[iallmutval][imutvar]
        if type(mutvars) is str:
          mutvars = [mutvars]
        mutvals = allmutvals[iallmutval][imutvar]
        for kmutvar in range(0,len(mutvars)):
          newVal = defVals[mutvars[kmutvar]]
          if mutvars[kmutvar].find('_Ih') > -1:
            updateThese = [1,1,1]
          elif mutvars[kmutvar].find('_Ca_HVA') > -1 or mutvars[kmutvar].find('_Ca_LVAst') > -1 or mutvars[kmutvar].find('_SKv3.1') > -1 or mutvars[kmutvar].find('_Ca_HVA') > -1 or mutvars[kmutvar].find('_SK_E2') > -1 or mutvars[kmutvar].find('_NaTa_t') > -1 or mutvars[kmutvar].find('_CaDynamics_E2') > -1:
            updateThese = [1,1,0]
          elif mutvars[kmutvar].find('_K_Pst') > -1 or mutvars[kmutvar].find('_K_Tst') > -1 or mutvars[kmutvar].find('_Nap_Et2') > -1: 
            updateThese = [1,0,0]
          elif mutvars[kmutvar].find('_Im') > -1:
            updateThese = [0,1,0]
          else:
            print "Error: str=" + str(mutvars[kmutvar])
            updatedVars = [0,0,0]
          for iupdated in range(0,3):
            if updateThese[iupdated]:
              h("""forsec L5PC."""+str(updatedVars[iupdated])+""" {
"""+mutvars[kmutvar]+""" = """+str(newVal[whichDefVal[iupdated]])+"""
}""")
      theseCoeffsMut.append(nextCoeffs[0]+0.0)
      picklelist = [nextCoeffs[0]+0.0,igene,imut,iallmutval,counter,MT]
      file = open('scalings_cs'+str(icell)+'_'+str(counter)+'.sav', 'w')
      pickle.dump(picklelist,file)
      file.close()

    theseCoeffsGene.append(theseCoeffsMut[:])
   theseCoeffsAll.append(theseCoeffsGene[:])
  theseCoeffsAllAll.append(theseCoeffsAll[:])


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