1. Information
    majorVersion:3 minorVersion:0 projectID:local projectVersionID:undef fileName:/home/ikeda/eclipse/workspace/macrophage/csml/ok/csml/17082566.csml convertedTime:2009.07.01.10:58

  2. Original Literature
  3. Model OverView
  4. Model Abstracts
  5. Model Detail
  6. Download
Original Literature Model OverView
Publication
Title Nucleic acid-sensing TLRs as modifiers of autoimmunity.
Authors Deane JA, Bolland S.
Affiliation Laboratory of Immunogenetics, National Institute of Allergy and InfectiousDiseases, National Institutes of Health, Rockville, MD 20852, USA.
Abstract The immune system requires precise regulation of activating and inhibitorysignals so that it can mount effective responses against pathogens whileensuring tolerance to self-components. Some of the most potent activationsignals are triggered by innate immune molecules, particularly those in the TLRfamily. Recent studies have shown that engagement of TLRs plays a significantrole in both innate and adaptive immunity. This review focuses on the ways thatTLR function might contribute to the etiology of lupus-like syndromes in thecontext of an autoimmune-prone environment. By considering the sources,localization, and expression of both nucleic acids and the molecules that bindthem, we discuss several ways that innate immunity can play a role in thedevelopment of systemic autoimmunity.
PMID 17082566
Model Abstract

Entity

G010227:IFNalpha G010262:IL-6 G010329:TNF-alpha MO000000212:TRAF6 MO000000213:IRAK1 MO000000289:TNF-alpha MO000007384:IL-6 MO000007702:IRF-7 MO000016573:MyD88 MO000016659:IFNalpha MO000019395:TLRs MO000019398:TLR3 MO000022224:dsRNA MO000041125:TRIF MO000041446:dsRNA:TLR3 MO000042007:TLR8 MO000042012:TLR9 MO000042126:TLR7 MO000103999:MDA5 e1: e10: e11: e12:poly I: C e13:poly I: C: TLR3 e14:imidazoquinilones e15:TLR ligand: TLR: MyD88 e16:ssRNA e17:imidazoquinilones : TLR8 e18:imidazoquinilones: TLR7 e19:ssRNA: TLR8 e2: e20:ssRNA: TLR7 e21:dsDNA e22:dsDNA: TLR9 e23:TLR ligand: TLR: TRIF e24:TLR ligand e25:TLR ligand: TLR e26:TLR ligand: TLR: MyD88: IRAK1 e27:TRAF6 {activated} e28:IRF-7 {activated} e29:small RNP e3: e30:small RNP: TLR7 e31:RIG-I e32:ssRNA: RIG-I e33:ssRNA: MDA5 e4: e5: e50: e51: e52: e53: e54: e55: e56: e57: e58: e59: e6: e60: e61: e62: e7: e8: e9:

Process

p1 p10 p11 p12 p13 p14 p15 p16 p17 p18 p19 p2 p20 p21 p22 p23 p24 p3 p4 p5 p6 p7 p8 p9
Model Detail
592.0, 1052.0
32.0, 32.0

IFNalpha

--

G010227

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

--

p16 p17 p18 p19 p20

true true true true

csml-variable:Double

m93216

10

false

infinite

0

unit false false false
TRANSFACG010227

--

Go back
662.0, 930.0
28.0, 28.0

IL-6

--

G010262

cso30:c:mRNA

cso30:i:CC_Nucleoplasm

--

--

p14

true true true true

csml-variable:Double

m93248

10

false

infinite

0

unit false false false
TRANSFACG010262

--

Go back
620.0, 876.0
31.0, 31.0

TNF-alpha

--

G010329

cso30:c:mRNA

cso30:i:CC_CellComponent

--

--

p12

true true true true

csml-variable:Double

m93309

10

false

infinite

0

unit false false false
TRANSFACG010329

--

Go back
608.0, 236.0
32.0, 32.0

TRAF6

--

MO000000212

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p13

true true true true

csml-variable:Double

m183

10

false

infinite

0

unit false false false
InterProIPR001841
TRANSPATHMO000000212

--

Go back
552.0, 184.0
32.0, 32.0

IRAK1

--

MO000000213

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p11

true true true true

csml-variable:Double

m184

10

false

infinite

0

unit false false false
InterProIPR000719
TRANSPATHMO000000213

--

Go back
816.0, 876.0
32.0, 32.0

TNF-alpha

--

MO000000289

cso30:c:Protein

cso30:i:CC_CellComponent

--

p12

--

true true true true

csml-variable:Double

m230

10

false

infinite

0

unit false false false
InterProIPR003636
TRANSPATHMO000000289

--

Go back
824.0, 928.0
32.0, 32.0

IL-6

--

MO000007384

cso30:c:Protein

cso30:i:CC_CellComponent

--

p14

--

true true true true

csml-variable:Double

m871

10

false

infinite

0

unit false false false
InterProIPR003573
TRANSPATHMO000007384

--

Go back
759.0, 231.0
34.0, 34.0

IRF-7

--

MO000007702

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p15

true true true true

csml-variable:Double

m980

10

false

infinite

0

unit false false false
TRANSPATHMO000007702

--

Go back
639.0, 183.0
34.0, 34.0

MyD88

--

MO000016573

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p8

true true true true

csml-variable:Double

m1572

10

false

infinite

0

unit false false false
InterProIPR000157
TRANSPATHMO000016573

--

Go back
865.0, 1105.0
30.0, 30.0

IFNalpha

--

MO000016659

cso30:c:Protein

cso30:i:CC_CellComponent

--

p16 p17 p18 p19 p20

--

true true true true

csml-variable:Double

m1635

10

false

infinite

0

unit false false false
InterProIPR000471
TRANSPATHMO000016659

--

Go back
746.0, 126.0
28.0, 28.0

TLRs

--

MO000019395

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p10

true true true true

csml-variable:Double

m3962

10

false

infinite

0

unit false false false
TRANSPATHMO000019395

--

Go back
304.0, 121.0
29.0, 29.0

TLR3

--

MO000019398

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p1 p2

true true true true

csml-variable:Double

m3965

10

false

infinite

0

unit false false false
InterProIPR000157
TRANSPATHMO000019398

--

Go back
382.0, 35.0
34.0, 34.0

dsRNA

--

MO000022224

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p1

true true true true

csml-variable:Double

m119368

10

false

infinite

0

unit false false false
TRANSPATHMO000022224

--

Go back
777.0, 185.0
29.0, 29.0

TRIF

--

MO000041125

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p9

true true true true

csml-variable:Double

m18998

10

false

infinite

0

unit false false false
TRANSPATHMO000041125

--

Go back
377.0, 114.0
36.0, 36.0

dsRNA:TLR3

--

MO000041446

cso30:c:Protein

cso30:i:CC_CellComponent

--

p1

--

true true true true

csml-variable:Double

m19314

10

false

infinite

0

unit false false false
TRANSPATHMO000041446

--

Go back
230.0, 494.0
28.0, 28.0

TLR8

--

MO000042007

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p3 p4

true true true true

csml-variable:Double

m19823

10

false

infinite

0

unit false false false
TRANSPATHMO000042007

--

Go back
227.0, 723.0
26.0, 26.0

TLR9

--

MO000042012

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p7

true true true true

csml-variable:Double

m19828

10

false

infinite

0

unit false false false
TRANSPATHMO000042012

--

Go back
231.0, 595.0
25.0, 25.0

TLR7

--

MO000042126

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p5 p6 p21

true true true true

csml-variable:Double

m19940

10

false

infinite

0

unit false false false
TRANSPATHMO000042126

--

Go back
201.0, 285.0
30.0, 30.0

MDA5

--

MO000103999

cso30:c:Protein

cso30:i:CC_CellComponent

--

--

p24

true true true true

csml-variable:Double

m76904

10

false

infinite

0

unit false false false
TRANSPATHMO000103999

--

Go back
119.75, 96.99690800911759
856.2594311764528, 1243.2886940682085

--

e1

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane

--

--

--

true true true true

csml-variable:Double

m1

0

false

infinite

0

unit false true false

--

Go back
128.0, 116.0
829.9775981223105, 1167.545103664102

--

e10

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytosol

--

--

--

true true true true

csml-variable:Double

m10

0

false

infinite

0

unit false true false

--

Go back
230.0, 374.2871257087593
275.52428270722294, 459.9854550281604

--

e11

cso30:c:EntityBiologicalCompartment

cso30:i:CC_EndosomeMembrane

--

--

--

true true true true

csml-variable:Double

m11

0

false

infinite

0

unit false true false

--

Go back
202.0, 40.0
42.91841883936081, 24.32043734230446

poly I: C

--

e12

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p2

true true true true

csml-variable:Double

m12

0

false

infinite

0

unit false false false

--

Go back
219.625, 112.5
31.1894267622063, 38.19113481086486

poly I: C: TLR3

--

e13

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

p2

--

true true true true

csml-variable:Double

m13

0

false

infinite

0

unit false false false

--

Go back
49.5, 599.25
45.0, 25.5

imidazoquinilones

--

e14

cso30:c:SmallMolecule

cso30:i:CC_Extracellular

--

--

p3 p6

true true true true

csml-variable:Double

m14

0

false

infinite

0

unit false false false

--

Go back
595.625, 103.5
33.418555240793204, 40.92067988668556

TLR ligand: TLR: MyD88

--

e15

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

p8

p11

true true true true

csml-variable:Double

m15

0

false

infinite

0

unit false false false

--

Go back
45.5, 543.625
45.0, 24.75

ssRNA

--

e16

cso30:c:Rna

cso30:i:CC_Extracellular

--

--

p4 p5 p23 p24

true true true true

csml-variable:Double

m16

0

false

infinite

0

unit false false false

--

Go back
486.625, 635.5
27.580361606398938, 33.7718713547742

imidazoquinilones : TLR8

--

e17

cso30:c:Complex

cso30:i:CC_Cytosol

--

p3

p17

true true true true

csml-variable:Double

m17

0

false

infinite

0

unit false false false

--

Go back
445.625, 730.5
29.131769705049155, 35.67155474087652

imidazoquinilones: TLR7

--

e18

cso30:c:Complex

cso30:i:CC_Cytosol

--

p6

p19

true true true true

csml-variable:Double

m18

0

false

infinite

0

unit false false false

--

Go back
472.625, 680.5
31.09960839860024, 38.08115314114315

ssRNA: TLR8

--

e19

cso30:c:Complex

cso30:i:CC_EndosomeLumen

--

p4

p18

true true true true

csml-variable:Double

m19

0

false

infinite

0

unit false false false

--

Go back
119.75, 96.99690800911759
856.2594311764528, 1243.2886940682085

--

e2

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m2

0

false

infinite

0

unit false true false

--

Go back
401.625, 774.5
28.160098316947177, 34.48175304115981

ssRNA: TLR7

--

e20

cso30:c:Complex

cso30:i:CC_EndosomeLumen

--

p5

p20

true true true true

csml-variable:Double

m20

0

false

infinite

0

unit false false false

--

Go back
41.5, 788.125
45.0, 15.75

dsDNA

--

e21

cso30:c:Dna

cso30:i:CC_Extracellular

--

--

p7

true true true true

csml-variable:Double

m21

0

false

infinite

0

unit false false false

--

Go back
229.625, 766.5
28.151933011164804, 34.47175470754874

dsDNA: TLR9

--

e22

cso30:c:Complex

cso30:i:CC_Cytosol

--

p7

--

true true true true

csml-variable:Double

m22

0

false

infinite

0

unit false false false

--

Go back
821.625, 106.5
28.42955340776537, 34.81169805032494

TLR ligand: TLR: TRIF

--

e23

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

p9

p15

true true true true

csml-variable:Double

m23

0

false

infinite

0

unit false false false

--

Go back
620.5, 15.375
39.37609841827767, 25.59446397188049

TLR ligand

--

e24

cso30:c:Protein

cso30:i:CC_Extracellular

--

--

p10

true true true true

csml-variable:Double

m24

0

false

infinite

0

unit false false false

--

Go back
696.625, 117.5
30.209590068321948, 36.99133477753708

TLR ligand: TLR

--

e25

cso30:c:Complex

cso30:i:CC_Extracellular

--

p10

p8 p9 p22

true true true true

csml-variable:Double

m25

0

false

infinite

0

unit false false false

--

Go back
515.875, 117.5
32.25, 45.0

TLR ligand: TLR: MyD88: IRAK1

--

e26

cso30:c:Complex

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

p11

p13

true true true true

csml-variable:Double

m26

0

false

infinite

0

unit false false false

--

Go back
612.0, 292.0
32.0, 32.0

TRAF6 {activated}

--

e27

cso30:c:Protein

cso30:i:CC_CellComponent

--

p13

p12 p14

true true true true

csml-variable:Double

m27

10

false

infinite

0

unit false false false
InterProIPR001841
TRANSPATHMO000000212

--

Go back
763.0, 279.0
34.0, 34.0

IRF-7 {activated}

--

e28

cso30:c:Protein

cso30:i:CC_CellComponent

--

p15

p16

true true true true

csml-variable:Double

m28

10

false

infinite

0

unit false false false
TRANSPATHMO000007702

--

Go back
348.5, 321.625
38.35892514395392, 21.097408829174665

small RNP

--

e29

cso30:c:Rna

cso30:i:CC_Cytosol

--

--

p21

true true true true

csml-variable:Double

m29

0

false

infinite

0

unit false false false

--

Go back
136.87518862352903, 114.12209663264667
822.0090539293948, 1209.0383168211513

--

e3

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m3

0

false

infinite

0

unit false true false

--

Go back
221.625, 434.5
29.139935010831532, 35.68155307448758

small RNP: TLR7

--

e30

cso30:c:Complex

cso30:i:CC_EndosomeMembrane

--

p21

--

true true true true

csml-variable:Double

m30

0

false

infinite

0

unit false false false

--

Go back
198.375, 186.5
27.445079086115992, 42.2231985940246

RIG-I

--

e31

cso30:c:Protein

cso30:i:CC_Cytosol

--

--

p23

true true true true

csml-variable:Double

m31

0

false

infinite

0

unit false false false

--

Go back
257.375, 243.5
21.61877877658408, 41.84279763209822

ssRNA: RIG-I

--

e32

cso30:c:Complex

cso30:i:CC_Cytosol

--

p23

--

true true true true

csml-variable:Double

m32

0

false

infinite

0

unit false false false

--

Go back
253.625, 322.5
29.00112481253124, 35.511581403099484

ssRNA: MDA5

--

e33

cso30:c:Complex

cso30:i:CC_Cytosol

--

p24

--

true true true true

csml-variable:Double

m33

0

false

infinite

0

unit false false false

--

Go back
168.55678757705792, 144.09117672382234
758.6458560223374, 1149.1001566387988

--

e4

cso30:c:EntityBiologicalCompartment

cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_

--

--

--

true true true true

csml-variable:Double

m4

0

false

infinite

0

unit false true false

--

Go back
230.0, 374.2871257087593
275.52428270722294, 459.9854550281604

--

e5

cso30:c:EntityBiologicalCompartment

cso30:i:CC_EndosomeLumen

--

--

--

true true true true

csml-variable:Double

m5

0

false

infinite

0

unit false true false

--

Go back
301.0, 814.0
465.6500709748862, 422.29345356567933

--

e50

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelopeLumen

--

--

--

true true true true

csml-variable:Double

m50

0

false

infinite

0

unit false true false

--

Go back
351.29367619468036, 824.0077409313898
272.27955732982184, 409.2864683429171

--

e51

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearPore

--

--

--

true true true true

csml-variable:Double

m51

0

false

infinite

0

unit false true false

--

Go back
307.06992643728904, 819.6363602631969
453.51021810030846, 411.0207330392853

--

e52

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearInnerMembrane

--

--

--

true true true true

csml-variable:Double

m52

0

false

infinite

0

unit false true false

--

Go back
307.93705878547314, 820.503492611381
451.7759534039399, 409.2864683429171

--

e53

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearLumen

--

--

--

true true true true

csml-variable:Double

m53

0

false

infinite

0

unit false true false

--

Go back
301.0, 814.0
465.6500709748862, 422.29345356567933

--

e54

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearOuterMembrane

--

--

--

true true true true

csml-variable:Double

m54

0

false

infinite

0

unit false true false

--

Go back
301.0, 814.0
465.6500709748862, 422.29345356567933

--

e55

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleus

--

--

--

true true true true

csml-variable:Double

m55

0

false

infinite

0

unit false true false

--

Go back
307.93705878547314, 820.503492611381
451.7759534039399, 409.2864683429171

--

e56

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleoplasm

--

--

--

true true true true

csml-variable:Double

m56

0

false

infinite

0

unit false true false

--

Go back
640.9158804881849, 987.4264696368292
29.091257918298922, 26.33524401024959

--

e57

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearBody

--

--

--

true true true true

csml-variable:Double

m57

0

false

infinite

0

unit false true false

--

Go back
564.6082338479803, 1108.8249983826097
82.37757307749382, 74.57338194383664

--

e58

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Nucleolus

--

--

--

true true true true

csml-variable:Double

m58

0

false

infinite

0

unit false true false

--

Go back
301.0, 814.0
465.6500709748862, 422.29345356567933

--

e59

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearEnvelope

--

--

--

true true true true

csml-variable:Double

m59

0

false

infinite

0

unit false true false

--

Go back
230.0, 374.2871257087593
275.52428270722294, 459.9854550281604

--

e6

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Endosome

--

--

--

true true true true

csml-variable:Double

m6

0

false

infinite

0

unit false true false

--

Go back
410.7511016961721, 1001.6637213250546
14.746453546866459, 7.100144300343119

--

e60

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Chromatin

--

--

--

true true true true

csml-variable:Double

m60

0

false

infinite

0

unit false true false

--

Go back
410.25867587120234, 980.4894108513561
50.4736470593979, 90.85256470691624

--

e61

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearChromosome

--

--

--

true true true true

csml-variable:Double

m61

0

false

infinite

0

unit false true false

--

Go back
431.43298634490145, 1039.5805098477247
7.878813199515761, 7.8788131995157675

--

e62

cso30:c:EntityBiologicalCompartment

cso30:i:CC_NuclearCentromere

--

--

--

true true true true

csml-variable:Double

m62

0

false

infinite

0

unit false true false

--

Go back
131.0, 102.0
839.7237354966342, 1189.8668429177399

--

e7

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell

--

--

--

true true true true

csml-variable:Double

m7

0

false

infinite

0

unit false true false

--

Go back
134.0, 123.0
805.5569854171277, 1169.6687428256696

--

e8

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cell_WithoutCellWall_

--

--

--

true true true true

csml-variable:Double

m8

0

false

infinite

0

unit false true false

--

Go back
142.0, 144.0
801.8791759029863, 1154.3288303559784

--

e9

cso30:c:EntityBiologicalCompartment

cso30:i:CC_Cytoplasm

--

--

--

true true true true

csml-variable:Double

m9

0

false

infinite

0

unit false true false

--

Go back
329.0, 62.0
27.0, 27.0

p1

p1

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000019398 MO000022224

MO000041446

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c4 : 1
stoichiometry:c5 : 1
stoichiometry:c6 : 1

m3965*m119368*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
700.0, 16.0
23.0, 23.0

p10

p10

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

e24 MO000019395

e25

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c22 : 1
stoichiometry:c26 : 1
stoichiometry:c28 : 1

m24*m3962*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
555.0, 67.0
25.0, 25.0

p11

p11

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

e15 MO000000213

e26

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c31 : 1
stoichiometry:c32 : 1
stoichiometry:c33 : 1

m15*m184*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
739.0, 879.0
25.0, 25.0

p12

p12

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010329 e27

MO000000289

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c39 : 1
stoichiometry:c41 : 1
stoichiometry:c37 : 1

m93309*m27*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
522.0, 294.0
27.0, 27.0

p13

p13

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

MO000000212 e26

e27

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c34 : 1
stoichiometry:c36 : 1
stoichiometry:c35 : 1

m183*m26*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
775.0, 931.0
25.0, 25.0

p14

p14

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010262 e27

MO000007384

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c40 : 1
stoichiometry:c42 : 1
stoichiometry:c38 : 1

m93248*m27*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
821.0, 249.0
30.0, 30.0

p15

p15

cso30:i:ME_UnknownActivation

cso30:i:CC_Cytosol

--

e23 MO000007702

e28

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c43 : 1
stoichiometry:c44 : 1
stoichiometry:c45 : 1

m23*m980*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
799.0, 987.0
25.0, 25.0

p16

p16

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010227 e28

MO000016659

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c47 : 1
stoichiometry:c48 : 1
stoichiometry:c46 : 1

m93216*m28*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
793.0, 1037.0
25.0, 25.0

p17

p17

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010227 e17

MO000016659

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c49 : 1
stoichiometry:c53 : 1
stoichiometry:c57 : 1

m93216*m17*0.1

nodelay

--

true

0

false

PMID: 17082566, 16330816 So far, human studies have shown that sera from lupus patients can stimulate IFN-alpha production in a TLR7/8-dependent manner.

Go back
792.0, 1080.0
26.0, 26.0

p18

p18

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010227 e19

MO000016659

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c50 : 1
stoichiometry:c54 : 1
stoichiometry:c58 : 1

m93216*m19*0.1

nodelay

--

true

0

false

PMID: 17082566, 16330816 So far, human studies have shown that sera from lupus patients can stimulate IFN-alpha production in a TLR7/8-dependent manner.

Go back
775.0, 1115.0
25.0, 25.0

p19

p19

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010227 e18

MO000016659

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c51 : 1
stoichiometry:c55 : 1
stoichiometry:c59 : 1

m93216*m18*0.1

nodelay

--

true

0

false

PMID: 17082566, 16330816 So far, human studies have shown that sera from lupus patients can stimulate IFN-alpha production in a TLR7/8-dependent manner.

Go back
269.0, 66.0
27.0, 27.0

p2

p2

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000019398 e12

e13

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c2 : 1
stoichiometry:c3 : 1

m3965*m12*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
755.0, 1147.0
25.0, 25.0

p20

p20

cso30:i:ME_Translation

cso30:i:CC_Cytosol

--

G010227 e20

MO000016659

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c52 : 1
stoichiometry:c56 : 1
stoichiometry:c60 : 1

m93216*m20*0.1

nodelay

--

true

0

false

PMID: 17082566, 16330816 So far, human studies have shown that sera from lupus patients can stimulate IFN-alpha production in a TLR7/8-dependent manner.

Go back
308.0, 440.0
23.0, 23.0

p21

p21

cso30:i:ME_Binding

cso30:i:CC_EndosomeLumen

--

e29 MO000042126

e30

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c61 : 1
stoichiometry:c62 : 1
stoichiometry:c63 : 1

m29*m19940*0.1

nodelay

--

true

0

false

PMID: 17082566, 16230478, 16330816, 16368889 Additionally, several studies have shown that endogenous mammalian ligands of TLR7 such as small RNPs are capable of stimulating B cells and plasmacytoid dendritic cells.

Go back
1005.0, 293.0
30.0, 30.0

p22

p22

cso30:i:CE_CellDifferentiation

cso30:i:CC_Extracellular

--

e25

--

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c64 : 1

m25*0.1

nodelay

--

true

0

false

PMID: 17082566 It is probable that both dendritic cell and B cell Ag presentation are enhanced upon signaling through TLRs, which could drive Th cell development and activation.

Go back
56.0, 252.0
23.0, 23.0

p23

p23

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

e31 e16

e32

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c65 : 1
stoichiometry:c66 : 1
stoichiometry:c67 : 1

m31*m16*0.1

nodelay

--

true

0

false

PMID: 17082566, 16625202, 16413926 For example, the RNA-sensing helicases RIG-I and MDA5 have been characterized recently and implicated in antiviral inflammatory responses in a TLR-independent manner.

Go back
82.0, 326.0
27.0, 27.0

p24

p24

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000103999 e16

e33

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c68 : 1
stoichiometry:c69 : 1
stoichiometry:c70 : 1

m76904*m16*0.1

nodelay

--

true

0

false

--

Go back
180.0, 496.0
23.0, 23.0

p3

p3

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000042007 e14

e17

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c11 : 1
stoichiometry:c15 : 1

m19823*m14*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
184.0, 544.0
23.0, 23.0

p4

p4

cso30:i:ME_Binding

cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_

--

MO000042007 e16

e19

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c8 : 1
stoichiometry:c13 : 1
stoichiometry:c16 : 1

m19823*m16*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
184.0, 656.0
23.0, 23.0

p5

p5

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000042126 e16

e20

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c9 : 1
stoichiometry:c14 : 1
stoichiometry:c18 : 1

m19940*m16*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
184.0, 600.0
23.0, 23.0

p6

p6

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000042126 e14

e18

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c12 : 1
stoichiometry:c17 : 1

m19940*m14*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
52.0, 724.0
23.0, 23.0

p7

p7

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000042012 e21

e22

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c20 : 1
stoichiometry:c21 : 1

m19828*m21*0.1

nodelay

--

true

0

false

PMID: 17082566 For the purposes of this review, it is important to highlight the four nucleic acid-sensing TLRs: TLR3 shows specificity for poly(I:C) compounds and dsRNA, while TLRs 7 and 8 recognize imidazoquinilones and ssRNA, and TLR9 binds dsDNA.

Go back
643.0, 67.0
25.0, 25.0

p8

p8

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000016573 e25

e15

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c23 : 1
stoichiometry:c29 : 1
stoichiometry:c24 : 1

m1572*m25*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
780.0, 56.0
23.0, 23.0

p9

p9

cso30:i:ME_Binding

cso30:i:CC_Extracellular

--

MO000041125 e25

e23

true true true true

--

and

mass

coefficient1:0.1
coefficient2:1.0
stoichiometry:c25 : 1
stoichiometry:c30 : 1
stoichiometry:c27 : 1

m18998*m25*0.1

nodelay

--

true

0

false

PMID: 17082566, 16410796, 15492225, 15361868 While some TLRs seem to rely mainly on MyD88 to produce cytokines like IL-6 and TNF-alpha, others also recruit adaptor molecules and transcription factors such as Toll/IL-1R-domain-containing adapter-inducing IFN-beta, TNFR-associated factor 6, IL-1R-associated kinase-1, and IFN regulatory factor-7 to potently stimulate the transcription of IFN-alpha.

Go back
295.326060730508, 99.72942780301243

c1

c1

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
214.97236606595902, 609.0

c10

c10

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
87.0, 523.2542459584336

c11

c11

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
95.0, 612.0

c12

c12

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
91.0, 556.0

c13

c13

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
82.0, 568.0

c14

c14

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
203.0, 513.0

c15

c15

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
207.0, 561.0

c16

c16

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
207.0, 618.0

c17

c17

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
207.0, 674.0

c18

c18

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
83.0, 736.0

c19

c19

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
245.0, 63.0

c2

c2

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
64.0, 755.0

c20

c20

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
75.0, 739.0

c21

c21

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
660.0, 28.0

c22

c22

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
656.0, 100.0

c23

c23

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
634.6568542494924, 92.0

c24

c24

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
792.0, 87.0

c25

c25

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
720.1309168643905, 46.36188560005348

c26

c26

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
800.0, 79.0

c27

c27

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
712.0, 39.0

c28

c28

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
673.6568542494924, 97.65685424949238

c29

c29

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
256.3813823519705, 93.0

c3

c3

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
727.0, 83.17784657548758

c30

c30

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
585.6568542494924, 97.65685424949238

c31

c31

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
568.0, 100.0

c32

c32

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
549.9977796279167, 92.0

c33

c33

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
555.7257215188587, 262.0

c34

c34

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
549.0, 308.0

c35

c35

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
533.0, 163.0

c36

c36

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
764.0, 892.0

c37

c37

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
800.0, 944.0

c38

c38

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
651.0, 892.0

c39

c39

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
325.0, 96.41173261697847

c4

c4

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
690.0, 944.0

c40

c40

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
631.0, 324.0

c41

c41

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
632.0, 324.0

c42

c42

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
836.0, 141.0

c43

c43

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
793.0, 253.0

c44

c44

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
803.9102312071875, 272.0

c45

c45

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
819.0, 1012.0

c46

c46

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
624.0, 1006.5557984638539

c47

c47

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
781.0, 313.0

c48

c48

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
624.0, 1051.754024724077

c49

c49

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
363.3677380085485, 59.0

c5

c5

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
624.0, 1070.0

c50

c50

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
624.0, 1073.0

c51

c51

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
624.0, 1077.0

c52

c52

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
513.0, 669.0

c53

c53

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
503.0, 719.0

c54

c54

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
475.0, 765.0

c55

c55

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
430.0, 806.0

c56

c56

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
818.0, 1061.0

c57

c57

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
818.0, 1098.0

c58

c58

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
800.0, 1121.7353353937362

c59

c59

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
355.0, 89.0

c6

c6

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
780.0, 1127.7410427608056

c60

c60

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
327.9843139777272, 343.0

c61

c61

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
250.0, 470.1770339065574

c62

c62

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
259.0, 452.0

c63

c63

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
727.0, 144.0

c64

c64

cso30:c:InputAssociation

--

true true true true

cso30:c:InputAssociation

threshold

--

0

1,

--

Go back
86.44067968072669, 213.0

c65

c65

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
68.0, 283.0

c66

c66

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
79.0, 264.0

c67

c67

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
116.58118570263419, 305.0

c68

c68

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
70.0, 360.9375820117202

c69

c69

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
211.0, 508.0

c7

c7

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
109.0, 340.0

c70

c70

cso30:c:OutputProcess

--

true true true true

cso30:c:OutputProcess

threshold

--

0

1,

--

Go back
212.65685424949237, 522.0

c8

c8

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back
210.91152490811936, 620.0

c9

c9

cso30:c:InputProcess

--

true true true true

cso30:c:InputProcess

threshold

--

0

1,

--

Go back