The Jing-Mai System
in Vertebrate Development and Evolution
Rainer Machne
Bled, February 2004
Institute for Theoretical Chemistry and Structural Biology
Institute of Microbiology and Genetics
University of Vienna
not:
Outline
• The Multiscale Complexity of Biological Signaling Networks
• Developmental Models: Morphogenes and Gene Regulatory Networks
• The Jing-Mai System and Neurocristophathies
• Vertebrate Innovations: Neural Crest and Hyaluronan
Outline
• Jing-Mai Hypotheses
• The Biochemistry of Yin and Yang
• Fractal Rythms
• TCM: a translation problem
Biological Signaling Networks
proliferation vs. differentiation, migration vs. adhesion
putting together the pieces, beginning to unravel the net
Hanahan and Weinberg 2000
A migrating cell
cells are gels, not aqueous bags
Li 2002, Pollack 2003
SBML - exchanging and merging models
0.05 0.1 0.15 0.2 0.25 0.3time [s]
1
2
3
4
5
6
Con
cent
ratio
n
GLCiATPG6PADPF6PF16bPAMPDHAPGAPNADBPGNADHP3GP2GPEPPYRAcAldGLCoF26bPCO2EtOHGlycerolGlycogenTrehaloseSuccinatecompartment
Yeast Glycolysis
-10 0 10 20 30 40 50 60 70 80 90time
-20
-15
-10
-5
0
5
10
15
20
25
30
35
40
45
50xyzEmptySetatmosphere
Lorenz EN (1963) Deterministic nonperiodic flow. Journal of the Atmospheric Sciences
0 100time [h]
0
1
2
3
4
5
6
7
8
Con
cent
ratio
n
Circadian rythms, birythmic
0 10 20 30 40 50 60 70 80 90 100time [min]
0
0.2
0.4
Con
cent
ratio
n
Cell Cycle
www.sbml.org
Metabolic Network of Chlamydia trachomatis
ATPSYN__45__RXN
PROTON_periplasm Pi
ADP
PROTON
SUPEROX__45__DISMUT__45__RXN
2
DIHYDROPICRED__45__RXN
ACETYL__45__COA__45__CARBOXYLTRANSFER__45__RXN
CARBPSYN__45__RXN
WATER
ACONITATEHYDR__45__RXN
ADDALT__45__RXN
GDPMANMANHYDRO__45__RXN
LIPIDXSYNTHESIS__45__RXN
UGD__45__RXN
IMP__45__DEHYDROG__45__RXN
LEUCINE__45__DEHYDROGENASE__45__RXN
GMP__45__SYN__45__GLUT__45__RXN
FGAMSYN__45__RXN
CTPSYN__45__RXN
TETHYDPICSUCC__45__RXN
PEPSYNTH__45__RXN
PRPPAMIDOTRANS__45__RXN
PEPCARBOX__45__RXN
CITSYN__45__RXN
OHMETHYLBILANESYN__45__RXN
_6PGLUCONOLACT__45__RXN
PALMITOYL__45__COA__45__HYDROLASE__45__RXNPSERPHOSPHA__45__RXNF16BDEPHOS__45__RXN
GLUCOSE__45__1__45__PHOSPHAT__45__RXN
GPH__45__RXN
SUCCDIAMINOPIMDESUCC__45__RXN
ASPARAGHYD__45__RXN
FORMYLMETHIONINE__45__DEFORMYLASE__45__RXN
FORMYLTHFDEFORMYL__45__RXN
DIHYDROOROT__45__RXN
METHENYLTHFCYCLOHYDRO__45__RXN
ADENODEAMIN__45__RXN
IMPCYCLOHYDROLASE__45__RXN
CYTDEAM__45__RXN
GTP__45__CYCLOHYDRO__45__II__45__RXN
3
CYTIDEAM__45__RXNCYTIDEAM2__45__RXNDCTP__45__DEAM__45__RXN
AMP__45__NUCLEOSID__45__RXN
INORGPYROPHOSPHAT__45__RXN
DUTP__45__PYROP__45__RXN
ATP
DARABKIN__45__RXN
SUCCCOASYN__45__RXN
2
GMP__45__SYN__45__NH3__45__RXN
GLYRIBONUCSYN__45__RXN
FORMATETHFLIG__45__RXN
DALADALALIG__45__RXN
DIHYDROFOLATESYNTH__45__RXN
UDP__45__NACMURALA__45__GLU__45__LIG__45__RXN
UDP__45__NACMUR__45__ALA__45__LIG__45__RXN
SAICARSYN__45__RXN DETHIOBIOTIN__45__SYN__45__RXN
AIRS__45__RXN
_6PFRUCTPHOS__45__RXN
SHIKIMATE__45__KINASE__45__RXND__45__RIBULOKIN__45__RXN
RIBOKIN__45__RXN
GALACTOKIN__45__RXN
RIBOFLAVINKIN__45__RXN
GLUCONOKIN__45__RXN
PEPDEPHOS__45__RXN
GLYCEROL__45__KIN__45__RXN
MANNKIN__45__RXN
INOSINEKIN__45__RXN
PHOSGLYPHOS__45__RXN
ACETATEKIN__45__RXN
ASPARTATEKIN__45__RXN
GLUC1PADENYLTRANS__45__RXN
FADSYN__45__RXN
ARGININE__45__KINASE__45__RXN
H2PTERIDINEPYROPHOSPHOKIN__45__RXN
UMPKI__45__RXN
ADENYL__45__KIN__45__RXN
UDPKIN__45__RXN
CDPKIN__45__RXN
CMPKI__45__RXN
GUANYL__45__KIN__45__RXN
DADPKIN__45__RXN
GDPKIN__45__RXN
DCDPKIN__45__RXN
DUDPKIN__45__RXN
DGDPKIN__45__RXN
DTMPKI__45__RXN
DTDPKIN__45__RXN
GARTRANSFORMYL2__45__RXN
PEPCARBOXYKIN__45__RXN
URA__45__PHOSPH__45__RXN
ADENPHOSPHOR__45__RXN
INOPHOSPHOR__45__RXN
GAPOXNPHOSPHN__45__RXN
ASPARTATE__45__SEMIALDEHYDE__45__DEHYDROGENASE__45__RXN
PHOSACETYLTRANS__45__RXN
URPHOS__45__RXN
THYM__45__PHOSPH__45__RXN
DAHPSYN__45__RXN
DEOXY__45__RIBOSE__45__1P
URACIL
DEOXYURIDINE
DEOXYADENPHOSPHOR__45__RXN
DEOXYINOPHOSPHOR__45__RXN
D__45__PPENTOMUT__45__RXN
PSEUDOURIDYLATE__45__SYNTHASE__45__RXN
_2OXOGLUTARATEDEH__45__RXN
SUC__45__COA
CARBON__45__DIOXIDE
NADH
_2__45__KETOGLUTARATE
SUCCINYLDIAMINOPIMTRANS__45__RXN
ASPAMINOTRANS__45__RXN
CO__45__A
PYRUVDEH__45__RXN
ACETALD__45__DEHYDROG__45__RXN MALSYN__45__RXN
NAD
GCVMULTI__45__RXN
2
DLACTDEHYDROGNAD__45__RXN MALIC__45__NAD__45__RXNMALATE__45__DEH__45__RXNGLYCDEH__45__RXNMETHYLENETHFREDUCT__45__RXN
FORMATEDEHYDROG__45__RXN
ALCOHOL__45__DEHYDROG__45__RXN
_2TRANSKETO__45__RXN
FRUCTOSE__45__6P
GAP
ERYTHROSE__45__4P
XYLULOSE__45__5__45__PHOSPHATE
_1TRANSKETO__45__RXN
L__45__GLN__45__FRUCT__45__6__45__P__45__AMINOTRANS__45__RXN
_2__46__7__46__1__46__90__45__RXN
TRANSALDOL__45__RXN
TRIOSEPISOMERIZATION__45__RXN
threo__45__d__40__s__41____45__iso__45__citrate
CIS__45__ACONITATE
ISOCITDEH__45__RXN
ISOCIT__45__CLEAV__45__RXN
AMMONIA
DEOXYINOSINE
DEOXYADENOSINE
RIBOSE__45__1P
ADENINE
ADENOSINE
PPENTOMUT__45__RXN
ETOH
ACETALD
CYTIDINEKIN__45__RXN
CMP
GDP
CYTIDINE
GTP
ADENYLOSUCCINATE__45__SYNTHASE__45__RXN URKI__45__RXN
MANNPGUANYLTRANGDP__45__RXN
DARABALDOL__45__RXN
GLYCOLALDEHYDE DIHYDROXY__45__ACETONE__45__PHOSPHATE
D__45__RIBULOSE__45__1__45__P
RIBULOSE
HYPOXANTHINE
HYPXPRIBOSYLTRAN__45__RXN
DIOHBUTANONEPSYN__45__RXN
DIHYDROXY__45__BUTANONE__45__P FORMATE
RIBULOSE__45__5P
RIBULP3EPIM__45__RXN
PYRUVFORMLY__45__RXN
ACETYL__45__COA
PYRUVATE
DIHYDRODIPICSYN__45__RXN
GLUCOSAMINE1PACETYL__45__RXN
METHYLENE__45__THF
GLY
THF
DIHYDROFOLATEREDUCT__45__RXNGLYOHMETRANS__45__RXN
METHYLENETHFDEHYDROG__45__NADP__45__RXNTHYMIDYLATESYN__45__RXN
PHOSGLUCOSAMINEMUT__45__RXN
GLUCOSAMINE__45__1P
D__45__GLUCOSAMINE__45__6__45__P
MANNOSE
GDP__45__MANNOSE
GDPMANDEHYDRA__45__RXN
N__45__ACETYL__45__D__45__GLUCOSAMINE__45__1__45__P
NAG1P__45__URIDYLTRANS__45__RXN
PPI
IMP
PRPP
PRTRANS__45__RXN
ADENPRIBOSYLTRAN__45__RXN
URACIL__45__PRIBOSYLTRANS__45__RXN
OROPRIBTRANS__45__RXN
BISOHMYR__45__GLUCOSAMINYL__45__1P
UMP
OH__45__MYRISTOYL
INOSINE
GLUCDEHYDROG__45__RXN
GLC__45__D__45__LACTONE
NADPH
GLC
GLUCISOM__45__RXN
NADP
UDPNACETYLMURAMATEDEHYDROG__45__RXN_6PGLUCONDEHYDROG__45__RXN SHIKIMATE__45__5__45__DEHYDROGENASE__45__RXNMALIC__45__NADP__45__RXN
GLU6PDEHYDROG__45__RXN
HOMOSERDEHYDROG__45__RXN
GLYC3PDEHYDROG__45__RXN
FADH2
FAD
SUCC__45__FUM__45__OXRED__45__RXN
GLYCEROL__45__3P
2
UDP__45__GLUCURONATE
UDP__45__GLUCOSE
GALACTURIDYLYLTRANS__45__RXN UDPGLUCEPIM__45__RXN
UDP__45__ACETYL__45__CARBOXYVINYL__45__GLUCOSAMINE
UDP__45__N__45__ACETYLMURAMATE
_6__45__P__45__GLUCONATE
_3__45__DEHYDRO__45__SHIKIMATE
SHIKIMATE
D__45__LACTATE
MAL
FUMHYDR__45__RXN
D__45__6__45__P__45__GLUCONO__45__DELTA__45__LACTONE
GLC__45__6__45__P
PGLUCISOM__45__RXN
OXALACETIC_ACID
OXALODECARB__45__RXN
DIHYDROXYACETONE
GLYCEROL
L__45__ASPARTATE__45__SEMIALDEHYDE
HOMO__45__SER
XANTHOSINE__45__5__45__PHOSPHATE
CATAL__45__RXN
2
OXYGEN__45__MOLECULE
HYDROGEN__45__PEROXIDE
2
PROTOPORGENOXI__45__RXN
COPROGENOXI__45__RXNDIHYDROOROTOX__45__RXN
_5__45__METHYL__45__THF
HOMOCYSMETB12__45__RXN
SUPER__45__OXIDE
2
_5__44__10__45__methenyl__45__thf
DIHYDROFOLATE
_2K__45__4CH3__45__PENTANOATE
LEU
FUM
SUC
DELTA__123__1__125____45__PIPERIDEINE__45__2__45__6__45__DICARBOXYLATE
_2__44__3__45__dihydrodipicolinate
2
PROTOPORPHYRIN_IX
PROTOPORPHYRINOGEN
2
2
COPROPORPHYRINOGEN_III
OROTATE
DI__45__H__45__OROTATE
DPG
L__45__BETA__45__ASPARTYL__45__P
MALONYL__45__COA
HCO3
GLT
GMP
AMP
GLN
PABASYN__45__RXN
ANTHRANSYN__45__RXN
GLUTRACE__45__RXN
2
CARBAMOYL__45__P
ASPCARBTRANS__45__RXN
_5__45__PHOSPHORIBOSYL__45__N__45__FORMYLGLYCINEAMIDINE
_5__45__P__45__RIBOSYL__45__N__45__FORMYLGLYCINEAMIDE
ADENYLOSUCC
L__45__ASPARTATE
ASPARTASE__45__RXN
AMPSYN__45__RXN
_5__45__PHOSPHO__45__RIBOSYL__45__GLYCINEAMIDE
PRA
GART__45__RXN
_10__45__FORMYL__45__THF
AICARTRANSFORM__45__RXN
CTP
UTP
GLUC1PURIDYLTRANS__45__RXN
D__45__ALA__45__D__45__ALA
D__45__ALANINE
_7__44__8__45__dihydropteroate
UDP__45__AA__45__GLUTAMATE
D__45__GLT
UDP__45__ACETYLMURAMOYL__45__ALA
L__45__ALPHA__45__ALANINE
_7KAPSYN__45__RXN
P__45__RIBOSYL__45__4__45__SUCCCARB__45__AMINOIMIDAZOLE
PHOSPHORIBOSYL__45__CARBOXY__45__AMINOIMIDAZOLE
AICARSYN__45__RXN
DETHIOBIOTIN
DIAMINONONANOATE
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D__45__SEDOHEPTULOSE__45__7__45__P
RIBOSE__45__5P
RIB5PISOM__45__RXN
N__45__SUCCINYL__45__2__45__AMINO__45__6__45__KETOPIMELATE
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_6__45__CARBOXYHEXANOYL__45__COA
DAPASYN__45__RXN
ACETYL__45__P
n__45__succinylll__45__2__44__6__45__diaminopimelate
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S__45__ADENOSYLMETHIONINE
PHOSPHO__45__ENOL__45__PYRUVATE
UDPNACETYLGLUCOSAMENOLPYRTRANS__45__RXN
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URIDINE
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F16ALDOLASE__45__RXN
SHIKIMATE__45__5P
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GALACTOSE__45__1P
GALACTOSE
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RIBOFLAVIN
GLUCONATE
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MANNPISOM__45__RXN
G3P
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PHOSMANMUT__45__RXN
GLC__45__1__45__P
PHOSPHOGLUCMUT__45__RXN
ADP__45__D__45__GLUCOSE
UDP__45__GLACTOSE
CPD__45__493
ARG
DIHYDROPTERIN__45__CH2OH__45__PP
AMINO__45__OH__45__HYDROXYMETHYL__45__DIHYDROPTERIDINE
H2PTEROATESYNTH__45__RXN
UDPCDP
DATP
DADP
DCTP
DCDP
DUTP
DUDP
DGTP
DGDP
TDP
TMP
TTP
_3__45__ENOLPYRUVYL__45__SHIKIMATE__45__5P
CHORISMATE__45__SYNTHASE__45__RXN
RIBOFLAVIN__45__SYN__45__RXN
RIBITYLAMINO__45__AMINO__45__DIHYDROXY__45__PYR
DIMETHYL__45__D__45__RIBITYL__45__LUMAZINE
2
P__45__AMINO__45__BENZOATE
PHOSPHORIBOSYL__45__FORMAMIDO__45__CARBOXAMIDE
AICAR
SER
TRYPSYN__45__RXN
CARBAMYUL__45__L__45__ASPARTATE
DUMP
MET
HOMO__45__CYS OROTIDINE__45__5__45__PHOSPHATE
OROTPDECARB__45__RXN
THYMINE
THYMIDINE
N__45____40__5__45__PHOSPHORIBOSYL__41____45__ANTHRANILATE
ANTHRANILATE
PRAISOM__45__RXN
DIAMINOPIMEPIM__45__RXN
MESO__45__DIAMINOPIMELATE
LL__45__DIAMINOPIMELATE
DIAMINOPIMDECARB__45__RXN
GSAAMINOTRANS__45__RXN
_5__45__AMINO__45__LEVULINATE
GLUTAMATE__45__1__45__SEMIALDEHYDE
PORPHOBILSYNTH__45__RXN
2
_2__45__PG
_2PGADEHYDRAT__45__RXN
DEOXY__45__RIBOSE__45__5P
DEOXYRIBOSE__45__P__45__ALD__45__RXN
DARABISOM__45__RXN
D__45__ARABINOSE
FRU
CARBOXYPHENYLAMINO__45__DEOXYRIBULOSE__45__P
IGPSYN__45__RXN
ADCLY__45__RXN
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UROGENDECARBOX__45__RXN
4
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INDOLE__45__3__45__GLYCEROL__45__P
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H2NEOPTERINALDOL__45__RXN
DIHYDRO__45__NEO__45__PTERIN
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HYDROXYMETHYLBILANE
TRP
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DEHYDROQUINATE
PSEUDOURIDINE__45__5__45__P
2
PORPHOBILINOGEN
4
GDP__45__4__45__DEHYDRO__45__6__45__DEOXY__45__D__45__MANNOSE
2
4
PALMITATE
PALMITYL__45__COA_3__45__P__45__SERINE
GLYCOLLATE
CPD__45__67ASN
N__45__FORMYLMETHIONINE
CYTOSINE
DIAMINO__45__OH__45__PHOSPHORIBOSYLAMINO__45__PYR
DEOXYCYTIDINE
2
metabolic networks: long known and well understood
Krieger 2004
Emergent Properties of BSN
MAPK_p
H10
H11
A5
MAPK_pp
H12
H2
E8
MAPK
H9
MAPKK_pp
MKP1
MAPKK
H5
MAPKK_p
H6
H7
H8
GTP_Ras_Raf_p
PP2A
Raf
H1
Raf_p
H3
H13
Raf_pp
H4
PKC_a
GTP_Ras
B4
B6
GDP_Ras
B7 B8 B9 A6
SHC_a
A4 A9
SHC
A7
SOS
A2
SOS_p
A3A10
GEF
B10 B11B12 B13
GEF_p
B2
GEF_ip
B1
GAP
B5
GAP_p
B3
PDE1
C13
C18
PDE
C12
C16
PDE_p
C15C17
AC2
C4 C8
AC2_p
C7 C10
C11
Ga_GDP
D10
Ga_GTP
D6
Gs_alpha
PIP2_PLA2
E12
Ca_PLA2
E5 E6
E13
DAG_Ca_PLA2
E10
PLA2_p
E2E7
Ca_PLA2_p
E9
PLA2_cyto
E3
E4
PIP2_Ca_PLA2
E11
PLCg
F1
PLCg_p
F2
Ca_PLCg
F4
F5
Ca_PLCg_p
F3F6
PLC
G1 G2
Gq_PLC
G5
Ca_PLC
G3
G8
Ca_Gq_PLC
G4 G9
Gq
G_GDP
CaMKII
I1
I6
CaMKII_ip
I5
CaMKII_T286p
I2
I7
I10 I12
I13
I14 I15
CaMKII_pp
I3
I8
PKC_i
K1
K3
K5
K7
Ca_PKC
K2
K4
K10
DAG_PKC
K6
AA_DAG_PKC
K8
DAG_Ca_PKC
K9
M5
M10
IP3R
L1
IP3R_a
L7
Ca_transp
L2
Ca2_Ca_transp
L3
Cap_channel
L6
Cap_channel_a
L5
CaM
M1
M4
Ca2_CaM
M2 N5
Ca3_CaM
M3 N4
Ca4_CaM
N3
C6
Ng
Ng_p
M6
M7
M8
M9
PP2B
N1
Ca2_PP2B
N2
Ca4_PP2B
O8
Il
O4
Il_p
O1
O5
O6
O7
O9
PP1
I4
PP1_a
EGF_EGFR
A8
EGF_EGFR_internal
SOS_GBR2
SHC_a_SOS_GRB2
SOS_p_GRB2
Gbg_GEFCaM_GEF
Gs_AC2
C9
Gs_AC2_p
C3
Gs_AC1u8
C1
Ca4_CaM_AC1u8
C2
Ca4_CaM_PDE1
C14
Glu_R
D9
Gabg_Glu_R_GTP
D8
Gbg
Gabg
D3D5
Gabg_R
D2
Gabg_Glu_R
D7
CaM_CaMKII
I9
I11
CaM_CaMKII_T286p
R2C2
J1
cAMP_R2C2
J2
cAMP2_R2C2
J3
cAMP3_R2C2
J4
cAMP4_R2C2
J5
cAMP4_R2C
J6
cAMP4_R2
PKA_inhib_PKA
Ng_CaM
Ca4_CaM_Ca4_PP2B
O12
Ca3_CaM_Ca4_PP2B
O11
Ca2_CaM_Ca4_PP2B
O10
Il_p_PP1
O2
Il_PP1
O3
Ca
L4
G6
PC
DAG
G7
Inositol
IP3
PIP2
E1
APC
AA
PIP2_p
D1
Glu
Synapse
D4
RGTP
GDP
PKA
A1
EGFEGFR
GRB2
cAMP
PKA_a
J7
PKA_inhib
Ca_stores
L9_Leak_stores
Ca_pumpCa_ext
L8_Leak_ext
ATP
PKC
C5
AC1u8
Gsalpha
AMP
a tiny fraction of the whole signaling network
Bhalla, Iyengar 1999
bioLogic: Inhibition-Activation scheme
PDGF
PDGFR
b
SHC
b+p
internalization
Grb2
b
SOS
b
Ras
GDPexchange
PKC
GEF
p
GAP
p
Raf
p GDPexchange GTPhydrolysis
GTPhydrolysis
b
ubiquitination
MKP1
deg
MEK
2p
ERK
p
transc 2p
PLA2
p
PP2A
2dep
2dep
dep
2p
2dep
MKP2
2dep
APC
lip
AA
lip
Ca
b
b
DAG
b
b
PIP2
b
b
abstraction of Bhalla, Ram, Iyengar 2001
⇒ intermingled feedback loops : switches and oscillators
Block diagram of the ’Hub’ protein p53 in Kohn notation
combinatorial complexity constrains conventional modelling approaches
Kohn 1999, Maimon 2001, Kitano 2002
‘Conceptual Biology’ : Biology as Literature Science
1950 1960 1970 1980 1990 2000 2010Year
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5000
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20000
Publ
icat
ions
in P
ubM
ed
MAPKhyaluronanmiRNAsiRNA
* Conceptual Continuity ⇒ integrating diverse data and knowledge
from atoms to medicine - from genes to society?
* Multiscale Complexity ⇒ compound graph
every edge/node is a complex network itself
* Dangerous Small World property ⇒ find your own ‘conspiracy’ theory
Blagosklonny 2002
Models of Sea Urchin Development
N
N
N
N
N N
N
N
N
N
N
N
N
N
N
N
NN
N
N
N
N
NN
N
N
N
N
N
N
N N
N
N
NN
N
N
N
N
N
N
N
N
N
N
N
N
NN
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NN
N
N
N
N
N
N
N
N
NN
N
N
N
N
N
N
N
N
N N
N
N
Beck 2004, Davidson 2002
Incomplete Phylogenetic Tree
cephalochordata vertebrata
eukaryotes
plants opisthokonts
fungi animals
protostomia deuterostomia
arthropoda mollusca echinodermata chordata
tunicata
The Jing-Mai System and Congenital Heart Diseases
Li-Ling 2001 and 2003
The Neural Crest Cells - ‘the’ Vertebrate Innovation
Knecht 2002, Gammill 2003, Srivastava 2000
Hyaluronan - another Vertebrate Innovation
Bio(electro)chemical properties:
⇒ long chains connected via hydrophobic interactions
⇒ forms a highly hydrated matrix
⇒ establishes diffusion and streaming potentials
⇒ conversion of mechanical force to potential difference and ionic current
Glycoforum, Toole 2001, Barrett 1975 and 1976
The third Polymer : Sugars
At CSLA11
At CSLA15
At CSLA10
At CSLA1
OsCSLA11At CSLA14
At CSLA3
At CSLA2Mt CSLA1I t CSLA2I t CSLA3At CSLA9OsCSLA2
OsCSLA4OsCSLA5
Os
CS
LA
7
At
CS
LA
7
Os
CSL
A3
OsC
SLA6
At CSLC8
At
CSL
C4
AtCSLC6
AtCSLC12
GmCSLG2
Mt
CS
LG
1
At CSLB3
At
CS
LB
2
AtC
SL
B4
AtCSLB1
AtCSLB5
AtCSLB6
AtCSLE1
MtCSLE3
OsCSLE2
OsCSLE1
LeCSLG1
MtCSLG4
AtCSLG1
AtCSLG2
AtCSLG3
OsCSLH1
OsCSLH2
AtCSLD2
OsCSLD2
AtCSLD3
PtrCSLD4
OsCSLD1
MtCSLD3
OsCSLD4
AtCSLD1
AtCSLD6
OsCSLF1
OsCSLF2
Os
CS
LF
4
Os
CS
LF
3
Os
CS
LF
6OsCSLF7
Mt
CE
SA
6Gm
CE
SA
3
Mt
CE
SA
1
At CESA10At CESA3At CESA2
At CESA9
At CESA6Br CESA1OsCESA9ZmCESA8OsCESA3PcCESA1Pt r CESA3EgCESA1
At CESA4Mt CESA2
OsCESA7
PyaO_HasSt u_HasSt ez_HasSt p_Has_
Ran_Has3Mm_Has3
Eqc_Has2Sus_Has2Bot _Has2Mm_Has2Ran_Has2
Hs_Has2
Dr _Has2
Dr _Has3
Mm_Has1
Ran_Has1
Hs_Has1
Xl _Has1
Rhgp_nodCRhe_nodC
Br I S_nac
Rhgb_nodC_
Mec_nac
Mem_nac
Me
l_
no
dC
Rhl
_n
od
c
Rh
t_nodC
Brj_nodC
Sim_nodC
Azc_nodC
Sut_Has
Luc_Chs1
Dm_Ch
s1
Trc_Chs2
Aea_Chs
Dm_Chs2
Di_Chs
Brm_Chs
Ex
d_
Ch
s4
Coi_Chs4
Tum_Chs
Glv_Chs
Nec_IV_Chs4Emn_VChsD_
Rmo_Chs3
Usm_IV_Chs5
Caa_III_Chs
Fin_Chs
Exd_VWdCHS5
Mag_VCsm1
Blg_VChs2
Asf_ChsE
Fuo_VChsV
Em
n_VChsD
Glg_VChsA
Co
p_
VCh
s7
Us
m_
VC
hs
6
Asf_VIChsD
Co
i_
VI
Ch
s
Exd_Chs2
Amq_ChsA
Emn_Chs1
Opn_ChsA
Scp_Chs1
Us
m_
Ch
s2
Phn_pChs
Ne
c_
Ch
s2
Exd_I I _Chs1
Coi _I I _Chs
Emn_ChsA
Sc_Chs2
Caa_I _Chs
Rmo_Chs2
Rmo_Chs1
Caa_Chs2Sc_Chs1
Pec_I I I _Chs
Emn_ChsBAsf _I I I _ChsGAr b_Chs2Exd_Chs3Nec_Chs3Ab_pChs
Sam_Chs
0.1
The 3 formgiving polysaccharides ?
Spicer 1998, Lee 2000
Some other Vertebrate Innovations and Hyaluronan
Heart: EMT into cavities, ECM expansion, eletrical environment in excitation?
Endothel: stimulated by fragments, migration in angiogenesis
Dynamic Epidermis: thick HA layer, high turnover rate, wound repair
Adaptive Immunity: stimulated by fragments, transport to lymph nodes, carrier of antigens?
Endoskeleton: condensation, major compound of cartilage, synovial fluid and connective
tissue
⇒ strongly hydrated ECM, embeds signaling molecules, single cell migration, electrome-
chanical signaling?
Shigei 2001, Shimeld 2000,
Karvinen 2003, Camenisch 2002, Schroeder 2003,
Mummert 2003, Termeer 2003, Roessler 2003,
Toole 2001, Knudson 2003
The ‘Interstitial Connective Tissue’ Hypothesis
Electromechanical signaling?
Langevin 2002
The ‘Electrophysiology of growth control’ Hypothesis
Shang 2001
Transepithelial Potentials and Galvanotaxis
Endogenous eletrical fields as directional signals in development and repair?
Robinson 2003, Altizer 2001, Zhao 2002, Song 2002, Hall 2000
Mapping the GRN on the Jing-Mai System?
Are the Xue (acupuncture points) Organizing Centers,
ie. Morphogen Sources
Bastiani
Establishment/Stabilization of Morphogen Gradients?
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22human FGFs
6
8
10
12
isoe
lect
rical
Poi
nt -
iP [p
H]
Fibroblast Growth Factors are differently charged at physiological pH
The Biochemistry of Yin and Yang
...
Yin-tonic herbs : antioxidant activity
Yang-tonic herbs : mitochondrial ATP production?
...
Ko 2004, Ou 2003
Fractal Rythms in Physiology and the Pulse Diagnosis
the Qi circulates through the Jing-Mai in circadian rythms
Noble 2002, Goldberger 2002
TCM : a translation problem
Jing-Mai: developmental paths and connections?
Yin/Yang: ATP production and REDOX management?
Qi: ‘life energy’ ? ‘natural air’
⇒ metabolism, mitochondrial oxidation?
Jing: the genes and the gene regulatory network?
Kaptchuck 2000, Li-Ling 2001 and 2003, Langevin 2002, Ko 2004, Ou 2003
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