Vol.
169,
June
No.
2, 1990
BIOCHEMICAL
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
Pages
15, 1990
725-729
BIFDNCTIOHALEFFECTSOF TRANSFORMING GROUTE FACTOR-BONMIGRATIONOF CDLTDREDRATAORTICSI'fOOTEMl.ISCLECELLS Noriyuki
Koyama,
Tomoko Koshikawa,
Yasushi The Second
Received
April
Saito
Morisaki,
and Sho Yoshida
Department of Internal Chiba University,
24,
Nobuhiro
Medicine, Chiba 280,
School Japan
of Medicine,
1990
of smooth muscle cells (SMC) in the arterial wall is SDNNARY -Migration important in the pathogenesis of atherosclerosis and is presumably regulated in both normal and atherosclerotic tissues. In this study, the effect of transforming growth factor-% (TGF-%) on the migration of rat aortic SMC was TGF-% alone enhanced the migration of SMC at concentrations of 10 examined. to 50 pg/ml and its maximal effect was similar to that of platelet-derived growth factor (PDGF). Checker board analysis showed that TGF-% had a chemotactic, but not a chemokinetic effect. PDGF also enhanced the migration in a dose-dependent manner and TGF-% inhibited the PDGF-induced migration dose-dependently at 1.0 pgfml to 1.0 nglml. These data suggest that TGF-% is a bifunctional regulator of the migration of aortic SMC. g 1990 Academic press, ~nc.
Migration intima
is
of arterial
smooth
a key process
Several
migration
process
(3).
Transforming platelets
(4),
in
the
muscle
formation
cells
of atheromatous
factors
such
as PDGF have
growth
factor-%
(TGF-%)
macrophages
(5)
of SMC (7),
and cocultures
fibroblasts
(10)
its
on the migration
work
effects showed
that
to enhance
and to inhibit TGF-8
is
been is
that it may have biological (61, suggesting Indeed, it has been shown to have stimulatory proliferation
(SMC) from
from
effects
cells
on vascular
and inhibitory
this
and SMC
cells. effects
of monocytes
of endothelial
regulator
(1,2).
aggregated
on the
(8,9) cells
of SMC have not yet been elucidated. a bifunctional
to the
to enhance
of endothelial
the migration
the migration
lesions
reported
released
the media
of the migration
and (11).
But
The present of aortic
SMC.
MATERIALSANDXfETEODS TGF-% and PDGF, purified R & D System Inc. (Minneapolis,
chemicals.
from
from MN).
human platelets,
were
purchased
Culture of SMC. SMC were rats
weighing
about
explanted from the thoracic aorta of male Wistar 200 g by the method of Fischer-Dzoga et al. (12), as COD6-29lX@O $1.50 125
Copyright 6 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
Vol.
169, No. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
reported in detail elsewhere (13,14). Briefly, primary cultures of SMC were established from the medial layer of the aorta in Dulbecco's modified Eagle's Medium (DME) supplemented with 10% fetal bovine serum in a CO, (5%) incubator. Cells from primary cultures were subcultured and grown to confluency in T-75 flasks. SMC at the 2nd passage were further subcultured at a 1:2 split ratio in T-75 flasks, and cells at the 3rd to 5th passages were used for assays of SMC migration. Assay of SMC Migration. Migration of SMC was assayed by a modification of Boyden's chamber method using a polycarbonate filter (Nuclepore, U.S.A.) with pores of 5.0 pm diameter (15). Cultured SMC were trypsinized and suspended at a concentration of 5.0x105 cells/ml in DME. A volume of 1 ml of the suspension was placed in the upper chamber of the apparatus and 0.9 ml of DME containing TGF-B, PDGF or both was placed in the lower chamber. The chamber was incubated at 37'C under 5% CO, in air for 4 hours, and then the SMC on the upper side of the filter were scraped off and the filter was removed. The SMC that had migrated to the lower side of the filter were fixed in ethanol, stained with hematoxylin and counted under a microscope (x400) for quantitation of SMC migration. Migration activity is expressed as the mean number of cells seen in 10 high-power fields (HPF). RESULTS Effects
of PDCF and TGF-B on !iMC Migration.
report
(3),
dependent
PDGF alone manner
of over
to that
of PDGF, increasing
Checker
Board
used
Analysis
(Fig.
activity
2).
migration
the mechanism When only
was significantly
the higher
of TGF-6.
model chamber
than
that
Checker
and two chemokinesis
of stimulation
lower
SMC migration increase in
in the cell
Its maximal effect was similar 10 times that of control cells.
to about Activity
of one chemotaxis
a previous
of SMC in a concentration-
50 pg/ml.
of Migration
consisting
to investigate
TGF-B
migration
1). TGF-B alone also enhanced of 10 to 50 pg/ml but caused little
at concentrations
analysis,
the
with
(Fig.
concentration-range migration
enhanced
Consistent
of the migration contained
obtained
TGF-B, when
board models,
of SMC by the migration
the neither
chamber
PDGF
Concentration
(w/ml)
Fig. 1. Effects of PDGF and TGF-6 on the migration SMC was placed in the upper chamber and DMJZ containing indicated concentration was assayed as described migration activity are
of SK.
A suspension of PDGF or TGF-5 at the was placed in the lower chamber. Migration activity under MATERIALS AND METHODS. Mean values for shown.
726
was
Vol.
169, No.. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
meaniSE
30,
20
10
0
03 blank
o+ :, IO0 1 0
IO’
Concentration
of
102 TGF-P
103 (w/ml)
chomolaxi8 chemokinrir
Fig. 2. Checker board analysis of migration activity of TGF-S. Checker board analysis was made with one chemotaxis model and two chemokinesis models. The suspension of SMC was placed in the upper chamber, and DME in the lower chamber. TGF-B was added to the lower chamber (chemotaxis model), or to the upper chamber, or both chambers (chemokinesis models) as indicated. The effects of TGF-S on SMC migration in the models were assayed in triplicate as described under MATERIALS AND METHODS. Columns and bars represent mean values for migration activity and standard errors of the means. Effect of TGF-S on PDGF-induced migration of SMC. Pig. 3. A suspension of SMC was placed in the upper chamber, and DME containing PDGF at 5.0 rig/ml and the indicated concentration of TGF-B was placed in the lower chamber. The migration activity at each concentration of TGF-S was assayed in duplicate as described under MATERIALS AND METHODS. Mean values of migration activity are shown.
contained chambers
TGF-B.
But when only
contained
results
were
These
results
it,
obtained
the migration with
indicate
chemokinetic,
of TGF-B on the concentrations
the presence in
Fig.
of 1.0
pg/ml,
effect
PDGF-induced of TGF-B rig/ml
and about
stimulated.
factor
(data
or both Similar
not
shown). not
of PDGF. Migration
on the migration which
caused
TGF-8,
of TGF-B was chemotactic, of SHC.
The effects
of SMC were
the PDGF-induced detectable
90% inhibition
or more. 727
inhibition
of
investigated
had a maximum effect
3, TGF-B inhibited it
contained
of SMC was not
to that
of PDGF at 5.0 the
concentration-dependently: tration
the
and was similar
Effects
chamber
PDGF as a migration
that
various As shown
the upper
in
on migration.
migration at the
at a concentration
of SMC low
concen-
of lOOpg/ml
Vol.
169,
No.
BIOCHEMICAL
2, 1990
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
DISCUSSION In the
present
study,
SMC in a chemotactic
we found
manner,
but
that
that
TGF-S
it
alone
enhance
inhibited
the
migration
PDGF-induced
of
migration
of
SMC. The inhibitory concentration
effect
was not
of 100 rig/ml,
of incorporated
TGF-6
due to damage did
3H-2-deoxy-D-glucose
of the
not
significantly
from
SMC (16),
SMC, because
at a
increase
release
which
is
the
a marker
of cell
injury. The mechanisms migration
are
of the
unknown.
PDGF-receptor
It
stimulatory
and inhibitory
is
that
on SMC, because
unlikely
effects
TGF-S binds
TGF-B has no homology
of TGF-B on the
competitively
in primary
to the
structure
with
PDGF. The interaction matrix the cell
is cell
of a cell
involved
in
adhesion
matrix
receptor
(24).
expression
of the
but
nothing
so far migration
Possibly adhesion is
(25),
but
to TGF-6,
the
other
hand,
On
others
subtypes their the
are
affected
some changes the
signal
by the conditions
and as a result
only
receptor
of the
exposure
was 4 hours. receptor
for
proliferation,
The expressions cells.
on 3T3
12-h
assays
signal
TGF-S has a negative
for
of PDGF
receptor
after
of migration
(7).
matrix,
receptor. in the
a positive
the
important
selectively-expressed
may transmit
a negative
most
of PDGF to its
the duration
(23)
extracellular
are
the
was observed
of the
cells
by affecting
of the
occur
binding
some distinct,
and synthesis
of matrix
to express
of
of receptor
Possibly
PDGF affects
effect
on migration
stimulatory
and
in
of PDGF.
We conclude
from
this
inhibitory
effects
on the
regulator
of their
migration
development
kinds
expression
endothelial
migration
and synthesis
decrease
SMC have
rat
extracellular
affects
(19,20)
regulates
what
the
TGF-6
SMC (22),
need
that
whereas
transmit
expressions presence
cells is
and some of these
whereas
about
TGF-B decreases
cells
subtypes
rabbit TGF-8
a significant
of the
with
(17,18).
receptor
known
possibility
or TGF-S on SMC.
receptor
of human fibroblasts
or how long
Another cells
migration
by human SMC (21),
and 3T3 cells
cell
cell
adhesion
of atherosclerosis
study
that
migration in
TGF-$
has both
of SMC and may be a bifunctional the vasculature.
requires
The role
of TGF-S
in
the
study.
REFERENCES 1. 2. 3.
ROSS, R. (1986) N. Engl. J. Med. 314, 488-500. Schwarz, S.M., Campbell, G.R., and Campbell, J.H. (1986) Circ. 427-444. Grotendorst, G.R., Seppa, H.E.J., Kleinman, H.K., and Martin, (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 3669-3672. 728
Res. G.R.
58,
Vol.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
169, No. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
Assoian, R.K. and Sporn, M.B. (1986) J. Cell Biol. 102, 1217-1223. Rappolee, D.A., Mark, D., Banda, M.J., and Werb, 2. (1988) Science 241, 708-712. Antonelli-Orlidge, A., Sauders, K.B., Smith, S.R., and D'Amore, P.A. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 4544-4548. Goodman, L.V. and Majack, R. (1989) J. Biol. Chem. 264, 5241-5244. Wahl, S.M., Hunt, D.A., Wakefield, L.M., McCartney-Francis, N., Wahl, Roberts, A.B., and Sporn, M.B. (1987) Proc. Natl. Acad. Sci. L.M., U.S.A. 84, 5788-5792. Wiseman, D.M., Polverini, P.J., Kamp, D.W., and Leibovich, S.J. (1988) Biochem. Biophys. Res. Commun. 157, 793-800. Postlethwaite, A.E., Keski-Oja, J., Moses, H.L., and Kang, A.H. (1987) J. Exp. Med. 165, 251-256. Madri, J.A., Reidy, M.A., Kocher, O., and Bell, L. (1989) J. Lab. Invest. 60, 755-765. Fischer-Dzoga, K., Jones, R.M., Vesselinovitch, D., and Wissler, R.W. (1973) Exp. Mol. Pathol. 18, 162-176. Morisnki, N., Kanzaki, T., Koshikawa, T., Saito, Y., and Yoshida, S. (1988) FEBS Lett. 230, 186-190. Morisaki, N., Koyama, N., Mori, S., Kanzaki, T., Koshikawa, T., Saito, Y ., and Yoshida, S. (1989) Atherosclerosis 78, 61-67. Ooyama, T., Fukuda, K., Oda, H., Nakamura, H., and Hikari, Y. (1987) Arteriosclerosis 7, 593-598. Ouchi, Y., Hirosumi, J., Watanabe, M., Hattori, A., Nakamura, T., and Orimo, H. (1988) Biochem. Biophys. Res. Commun. 157, 301-307. Toole, B.P., Goldberg, R.L., Chi-Rossi, G., Underhill, C.B., and Orkin, R.W. (1984) in The Role of Extracellular Matrix in Development (Trestad, R.L., ed.), pp. 43-66, Alan R. Liss, New York. Albini, A., Allavena, G., Melchiori, A., Gioncotti, F., Ricthter, H., Comoglio, P.P., Parodi, S., Martin, G.R., and Tarone, G. (1987) J. Cell Biol. 105, 1867-1872. Allen-Hoffman, L., Crankshaw, C.L., and Mosher, D.F. (1988) Mol. Cell Biol. 8, 4234-4242. Heino, J., Ignotz, R.A., Hemler, M.E., Crouse, C., and Massague, J. (1989) J. Biol. Chem. 264, 380-388. Chen, J-K., Hoshi, H., and Makeehan, W.L. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 5287-5291. Liau, G. and Chan, L.M. (1989) J. Biol. Chem. 264, 10315-10320. Madri, J.A., Pratt, B.M., and Tucker, A.M. (1988) J. Cell Biol. 106, 1375-1384. Penttinen, R.T., Kobayashi, S., and Bornstein, P. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 1105-1108. Gronwald, R.G.K., Seifort, R.A., and Bowen-Pope, D.F. (1989) J. Biol. Chem. 264, 8120-8125.
729
169,
June
No.
2, 1990
BIOCHEMICAL
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
Pages
15, 1990
725-729
BIFDNCTIOHALEFFECTSOF TRANSFORMING GROUTE FACTOR-BONMIGRATIONOF CDLTDREDRATAORTICSI'fOOTEMl.ISCLECELLS Noriyuki
Koyama,
Tomoko Koshikawa,
Yasushi The Second
Received
April
Saito
Morisaki,
and Sho Yoshida
Department of Internal Chiba University,
24,
Nobuhiro
Medicine, Chiba 280,
School Japan
of Medicine,
1990
of smooth muscle cells (SMC) in the arterial wall is SDNNARY -Migration important in the pathogenesis of atherosclerosis and is presumably regulated in both normal and atherosclerotic tissues. In this study, the effect of transforming growth factor-% (TGF-%) on the migration of rat aortic SMC was TGF-% alone enhanced the migration of SMC at concentrations of 10 examined. to 50 pg/ml and its maximal effect was similar to that of platelet-derived growth factor (PDGF). Checker board analysis showed that TGF-% had a chemotactic, but not a chemokinetic effect. PDGF also enhanced the migration in a dose-dependent manner and TGF-% inhibited the PDGF-induced migration dose-dependently at 1.0 pgfml to 1.0 nglml. These data suggest that TGF-% is a bifunctional regulator of the migration of aortic SMC. g 1990 Academic press, ~nc.
Migration intima
is
of arterial
smooth
a key process
Several
migration
process
(3).
Transforming platelets
(4),
in
the
muscle
formation
cells
of atheromatous
factors
such
as PDGF have
growth
factor-%
(TGF-%)
macrophages
(5)
of SMC (7),
and cocultures
fibroblasts
(10)
its
on the migration
work
effects showed
that
to enhance
and to inhibit TGF-8
is
been is
that it may have biological (61, suggesting Indeed, it has been shown to have stimulatory proliferation
(SMC) from
from
effects
cells
on vascular
and inhibitory
this
and SMC
cells. effects
of monocytes
of endothelial
regulator
(1,2).
aggregated
on the
(8,9) cells
of SMC have not yet been elucidated. a bifunctional
to the
to enhance
of endothelial
the migration
the migration
lesions
reported
released
the media
of the migration
and (11).
But
The present of aortic
SMC.
MATERIALSANDXfETEODS TGF-% and PDGF, purified R & D System Inc. (Minneapolis,
chemicals.
from
from MN).
human platelets,
were
purchased
Culture of SMC. SMC were rats
weighing
about
explanted from the thoracic aorta of male Wistar 200 g by the method of Fischer-Dzoga et al. (12), as COD6-29lX@O $1.50 125
Copyright 6 1990 by Academic Press, Inc. All rights of reproduction in any form reserved.
Vol.
169, No. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
reported in detail elsewhere (13,14). Briefly, primary cultures of SMC were established from the medial layer of the aorta in Dulbecco's modified Eagle's Medium (DME) supplemented with 10% fetal bovine serum in a CO, (5%) incubator. Cells from primary cultures were subcultured and grown to confluency in T-75 flasks. SMC at the 2nd passage were further subcultured at a 1:2 split ratio in T-75 flasks, and cells at the 3rd to 5th passages were used for assays of SMC migration. Assay of SMC Migration. Migration of SMC was assayed by a modification of Boyden's chamber method using a polycarbonate filter (Nuclepore, U.S.A.) with pores of 5.0 pm diameter (15). Cultured SMC were trypsinized and suspended at a concentration of 5.0x105 cells/ml in DME. A volume of 1 ml of the suspension was placed in the upper chamber of the apparatus and 0.9 ml of DME containing TGF-B, PDGF or both was placed in the lower chamber. The chamber was incubated at 37'C under 5% CO, in air for 4 hours, and then the SMC on the upper side of the filter were scraped off and the filter was removed. The SMC that had migrated to the lower side of the filter were fixed in ethanol, stained with hematoxylin and counted under a microscope (x400) for quantitation of SMC migration. Migration activity is expressed as the mean number of cells seen in 10 high-power fields (HPF). RESULTS Effects
of PDCF and TGF-B on !iMC Migration.
report
(3),
dependent
PDGF alone manner
of over
to that
of PDGF, increasing
Checker
Board
used
Analysis
(Fig.
activity
2).
migration
the mechanism When only
was significantly
the higher
of TGF-6.
model chamber
than
that
Checker
and two chemokinesis
of stimulation
lower
SMC migration increase in
in the cell
Its maximal effect was similar 10 times that of control cells.
to about Activity
of one chemotaxis
a previous
of SMC in a concentration-
50 pg/ml.
of Migration
consisting
to investigate
TGF-B
migration
1). TGF-B alone also enhanced of 10 to 50 pg/ml but caused little
at concentrations
analysis,
the
with
(Fig.
concentration-range migration
enhanced
Consistent
of the migration contained
obtained
TGF-B, when
board models,
of SMC by the migration
the neither
chamber
PDGF
Concentration
(w/ml)
Fig. 1. Effects of PDGF and TGF-6 on the migration SMC was placed in the upper chamber and DMJZ containing indicated concentration was assayed as described migration activity are
of SK.
A suspension of PDGF or TGF-5 at the was placed in the lower chamber. Migration activity under MATERIALS AND METHODS. Mean values for shown.
726
was
Vol.
169, No.. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
meaniSE
30,
20
10
0
03 blank
o+ :, IO0 1 0
IO’
Concentration
of
102 TGF-P
103 (w/ml)
chomolaxi8 chemokinrir
Fig. 2. Checker board analysis of migration activity of TGF-S. Checker board analysis was made with one chemotaxis model and two chemokinesis models. The suspension of SMC was placed in the upper chamber, and DME in the lower chamber. TGF-B was added to the lower chamber (chemotaxis model), or to the upper chamber, or both chambers (chemokinesis models) as indicated. The effects of TGF-S on SMC migration in the models were assayed in triplicate as described under MATERIALS AND METHODS. Columns and bars represent mean values for migration activity and standard errors of the means. Effect of TGF-S on PDGF-induced migration of SMC. Pig. 3. A suspension of SMC was placed in the upper chamber, and DME containing PDGF at 5.0 rig/ml and the indicated concentration of TGF-B was placed in the lower chamber. The migration activity at each concentration of TGF-S was assayed in duplicate as described under MATERIALS AND METHODS. Mean values of migration activity are shown.
contained chambers
TGF-B.
But when only
contained
results
were
These
results
it,
obtained
the migration with
indicate
chemokinetic,
of TGF-B on the concentrations
the presence in
Fig.
of 1.0
pg/ml,
effect
PDGF-induced of TGF-B rig/ml
and about
stimulated.
factor
(data
or both Similar
not
shown). not
of PDGF. Migration
on the migration which
caused
TGF-8,
of TGF-B was chemotactic, of SHC.
The effects
of SMC were
the PDGF-induced detectable
90% inhibition
or more. 727
inhibition
of
investigated
had a maximum effect
3, TGF-B inhibited it
contained
of SMC was not
to that
of PDGF at 5.0 the
concentration-dependently: tration
the
and was similar
Effects
chamber
PDGF as a migration
that
various As shown
the upper
in
on migration.
migration at the
at a concentration
of SMC low
concen-
of lOOpg/ml
Vol.
169,
No.
BIOCHEMICAL
2, 1990
AND
BIOPHYSICAL
RESEARCH
COMMUNICATIONS
DISCUSSION In the
present
study,
SMC in a chemotactic
we found
manner,
but
that
that
TGF-S
it
alone
enhance
inhibited
the
migration
PDGF-induced
of
migration
of
SMC. The inhibitory concentration
effect
was not
of 100 rig/ml,
of incorporated
TGF-6
due to damage did
3H-2-deoxy-D-glucose
of the
not
significantly
from
SMC (16),
SMC, because
at a
increase
release
which
is
the
a marker
of cell
injury. The mechanisms migration
are
of the
unknown.
PDGF-receptor
It
stimulatory
and inhibitory
is
that
on SMC, because
unlikely
effects
TGF-S binds
TGF-B has no homology
of TGF-B on the
competitively
in primary
to the
structure
with
PDGF. The interaction matrix the cell
is cell
of a cell
involved
in
adhesion
matrix
receptor
(24).
expression
of the
but
nothing
so far migration
Possibly adhesion is
(25),
but
to TGF-6,
the
other
hand,
On
others
subtypes their the
are
affected
some changes the
signal
by the conditions
and as a result
only
receptor
of the
exposure
was 4 hours. receptor
for
proliferation,
The expressions cells.
on 3T3
12-h
assays
signal
TGF-S has a negative
for
of PDGF
receptor
after
of migration
(7).
matrix,
receptor. in the
a positive
the
important
selectively-expressed
may transmit
a negative
most
of PDGF to its
the duration
(23)
extracellular
are
the
was observed
of the
cells
by affecting
of the
occur
binding
some distinct,
and synthesis
of matrix
to express
of
of receptor
Possibly
PDGF affects
effect
on migration
stimulatory
and
in
of PDGF.
We conclude
from
this
inhibitory
effects
on the
regulator
of their
migration
development
kinds
expression
endothelial
migration
and synthesis
decrease
SMC have
rat
extracellular
affects
(19,20)
regulates
what
the
TGF-6
SMC (22),
need
that
whereas
transmit
expressions presence
cells is
and some of these
whereas
about
TGF-B decreases
cells
subtypes
rabbit TGF-8
a significant
of the
with
(17,18).
receptor
known
possibility
or TGF-S on SMC.
receptor
of human fibroblasts
or how long
Another cells
migration
by human SMC (21),
and 3T3 cells
cell
cell
adhesion
of atherosclerosis
study
that
migration in
TGF-$
has both
of SMC and may be a bifunctional the vasculature.
requires
The role
of TGF-S
in
the
study.
REFERENCES 1. 2. 3.
ROSS, R. (1986) N. Engl. J. Med. 314, 488-500. Schwarz, S.M., Campbell, G.R., and Campbell, J.H. (1986) Circ. 427-444. Grotendorst, G.R., Seppa, H.E.J., Kleinman, H.K., and Martin, (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 3669-3672. 728
Res. G.R.
58,
Vol.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
169, No. 2, 1990
BIOCHEMICAL
AND BIOPHYSICAL
RESEARCH COMMUNICATIONS
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