1- and ß-adrenoceptor stimulation differentially activate p38-MAPK and atrial natriuretic peptide production in the perfused amphibian heart
1 Department of Animal and Human Physiology, School of Biology, Faculty of
Sciences, University of Athens, Panepistimioupolis, Athens, Greece 157
84
2 Laboratory of Animal Physiology, Department of Zoology, School of Biology,
Aristotle University of Thessaloniki, Thessaloniki, Greece 54 006
* Author for correspondence (e-mail: ibeis{at}biol.uoa.gr )
Accepted 15 May 2002
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Summary |
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Key words: p38-MAPK, adrenoceptor, amphibian heart, atrial natriuretic peptide, adrenergic agonist, Rana ridibunda
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Introduction |
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The neurotransmitter released in amphibians is epinephrine, which exerts
its actions mainly via ß-ARs
(Stene-Larson and Helle, 1978;
Herman and Sandoval, 1983
;
Herman and Mata, 1985
).
However, existing data concerning the morphological and functional
relationships of amphibian heart
- and ß-adrenoceptors is limited
and, to a certain extent, controversial. Thus, although it is generally
accepted that the anuran heart contains predominantly ß-ARs
(Stene-Larson and Helle,
1978
), which are considered to be `beta-2-like'
(Stene-Larson and Helle, 1978
;
Hieble and Ruffolo, 1991
), the
presence of
-ARs has been questioned by several investigators
(Benfey, 1982
;
Ask, 1983
). However, in a
recent study we confirmed the presence of
1-ARs in Rana
ridibunda hearts by competitive binding assay. In addition, we showed
that these receptors are functional and coupled to phosphoinositide hydrolysis
(Lazou et al., 2002
).
A large number of reports have already demonstrated that MAPKs
(mitogen-activated protein kinases) are also included among the multiple
signal transduction pathways activated by AR-stimulation in the mammalian
heart (Bogoyevitch et al.,
1993,
1995
;
Yamazaki et al., 1997
;
Clerk et al., 1998
;
Lazou et al., 1998
). In this
large family of widely expressed protein kinases, three subfamilies have been
clearly identified: extracellular signal-related kinases (ERKs), c-Jun
N-terminal kinases (JNKs) and p38 reactivating kinases (p38-MAPKs). ERKs are
largely involved in cell growth, division and differentiation, whereas JNKs
and p38-MAPKs respond preferentially to cellular stresses
(Schaeffer and Weber, 1999
;
Widmann et al., 1999
). Members
of all three subfamilies are present in the heart
(Widmann et al., 1999
;
Bogoyevitch, 2000
;
Kyriakis and Avruch, 2001
);
however, the exact role of each subfamily has not yet been clarified and their
coupling to ARs appears to be cell-type-specific. Therefore, it was of great
interest to assess their possible involvement in AR signalling in the
amphibian heart, given that its physiology is fundamentally different from
that of mammals. In preliminary experiments we assessed the activation of all
three MAPK subfamilies by adrenergic agonists in the amphibian heart. However,
since ERKs responded in a constant and sustained manner and JNKs activation
was moderate, we focussed on p38-MAPK activation under these conditions.
In rat hearts, an additional effect mediated by - as well as
ß-AR is the release of atrial natriuretic peptide (ANP) after infusion or
heart perfusion with respective agonists
(Currie and Newman, 1986
;
Garcia et al., 1986
). However,
the role of this hormone as a modulator of the various AR-stimulated effects
on heart muscle has not yet been clarified
(Ruskoaho, 1992
). We have
already shown the presence of ANP in the isolated perfused amphibian heart
(Aggeli et al., 2002
). Since
the MAPKs signalling pathway was recently suggested to be involved in its
regulation (Thuerauf et al.,
1998
; Ng et al.,
2001
), we also studied the ANP presence and localisation pattern
in sections from AR-stimulated frog hearts.
Our results demonstrate, for the first time in the amphibian heart, that
both - and ß-adrenergic agonists activate p38-MAPK in a diverse,
time-dependent manner. Activation by phenylephrine is rapid and transient,
whereas activation by isoproterenol is more sustained and
temperature-dependent. In addition, the enchanced presence of ANP observed in
both phenylephrine (PHE)- and isoproterenol (ISO)-stimulated amphibian hearts
was blocked by 1 µmol l-1 SB203580. These results provide
evidence of a direct link between p38-MAPK signalling pathway and ANP
production under these conditions.
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Materials and methods |
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Rabbit polyclonal antibodies specific for total ERKs and p38-MAPK, as well as for the dual-phosphorylated ERKs, p38-MAPK and JNKs, were obtained from New England Biolabs (Beverly, MA, USA). The antibody raised against a peptide corresponding to an amino acid sequence mapping at the carboxy terminus of JNK1 of human origin, was obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). Rabbit polyclonal antibody to human ANP (1-28) was purchased from Biogenesis Ltd (Poole, UK). Prestained molecular mass markers were from New England Biolabs. Biotinylated anti-rabbit antibody was from DAKO A/S (DK-2600 Glostrup, Denmark). X-OMAT AR 13x18 cm and Elite chrome 100 films were purchased from Eastman Kodak Company (New York, USA).
Animals
Frogs (Rana ridibunda Pallas) weighing 100-120 g were caught in
the vicinity of Thessaloniki, Greece, and supplied by a local dealer. They
were kept in containers in fresh water and used a week after arrival. Care of
the animals conformed to Good Laboratory Practice.
Heart perfusions
R. ridibunda hearts were perfused in non-recirculating Langendorff
mode at a pressure of 4.5 kPa (31.5 mmHg) with bicarbonate-buffered saline
(23.8 mmol l-1 NaHCO3, 103 mmol l-1 NaCl, 1.8
mmol l-1 CaCl2, 2.5 mmol l-1 KCl, 1.8 mmol
l-1 MgCl2, 0.6 mmol l-1
NaH2PO4, pH 7.4 at 25°C) supplemented with 10 mmol
l-1 glucose and equilibrated with 95% O2/5%
CO2. The temperature of the hearts and perfusates was maintained at
25°C by the use of a water-jacketed apparatus. All hearts were
equilibrated for 15 min under these conditions. At the end of the
equilibration period, hearts were perfused with 50 µmol l-1 of
either PHE or ISO for a further 0.5-60 min period, in the presence or absence
of various antagonists. When used, adrenergic antagonists were added 15 min
prior to the 1- or ß-AR agonists and were present
throughout the perfusion with the latter. In particular, depending on the time
point of maximal p38-MAPK activation, perfusion with antagonists in the
presence of PHE or ISO lasted 0.5 or 5 min, respectively. Similarly, hearts
perfused with 0.5 mol l-1 sorbitol for 15 min after the
equilibration period were used as positive controls. When the inhibitor
SB203580 was used, it was added 15 min before the addition of PHE and was
present at a concentration of 1 µmol l-1 throughout the
perfusion with this
1-AR agonist. PHE (a selective
1-AR agonist), ISO (a nonselective ß-AR agonist) and
propranolol (a nonselective ß-AR antagonist) were dissolved in 100
µmol l-1 L-ascorbic acid and used fresh daily. Prazosin (a
selective
1-AR antagonist), yohimbine (a selective
2-AR antagonist) and phentolamine (a nonselective
-AR
antagonist) were dissolved in dimethylsulfoxide (DMSO). In control
experiments, we established the effect of ascorbic acid, DMSO or various
AR-antagonists on the variables measured.
At the end of the perfusions, hearts were `freeze-clamped' between aluminium tongs cooled in liquid N2, and after the removal of the atria, ventricles were pulverized under liquid N2 and powders were stored at -80°C.
Tissue extractions
Heart powders were homogenized with 3 ml g-1 of buffer [20 mmol
l-1 Tris-HCl, pH 7.5, 20 mmol l-1
ß-glycerophosphate, 20 mmol l-1 NaF, 2 mmol l-1
EDTA, 0.2 mmol l-1 Na3VO4, 5 mmol
l-1 dithiothreitol (DTT), 10 mmol l-1 benzamidine, 200
µmol l-1 leupeptin, 120 µmol l-1 pepstain A, 10
µmol l-1 trans-epoxy succinyl-L-leucylamido-(4-guanidino)
butane, 300 µmol l-1 phenyl methyl sulphonyl fluoride (PMSF),
0.5 % (v/v) Triton X-100] and extracted on ice for 30 min. The samples were
centrifuged (10 000g, 5 min, 4 °C) and the supernatants
boiled with 0.33 volumes of SDS-PAGE sample buffer [0.33 mol l-1
Tris-HCl, pH 6.8, 10 % (w/v) SDS, 13 % (v/v) glycerol, 20 % (v/v)
2-mercaptoethanol, 0.2 % (w/v) Bromophenol Blue]. Protein concentrations were
determined using the BioRad Bradford assay.
SDS-PAGE and immunoblot analysis
Proteins were separated by SDS-PAGE on 10 % (w/v) acrylamide, 0.275 % (w/v)
bisacrylamide slab gels and transferred electrophoretically onto
nitrocellulose membranes (0.45 µm). Membranes were then incubated in TBS-T
[20 mmol l-1 Tris-HCl, pH 7.5, 137 mmol l-1 NaCl, 0.1 %
(v/v) Tween 20] containing 5 % (w/v) non-fat milk powder for 30 min at room
temperature. Subsequently, the membranes were incubated with the appropriate
antibody according to the manufacturer's instructions. After washing in TBS-T
(3x 5 min) the blots were incubated with horseradish peroxidase-linked
anti-rabbit IgG antibodies (1:5000 dilution in TBS-T containing 1 % (w/v)
non-fat milk powder, 1 h, room temperature). The blots were washed again in
TBS-T (3x 5 min) and the bands were detected using ECL with exposure to
X-OMAT AR film. Blots were quantified by laser scanning densitometry.
Immunolocalisation of phospho-p38 MAPK and atrial natriuretic
peptide
At the end of the perfusions, atria were removed and ventricles were
immersed in Uvasol/isopentane pre-cooled in liquid N2 and stored at
-80 °C. Tissues were sectioned with a cryostat at a thickness of 5-6
µm, fixed with ice-cold acetone (10 min, at room temperature) and specimens
were stored at -30 °C until use. Tissue sections were washed in TBS-T and
non-specific binding sites were blocked with 3 % (w/v) BSA in TBS-T (1 h, at
room temperature). Specimens were incubated with primary antibody specific
either for phospho-p38-MAPK or for human ANP (1-28), diluted in 3 % BSA (w/v)
in TBS-T (overnight, 4 °C), according to the method previously described
(Aggeli et al., 2002). All
sections were immunostained by the alkaline phosphatase method using a Kwik
kit, according to the manufacturer's instructions. The alkaline phosphatase
label was visualised by exposing the sections to Fast Red chromogen and nuclei
were counterstained with Haematoxylin. Slides were mounted, examined with a
Zeiss Axioplan microscope and photographed with a Kodak Elite chrome 100
film.
Statistical evaluations
All data are presented as means ± S.E.M. Comparisons between control
and treatments were performed using Student's paired t-test. A value
of P<0.05 was considered to be statistically significant. MAPK
activation in `control' hearts was set at 1, and the stimulated MAPK
activation in treated hearts was expressed as -fold activation over `control'
hearts.
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Results |
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|
Although ERK phosphorylation by PHE was quite robust, the activation
profile observed was constant and sustained over the time points examined,
which is a common, widespread response of ERKs to various stimuli examined
(Steinberg, 2000). On the
other hand, JNK phosphorylation by this agonist was low compared to previous
reports of the response of this kinase to various stressful stimuli such as
hyperosmotic stress or mechanical overload (Aggeli et al.,
2001a
,b
).
Therefore, we focused on the response of p38-MAPK to adrenergic
stimulation.
SB203580 (1 µmol l-1 in DMSO), a widely used specific
inhibitor of p38-MAPK shown to selectively inhibit the kinase activation in
this physiological setting (Aggeli et al.,
2001a), abolished p38-MAPK phosphorylation by 50 µmol
l-1 of PHE (Fig.
2Ai,B). To ensure that equal amounts of protein were loaded,
western blots were also performed using an antibody detecting total
(phosphorylation state-independent) kinase levels
(Fig. 2Aii). Inclusion of
SB203580 alone in the perfusion medium had a slight effect on p38-MAPK
phosphorylation, which was taken into consideration during the evaluation of
the inhibitor's effect on the kinase activation.
|
To confirm that the effect of PHE on p38-MAPK phosphorylation was
1-receptor-mediated, hearts were perfused with 50 µmol
l-1 of this agonist in the presence of various AR antagonists.
Prazosin (1 µmol l-1), a selective
1-AR
antagonist, and phentolamine (1 µmol l-1), a nonselective
-AR reversible antagonist, completely inhibited p38-MAPK
phosphorylation (hence activation) by PHE
(Fig. 3Ai,Aii,C). In addition,
phosphorylation levels of the kinase were not altered in the presence of 1
µmol l-1 yohimbine, a specific
2-AR antagonist
(Fig. 3Aiii,C), nor in the
presence of 1 µmol l-1 propranolol, a nonselective ß-AR
antagonist (Fig. 3Aiv,C). These
results indicate that in this experimental model, p38-MAPK activation by PHE
is mediated via
1-ARs. In
Fig. 3B, total p38-MAPK
immunoreactivity in identical heart samples is shown.
|
The time course of the ISO effect on p38-MAPK phosphorylation was also examined using antibodies detecting the respective dual-phosphorylated species. Western blotting was performed with extracts from hearts perfused under control conditions or in the presence of 50 µmol l-1 ISO. At 25 °C, the normal perfusion temperature used in our experiments, a strong activation of p38-MAPK was detected from as early as 30 s (4.5±0.3-fold, relative to controls), which maximised at 5 min (6.5±0.4-fold, relative to controls). The kinase phosphorylation was sustained at considerable levels for at least 30 min (6.0±0.4-fold, relative to controls), reaching basal values after 60 min (Fig. 4A,C).
|
The cardiac effects of ISO in amphibians are markedly dependent on
temperature (Volkmann, 1985).
Therefore, p38-MAPK activation by this agonist was also examined at a lower
temperature (18 °C). Under these conditions, the kinase phosphorylation
profile was different, with a slight but significant increase detected from as
early as 1 min (2.3±0.2-fold, relative to controls, P<0.01)
and maximal activation attained at 5 min (4.7±0.3-fold, relative to
controls). Subsequently, p38-MAPK phosphorylation levels declined, reaching
basal values at 30 min (1.6±0.1-fold, relative to controls)
(Fig. 4Bi,C). Equivalent
protein loading was confirmed using antibodies recognising total
(phosphorylation state-independent) levels of p38-MAPK
(Fig. 4Bii). No
temperature-dependent effect was observed in respective samples from
PHE-stimulated hearts (data not shown).
We confirmed that p38-MAPK activation by ISO was mediated through
ß-ARs, by perfusion of hearts (at 25 °C) with 50 µmol
l-1 of this agonist in the presence of 1 µmol l-1
propranolol (a ß-AR antagonist). This antagonist completely inhibited
p38-MAPK phosphorylation by ISO (Fig.
5Ai,B), while prazosin (10 µmol l-1), a selective
1-AR antagonist, had no inhibitory effect on the kinase
activation by this agonist (Fig.
5Aii,B). Equivalent protein loading was verified in identical
heart samples, with an antibody detecting total kinase levels
(Fig. 5Aiii).
|
In order to investigate the localisation pattern of the activated p38-MAPK
immunohistochemically, under 1- or ß-AR stimulation,
frog hearts were perfused with 50 µmol l-1 of either PHE (for 30
s) or ISO (for 5 min), in the presence or absence of the respective specific
antagonists or 1 µmol l-1 SB203580. After the removal of atria,
the ventricle was sectioned and the respective specimens were processed using
an antibody specific for the dual-phosphorylated p38-MAPK. No immunoreactivity
was detected in control hearts (Figs
6A,
7A), nor in specimens incubated
either with the secondary antibody or with the chromogen alone (data not
shown). In specimens from hearts perfused with 50 µmol l-1 of
either PHE or ISO, immunoreactivity staining was observed within the cytoplasm
as well as in the perinuclear region (Figs
6B,
7B). In accordance with the
results of the biochemical studies, PHE-induced phospho-p38-MAPK
immunostaining was abolished by prazosin and SB203580, while propranolol and
SB3203580 completely blocked the ISO-stimulated activation of the kinase (Figs
6C,E,
7D,E). Therefore, PHE effect on
p38-MAPK activation was confirmed to be
1-AR mediated and
the ISO effect, ß-AR mediated.
|
|
Atrial natriuretic peptide (ANP), particularly the circulating
28-amino-acid, biologically active form of this hormone, has been previously
reported to be released by -as well as by ß-adrenergic stimulation
in rat atria, although the physiological significance of this effect remains
questionable. Thus, it was of interest to examine the production and
localisation pattern of ANP in sections from Rana ridibunda hearts
perfused with PHE or ISO. For this purpose, we used an antibody detecting the
human (1-28) active form of the peptide, as important homologies exist between
the C-terminal regions of mammalian and amphibian ANP
(Netchitailo et al., 1988
).
Our immunohistochemical study in cryosections from hearts revealed
considerably enhanced ANP staining in both PHE- and ISO-perfused hearts
compared to the controls (Figs
8B,
9B, respectively). A discreet
pattern of ANP immunoreactivity was observed in the perinuclear region as well
as widely in the cytoplasm. We confirmed that this effect stimulated by PHE
was attributed to
1-ARs, by the significantly decreased
staining observed in sections from hearts perfused with this agonist (50
µmol l-1) in the presence of 1 µmol l-1 prazosin
(Fig. 8C), while propranolol (1
µmol l-1) had no effect on the ANP immunoreactivity detected
(Fig. 8D). Furthermore, the
increase in ANP immunoreactivity complexes observed in sections from hearts
perfused with ISO (50 µmol l-1), was verified to be ß-AR
mediated, as 1 µmol l-1 propranolol inhibited this effect
(Fig. 9D) in contrast to 10
µmol l-1 prazosin, which resulted in no such inhibition
(Fig. 9C). Interestingly, in
the presence of SB203580 (1 µmol l-1), both PHE- and
ISO-stimulated ANP accumulation were completely inhibited (Figs
8E,
9E). When sections were
incubated with secondary antibody only, no immunoreactivity was detected (data
not shown).
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Discussion |
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Focusing on p38-MAPK, SB203580 was found to abolish the activation of this
kinase by PHE in both biochemical and immunohistochemical studies (Figs
2,
6E). Among the several isoforms
of the kinase that have been identified
(Kumar et al., 1997;
Zhong and Minneman, 1999
),
only two are strongly inhibited by SB203580;
and ß1
(Li et al., 1996
;
Zhong and Minneman, 1999
).
Although it was not possible to determine whether any specific p38-MAPK
isoform is activated under the conditions examined in this experimental model,
our results demonstrate that at least one of the above two is present and
responsive to
1 adrenergic stimulation.
We also investigated the ability of a range of pharmacological inhibitors
to interfere with PHE-induced activation of p38-MAPK. Neither propranolol
(nonselective ß antagonist, 1 µmol l-1) nor yohimbine
(2 antagonist, 1 µmol l-1) had any inhibitory
effect on the kinase phosphorylation by PHE. In addition, phentolamine
(nonselective
antagonist, 1 µmol l-1) as well as
prazosin (
1 selective antagonist, 1 µmol l-1)
both abolished the kinase activation, demonstrating that PHE-induced p38-MAPK
activation is
1-AR mediated
(Fig. 3). These data further
support a functional role for
1 adrenoceptors in frog
heart.
The temporal profile of p38 MAPK response to ISO was entirely different
from the one induced by PHE, with the maximal kinase phosphorylation levels
reaching higher values (6.5±0.4 and 4.8±0.6-fold relative to
controls, respectively) and remaining elevated over a considerably longer
period of time (Figs 1C
versus 4A).
Stimulation with ISO was found to considerably increase the contractility of
our experimental setting, whereas PHE did not. This effect could account to a
certain extent for the different p38-MAPK activation profiles induced by the
stimulation of the two types of adrenoceptors. However, recent data show a
rapid phosphorylation profile of p38 MAPK by mechanical overload
(Aggeli et al., 2001b), in
contrast to the sustained one triggered by ß-AR stimulation. Therefore,
factors other than contractility may account for the distinct response of the
kinase under
1- and ß-AR stimulation. That ISO-induced
p38-MAPK activation is mediated via ß-ARs was also confirmed by
its complete inhibition by propranolol (ß-AR antagonist) and the lack of
an analogous effect by prazosin (
1-AR antagonist)
(Fig. 5). The
immunohistochemical data correlated with the above results. Thus, ISO was
found to induce a more intense p38-MAPK response than PHE (Figs
7B versus
6B), and these effects were
mediated by ß- and
1-ARs, respectively (Figs
7C,D versus
6C,D). p38-MAPK response to ISO
was found to be temperature-dependent, a feature not observed with PHE
stimulation. Previous studies have shown that ISO induces subcellular damage
in ectotherms at 25 °C (Volkmann,
1985
; Herman et al.,
1986
). Therefore, the sustained, marked p38-MAPK phosphorylation
by ISO observed at 25 °C (Fig.
4), which was completely different from the response at 18 °C
(Fig. 4), may indicate that the
kinase exerts a protective role under such conditions. A protective role for
p38-MAPK has been also described in adult rat cardiomyocytes stimulated with
ISO (Communal et al.,
2000
).
DeBold et al. (1981) and
DeBold and Salerno (1983
) were
the first to report the production of a hormone involved in the regulation of
extracellular fluid volume and electrolyte balance by atria of various animal
species. Adrenergic compounds exert a positive inotropic effect on vertebrate
cardiac muscle and ANP has been shown to function as a potential modulator of
systemic blood pressure in AR-stimulated rat heart
(Lang et al., 1985
;
Currie and Newman, 1986
;
Garcia et al., 1986
). In
frogs, immunoreactive ANP is detected in both atrial and ventricular cardiac
myocytes (Mifune et al.,
1996
). Therefore, it was interesting to investigate the
immunolocalisation pattern of this hormone in specimens from control as well
as AR-stimulated amphibian heart ventricles. The enhanced presence of ANP
observed in specimens from hearts perfused with PHE as well as ISO could
reflect an involvement of this peptide hormone in the cardiac muscle response
to the haemodynamic changes induced under such conditions (Figs
8B,
9B). Furthermore, since ANP
immunostaining was considerably decreased in specimens from hearts perfused
with PHE or ISO in the presence of their respective antagonists (Figs
8C,
9D), ANP accumulation seems to
constitute a direct stimulation effect by AR, in this specific experimental
model.
Certain forms of stress inducing p38-MAPK activation have been found to
lead to the transcriptional activation of several genes with a probable
compensatory effect, including the ANP gene
(Thuerauf et al., 1998). In
light of the observed inhibition of ANP immunoreactivity by SB203580, a
p38-MAPK pathway regulatory role in AR-stimulated ANP production could be
proposed. However, since the increase in ANP immunoreactivity induced by PHE
or ISO is quite rapid, it is more likely to be a consequence of the release of
this peptide hormone from its storage granules
(Mifune et al., 1996
;
Ruskoaho, 1992
), rather than
an enhancement of ANP synthesis. It is therefore evident that further
investigation is required in order to detect any involvement of p38-MAPK in
the transcriptional activation of ANP. In addition, since the localisation
patterns of p38 MAPK and ANP seem to be similar to a certain extent, a more
thorough immunohistochemical study via electron transmission
microscopy, could reveal any physical correlation between them.
In conclusion, the present study demonstrates that stimulation by both
1- and ß-AR differentially activates p38-MAPK in the
amphibian heart. Furthermore, a functional link between
1-
as well as ß-AR-induced p38-MAPK stimulation and the enhanced presence of
ANP is documented, suggestive of a regulatory role of this hormonal modulator,
under these conditions.
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Acknowledgments |
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