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Cardiac and Hypertension Research Laboratories, Bronx Veterans Affairs Medical Center; and Department of Medicine, Mount Sinai School of Medicine, New York, New York 10468
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Progressive ventricular dilatation commonly accompanies the transition to overt failure in chronically overloaded hearts; however, only recently have studies begun to elucidate underlying molecular alterations. In particular, the potential role of altered myocardial expression of the procollagenase gene in this process has not previously been examined. Biventricular hypertrophy and dilatation were produced in rats by creating an abdominal aortocaval fistula. The time courses of changes in expression of collagen I and III genes and of the procollagenase gene (matrix metalloproteinase-1, MMP-1) were assessed by Northern blot hybridization. Expression of all three genes increased promptly; however, collagenase gene expression peaked much earlier (8 h) than did expression of either of the collagen genes (7 days), and all returned to baseline levels by 45 days. These data corroborate earlier reports of increased collagen gene expression in this model, but more importantly, they provide the first evidence of concurrent activation of collagenase gene expression, suggesting that enhancement of collagen degradation may be a prerequisite for structural cardiac dilatation.
hypertrophy; metalloproteinases; molecular biology; myocardium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIAC DILATATION IS A HALLMARK of end-stage congestive heart failure in humans (8, 13, 32). Despite its potential compensatory value (13, 18) enlargement of the ventricular chambers can clearly progress to the point where heart failure ensues, and clinical data suggest that morbidity and mortality are reduced by agents that limit dilatation (24). The mechanisms by which remodeling of the myocardial matrix occurs are incompletely understood. Although induction of collagen gene expression has been reported in most models of cardiac overload, there are no comparable data on the influence of these models on collagenase gene expression.
Knowledge of factors involved in collagen degradation is particularly critical to understanding cardiac volume overload models that typically manifest marked eccentric ventricular remodeling in the absence of collagen accumulation (22). Recent studies in the rat aortocaval fistula (AVF) model (19) and the dog rapid-pacing model (28) have found myocardial collagenolytic activity to be increased within 1 day. Human dilated cardiomyopathy (31) has also been associated with increased myocardial collagenolytic activity together with decreased gene expression of tissue inhibitor of metalloproteinase (TIMP). Another study reported a marked increase in collagenolytic activity soon after creating myocardial infarction in rats (6) despite increased TIMP gene expression at the same time point. Thus the present literature suggests that irrespective of specific etiology, increased myocardial collagenolytic activity is a common, if not ubiquitous accompaniment of ventricular structural dilatation. However, less is known about the mechanism(s) responsible for this increase, which could be triggered by activation of in situ procollagenase and/or an increase in its synthesis.
The present study examined the time course of changes in expression of genes for collagen I, collagen III, and collagenase (matrix metalloproteinase-1, MMP-1) in the rat AVF model. This particular model was chosen for the rapid changes in both cardiac mass and chamber dilatation it induces, as well as its reproducibility. Before the molecular studies, necropsy and echocardiographic analysis of a large cohort of normal rats, sham-operated rats, and rats with AVF were used to establish the time frame in which these gross structural changes occurred, and this served as the basis for selection of samples for the gene expression study.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Aortocaval shunt model. An AVF was created in anesthetized (pentobarbital sodium, 50 mg/kg) male rats (Charles River, CD, 250-350 g body mass) by the method of Garcia and Diebold (12). The sham operation was done in exactly the same manner, except that the wall of the vena cava was not perforated. Both procedures involved occlusion of the abdominal aorta (between the renal and mesenteric arterial branches) during perforation of the aorta and its subsequent repair. Successful creation of the AVF was verified in each rat by high power (×40) observation of "jetting" of arterial blood into the inferior vena cava.
Preliminary characterization of time course of hypertrophy and dilatation. Before the molecular studies, data from this laboratory on a large cohort of normal, sham-operated, and AVF rats were analyzed 1) to document the degree of ventricular hypertrophy and structural dilatation produced by this model "in our hands," and 2) to help define the time points for which samples would be obtained for the ensuing molecular studies. Atria, ventricles, and lungs of normal, sham-operated, and AVF rats were dissected, blotted, and weighed on an analytical balance (Mettler). Serial echocardiography (7.5 MHz probe, two-dimensional guided M-mode, Accuson) was done on lightly anesthetized (pentobarbital sodium, 25 mg/kg ip) rats to assess the time course of geometric changes in the intact heart after creating the fistula. These data defined the relationship of left ventricular internal diastolic dimension (LVIDD) to body mass (see RESULTS) with normal growth. Because of the need to rapidly dissect and freeze samples for Northern hybridization, as well as the desire to minimize possible effects of prolonged anesthesia, no samples from this initial cohort were included in the subsequent molecular studies.
Heart fixation and assessment of ventricular chamber volumes. In eight normal and nine AVF rats, chamber volumes of the left ventricle (LV) and right ventricle (RV) at zero transmural stress (V0) were assessed postmortem at 45 days after surgery. After each rat was anesthetized (pentobarbital sodium, 60 mg/kg ip), the heart was arrested in diastole by retrograde injection of isotonic phosphate buffer containing 75 mM KCl and 30 mM butanedione monoxime via the abdominal aorta and was then removed and mounted on a Langendorff apparatus for perfusion (at 100 cmH2O) with fixative (Karnovsky's). The LV was vented to prevent pressure buildup from thebesian flow and/or retrograde seepage through the aortic valve. Perfusion fixation was maintained for 5 min. After fixation, the heart was trimmed of the atria and great vessels and mounted vertically on a preweighed stand that sealed the original venting hole through the apex. Both ventricular chambers were then emptied by suctioning. Chamber volumes were determined by recording the change in weight on an analytical balance (Mettler) after successively filling each chamber with fixative (specific gravity ~1.0). The average of three such determinations was taken as V0.
Sample preparation for Northern analysis.
Total RNA was prepared from the LV and RV of 11 normal, 10 sham-operated, and 31 AVF rat hearts in the following manner. Rats were
anesthetized with pentobarbital sodium (60 mg/kg), after which the
heart was removed, and the LV and RV were quickly dissected, weighed
and placed in liquid nitrogen. Total RNA was isolated from these
samples as described by Chomczynski and Sacchi (3). The
final RNA pellet was resuspended in 0.5% SDS solution and stored at
70°C.
cDNA probes.
The following cDNA probes, obtained from the American Type Culture
Collection, were used for Northern blot analysis: 1) human collagen, type I, 
-2 (Col1A2), clone Hf32 (insert size 2.1 kb) cloned from human skin fibroblast, coding for 480 residues of the
collagenous region and most of the COOH-terminal propeptide (1); 2) human collagen, type III, -1
(Col3A1), clone Hf934 (insert size 1.3 kb), cloned from human
fibroblast. This insert includes the sequence beginning about 0.8 kb
upstream of the stop codon and a 3' noncoding sequence of 223 bp and
poly(A) (4); and 3) human collagenase, clone
pCllase-1 (MMP-1, insert size 2.2 kb), cloned from human fibroblasts
containing the complete coding sequence (29).
Additionally, human G3PDH cDNA used as a control probe was obtained
from Clontech.
Northern blot analysis.
Total RNA (20 µg) was denatured in 50% formamide-2.2 M formaldehyde
solution, fractionated on a 1% agarose-formaldehyde gel (21), transferred to a nylon membrane (Amersham) by
capillary action with 20× standard saline citrate (SSC) according to
the method of Thomas (30), and then immobilized by baking
at 80°C for 2 h. Prehybridization and hybridization were done
using a shaking water bath at 42°C in buffer (5 Prime 
3 Prime) to
which 50 µg/ml yeast RNA and 100 µg/ml sheared salmon sperm DNA
were added. Inserts were isolated from the above-mentioned cDNAs and radioactively labeled with [-32P]dCTP (3,000 Ci/mmol;
New England Nuclear) by the nick translation reaction using an Amersham
nick translation kit. Blots were hybridized overnight at 42°C with
1 × 106 cpm/ml of the labeled probe. After
hybridization the membrane was washed twice in 2× SSC and 0.2% SDS at
room temperature for 20 min and then exposed for 24 h to Kodak
X-OMAT film at 70°C. Hybridization signals on the autoradiographs
were quantified using an Ultroscan SL laser densitometer. From these
data, ratios representing expression of collagenase and types I and III
collagen genes relative to G3PDH gene expression were determined.
Statistics. Because pilot work had indicated that the sham operation might also affect expression of collagen and collagenase genes, expression levels in normal rat hearts were also assessed to provide references for both the sham and AVF groups. Comparison of the time course of changes between sham and AVF groups was done by two-way ANOVA. Additionally, comparison of the time course in each of these groups with normals was done by one-way ANOVA followed by the Newman-Keuls test (where one-way ANOVA was statistically significant) to assess significance of differences between values at each time point with that of normal rats. Differences between two groups (comparison of V0 between groups of normal and AVF rats) were assessed by Student's t-test. Correlation analysis was done by the method of least squares. A probability level of P < 0.05 was taken to be statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Echocardiographic findings.
Figure 1 is a scatterplot of in vivo
assessments of LVIDD derived from M-mode echocardiographic measurements
corresponding to body weights. LVIDD increased with body growth in
normal rats (Fig. 1), and this regression was used to differentiate
true LV dilatation from the normal growth of the LV chamber. The
difference between measured LVIDD and that predicted from this
regression (LVIDDPRED) divided by LVIDDPRED
represents the experimentally induced fractional increase in LVIDD. In
AVF rats, these values (expressed in percent) increased significantly
by 7 days postoperative and still further by 21 days (Fig.
2A, P < 0.01 in both cases). The increment between 21 and 42 days was not
statistically significant. The ratio of LV wall thickness to LVIDD,
which is largely independent of body weight but sensitive to acute
cardiac failure (10), was also recorded. In these AVF
rats, it decreased markedly by day 7 (P < 0.01) and remained depressed for the duration of the study.
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LV and RV hypertrophy.
Table 1 shows the progressive changes in
LV and RV masses in sham-operated and AVF rats. At 2 days
postoperative, body weights did not differ significantly between
sham-operated and AVF rats, whereas both LV and RV masses were slightly
but significantly elevated in the AVF group. Body weight, but not LV or
RV masses of AVF rats, was significantly less than that of
sham-operated rats at 7 days postoperatively. By 42 days, body weights
of these two groups were nearly the same, but LV and RV masses were
significantly greater in AVF rats compared with values of sham-operated
rats. In Fig. 2B these same data are presented as ratios of
LV and RV mass-to-body mass to illustrate the time course of changes in relative hypertrophy. These findings show a very rapid increase in
relative LV and RV hypertrophy during the first week, with eventual
development of substantial biventricular hypertrophy in absolute terms.
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LV and RV chamber volumes at
V0.
Hearts of AVF rats (n = 9 rats) killed 45 days
postoperatively had significantly larger LV and RV chamber volumes at
V0 (Fig. 3) compared with
those of normal rats (n = 8 rats) despite the fact that
both groups had identical final body weights (468 ± 52 vs.
468 ± 43 g, means ± SD, respectively). The near
doubling of both chamber volumes in AVF rats at 42 days is consistent
with the 35% increase in LVIDD seen in AVF at approximately the same time point (i.e., 1.353 = 2.46) and suggests that most
of the dilatation is due to structural remodeling as opposed to a
simple increase in filling pressure. V0 of the RV was
significantly larger than that of the LV in both normal and AVF rats,
possibly due to inclusion of appreciable RV outflow tract volume in
this measurement.
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Atrial masses and lung mass.
By 7 days postoperative, left and right atrial mass-to-body mass ratios
in the AVF group increased markedly compared with normals (Fig.
4A). These changes presumably
reflect substantial increases in atrial filling pressures consistent
with the volume-overload state. Wet lung mass-to-body mass ratio, used
here as an index of pulmonary congestion, increased sharply during the
first postoperative week (Fig. 4B) but did not increase
thereafter. There was also a significant, albeit transient, increase in
this ratio at 2 days in sham-operated rats.
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Mortality and signs of heart failure. Of a total of 114 rats with AVF, 23 died before the scheduled date of death (these scheduled dates ranged from 8 h to several months postoperatively). This appreciable mortality raises the issue of selection and how it might affect interpretation of these findings. If these deaths occurred in rats subjected to slightly larger shunts, one might expect greater ventricular hypertrophy and pulmonary congestion, and such evidence would suggest that changes in gene expression (derived only from survivors) might have been even more pronounced had these nonsurvivors been included. On the other hand, any evidence that these deaths were frequently associated with a ruptured shunt and/or infection would carry a different interpretation.
Of the AVF rats that died, six rats failed to recover from the anesthesia and died with hours of the operation. Another six died within 3 days, with evidence of intra-abdominal bleeding (clots) around the site of the fistula in two rats. Seven more AVF rats died by 1 wk, and the others died at 14, 15, 29, and 39 days. No evidence of intra-abdominal bleeding was seen in AVF rats that died more than 3 days postoperatively. Ventricular, atrial, and lung wet masses were obtained from eight AVF rats for which the time of death (±12 h) could determined. This group (410 ± 109 g body wt, 16 ± 14 days survival, means ± SD) was compared with a group of surviving AVF rats killed over the same range of postoperative times (n = 20, 405 ± 88 g body wt, killed at 17 ± 18 days, means ± SD). Those that died had a lung mass-to-body mass ratio of 12.88 ± 7.31 vs. 6.66 ± 3.51 g/kg in surviving AVF rats (P < 0.01) and this ratio was approximately four times normal (See Fig. 4B). Respective differences between these subgroups in terms of tissue mass-to-body ratios (g/kg) for LV (2.84 ± 0.27 vs. 2.59 ± 0.37), RV (1.03 ± 0.22 vs. 0.88 ± 0.16), left atrium (0.17 ± 0.06 vs. 0.17 ± 0.06), and right atrium (0.26 ± 0.06 vs. 0.23 ± 0.07) indicated nonsignificant trends toward greater hypertrophy. This analysis suggests that most deaths in the AVF group occurred due to a more severe shunt and consequently greater hemodynamic and/or neurohumoral stress.Collagenase expression.
Figure 5 illustrates typical findings in
which the collagenase gene (rat mRNA, 1.4 kb) was barely expressed in
LV RNA samples from either normal or sham-operated rats but strongly
expressed in all samples from AVF rats at 2 h (not shown) and
8 h postoperative. Thereafter, expression level in the AVF group
decreased and by 14 days approached baseline values.
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Collagen expression.
Figure 8 shows Northern blot
hybridizations for collagen I in LV samples from sham-operated and AVF
rats killed at 30 and 45 days postoperatively. Increased collagen I
gene expression compared with the sham group is seen in the samples
from AVF rats killed at 30 days but not in AVF rats killed at 45 days.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We report here for the first time that collagenase gene expression rises sharply from barely detectable levels to a peak within 1 day of induction of an AVF in rats. In our data, this was followed by increases in expression of collagen I gene and collagen III gene, both of which peaked at 7 days. A prior study of this same model (19) showed a rapid rise in myocardial collagenase enzyme activity, which peaked at day 5 and corresponded to a markedly reduced collagen volume fraction. Taken together, these findings suggest that the ventricular dilatation seen in this model follows an initial phase of net collagen degradation due at least in part to increased procollagenase synthesis.
LV structural dilatation is paralleled by increases in both MMP-1 protein levels and activity in the dog rapid-pacing model (28) and in human dilated cardiomyopathy (31). The latter work (31) also reported a corresponding increase in MMP-1 gene expression as well as sharp decreases in both TIMP levels and its gene expression. Another study found increases in both MMP-1 activity and in TIMP gene expression 2 days after myocardial infarction in rats (6). A subsequent study by Spinale et al. (27) noted that the administration of a synthetic MMP inhibitor to pigs with pacing-induced heart failure markedly reduced the ventricular dilatation normally seen in that model. The common elements to all of these studies are increased LV dilatation in the presence of increased collagenase activity. Despite the potential inhibitory influence of TIMP, these data suggest an early phase in each of these models in which factors favoring collagenase synthesis and activation predominate.
The present study shows a dissociation between the peak of collagenase gene activation and the peak of collagen gene activation, with the former occurring earlier, then subsiding, whereas collagen gene activation persisted for over 1 mo. This pattern is consistent with findings by Namba et al. (23), who showed that after AVF in rats, expression of collagen I and collagen III genes was elevated at 1 mo, whereas myocardial collagenase activity was normal at that time. However, that study did not examine collagenase activity at any earlier time points, and did not include assessment of collagenase gene expression. The present study, together with the findings of Janicki et al. (19), suggests that in the rat AVF model, major changes in collagenase gene expression and in collagenolytic activity occur within the first postoperative week. During this same period, our echocardiographic data show that more than half of the LV dilatation occurred. Additional studies are needed to elucidate the interplay of pre- and posttranslational factors over the entire remodeling period. However, the marked increase in collagenase gene expression within hours of creating the AVF suggests that transcriptional regulation may be an important determinant of the acute rise in collagenolytic activity, in addition to its role in long-term maintenance of procollagenase stores.
The observation of MMP-1 expression in the rat heart is, itself, noteworthy. An interstitial collagenase originally isolated from the rat heart and believed to be MMP-1 (25) was later determined to be much more homologous to human MMP-13 than to human MMP-1 (20). The cDNA probe encoding this protein has been used to study changes in metalloproteinase gene expression in rats after myocardial infarction (6), but to date, there have been no reports in rats utilizing a cDNA probe for MMP-1. Collagenase with high homology to human MMP-1 has recently been cloned and sequenced in the hamster and guinea pig (16). This suggests that a homologous MMP-1 exists throughout the Rodentia order. Of note, the human cDNA probe for MMP-1 utilized in this study would not be expected to hybridize with either human MMP-13 or rat collagenase 3 under the experimental conditions employed here.
Questions regarding the mechanism(s) by which both collagen and
collagenase production are regulated necessarily focus on the cardiac
fibroblast. In vitro studies (5, 7, 11, 14) have shown
that agents such as angiotensin II, endothelin (ET)-1, ET-3,
transforming growth factor-
, and PGE-2 interact to modify collagen
and collagenase gene expression and protein synthesis, as well as
collagenolytic activity. In many, but not all cases, there appears to
be a reciprocal relationship between a particular agent's effects on
collagen synthesis and collagenolytic activity (11, 14)
and between its effects on collagen gene expression and collagenase
gene expression (5). Because the humoral and/or tissue
levels of these agents are commonly altered in various disease states,
such changes may mediate the specific form of remodeling that ensues.
Moreover, there is evidence that the cardiac fibroblasts themselves
undergo phenotypic changes in the aortocaval model (9),
which could further differentiate their responses to humoral agents.
The present results must be considered in the context of stress severity. Although most studies using the rat AVF model report low mortality, a shunt slightly larger than the one used here precipitates acute heart failure (15). Our observations of early mortality coupled with a significant decline in LV wall thickness to chamber diameter in AVF survivors suggest that the stress level was near-maximal in these rats. Thus the sequelae reported here could differ from those occurring in the AVF rats that died and/or in rats subjected to a smaller fistula.
The increased expressions of collagens I and III and collagenase in the
sham-operated rats compared with normals were unexpected. They suggest
a contribution by some factor(s) other than actual establishment of the
AVF. In this regard it must be noted that the sham operation employed
here included cross-clamping the abdominal aorta for 10 min. This is
the period during which the abdominal aorta was punctured with an
18-gauge needle with ensuing repair of the puncture site (thus
duplicating those same steps in the experimental group). The increased
lung wet mass of shams at 2 days suggests that operative procedures in
this group may have caused sufficient hemodynamic overload to induce
the observed transient gene activations. Thus to the extent that
activation of these genes may result from mechanical distention of the
LV, and both the AVF and sham procedures share a step likely to induce severe transient LV overload, transiently increased expression of these
genes in the sham-operated group would not be surprising. The fact that
the AVF group manifested early spikes in collagen and collagenase gene
expression that were concurrent with the transient increases in
expression of these genes in the sham-operated animals adds
plausibility to this interpretation. There are other possible
interpretations. In the rat, experimental laparotomy has been shown to
increase blood levels of tumor necrosis factor (TNF)-
(26). Activation of cytokines appears to be an integral part of the host response to general injury or trauma, and because TNF- and interleukin-1 induce MMP gene expression, it is plausible that the transient increase in MMP gene expression in the sham-operated animals may be due to this release of cytokines from surgical trauma.
Further studies are needed to investigate these possibilities.
In conclusion, the present results show that in the first week after induction of an AVF in the rat, major changes in LV hypertrophy and dilatation are accompanied by marked increases in expression of collagens I and III genes and of collagenase gene. Subsequently, LV hypertrophy and dilatation progress more gradually, with expression of collagenase and collagen III genes returning to normal by 2 wk and expression of collagen I gene returning to normal by ~6-7 wk. Thus the period of rapid remodeling is accompanied by significant changes in expression of these genes. The increased collagenase gene expression seen in AVF rats may be critical to a remodeling process involving cardiac dilatation without net collagen accumulation.
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ACKNOWLEDGEMENTS |
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This study was supported in part by a Merit Review grant from the Department of Veterans Affairs (to S. A. Atlas) and National Heart, Lung, and Blood Institute RO1-HL-27219 (to C. Eng).
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. M. Siri, Cardiovascular Research Laboratory, Bronx VA Medical Center, 130 West Kingsbridge Rd., Bronx, New York, NY 10468 (E-mail: fmsiri{at}systec.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 24 February 2000; accepted in final form 9 February 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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