Mol. Hum. Reprod. Advance Access originally published online on March 11, 2008
Molecular Human Reproduction 2008 14(4):215-223; doi:10.1093/molehr/gan008
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Prostaglandin F2-alpha receptor regulation in human uterine myocytes
1Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing 430038, People's Republic of China 2Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK 3Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus DuCane Road, London W12 0NN, UK 4Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, 21 Bethesda Avenue, Cincinnati, OH 45267, USA
5 Correspondence address. Tel: +44-20-8846-7892; Fax: +44-20-8846-7796; E-mail: mark.johnson{at}imperial.ac.uk
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Abstract |
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Investigations of the modulation of prostaglandin F2
receptor (FP) expression in primary cultures of human uterine myocytes showed that FP mRNA expression was reduced by progesterone, unaltered by cAMP (8-bromo cAMP or forskolin), but increased by the PKA antagonist H89. Interleukin (IL)-1β, tumour necrosis factor-alpha and oxytocin increased FP mRNA expression and IL-6 and prostaglandin E2 reduced FP mRNA expression. The changes in FP protein levels were similar to the mRNA responses. We found that the IL-1β-induced increase in FP expression was mediated at least in part via protein kinase C (PKC), but was independent of mitogen-activated protein kinase, phospholipase C and PI3 kinase. Since IL-1β activates NF
B, AP-1 and C/EBP, we over-expressed these transcription factors alone and in combination and found that only NFB alone increased FP mRNA expression. Finally, we found that the IL-1β-induced increase in FP expression was unaffected by progesterone and/or cAMP, but was accentuated by H89. These data suggest that the pregnancy-induced down-regulation in myometrial FP expression is mediated by progesterone and cAMP and that the increase with labour is induced by inflammatory cytokine activation of PKC and NFB.
Key words:
Prostaglandin F2 receptor/labour/progesterone/inflammatory cytokines/NFB
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Introduction |
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Prostaglandin F2
(PGF2) plays a key role in the onset and progression of labour in several species. It acts via the PGF2 receptor (FP), a member of the seven trans-membrane G-protein-linked receptor family, to promote myometrial contractility (Peri et al., 2002). Existing data suggest that myometrial FP mRNA expression is increased with the onset of labour and that in most models of preterm labour, FP antagonists are inhibitory (Chollet et al., 2007; Cirillo et al., 2007; Olson and Ammann, 2007). However, neither the human nor the animal data are consistent. Myometrial FP mRNA expression and in some cases FP protein levels have been reported to increase with the onset of labour in the rat, mouse and sheep (Brodt-Eppley and Myatt, 1998; Ma et al., 1999; Al-Matubsi et al., 2001), but to be unchanged in the baboon and in a second study in the sheep (Smith et al., 2001; Palliser et al., 2005). In the human, FP declines with pregnancy (Matsumoto et al., 1997) and has been found to increase in lower segment samples obtained from labouring women (Brodt-Eppley and Myatt, 1999). These data are consistent with our own data derived from primary cultures of human uterine myocytes in which we found that FP was down-regulated by pregnancy and that this was partially reversed with the onset of labour (Sooranna et al., 2005b). In our most recent study, we found that FP mRNA expression tended to increase with preterm and term labour in the upper and lower uterine segment samples, but that this increase did not reach statistical significance (Grigsby et al., 2006). Thus, overall, the human data suggest that myometrial FP mRNA expression is reduced during pregnancy and then rises with the onset of labour.
The factors responsible for the maintenance of myometrial quiescence during human pregnancy are not known, but almost certainly include progesterone and the intracellular levels of cAMP and cGMP. Whether these factors influence myometrial FP mRNA expression in the human is uncertain, but in animal studies, progesterone represses and estradiol promotes rat myometrial FP expression (Dong and Yallampalli, 2000) and cAMP has been shown to enhance FP expression in bovine corpus luteum cells (Mamluk et al., 1998). With the onset of labour, the uterus is subjected to a variety of stimuli including physical stretch, inflammatory cytokines, interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-) and IL-6, chemokines, IL-8 and pro-labour factors including prostaglandins and oxytocin (OT). In an earlier study, we found that mechanical stretch of uterine myocytes had no effect on FP mRNA expression (Sooranna et al., 2005b), consistent with the animal data (Ou et al., 2000), but IL-1β has been found to increase FP mRNA expression in uterine myocytes cell line via NFB activation (Olson et al., 2003; Zaragoza et al., 2006).
In this study, we have investigated the mechanisms that are responsible for the pregnancy-associated reduction in FP mRNA expression and the later increase with the onset of labour.
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Materials and Methods |
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Cell culture
Biopsies (0.5 x 0.5 cm3) of term human myometrium were collected at the time of Caesarean section (LSCS) from women not in labour and stored in DMEM medium containing 100 mU/ml penicillin and 100 µg/ml streptomycin. Samples were stored at 4°C for no more than 3 h prior to cell preparation for culture. The mean maternal age was 30 (24–39) years with a gestational age of 39 (38+3–39+5) weeks. The indications for LSCS in this group of women were previous LSCS, breech presentation and maternal request. All specimens were obtained after patient consent, and the Riverside Research Ethics Committee approved the study.
Primary human uterine myocytes were isolated using a mixture of collagenases and cultured in DMEM medium 7.5% fetal calf serum (FCS), 100 munits/ml penicillin and 100 µg/ml streptomycin in T75 in an atmosphere of 5% CO2:95% air at 37°C (Sooranna et al., 2005a). Myometrial cells grown in this manner have previously been characterized (Sooranna et al., 2005a). Cells from passages 1 to 4 were trypsinized in 0.25% trypsin containing 0.02% EDTA in phosphate-buffered saline (PBS) and cultured in 6-well plates. When cells were 80–90% confluent (Days 3–4), old medium was removed and replaced with 1.5 ml of fresh medium supplemented with 7.5 mM HEPES with 1% FCS overnight. After 16–18 h various additions were made.
Progesterone/cAMP studies
After 16–18 h, cells were incubated for 48 h with 1 µM 6 alpha-methyl-17 alpha-hydroxy-progesterone acetate, 0.2 mM sodium salt of 8-bromoadenosine 3',5'-cyclic monophosphate, 100 µM forskolin and 1 µM H89 were added either alone or in combination; 1 ng/ml Il-1β was then added to some of the cells for 360 min. Media were then removed and cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA.
Cytokine, chemokine and pro-labour factor studies
After 16-18 h, cells were incubated for 1, 6 and 24 h with either 1 ng/ml IL-1β, 1 ng/ml TNF-, 1 ng/ml IL-6, 1 ng/ml IL-8, 10 nM PGE2, 10 nM PGF2 or 100 nM OT after which media were then removed and cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA.
Mitogen-activated protein kinase studies
After overnight serum depletion, cells were exposed to IL-1β at 1 ng/ml for 360 min after which media were removed and the cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA. In some cases, cells were pre-incubated with specific inhibitors of extracellular signal-regulated kinases [U0126, 10 µM for 2 h, New England Biolabs (UK) Ltd, Hitchin, Hertfordshire, UK], C-Jun N-terminal kinases (JNK) (SP600125, 20 µM for 1 h, Tocris Cookson Ltd, Northpoint, Fourth Way, Avonmouth, Bristol, UK) or p38 (SB203580, 10 µM for 30 min, Tocris Cookson Ltd) prior to exposure to IL-1β. Cells were also incubated with 0.2 µM the JNK and p38 activator, anisomycin, for 6 h.
Phospholipase C, P13 kinase and protein kinase C studies
In some cases, cells were incubated with 25 µM m-3M3FBS [a phospholipase C (PLC) activator], 10 µM U73122
[GenBank]
(phospholiase C inhibitor), 25 µM SC10 [a protein kinase C (PKC) activator], 10 µM GF109203X (a PKC inhibitor), 12.5 µg/ml PDGFR740-YP [a PI3-kinase (PI3K) activator] for 6 h and Wortmannin (100 nM, a PI3K inhibitor). These reagents were purchased from Tocris Cookson Ltd. After incubation, medium was removed and cells were similarly frozen for RNA extraction. More than 95% of cells remained attached to the 6-well culture plates with these protocols.
Transcription factor over-expression
Cells were grown in 6-well plates to 80% confluence. Transient transfections were carried out using a liposome-mediated method with Fugene-6 transfection reagent (Roche Products Limited, Shire Park, Welwyn Garden City, UK). Cytomegalovirus-Renilla vector (1/10th of reporter) was used to control for transfection efficiency and cell number. Expression constructs for C/EBP (LAP), NF-B(p65,ReLA), AP-1 (cFos and cJun) were transfected either alone or in different combinations. The empty expression vector pSG5 was included as a filler construct when required so that the total amount of transfected DNA per well was constant. Cells were cultured for 24 h, after which medium was removed and cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA.
Expression vectors for C/EBP (pSG5 C/EBPβ LAP) and AP-1 (pcDNA AP-1 cJun, pcDNA AP-1 cFos) were kindly provided by Dr Birgit Gellersen (Hamburg, Germany). Expression vectors for NF-B (pSG5 NF-B p65) were a kind gift from Dr John White (Swansea University, UK). Transfection efficiency was measured using green fluorescent protein construct and found to be between 20% and 30% in all experiments.
Quantitative RT–PCR
Total RNA was extracted and purified from cells grown in 6-well plates pre-coated with collagen type I using the RNAeasy mini kit from Qiagen Ltd, Crawley, West Sussex, UK. After quantification, 1.0 µg was reverse transcribed with oligo dT random primers using MuLV reverse transcriptase (Applied Biosystems Ltd, Warrington, Cheshire, UK). Paired oligonucleotide primers for amplification of human FP receptor were designed using Primer Designer (Scientific and Educational Software, Durham, NC, USA) against the sequence downloaded from GenBank. The primer sets used (Table I) produced amplicons of the expected size and flanked intron/exon junctions. Assays were validated for all primer sets by confirming that single amplicons of appropriate size and sequence were generated. Quantitative PCR was performed in the presence of SYBR Green (Qiagen Ltd), and amplicon yield was monitored during cycling in a RotorGene Sequence Detector (Corbett Research Ltd, Mortlake, Sydney, Australia) that continually measures fluorescence caused by the binding of the dye to double-stranded DNA. Pre-PCR cycle was 10 min at 95°C followed by up to 45 cycles of 95°C for 20 s, 58–60°C for 20 s and 72°C for 20 s followed by an extension at 72°C for 15 s. The final procedure involves a melt over the temperature range of 72–99°C rising by 1° steps with a wait for 15 s on the first step followed by a wait of 5 s for each subsequent step. The cycle at which the fluorescence reached a preset threshold (cycle threshold) was used for quantitative analyses. The cycle threshold in each assay was set at a level where the exponential increase in amplicon abundance was approximately parallel between all samples. The r2 values and efficiencies for the primers pairs are given in Table I. mRNA data were expressed relative to the amount of the constitutively expressed housekeeping gene GAPDH.
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Western analysis
After treatment protocols were complete, media were removed and the cells washed once with ice-cold PBS. Cells from each well (1 x 106) were lysed in 0.2 ml of a buffer containing 20 mM Tris–HCl (pH 7.4), 150 mM NaCl, 1% triton X-100, 1 mM EDTA, 1 mM EGTA, 2.5 mM Na Pyrophosphate, 1 mM β-glycerophosphate, 2 mM dithiotreitol, 1 mM Na3VO4, 1 mM phenylmethylsulphonyl fluoride and 1 µg/ml leupeptin. After a further 5 min incubation on ice, the cells were scraped off the plate, transferred to microcentrifuge tubes, aliquoted and frozen at –80°C. Protein concentrations were determined by Protein assay (Bio-Rad Laboratories, Hercules, CA, USA) and bovine serum albumin (BSA) reference standards. Electrophoresis was carried out on 15 µg aliquots of protein samples, in 2x loading buffer [4% sodium dodecyl sulphate (SDS), 20% glycerol, 10% 2-mercaptoethanol, 0.004% bromophenol blue and 0.125 M/l Tris–HCl, pH 6.8]. Samples were boiled for 5 min, quenched on ice and subsequently run on a 10% SDS–polyacrylamide gel (Bio-Rad Laboratories).
Western blotting was carried out following electrophoretic transfer, in 25 mM/l Tris, 192 mM/l glycine and 20% v/v methanol, pH 8.3, on to Hybond ECL nitro-cellulose membrane (Amersham Life Science, Little Chalfont, UK). Membranes were blocked in 5% milk protein in 0.1% Tween–PBS, for 1 h at room temperature. Specific rabbit polyclonal antibody directed against the FP (Cayman Chemical Company, Tallinn, Estonia) at a dilution of 1:200, and incubated overnight at 4°C. Mouse monoclonal antibody directed against the β-actin (Sigma Chemical Company, Poole, Dorset, UK) at a dilution of 1:10 000 was also used. Membranes were washed in 0.1% Tween–PBS and then incubated with anti-goat immunoglobulin G–horseradish peroxidase (IgG–HRP) secondary antibody at a dilution of 1:2000 for 1 h at room temperature. ECL western blotting detection was carried out using standard chemiluminescence protocols (Perbio Science UK Ltd, Tatenhall, Cheshire, UK). Protein band size was determined using a biotinylated protein ladder followed by HRP-linked anti-biotin antibody [New England Biolabs (UK) Ltd.] Rainbow coloured protein molecular weight markers (Amersham Life Science). Western autoradiographs were quantified by digital densitometry using the Image Master VDS gel documentation system and Image Master VDS Software (Pharmacia Biotech). Protein bands were digitized, ensuring that the range of pixel densities did not extend to either the minimum or maximum values. Mean pixel density for each band was assessed using a sample gate of the same size. To allow comparisons between blots prepared on different occasions, a single control sample was included on each blot. The final pixel density was adjusted to ensure that this control sample carried the same value for each blot. Loading was controlled with β-actin.
Statistical analysis
Since the data were not normally distributed, they were expressed as median and range and differences analysed by Mann–Whitney U-test for paired samples and where appropriate a Kruskal–Wallis test and post testing with Mann–Whitney U-test. Differences were considered statistically significant at P<0.05. Data were analysed using Prism 4 for MacIntosh, GraphPad, San Diego, USA.
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Results |
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Exposure of primary cultures of uterine myocytes to progesterone reduced FP expression (P < 0.05, Fig. 1a), but the addition of either 8-bromocyclic AMP or forskolin had no effect (Fig. 1a). In contrast, the addition of the PKA antagonist, H89, increased FP mRNA expression (P < 0.05, Fig. 1a). The combination of med oxyprogesterone (MPA) and either 8-bromocyclic AMP or forskolin had no effect (Fig. 1b). However, the presence of H89 blocked the negative effect of MPA on FP mRNA expression (Fig. 1b).
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Uterine myocytes expression of FP mRNA was increased by the addition of IL-1β (6 h P < 0.05, Fig. 2a), TNF-
(6 and 24 h, P < 0.05, Fig. 2b) and OT (1 h, P < 0.05, Fig. 2g), reduced by IL-6 (1 h, P < 0.05, Fig. 2c) and PGE2 (6 h, P < 0.05, Fig. 2e). There was no effect of either IL-8 or PGF2 (Fig. 2d and f). Western analysis confirmed these data showing increasing in FP protein levels in response to IL-1β (Fig. 3a, P < 0.05 at 6 h), TNF- (Fig. 3b, P
0.05 at 6 h) and OT tending to increase at 6 h, (Fig. 3f, P = 0.0625) and a reduction in FP protein levels in response to IL-6 at 24 h (Fig. 3c, P < 0.05). There was no significant change in FP protein levels in response to PGE2, PGF2 or IL-8 (Fig. 3d, e and g).
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The IL-1β-induced increase in FP mRNA was unaffected by mitogen-activated protein kinase (MAPK) inhibitors and FP mRNA expression was unaltered by exposure to the JNK and p38 activator anisomycin (Fig. 4a). Similarly, neither PLC or PI3K activators nor inhibitors affected basal or the IL-1β-induced increase in FP mRNA expression (Fig. 4b and c). In contrast, the PKC inhibitor, GF109203X, significantly inhibited the IL-1β-induced increase in FP mRNA expression (Fig. 4d, P < 0.05).
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represents a significant difference versus IL-1β alone of P < 0.05.In order to define which of the IL-1β-activated transcription factors were involved in the increase in FP mRNA expression, we over-expressed NF
B, C/EBP and the AP-1 transcription factors c-fos and c-jun. We found that only NFB (P < 0.05, Fig. 5a) increased FP expression and that there was a trend for this effect to be increased by the combination of NFB and C/EBP, but that the combination of NFB and c-jun reduced FP expression (P < 0.05, Fig. 5b).
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Finally, we investigated whether either progesterone and/or cAMP would reduce the IL-1β-induced increase in FP mRNA expression. The addition of either progesterone (Fig. 6a) and/or cAMP agonists (Fig. 6b) had no effect on the IL-1β-induced increase in FP mRNA expression, whereas the PKA antagonist, H89, increased the IL-1β-induced increase FP expression in the presence or absence of MPA (Fig. 6b, P < 0.05).
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Discussion |
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The maintenance of myometrial quiescence is essential for the normal progression of pregnancy. In most animal models of pregnancy, progesterone maintains myometrial quiescence and its systemic withdrawal precipitates the onset of labour. Also, cAMP contributes to the maintenance of uterine relaxation and in contrast to progesterone a withdrawal in myometrial cAMP has been shown with the onset of labour in the human (MacDougall et al., 2003; Ku et al., 2005). Further, endogenous uterine relaxants, such as calcitonin-gene-related peptide and relaxin, and therapeutic agents, such as the β-agonists, act by increasing intracellular cAMP concentrations. Thus, it seems likely that both progesterone and cAMP act together to prolong pregnancy. In this study, we found that progesterone inhibited basal FP expression; however, when we used 8-bromo-cAMP to increase cAMP action, it had no effect and the effect of MPA was not enhanced by the combination. We reasoned that our pre-labour cells may either have high endogenous cAMP activity or, alternatively, that the 8-bromo-cAMP may have been metabolized. We therefore repeated the studies exposing cells to forskolin, an adenyl cyclase agonist, or H89, a PKA antagonist. We found that forskolin had no effect on FP mRNA expression, but that H89 increased it. Interestingly, H89 blocked the repressive effect of MPA completely. To clarify whether the endogenous cAMP activity was high in our cells, we assessed cAMP response element-binding phosphorylation before and after exposure to forskolin and found that it was increased in two cell preparations and unchanged in two (data not shown), suggesting that in some cell preparations, basal cAMP levels are already elevated. Overall, these data suggest that during pregnancy, FP mRNA expression is negatively regulated by both progesterone and cAMP and that progesterone action may be dependent on PKA activity.
With the onset of labour, FP mRNA expression is increased (Brodt-Eppley and Myatt, 1999). On the basis of the data discussed above, this may be a reflection of decreased cAMP activity and/or progesterone withdrawal. Alternatively, the marked inflammatory infiltration of the myometrium and associated increase in inflammatory cytokine expression may be responsible. We found that FP mRNA expression was markedly up-regulated by both IL-1β and TNF-. Others too have reported that FP increases in response to IL-1β in human myometrial cell line (Olson et al., 2003; Zaragoza et al., 2004), in the same cells IL-6 also increased FP expression, but only at 24 h of incubation (Makino et al., 2007), consistent with our data which showed a trend for IL-6 to increase FP expression at 24 h only. The temporal variation in the FP response to the cytokines probably reflects the different intracellular pathways activated by each agent. In another study, we found that TNF- mRNA expression was not increased in myometrial samples from either preterm or term labour, whereas that of IL-1β was consistently increased (Tattersall et al., 2007). We therefore chose to investigate the mechanisms responsible for IL-1β-induced increase in FP mRNA expression. In an earlier study, we demonstrated that the IL-1β-induced increase in PGHS-2 and IL-8 mRNA expression was MAPK-dependent (Sooranna et al., 2005a). In this study, we failed to demonstrate any role for MAPK in FP regulation, supported by the fact that anisomycin, a JNK and p38 activator, did not affect FP mRNA expression. Nor did we find any role for PLC or PI3K. We did, however, find that PKC may be important, this is supported by the recent observations that in primary cultures of myometrial cells, PKC mediates the IL-1β-induced activation of NFB (Duggan et al., 2007) and that NFB has been shown to mediate the IL-1β-induced increase in FP mRNA expression in studies using a human myometrial cell line (Olson et al., 2003; Zaragoza et al., 2006). We also studied the effects of IL-6 and found a slight decrease at 1 h and then a gradual increase in FP mRNA expression; the response to IL-8 was similar. Pro-labour factors, PGE2, PGF2 and OT had no consistent effects.
Given that IL-1β activates transcription factors other than NFB, and that the FP promoter contains response elements for C/EBP and AP-1 (Zaragoza et al., 2004), we investigated the possibility that C/EBP and AP-1 may be involved either alone or in combination with NFB in the regulation of FP mRNA expression. We found that only RelA increased FP mRNA expression, but that the combination of RelA and C/EBP tended to increase FP-mRNA expression whereas the addition of c-jun significantly reduced the RelA-induced increase in FP mRNA expression. NFB and C/EBP have been reported to act synergistically at the OTR promoter and to enhance uterine myocytes PGHS-2 mRNA expression (Soloff et al., 2004; Terzidou et al., 2006), supporting the idea that they may act together to increase FP expression. Since c-jun can form homodimers, it is possible that there may have been competition between RelA and c-jun for an essential co-activator.
Prophylactic progesterone administration has been shown to reduce the risk of preterm labour in high-risk women (da Fonseca et al., 2003; Meis et al., 2003; Fonseca et al., 2007), but its administration to women in threatened preterm labour was less beneficial (Erny et al., 1986; Noblot et al., 1991). Consistent with these observations, we found that progesterone reduced basal FP expression, but had no effect when FP mRNA expression was increased by IL-1β. The addition of cAMP did not alter the effect of MPA, but the inhibition of PKA increased the IL-1β-induced FP mRNA expression in the presence or absence of MPA.
Our study is consistent with the pregnancy-induced decline in myometrial FP expression being mediated by progesterone and cAMP, and further, with the later labour-associated rise in myometrial FP expression being induced by the increase in inflammatory cytokines. Interestingly, neither progesterone nor cAMP inhibited the IL-1β-induced increase in FP suggesting that therapeutic approaches using either are unlikely to suppress the cytokine-induced increase in FP expression.
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This work was supported by a grant from Wellbeing, the Barclay Foundation and a donation from Will Greenwood.
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References |
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Submitted on October 11, 2007; resubmitted on December 15, 2007; accepted on February 6, 2008.
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