Molecular Human Reproduction, Vol. 8, No. 5, 475-484,
May 2002
© 2002 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Global analysis of differentially expressed genes in early gestational decidua and chorionic villi using a 9600 human cDNA microarray
1 Department of Clinical Research, National Taiwan University Hospital, Taipei, 2 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei and 3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Abstract |
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The global gene expression profiles of the decidua and chorionic villi of early human pregnancies were analysed by using cDNA microarray technology. Decidual and villous placental tissues were obtained from first trimester abortus and mRNA was extracted for cDNA microarray analysis. The human cDNA microarray [9600 clones, including known regulatory genes and expressed sequence tags (EST)] with colorimetric detection was used to identify differentially expressed genes between early gestational decidua and villi. According to cDNA microarray analysis, we have identified 641 genes with highly expressed mRNA in both decidua and villi, 49 genes with higher expressions in decidua, and 75 genes with higher expression in chorionic villi. These differentially expressed genes were further grouped into categories by their putative functions, including: cell growth-related factors, hormones/cytokines, cell adhesion molecules, signal transduction molecules, apoptosis-related factors, cytoskeleton/extracellular matrix proteins, and EST. Immunohistochemical stainings of cathepsin L, leukaemia inhibitory factor-receptor, and proliferative cell nuclear antigen showed results consistent with the microarray data. Identification of the differentially expressed genes between decidua and villi by microarray provide a global profiling of the gene expression pattern. This work adds to our understanding of placentation by reporting the gene expression profiles during first trimester human pregnancies using cDNA microarray.
chorionic villi/decidua/first trimester/gene expression/microarray
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Introduction |
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The placenta and fetal membranes separate the fetus from the mother but allow an interchange of substances between the maternal and fetal blood streams. Placentation, which supports normal human embryo/fetal development, is the result of a well-orchestrated sequence of events of cellular adhesion with limited invasion controlled by relatively unknown genetic processes (Dizon-Townson et al., 2000
). The growth of the embryo and the contiguous placental structures are fundamental to human reproduction and survival. The cell–cell interactions and gene expression in human decidua and chorionic villi during the first trimester of pregnancy constitute critical regulators of placentation and thus of early development. However, little is known about the mechanisms of these processes during early implantation and further placental development.
Common obstetric diseases, such as pre-eclampsia, intrauterine growth restriction, preterm birth, and recurrent pregnancy loss, are hypothesized to be associated with abnormal or impaired placentation (Pijnenborg et al., 1996; Rogers et al., 1999). If so, the genes expressed by the placenta may serve as genetic markers for disease risk or prognosis. Information on gene expression will also help in the understanding of the cell–cell interactions between decidua and chorionic villi. Several factors have been reported to be involved in normal embryo development and uterine decidualization during early pregnancy; these include urokinase plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1) and 2 (PAI-2), urokinase receptor, cystatin C, cathepsins, and decidual aspartyl protease 1 (DAP1) (Afonso et al., 1997; Moses et al., 1999; Feng et al., 2000). However, the molecular mechanism(s) responsible for human placental development, in particular the gene regulation and cytokine/hormone interactions in the uterus during pregnancy, is still unclear.
The human placenta is a complex organ that expresses >12000 genes (Dizon-Townson et al., 2000). In the past, however, most molecular biologists have had access only to term placentas for study. Early first trimester human gestational tissues have therefore been studied relatively little. Although some of the molecules concerning adhesion, migration, and controlled invasion are critical to normal development of first trimester decidua and chorionic villi, little is known regarding the genetic regulation of these processes in human placenta (Dizon-Townson et al., 2000). Microarray analysis, a well established method and a powerful tool for massively parallel analysis of gene expression, has been applied in various biological studies for identifying differentially expressed genes (Chen et al., 1998, 2001; Hong et al., 2000). Using a cDNA microarray with colorimetric detection system, we were able to characterize the genes that are differentially expressed between the decidua and chorionic villi during the first trimester.
We hope this work may provide insight into the interactions between human trophoblastic cells and decidua. The results may help us to understand decidual gene regulation and placental development, and may also provide information for genetic diagnosis or gene therapy in some obstetric diseases.
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Materials and methods |
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Tissue collection
Institutional Review Board approval was obtained before initiation of this investigation by the Taipei Medical University Hospital. Tissues (decidua and chorionic villi) were obtained from first trimester (6–8 weeks) abortus following the patients' consent (n = 8). Samples were obtained aseptically by curettage. Inclusion criteria were as follows: maternal age <35 years, proven fertility with a history of at least one live birth, and confirmation of gestational age. Confirmation of gestational age was by menstrual history, physical examination, and ultrasonographic evaluation. First-trimester placental tissue was separated from surrounding membranes, and villous tissue was carefully dissected, avoiding decidual and embryonal tissue as confirmed by the use of a dissecting microscope as previously described (Currie et al., 1992
; Downing et al., 1995). After gross examination, the tissues were rinsed free of blood with phosphate-buffered saline (PBS) and divided into two parts; one part for RNA extraction was flash-frozen in liquid nitrogen and the other one was fixed in 3.7% paraformaldehyde for immunohistochemistry. Chorionic villous samples had the presence of fetal villi and the absence of maternal decidua confirmed histologically while decidual tissues had the opposite confirmation. The samples were then used for total RNA extraction using RNAzolTM B reagents (Life Technologies, Gaithersburg, MD, USA). Because the amount of the total RNA (from decidual or chorionic villous tissues) from a single patient was not enough for the following experiments and in order to reduce the effect of individual differences between patients, we pooled the RNA from four patients together, randomly. The hybridization experiments were then performed in duplicate. The poly (A)+ RNA was isolated using Oligotex mRNA Spin-Column system (Qiagen, Hilden, Germany), according to the manufacturer's specifications. The quantity and quality of each sample was determined spectrophotometrically by A260 and A260:280 ratio, and checked by electrophoresis on a 1.0% agarose/formaldehyde gel.
Microarray system
Preparation of cDNA probes and microarray hybridization mRNA samples (5 µmg each) derived from decidual or villous placental tissues in the same patient group (n = 4) were labelled with biotin during reverse transcription and applied to the array which has been described in our previous reports (Chen et al., 1998; Hong et al., 2000). The cDNA microarray (measuring 18 mm by 27 mm) carrying 9600 PCR-amplified cDNA fragments (with lengths of 0.5~3.0 kb, and averages of ~1.0 kb) were prepared by an arraying machine (Wittech, Taipei, Taiwan). The 9600 non-redundant expressed sequence tag (EST) clones were Integrated Molecular Analysis of Genomes and their Expression (IMAGE) human cDNA clones, each representing a putative gene cluster with an assigned gene name in the Unigene clustering (Schuler, 1997). Partial sequencing of the clones indicated that there were 75% matched named genes. The details of probe preparation, hybridization, and colour development have been described previously (Chen et al., 1998).
Colorimetry detection and image processing
After colour development, the cDNA molecules labelled with biotin yield a blue chromogen. The microarray images were scanned and digitized using a flatbed scanner (PowerLook 3000; Umax, Taipei, Taiwan). The scanner provided 3000 dpi resolutions and was suitable for larger arrays such as those of 9600 elements. The microarray images were processed by commercial image processing programs to convert the true-colour images into gray scale images, and then the image analysis and spot quantification were done using the GenePix 3.0 (Axon, Union City, CA, USA).
Immunohistochemistry
After gross examination of the decidual and villous placental tissues, the samples were rinsed with PBS and fixed in 3.7% paraformaldehyde, and then were ready for immunohistochemistry as in previous reports (Mutasa and Pearson, 1988). The polyclonal cathepsin L, mouse monoclonal leukaemia inhibitory factor receptor (LIF-R), and proliferating cell nuclear antigen (PCNA) antibodies (Santa Cruz, Biotech Inc., CA, USA) were used at a dilution of 1/200. The immunohistochemistry was carried out using the goat IgG or mouse IgG Vectastain ABC kits (Vector, Peterborough, UK) according to the manufacturer's instructions. Negative control slides without primary antibody were included for each staining. Finally, DAB (3,3'-diaminobenzidine, Sigma, St Louis, MO, USA) was used to develop the colour (brown), and haematoxylin was used for counterstaining.
Statistical analysis
Gene expression data obtained from the microarray experiments were processed and normalized using a previously described protocol and programme (DeRisi et al., 1996; Iyer et al., 1999). After spot quantification was done using the GenePix 3.0 (Axon, Union City, CA, USA), the mean and SD of expression as well as the ratios of the mean decidua expression versus mean villi expression were calculated and used for comparison. Differentially expressed genes were chosen as those beyond the 95% predicted regression line. Next, the conventional criteria of 3- and 5-fold differences were used to subclassify the significantly different genes. The differentially expressed genes were considered to be significantly down- or up-regulated by a factor of 
3.0-fold between decidua and chorionic villi and were sequence-verified. Expression differences of <2- or <3-fold have usually been considered at the limit of detection in other previous analyses (DeRisi et al., 1996; Tanaka et al., 2000; Cavallaro et al., 2001; Popoviciet al., 2001). The differentially expressed genes were grouped into categories by their putative functions on the basis of literature reports. Genes with multiple roles were included in more than one category.
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Results |
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The decidual and villous tissues were stained with haematoxylin and eosin for histological examination (Figure 1
). The decidual tissue during the first trimester of pregnancy was shown by the characteristic pale-staining decidual cells. These glycogen- and lipid-laden cells are highly modified stromal cells. The cytotrophoblast (inner) and syncytiotrophoblast cells (outer) forming the shell of villi are also shown in Figure 1. According to this morphological examination, the unique parts of the decidual and villous tissues were used for the following cDNA microarray analysis.
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A representative gene expression profile of decidual and villous placental tissues from the same patient group is depicted in Figure 2A
. The array signal intensities of decidua were compared with the intensities of villous tissue from the same patient group. Figure 2B shows a collection of cropped microarray images (5x5 spots) showing the different gene expression patterns between decidua and villi. As shown in Figure 2B, most of the spots had similar signal intensities between two profiles; however, some of the spots revealed different signal intensities (close-up view of the cDNA microarray). In the upper panel of Figure 2B, the cropped microarray images of cathepsin L are shown in the circles, higher expression in decidua. The expression levels of LIF-R and keratin 8 genes are shown in the lower panel to be higher in chorionic villi.
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Microarray analysis revealed that only 3324 genes out of 9600 EST clones were detectable (with an expression level
3000 IU over the background) in human decidua and chorionic villi (Figure 2C
). Among these genes, 641 genes were highly expressed (with 15 030 arbitrary units for the mean of expressed level) in both decidua and chorionic villi (Figure 2C). Many cell growth regulators (GTPase-activated protein, ras/p21) and cytokine- or hormone-related genes were highly expressed between decidua and chorionic villi, including FGFBP (fibroblast growth factor binding protein), FGF-R4 (FGF receptor 4), TGF-ß (transforming growth factor ß), TNF-R14 (tumour necrosis factor-receptor superfamily 14), BMP-1 (bone morphogenetic protein 1), glucocorticoid receptor, and androgen receptor (Table I). Some of these genes that are highly expressed in both decidua and chorionic villi are shown in Table I. These genes listed relate to cell growth and cell cycle, apoptosis, hormones or cytokines, stress responses, signal transduction, cell surface antigens/cell adhesion, metabolism, transcription factors, cytoskeleton/extracellular matrix, and housekeeping functions. Some ESTs were also detected.
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The differentially expressed genes were chosen as those beyond the 95% confidence interval (CI) of the prediction line (the red curve in Figure 2C
). Next, the conventional criteria of 3- and 5-fold differences was used to subclassify the significantly different genes. A set of 49 genes that showed a 5-fold higher expression in chorionic villi than in decidua were classified as villous-specific genes (the left upper corner beyond the red curve and purple line in Figure 2C). A set of 26 genes with expression levels between 3- and 5-fold higher in villi were classified as predominantly expressed in chorionic villi. On the other hand, 27 genes that showed a 5-fold higher expression in decidua than in chorionic villi were classified as decidua-specific genes (the right lower corner beyond the red curve and purple line in Figure 2C). A set of 24 genes with expression levels between 3- and 5-fold higher in decidua were classified as predominantly expressed in decidua. Expression differences of <2- or <3-fold have usually been considered at the limit of detection in other previous reports (DeRisi et al., 1996; Tanaka et al., 2000; Cavallaro et al., 2001; Popoviciet al., 2001). Tables II and III list some of the genes that were significantly expressed in decidua (decidua/villi values 3.0, Table II) and in chorionic villi (villi/decidua values 3.0, Table III).
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The differentially expressed genes were grouped into categories on the basis of their cellular functions (Tables I–III
). These categories included cell growth-related factors, cell adhesion molecules, signal transduction molecules, apoptotsis-related factors, hormones/cytokines, cytoskeleton/extracellular matrix proteins, and some EST. Interestingly, one of the 27 genes with 5-fold expression in the decidua was IGFBP-1 (insulin-like growth factor binding protein-1), a decidualization marker, with 9.85-fold higher expression in decidua. From the IGF family, IGFBP-4 was also highly expressed in decidua (9.72-fold), while IGFBP-3 precursor and IGFBP-5 were highly expressed in both decidua and villi (Tables I and II). The insulin receptor was also increased 6.91-fold in decidua.
Of the 49 genes with 5-fold higher expression in the chorionic villi (Table III), 11 genes were related to cell growth, including cdc45 (cell division cycle 45), GH1 and GH2 (growth hormone variant), S-100 protein, inhibin ßA, myogenic factor 5 and RAB3B (member of the ras oncogene family) (Table III). Another cell cycle-related gene, PCNA, was also increased in chorionic villi but did not show as much of a difference as the others (3.10-fold). Of the 21 genes that were increased >10-fold in villi compared with decidua, 10 were hormone-associated genes including LIF-R, chorionic gonadotrophin-ß, PP5 (placental protein 5), placental lactogen (chorionic somatomammotrophin hormone 1), inhibin ßA, and the SP-1 family (pregnancy-specific ß1 glycoprotein). Furthermore, one such gene was an important signal transducer gene (GTPase-activated protein, ras, p21), also related to cell cycle progression.
To demonstrate that the protein expression of some identified genes was also consistent with the microarray analysis, three genes (cathepsin L, LIF-R and PCNA) were chosen for immunohistochemical analysis, as they were sequence-verified and their antibodies were commercially available. Figure 3 shows the protein level and location of cathepsin L, LIF-R and PCNA in decidua and/or chorionic villi. Of these, the cell proliferating marker, PCNA was increased 3.10-fold in chorionic villous, close to the conventional criteria of 3-fold difference in the microarray image. The percentage of the PCNA-positive cells in the chorionic villi was also higher than in decidua (Figure 3A). Additionally, we found that PCNA was more predominantly expressed in the cytotrophoblast than syncytiotrophoblast in the chorionic villi. Cathepsin L mRNA was highly expressed in decidua (4.87-fold) in microarray data, and the protein was also more highly expressed in the decidua (Figure 3B). The immunohistochemistry also showed that the LIF-R protein is highly expressed in the villi, consistent with the microarray data. Significantly, the intracellular positive staining for LIF-R was observed within both multinucleated syncytiotrophoblasts and cytotrophoblasts (Figure 3C).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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For the first time, differentially expressed genes in early gestational decidua and chorionic villi have been identified by cDNA microarray. During the past decade, once a gene had been described, investigators had to study the gene expression in the placenta with the techniques of Northern blot analysis or in-situ hybridization. The development of cDNA microarray technology allows us to monitor quantitatively the expression of thousands of genes in parallel (Abdellatif, 2000
). In 2000, a genome-wide expression profiling of mouse mid-gestation placenta and embryos was reported using a 15 000 mouse cDNA microarray (Tanaka et al., 2000). In this study, a high density cDNA microarray (9600 genes) with a colorimetric detection technique was used to identify the differential expression profiles of human first trimester decidual and villous tissues. This study may lead to new paradigms for the understanding of the placentation and the tissue–tissue interactions between decidua and villi during early pregnancy.
According to cDNA microarray analysis, we identified 641 genes whose mRNA were highly expressed in both decidua and villi, 49 genes with higher expression in decidua, and 75 genes with higher expression in chorionic villi. Some of these genes (androgen receptor, BMP-1, cathepsin B, TGF-ß, FGF-receptor-4, midkine, IGFBP-5, phospholipase A2, and glucocorticoid receptor) have been previously reported to be related to placentation (Horie et al., 1992; Takahara et al., 1994; King et al., 1995; Afonso et al., 1999; Boos et al., 2000; Fan et al., 2000; Lappas et al., 2001). However, many of the genes have not been reported during pregnancy; these include myeloid leukaemia factor 2, lymphotoxin-ß receptor, integrin-linked kinase, disintegrin and metalloproteinase domain 12, GTPase-activating protein ras p21, and some cell surface antigens (CD3D, CD8, CD36, CD37, CD59, CD63 and CD151).
The decidualization of the endometrial stroma cells is a prerequisite for successful implantation and placentation. A previous study has demonstrated differential expression of genes during progestrone-induced decidualization in vitro for the first time by microarray technology (Popoviciet al., 2001). Comparing the data between in-vitro decidualization and in-vivo decidual tissues, we observed that IGFBP-1, IGFBP-3, IGFBP-4 and IGFBP-5 are highly expressed in decidua both in vitro and in vivo. Surprisingly, we also found that the insulin receptor is highly expressed in decidua in vivo, supporting an earlier report (Popoviciet al., 2001). IGFBP-1 has been reported as a major product of the endometrium of pregnancy (i.e. decidua), and may interact with invading cytotrophoblasts expressing 
5ß1 integrin to modulate their invasion, and this effect can be regulated by insulin (Irwin and Giudice, 1998). Furthermore, the earlier reports also suggest that insulin may have a role in the regulation of prolactin synthesis and release through the insulin receptor from human decidua (Thrailkill et al., 1989). These findings suggest that IGFBP and insulin receptor may modulate trophoblast invasiveness and hormone secretion during early pregnancy.
During the process of placental development, cytokine or hormone-related factors play important roles in the regulation of cell growth, migration from villi into the decidua, and angiogenesis (Murray and Lessey, 1999). Furthermore, the decidual and villous tissues are also thought to be involved in hormone production (Carbillon et al., 2000). In addition to the IGF family, several factors previously identified to be expressed during decidualization in vitro were also found in the decidual tissues in vivo in this study; these include TGF-ß, interferon-, TNF-, TNF-R, angiotensin receptor, and PDGF-R (Popoviciet al., 2001). Another report has demonstrated that TNF-, TGF-ß1, colony-stimulating factor (CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are also involved in placentation (King et al., 1995). In the present study, several other hormone or cytokine-related factors (PDGF-Rß, IL-1 receptor, INF--induced protein, and neuropeptide Y receptor-1) were highly expressed in the decidual tissue. On the other hand, growth hormone-variant (GH1 and GH2), chorionic gonadotrophin ß, chorionic somatomammotrophin hormone (placental lactogen), and LIF-R were increased in the villous tissue. In addition, BMP-1, fibroblast growth factor receptor 4 (FGF-R4) and FGF binding protein, glucocorticoid receptor, androgen receptor, and myeloid leukaemia factor 2 were highly expressed in both decidua and villi. Further studies are essential to identify the roles of these hormone- or cytokine-related genes in the decidua or chorionic villi.
Implantation of the mouse embryo requires controlled invasion of the uterine stroma by the embryonic trophoblast (Duc-Goiran et al., 1999). This event is dependent, in part, on the secretion of serine proteinases for the extracellular degradation of the uterine matrix (Salamonsen, 1999). Proteinase activity is controlled by stromal decidualization and specific proteinase inhibitors. The cysteine proteinases, cathepsins B and L, have been reported to be essential for embryo development and decidualization in mice (Afonso et al., 1997). In this study, we also found that cathepsin B is highly expressed in both decidua and villi, whereas cathepsin L is more highly expressed in decidual tissue. The immunohistochemical data confirmed that the protein level of cathepsin L was also higher in decidual cells than in chorionic villi. However, cathepsin L was shown to have 4.87-fold higher mRNA expression level in decidua by microarray, while the difference detected by immunohistochemistry was >10-fold. This result suggests that the protein might be accumulated with a longer half-life than the mRNA, and it is the protein level that would be more important for its physiological functions.
A previous study has demonstrated that deleting the LIF-R gene results in abnormal growth and development of the placenta in mice (Sharkey et al., 1999). In this study, we found that both mRNA and protein levels of LIF-R are highly expressed in the villous tissue. According to the previous report and this study, LIF-R is localized in villi and in endothelial cells of the fetal villi, indicating that LIF-R may play a critical role in controlling villous development and angiogenesis in the placental villi (Sharkey et al., 1999).
Pregnancy-specific ß1-glycoprotein (SP-1) is found in maternal serum very early in gestation in both human and non-human primates (Tease et al., 1989). According to both previous data and our own, the major source of SP-1 is from the syncytial trophoblast in the villi, but little is known about its function, although one report has indicated that SP-1 is involved in hormone secretion (Schlafke et al., 1992). We also found that pregnancy-specific ß1-glycoprotein 4, 7, 11 and 13 are highly expressed in the villous tissue, indicating that these glycoproteins may have the physiological roles in villi. The levels of SP1 are lower in pregnancies associated with Down's syndrome, leading to the suggestion that it could be used as an antenatal screening test for Down's syndrome in the first trimester (Wald et al., 1999).
The use of cDNA microarray is a powerful molecular technique for studying gene expression and regulation of any fetal or adult organ system. We are learning that many obstetric diseases, such as pre-eclampsia, intrauterine growth restriction, and fetal death, are associated with abnormal placentation during first trimester gestation (Pijnenborg et al., 1996; Rogers et al., 1999; Dizon-Townson et al., 2000). Expression of previously unrecognized genes differentially regulated between decidualized human endometrium and chorionic villi suggests that some mechanisms during placentation are not yet appreciated. In addition, differentially expressed cytokines, chemokines, growth factors, apoptosis modulators, and their receptors in these tissues, support a major role for paracrine interactions between decidualized human endometrium and chorionic villi within the placenta during early pregnancy. These results from microarray analyses may improve our knowledge of the gene regulation at the maternal–fetal interface, and may provide insight into the aetiology of the physiological and pathological processes for direct diagnostic tests and therapeutic regimens in the future.
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This study was supported by grants from the National Science Council, Taiwan (Grant No. 90-2314-B-038-049) and the National Taiwan University Hospital, Taiwan (NTUH89A021 and NTUH89A023-10).
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Notes |
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4 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, No. 252, Wu-Hsing Street, Taipei, Taiwan; E-mail: tzengcr{at}tmu.edu.tw
* J.J.W.Chen and C.R.Teng contributed equally to this work.
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Submitted on July 2, 2001; resubmitted on November 1, 2001; accepted on February 18, 2002.
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