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Regular Article |
a Department of Plant & Animal Sciences, Nova Scotia Agricultural College, Truro, Nova Scotia, Canada B2N 5E3
b Agriculture & Agri-Food Canada, Research Centre, Brandon, Manitoba, Canada R7A 5Y3
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1, 3, and 6 as well as the extracellular matrix (ECM) components collagen IV and laminin in implanting bovine trophoblast and endometrium. Immunohistochemical staining of cryostat sections prepared from nonpregnant endometrium, of preattachment through to early villus development pregnant endometrium (Days 18, 21, 24, and 30), and of isolated trophoblast binucleate cells was performed. Trophoblast down-regulated the integrin 1 subunit as attachment proceeded, whereas reactivity scores for 6 antibody tended to increase from Day 18 through 24 and remained high. A subpopulation of trophoblast binucleate cells expressed the 3 integrin subunit. Uterine epithelium constitutively expressed 3 and 6 integrin subunits, but the 1 subunit was down-regulated as the luminal epithelium was modified. Collagen IV and laminin reactivity increased in the basal lamina and underlying subepithelial stroma as pregnancy proceeded. The results suggest that binucleate cell fusion with the maternal epithelium initiates integrin and ECM changes in the subepithelial stroma.
female reproductive tract, implantation, placenta, trophoblast, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The integrins, a family of transmembrane glycoproteins that govern cellular interactions with the ECM, have been implicated in the establishment of uterine receptivity and successful embryo implantation and trophoblast invasion [5–7]. Whereas the extracellular domains of the integrins interact with the ECM glycoproteins or other cell adhesion molecules, the intracellular domains bind with the cytoskeleton and signal-transducing proteins, facilitating the transduction of signals from the ECM to the cytosol and vice versa [8, 9]. Integrins work synergistically with other cell adhesion molecules and growth factor receptors to help determine the differentiated phenotype of the cell and to modulate the expression of other integrins, ECM components, metalloproteinases and their inhibitors, and growth factors [8, 10].
Endometrial integrin expression is modulated during the estrous cycle in cattle, and changes in integrin expression correlate with key cycle events [11]. In preimplantation and peri-implantation bovine trophoblast, 5 and ß1 integrin subunit expression has been shown to be distinct from that in other species, including the pig [12–15]. The 5 subunit is not expressed in bovine trophectoderm, and the distribution of the ßl subunit suggests that ßl integrins are involved in binucleate cell migration [12]. This is not surprising, given that several ßl integrins, including lßl, 2ßl, 3ßl, and 6ßl, are typically expressed in epithelial cells, including human endometrial epithelia, and bind one or both of the major basement membrane proteins laminin and collagen IV [5, 7]. Apposition, adhesion, and formation of the fetomaternal hybrid epithelium are dynamic activities of the trophoblastic and uterine luminal epithelia that conceivably may involve associated changes in epithelial cell integrins and major basement membrane components. Results of a study of the distributions of the ßl integrin subunit, types I and IV collagen, and laminin during early goat implantation suggest that their expression declines in endometrium as trophoblast attaches [16]. However, there is no information on the subunits associating with ß1 integrin or on ECM expression past Day 21 of pregnancy. The purpose of the present study was to determine the distributions of integrin subunits 1, 3, and 6 as well as the ECM components collagen IV and laminin in implanting bovine trophoblast and endometrium.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All animals used in the study were managed in accordance with the guidelines of the Canadian Council on Animal Care [17]. Natural or artificial inseminations occurred after observed natural or synchronized (prostaglandin F2) estrus (Day 0) in mixed breed heifers and cows. Three reproductive tracts each at 18, 21, 24, and 30 days of gestation as well as 3 nonpregnant uteri (Day 18 of the estrous cycle) were collected after exsanguination of the animals at a government-inspected slaughter plant. Each uterus was cut across the horn into pieces approximately 1 cm long, and the pieces were snap frozen in liquid nitrogen and stored at -70°C until processing.
Antibodies
A polyclonal affinity-purified rabbit antibody against the cytoplasmic domain of the human integrin 3 subunit was purchased from Chemicon (Temecula, CA), as was a polyclonal rabbit antiserum to the human integrin 1 subunit. Also purchased from Chemicon was a monoclonal antibody against the human integrin subunit 6. A rat monoclonal antibody to the murine ß1 integrin subunit was kindly provided by Dr. Caroline Damsky (Department of Stomatology and Anatomy, University of California San Francisco, San Francisco, CA). Polyclonal antisera to laminin and collagen IV were purchased from ICN Biomedicals, Inc. (Montreal, PQ, Canada). Purified mouse immunoglobulin G1 (IgG1) (Cedar Lane, Hornby, ON, Canada), rabbit IgG (Boehringer Mannheim, Laval, PQ, Canada), rat IgG (Boehringer Mannheim), or normal rabbit serum (ICN) were used as negative controls.
Immunohistochemistry
Cryostat cross-sections (8–10 µm) were prepared from frozen uteri and mounted on 3-aminopropyltriethoxysilane-coated slides before acetone fixation. After a rehydration in PBS, nonspecific binding sites were blocked with 2% BSA in PBS for 30 min at room temperature (RT). The integrin-specific antibodies or the appropriate controls were diluted in 1% BSA in PBS (final IgG concentration, 10–100 µg/ml) and applied to the sections for 2 h at RT. The exception was anti-1 integrin, which was applied overnight at RT. After the sections were washed in PBS, they were incubated with horseradish peroxidase-conjugated secondary antibody specific to the species of primary antibody for 1 h at RT. After the sections were washed in PBS, antibody binding was detected with 3,3'-diaminobenzidine tetrachloride (DAB) or 3-amino-9-ethylcarbazole (AEC). Aqueous hematoxylin was used to counterstain the nuclei, followed by the addition of aqueous mounting media (Aquaperm; Fisher Scientific, Ottawa, ON, Canada).
All experiments were performed on samples from 3 animals and replicated at least twice. Staining intensity was scored on a 6-point scale (i.e., absent, 0; positive but very weak, 1; positive but weak, 2; moderate, 3; strong, 4; and very strong, 5) for mesoderm, trophoblast, maternal luminal epithelium, maternal shallow glandular epithelium, maternal subepithelial stroma (the region immediately adjacent to the uterine epithelium), and the maternal stroma contraluminal to the subepithelial stroma but still in the stroma compactum. Caruncular and intercaruncular endometrium were scored separately. The Shapiro-Wilkinson and Kolmogorov-Smirov test statistics were used to test for normality of scores within day [18]. Both parametric (ANOVA) and nonparametric (Kruskal-Wallis test of population medians) analyses were carried out to analyze the effect of day on staining intensity score for each cell type [18]. The Duncan multiple range test was used to compare mean scores by day [18].
Binucleate Cell Isolation
Bovine placentomes were isolated from an animal that was approximately 70 days pregnant (determined by measuring crown-rump length). Fetal and maternal tissues were manually separated, and cotyledonary tissue was scraped with a sterile scalpel blade into PBS. After several washes in PBS, the methods of Morgan et al. [19] were used to isolate the binucleate cells via a Ficoll (Sigma, Oakville, ON, Canada) density gradient. The cells were placed on microscope slides and allowed to settle 30 min before fixation in acetone. Immunohistochemical analysis was performed as described previously.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Trophectoderm expressed the 1, 3, and 6 integrin subunits (Fig. 1). The 1 subunit was diffusely distributed in trophoblast epithelium on Day 18 and in some sections on Day 21 but was not detectable on Days 24 or 30 (P < 0.05) (Fig. 2). The 3 subunit was not expressed in most trophoblastic cells, but occasional binucleate cells appeared positive in the cryosections. A small proportion of isolated binucleate cells from the Day 70 conceptus chorion were positive (Fig. 1).
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At Day 18, the basal surface of the trophoblast epithelium reacted strongly with the 6 antibody, but the lateral and apical aspects of both the uninucleate and binucleate cells of the trophoblast were essentially negative (Fig. 1). Beginning on Day 21, staining was evident on the lateral and apical cell surfaces, and by Day 24, both the uninucleate and binucleate cells of the trophoblast strongly expressed the 6 subunit on their basal and lateral aspects. Many cells appeared not to express the integrin subunit at their apical border, although some clearly did. The overall scores for this subunit did not change between Days 18 and 30 (Fig. 2), despite the changes in distribution.
Fetal mesenchyme did not express the 1 or 3 subunits, but 6 and ß1 subunit reactivities were pronounced in this compartment in sections from Day 24 and 30 animals. The 6 integrin subunit was not expressed in allantois, however. The ß1 integrin subunit was also observed in mesoderm of some sections up to Day 21 and was strongly expressed in allantois of sections from Day 24 and 30 animals (data not shown).
Integrin Expression in Uterine Epithelium
Uterine epithelium expressed 1, 3, and 6 integrin subunits (Fig. 1). There were no differences in expression between caruncular and intercaruncular endometrium (P > 0.10, data not shown). Moderate 1 staining was evident in columnar luminal and glandular uterine epithelium at all stages examined, but regions of luminal epithelium that were cuboidal or syncytial did not display such staining (Fig. 1). Accordingly, the luminal epithelium scores for 1 reactivity declined (P < 0.05) from Day 18 (mean ± SEM, 2.4 ± 0.43) to Day 24 (0.5 ± 0.22) (Fig. 2). Moderate reactivity for the 3 subunit was consistently observed in both the luminal (Fig. 1) and glandular (data not shown) compartments, regardless of stage of pregnancy. Although these cells were diffusely stained, reactivity was concentrated along the basal aspects of the cells. Staining for the 6 integrin subunit also was more concentrated on the basal cell surface, although there was variation among animals in the degree of concentration. The epithelia of nonpregnant and Days 18, 21, and 24 pregnant animals stained moderately for the integrin 6 subunit, and reactivity tended to increase (P = 0.09) with advancing pregnancy in glandular epithelium (Day 18, 3.0 ± 0.24 versus Day 30, 3.88 ± 0.13). Reactivity for the ß1 subunit showed a pattern similar to that of the 6 subunit (data not shown).
Integrins in Stromal Endometrium
As was the case for epithelial endometrium, there were no differences between caruncular and intercaruncular stroma in integrin subunit expression (P > 0.10, data not shown). The distribution of 1 subunit reactivity changed as pregnancy proceeded (Figs. 1 and 2). Day 18 pregnant animals had a distribution of this integrin subunit that was similar to that in Day 18 cyclic animals, exhibiting weak but specific staining of the subepithelial stromal cells, which appeared to be concentrated around the capillaries. Similarly, there was basement membrane staining around the larger vessels deep in the endometrium (data not shown). The subepithelial stroma displayed a broader expression of the 1 subunit as pregnancy proceeded, with an inverse relationship between staining intensity and distance from the uterine lumen.
Endometrial expression of the 3 subunit was not different between pregnant and nonpregnant animals, and it did not change through the stages of pregnancy examined. The 3 subunit was expressed in the smooth muscle of endometrial arterioles (Fig. 1).
In Day 18 cyclic and all pregnant animals studied, there was prominent 6 subunit staining of a subpopulation of cells within the stroma, primarily those surrounding capillaries (Fig. 1). The relative intensity of this staining varied neither among the stages of pregnancy examined nor between caruncular and intercaruncular endometrium.
Stromal expression of the ß1 subunit overlapped with that of all of the aforementioned subunits, so that most if not all of the stromal cells reacted with this antibody to some degree, although the deep caruncular stroma tended to exhibit less reactivity (data not shown). Similar to the pattern noted in the sections stained with the 6 antibody, blood vessel walls and selected individual stromal cells were intensely reactive with the ß1 antibody.
Uterine Laminin and Collagen IV Expression
Laminin and collagen IV were both present in bovine endometrium and displayed similar distribution patterns. There were no differences in expression between caruncular and intercaruncular regions (P > 0.10, data not shown). Collagen IV and laminin were present in the basement membrane region and the underlying stroma of the uterine epithelium at all stages examined, with no clear differentiation between these two compartments in most sections (Fig. 3). The intensity of this staining increased from Day 18 to 30 and extended further away from the lumen, such that the median scores for this region increased (Fig. 4). This effect was more pronounced for collagen IV than for laminin. Moderate reactivity was observed in the basement membrane of all glandular epithelium, capillaries, and larger blood vessels, as well as myometrium. Weak but consistent staining of the deep caruncular and intercaruncular stroma was also observed. Cyclic and Day 18 pregnant endometrium showed similar expression patterns for both ECM proteins (Fig. 4). Collagen IV and laminin were components of the mesoderm underlying the trophectoderm at Day 18 but not at later stages of pregnancy, although the developing allantois reacted strongly with both collagen IV and laminin antibodies.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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integrin subunits examined, 1, 3, and 6, displayed patterns of expression suggesting possible roles in attachment and implantation, and both of the ECM ligands studied, collagen IV and laminin, showed changed distributions as implantation began. In the cow, maternal recognition occurs before attachment and implantation, which begin at about Day 19 in the region of the embryonic disk and spread outward [2]. Trophoblast expressed the 1 subunit until attachment. This subunit is known to heterodimerize with the ß1 subunit to form 1ß1, an integrin that has been suggested to promote attachment of human trophoblast to laminin, since antibodies to 1ß1 block attachment of JAR choriocarcinoma cells to this substrate [20]. The 1ß1 integrin has been proposed to promote human trophoblast invasion of the laminin- and collagen IV-rich decidua [14] and is up-regulated during outgrowth of murine trophoblast [15]. Therefore, loss of the 1 integrin subunit by the relatively noninvasive trophoblast of cattle after attachment is not surprising. Laminin and collagen IV were observed in the trophoblast in the current study at Day 18 of pregnancy, but not at later stages, suggesting coordinate regulation of the 1 integrin subunit and its ligands. In contrast, porcine trophoblast weakly expresses the 1 subunit from Days 11–15, with no apparent down-regulation at attachment, and the underlying basal lamina consistently reacts with laminin and collagen IV antibodies [13]. There may be no need to reduce integrin 1 subunit expression in the pig, since the trophoblast does not penetrate the epithelium. Alternately, the reduced expression of laminin, collagen IV, and the 1 subunit observed in attached bovine trophoblast may be indicative of differentiation of the tissue to support binucleate cell migration and fusion, which does not occur in the pig.
In contrast to the integrin 1 subunit, the integrin 6 subunit became more prominent in trophoblast as implantation proceeded. In sections from Day 18 pregnant animals, this integrin was confined primarily to the basal borders of trophoblast cells, but by Day 21, expression was evident over most of the cell surface. The intense staining of this subunit in both uninucleate and binucleate cells may reflect a role in the development of the fetomaternal syncytial epithelium. The binucleate cells are the migratory cells of the trophoblast, migrating between the apical tight junctions of adjacent uninucleate cells to fuse with maternal epithelial cells [2, 3]. This migration is maximal about Day 24 of pregnancy [2], which is the same time at which the 6 subunit reaches its maximum reactivity along the lateral surfaces of the trophoblast cells. The apparently coincident up-regulation of the 6 integrin subunit at sites of intercellular contact suggests that an 6 integrin may be facilitating binucleate cell migration and/or fusion.
The 6 subunit can heterodimerize with either the ß1 or ß4 subunit, although it most commonly and preferentially is found dimerized with ß4 [21]. Despite numerous attempts, we were unable to find a suitable ß4 antibody to determine whether this subunit is present in bovine trophoblast or endometrium. However, previous studies of Day 14, 18, 21, and 24 trophoblast have shown that the distribution of ß1 mirrors that of 6 in the present study [12], and human interstitial trophoblast expresses 6ß1 [20]. Ligands for 6ß1 are laminin and fertilin, whereas laminin, merosin, and kallikrein are the known ligands for 6ß4 [22]. Laminin is a major component of most basement membranes, and it is quite possible that either 6ß4 or 6ß4 and 6ß1 are involved in adherence to the basement membrane in trophoblast expressing this ligand. The strong lateral expression of both the 6 and ß1 integrin subunits suggests that they may be mediating cell-cell rather than cell-ECM adhesion, and if they are dimerizing, fertilin or ADAM (a disintegrin and metalloproteinase) protein may be the ligand. Interestingly, cell rounding and migration are stimulated by integrin 6ß1 binding to ADAM-9, whereas the same cells display an adherent phenotype when laminin is the ligand for 6ß1 [23]. Although this study involved fibroblasts, there is precedent for 6ß1-mediated migration of epithelial cells [24]. Integrin 6ß1 on the surface of uterotubal epithelium has been proposed to facilitate sperm migration into the oviduct by interacting with ADAM-2 [25]. ADAM family members have been detected in human and mouse placenta [26], but the ADAM profile of bovine placenta has not yet been characterized.
The functional significance of 3 subunit expression in a subpopulation of binucleate cells is not clear. There was neither geographic preference nor obvious morphologic differences detected for these 3-positive cells. This subunit dimerizes with ß1 to form a receptor that has been shown to bind to several ECM ligands including laminin, collagen, fibronectin, entactin, and kallikrein [22]. Although binucleate cells are considered epithelial, they are not attached to a basement membrane, so interaction with ECM seems less likely than interaction with a cellular ligand. It has been suggested that 3ß1 may mediate heterotypic cell-cell adhesion in keratinocytes [27], and this integrin has been shown to be complexed with the tetraspanin protein CD9 and the membrane-anchored heparin-binding epidermal growth factor-like growth factor in some tissues [28, 29].
Bovine uterine epithelium expressed the 1, 3, and 6 subunits, as has been observed in human endometrial epithelia [5, 7, 29–31]. Our earlier studies suggested that the 3 and 6 integrin subunits were expressed throughout the estrous cycle, although 6 expression was decreased during proestrus [11]. The 3 integrin subunit has also been observed in swine uterine epithelium, regardless of stage of the estrous cycle or pregnancy [13]. Expression of both of these integrin subunits was pronounced basolaterally, suggesting a role in cell-substratum interactions in all these species. However, expression was not restricted to these regions of the cell, so a role in cell-cell adhesion cannot be ruled out. The distribution of the 6 subunit along the lateral aspects of trophoblast cells and the expression of the 3 subunit on selected binucleate cells support the hypothesis that binucleate cell migration and/or fusion with uterine epithelial cells involves 3 and 6 integrins in trophoblast and uterine epithelium.
Integrin subunit expression in human and murine endometrium and placenta has been well studied [5–7, 14, 15, 29–31], but the corresponding information for ungulates, which develop noninvasive placentation, has large gaps. A key difference between these groups is that the trophoblast of the latter continuously interacts with the uterine luminal epithelium, whereas the trophoblast of the more invasive implanters has a transient interaction with this tissue until it reaches the underlying stroma. Accordingly, it might be expected that integrins present at the time of apposition could serve similar functions across species, including the proposed bridging of trophoblast and luminal epithelia by ECM protein that has been suggested by several authors for the V integrins [5, 6, 32]. In contrast, firm attachment and formation of a microvillar junction between the epithelia and subsequent binucleate cell migration and fusion with maternal epithelium, as occurs in ruminants, should be expected to involve integrins that are different from those mediating invasive placentation. From this perspective, it is not surprising that bovine trophoblast does not express the invasion-associated integrin 1 subunit once attachment takes place, does not express the fibronectin receptor 5ß1 [12], and does express the 3 and 6 subunits in a pattern to suggest facilitation of binucleate cell activities.
The distribution of the integrin ß1 subunit, but not its 1, 3, or 6 partners, has been studied in the very early stages of attachment in the sheep and goat, which, like the cow, display synepitheliochorial placentation [3]. Day 16 caprine and ovine luminal epithelium show a basolateral distribution of the ß1 subunit that is consistent with results in the cow, and trophoblast also displays ß1 reactivity [16, 33]. In contrast to the pattern noted in the cow, by Day 21, caprine endometrial expression of this subunit was reduced in regions of trophoblast attachment [16]. This observation suggests that there may be differences in integrin expression among the ruminant species, which are interesting in light of the subtle differences in placentation.
The changes observed in collagen IV and laminin distribution from Day 18 to 30 of pregnancy were different from those that have been reported for the goat. From Day 15 to 21 of pregnancy in the goat, Guillomot [16] observed that collagen IV and laminin disappeared from the basement membrane and subepithelial stroma, including the surrounding capillaries. Whether these matrices would be up-regulated after Day 21 as was the case in cattle remains to be seen. In the current study, reactivity to collagen IV and laminin antibodies changed between Days 18 and 30 from a narrow zone associated with the basement membrane of the luminal uterine epithelium to a wide band of reactivity extending adluminally well into the compact stroma. The changes in 1 integrin subunit expression followed a similar pattern. Decidualization is not a characteristic of the surface implanters, and there is little known about the nature of endometrial ECM changes associated with implantation in ruminants. An ultrastructure study showed a change in the profile of the basal lamina of the bovine uterine epithelium from straight at Day 20 to scalloped by Day 29 of pregnancy [1]. These investigators also reported that after Day 26, there was a distinct band of cells in the connective tissue underlying the basal lamina that had different staining characteristics from the other cells of the stroma. These observations, taken together with the changes in 1 subunit, collagen IV, and laminin expression noted in the present study, make it tempting to conclude that trophoblast attachment and associated binucleate migration and fusion with the uterine epithelium induce these and likely other changes in the stromal cells adjacent to the luminal epithelium. Significant binucleate cell fusion with maternal epithelium occurs by Day 24 [2], and it may be that it is this hybrid epithelium that has the potential to induce the stromal changes observed. Certainly, there is precedent for such epithelial-stromal cell interactions [34]. Since it is also well established that ECM changes affect the overlying epithelium [35], changes in integrin and ECM expression induced by the hybrid epithelium may in turn regulate that epithelium.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Funded by grants from the Dairy Farmers of Canada, Nova Scotia Department of Agriculture and Marketing, and the Natural Sciences and Engineering Research Council. 
2 Correspondence: Leslie MacLaren, Department of Plant and Animal Sciences, Nova Scotia Agricultural College, 58 River Rd., Box 550, Truro, NS, Canada B2N 5E3. FAX: 902 895 6734; l.maclaren{at}nsac.ns.ca
Accepted: December 10, 2001.
Received: May 24, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5 and ß1 integrin subunits in bovine embryos. Biol Reprod 1995; 53:153-165[Abstract]1ß1 and 6ß1 integrin heterodimers mediate cell attachment to distinct sites on laminin. J Cell Biol 1990; 110:2175-21846ß4 integrin, ß1 integrins, and an E3 laminin receptor to signal morphogenesis and ß-casein expression in mammary epithelial cells. Mol Biol Cell 1999; 10:2817-2828
(ADAM 9) mediates cellular adhesion through 6ß1 integrin, leading to a marked induction of fibroblast cell motility. J Cell Sci 2000; 113:2319-2328[Abstract]3ß1 and 2ß1: potential role in keratinocyte intercellular adhesion. J Cell Biol 1993; 120:523-5353ß1 at cell-cell contact sites. J Cell Biol 1995; 129:1691-17056, 3, and ß1. Mol Hum Reprod 2000; 6:252-257Vß3 integrin expression in the ovine uterus and conceptus during the peri-implantation period. Biol Reprod 1999; 61:892-899This article has been cited by other articles:
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V. Emond, L. A. MacLaren, S. Kimmins, J. A. Arosh, M. A. Fortier, and R. D. Lambert Expression of Cyclooxygenase-2 and Granulocyte-Macrophage Colony-Stimulating Factor in the Endometrial Epithelium of the Cow Is Up-Regulated During Early Pregnancy and in Response to Intrauterine Infusions of Interferon-{tau} Biol Reprod, January 1, 2004; 70(1): 54 - 64. [Abstract] [Full Text] [PDF]
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G. A. Johnson, R. C. Burghardt, M. M. Joyce, T. E. Spencer, F. W. Bazer, C. A. Gray, and C. Pfarrer Osteopontin Is Synthesized by Uterine Glands and a 45-kDa Cleavage Fragment Is Localized at the Uterine-Placental Interface Throughout Ovine Pregnancy Biol Reprod, July 1, 2003; 69(1): 92 - 98. [Abstract] [Full Text] [PDF]
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