Hum. Reprod. Advance Access originally published online on June 28, 2006
Human Reproduction 2006 21(9):2238-2245; doi:10.1093/humrep/del189
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MUC4 gene polymorphism and expression in women with implantation failure
1 Laboratoire de Biologie de la Reproduction, C.M.C.O., Schiltigheim Cedex 2 INSERM Unité 560, Place de Verdun 3 Laboratoire de Biologie de la Reproduction, Hôpital Jeanne de Flandre, Lille Cedex 4 IGBMC, Illkirch 5 Laboratoire de Biochimie et Biologie Moléculaire, Parc Eurasanté, CHRU de Lille 6 Faculté de Médecine, Département de Biochimie et Biologie Moléculaire, Université de Lille II and 7 Faculté de Médecine, Laboratoire d’Histologie et d’Embryologie, Faculté de Médecine, Place de Verdun, Lille Cedex, France
8 To whom correspondence should be addressed at: Laboratoire de Biologie de la Reproduction, C.M.C.O., Schiltigheim Cedex; E-mail: isabelle.koscinski{at}chru-strasbourg.fr
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Abstract |
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INTRODUCTION: The molecular mechanism of human embryo implantation is poorly understood. The role of MUC4 mucin, present in endometrial epithelium, has never been explored, and results obtained in animal studies strongly suggest a role in implantation. We investigated the role of MUC4 in human embryo implantation. METHODS AND RESULTS: We analysed the MUC4 variable number of tandem repeat (VNTR) polymorphism in three populations by Southern blot analysis: spontaneously fertile patients (C), infertile patients with repeated unexplained implantation failures after IVF (IF) and patients with a child after IVF (IVF-C). We found no differences in the size or allelic distribution of MUC4 VNTR between these three populations. We also examined, in IVF-C and IF groups, the endometrial expression of MUC4 mRNA as well as the expression of the MUC4 glycoprotein together with estrogen receptor (ER) and progesterone receptor (PR). No expression differences could be detected. However, we noticed a pattern of expression for MUC4 protein, which is limited to patches of cells in the luminal and glandular epithelium. CONCLUSIONS: We conclude that the different-sized MUC4 alleles do not interfere with implantation. The absence of coexpression of MUC4 and the steroid receptors suggests that MUC4 expression is not directly regulated by steroids.
Key words: endometrium/implantation failure/infertility polymorphism/MUC4
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Introduction |
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The molecular mechanism of human embryo implantation is still not understood. It is generally accepted that embryo implantation depends on the quality of the blastocyst and endometrium and on the synchronization of their development (Aplin, 2000
; Horne et al., 2000). Interactions between the outer trophectoderm layer of the blastocyst and the luminal epithelium probably require soluble as well as surface-linked molecules (Aplin, 1999; Aplin and Kimber, 2004).
The receptivity of the endometrial mucosa to embryo attachment is optimal during a period called window of implantation (Simon and Valbuena, 1999), which occurs in women between the seventh and the eleventh day after the LH peak (Meseguer et al., 1998). In addition to hormonal control, endometrial receptivity results from early embryo–maternal dialogue (Aplin and Kimber, 2004), with the acquisition of adhesion ligands or receptors and the loss of anti-adhesion molecules. In this respect, mucins appear particularly as interesting candidates to explore, especially MUC1 and MUC4 which are the two major mucins present in endometrial epithelium (Gollub et al., 1993; Audie et al., 1995). These bulky membrane-anchored proteins represent an abundant component of the glycocalyx. The role of MUC1 polymorphism in human embryo implantation has been recently investigated with contradictory results (Horne et al., 2002; Goulart et al., 2004). MUC4 has never been explored in the context of embryo implantation failure.
MUC4 gene is located on chromosome 3 in region q29 and comprises 25 exons/introns over 100 kb (Porchet et al., 1991; Nollet et al., 1998; Moniaux et al., 1999; Escande et al., 2002). It encodes a 930-kDa transmembrane mucin predicted to protrude over 2 µm above the cell surface. MUC4 is characterized by the presence of an extracellular repetitive domain rich in serine and threonine, three epidermal growth factor (EGF)-like domains, a transmembrane domain and a short cytoplasmic tail containing one potential tyrosine phosphorylation site.
The extracellular repetitive domain consists mainly of a tandem repeat (TR) array with a repeating unit of 16 amino acid residues carrying a great number of O-glycosylation sites (Moniaux et al., 1999). This TR domain, that is entirely encoded by the second of the 25 exons of the MUC4 gene, is polymorphic due to a variable number of tandem repetitions (VNTRs) (from 145 to 395 repeats) (Nollet et al., 1998). MUC4 is expressed physiologically at the apical surface of most epithelia including the endometrium (Audie et al., 1995; Gipson et al., 1997; Brayman et al., 2004) and over-expressed in many carcinomas (for review, Moniaux et al., 2001).
Studies conducted in various species suggest that MUC4 is involved in embryo implantation. In pig, where the implantation is not invasive, endometrial Muc4 increases during the period of trophoblastic attachment to the uterine luminal surface (Ferrell et al., 2003). On the other hand, in rodents, where the implantation is of invasive type, Muc4 (also called sialo mucin complex or SMC) appears to block blastocyst implantation. For instance, rat Muc4 is down-regulated during the implantation window, probably in response to increased progesterone, perhaps through the increased transforming growth factor (TGF)-
expression (Idris and Carraway, 2000).
In addition, Muc4 has been characterized as a ligand for the receptor tyrosine kinase ErbB2 (Carraway et al., 1999), which is up-regulated in the mouse and rabbit blastocyst trophectoderm (Klonisch et al., 2001; Brown et al., 2004). In human, MUC4 is also a ligand for ErbB2/c-erbB2 (Weed et al., 2004) which has been described in invasive cytotrophoblasts (Goffin et al., 2003). The human MUC4 is a much longer molecule than its rat orthologue, strongly suggesting steric hindrance to implantation. Until now, this hypothesis has never been explored.
To examine the role of MUC4 in fertility, we attempted to establish whether implantation failures may be linked to (i) inherited VNTR polymorphism and (ii) differences in the expression of MUC4 mRNA and protein in endometrium.
The VNTR polymorphism was studied by Southern blot in 26 fertile and 25 infertile women including 12 presenting repeated and unexplained failures of implantation. For ethical reasons, the expression of MUC4 mRNA as well as the MUC4 protein was studied in endometrial biopsies of the infertile group only, by RT–PCR and immunohistochemistry.
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Materials and methods |
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Patients
Three groups of patients were included in this study. A population with unexplained embryo implantation failures (population IF) comprised of 12 patients who had at least two unexplained embryo implantation failures after IVF with transfer of at least two high-quality embryos. This population (IF) was compared with two control populations: population C, comprising 26 spontaneously pregnant women, and population IVF-C comprising 13 women attending our centre for second child and who already had a first child conceived spontaneously or after IVF (first or second attempt).
Patients included in this study were consulting the obstetrics department (for the population C) or the reproductive medicine department (for populations IVF-C and IF) of the CHRU of Lille from November 2002 to July 2003. All were within the age range of 18–38 years and of Caucasian origin. All gave their full informed consent for the study, which was approved by the local committee of ethics and of the Consultative Committee for the Protection of People in Biomedical Research (CCPPRB CP02/52).
The first part of the study (polymorphism analysis) involved all three patient groups, whereas the second part (mRNA and protein endometrial expression) requiring an endometrial biopsy involved only IF and IVF-C populations for ethical reasons.
Biological materials
Peripheral blood (10 ml) was taken from each patient for the Southern blot polymorphism study.
RT–PCR and immunohistochemistry expression studies were performed on endometrial biopsies taken during a spontaneous cycle or during an ovulation induction cycle. An endometrial biopsy of 
100 mm3 was taken with a Cornier Pipelle® (CCD, Paris, France) between the seventh and the eleventh day after the LH peak. The retrieved tissue was divided into two parts: the first was fixed for 48 h in 4% (w/v) paraformaldehyde for histology and immunohistochemistry, and the second was utilized for RT–PCR analysis.
Southern blot analysis of MUC4 VNTR polymorphism
Genomic DNA was extracted from blood using the QIAamp® DNA Blood Maxi kit (Qiagen, Courtaboeuf, France). DNA (5 µg) was digested with the restriction enzymes PstI and EcoRI (Roche Diagnostics, Meylan, France) which cut 503 bp upstream and 425 bp downstream of the TR region of MUC4, respectively. DNA fragments were separated by agarose gel electrophoresis [0.5% (w/v) agarose] for 43 h in two steps, as previously described (Vinall et al., 2000). Membranes were probed using standard procedures with a cDNA probe (JER64) homologous to the MUC4 TR radiolabelled with 
-[32P] (Porchet et al., 1991).
Autoradiographs were developed after 1-week exposure. The size marker used was the Raoul molecular weight marker (Qbiogene, Illkirch, France).
Statistical methods
Comparisons of medians of allele’s size were performed using a Kruskal–Wallis test (non-parametric analysis). Post hoc tests were performed with a Bonferroni correction. Receiver operating characteristic (ROC) graphs were performed to determine thresholds between the populations IF and C + IVF-C and between the populations C and IF + IVF-C. The comparison of the recoded values was performed with Pearson’s chi-square statistic test. For all comparisons, significance levels were set to 5%.
RT–PCR analysis
Total RNA was extracted from biopsies using the NucleoSpin® RNA II kit (Macherey Nagel, Hoerdt, France) including a DNase treatment. Total mRNA (1.5 µg) was reverse transcribed using the AdvantageTM RT-for-PCR kit (ClonTech, Heidelberg, Germany) and oligodT according to the manufacturer’s instructions. First-strand cDNA was amplified with specific primers for MUC4: F-CGCGGTGGTGGAGGCGTTCTT and R-GAAGAATCCTGACA GCCTTCA. Non-quantitative PCR reactions were conducted in 50 µl of buffer (10 mM Tris/HCl, 1.5 mM MgCl2, 50 mM KCl, pH 8.3), containing DNAs (200 µM), primers (300 nM of each), 1 U of Taq DNA polymerase (Roche) and 1.5 µl of first-strand cDNA as template. The cDNA was denatured at 94°C for 4 min, followed by 35 cycles at 94°C for 30 s, 58°C for 30 s and 72°C for 1 min, followed by a final extension at 72°C for 7 min. Amplifications were performed in a GeneAmp® PCR System 9700 (Applied Biosystems, Courtaboeuf, France). Glyceraldehyde-3-phosphatedehydrogenase (GAPDH) was also amplified according to manufacturer’s instructions (AdvantageTM RT-for-PCR kit) (94°C for 4 min, followed by 35 cycles at 94°C for 30 s, 58°C for 30 s and 72°C for 1 min, followed by a final extension at 72°C for 7 min) to check the quality of the cDNAs. Negative control (sterile water instead of cDNA) was included for each PCR. PCR products were analysed on a 2% (w/v) agarose gel.
Endometrial immunohistochemistry analysis of MUC4, ER and PR
Classical non-quantitative immunohistochemistry was performed using monoclonal antibodies raised against MUC4 (kindly provided by Prof. Batra Omaha, Nebraska), estrogen receptor (ER) and progesterone receptor (PR) A (Santa Cruz Biotechnology, Tebu-Bio S.A., Le Perray en Yvelines, France). The MUC4 monoclonal antibody was raised against the TR domain and recognizes the native MUC4 protein (Moniaux et al., 2004). Six-micrometre-thick sections from paraffin-embedded tissue were cut and mounted on Superfrost® slides (CML, Dutscher, Brumath, France). The staining procedure was conducted as previously described (Copin et al., 2001) with minor modifications. For MUC4 staining, slides were pretreated in a microwave twice for 10 min each in citrate buffer (pH 6.0), and for ER and PR, staining slides were pretreated for 20 min in a pressure cooker. Antibodies were used at dilutions of 1:2000 for MUC4, 1:20 for ER and 1:50 for PR. Normal bronchus known to express MUC4 was used as a positive control (Copin et al., 2000).
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MUC4 VNTR polymorphism
Southern blot analysis of the 51 patients revealed 18 distinct alleles of MUC4 (Figure 1 and Table I). Initially, since the expression of the MUC4 alleles is codominant, we identified for each patient a largest allele and a smallest one. The allele sizes ranged from 6.5 to 21.5 kb, showing a trimodal distribution in all three populations (Figure 2A). The first frequency peak was around 17.5 kb and included 45% of all the alleles (Figure 2A) and 71% of all the largest alleles in the total of 51 patients (respectively 74% of the largest allele in population C, 77% in population IVF-C and 67% in population IF) (Figure 2B). Between 6.5 and 12.5 kb, two groups of alleles are distinguished: a first small peak at 8 kb (16% of all alleles and 31% of the smallest alleles) and a second peak around 11 kb, including 33% of all the alleles and 66% of the smallest alleles in all the 51 patients (respectively 65% of the largest allele in population C, 62% in population IVF-C and 75% in population IF) (Figure 2B). The mean size of the largest allele was similar in the three populations (15.38 kb in population C, 16.27 kb in population IVF-C and 16.12 kb in population IF). The mean size of the smallest allele was also similar in the three populations (11.08 kb in population C, 11.81 kb in population IVF-C and 11.75 kb in population IF). ROC graph analyses have been performed to determine size thresholds, first between the population presenting implantation failure (IF) and populations without implantation failure (C and IVF-C) and then between infertile populations (IF and IVF-C) and the fertile population C. No threshold was found between these different populations.
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Taking into consideration a probable association of large VNTR domain (containing a lot of O-glycosylation sites), with an improved function, we arbitrarily applied a threshold of 13.5 kb to classify alleles as short (<13.5 kb) coded S or large (
13.5 kb) coded L. Thereafter, we evaluated the MUC4 genotype distribution in the three populations: the short alleles (S) were as frequent in infertile populations as in the fertile one. Taking into consideration the association of the two alleles, we observed that the frequency of the SS genotype was not significantly higher in the fertile population C (31%) compared with IVF-C (15%) or IF (25%) or all infertile patients (20%). The genotype LL was more frequent in the IVF-C population (62%) than in IF (25%) or C (23%), although this difference was not statistically significant (Figure 3). The genotype LS was observed in 46% of the fertile patients versus 36% in the infertile ones (23% for population IVF-C and 50% for population IF). Therefore, no association of particular MUC4 VNTR polymorphisms was found with embryo implantation in this study.
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Endometrial expression of MUC4
RT–PCR and immunohistochemistry experiments were carried out to determine whether differences in MUC4’s expression pattern could explain the implantation failure in population IF. Expression of MUC4 RNA transcripts was determined by non-quantitative RT–PCR in endometrial biopsies of IVF-C and IF populations; MUC4 mRNA was detected in all samples from both IVF-C and IF populations (Figure 4).
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By immunohistochemistry, anti-MUC4 antibody staining was observed in the glandular epithelium (Figure 5a) and the luminal (Figure 5b) without reaching the subjacent stromal tissue. The staining was very focused on one cell or a small group of cells forming patches. In the luminal epithelium, the whole of the cell was stained, but the staining was more intense at the apical pole and at the latero-apical tail of the cell (Figure 5a), whereas at the glandular epithelium, the staining was intense only at the apical pole of the cells. To see whether MUC4 expression could be under the control of steroid hormones, we examined steroid-receptor expression on serial biopsy sections using anti-PR and anti-ER antibodies. Anti-PR antibody staining was limited to the nucleus and present in numerous stromal cells and rare scattered epithelial cells (Figure 5c). There was no difference in anti-PR antibody staining between the two groups (data not shown). Anti-ER staining, more intense in nucleus than in cytoplasm, was observed not only in the luminal and glandular epithelial cells but also in many stromal cells (Figure 5e). The endometrial expression of the MUC4, ER and PR peptides by immunohistochemistry presented the same expression pattern in both IVF-C and IF populations.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
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In IVF, many women experience unexplained implantation failures despite repeated transfers of morphologically normal embryos. In addition to embryo quality and hormone-dependent uterine receptivity, a possible genetic aetiology has been recently advanced by Horne and collaborators (Horne et al., 2001
). They found a correlation between embryo implantation failures and small MUC1 allele size. The large size of the mucin MUC1 results from the TR size and its glycosylation state and suggests a role of MUC1 in embryo implantation by steric hindrance. It has been hypothesized that MUC1 cleavage at the implantation site could be due to the embryo itself (Chervenak and Illsley, 2000). Embryo implantation failure seems associated with an abnormal endometrial expression of MUC1 (Horne et al., 2005). The implication of MUC1 polymorphism in embryo implantation failures has not been confirmed by others (Goulart et al., 2004).
In a recent study, authors investigated the quantitative expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8, but not MUC4) in human endometrium and cervix and compared in normal and cancerous tissues. Endometrial tumours showed increased expression of MUC1, MUC5B and MUC8 over normal tissues (Hebbar et al., 2005). The involvement of mucins in adhesion followed by invasive processes such as cancer genesis or metastasis dissemination led us to investigate the potential role in implantation of another, much larger mucin, MUC4. In this study, we examined allelic variation of possible significance in the MUC4 gene as candidate for susceptibility to deficient embryo implantation. Our main hypothesis, as in the MUC1 studies, was that the variation in the length of the very large glycosylated TR domain is likely to affect mucin function by altering physicochemical properties or by masking implantation sites. We included three patient populations in our study: a population presenting unexplained embryo implantation failure (IF) and two control populations, one of spontaneously pregnant women (C) and one of pregnant women after IVF attempts (IFV-C). In addition to testing VNTR variation, we analysed endometrial MUC4 mRNA and protein expression in IF and IVF-C populations.
By Southern blot analysis, the MUC4 VNTR alleles observed in the three populations ranged from 6.5 to 21.5 kb in size with a trimodal distribution, as previously observed by others (Vinall et al., 2000). There was no difference in alleles’ frequency in the three groups. To maximize the differences between the large (L) and the short (S) alleles, an arbitrary threshold of 13.5 kb was established. Considering, like other authors, the codominant expression of mucin gene alleles (Carvalho et al., 1997; Vinall et al., 2002), we also studied the combination of largest and smallest alleles in each individual: We found no specific genotype associated with implantation failures or fertility. Therefore, we could conclude that the size of the MUC4 VNTR is not predictive of implantation failure.
The role of a fine regulation in the expression of Muc4 in implantation has been shown in rat and pig. In the rat uterus, Muc4 is globally lost from the apical surface of uterine cells during the implantation window, removing its potential steric inhibition for blastocyst implantation. It has been proposed that its loss contributes to the implantation receptivity (McNeer et al., 1998; Carraway and Idris, 2001). In porcine endometrium, the maintenance of Muc4 during the implantation period could modulate the proteolytic activity of porcine embryo, resulting in a non-invasive type of implantation (Ferrell et al., 2003).
So, to test whether endometrial MUC4 expression, rather than the size of the VNTR array, could influence the embryo implantation in human, we analysed MUC4 profile of expression by RT–PCR and immunohistochemistry. Our results showed the expression of MUC4 mRNA in all cases of IVF-C and IF populations. No quantitative analysis was performed since the pattern of MUC4 expression is not homogeneous, but in localized patches at the apico-lateral surface of one or a few epithelial cells. Using an antibody recognizing the VNTR domain, a similar expression pattern of MUC4 was observed in all cases. Such a focused expression has not been described in rat or pig. It would, therefore, be interesting to check whether, in women, the MUC4 patchy expression is associated with implantation sites. The anti-adhesive properties of MUC4 could create among those endometrial cells that express MUC4, a point of weakness for easier trophoblastic invasion.
The steroid regulation of MUC4 expression has been suggested by animal studies: In rat, at the time of implantation receptivity, increased progesterone levels lead to down-regulation of MUC4 homologue in the uterine luminal epithelium via an indirect effect on stromal cells involving paracrine action of TGF-. In humans, the literature about the steroid regulation of MUC4 expression is limited. In the human cervix, an increase of MUC4 gene transcription has been described during the progestative phase (Audie et al., 1995). In the endometrium, northern blot analysis showed that MUC4 mRNA is expressed in both the proliferative and the luteal phases with no obvious difference in the level between the two (Gollub et al., 1993). To determine the potential for regulation of MUC4 expression by steroids, PR and ER staining was performed. There was no difference in anti-PR antibody staining between the two groups, suggesting that in IF group, embryo implantation failure was not a consequence of a luteal phase defect (Lessey et al., 1996). Anti-ER staining was observed in the luminal and glandular epithelial cells and in stromal cells (Figure 5c). This pattern of expression at this time of menstrual cycle is in accordance with previous published results (Horne et al., 2005). The pattern of endometrial expression of the MUC4, ER and PR peptides by immunohistochemistry was similar in both IVF-C and IF populations, and MUC4 staining areas did not correspond in any obvious way with areas staining for steroid receptors.
It is interesting to note that, in animal studies, Muc4 has been characterized as a ligand for ErbB2 homologue (Carraway et al., 1999). Therefore, MUC4 could play a role in the dialogue between human trophoblastic and endometrial cells via signal transduction function of MUC4 through ErbB2/c-erbB2 since ErbB2 is expressed by the human cytotrophoblasts during the invasive phase (Klonisch et al., 2001; Goffin et al., 2003; Brown et al., 2004).
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Conclusions |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionsAcknowledgementsReferences |
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Our present study of MUC4 VNTR polymorphism did not show any statistically significant difference between the spontaneous fertile population and the infertile populations with or without unexplained embryo implantation failures. Epithelial MUC4 mRNA or protein expression was always observed regardless of the implantation status of the patients. Nevertheless, the novel patchy MUC4 expression we described in the human luminal uterine epithelium has to be further explored for a better comprehension of the embryo to endometrial cell dialogue at the beginning of the implantation process. These preliminary results do not support a role for MUC4 in endometrial/embryo interactions, but complementary experiments are needed to completely exclude it. For this purpose, it would be interesting to check whether the MUC4 patches are associated with implantation sites for two reasons: first, the anti-adhesive properties of MUC4 could create points of weakness in the endometrial epithelium for easier trophoblastic invasion at these points, and second, as a probable ErbB2/c-erbB2 receptor, MUC4 could induce a signal pathway leading to changes in the endometrial epithelial cells necessary for embryo invasive implantation. As a continuation of this work, we intend to analyse the pattern of expression of MUC4 on endometrial cells after embryo co-culture.
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Acknowledgements |
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We appreciate the helpful comments and critical reading of the manuscript by A. M. Sharkey. We thank R. M. Siminski, M. H. Gevaert and B. Hemon for their technical help, P. Meyer for statistical help and R. Dolan for language corrections.
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References |
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Submitted on February 27, 2006; resubmitted on April 6, 2006; accepted on April 24, 2006.
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