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Distribution of Adipocyte-derived Leucine Aminopeptidase (A-LAP)/ER-aminopeptidase (ERAP)-1 in Human Uterine Endometrium

Daijiro Shibata, Hisao Ando, Akira Iwase, Tetsuro Nagasaka, Akira Hattori, Masafumi Tsujimoto and Shigehiko Mizutani

Departments of Obstetrics and Gynecology (DS,HA,AI,SM) and Laboratory Medicine (TN), Nagoya University Graduate School of Medicine, Nagoya, Japan, and Laboratory of Cellular Biochemistry (AH,MT), RIKEN, Wako, Japan

Correspondence to: H. Ando, MD, PhD, Dept. of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: ando{at}med.nagoya-u.ac.jp


    Summary
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 Materials and Methods
 Results
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 Literature Cited
 
Adipocyte-derived leucine aminopeptidase (A-LAP, endoplasmic reticulum aminopeptidase ERAP1) is specialized to produce peptides presented on the class I major histocompatibility complex (MHC) by trimming epitopes to eight or nine residues, in addition to its enzymatic activity to degrade angiotensin II. Previously we identified placental leucine aminopeptidase (P-LAP), another member of the oxytocinase subfamily of aminopeptidases, in human uterine endometrial epithelial cells. Here we analyzed the distribution of A-LAP in human cyclic endometrium. Western blotting analysis showed that A-LAP was present in the endometrial tissue throughout the menstrual cycle. Immunohistochemical (IHC) analysis of A-LAP showed a similar distribution to that of P-LAP. A-LAP was localized predominantly in the endometrial glands and the luminal surface epithelium. However, the intracellular localization change that accompanied apocrine secretion, which was observed in P-LAP, was not shown in A-LAP. Subcellular localization of A-LAP, demonstrated by immunofluorescence, was ER in the cultured glandular epithelial cells. Our results indicate that A-LAP may fit the endometrial localization as an antigen-presenting ER aminopeptidase. Further understanding of the function(s) of A-LAP in the endometrium appear likely to yield insights into the cyclic changes during the normal endometrial cycle.

(J Histochem Cytochem 52:1169–1175, 2004)

Key Words: adipocyte-derived leucine • aminopeptidase • aminopeptidase • endometrium • endoplasmic reticulum • implantation • puromycin-insensitive • leucyl-specific • aminopeptidase (PILSAP)


    Introduction
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 Introduction
 Materials and Methods
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 Literature Cited
 
AMINOPEPTIDASES hydrolyze N-terminal amino acids of proteins or peptide substrates. They are distributed widely in prokaryotic and eukaryotic cells, suggesting that they play important roles in various biological processes. They are essential for protein maturation, for activation, modulation, and degradation of bioactive peptides, and for determination of protein stability (Taylor 1993Go). In addition, several aminopeptidases are known to be differentiation antigens and control cell proliferation and differentiation in mammalian tissues (Look et al. 1989Go; Wu et al. 1990Go; Nanus et al. 1993Go).

In our previous work, we cloned a cDNA encoding placental leucine aminopeptidase (P-LAP)/oxytocinase, a type II membrane-spanning protein that belongs to the M1 zinc-metallopeptidase (gluzincin) family (Rogi et al. 1996Go). We then cloned a cDNA for the adipocyte-derived leucine aminopeptidase (A-LAP), which was also designated as endoplasmic reticulum (ER)-aminopeptidase (ERAP)-1 or puromycin-insensitive leucyl-specific aminopeptidase (PILSAP), as a highly homologous protein to P-LAP (Hattori et al. 1999Go; Schomburg et al. 2000Go; Saric et al. 2002Go). A-LAP trims certain precursors to major histocompatibility complex (MHC) class I-presented antigenic peptides (Serwold et al. 2002Go). The proteolytic activity of A-LAP is controlled by the size rather than the NH2 terminus of the peptide substrate (York et al. 2002Go). Gluzincin aminopeptidases share the consensus His-(X)18-Glu motif essential for enzymatic activity (Hooper 1994Go). This growing family of mammalian zinc-containing membrane-bound aminopeptidases includes P-LAP, A-LAP, thyrotropin-releasing hormone-degrading enzyme, aminopeptidase A, and aminopeptidase N (Olsen et al. 1988Go; Wu et al. 1990Go; Nanus et al. 1993Go; Schauder et al. 1994Go; Rogi et al. 1996Go; Hattori et al. 1999Go). In addition, we have recently cloned a cDNA encoding a novel aminopeptidase, leukocyte-derived arginine (R) aminopeptidase (L-RAP) (Tanioka et al. 2003Go). We have reported that, like A-LAP, L-RAP is an aminopeptidase normally retained in the ER and trims certain precursors to MHC class I-presented antigenic peptides (Tanioka et al. 2003Go). Moreover, three human genes of P-LAP, A-LAP, and L-RAP are located contiguously around chromosome 5q15 (Horio et al. 1999Go; Hattori et al. 2001Go; Tanioka et al. 2003Go). These results strongly support the latest divergence of three genes from a single ancestral gene, and therefore we have proposed that these three aminopeptidases should be classified in the oxytocinase subfamily of M1 aminopeptidases (Tanioka et al. 2003Go).

Human endometrium undergoes dramatic morphological and functional changes during the menstrual cycle. In an effort to elucidate the biological significance of the M1 family of aminopeptidases in human reproductive processes, including implantation and menstruation, we have recently reported the expression and localization of P-LAP and aminopeptidase A in the endometrium (Ando et al. 2002Go; Toda et al. 2002Go). The endometrium is the maternal frontier to the implanted embryo, a semi-allograft, which is initially recognized by the uterine leukocytes. Furthermore, the endometrium may be susceptible to foreign organisms via the vagina. We studied the distribution and intracellular localization of A-LAP in human endometrium. We speculated that A-LAP and P-LAP, both of which belong to the same subfamily of aminopeptidases, might show some similarities and differences in their distribution in human cyclic endometrium.


    Materials and Methods
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 Summary
 Introduction
 Materials and Methods
 Results
 Discussion
 Literature Cited
 
Tissue Collection for Western Blotting
Fresh endometrial tissues were collected by curettage from women with regular menstrual cycles, aged 34–46 years, during hysterectomy for leiomyoma at Nagoya University Hospital as described previously (Ando et al. 2002Go). Written informed consent was obtained from the women before surgery. Curetted samples were quickly washed with cold PBS to remove blood and secretions. Samples were immediately moved to our laboratory in an ice bucket. PBS was removed by brief centrifugation and the samples were stored at –80C until use for protein extraction. Pathological slides of the endometrium were then reviewed and normal cases were further selected on the basis of consistent histological findings anywhere in the sample without any discrepancy against the cycle day. Endometrial dating criteria were used to assess the phase of the menstrual cycle (Noyes et al. 1950Go). Briefly, the endometrial subphase was determined on the basis of gland mitoses, pseudostratification of nuclei, basal vacuolation, gland secretion, stromal edema, pseudodecidual reaction, stromal mitoses, and leukocyte infiltration. Endometrial dating was strictly defined histologically by an expert pathologist in this technique (TN). Accordingly, the fresh endometrial tissue samples were allocated to six groups: three early proliferative phase, five mid-proliferative phase, sic late proliferative phase, seven early secretory phase, six mid-secretory phase, and eight late secretory phase. Fresh endometrial tissue samples were also collected from patients, aged 34–44 years, who had received oral administration of estrogen (one Premarin tablet daily, 0.625 mg of conjugated estrogens made from pregnant mare's urine; Wyeth Lederle Japan, Tokyo, Japan; n=3) or of an estrogen–progestin combination (one Dolton tablet daily, 500 µg of norgestrel and 50 µg of ethinyl estradiol; Nihon Schering, Osaka, Japan; n=4) for 21–28 days during hysterectomy for leiomyoma Moreover, fresh endometrial tissue samples were collected by curettage from four ectopic pregnancy patients at 6–8 weeks during laparoscopic surgery.

Tissue Collection for Immunohistochemistry
We retrieved endometrial biopsy specimens from the pathology files at Nagoya University Hospital, Nagoya, Japan as described previously (Ando et al. 2002Go). Patient clinical charts were reviewed and cases were selected on the basis of a history of regular menstrual cycles and no use of any intrauterine device or hormone therapy for at least 6 months before the biopsy. Histological slides of the endometrium were reviewed and cases were further selected on the basis of consistent histological findings. As a result of these reviews, biopsy specimens from 39 patients, aged 34–43 years, were available for examination. Endometrial dating criteria were used to assess the phase of the menstrual cycle (Noyes et al. 1950Go). The results of this histological classification were as follows: 14 proliferative phase, eight early secretory phase, eight mid-secretory phase, nine late secretory phase. Endometrial dating was strictly defined histologically by an expert pathologist in this technique (TN). All biopsy samples had been proved to be histologically benign. The use of pathology specimens for this research was approved by the institutional review board. These samples, which had been fixed in 10% formalin and embedded in paraffin, were used for IHC.

Tissue Collection for Endometrial Cell Culture
Fresh endometrial tissues in the late proliferative phase were collected by curettage from six women with regular menstrual cycles, aged 34–46 years, during hysterectomy for leiomyoma at Nagoya University Hospital. Written informed consent was obtained from the women before surgery. Individual curetted samples were quickly washed with cold PBS to remove blood and secretions. Samples were immediately moved to our laboratory in an ice bucket. PBS was removed by brief centrifugation and then the samples were used for cell culture after glands and stroma were separated as described below.

Endometrial Cell Culture
Endometrial stromal cells (ESCs) and endometrial glandular epithelial cells (EECs) were separated essentially as described previously (Satyaswaroop et al. 1979Go) with only slight modification (Ando et al. 2002Go). Briefly, endometrial tissue was minced into small pieces (~1 mm3) and these pieces were filtered through a cell strainer consisting of 100-µm pore size nylon mesh (Becton Dickinson; Franklin Lakes, NJ) to remove blood cells. Then the minced tissue was incubated with stirring at 37C for 20 min in PBS, 0.5% collagenase (Wako; Osaka, Japan), and DNase (0.1 mg/ml; Sigma, St Louis, MO). For separating EECs, the incubation time was extended to 30 min. The dispersed ESCs were separated from endometrial glands and undigested tissues by filtration through a cell strainer consisting of 70-µm pore size nylon mesh (Becton Dickinson). The glands were obtained by the backflash of the nylon mesh with PBS. To ensure purity, the glands were sorted microscopically. Then the glands were incubated with stirring at 37C for 5 min in PBS containing 0.25% trypsin (Sigma). The separated ESCs and EECs were washed and pelleted by centrifugation (400 x g, 10 min) and then suspended (106 cells/ml) in RPMI 1640 (Sigma) containing FCS (10% v/v; Life Technologies, Gaithersburg, MD), 100 IU/ml penicillin, and 100 µg/ml streptomycin. For Western blotting, ESCs and EECs were plated onto 10-cm Falcon dishes (Becton Dickinson) and 10-cm collagen-coated dishes (Sumitomo Bakelite; Tokyo, Japan), respectively, for 48 hr at 37C in a humidified atmosphere of 5% CO2 in air. For immunofluorescent cytochemistry, cells were grown on the Chamber-Tek chamber slide (Miles; Naperville, IL) for 48 hr at 37C in a humidified atmosphere of 5% CO2 in air. The purity of ESCs and EECs was ≥99% and ≥94%, respectively.

Western Blotting Analysis
The frozen tissue samples or the harvested cell samples were homogenized using a motor-driven Teflon pestle for 10 min on ice in PBS extraction buffer containing 1% Triton X-100 and protease inhibitors (1 mM phenylmethylsulfonyl fluoride, 1 µg/ml aprotinin, 10 µg/ml leupeptin). Tissue extracts were obtained as supernatants after centrifugation at 15,000 x g for 30 min at 4C and were stored at –80C. Protein concentrations were determined using a protein assay kit (Bio-Rad Laboratories; Hercules, CA). Immunoblotting analysis was carried out according to the method reported previously (Ando et al. 2002Go). In brief, 10 µg of protein was equally diluted in a sample buffer and denatured at 95C for 5 min. Proteins were separated by SDS-PAGE and transferred onto nitrocellulose membranes. Membranes were blocked with 5% skim milk and then immunoblotted with anti–A-LAP antibody (1:1000 dilution). Rabbit polyclonal IgG antibody was raised against recombinant human A-LAP expressed in Chinese hamster ovary cells (Hattori et al. 2000Go). It is highly specific and it does not crossreact with recombinant human P-LAP expressed in Chinese hamster ovary cells (Matsumoto et al. 2000Go). After washing with PBS, membranes were treated with an ECL blotting detection system (Amersham Pharmacia Biotech; Piscataway, NJ). Then the membranes were dehybridized and then immunoblotted with anti–ß-actin antibody. Densitometric analysis was applied for statistical comparison (Image Master 1D; Amersham Biosciences, Piscataway, NJ). Densitometric data from three independent experiments were expressed as the mean ± SD.

Immunohistochemistry
Formalin-fixed, paraffin-embedded tissue sections were cut to a thickness of 3 µm. Deparaffinized sections in 0.01 M citrate buffer were treated three times for 5 min at 90C at 750 W in an H2500 microwave oven (M and M; Tokyo, Japan) for heat-induced epitope retrieval. Endogenous peroxidase activity was blocked by incubation with 0.5% (w/v) H2O2 in methanol for 10 min, and nonspecific immunoglobulin binding was blocked by incubation with 10% normal goat serum in PBS for 10 min. IHC staining was carried out based on the labeled streptavidin–biotin (LSAB) method. A Ventana Basic DAB Detection Kit (Ventana Medical Systems; Tucson, AZ), yielding a brown product from diaminobenzidine (DAB)/copper sulfate, was used to detect A-LAP. Staining procedures were done automatically using a Ventana BenchMark IHC Staining System (Ventana Medical Systems) according to the manufacturer's instructions. This system is a completely automatic computerized staining system that yields stable and reproducible data. The primary antibody against A-LAP was diluted 1:100 in PBS. In negative control sections, the primary antibody was replaced with rabbit IgG. Human kidney sections were used as a positive staining control. The slides were counterstained with hematoxylin before mounting. Stained sections were observed under an Olympus (Tokyo, Japan) BH2 microscope and photographed using a CCD Color Camera CS600 (Olympus). The staining intensity was classified as follows: strong, moderate, weak, very weak, and negative. Multiple sections obtained from the same tissue block were stained repeatedly over a 2-month period.

Immunofluorescent Microscopy
EECs and ESCs on chamber slides after fixation with 3.7% formaldehyde in PBS were treated with 0.2% Triton X-100 in PBS for 10 min and soaked in PBS containing 1% BSA (BSA-PBS) and 5% skim milk for 30 min. Cells were then incubated with anti-ER retention signal KDEL Antibody (StressGen Bioreagents; Victoria, Canada) and anti–A-LAP antibody, diluted with BSA-PBS (1:200 dilution) for 1 hr, washed three times for 5 min with BSA-PBS, and incubated with secondary antibodies, rhodamine-conjugated anti-goat IgG (Jackson ImmunoResearch Laboratories; West Grove, PA) and FITC-conjugated anti-mouse IgG (Santa Cruz Biotechnology; Santa Cruz, CA) for 1 hr. Cells were examined using an confocal microscope (Radiance; Bio-Rad Laboratories).


    Results
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 Materials and Methods
 Results
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 Literature Cited
 
Tissue Sample Studies
Endometrial tissue samples at various subphases of the menstrual cycle from each individual were analyzed by Western blotting. Proteins with molecular mass of 105–110 kD were detected in the endometrial tissue samples (Figure 1) . The immunoreactive band was conspicuous in the samples from mid-proliferative to late secretory endometrium, and also in the specimens from patients treated with estrogen or estrogen/progestin tablets. However, immunoreactive protein was less abundant in the samples from the early proliferative phase, in which the proportion of luminal surface epithelium and glands is very small. The signal was also low in the samples from ectopic pregnancy at 6–8 weeks. It is noteworthy that the endometrial tissues are highly decidualized, so-called deciduas, and include only apoptotic degenerated glands and epithelium.



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Figure 1

Western blotting analysis of A-LAP in human endometrial tissue samples. (A) A-LAP was detected as a 105–110-kD band (upper panel). Protein samples from each individual were prepared from the early (Lane a), the mid- (Lane b), and the late (Lane c) proliferative phase endometrium; from the early (Lane d), the mid- (Lane e), and the late (Lane f) secretory phase endometrium; from endometrium collected from a woman with tubal pregnancy at 6 weeks (Lane g); from endometrium collected from women who had been taking estrogen tablets for 3 weeks (lane h) and estrogen/progestin tablets for 3 weeks (Lane i); and from placental trophoblast at 38 weeks (Lane j). For the negative control lane (Lane k), non-immune rabbit IgG was used as a primary antibody. In each lane, 10 µg of protein extract was applied. The results shown are representative of six independent experiments. (B) The immunoblots were quantified by densitometry. The A-LAP/ß-actin ratio is shown as mean ± SD from each individual sample. *Significantly different (p<0.05) from the other subphases (Lanes b–f).

 
IHC localization for A-LAP was studied using specimens at various subphases of the menstrual cycle. A-LAP was localized predominantly in the endometrial epithelial cells (Figure 2) . Stromal cells in the mid-secretory phase and decidualized stromal cells, which are differentiated from stromal cells around spiral arteries/arterioles in the late secretory phase, showed weak or very weak immunoreactivity for A-LAP (Figure 2). The intracellular staining pattern of the epithelial cells was homogeneous throughout the menstrual cycle. Unlike P-LAP (Toda et al. 2002Go), intracellular localization change along with apocrine secretion was not observed in the glandular epithelial cells (Figure 2).



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Figure 2

Immunohistochemical localization of A-LAP in endometrium during the ovulatory cycle. (A–C) Late proliferative phase; (D–F) early secretory phase; (G–I) mid-secretory phase; (J–L) late secretory phase. (A,B,D,E,G,H,K) Strong or moderate immunoreactivity for A-LAP is observed in both luminal surface (small dots) and glandular epithelial cells. Very weak or weak immunoreactivity for A-LAP is observed in stromal cells in the mid-secretory phase and in decidual cells in the late secretory phase. The area indicated by arrows is the decidualized region. (C,I,F,L) Sections were incubated with non-immune rabbit IgG (negative controls). Bars = 50 µm.

 
Cell Culture Studies
The cell type expression and subcellular localization of A-LAP in the endometrium were also studied using cultured endometrial cells. Immunoblotting analysis for A-LAP gave a single protein band in the sample from cultured endometrial epithelial cells (Figure 3A) . The sample from stromal cells did not show a clear band (Figure 3A). To visualize the intracellular localization of A-LAP, we performed immunofluorescence of the cultured glandular epithelial cells using antibodies to A-LAP and to KDEL, the ER-retention sequence. This analysis revealed that A-LAP was localized in the ER (Figure 3B).



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Figure 3

Protein expression and subcellular localization of A-LAP in cultured cells after the separation into epithelial and stromal cells. (A) Western blot for A-LAP in cultured endometrial glandular epithelial (Lane 1) and stromal (Lane 2) cell samples. (B) Immunocytochemical detection was done in cultured endometrial glandular epithelial cells with antibodies to human A-LAP and KDEL, the ER retention sequence. A-LAP–stained (upper panel), KDEL-stained (middle panel), and merged (lower panel) images are shown. Bar = 10 µm.

 

    Discussion
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 Summary
 Introduction
 Materials and Methods
 Results
 Discussion
 Literature Cited
 
In this study we demonstrated expression and localization of A-LAP protein in human cyclic endometrium. A-LAP was localized predominantly in the endometrial epithelial cells throughout the menstrual cycle. A-LAP was not localized in the stroma except during the mid- and late secretory phases, with weak or very weak immunolocalization. Our present and previous (Toda et al. 2002Go) results showed that A-LAP and P-LAP, both of which belong to the oxytocinase subfamily of M1 aminopeptidases, were present in the human endometrium and localized predominantly in the epithelial cells rather than the stromal cells. In contrast, aminopeptidases A and N, both of which are M1 aminopeptidases but do not belong to the oxytocinase subfamily, were localized mainly in the endometrial stromal cells (Imai et al. 1992Go; Ando et al. 2002Go). Because both endometrial epithelial cells and stromal cells share the same stem cells, these aminopeptidases should be good differentiation markers for epithelial cells.

Although tissue distribution of A-LAP is broad (Schomburg et al. 2000Go; Serwold et al. 2002Go), its localization in each organ has not been studied as extensively as that of P-LAP (Nagasaka et al. 1997Go). A heterograft recognition system may be activated in the cyclic endometrium because the endometrium is susceptible to foreign organisms, such as bacteria and fungi. Precursors to MHC class I-presented peptides with extra N-terminal residues are trimmed to mature epitopes in the ER. The peptides are first cleaved from endogenously synthesized proteins by proteasome or tripeptidyl peptidase II in the cytoplasm, transported into the ER lumen, and then trimmed by A-LAP. Therefore, our data on the distribution of A-LAP may contribute to elucidation of the immune system in the cyclic endometrium.

Intracellular localization of A-LAP was homogenous throughout the menstrual cycle. In contrast to the intracellular localization change of P-LAP along with the apocrine secretion of endometrial glands (Toda et al. 2002Go), the intracellular localization of endometrial A-LAP was unchanged. Therefore, A-LAP was still localized when P-LAP disappeared after apocrine secretion was finished in the late secretory phase. Enzymatically, aminopeptidases hydrolyze N-terminal amino acids of peptide substrates with their own specificity. P-LAP specifically degrades oxytocin, vasopressin, and angiotensin III (Tsujimoto et al. 1992Go), while A-LAP degrades angiotensin II and kallidin (Hattori et al. 2000Go). Among the bioactive peptides, it appears that angiotensin II may play important roles in such processes as angiogenesis, vasoconstriction, and trophoblast invasion in the cyclic endometrium (Li and Ahmed 1996Go; Ando et al. 2002Go; Xia et al. 2002Go). The spatiotemporal localization of angiotensin II is highly regulated by the local renin–angiotensin system and by angiotensin-degrading enzymes (Vinson et al., 1997Go; Ando et al., 2002Go). It is unclear at present how A-LAP as an ER aminopeptidase may contribute to the degradation of angiotensin II in the endometrium. Recently, our group identified A-LAP in human invasive trophoblastic cells (Ino et al. 2003Go). It is noteworthy that A-LAP was present at a detectable level only in the endometrial tissue of ectopic pregnancy at 6–8 weeks. Further studies are necessary to clarify the distribution and function of A-LAP in the endometrium and invasive trophoblasts during the establishment of pregnancy.

In conclusion, we showed the presence and distribution of A-LAP in human cyclic endometrium. Belonging to the same subfamily of aminopeptidases, A-LAP and P-LAP share similarities in endometrial distribution. However, each leucine aminopeptidase has its unique intracellular localization in glandular epithelial cells. Further understanding of the function of A-LAP in the endometrium appears likely to yield insights into the cyclic changes during the normal menstrual cycle, although extensive work will be required to prove the involvement of this enzyme in various physiological changes of the endometrium.


    Acknowledgments
 
Supported in part by a Grant-in-Aid for Scientific Research to HA (no. 15591741) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a research grant to HA (2002) from Showa-kai, the Alumni of Department of Obstetrics and Gynecology, Nagoya University School of Medicine.

We are grateful for the technical assistance of Hiroko Sato in the immunohistochemical analysis.


    Footnotes
 
Received for publication December 8, 2003; accepted April 29, 2004


    Literature Cited
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