CN115919904A - Bifidobacterium breve capable of protecting intestinal epithelial cell layer and application thereof - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The invention discloses bifidobacterium breve capable of protecting an intestinal epithelial cell layer and application thereof, and belongs to the technical field of biology. The invention provides a new application of bifidobacterium breve CCFM683 in the aspect of protecting an intestinal epithelial cell layer; intervention of bifidobacterium breve CCFM683 can obviously improve DSS-induced damaged intestinal epithelial cell layer, reduce injury of colon epithelial cells and protect the integrity of the intestinal epithelial cell layer; up-regulating anti-apoptosis protein Bcl-2 and down-regulating pro-apoptosis protein Bad; remarkably reducing the number of epithelial cell apoptosis and maintaining the integrity of epithelial cell layers; and can prevent intestinal bacteria from translocating to the lamina propria through the epithelial cell layer to cause intestinal immune response. The bifidobacterium breve CCFM683 can be used as the main component of a probiotic preparation for protecting intestinal barrier and has wide market prospect.
Description
Technical Field
The invention relates to bifidobacterium breve capable of protecting an intestinal epithelial cell layer and application thereof, belonging to the technical field of microorganisms.
Background
The intestinal barrier is the sum of structures and functions which can prevent pathogenic bacteria and toxins in the intestinal cavity from penetrating through intestinal mucosa to enter a blood system and other tissues and organs, and plays an important role in human health. The intestinal barrier is composed of a mechanical barrier, an immunological barrier, a biological barrier and a chemical barrier. The intestinal mucus layer, the epithelial cell layer and the close connection form a first defense line of the intestinal tract, namely an intestinal tract mechanical barrier, and play a role in maintaining the intestinal tract barrier function. The intestinal epithelial cell layer is a compact structure formed by goblet cells, M cells, pan cells and other cells, prevents harmful microorganisms and toxins in the intestinal tract from entering the intestinal lamina propria and has important influence on the intestinal function. Many gut-related diseases, such as colitis, irritable bowel disease, diarrhea, constipation, etc., are directly associated with the destruction of the epithelial cell layer of the gut. Therefore, maintaining the normal epithelium of the intestine is one of the keys to protecting the health of the intestine. Intestinal diseases such as colitis, constipation, diarrhea, irritable bowel inflammation and the like can cause great influence on the intestinal tract, can influence the life quality of patients, and cause changes in social, psychological and professional fields. There is an increasing search for conventional treatments using drugs with the aim of reducing symptoms and inflammation. Long-term use of drugs (inhibitors, hormones, antibiotics) associated with intestinal inflammation may cause hypertension, diabetes, osteoporosis and other diseases, thereby affecting the success of treatment.
In view of the various problems with existing treatment regimens, alternatives to traditional approaches are particularly important, and new treatment regimens include monoclonal antibodies, prebiotics, probiotics, and the like. The feasibility of the above-mentioned therapies has also prompted us to continue to search for dietary supplements that have broader application and greater potential, and at the same time, have the effect of protecting the epithelial cell layer of the intestinal tract. The probiotics have obvious improvement effect on constipation, enteritis, diarrhea, non-alcoholic fatty liver, glycolipid metabolic disorder, emotion and behavior disorder, and are closely related to the protection of intestinal epithelial cell layer by the probiotics. Therefore, it is very important to select probiotics which have protective effect on the intestinal epithelial cell layer.
Disclosure of Invention
The invention provides application of Bifidobacterium breve (Bifidobacterium breve) CCFM683 in preparing a product for protecting an intestinal epithelial cell layer, wherein the Bifidobacterium breve CCFM683 is preserved in a China general microbiological culture collection center of China Committee for Culture Collection of Microorganisms (CCMCC) No.11828 on 12 days 2015 and disclosed as CN106038611A.
In one embodiment, the product is a pharmaceutical or nutraceutical.
In one embodiment, the medicament further comprises a pharmaceutical carrier and/or a pharmaceutical excipient.
In one embodiment, the product is a preparation containing the Bifidobacterium breve CCFM683, and the number of the Bifidobacterium breve CCFM683 in the preparation is more than or equal to 1 × 10 10 CFU/g or 1X 10 10 CFU/mL。
In one embodiment, the formulation is a bacterial suspension of bifidobacterium breve CCFM 683.
In one embodiment, the formulation is lyophilized powder of bifidobacterium breve CCFM 683.
In one embodiment, the bacterial suspension is prepared by the following steps: inoculating the bifidobacterium breve CCFM683 into a seed culture medium for culture to obtain a seed solution; inoculating the seed solution into a fermentation culture medium for culturing to obtain a cell culture solution; centrifuging the cell culture solution, and collecting bacterial sludge; and washing the bacterial sludge, and then re-suspending to obtain bacterial suspension.
In one embodiment, the lyophilized powder is prepared by: adding a freeze-drying protective agent into the bacterial suspension to obtain a mixed solution; and (4) carrying out vacuum freeze drying on the mixed solution to obtain freeze-dried powder.
In one embodiment, the seed solution is inoculated into a culture medium in an amount of 2 to 4% (v/v) for culture.
In one embodiment, the components of the lyoprotectant include skim milk powder, trehalose, sucrose, and water.
In one embodiment, the lyoprotectant is a solution containing 80-120g/L skim milk powder, 80-140g/L trehalose, and 140-180g/L sucrose.
In one embodiment, the components of the lyoprotectant are 100g/L skim milk powder, 100g/L trehalose, and 160g/L sucrose.
In one embodiment, the addition amount of the lyoprotectant in the resuspension solution is 2 to 4 times of the total weight of the bacterial sludge.
In one embodiment, the seed medium is a mrs solid medium and the fermentation medium is a mrs liquid medium.
In one embodiment, the MRS liquid medium is a cysteine hydrochloride-added MRS liquid medium.
In one embodiment, the cysteine hydrochloride is added in an amount of 0.04 to 0.1% by mass.
In one embodiment, the seed solution is inoculated into the mrss liquid medium in an inoculum size of 2-4% under the following culture conditions: anaerobic culture at 34-38 deg.c for 24-36h, centrifuging at 7000-12000rmp for 20-30 min, collecting bacterial sludge, washing with physiological saline for 3-4 times and re-suspending.
In one embodiment, the protecting the intestinal epithelial cell layer comprises alleviating and/or treating intestinal epithelial cell layer damage.
In one embodiment, the damage to the intestinal epithelial cell layer is DSS-induced damage to the intestinal epithelial cell layer.
In one embodiment, the alleviating and/or treating damage to the epithelial cell layer of the gut comprises at least one of:
(1) Protection of epithelial cell integrity;
(2) Reducing epithelial cell apoptosis promoting protein, and up-regulating anti-apoptosis protein;
(3) Inhibiting epithelial cell apoptosis;
(4) Preventing translocation of intestinal bacteria through the epithelial cell layer.
Has the advantages that:
(1) The Bifidobacterium breve (Bifidobacterium breve) CCFM683 provided by the invention is separated from the intestinal flora of the newborn, and the strain has no toxic or side effect on the human body, so that the medicament prepared by adopting the Bifidobacterium breve CCFM683 provided by the invention has certain advantages compared with the traditional medicament for protecting the epithelial cell layer of the intestinal tract, and the strain can be used for preparing probiotic preparations and the like and has wide market prospect;
(2) The invention provides a new application of bifidobacterium breve CCFM683 in the aspect of protecting an intestinal epithelial cell layer; intervention by bifidobacterium breve CCFM683 can reduce the damage of colon epithelial cells and protect the integrity of an intestinal epithelial cell layer; up-regulating anti-apoptosis protein Bcl-2 and down-regulating pro-apoptosis protein Bad; remarkably reducing the number of epithelial cell apoptosis and maintaining the integrity of epithelial cell layers; and can prevent intestinal bacteria from translocating to lamina propria through epithelial cell layer to cause intestinal immune response.
Drawings
FIG. 1: effect of bifidobacterium breve CCFM683 on colonic epithelial cell layer in mice;
FIG. 2: effect of bifidobacterium breve CCFM683 on mouse colonic apoptosis-related proteins;
FIG. 3: effect of bifidobacterium breve CCFM683 on apoptosis of colonic epithelial cells in mice;
FIG. 4: effect of bifidobacterium breve CCFM683 on intestinal bacterial translocation;
in fig. 1 to 4, ", and" each indicate a significant difference compared to the DSS group, the more the significant difference, the larger the error is shown in the form of a Mean ± SEM.
Detailed Description
The invention is further elucidated with reference to a specific embodiment and a drawing.
Bifidobacterium breve CCFM683 is a strain owned by the research team, and has been preserved in the China general microbiological culture Collection center of the China Committee for culture Collection of microorganisms at 12 days 04 in 2015 with the preservation number of CGMCC No.11828 and the publication number of CN106038611A.
The mice referred to in the following examples were male SPF (Specific pathogen free) grade C57BL/6J mice 8 weeks old, purchased from syngamy; the skim milk powder, trehalose, sucrose, and paraformaldehyde referred to in the following examples were purchased from national pharmaceutical group chemical agents, ltd; dextran Sulfate Sodium (DSS) referred to in the following examples was purchased from baikesy corporation, south kyo.
The media involved in the following examples are as follows:
mrss liquid medium: 10g/L of tryptone, 10g/L of beef extract, 5g/L of yeast powder, 20g/L of glucose, 2g/L of anhydrous sodium acetate, 0.5g/L of magnesium sulfate heptahydrate, 0.25g/L of manganese sulfate monohydrate, 2g/L of diammonium hydrogen citrate, 2.6g/L of dipotassium hydrogen phosphate trihydrate, 80 mL/L of Tween and 0.5g/L of cysteine hydrochloride.
mrss solid medium: 10g/L of tryptone, 10g/L of beef extract, 5g/L of yeast powder, 20g/L of glucose, 2g/L of anhydrous sodium acetate, 0.5g/L of magnesium sulfate heptahydrate, 0.25g/L of manganese sulfate monohydrate, 2g/L of diammonium hydrogen citrate, 2.6g/L of dipotassium hydrogen phosphate trihydrate, 80 mL/L of Tween, 0.5g/L of cysteine hydrochloride and 20g/L of agar.
The detection methods referred to in the following examples are as follows:
colon tissue various stains:
after the model is made and the mouse is dissected, taking 1cm of far colon (1 cm away from the anus) and quickly placing the far colon in 4% paraformaldehyde solution to soak for 24-48h at 4 ℃ to obtain fixed far colon tissue; dehydrating, transparentizing and waxing the fixed colon tissue, and embedding the tissue by using a paraffin embedding machine to obtain an embedded colon tissue wax block; wherein, the specific steps of dehydration, transparentization and waxing refer to the method of Wangjuntong et al (Wangjuntong [ D ]. Jiangnan university, 2016). And (3) slicing the wax block embedded with the colon tissue by using a Lycra manual rotary microtome, wherein the slicing thickness is 5 mu m, and thus obtaining the colon tissue slice.
Immunofluorescence staining of colon tissue: for a specific staining method, a doctor paper of zhuyilong (zhuyilong [ D ]. University of south of the river, 2018.) was referred to.
Fluorescence in situ hybridization of colon tissue: colon tissue fluorescence in situ hybridization refers to the Wenzhong doctor paper (Wenzhong [ D ]. Nanjing university of traditional Chinese medicine, 2019.).
Colon tissue transmission electron microscopy analysis: reference is made to Tan Yue doctor paper (Tan Yue [ D ]. University of Chinese medical science, 2018.) for transmission electron microscopy of colon tissue.
Colon tissue Tunnel staining: the colon tissue Tunnel staining method refers to the Tunnel kit instruction of Nanjing Nuozhen Biotechnology Co.
Example 1: preparation of Bifidobacterium breve CCFM683 bacterial suspension
(1) Streaking a bacterial liquid dipped with Bifidobacterium breve CCFM683 from a glycerol tube on a mMRS solid culture medium, and culturing for 48h at 37 ℃ in an anaerobic environment to obtain a single bacterial colony; and selecting a single colony, inoculating the single colony in an mMRS liquid culture medium, culturing for 48h at 37 ℃ in an anaerobic environment for activation culture, and repeating the operation for 3 times to obtain activated bacteria liquid.
(2) Inoculating the activated bacterial liquid obtained in the step (1) into a mMRS liquid culture medium according to the inoculation amount of 2% (v/v), culturing at 37 ℃ for 24h to obtain a fermentation liquid, centrifugally collecting the thalli from the fermentation liquid, resuspending the thalli by using normal saline, and adjusting the number of viable bacteria to be 5 multiplied by 10 9 CFU/mL, and preparing bacterial suspension.
Example 2: effect of Bifidobacterium breve CCFM683 on colonic epithelial cell layer in mice
The molding steps are as follows:
(1) Preparing a 2.5% Dextran Sodium Sulfate (DSS) solution: DSS was made up with sterile tap water to a concentration of 2.5% (w/v) DSS solution.
(2) 24 healthy male C57BL/6J mice of 8 weeks old are taken and randomly divided into 3 groups, wherein the 3 groups are respectively named as: control group (Control), modeling group (DSS), bifidobacterium breve CCFM683 intervention group (CCFM 683+ DSS); the experimental protocol and treatment regimen for each group of mice using 8 mice per group are shown in table 1.
(3) The Control group (Control), the modeling group (DSS) and the bifidobacterium breve CCFM683 dry and pre-group are treated according to the following methods:
wherein the processing method of the bifidobacterium breve CCFM683 dry pre-group comprises the following steps: the Bifidobacterium breve CCFM683 dry pre-group was gavaged with 5X 10 gastric lavage daily on days 1-7 of the experiment 9 CFU/mL Bifidobacterium breve CCFM683 bacterial suspension 200 μ L, drinking distilled water freely; the Bifidobacterium breve CCFM683 dry pre-group was gavaged with 5X 10 gastric lavage daily on day 8-14 of experiment 9 200. Mu.L of Bifidobacterium breve CCFM683 bacterial suspension with the bacterial count of CFU/mL is freely drunk as 2.5 percent DSS solution.
The processing method of the building module (DSS) comprises the following steps: on the 1 st to 7 th days of the experiment, the DSS group drenches 200 mu L of normal saline every day and freely drinks distilled water; on the 8 th to 14 th days of the experiment, the DSS group was administered with 200. Mu.L of normal saline daily and 2.5% DSS solution was freely drunk.
The Control group (Control) processing method comprises the following steps: in the experimental process, the control group was infused with 200 μ L of normal saline daily and freely drunk with distilled water.
Table 1 experimental mouse treatment protocol
After the molding is finished, the mouse is sacrificed, and 1cm of distal colon tissue is taken out for fixing, dehydrating, embedding and dyeing. And detecting the intestinal microstructure by using a transmission electron microscope. The tight junction is positioned at the top of the junction between the intestinal epithelial cells, the tight junction between the control group mouse epithelia shows compact bands, the desmosomes among the cells are clearly visible, and the intestinal villi positioned on the epithelial cells are smooth, neat and complete, which indicates that the intestinal epithelial cell layer is complete; and the close connection and the adhesive connection among the intestinal epithelial cells of the mice in the DSS group are loose and even broken, the desmosome structure almost disappears, the intestinal villi is shortened and even broken, the length is different, the intercellular space is obviously widened, and the epithelial cell layer is damaged. After the bifidobacterium breve CCFM683 dried, the villus fracture, the tight junction fracture and the damage of the epithelial cell layer are obviously improved (figure 1). Therefore, CFM683 can regulate the upper part of tight junction protein, improve the tight junction mechanism of intestinal tract, repair damaged epithelial cell layer, and protect intestinal epithelial cell layer.
Example 3: effect of Bifidobacterium breve CCFM683 on mouse colonic apoptosis-related proteins
The molding method was the same as in steps (1) to (3) of example 2; and (3) killing the mouse after the molding is finished, taking 1cm of distal colon tissue for fixing, dehydrating and embedding, and carrying out immunofluorescence staining and analysis on the colon tissue apoptosis protein. The anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bad are key proteins for regulating apoptosis. Immunofluorescence analysis was performed on Bcl-2 and Bad proteins in different groups of mice, and the fluorescence intensity of Bad proteins in the colon of DSS group mice was significantly increased (FIG. 2A). In contrast, DSS treatment down-regulated Bcl-2 expression, bifidobacterium breve CCFM683 treatment up-regulated Bcl-2, down-regulated Bad expression (FIG. 2A).
As can be seen from fig. 2B and 2C, DSS treatment increased the concentration of pro-apoptotic protein Bad in colon tissue to an average optical density of 0.58, whereas bifidobacterium breve CCFM683 treatment significantly decreased the average optical density of pro-apoptotic protein Bad (0.16), even below the blank (0.19). As can be seen from FIG. 2C, DSS treatment reduced the concentration of anti-apoptotic protein Bcl-2 in colon tissue to an average optical density of 0.10, while Bifidobacterium breve CCFM683 treatment significantly increased the average optical density of anti-apoptotic protein Bcl-2 (0.39), slightly below that of blank (0.45), indicating that Bifidobacterium breve CCFM683 inhibited pro-apoptotic protein Bad, up-regulating anti-apoptotic protein Bcl-2.
Example 4: effect of Bifidobacterium breve CCFM683 on apoptosis of mouse colonic epithelial cells
The molding method was the same as in steps (1) to (3) of example 2; the mice were sacrificed after the molding was completed, and 1cm of distal colon tissue was taken for fixation, dehydration, embedding, and colon tissue Tunnel staining and analysis. The effect of bifidobacterium breve CCFM683 on epithelial apoptosis was analysed by Tunnel staining. Compared with the blank group, the mice induced by the DSS alone have obviously increased apoptosis of the colon epithelial cells, which shows that the DSS has very obvious destructive effect on the colon epithelial cells of the mice; bifidobacterium breve CCFM683 group of mice did not show significant apoptosis in epithelial cells, almost similar to the blank group of mice (fig. 3A).
As can be seen from fig. 3B, DSS treatment increased the ratio of apoptotic cell numbers in colon tissue to 0.8% to 6.1% of the blank group, while bifidobacterium breve CCFM683 treatment significantly decreased the ratio of apoptotic cell numbers in colon tissue (1.2%). This indicates that bifidobacterium breve CCFM683 has a significant modulatory effect on DSS-induced apoptosis of colonic epithelial cells.
Example 5: effect of Bifidobacterium breve CCFM683 on intestinal bacterial translocation
One important cause of intestinal bacterial translocation is damage to the epithelial cell layer of the intestine. When the intestinal epithelial cell layer is damaged, the mucus layer becomes thin and even disappears completely in severe cases, which results in the complete exposure of epithelial cells in the intestinal lumen, allowing harmful bacteria and antigens, etc. to come into direct contact with the epithelial cells. EUB338/MUC2 fluorescence in situ hybridization can show the spatial distribution of intestinal mucin and bacteria and translocation of intestinal flora.
The molding method was the same as in steps (1) to (3) of example 2; and (3) killing the mice after the molding is finished, taking 1cm of distal colon tissue for fixing, dehydrating, embedding, and carrying out EUB338/MUC2 fluorescence in situ hybridization analysis on the colon tissue, wherein the result shows that the liquid layer of the DSS group mice is almost completely damaged, and a large amount of bacteria in the intestinal cavity are found to be shifted to epithelial cells. The dry prognosis of bifidobacterium breve CCFM683 left the mucus layer of the colon tissue intact, better preventing the bacteria in the intestinal lumen from invading the epithelial tissue of the colon (fig. 4). Thus, bifidobacterium breve CCFM683 significantly prevented translocation of bacteria in the colonic lumen to the colonic epithelium.
Example 6: preparation method of Bifidobacterium breve CCFM683 preparation
The method comprises the following specific steps:
(1) Activation of the strain: streaking a bacterial liquid dipped with Bifidobacterium breve CCFM683 from a glycerol tube on a mMRS solid culture medium, and culturing for 48h at 37 ℃ in an anaerobic environment to obtain a single bacterial colony; and selecting a single colony, inoculating the single colony in a mMRS liquid culture medium, culturing for 48h at 37 ℃ in an anaerobic environment for activation culture, and repeating the operation for 3 times to obtain activated bacterial liquid.
(2) Inoculating the bacterial liquid obtained in the step (1) into an mMRS liquid culture medium according to the inoculation amount of 3%, performing anaerobic culture at 37 ℃ for 28h to obtain fermentation liquor, centrifuging the obtained fermentation liquor at 10000rpm for 20min, collecting bacterial sludge, washing the bacterial sludge for 3 times for later use by using normal saline, and adjusting the number of viable bacteria to be 1 multiplied by 10 11 CFU/mL to obtain liquid preparation.
(3) Preparing a freeze-drying protective agent: 100g/L of skim milk powder, 100g/L of trehalose, 160g/L of sucrose and the balance of water are mixed to obtain the freeze-drying protective agent.
(4) And (3) adding the freeze-drying protective agent prepared in the step (3) into the bacterial sludge obtained in the step (2), wherein the weight of the freeze-drying protective agent is 3 times of that of the bacterial sludge, and after being uniformly mixed, carrying out vacuum freeze-drying to obtain the freeze-dried preparation.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. The application of Bifidobacterium breve (Bifidobacterium breve) CCFM683 in preparing products for protecting intestinal epithelial cell layers is characterized in that the preservation number of the Bifidobacterium breve CCFM683 is CGMCC No.11828.
2. The use according to claim 1, wherein the product is a pharmaceutical or nutraceutical product.
3. The use according to claim 2, wherein the medicament further comprises a pharmaceutical carrier and/or a pharmaceutical excipient.
4. Use according to claim 1, characterized in thatCharacterized in that the product is a microbial preparation containing the bifidobacterium breve CCFM683, and the number of the bifidobacterium breve CCFM683 in the microbial preparation is more than or equal to 1 x 10 10 CFU/g or 1X 10 10 CFU/mL。
5. The use according to claim 4, wherein the microbial agent is a suspension of Bifidobacterium breve CCFM 683.
6. The use according to claim 4, wherein the microbial agent is lyophilized powder of Bifidobacterium breve CCFM 683.
7. The use according to claim 5, wherein the bacterial suspension is prepared by a method comprising: inoculating the bifidobacterium breve CCFM683 into a seed culture medium for culture to obtain a seed solution; inoculating the seed solution into a fermentation culture medium for culture to obtain a cell culture solution; centrifuging the cell culture solution, and collecting bacterial sludge; and washing the bacterial sludge, and then re-suspending to obtain bacterial suspension.
8. The use of claim 6, wherein the lyophilized powder is prepared by: adding a freeze-drying protective agent into the bifidobacterium breve CCFM683 bacterial suspension to obtain a mixed solution; and (4) carrying out vacuum freeze drying on the mixed solution to obtain freeze-dried powder.
9. The use of any one of claims 1 to 8, wherein the protection of the intestinal epithelial cell layer comprises the alleviation and/or treatment of damage to the intestinal epithelial cell layer.
10. The use of claim 9, wherein the alleviation and/or treatment of damage to the epithelial cell layer of the gut comprises at least one of the following:
(1) Protection of epithelial cell integrity;
(2) Reducing the expression level of the epithelial cell apoptosis-promoting protein and up-regulating the expression level of the anti-apoptosis protein;
(3) Inhibiting epithelial cell apoptosis;
(4) Preventing translocation of intestinal bacteria through the epithelial cell layer.
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