© 2000 by The Society for Integrative and Comparative Biology
Evolution of the Cholecystokinin and Gastrin Peptides and Receptors1
1 Departments of Cell Biology and Medicine, Box 3709, Duke University Medical Center, Durham, North Carolina 27710
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 SYNOPSIS INTRODUCTIONEVOLUTION OF CHOLECYSTOKININ AND...EVOLUTION OF CHOLECYSTOKININ...CONCLUSIONSReferences |
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The intestinal hormone, cholecystokinin (CCK), and the stomach hormone, gastrin, form a simple two member family of peptides with much to offer students of hormone and receptor evolution. They share a common carboxyl-terminal tetrapeptide sequence, which is the bioactive site of each peptide and is also antigenic, making heterologous biological and immunological assays feasible. Current evidence indicates that CCK evolved in chordate ancestors and that gastrin-like peptides that separately regulate stomach functions evolved from an ancestral CCK at the level of the divergence of tetrapods from fish. This tentative conclusion may require modification when the two separate CCK- and gastrin-like peptides recently identified in the dogfish shark are characterized further. The CCK-X receptor appears to be ancestral to the CCK-A and CCK-B receptors identified in amniotes. The evolution of gastrin and of CCK-A and -B receptors may have played roles in the evolution of the stomach and the evolution of endothermy in vertebrate phylogeny.
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SYNOPSISINTRODUCTIONEVOLUTION OF CHOLECYSTOKININ AND...EVOLUTION OF CHOLECYSTOKININ...CONCLUSIONSReferences |
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Analysis of the evolution of peptide hormone families is a common goal of research in comparative endocrinology. Ideally, understanding the evolutionary changes in the structure of the peptides and their receptors can lead to understanding of the functional roles served by these regulatory systems in the adaptive success of the organisms. Unfortunately, this ideal is not always achieved in comparative endocrinological studies (Bern, 1972
) and this failure can sometimes be traced to the sheer complexity of the systems studied. The peptides cholecystokinin (CCK) and gastrin are members of a relatively simple peptide hormone family that has much to offer students of comparative endocrinology. One feature of this family that makes it attractive for comparative studies is its very simplicity; it only contains two members—CCK and gastrin (although the frog skin peptide, caerulein, can be considered a member of the CCK/gastrin family, it is a distant evolutionary side branch and will not be emphasized here; see below). In addition, although both peptides are expressed in multiple molecular forms, the active site in all species is identical, which greatly facilitates biological and receptor assays. Furthermore, the active site is antigenic and this has led to the widespread use of homologous and, especially important in comparative studies, heterologous radioimmunoassays. Heterologous radioimmunoassays are important for comparative studies because they can be used to follow the purification of new CCKs and gastrins from tissue extracts in a wide variety of species. Finally, the physiological roles of CCK and gastrin are fundamental to digestion, important to the adaptive success of all animals, and therefore are expected to be strongly conserved.
Cholecystokinin and gastrin are both candidate neurotransmitters as well as gastrointestinal hormones, but little is known of what roles they may have played in the evolution of the nervous system and so their roles as gastrointestinal hormones will be the focus of this review. The physiological actions of CCK and gastrin have been extensively studied in mammals but have been investigated little in nonmammalian species (reviewed in Vigna, 1983). However, the concept that gastrin primarily regulates the gastric phase of digestion whereas CCK is responsible for regulating the intestinal phase of digestion has emerged from studies in both mammals and nonmammals. Gastrin is secreted from gastric endocrine cells in response to eating a meal and regulates the secretion of gastric acid, the motility of the stomach, and perhaps also regulates the growth of the mucosal epithelium lining the body of the stomach. Cholecystokinin, on the other hand, is secreted from endocrine cells in the small intestine in response to meals and regulates gallbladder contraction, pancreatic enzyme secretion, gastric emptying, and perhaps the growth of the exocrine pancreas. Both hormones, while apparently regulating the activities of distinct segments of the gut, are important in coordinating the delivery of ingested food and potent exocrine secretions such as hydrochloric acid, bile, and digestive enzymes, to the appropriate segments of the gastrointestinal tract.
This review will emphasize the evolution of the structures of CCK, gastrin, and their receptors and the roles these structural changes may have played in the evolution of regulation of digestion in vertebrates, with emphasis on those features that result in the separate regulation of the gastric and intestinal phases of digestion by gastrin and CCK, respectively. Since, as will be seen, CCK is the ancestral member of the peptide family, most attention will be given to the evolution of gastrin and gastrin receptors from CCK-like ancestors.
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EVOLUTION OF CHOLECYSTOKININ AND GASTRIN |
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All biologically active forms of CCK and gastrin contain the same carboxyl-terminal tetrapeptide amide (-Trp-Met-Asp-Phe-NH2; Tables 1, 2) which is the molecular center of biological activity of the full peptides. This observation led Barrington and Dockray (1976)
to suggest that CCK and gastrin arose from an ancestral molecule by gene duplication and subsequent independent evolution. In mammals, the functionally important difference between the two peptides is in the position of the tyrosine residue adjacent to the active tetrapeptide domain. In all known forms of CCK, there is a tyrosine in the seventh position from the carboxyl terminus (Table 1) whereas in mammalian gastrins, the tyrosine is in the sixth position from the carboxyl terminus (Table 2). In addition, this tyrosine is always sulfated in CCKs but may or may not be sulfated in mammalian (and chicken) gastrins. It was previously thought that the position of the tyrosine residue was crucial in allowing CCK/gastrin receptors to differentiate CCK from gastrin, but this concept has now been discarded with the demonstration that all nonmammalian gastrins so far characterized have tyrosine in the seventh position from the carboxyl terminus (Table 2).
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The conclusion that CCK is the ancestral member of the CCK/gastrin molecular family is based on the highly conserved carboxyl-terminal amino acid sequences of all known CCKs (including the sulfated tyrosine in the seventh position from the carboxyl terminus), the discovery of a CCK-like peptide and not gastrin in a protochordate, Ciona (Johnsen and Rehfeld, 1990
), the finding that preproCCK has been more highly conserved during evolution than preprogastrin (Johnsen et al., 1997; Rourke et al., 1997), and the fact that CCK is expressed in the chordate intestine and the intestine predates the origin of the main source of gastrin, the stomach, in vertebrate phylogeny (Barrington, 1942). The question of when gastrin evolved from a CCK-like ancestral peptide, presumably by gene duplication and subsequent independent evolution, has been posed many times. The answer to the question previously seemed simple, but with the discovery of the cDNA and amino acid sequences of more nonmammalian CCKs and gastrins, it has become more complex. Using immunochemical techniques, Larsson and Rehfeld (1977) originally proposed that gastrin evolved from an ancestral CCK at the level of the divergence of reptiles and amphibia in vertebrate phylogeny. More recently, the structures of several nonmammalian gastrins and gastrin cDNAs have been determined (Table 2) and this new information has led to earlier estimates of when gastrin first evolved in vertebrate phylogeny. In particular, the isolation of separate bullfrog (Rourke et al., 1997) and dogfish shark (Johnsen et al., 1997) gastrin- and CCK-like peptides suggests that gastrin evolved much earlier than originally hypothesized. Johnsen (1998) has proposed that gastrin first arose in the lineage leading to chondrichthyeans which is also the group in which an acid-secreting stomach is thought to have first appeared (Barrington, 1942).
The structures of bullfrog and dogfish shark gastrins are particularly interesting (Table 2). Both peptides have all of the structural hallmarks of mammalian CCKs including the sulfated tyrosine residue in the seventh position from the carboxyl-terminus. Indeed, it has been demonstrated that bullfrog gastrin exhibits the receptor selectivity of mammalian CCK when tested in mammalian bioassay systems (Nielsen et al., 1998). However, when tested on bioassay systems in bullfrog tissues, bullfrog gastrin acts as a gastrin in the sense of exhibiting selectivity for gastric vs. pancreatic CCK receptors (Nielsen et al., 1998). These important findings suggest that a true gastrin in terms of having the ability to regulate gastric functions separately from CCK regulation of intestinal functions may have evolved in the amphibian lineage. Also, these results indicate that bullfrogs express at least two different CCK receptors with different agonist selectivities than mammalian CCK receptors (as discussed below). Shark gastrin presumably also will act like mammalian CCK in mammalian systems since it is identical in its carboxyl-terminal heptapeptide sequence to frog skin caerulein (Tables 1, 2). Frog skin caerulein is a CCK-like peptide (when tested in mammals) that is a defensive exocrine secretion with no gastrointestinal regulatory functions and clearly represents a side branch in vertebrate CCK/gastrin evolution (Wechselberger and Kreil, 1995). It will be important in future studies to examine the receptor selectivity of shark gastrin and CCK on shark CCK receptors.
It seems clear from the structures of the known vertebrate gastrins that gastrin evolved from CCK-like ancestral peptides by gene duplication and subsequent independent evolution by two different mechanisms. First, the carboxyl-terminal heptapeptide sequences of the nonmammalian gastrins could have evolved from an ancestral CCK by single or multiple base changes in the codon for the residue in the sixth position from the carboxyl terminus. Two of these amino acids, threonine in dogfish shark gastrin and alanine in bullfrog gastrin, have no effect on the CCK- vs. gastrin-like properties of the peptides in mammalian systems, but in the case of the bullfrog result in separate functions in bullfrogs. Further work is needed to establish whether the homologous CCK and gastrin act as separate peptides in dogfish sharks. Proline is the sixth amino acid from the carboxyl terminus of reptile and chicken gastrins. The tyrosine residue in the seventh position is unsulfated in reptiles and is variably sulfated in chickens. The nonsulfation of the tyrosine residue in reptilian gastrins confers a gastrin-like pattern of specificity to alligator gastrin (Oliver and Vigna, 1997) and the proline in the sixth position of sulfated chicken gastrin gives it its functional specificity (Dimaline and Lee, 1990).
A second mechanism must be invoked to explain the evolution of mammalian gastrins. Mammalian gastrins are unique among vertebrate gastrins in having a variably sulfated tyrosine residue in the sixth position from the carboxyl terminus (Table 2). Among the known CCK/gastrin structures, mammalian gastrins most closely resemble cionin, the protochordate CCK (Johnsen, 1998). The evolution of a putative primitive mammalian gastrin from an ancestral reptilian gastrin requires several nucleotide base changes as well as the introduction of gaps (Johnsen, 1998) and therefore is not easily explained. In any case, it is clear that the mechanism of evolution of mammalian gastrins is more complex than the evolution of the other vertebrate gastrins. An excellent analysis of the evolution of the CCK/gastrin peptide family has recently appeared (Johnsen, 1998).
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EVOLUTION OF CHOLECYSTOKININ RECEPTORS |
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SYNOPSISINTRODUCTIONEVOLUTION OF CHOLECYSTOKININ AND...EVOLUTION OF CHOLECYSTOKININ...CONCLUSIONSReferences |
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Mammalian CCK receptors are classified as CCK-A receptors (CCK-AR) and CCK-B receptors (CCK-BR) and are members of the G protein-coupled receptor (GPCR) superfamily. The type A receptors are specific for peptides sulfated at the tyrosine residue in the seventh position from the carboxyl terminus (all vertebrate CCKs; Table 3) and are expressed in several mammalian organs including the pancreas and gallbladder where they are involved in CCK-mediated regulation of the intestinal phase of digestion. The type B receptors have similarly high affinity for both sulfated and nonsulfated CCK and gastrin peptides (Table 3) and are expressed in several organs including the stomach where they mediate the gastrin-stimulated gastric phase of digestion. Before the structures of the mammalian receptors were determined, a separate gastrin receptor mediating gastric acid secretion was thought to be a third type of receptor in this family. However, subsequent cloning of the stomach gastrin receptor and the brain CCK-B receptor revealed their molecular identity, resulting in the classification of gastrin receptors as CCK-BR (Wank, 1995
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Cholecystokinin receptors appeared early in vertebrate phylogeny because saturable CCK binding has been observed in representative species of all vertebrate Classes from Agnatha to Mammals (Williams et al., 1985
; Vigna et al., 1986). It was proposed in 1986 on the basis of radioligand binding studies that ectothermic vertebrates express only one type of CCK receptor that is different from both the mammalian and avian (endotherm) CCK-AR and CCK-BR and that this ectotherm CCK receptor was ancestral to both CCK-A and -B receptors (Vigna et al., 1986). This putative ancestral CCK receptor subtype exhibited high affinity for sulfated CCKs and gastrins, but was indifferent to the sixth or seventh position from the carboxyl terminus of the sulfated tyrosine residue, and thus clearly differed in agonist selectivity from the endotherm CCK receptors. Subsequently, a cDNA from Xenopus laevis brain was characterized and shown to encode a novel CCK receptor termed the CCK-XL receptor (CCK-XR) (Schmitz et al., 1996). The agonist selectivity of the cloned CCK-XR closely matched that observed previously in radioligand binding studies using membrane preparations from ectotherms (Vigna et al., 1986) and thus the CCK-X receptor is a strong candidate to be the ancestral CCK receptor subtype from which the CCK-A and -B receptors evolved.
The proposal that the CCK-XR is ancestral to the CCK-A and -B receptors is also supported by comparison of the structures of the three CCK receptor subtypes (Table 4). It is clear that the mammalian CCK-B receptors are about 90% identical to each other in amino acid sequences and about 50% identical to mammalian CCK-A receptors. These similarities are typical of those seen in other GPCR families for species and subtype differences (Wank, 1995). In contrast, the cloned Xenopus CCK-XR is 55% identical to the rat CCK-AR and 56% identical to the human CCK-BR, indicating that it is a distinct CCK receptor subtype and is equally similar to both mammalian CCK receptor subtypes.
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Further support for the hypothesis that the CCK-XR is the ancestral member of the CCK receptor family came from radioligand binding studies of mako shark brain, gallbladder, stomach, and intestine membranes (Oliver and Vigna, 1996
). The same CCK-XR-like pattern of agonist selectivity was observed in all organs, indicating that a single subtype of CCK receptor corresponding to the pharmacological profile of the CCK-XR is expressed. However, it is impossible to prove that a single CCK receptor subtype is expressed in tissues by performing radioligand binding studies because this technique is not very well able to detect multiple CCK receptor subtypes in a single organ or tissue and because the endogenous mako shark CCK-like peptides are not available to perform homologous tests of specificity. Strong support for or against the hypothesis will only come from determining the structures of the receptors and their genes in future studies.
To test the hypothesis suggested earlier that CCK-AR and CCK-BR evolved in the lineage leading to endotherms (Vigna et al., 1986), we examined the agonist selectivities of alligator gallbladder and stomach CCK receptors by radioligand binding. We showed that the alligator gallbladder has a CCK-AR and a CCK-B-like receptor was observed in the alligator stomach (Oliver and Vigna, 1997). Thus, we have revised our estimate of when separate CCK-A and CCK-B receptors evolved from the ancestral CCK-XR from the endotherm lineage to the amniote lineage (Table 3). The alligator stomach receptor exhibited agonist selectivity patterns that are intermediate between the Xenopus CCK-XR and the mammalian CCK-BR, suggesting either that both receptors may be expressed in this organ or that the alligator stomach CCK receptor is an intermediate subtype. Notably, alligator gastrin had higher affinity for the stomach receptor than for the gallbladder receptor, suggesting that it does indeed regulate the gastric phase of digestion in alligators (Oliver and Vigna, 1997).
In an early study, the bullfrog brain and pancreas appeared to express a single subtype of CCK receptor consistent in its pharmacological profile with the CCK-XR (Vigna et al., 1984). This finding was supported by a study of the agonist specificity of a toad retina CCK receptor (Bone and Rosenzweig, 1988). However, it was later shown that the bullfrog gallbladder and stomach CCK receptors appear to represent separate CCK receptor subtypes (Nielsen et al., 1998). This apparent discrepancy may be explained by the use of different organs in the studies, the use of different techniques (radioligand binding in the brain/pancreas and retina studies and bioassay in the gallbladder/stomach study), or, more probably, by the use of the homologous bullfrog peptides in the more recent study. The question of whether the bullfrog gallbladder or stomach CCK receptors correspond pharmacologically to the CCK-XR cannot be answered because sulfated mammalian gastrins were not tested (Nielsen et al., 1998).
The nucleotide sequence similarities among the three cloned vertebrate CCK receptors, CCK-XR, CCK-AR, and CCK-BR, and the apparent expression of the CCK-XR in anamniote vertebrates and of the CCK-A and -B receptors in amniotes, suggests that the two separate amniote receptors evolved from the ancestral CCK-X receptor by gene duplication in the amniote lineage and subsequent independent evolution (Table 3).
It is clear that the major functional difference among the three receptors that may have been the critical feature in the selection pressure driving their evolution is the relative affinities of the receptors for gastrin. All three receptors exhibit high affinity for CCK whereas only the CCK-BR exhibits high affinity for mammalian gastrins (Table 3). Although the CCK-XR receptor has a high affinity for sulfated mammalian gastrins, it has a low affinity for the endogenous anamniote gastrins it encounters physiologically. Thus, some effort has been directed toward determining the sites or domains in the mammalian CCK-BR that confer high gastrin affinity and thus CCK/gastrin selectivity, resulting in the separate regulation of the intestinal and gastric phases of digestion by CCK and gastrin, respectively. Although no consensus has emerged, there is evidence that several sites clustered in the portion of the transmembrane domains adjacent to the cell surface (Kopin et al., 1995), in the amino-terminal one-third of the receptor (Schmitz et al., 1996), or in a pentapeptide segment in the second extracellular loop (Silvente-Poirot and Wank, 1996) are important determinants of CCK-BR selectivity for gastrin. Interestingly, the CCK-XR exhibits similarities to both the CCK-AR and CCK-BR in this pentapeptide sequence but is not identical to either (Schmitz et al., 1996), possibly reflecting the differences in gastrin affinity among the three receptor subtypes. It remains for future studies to determine the specific sites or domains in the CCK receptor subtypes that account for the evolution of their important physiological properties.
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SYNOPSISINTRODUCTIONEVOLUTION OF CHOLECYSTOKININ AND...EVOLUTION OF CHOLECYSTOKININ...CONCLUSIONSReferences |
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It now appears that gastrin evolved from a CCK-like ancestor earlier than in the amniote lineage as originally proposed (Larsson and Rehfeld, 1977
). Bullfrogs have a separate CCK and gastrin, although factors other than the carboxyl-terminal amino acid sequence of gastrin must be postulated to account for the selectivity of bullfrog gastrin for bullfrog stomach receptors, because bullfrog gastrin has the physiological properties of CCK when tested in mammals (Nielsen et al., 1998). This suggests that bullfrog gallbladder and stomach also have two different CCK receptors, although evidence from radioligand binding studies of bullfrog brain and pancreas and toad retina indicated that a single CCK-XR was expressed in those organs. A separate CCK and gastrin have also been described in dogfish shark, suggesting that the first evolution of gastrin occurred in the chondrichthyean lineage (Johnsen et al., 1997), although the ability of dogfish shark gastrin to regulate gut functions separately from CCK has not yet been demonstrated. The evidence currently available suggests that the CCK-XR found in anamniote vertebrates is ancestral to the amniote CCK-A and -B receptors which probably evolved from a CCK-X-like receptor by gene duplication and subsequent independent evolution, although this conclusion may require modification once the CCK receptors in such species as dogfish shark and bullfrog are structurally and functionally characterized.
Is it possible to envision a role for the evolution of the CCK and gastrin peptides and their receptors in the phylogeny of vertebrates? One landmark event in vertebrate evolution was the evolution of jaws from agnathan ancestors, which was followed by the first appearance of the stomach (Barrington, 1942) (although this concept may have to be modified in light of the description of a microphagous fossil agnathan with a gut structure interpreted to be a stomach; Wilson and Caldwell et al., 1993). It has been argued previously that the evolution of the stomach at this point in phylogeny may have been facilitated by regulatory mechanisms acting to restrict gastric secretions to periods when food was present in the stomach (Vigna, 1983). The evolution of the stomach and regulatory mechanisms to control it were accompanied by a great increase in the physical activity of primitive fishes as evidenced by the first appearance of paired appendages and a reduction of dermal armor (Denison, 1961), and this was in turn accompanied by a nearly explosive radiation of fishes in the Devonian. Thus, if gastrin first evolved in primitive chondrichthyeans as a new hormone able to regulate the gastric phase of digestion separately from the intestinal phase regulated by CCK, as suggested by the recent description of a separate CCK and gastrin in sharks (Johnsen et al., 1997), this may have facilitated a major advance in vertebrate phylogeny.
A second major landmark is the evolution of endothermy in vertebrates. Endothermy gives birds and mammals the capacity for more activity than ectotherms and an increased capacity for activity is a profound selective advantage (Bennett and Ruben, 1979). However, endothermy is accompanied by increased energetic costs. It has been shown that mammals have metabolic rates and therefore nutrient requirements exceeding those of extant reptiles by an order of magnitude and yet nutrient absorption rates per unit of intestinal surface area are approximately equal in these two groups (Karasov and Diamond et al., 1985). The main basis for the faster absorption of nutrients in mammals to fuel endothermy and increased activity relative to reptiles has been shown to be a much greater intestinal surface area in mammals (Karasov et al., 1986; Karasov and Diamond, 1985). In other words, mammals take in more food and process it much more quickly than do reptiles. It seems likely that the evolution of endothermy required the evolution of more efficient mechanisms of regulation of digestion to cope with the increased demands on the gastrointestinal tract. Endothermy has evolved at least three times in vertebrate phylogeny—in a presumed amniote ancestor common to dinosaurs (Bakker, 1972), birds, and mammals, and in the lamnid shark and tuna lineages (Oliver and Vigna, 1996). We have shown that CCK-A and -B receptors may have evolved from the ancestral CCK-XR in the amniote lineage. We pointed out earlier that the first appearance of two CCK receptors was necessary for the separate regulation of the gastric vs. the intestinal phases of digestion by gastrin and CCK, respectively. It seems likely that this increased efficiency of regulation of digestion may have played a role in the evolution of endothermy in the amniote lineage.
We also tested the hypothesis that the evolution of two separate CCK receptor subtypes was necessary for the evolution of endothermy by characterizing CCK receptors in an endothermic fish, the mako shark (Oliver and Vigna, 1996). However, we only found evidence for a single CCK-X type of CCK receptor in several mako shark organs and we concluded that the evolution of two separate CCK receptors is not part of the suite of characters necessary for the evolution of endothermy in fishes. Does this conclusion affect the hypothesis that CCK receptor evolution may have played a role in the evolution of endothermy in the amniote lineage? Not necessarily, because endothermy clearly evolved by different mechanisms in fishes and in amniotes. Endothermic fish do not generate heat by utilizing high metabolic rates in most body tissues as birds and mammals do, but instead retain metabolic heat by using countercurrent heat exchangers in the body musculature, stomach, eye, and brain (Oliver and Vigna, 1996). Thus, endothermic fish do not exhibit the same high metabolic rates found in birds and mammals and thus do not require the same high degree of digestive efficiency that the presence of two separate CCK receptors may provide in birds and mammals. In any case, the study of the evolution of CCK, gastrin, and their receptors provides an interesting example of the potential contribution of comparative endocrinological investigations to understanding vertebrate phylogeny.
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1 From the symposium A Tribute to Erika M. Plisetskaya: New Insights on the Function and Evolution of Gastroenteropancreatic Hormones presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 6–10 January 1999, at Denver, Colorado.
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