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60-510: OPG may refer to: Osteoprotegerin Office of the Public Guardian (disambiguation) Office of HM Paymaster General Online Policy Group Ontario Power Generation Open Government Partnership Optical parametric generator Orthopantomograph, a panoramic radiograph Orthopantogram or Panoramic radiograph Topics referred to by
120-451: A bone compartment separate from the general extracellular fluid. The osteoblasts are also connected by gap junctions , small pores that connect osteoblasts, allowing the cells in one cohort to function as a unit. The gap junctions also connect deeper layers of cells to the surface layer ( osteocytes when surrounded by bone). This was demonstrated directly by injecting low molecular weight fluorescent dyes into osteoblasts and showing that
180-594: A causal factor for abnormal bone remodeling during disease manifestation. This is a rare autosomal recessive disease that is associated with mutations in this gene. Osteoblast Osteoblasts (from the Greek combining forms for " bone ", ὀστέο-, osteo- and βλαστάνω, blastanō "germinate") are cells with a single nucleus that synthesize bone . However, in the process of bone formation , osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with
240-416: A closed system as mineral precipitates, acid accumulates, rapidly lowering the pH and stopping further precipitation. Cartilage presents no barrier to diffusion and acid therefore diffuses away, allowing precipitation to continue. In the osteon, where matrix is separated from extracellular fluid by tight junctions, this cannot occur. In the controlled, sealed compartment, removing H drives precipitation under
300-526: A decoy receptor for RANKL, OPG inhibits RANK-RANKL interactions thus suppressing osteoclastogenesis and bone resorption. OPG is also a decoy receptor for TRAIL, another regulator of osteoclastogenesis in osteoclast precursor cells and an autocrine signal for mature osteoclast cell death. TRAIL induces osteoclastogenesis by binding to specific TRAIL receptors on osteoclast precursor cell surfaces, inducing TRAF6 signalling, activating NF-κB signalling and upregulating NFATc1 expression. During osteoclastogenesis
360-485: A key enzyme that provides high concentrations of phosphate at the mineral deposition site. Key growth factors in endochondral skeletal differentiation include bone morphogenetic proteins (BMPs) that determine to a major extent where chondrocyte differentiation occurs and where spaces are left between bones. The system of cartilage replacement by bone has a complex regulatory system. BMP2 also regulates early skeletal patterning. Transforming growth factor beta (TGF-β),
420-404: A protein that inhibits a pathway that maintains osteoblast activity. Thus, when the osteon reaches a limiting size, it deactivates bone synthesis. Hematoxylin and eosin staining (H&E) shows that the cytoplasm of active osteoblasts is slightly basophilic due to the substantial presence of rough endoplasmic reticulum . The active osteoblast produces substantial collagen type I. About 10% of
480-419: A role in tumour growth and metastasis, heart disease, immune system development and signalling, mental health, diabetes, and the prevention of pre-eclampsia and osteoporosis during pregnancy. OPG is largely expressed by osteoblast lineage cells of bone, epithelial cells of the gastrointestinal tract, lung, breast and skin, vascular endothelial cells, as well as B-cells and dendritic cells in
540-421: A strain and recover its shape without damage. This is called elastic deformation . Forces that exceed the capacity of bone to behave elastically may cause failure, typically bone fractures . Bone is a dynamic tissue that is constantly being reshaped by osteoblasts , which produce and secrete matrix proteins and transport mineral into the matrix, and osteoclasts , which break down the tissues. Osteoblasts are
600-419: A wide variety of extracellular conditions, as long as calcium and phosphate are available in the matrix compartment. The mechanism by which acid transits the barrier layer remains uncertain. Osteoblasts have capacity for Na /H exchange via the redundant Na/H exchangers, NHE1 and NHE6. This H exchange is a major element in acid removal, although the mechanism by which H is transported from the matrix space into
660-721: Is a cytokine receptor of the tumour necrosis factor (TNF) receptor superfamily encoded by the TNFRSF11B gene. OPG was first discovered as a novel secreted TNFR related protein that played a role in the regulation of bone density and later for its role as a decoy receptor for receptor activator of nuclear factor kappa-B ligand ( RANKL ). OPG also binds to TNF-related apoptosis-inducing ligand ( TRAIL ) and inhibits TRAIL induced apoptosis of specific cells, including tumour cells. Other OPG ligands include syndecan-1 , glycosaminoglycans , von Willebrand factor , and factor VIII -von Willebrand factor complex. OPG has been identified as having
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#1732851670837720-399: Is a common cause of osteoporosis that can be seen in other conditions such as ovariectomy, ovarian failure, anorexia, and hyperprolactinaemia. Osteoblastic synthesis of bone does not increase to compensate for the accelerated bone resorption as the lower estrogen levels result in increased rates of osteoblast apoptosis . The higher rate of bone resorption compared to bone formation leads to
780-447: Is a critical pathway in maintaining the symbiosis between bone resorption by osteoclasts and bone formation by osteoblasts. RANKL is released by osteoblast lineage cells and binds to receptor RANK on the surface of osteoclast progenitor cells RANK-RANKL binding activates the nuclear factor kappa B (NF-κB) pathway resulting in the upregulation of the transcription factor nuclear factor of activated T-cells cytoplasmic 1 ( NFATc1 ). NFATc1
840-432: Is a large organ that is formed and degraded throughout life in the air-breathing vertebrates. The skeleton, often referred to as the skeletal system, is important both as a supporting structure and for maintenance of calcium, phosphate, and acid-base status in the whole organism. The functional part of bone, the bone matrix , is entirely extracellular. The bone matrix consists of protein and mineral . The protein forms
900-465: Is a master regulator for the expression of essential cytokines during the differentiation of osteoclast precursor cells into mature osteoclasts, known as osteoclastogenesis. Mature osteoclasts then bind to bone through tight junctions and release digestive enzymes to resorb the old bone. As bone is resorbed, collagen and minerals are released into the local microenvironment creating both the space and minerals needed for osteoblasts to lay down new bone. As
960-410: Is a specific marker for bone matrix synthesis. These proteins link organic and mineral component of bone matrix. The proteins are necessary for maximal matrix strength due to their intermediate localization between mineral and collagen. However, in mice where expression of osteocalcin or osteopontin was eliminated by targeted disruption of the respective genes ( knockout mice ), accumulation of mineral
1020-484: Is a type of cancer involving malignant plasma cells, called myeloma cells, within the bone marrow. Multiple myeloma is associated with osteolytic bone lesions as the usually high levels of OPG in the bone marrow are diminished resulting in increased osteoclastic absorption. The reduced OPG in multiple myeloma is caused by suppression of both constitutive OPG transcription and the OPG inducing cytokines TGF-β and Wnt. In addition,
1080-566: Is also modified for reproduction and in response to nutritional and other hormone stresses; it responds to steroids , including estrogen and glucocorticoids , which are important in reproduction and energy metabolism regulation. Bone turnover involves major expenditures of energy for synthesis and degradation, involving many additional signals including pituitary hormones. Two of these are adrenocorticotropic hormone (ACTH) and follicle stimulating hormone . The physiological role for responses to these, and several other glycoprotein hormones,
1140-453: Is clearly distinct from the phylogenetically older process by which cartilage is mineralized: tetracycline does not label mineralized cartilage at narrow bands or in specific sites, but diffusely, in keeping with a passive mineralization mechanism. Osteoblasts separate bone from the extracellular fluid by tight junctions by regulated transport. Unlike in cartilage, phosphate and calcium cannot move in or out by passive diffusion, because
1200-439: Is different from Wikidata All article disambiguation pages All disambiguation pages Osteoprotegerin 4982 18383 ENSG00000164761 ENSMUSG00000063727 O00300 O08712 NM_002546 NM_008764 NP_002537 NP_032790 Osteoprotegerin ( OPG ), also known as osteoclastogenesis inhibitory factor ( OCIF ) or tumour necrosis factor receptor superfamily member 11B ( TNFRSF11B ),
1260-408: Is essential to support the metabolic activity of bone. The balance of bone formation and bone resorption tends to be negative with age, particularly in post-menopausal women, often leading to a loss of bone serious enough to cause fractures, which is called osteoporosis . Bone is formed by one of two processes: endochondral ossification or intramembranous ossification . Endochondral ossification
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#17328516708371320-445: Is not a significant mechanism supporting osteoblast bone formation, except in the condition of low dietary calcium; further, abnormally high dietary calcium raises the risk of serious health consequences not directly related to bone mass including heart attack and stroke . Intermittent PTH stimulation increases osteoblast activity, although PTH is bifunctional and mediates bone matrix degradation at higher concentrations. The skeleton
1380-422: Is not dense or strong. In the air breathing vertebrates it is used as a scaffold for formation of cellular bone made by osteoblasts, and then it is removed by osteoclasts , which specialize in degrading mineralized tissue. Osteoblasts produce an advanced type of bone matrix consisting of dense, irregular crystals of hydroxyapatite , packed around the collagen ropes. This is a strong composite material that allows
1440-572: Is not fully understood, although it is likely that ACTH is bifunctional, like PTH, supporting bone formation with periodic spikes of ACTH, but causing bone destruction in large concentrations. In mice, mutations that reduce the efficiency of ACTH-induced glucocorticoid production in the adrenals cause the skeleton to become dense ( osteosclerotic bone). In well-preserved bone studied at high magnification via electron microscopy , individual osteoblasts are shown to be connected by tight junctions , which prevent extracellular fluid passage and thus create
1500-404: Is often triggered in post-menopausal women due to reduced estrogen levels associated with the depletion of hormone-releasing ovarian follicles. Decreasing estrogen levels result in the downregulation of OPG expression and reduced inhibition of RANKL. Therefore RANKL can more readily bind to RANK and cause the increased osteoclastogenesis and bone resorption seen in osteoporosis. Decreased estrogen
1560-467: Is part of a superfamily of proteins that include BMPs, which possess common signaling elements in the TGF beta signaling pathway . TGF-β is particularly important in cartilage differentiation, which generally precedes bone formation for endochondral ossification. An additional family of essential regulatory factors is the fibroblast growth factors (FGFs) that determine where skeletal elements occur in relation to
1620-447: Is the adult skeleton in cartilaginous fishes such as sharks . It develops as the initial skeleton in more advanced classes of animals. In air-breathing vertebrates, cartilage is replaced by cellular bone. A transitional tissue is mineralized cartilage . Cartilage mineralizes by massive expression of phosphate-producing enzymes, which cause high local concentrations of calcium and phosphate that precipitate. This mineralized cartilage
1680-413: Is the process of forming bone from cartilage and this is the usual method. This form of bone development is the more complex form: it follows the formation of a first skeleton of cartilage made by chondrocytes , which is then removed and replaced by bone, made by osteoblasts. Intramembranous ossification is the direct ossification of mesenchyme as happens during the formation of the membrane bones of
1740-429: The bone mineral , that is deposited in a highly regulated manner, into the inorganic matrix forming a strong and dense mineralized tissue , the mineralized matrix. The mineralized skeleton is the main support for the bodies of air breathing vertebrates . It is also an important store of minerals for physiological homeostasis including both acid-base balance and calcium or phosphate maintenance. The skeleton
1800-451: The organic matrix. It is synthesized and then the mineral is added. The vast majority of the organic matrix is collagen , which provides tensile strength . The matrix is mineralized by deposition of hydroxyapatite (alternative name, hydroxylapatite). This mineral is hard, and provides compressive strength . Thus, the collagen and mineral together are a composite material with excellent tensile and compressive strength, which can bend under
1860-432: The tight osteoblast junctions isolate the bone formation space. Calcium is transported across osteoblasts by facilitated transport (that is, by passive transporters, which do not pump calcium against a gradient). In contrast, phosphate is actively produced by a combination of secretion of phosphate-containing compounds, including ATP , and by phosphatases that cleave phosphate to create a high phosphate concentration at
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1920-546: The absence of aromatase enzymes converting testosterone into estrogen, testosterone and DHT downregulate OPG mRNA expression. OPG plays an important role in bone metabolism as a decoy receptor for RANKL in the RANK/RANKL/OPG axis, inhibiting osteoclastogenesis and bone resorption. OPG has also been shown to bind and inhibit TNF-related apoptosis-inducing ligand (TRAIL) which is responsible for inducing apoptosis in tumour, infected and mutated cells. The RANK/RANKL/OPG axis
1980-403: The barrier osteoblast is not known. In bone removal, a reverse transport mechanism uses acid delivered to the mineralized matrix to drive hydroxyapatite into solution. Feedback from physical activity maintains bone mass, while feedback from osteocytes limits the size of the bone-forming unit. An important additional mechanism is secretion by osteocytes, buried in the matrix, of sclerostin ,
2040-1001: The bone and release cytokines such as parathyroid hormone-related protein (PTHrP), IL-8 and PGE2 . These cytokines act on osteoblasts to increase RANKL and decrease OPG expression resulting in excess bone resorption. During resorption osteoclasts release nutrients such as growth factors and calcium from the mineralised bone matrix which cultivates a supportive environment for the proliferation and survival of tumour cells. Most bone metastases result in osteolytic lesions, however prostate cancer causes osteoblastic lesions characterised by excess bone formation and high bone density. Prostate cancer releases cytokines such as insulin-like growth factor (IGF), endothelin-1 , bone morphogenetic proteins (BMPs), sclerostin and Wnt proteins that act on local bone to increase osteoblast proliferation and activity. Wnt proteins also act on osteoblasts to upregulate OPG expression through β-catenin signalling and suppress osteoclastic bone resorption. Multiple myeloma
2100-427: The bone made by a unit of cells is usually called the osteon . Osteoblasts are specialized, terminally differentiated products of mesenchymal stem cells . They synthesize dense, crosslinked collagen and specialized proteins in much smaller quantities, including osteocalcin and osteopontin , which compose the organic matrix of bone. In organized groups of disconnected cells, osteoblasts produce hydroxyapatite ,
2160-457: The bone matrix is collagen with the balance mineral. The osteoblast's nucleus is spherical and large. An active osteoblast is characterized morphologically by a prominent Golgi apparatus that appears histologically as a clear zone adjacent to the nucleus. The products of the cell are mostly for transport into the osteoid, the non-mineralized matrix. Active osteoblasts can be labeled by antibodies to Type-I collagen , or using naphthol phosphate and
2220-529: The bone-forming unit is not actively synthesizing bone, the surface osteoblasts are flattened and are called inactive osteoblasts . Osteocytes remain alive and are connected by cell processes to a surface layer of osteoblasts. Osteocytes have important functions in skeletal maintenance. Osteoclasts are multinucleated cells that derive from hematopoietic progenitors in the bone marrow which also give rise to monocytes in peripheral blood. Osteoclasts break down bone tissue, and along with osteoblasts and osteocytes form
2280-432: The cell nucleus where it binds an estrogen response element in the promoter region of the OPG gene to upregulate OPG mRNA transcription. Estrogens can also post-transcriptionally regulate OPG protein expression through the suppression of the microRNA (miRNA) miR-145. miR-145 binds miRNA binding sites in the 3’UTR of OPG mRNA transcripts and suppresses the translation of OPG proteins. Estrogen binds its ER-β receptor on
2340-448: The cell surface to suppress many miRNAs, including miR-145, thus blocking inhibition of OPG mRNA translation. Estrogen suppresses osteoclastogenesis through the upregulation of OPG expression in osteoblast lineage cells. Androgens such as testosterone and DHT also inhibit osteoclastogenesis, however androgens act directly through androgen receptors on osteoclast precursor cells without affecting OPG expression in osteoblasts. Further, in
2400-513: The contiguous group of bone-forming osteoblasts. They occur at a narrow (sub- micrometer ) mineralization front. Most bone surfaces express no new bone formation, no tetracycline uptake and no mineral formation. This strongly suggests that facilitated or active transport , coordinated across the bone-forming group, is involved in bone formation, and that only cell-mediated mineral formation occurs. That is, dietary calcium does not create mineral by mass action. The mechanism of mineral formation in bone
2460-602: The different TRAIL receptors on the cell surface change resulting in an increase of apoptosis inducing TRAIL receptors expressed on mature osteoclasts. As a decoy receptor for both RANKL and TRAIL, OPG simultaneously suppresses osteoclastogenesis while also inhibiting TRAIL induced cell death of mature osteoclast cells. OPG has an equally high affinity for RANKL and TRAIL suggesting that it is equally effective at blocking osteoclastogenesis and inhibiting osteoclast apoptosis. A normal steady state of bone metabolism seems to be present in patients with atrophic nonunion fractures, despite
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2520-446: The dimerisation of OPG. Domain 7 is a C-terminal heparin-binding domain ending with a cysteine (Cys-400) which also plays an important role in the dimerisation of OPG. OPG expression can be upregulated by IL-1β, 1α,25(OH) 2 D 3 , Wnt/β-catenin signalling through Wnt16, Wnt4 and Wnt3a TNFα and estrogen. OPG expression can also be upregulated transcriptionally through DNA binding sites for estrogen receptor α (ER-α) and TCF in
2580-453: The dye diffused to surrounding and deeper cells in the bone-forming unit. Bone is composed of many of these units, which are separated by impermeable zones with no cellular connections, called cement lines. Almost all of the organic (non-mineral) component of bone is dense collagen type I, which forms dense crosslinked ropes that give bone its tensile strength. By mechanisms still unclear, osteoblasts secrete layers of oriented collagen, with
2640-590: The efficacy of OPG in bone marrow is impeded with multiple myeloma by excessive binding to syndecan-1 . OPG binds to syndecan-1 on the surface of normal and multiple myeloma plasma cells to be internalised and degraded. However the overabundance of proliferating myeloma cells results in the excessive binding and inhibition of OPG by syndecan-1. Simultaneously, multiple myeloma is associated with unusually high levels of osteoclastogenesis-inducing factors. The decreased OPG transcription and increased OPG protein degradation combined with increased osteoclastogenesis result in
2700-426: The high serum OPG. Only serum OPG was significantly higher in the patients compared to healed and healing controls. (49) Osteoporosis is a bone-related disease caused by increased rates of bone resorption compared to bone formation. A higher rate of resorption is often caused by increased osteoclastogenesis and results in symptoms of osteopenia such as excessive bone loss and low bone mineral density. Osteoporosis
2760-688: The immune system. OPG is a soluble glycoprotein which can be found as either a 60-kDa monomer or a 120-kDa dimer linked by disulfide bonds . The dimerisation of OPG is necessary for RANK-RANKL inhibition as dimerisation increases the affinity of OPG for RANKL (from a K D of 3 μM as a monomer to 10nM as a dimer). As a monomer, OPG would have insufficient affinity for RANKL to compete with RANK and effectively suppress RANK-RANKL interactions. OPG proteins are made up of 380 amino acids which form seven functional domains. Domains 1-4 are cysteine-rich N-terminal domains that interact with RANKL during binding. Domains 5-6 are death domains that contribute to
2820-562: The increased porosity and low bone mineral density of individuals with osteoporosis. Tumour endothelial cells have been found to express higher levels of OPG when compared to normal endothelial cells. When in contact with tumour cells, endothelial cells express higher levels of OPG in response to integrin α v β 3 ligation and the stimulation of NF-kB signalling. OPG expression has been found to promote tumour growth and survival through driving tumour vascularisation and inhibiting TRAIL-induced apoptosis. OPG has been identified as one of
2880-482: The layers parallel to the long axis of the bone alternating with layers at right angles to the long axis of the bone every few micrometers . Defects in collagen type I cause the commonest inherited disorder of bone, called osteogenesis imperfecta . Minor, but important, amounts of small proteins, including osteocalcin and osteopontin , are secreted in bone's organic matrix. Osteocalcin is not expressed at significant concentrations except in bone, and thus osteocalcin
2940-409: The major cellular component of bone. Osteoblasts arise from mesenchymal stem cells (MSC). MSC give rise to osteoblasts, adipocytes , and myocytes among other cell types. Osteoblast quantity is understood to be inversely proportional to that of marrow adipocytes which comprise marrow adipose tissue (MAT) . Osteoblasts are found in large numbers in the periosteum , the thin connective tissue layer on
3000-510: The many pro-angiogenic factors involved in the vascularisation of tumours. Tumour angiogenesis is required for tumour growth and movement as it supplies the tumour with nutrients and allows metastatic cells to enter the bloodstream. As a decoy receptor for TRAIL, OPG also promotes tumour cell survival by inhibiting TRAIL-induced apoptosis of tumour cells. Bone is a common site of metastasis in cancers such as breast, prostate and lung cancer. In osteolytic bone metastases, tumour cells migrate to
3060-411: The mineralization front. Alkaline phosphatase is a membrane-anchored protein that is a characteristic marker expressed in large amounts at the apical (secretory) face of active osteoblasts. At least one more regulated transport process is involved. The stoichiometry of bone mineral basically is that of hydroxyapatite precipitating from phosphate, calcium, and water at a slightly alkaline pH : In
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#17328516708373120-549: The osteolytic lesions that are characteristic of multiple myeloma. Otosclerosis is a disorder of the middle ear, characterized by abnormal bone growth at the foot plate of the stapes which affect its mobility, resulting in progressive hearing loss. OPG gene polymorphisms c.9C>G and c.30+15C> have shown genetic association with OTSC in Indian and Tunisian populations. Some of the reports have shown significantly reduced or missing OPG expression in otosclerotic tissues which might be
3180-415: The outside surface of bones, and in the endosteum . Normally, almost all of the bone matrix, in the air breathing vertebrates , is mineralized by the osteoblasts. Before the organic matrix is mineralized, it is called the osteoid . Osteoblasts buried in the matrix are called osteocytes . During bone formation, the surface layer of osteoblasts consists of cuboidal cells, called active osteoblasts . When
3240-438: The promoter region of the OPG gene. Downregulation of OPG can be effected by TGF-β1, PTH and DNA methylation of a CpG island in the OPG gene. OPG expression in osteoblast lineage cells is highly regulated by estrogens such as estradiol (E2). E2 transcriptionally regulates OPG expression through binding estrogen receptors (predominantly ER-α) on osteoblast lineage cell surfaces. The E2-ERα complex then translocates into
3300-403: The same term [REDACTED] This disambiguation page lists articles associated with the title OPG . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=OPG&oldid=1213874050 " Category : Disambiguation pages Hidden categories: Short description
3360-412: The skeleton to be shaped mainly as hollow tubes. Reducing the long bones to tubes reduces weight while maintaining strength. The mechanisms of mineralization are not fully understood. Fluorescent, low-molecular weight compounds such as tetracycline or calcein bind strongly to bone mineral, when administered for short periods. They then accumulate in narrow bands in the new bone. These bands run across
3420-585: The skin Many other regulatory systems are involved in the transition of cartilage to bone and in bone maintenance. A particularly important bone-targeted hormonal regulator is parathyroid hormone (PTH). Parathyroid hormone is a protein made by the parathyroid gland under the control of serum calcium activity. PTH also has important systemic functions, including to keep serum calcium concentrations nearly constant regardless of calcium intake. Increasing dietary calcium results in minor increases in blood calcium. However, this
3480-494: The skull and others. During osteoblast differentiation , the developing progenitor cells express the regulatory transcription factor Cbfa1/Runx2 . A second required transcription factor is Sp7 transcription factor . Osteochondroprogenitor cells differentiate under the influence of growth factors , although isolated mesenchymal stem cells in tissue culture may also form osteoblasts under permissive conditions that include vitamin C and substrates for alkaline phosphatase ,
3540-408: The structural components of bone. In the hollow within bones are many other cell types of the bone marrow . Components that are essential for osteoblast bone formation include mesenchymal stem cells (osteoblast precursor) and blood vessels that supply oxygen and nutrients for bone formation. Bone is a highly vascular tissue, and active formation of blood vessel cells, also from mesenchymal stem cells,
3600-509: Was not notably affected, indicating that organization of matrix is not significantly related to mineral transport. The primitive skeleton is cartilage , a solid avascular (without blood vessels) tissue in which individual cartilage-matrix secreting cells, or chondrocytes , occur. Chondrocytes do not have intercellular connections and are not coordinated in units. Cartilage is composed of a network of collagen type II held in tension by water-absorbing proteins, hydrophilic proteoglycans . This
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