Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/52—Cytokines; Lymphokines; Interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
  • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence

Definitions

• the field of this invention is polypeptide molecules which regulate cell function, nucleic acid sequences encoding the polypeptides, and methods of using the nucleic acid sequences and the polypeptides.
• Tumor necrosis factor-alpha is a cytokine primarily produced by activated macrophages. TNF-alpha stimulates T-cell and B-cell proliferation and induces expression of adhesion molecules on endothelial cells. This cytokine also plays an important role in host defense to infection.
• TNF-alpha activities are mediated through two distinct receptors, TNFR-p55 and TNFR-p75. These two receptors also mediate activities triggered by soluble lymphotoxin-alpha (LT-alpha) secreted mainly by activated lymphocytes.
• LT-alpha soluble lymphotoxin-alpha
• Specific stimulation of TNFR-p55 induces TNF activities such as in vitro tumor cell cytotoxicity, expression of adhesion molecules on endothelial cells and keratinocytes, activation of sphingomyelinase with concomitant increases of ceramide, activation of NF-kappaB and induction of manganese superoxide dismutase mRNA.
• Specific stimulation of TNFR- p75 results in proliferative response of mouse and human thymocytes and cytoxic T cells, fibroblasts and natural killer cells and in GM-CSF secretion in PC60 cells.
• TNF gamma.-interferon
• IFN-. gamma. gamma.-interferon
• TNF-. alpha gamma.-interferon
• antitumor therapy have been disappointing, however, because the toxic side effects of TNF have prevented obtaining effective dose levels in man.
• These toxic side effects have been attributed to TNF binding to the TNFR-p75 receptor while the cytotoxic activity on malignant cells has been attributed to binding of TNF to the TNFR-p55 receptor.
• the subject invention is a molecule that is homologous to tumor necrosis factor (TNF).
• TNF tumor necrosis factor
• the invention provides methods and compositions relating to the molecule, HUMAN NTN-2 polypeptide, and related nucleic acids. Included are polypeptides comprising a HUMAN NTN-2-specific domain and having HUMAN NTN-2 -specific activity. The polypeptides may be produced recombinantly from transformed host cells with the subject nucleic acids.
• the invention provides binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis (e.g., genetic hybridization screens for HUMAN NTN-2 transcripts), therapy (e.g., gene therapy to modulate HUMAN NTN-2 gene expression) and in the biopharmaceutical industry (e.g., reagents for screening chemical libraries for lead pharmacological agents).
• diagnosis e.g., genetic hybridization screens for HUMAN NTN-2 transcripts
• therapy e.g., gene therapy to modulate HUMAN NTN-2 gene expression
• biopharmaceutical industry e.g., reagents for screening chemical libraries for lead pharmacological agents.
• Preferred uses for the subject HUMAN NTN-2 polypeptides include modifying the physiology of a cell comprising an extracellular surface by contacting the cell or medium surrounding the cell with an exogenous HUMAN NTN-2 polypeptide under conditions whereby the added polypeptide specifically interacts with a component of the medium and/ or the extracellular surface to effect a change in the physiology of the cell.
• Also preferred are methods for screening for biologically active agents which methods involve incubating a HUMAN NTN-2 polypeptide in the presence of an extracellular HUMAN NTN-2 polypeptide-specific binding target and a candidate agent, under conditions whereby, but for the presence of the agent, the polypeptide specifically binds the binding target at a reference affinity; detecting the binding affinity of the polypeptide to the binding target to determine an agent-biased affinity, wherein a difference between the agent-biased affinity and the reference affinity indicates that the agent modulates the binding of the polypeptide to the binding target.
• HUMAN NTN-2 Based upon its homology to TNF, it is expected that HUMAN NTN-2 will be a mediator of immune regulation and inflammatory response, closely linked to the development of disease. It may be useful for regulating development, proliferation and death of cells of the lymphoid, hematopoitic and other lineages. Also, HUMAN NTN-2 may be of use in the prevention of septic shock, autoimmune disorders and graft-host disease. Furthermore, HUMAN NTN-2 polypeptide may be used to identify its receptor.
• FIGURE 1 Northern analysis of various human tissue specific RNAs using a 608 nucleotide fragment of the HUMAN NTN-2 sequence as a probe.
• Lanes 1 - 8 in order as follows: Heart, Brain, Placenta, Lung, Liver, Skeletal Muscle, Kidney and Pancreas.
• the invention provides HUMAN NTN-2 polypeptide which includes natural HUMAN NTN-2 polypeptide and recombinant polypeptides comprising a HUMAN NTN-2 amino acid sequence, or a functional HUMAN NTN-2 polypeptide domain thereof having an assay-discernable HUMAN NTN-2-specific activity.
• the polypeptides may be deletion mutants of the disclosed natural HUMAN NTN-2 polypeptides and may be provided as fusion products, e.g., with non- HUMAN NTN-2 polypeptides.
• the subject HUMAN NTN-2 polypeptide domains have HUMAN NTN-2-specific activity or function.
• HUMAN NTN-2 may be useful in the study and treatment of conditions similar to those which are treated using TNF.
• the HUMAN NTN-2 cDNA may be useful as a diagnostic tool, such as through use of antibodies in assays for polypeptides in cell lines or use of oligonucleotides as primers in a PCR test to amplify those with sequence similarities to the oligonucleotide primer, and to see how much HUMAN
• HUMAN NTN-2 is present.
• the isolation of HUMAN NTN-2 also provides the key to isolate its putative receptor, other HUMAN NTN-2 binding polypeptides, and/or study its antagonistic properties.
• HUMAN NTN-2-specific activity or function may be determined by convenient in vitro, cellbased, or in vivo assays - e.g., in vitro binding assays, cell culture assays, in animals (e.g., immune response, gene therapy, transgenics, etc.), etc. Binding assays encompass any assay where the specific molecular interaction of a HUMAN NTN-2 polypeptide with a binding target is evaluated.
• the binding target may be a natural binding target, or a non-natural binding target such as a specific immune polypeptide such as an antibody, or a HUMAN NTN-2 specific agent such as those identified in assays described below.
• the claimed polypeptides may be isolated or pure - an "isolated" polypeptide is one that is no longer accompanied by some of the material with which it is associated in its natural state, and that preferably constitutes at least about 0.5%, and more preferably at least about 5% by weight of the total polypeptide in a given sample; a "pure" polypeptide constitutes at least about 90%, and preferably at least about 99% by weight of the total polypeptide in a given sample.
• the subject polypeptides and polypeptide domains may be synthesized, produced by recombinant technology, or purified from cells.
• the subject polypeptides find a wide variety of uses including use as immunogens, targets in screening assays, bioactive reagents for modulating cell growth, differentiation and /or function, etc.
• the invention provides methods for modifying the physiology of a cell comprising an extracellular surface by contacting the cell or medium surrounding the cell with an exogenous HUMAN NTN-2 polypeptide under conditions whereby the added polypeptide specifically interacts with a component of the medium and /or the extracellular surface to effect a change in the physiology of the cell.
• the extracellular surface includes plasma membrane-associated receptors;
• the exogenous HUMAN NTN-2 refers to a polypeptide not made by the cell or, if so, expressed at non-natural levels, times or physiologic locales; and suitable media include in vitro culture media and physiological fluids such as blood, synovial fluid, etc.
• the polypeptides may be may be introduced, expressed, or repressed in specific populations of cells by any convenient way such as microinjection, promoter-specific expression of recombinant enzyme, targeted delivery of lipid vesicles, etc.
• HUMAN NTN-2-specific binding agents include HUMAN NTN-2-specific receptors, such as somatically recombined protein receptors like specific antibodies or T-cell antigen receptors (See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory) and also includes other natural binding agents identified with assays such as one-, two- and three- hybrid screens, and non-natural binding agents identified in screens of chemical libraries such as described below. Agents of particular interest modulate HUMAN NTN-2 function.
• the invention provides HUMAN NTN-2 nucleic acids, which find a wide variety of applications including use as translatable transcripts, hybridization probes, PCR primers, diagnostic nucleic acids, etc., as well as use in detecting the presence of HUMAN NTN-2 genes and gene transcripts and in detecting or amplifying nucleic acids encoding additional HUMAN
• the subject nucleic acids are of synthetic/non-natural sequences and/or are isolated, i.e., no longer accompanied by some of the material with which it is associated in its natural state, preferably constituting at least about 0.5%, more preferably at least about 5% by weight of total nucleic acid present in a given fraction, and usually recombinant, meaning they comprise a non- natural sequence or a natural sequence joined to nucleotide(s) other than that which it is joined to on a natural chromosome.
• Nucleic acids comprising the nucleotide sequence disclosed herein and fragments thereof contain such sequence or fragment at a terminus, immediately flanked by a sequence other than that to which it is joined on a natural chromosome, or flanked by a native flanking region fewer than 10 kb, preferably fewer than 2 kb, which is immediately flanked by a sequence other than that to which it is joined on a natural chromosome. While the nucleic acids are usually RNA or DNA, it is often advantageous to use nucleic acids comprising other bases or nucleotide analogs to provide modified stability, etc.
• amino acid sequences of the disclosed HUMAN NTN-2 polypeptide is used to back translate HUMAN NTN-2 polypeptide-encoding nucleic acids optimized for selected expression systems (Holler, et al. (1993) Gene 136: 323- 328; Martin, et al. (1995) Gene 154: 150-166) or used to generate degenerate oligonucleotide primers and probes for use in the isolation of natural
• HUMAN NTN-2 encoding nucleic acid sequences (“GCG” software, Genetics Computer Group, Inc., Madison, WI).
• HUMAN NTN-2 encoding nucleic acids may be part of expression vectors and may be incorporated into recombinant host cells, e.g., for expression and screening, for transgenic animals, for functional studies such as the efficacy of candidate drugs for disease associated with HUMAN NTN-2 mediated signal transduction, etc.
• Expression systems are selected and /or tailored to effect HUMAN NTN-2 polypeptide structural and functional variants through alternative post- translational processing.
• the invention also provides for nucleic acid hybridization probes and replication /amplification primers having a HUMAN NTN-2 cDNA specific sequence and sufficient to effect specific hybridization with SEQ. I.D. NO. 1.
• Demonstrating specific hybridization generally requires stringent conditions, for example, hybridizing in a buffer comprising 30% formamide in 5 x SSPE (0.18 M NaCl, 0.01 M NaP0 4 , pH7.7, 0.001 M EDTA) buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 0.2 x SSPE; preferably hybridizing in a buffer comprising 50% formamide in 5 x SSPE buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 0.2x SSPE buffer at 42°C.
• HUMAN NTN-2 cDNA specific sequence and sufficient to effect specific hybridization with SEQ. I.D. NO. 1.
• Demonstrating specific hybridization generally requires stringent conditions, for example, hybridizing in
• NTN-2 cDNA homologs can also be distinguished from other polypeptides using alignment algorithms, such as BLASTX (Altschul, et al. (1990) Basic Local Alignment Search Tool, J. Mol. Biol. 215: 403-410).
• HUMAN NTN-2 hybridization probes find use in identifying wild-type and mutant alleles in clinical and laboratory samples. Mutant alleles are used to generate allele-specific oligonucleotide (ASO) probes for high-throughput clinical diagnoses.
• HUMAN NTN-2 nucleic acids are also used to modulate cellular expression or intracellular concentration or availability of active HUMAN NTN-2.
• HUMAN NTN-2 inhibitory nucleic acids are typically antisense - single stranded sequences comprising complements of the disclosed natural HUMAN NTN-2 coding sequences. Antisense modulation of the expression of a given HUMAN NTN-2 polypeptide may employ antisense nucleic acids operably linked to gene regulatory sequences.
• Cells are transfected with a vector comprising a HUMAN NTN-2 sequence with a promoter sequence oriented such that transcription of the gene yields an antisense transcript capable of binding to endogenous HUMAN NTN-2 encoding mRNA.
• Transcription of the antisense nucleic acid may be constitutive or inducible and the vector may provide for stable extrachromosomal maintenance or integration.
• single- stranded antisense nucleic acids that bind to genomic DNA or mRNA encoding a given HUMAN NTN-2 polypeptide may be administered to the target cell, in or temporarily isolated from a host, at a concentration that results in a substantial reduction in expression of the targeted polypeptide.
• An enhancement in HUMAN NTN-2 expression is effected by introducing into the targeted cell type HUMAN NTN-2 nucleic acids which increase the functional expression of the corresponding gene products.
• nucleic acids may be HUMAN NTN-2 expression vectors, vectors which upregulate the functional expression of an endogenous allele, or replacement vectors for targeted correction of mutant alleles.
• Techniques for introducing the nucleic acids into viable cells are known in the art and include retroviral- based transfection, viral coat protein-liposome mediated transfection, etc.
• the invention provides efficient methods of identifying agents, compounds or lead compounds for agents active at the level of HUMAN NTN-2 modulatable cellular function.
• these screening methods involve assaying for compounds which modulate HUMAN NTN-2 interaction with a natural HUMAN NTN-2 binding target.
• assays for binding agents are provided including protein-protein binding assays, immunoassays, cell based assays, etc.
• Preferred methods are amenable to automated, cost-effective high throughput screening of chemical libraries for lead compounds.
• In vitro binding assays employ a mixture of components including a HUMAN NTN-2 polypeptide, which may be part of a fusion product with another peptide or polypeptide, e.g., a tag for detection or anchoring, etc.
• the assay mixtures comprise a natural HUMAN NTN-2 binding target. While native binding targets may be used, it is frequently preferred to use portions thereof as long as the portion provides binding affinity and avidity to the subject HUMAN NTN-2 conveniently measurable in the assay.
• the assay mixture also comprises a candidate pharmacological agent.
• Candidate agents encompass numerous chemical classes, though typically they are organic compounds, preferably small organic compounds, and are obtained from a wide variety of sources including libraries of synthetic or natural compounds.
• a variety of other reagents such as salts, buffers, neutral proteins, e.g., albumin, detergents, protease inhibitors, nuclease inhibitors, antimicrobial agents, etc., may also be included.
• the mixture components can be added in any order that provides for the requisite bindings and incubations may be performed at any temperature which facilitates optimal binding.
• the mixture is incubated under conditions whereby, but for the presence of the candidate pharmacological agent, the HUMAN NTN-2 specifically binds the cellular binding target, portion or analog with a reference binding affinity. Incubation periods are chosen for optimal binding but are also minimized to facilitate rapid, high throughput screening.
• the agent-biased binding between the HUMAN NTN-2 and one or more binding targets is detected by any convenient way.
• a separation step is often used to separate bound from unbound components. Separation may be effected by precipitation, immobilization, etc., followed by washing by, e.g., membrane filtration or gel chromatography.
• one of the components usually comprises or is coupled to a label.
• the label may provide for direct detection as radioactivity, luminescence, optical or electron density, etc., or indirect detection such as an epitope tag, an enzyme, etc.
• a variety of methods may be used to detect the label depending on the nature of the label and other assay components, e.g., through optical or electron density, radiative emissions, nonradiative energy transfers, or indirectly detected with antibody conjugates, etc.
• a difference in the binding affinity of the HUMAN NTN-2 polypeptide to the target in the absence of the agent as compared with the binding affinity in the presence of the agent indicates that the agent modulates the binding of the HUMAN NTN-2 polypeptide to the corresponding binding target.
• a difference is statistically significant and preferably represents at least a 50%, more preferably at least a 90% difference.
• the invention provides for a method for modifying the physiology of a cell comprising an extracellular surface in contact with a medium, said method comprising the step of contacting said medium with an exogenous HUMAN NTN-2 polypeptide under conditions whereby said polypeptide specifically interacts with at least one of a component of said medium and said extracellular surface to effect a change in the physiology of said cell.
• the invention further provides for a method for screening for biologically active agents, said method comprising the steps of a) incubating a HUMAN
• NTN-2 polypeptide in the presence of an extracellular HUMAN NTN-2 polypeptide specific binding target and a candidate agent, under conditions whereby, but for the presence of said agent, said polypeptide specifically binds said binding target at a reference affinity; b) detecting the binding affinity of said polypeptide to said binding target to determine an agent- biased affinity, wherein a difference between the agent-biased affinity and the reference affinity indicates that said agent modulates the binding of said polypeptide to said binding target.
• One embodiment of the invention is an isolated HUMAN NTN-2 polypeptide comprising the amino acid sequence as set forth herein or a fragment thereof having HUMAN NTN-2-specific activity.
• Another embodiment of the invention is a recombinant nucleic acid encoding HUMAN NTN-2 polypeptide comprising the amino acid sequence as set forth herein or a fragment thereof having HUMAN NTN-2- specific activity.
• Still another embodiment is an isolated nucleic acid comprising a nucleotide sequence as set forth herein or a fragment thereof having at least 18 consecutive bases and sufficient to specifically hybridize with a nucleic acid having the sequence of set forth herein in the presence of natural HUMAN NTN-2 cDNA.
• the present invention also provides for antibodies to the HUMAN NTN-2 polypeptide described herein which are useful for detection of the polypeptide in, for example, diagnostic applications.
• antibodies to the HUMAN NTN-2 polypeptide described herein which are useful for detection of the polypeptide in, for example, diagnostic applications.
• any technique which provides for the production of antibody molecules by continuous cell lines in culture may be used.
• the monoclonal antibodies for diagnostic or therapeutic use may be human monoclonal antibodies or chimeric human-mouse (or other species) monoclonal antibodies.
• Human monoclonal antibodies may be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; Olsson et al., 1982, Meth. Enzymol. 92:3-16).
• Chimeric antibody molecules may be prepared containing a mouse antigen-binding domain with human constant regions (Morrison et al., 1984, Proc. Natl. Acad. Sci. U.S.A. 81:6851, Takeda et al., 1985, Nature 314:452).
• HUMAN NTN-2 polypeptide described herein.
• various host animals can be immunized by injection with the HUMAN NTN-2 polypeptide, or a fragment or derivative thereof, including but not limited to rabbits, mice and rats.
• adjuvants may be used to increase the immunological response, depending on the host species, and including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (Bacille Calmette-Guerin) and Corynebacterium parvum.
• BCG Bacille Calmette-Guerin
• a molecular clone of an antibody to a selected HUMAN NTN-2 polypeptide epitope can be prepared by known techniques. Recombinant DNA methodology (see e.g., Maniatis et al., 1982, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York) may be used to construct nucleic acid sequences which encode a monoclonal antibody molecule, or antigen binding region thereof.
• Antibody fragments which contain the idiotype of the molecule can be generated by known techniques.
• fragments include but are not limited to: the F(ab') 2 fragment which can be produced by pepsin digestion of the antibody molecule; the Fab' fragments which can be generated by reducing the disulfide bridges of the F(ab') 2 fragment, and the Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent.
• Antibody molecules may be purified by known techniques, e.g., immunoabsorption or immunoaffinity chromatography, chromatographic methods such as HPLC (high performance liquid chromatography), or a combination thereof.
• Terminator Cycle Sequencing Kit (Applied Biosystems, Inc., Foster City, CA). Alignment of the two additional clones with SEQ. I.D. NO. 1 indicated a total length of 680 nucleotides. Oligonucleotides were designed based on the partial human sequence and used as primers for the reverse transcriptase reaction and for PCR. A 608 nucleotide long sequence was obtained and used as a probe to isolate the full length sequence as described below. EXAMPLE 2 - ISOLATION AND SEQUENCING OF FULL LENGTH cDNA CLONE ENCODING HUMAN NTN-2
• a human placenta cDNA library in lambda gt-10 was obtained from Clontech Laboratories, Inc. (Palo Alto, CA). Plaques were plated at a density of 1.25 x 10 6 /20x20 cm plate, and replica filters taken following standard procedures (Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., page 8.46, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York). Filters were screened at normal stringency (2 x SSC, 65°C) with a probe corresponding to nucleotides 216 to 824 of the hNTN-2 sequence shown in SEQ. I.D. NO. 3.
• the probe was hybridized at 65°C in hybridization solution containing 0.5 mg/ml salmon sperm DNA to decrease non-specific binding of the probe to the filter. Filters were washed in 2 x SSC at 65° C and exposed overnight to X-ray film. Five positive clones were picked that showed strong hybridization signals and also produced fragments when
• the coding region from each of the five clones was sequenced using the ABI 373A DNA sequencer and Taq Dyedeoxy Terminator Cycle Sequencing Kit
• a fragment corresponding to nucleotides 216 to 824 of the hNTN-2 sequence shown in SEQ. I.D. NO. 3 was radiolabeled and utilized in Northern analysis of various human tissue specific RNAs.
• the Northern blot containing polyA+ RNA from several human tissues was obtained from Clontech Laboratories, Inc. (Palo Alto, CA) and was hybridized at 65°C to the radiolabeled hNTN-2 probe in the presence of 0.5M NaP04 (pH 7), 1% bovine serum albumin (Fraction V, Sigma), 7% SDS, 1 mM EDTA and 100 ng/ml sonicated, denatured salmon sperm DNA. The filter was washed at
• the hNTN-2 probe hybridized strongly to a 2.7 kb transcript in human heart, placenta, pancreas and lung tissue (Figure 1) and hybridized weakly to
• RNA from brain and liver could also be found in skeletal muscle and kidney.
• High expression of hNTN-2 in heart tissue may suggest that the present invention may be utilized to treat heart disease.
• Expression of hNTN-2 in lung and pancreas tissue may suggest that the present invention may be utilized to treat lung and /or pancreas related disorders.

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