WebThe resulting pathway/genome database (PGDB) includes information on 28,783 genes, their products and the metabolic reactions and pathways they catalyze. Federal government websites often end in .gov or .mil. Bookshelf While curating MetaCyc content, curators prepare and submit new and revised entries to the EC, leading to the creation of hundreds of new and modified EC entries over the past 2 years. More information about the subscription model is available at http://www.phoenixbioinformatics.org/biocyc/index.html. As of August 2019, a total of 16161 reactions (92.4% of the total reactions) are balanced. pathway Here, we present Enteropathway, a metabolic pathway database that integrates 3,121 compounds, 3,460 reactions, and 837 modules that were obtained from 835 manually curated scientific literature. Here, we present Enteropathway, a database 8600 Rockville Pike The MetaCyc database is openly available to all. An official website of the United States government. 2023 Apr 6;14:1118291. doi: 10.3389/fmicb.2023.1118291. Figure Figure11 shows an example of a MetaCyc pathway diagram. It contains more than 2570 pathways derived from >54 000 publications, making it the largest curated collection of metabolic pathways. GenePath -- from mutations to genetic networks and back MetaCyc -- A Multiorganism Database of Metabolic Pathways and Enzymes. A short pathway was selected for this figure; the. Tel: +1 650 859 5323; Email: Received 2017 Sep 11; Revised 2017 Sep 28; Accepted 2017 Oct 2. MetaCyc contains a vast number of plant-specific secondary metabolism pathways. It contains data about chemical compounds, reactions, enzymes and metabolic pathways that have been experimentally validated and reported in the scientific literature (1). Users can define areas of interest in several ways: For example, after specifying the MetaCyc pathway class Sulfur Compounds Metabolism, users will receive updates about new or revised pathways that are classified under that class. However, for version 22.0 of Pathway Tools, these issues were resolved, allowing us to convert a large number of pathways to the symbolic representation format. Stand. MetaCyc and EcoCyc [the PGDB for Escherichia coli K-12, (22)] remain freely available to all and do not require a subscription. It contains 2749 pathways derived from more than 60000 publications, making it the largest curated collection of metabolic pathways. Due to its exclusively experimentally determined data, intensive curation, extensive referencing, and user-friendly and highly integrated interface, MetaCyc is commonly used in various fields, including genome annotation, biochemistry, enzymology, metabolomics, genome and metagenome analysis, and metabolic engineering. This allows, for example, to depict how an oligosaccharide is connected to a lipid membrane anchor or to a glycoprotein (see Figure Figure2).2). Conflict of interest statement. 2000; 28:5659. Mucosal Microbiota from Colorectal Cancer, Adenoma and Normal Epithelium Reveals the Imprint of. Thus, both systems operate in animalsthe type I system in the cytosol and the type II system in the mitochondria. Caspi R., Billington R., Ferrer L., Foerster H., Fulcher C.A., Keseler I.M., Kothari A., Krummenacker M., Latendresse M., Mueller L.A. et al.. database Before Metagen Therapeutics Inc. is working on the development of the intestinal microbiota bank to effectively implement fecal microbiota transplantation. The site is secure. Nucleic Acids Res. 2013 Aug;345(2):85-93. doi: 10.1111/1574-6968.12194. Accessibility In addition, PathoLogic now extracts organism metadata from its input files for inclusion in a PGDB. Inclusion in an NLM database does not imply endorsement of, or agreement with, (11) and Alberty (12). These objects are called modules, and as of 20 August 2019 KEGG contains 391 metabolic modules (other modules describe other processes such as transport). Tel: +1 650 859 4358; Email: Received 2019 Sep 10; Revised 2019 Sep 19; Accepted 2019 Oct 1. -, Karp P.D., Billington R., Caspi R., Fulcher C.A., Latendresse M., Kothari A., Keseler I.M., Krummenacker M., Midford P.E., Ong Q. et al. MetaCyc (MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. We routinely host workshops and tutorials (on site and at conferences) that provide training and in-depth discussion of our software for both beginning and advanced users. The responsible enzymes are unrelated in bacteria, unicellular algae, coelenterates, beetles, fishes and other organisms, although all systems involve exergonic reactions of molecular oxygen with different substrates (luciferins) and enzymes (luciferases), resulting in photons of visible light. The MetaCyc database is freely and openly available to all. MetaCyc reactions have a total of 15 779 links to UniProt, Rhea and KEGG. Nat Commun. It contains 2749 pathways derived from more than 60 000 publications, making it the largest curated collection of metabolic pathways. -, Karp P.D., Latendresse M., Caspi R.. The four planar coordination sites are provided by a corrin ring, while the other two are provided by upper (Co) and lower (Co) ligands. The human gut microbiota produces diverse, extensive metabolites which have the potential to affect host physiology. Although SmartTables are not a new feature in MetaCyc, we would like to mention them to ensure that all users are familiar with this powerful tool. Metabolic pathway databases and model repositories MetaCyc contains a number of pre-formed SmartTables that provide access to results of, MeSH Databases of metabolic pathways - IUBMB Sequence Nucleic Acids Res. Walsh J.R., Schaeffer M.L., Zhang P., Rhee S.Y., Dickerson J.A., Sen T.Z.. The https:// ensures that you are connecting to the The researchers, who published their work June 19 in Nature Metabolism, created the Cancer Atlas of Metabolic Profiles (CAMP) by combining new and existing datasets on metabolites and gene activity. 2011; 5:424429. The Metabolism Disease Database | Systems Biology Research PMC During this process, certain oligosaccharides are attached to an L-asparagine residue in the polypeptide chain of target proteins. A metabolic pathwayby denition is a linked series of enzyme-catalyzedchemical reactions that occur in a cell [1]. A comparison of the reactions content of MetaCyc and the KEGG database. The number of total reactions (including non-enzymatic) is 15 691. MetaCyc (MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. In non-photosynthetic organisms, carotenoids serve multiple roles as antioxidants, virulence factors and modulators of membrane function. . FOIA Myers KS, Ingle AT, Walters KA, Fortney NW, Scarborough MJ, Donohue TJ, Noguera DR. Front Bioeng Biotechnol. This article provides an update on the developments in MetaCyc during September 2017 to August 2019, up to version 23.1. National Library of Medicine et al http://creativecommons.org/licenses/by-nc/4.0/, http://www.phoenixbioinformatics.org/biocyc/index.html, http://www.metacyc.org/MetaCycUserGuide.shtml, http://biocyc.org/PGDBConceptsGuide.shtml. Altman T., Travers M., Kothari A., Caspi R., Karp P.D.. A systematic comparison of the MetaCyc and KEGG pathway databases. See this image and copyright information in PMC. Enteropathway: the metabolic pathway database for the human gut microbiota, School of Life Science and Technology, Tokyo Institute of Technology, Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, Graduate School of Medical and Dental Sciences, Niigata University. National Library of Medicine Conflict of interest statement. In these series Would you like email updates of new search results? MetaCyc contains a number of pre-formed SmartTables that provide access to results of popular searches. The modifications, introduced by the SRI International, allow the software to display text strings or other, non-glycan, compounds as part of the structure (shown as R in this example). and transmitted securely. A survey of metabolic databases emphasizing the MetaCyc family. The search can also be refined by specifying (i) the full name (or part of the name) of a metabolic pathway or a functional feature (e.g. Other new pathways describe the various ways in which hydrogen sulfide is produced and oxidized in mammalian tissues, as well as the metabolism of 5-oxo-L-proline (also known as L-pyroglutamate), which is formed via the spontaneous cyclization of L-glutamine. We have added several pathways that describe bacterial biosynthesis of organobromine compounds. 2016; 44:D471480. 2012 Jan;40(Database issue):D742-53. An official website of the United States government. Each item in a pathway diagram is a clickable hyperlink to a dedicated page for that item. To whom correspondence should be addressed. MetaCyc database The database contains chemical structures of xenobiotic biotransformations with substrate atoms annotated as reaction centra, the resulting product formed, and the catalyzing enzyme, type of experiment, and literature references. -. 2011; 5:424429. Before Of the two basic types of fatty acid biosynthesis systems, type I systems are found in lower eukaryotes and animals, while type II systems are found in bacteria, plants, parasites of the Apicomplexa phylum and mitochondria. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, By entering one or more specific pathways of interest, By defining a SmartTable listing pathways of interest. As of 20 August 2019 KEGG contains 536 such maps. Tel: +1 650 859 5323; Email: Correspondence may also be addressed to Peter D. Karp. 2023 Jun 29;8(3):e0102722. During this partially automated process, the predicted metabolic network is captured in the form of a Pathway/Genome Database (PGDB). is the founder of Omixer Solutions which develops and provides bioinformatics services and consulting. A number of metabolic databases are accessible via the Web. PlantPathMarks (PPMdb): an interactive hub for pathways-based Oligosaccharide composition and structure vary greatly among kingdoms and to a lesser degree among species. The database is accessible from a web application (https://enteropathway.org) that offers a metabolic diagram for graphical visualization of metabolic pathways, a customization interface, and an enrichment analysis feature for highlighting enriched modules on the metabolic diagram. Many other diagrams that are available only when browsing organism-specific PGDBs (and thus not applicable to MetaCyc) have also been enhanced. Please enable it to take advantage of the complete set of features! MetaCyc (MetaCyc.org) (pronounced met-a-sike, as in encyclopedia) is a highly curated reference database of metabolism from all domains of life that has been curated for over 20 years (1). Disclaimer. MetaCyc now contains N-glycosylation pathways for bacteria, yeast, plants, vertebrates and the archaeons Haloferax volcanii and Methanococcus voltae. Notably, 757 modules of these modules are new entries and cannot be found in any other databases. Here we present a review of the most popular metabolic pathway databases and model repositories, focusing on their scope, content including reactions, enzymes, 2018; 46:D633D639. -, Karp P.D., Paley S.M., Krummenacker M., Latendresse M., Dale J.M., Lee T.J., Kaipa P., Gilham F., Spaulding A., Popescu L. et al. Interested scientists may adopt any of the SRI PGDBs through the BioCyc website for further curation (https://biocyc.org/adopted.shtml). Karp P.D., Latendresse M., Paley S.M., Krummenacker M., Ong Q.D., Billington R., Kothari A., Weaver D., Lee T., Subhraveti P. et al.. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology, The pathway tools pathway prediction algorithm. Front Microbiol. MACADAM database: a MetAboliC pAthways DAtabase for MetaCyc ( MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. Unauthorized use of these marks is strictly prohibited. Issue Section: Original Article Introduction The update notifications are sent to users in a single email in conjunction with each of the three yearly MetaCyc releases. -, Karp P.D., Latendresse M., Paley S.M., Krummenacker M., Ong Q.D., Billington R., Kothari A., Weaver D., Lee T., Subhraveti P. et al. official website and that any information you provide is encrypted Access to the website is free; users are required to register for a free account after viewing more than 30 pages in a given month. None declared. As in non-glycan type pathways, each item in the diagram is a clickable hyperlink to a dedicated page for that item. Most data in MetaCyc concerns small molecule metabolism, although an increasing amount of macromolecular metabolism (e.g. All compounds in MetaCyc are protonated to the state most prevalent at pH 7.3. 2017; doi:10.1093/bib/bbx085. Accessibility Starting with version 22.0, pathway diagrams can include detailed regulatory information for each step, provided such data are present. Bethesda, MD 20894, Web Policies and transmitted securely. The green captions are links to the upstream and downstream pathways that produce the inputs and outputs for this pathway. The number of referenced organisms increased by 6% to 3045. Our aim is to have as many M-numbers as possible eventually replaced by official EC numbers. MetaCyc database of metabolic pathways and enzymes - a 2019 Previously, one difference between the proteins curated in MetaCyc and those in organism-specific PGDBs was that MetaCyc proteins did not contain sequence information, preventing users from performing BLAST searches within MetaCyc. The enzymes in this pathway have not yet been classified by the Enzyme Commission and were assigned M-numbers (see text). When data are available, MetaCyc pathways include curated representative enzymes for each enzymatic step. FEMS Microbiol Lett. We have also added 910 new enzymes (an increase of 8%), 1687 reactions (12%) and 1806 chemical compounds (13%). Nucleic Acids Res. The enzymes in this pathway have not yet been classified by the Enzyme Commission and were assigned. Karp P.D., Riley M., Saier M., Paulsen I.T., Paley S.M., Pellegrini-Toole A.. Caspi R., Billington R., Fulcher C.A., Keseler I.M., Kothari A., Krummenacker M., Latendresse M., Midford P.E., Ong Q., Ong W.K. In photosynthetic organisms, carotenoids participate in light harvesting and provide protection against photooxidative stress through energy-dissipation of excess light absorbed by the antenna pigments. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology. During the curation process, MetaCyc curators come across thousands of enzymes that have not yet been classified by the EC. Karp P.D., Ong W.K., Paley S., Billington R., Caspi R., Fulcher C., Kothari A., Krummenacker M., Latendresse M., Midford P.E. The MetaCyc database of metabolic pathways and enzymes. Two new protein glycosylation pathways describe the formation of the core M3 glycan on mammalian proteins, and its extension to the complex glycan found on the -dystroglycan protein. official website and that any information you provide is encrypted doi: 10.1093/nar/gkv1164. In the past, MetaCyc contained a pathway describing only the first stage. 9442 of these compounds participate in reactions, and 13 725 have structures. MetaCyc currently contains 46 glycan biosynthesis pathways, 11 glycan degradation pathways and 3 O-antigen biosynthesis pathways that are drawn using symbolic representation. While users can create their own SmartTables, several SmartTables are already available for users, including such tables as all compounds in MetaCyc, all pathways in MetaCyc, all polypeptides of MetaCyc, etc. Epub 2011 Nov 18. . PPMdb is freely available at http://ppmdb.easyomics.org. Since the last Nucleic Acids Research publication (two years ago) (1), we added 219 new base pathways (pathways comprised of reactions only, where no portion of the pathway is designated as a subpathway) and four superpathways (pathways composed of at least one base pathway plus additional reactions or pathways), and updated 112 existing pathways, for a total of 335 new and revised pathways. MetaCyc (MetaCyc.org) is a comprehensive reference database of metabolic pathways and enzymes from all domains of life. For example, searching separately for dechlorination reactions that utilize water (water on one side, chlorine on the other side) or dechlorination reactions that produce water (water and chlorine on the same side) is now possible. We also added several pathways describing the biosynthesis of (Kdo)2-lipid A in Pseudomonas putida. ConsensusPathDB: a molecular functional interaction database, integrating information from 12 others Entrez ( National Center for Biotechnology Information) WebAbout ccmGDB Cancer Cell Metabolism Gene Database (ccmGDB) is a comprehensive annotation resource for cell metabolism genes in cancer. They are essential components of the plasma membrane in all eukaryotic cells. et al. The KEGG project consists of both a reference pathway database and the resulting projection of the reference pathways onto organisms with sequenced genomes. Like a spreadsheet, a SmartTable is organized by rows and columns that users can add to or delete. VLCFAs are synthesized in eukaryotes in the endoplasmic reticulum (ER) by a membrane-bound enzyme complex known as the elongase. We have upgraded many web visualizations produced by Pathway Tools in its web server mode to use modern graphics and fonts, including pathways, enzymatic reactions and transport reactions. Analysis of gut microbiota in patients with Williams-Beuren Syndrome reveals dysbiosis linked to clinical manifestations. Enteropathway: the metabolic pathway database for the While the type I system continues to extend the fatty acids to palmitate and stearate, the type II system in mitochondria mostly forms octanoate (for synthesis of (R)-lipoate) and possibly myristate. Several new pathways, all drawn using the symbolic representation of glycans mentioned above, describe the degradation of the large plant-produced polymers glucuronoarabinoxylan, homogalacturonan, rhamnogalacturonan type I and plant arabinogalactan type II. .. Pathway Tools version 19.0 update: software for pathway/genome informatics and systems biology. a set of compounds generated by a search). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (. Despite significant efforts to identify metabolic pathways for producing these microbial metabolites, a comprehensive metabolic pathway database for the human gut microbiota is still lacking. Out of these 12457 are associated with an enzymatic activity. Each database in the BioCyc collection describes the genome and metabolic pathways of a single organism. . SmartTables provide a powerful way for users to arrange and manipulate data in MetaCyc and other PGDBs. MetaCyc proteins have a total of 144347 links to a number of protein databases that include (only databases with more than 1000 links are listed) InterPro, PDB, Pfam, UniProt, Protein Model Portal, PROSITE, SMR, PRIDE, PID, PANTHER, PRINTS, MODBASE, SMART, RefSeq, EcoliWiki, PortEco, DIP, MINT, ProDB, SwissModel and PhylomeDB. 2011 Sep;85(9):1015-33. doi: 10.1007/s00204-011-0705-2. While describing in this limited space the various additions to MetaCyc data during the past two years is impossible, the following partial list of new or completely revised pathways may illustrate the breadth of topics that have been covered during this time. WebMetaCyc is a database of nonredundant, experimentally elucidated metabolic pathways. Unfortunately, a myriad of technical complications prevented us from using this useful addition for several years. sharing sensitive information, make sure youre on a federal A typical MetaCyc pathway. The database contains curated information on MetaCyc contains regulatory data for many enzymes, primarily substrate-level enzyme activation and inhibition and required cofactors (additional types of regulation, such as transcriptional and translational regulation, are available in some other BioCyc PGDBs). The endocannabinoids are the endogenous agonists of the cannabinoid receptors, CB1 and CB2. Most MetaCyc compounds also contain standard Gibbs free energy of formation (fG) values, most of which are computed by Pathway Tools using an algorithm developed internally that is based on techniques by Jankowski etal. Herget S., Ranzinger R., Maass K., Lieth C.W.. GlycoCT-a unifying sequence format for carbohydrates. Data for KEGG are available only since 2008. Karp P.D., Paley S.M., Krummenacker M., Latendresse M., Dale J.M., Lee T.J., Kaipa P., Gilham F., Spaulding A., Popescu L. et al.. Pathway Tools version 13.0: integrated software for pathway/genome informatics and systems biology. In 2012, we integrated the GlycanBuilder software with Pathways Tools (18,19), which enabled the drawing of glycan structures using colored symbols to represent the different monosaccharide building blocks of the glycan molecule, thus making it easier for users to comprehend the structures of complex polysaccharides (12). In some marine sponges within the Dysideidae family, polybrominated diphenyl ethers can exceed 10% of the sponge tissue by dry weight. Y.D. Nat Commun. The HMA is a unique tool for studying human metabolism, ranging in scope from an individual cell, to a specific organ, to the overall human body. Balanced reactions are also processed by an atom mapping algorithm, and currently 14403 reactions have atom mapping data. The data in MetaCyc is strictly evidence-based and richly curated, resulting in an encyclopedic reference tool for metabolism. See this image and copyright information in PMC. Data for KEGG are available only since 2008. The total number of base pathways grew by 9%, from 2363 (version 19.1) to 2572 (version 21.1) (the total increase is <219 pathways, because some existing pathways were deleted from the database during this period). A section from a pathway that describes the biosynthesis of Lewis-type epitopes by the bacterium Helicobacter pylori. The majority of MetaCyc pathways are small-molecule metabolic pathways that have been experimentally determined. National Library of Medicine database A short pathway was selected for this figure; the average number of metabolites in a MetaCyc pathway is 12.8, with the largest pathway containing 204 metabolites. MetaCyc (https://MetaCyc.org) is a highly curated reference database of metabolism from all domains of life. Pathway Tools also provides browsing and searching capabilities to explore the databases as well as editing tools for improving and updating the computationally generated PGDBs by manual curation. PMC Published by Oxford University Press on behalf of Nucleic Acids Research. MetaCyc proteins have a total of 17 669 links to a number of protein databases that include (only databases with more than 1000 links are listed) InterPro; PDB; Pfam; UniProt; Protein Model Portal; PROSITE; SMR; PRIDE; PID; PANTHER; PRINTS; MODBASE; SMART; RefSeq; EcoliWiki; PortEco; DIP; MINT; ProDB; SwissModel; PhylomeDB; PhosphoSite; and CAZy. Epub 2011 Apr 27. Some of these groups have further improved those databases by performing their own curation. Very-long-chain fatty acids (VLCFAs), components of eukaryotic cells, are involved in many different physiological functions in different organisms. For example, the statement Tenericutes 18 means that experimental evidence exists for the occurrence of at least 18 MetaCyc pathways in members of this taxonomic group. The .gov means its official. Kanehisa M., Sato Y., Furumichi M., Morishima K., Tanabe M.. New approach for understanding genome variations in KEGG. Nucleic Acids Res. Genomic Sci. The integrating role of metabolic pathway databases in bioinformatics is well recognized nowadays. WebA database of curated links between metabolism and disease. SmartTables are spreadsheet-like structures that can contain both PGDB objects and other data such as numbers or text. a query with nitrate limits The Metabolic Pathwasy Database (MPW) (www.biobase.com/emphome.html/homepage. SRI has used MetaCyc to create almost 11 000 PGDBs (as of August 2017), which are available through the BioCyc (https://BioCyc.org) website (5). 2013 Aug;345(2):85-93. doi: 10.1111/1574-6968.12194. A year later, we introduced a new type of pathway diagram based on these structures to describe the complex process of glycan degradation. It is useful to compare occasionally the data content of MetaCyc and the KEGG reference pathway database, and a thorough comparison was last published in 2013 (21). Before 2023 May 9;14:1173609. doi: 10.3389/fmicb.2023.1173609. digzyme Inc is focused on discovering enzymes through a bioinformatics approach. Clipboard, Search History, and several other advanced features are temporarily unavailable. Most readers are likely familiar with adenosylcobalamin, the cofactor used by eukaryotic organisms in which the two ligands are 5-deoxyadenosyl and 5,6-dimethylbenzimidazole, respectively. MetaCyc has a new capability to inform users of newly curated information in specified areas of interest. Table Table11 lists species with >20 experimentally elucidated pathways in MetaCyc, and Table Table22 shows the taxonomic distribution of all MetaCyc pathways. The .gov means its official. Walsh J.R., Schaeffer M.L., Zhang P., Rhee S.Y., Dickerson J.A., Sen T.Z.. The .gov means its official. The data in MetaCyc is strictly evidence-based and richly curated, resulting in an encyclopedic reference tool for metabolism. In addition to its role as a general reference on metabolism, MetaCyc is used by the PathoLogic component of the Pathway Tools software (3,4) as a reference database, enabling the computational prediction of the metabolic reactions and pathways of any organism that has a sequenced and annotated genome (5). Objects in MetaCyc are extensively linked to other leading databases in the field, with a total of 264375 links. FEMS Microbiol Lett. the contents by NLM or the National Institutes of Health. . Caspi R, Billington R, Ferrer L, Foerster H, Fulcher CA, Keseler IM, Kothari A, Krummenacker M, Latendresse M, Mueller LA, Ong Q, Paley S, Subhraveti P, Weaver DS, Karp PD. In addition, curation exposes errors in older existing EC entries. HHS Vulnerability Disclosure, Help Despite significant efforts to identify metabolic The total number of compounds grew by 13%, from 12 362 (version 19.1) to 14 003 (version 21.1). The carboxylation is catalyzed by EC 4.1.1.90, peptidyl-glutamate 4-carboxylase, an enzyme that uses various vitamin-K hydroquinones, including menaquinol, as co-substrates that are epoxidated during the reaction, generating vitamin K 2,3-epoxide. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Piloto-Sardias E, Cano-Argelles AL, Maitre A, Wu-Chuang A, Mateos-Hernndez L, Corduneanu A, Obregn D, Oleaga A, Prez-Snchez R, Cabezas-Cruz A. In the presence of oxygen, ferrous iron is rapidly oxidized to ferric iron, which tends to form insoluble compounds and becomes unavailable to organisms. The green captions are links to the upstream and downstream pathways that produce the inputs and outputs for this pathway. Below each pathway is a summary and additional information such as the pathways taxonomic range, some taxa known to possess it, the pathways position within the pathway ontology, and potential pathway variants (not shown). In past papers in the database issue of Nucleic Acids Research we described the MetaCyc database together with the BioCyc PGDB collection (6). Starting with version 22.0, PathoLogic can accept input genomes in GFF format in addition to Genbank and PathoLogic format files.
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