Michigan Molecular Interactions User Manual
Contents
1. OMIM PubMed or semantically summarized extracts through GIN Gene2MeSH for enriched MeSH terms related to a selected gene Analyze multidimensional relationships Move to Netbrowser an interactive visualization workspace linked to MiMI Web for a quick way of exploring such associations as direct and indirect interactions conceptual similarities shortest paths between proteins and shared pathways Move to Cytoscape an interactive visualization workspace linked to MiMI Web for more in depth exploratory analysis to uncover subgraphs map subgraphs to associated canonical pathways via SAGA to expand select neighbors to cluster by biological concepts to find the shortest paths Use filtering and perceptual encoding in Cytoscape e g color shape size to isolate relationships of interest and visually bring in more attributes Infer causal associations relevant to disease mechanisms Move to Cytosapce to relate MiMI data to your own data for explanatory insights about causes and effects e g expression data Save and export information Use MiMI and Cytoscape save and export functions to share information with colleagues Annotate genes gene products and interactions in Cytoscape save them for next sessions and if desired share them publicly Navigate across sources to construct biological stories 1 3 What Attributes Can You Analyze MIMI provides the following data See more detail in the sections on Information on each s2. a source indicates that the organism is unknown MiMI will as well Other protein interaction data sources are created by human curators These curators read relevant publications and manually enter information into protein interaction databases These curators provide an invaluable service by filtering information and reducing large papers into a few distinct salient facts Unfortunately these curators are also human and as such they may make human assumptions and decisions For example human curators may gravitate towards a favorite protein name instead of listing all known synonyms Additionally each source dataset has a subset of identifiers used For example DIP concentrates on using SwissProt identifiers while BIND uses gi To help scientists judge the usefulness of a piece of data MiMI tracks the provenance of all data and gives users a link to the sources curators used to make decisions to include information about a molecule and its interactions By presenting the sources MiMI builds on your own expertise and lets you judge the data based on what you know about the source 3 Selecting and Using a Search Method MIMI allows you to search using several different methods e Free Text 1 Keywords Gene Symbols or Gene IDs Recommended for newcomers e Gene List 2 Gene Names or Gene IDs typed into the search box or imported as a file e Query Interactions The MiMI Free Text search uses the open source Lucene search engine for e
3. in any of the gene related fields intersecting Results may be sparse or null OR e g insulin OR receptor Record that contain any of the terms in any of the gene related fields union Results may be numerous Phrases Multiple terms unconnected by AND OR e g insulin receptor Records in which any of the terms in the phrase or the phrase itself occur in any gene related field e g records that reference insulin receptor insulin receptor Quotation marks Multiple terms enclosed in quotations e g insulin receptor Records that have only the exact phrase in any of the gene related fields Mixed AND and OR Multiple terms connected by AND s and OR s e g Insulin OR Receptor AND Oxidation Records that satisfy reading left to right the combinations specified e g Records that have either insulin or receptor in a gene related field along with oxidation Field name statements Multiple terms with one or more specified by a MiMI gene related field name e g insulin receptor AND cellularComponent nucleus e g geneid 1436 In the first example Records for genes localized in the nucleus with no attention to nucleus occurring in any other fields combined with records that contain the phrase insulin receptor in any of the fields NOTE Searching only on the Organism field can be done through the pull down list instead of a query Complex search statements Multiple terms in
4. this information from many other biological sources You can link out to these other databases and auxiliary sources from MiMI as well They include BIND Max Delbreuck Center BioGRID MiBLAST CCSB at Harvard NCBI Gene CPath OrganellDB DIP Ortho MCL GO PFam HPRD ProtoNet IntAct PubMed InterPro PubMed NLP Mining IPI Reactome KEGG MiMI merges data from these sources with deep integration see How MiMI Merges Data section into its single database A simple yet powerful user interface enables you to query the database freeing you from the onerous task of having to know the data format or having to learn a query language MiMI allows you to query all data whether corroborative or contradictory and specify which sources to utilize MIMI displays results of your queries in easy to browse interfaces and provides you with workspaces to explore and analyze the results Among these workspaces is an interactive network of protein protein interactions displayed in Cytoscape and accessed through MiMI via a MiMI Cytoscape plug in 1 2 What Tasks Can You Perform With MiMI you can explore publicly available data on genes and gene products and find relationships based on biological concepts canonical pathways and semantic text mining From this rich array of data MiMI helps you uncover previously unknown knowledge within and across organisms Insights you gain can lead to novel hypotheses about mechanisms of diseases or other biological
5. Michigan Molecular Interactions User Manual Last updated November 4 2008 Table of Contents Preface Licensing Terms of Use Software Products Used How to Cite MiMI 1 Background 1 1 What Is MiMI 1 2 What Tasks Can you Perform 1 3 What Attributes Can you Analyze 1 4 What is Unique About MiMI 2 The MiMI Merge Process 2 1 Rules and Assumptions 2 2 Curation and Sources of the Displayed Data 3 Selecting and Using a Search Method 3 1 Free Text Search 3 2 Gene List Search 3 3 Query Interactions Search 4 Scanning the Search Results Overview 4 1 Interacting with the Search Results Screen 4 2 Information found on the Screen Other sections are In progress Updates due November 6 2008 Preface Licensing Terms of Use MiMI is both a web service that integrates data and the application of research and open source software to the problem of supporting that web service For use of the supporting software please refer to that list see Software Products Used below The data provided on this website has been compiled and merged from multiple sources See Sources of Data below The Regents of the University of Michigan does not check this data for errors or omissions and by its nature the data included herein likely contains errors and omissions Access and use is provided as is without representation as to its fitness for any purpose and without warranty of any kind either express or implied including without limi
6. actions Articles Pathways Save and export Figure 4 1 Search Results Overview Screen and Interactions You Can Perform 16 4 2 Information found on the screen The fields in the Query Results Overview screen give the following information Field Name Gene Organism Type Other Names Description Cellular Components Biological Processes Molecular Functions Int Doc Path Description The gene symbol or name The name of the organism the gene is found in Gene Type Several types of molecules exist within MiMI These include protein DNA RNA polymer complex small molecule and photon A list of synonyms aliases for this gene Please note that this list is not complete but merely the set of names found within all of our merged sources Description content is created by curators of the source datasets MiMI retains information from all sources even if it is contradictory In the case of descriptions we will not repeat exact matches However since descriptions are normally English sentences there are usually no exact matches and all versions are retained GO annotations found in the original sources indicating where this molecule is found within the cell GO annotations found in the original sources indicating all processes associated with this molecule GO annotations found in the original sources indicating this molecule s function within the cell The number of interactors this ge
7. compound and nested In the example Records for genes localized in the nucleus for either humans or fruit flies that also 10 You enter You get relationships specifically reference insulin receptor e g insulin receptor AND cellularComponent nucleus AND organism homo OR organism dro Wildcards Records that have any combinations that match your Use after prefixes e g phosphor WEE root entry Use in the middle of a term e g c fir Commas MIMI does not recognize commas and will not Multiple keywords gene IDs or symbols provide results separated by commas no spaces Step by step procedures 1 Enter your search term or terms in the search bar a keyword gene symbol gene ID or any combination of the three Figure 1 Select an Organism from the pull down list or choose All organisms You can choose only one organism in this version of MiMI the default is Homo Sapiens as Michigan Molecular Interactions MiM NCiBI Integrating Gene and Molecule Interactions ou Eee eae MIMI Search r latabase Filter by Organism Figure 3 1 Search box and Organism Filter Click on the MiMI Search button The Query Results Overview appears Figure 2 For example the search terms prostate cancer produces results for all genes in which the words prostate cancer appear in one of the fields associated with the gene In Figure 3 2 121 gene records were retrieved and th
8. creen Genes Interactions Chromosome Component Component Function Description Gene Names Function Interaction type Gene name Process Gene type Provenance KEGG pathway PubMed Locustag TextSource ilnfo Map_loc Interaction Organism Other gene names Pathway Process Process Taxid 1 4 What is Unique About MiMI MiMI gives you access to more information than you can get from any one protein interaction source In MiMI unlike in individual resources you can use many different synonyms to find a protein and any number of protein identifiers MiMi lets you query all fields for your search term or only specified fields e g p53 only in molecule name MIMI provides result sets on pair wise interactions and presents information and linkouts to integrated tools such as Cytoscape that help you infer indirect interactions MIMI presents provenance to help you determine your confidence in displayed details and to make judgments about descriptive information that may be contradictory MIMI lets you quickly see the gene and gene product information that is available across source databases For example it presents GO annotations when any one of the databases include it A blank field shows you that this information is missing across biological resources 2 The MiMI Merge Process Protein interaction data exists in a number of repositories Each repository has its own data format molecule identifier and supp
9. e first of 20 pages is displayed Overview details summarize gene aliases descriptions and GO annotations and they indicate the number of interactors the gene product has the number of articles associated with the gene and the number of pathways containing it If no records meet your search criteria or if the search does not meet Lucene rules MiMI provides a message 4 Click on the gene name hyperlinked to view more details for that gene Figure 3 11 Ne nes Michigan Molecular Interactions Integrating Gene and Molecule Interactions NC BI Search Results ean Kendal Ane Lias ier asa SR ELECTED EEN TRE SST a ck OO SS RE Ck ND Home sapien Hogs Homo unknown E SE sapiens sap Homo wbnson sn Figure 3 2 Query Results Overview Screen 3 2 Gene List Search Entering a gene list search and MiMI s search for results The Gene List search mode uses a different entry box Click on Gene List Search next to the free text search box to conduct a gene list search You get the display shown in Figure 3 s Michigan Molecular Interactions s Gat lt i aea a i NCBI Integrating Gene and Molecule Interactions Figure 3 3 Gene List Search entry form You can search on a list in one of two ways e Type or copy paste a linear list of gene symbols or ID into the text box If you enter only one gene symbol or ID MiMI will still conduct and complete your search e Upload a txt f
10. fficient full text search capabilities 3 1 Free Text Search What is Free Text Search Using the Free Text search bar at the top of the Main Search page you can enter a single Keyword Gene symbol or Gene ID and retrieve matching genes see Figure 1 This version does not warn you ahead of time if the term is acceptable according to Lucene rules For problems MiMI responds Processing error To retrieve results MiMI searches all fields within the MiMI dataset that relate to Genes This version of MiMI does not yet search fields related to Interactions e g Interaction Type If your query term appears in any of the Gene fields the gene record will be retrieved and displayed in Results TIP To search for a keyword Gene symbol or Gene ID that occurs only in one field query by a specified field name e g cellularComponent nucleus Gene related fields that MiMI searches include the following biologicalProcess GO annotations moldescription Molecule descriptions from free text mining and provenance sources cellularComponent GO annotations molecularFunction GO annotations externalref External Reference molname Molecular Name gdesc Gene descriptions from free text mining and provenance sources othernames Gene synonyms aliases geneid From NCBI Entrez Gene organism MiMI distinguishes 11 organisms at a high level and numerous lower level ones genes
11. ile listing your genes symbols or IDs with 1 entry per line When MiMI searches for your list of genes in its dataset it treats returns all gene records that contain any one of your listed genes in the Gene Name or Gene ID field You can use wildcards with prefixes e g pw or in the middle 1476 of gene names or IDs Constraints Genes must be listed linearly MiMI does not search on strings separated by commas MiMI searches only the Gene Name or Gene ID field depending on whether you enter a symbol or ID value It does not search the Other Gene Name field or any other field You can only filter by Organism and only one at a time through the Organism pull down list Step by step procedures 12 Move to the Gene List Search display from MiMI home by clicking Gene List Search Enter a list in the text box Type or paste in a linear list of gene symbols or IDs Click the appropriate radio button next to the box Either Symbols or ID values Upload a list Use the Upload Gene List section Browse to the text file that contains the list of gene symbols or gene ID values by clicking on the Browse button After you have selected your file in the Browse window click the Copy to Text Box button The genes listed in your file are now displayed in the text box Click the appropriate radio button next to the box Either Symbols or ID values Filter by an Organism from the pull down list or choose All organisms You can choose only
12. lementary information Michigan Molecular Interactions MiMI assists scientists searching through this overwhelming amount of protein interaction data MiMI gathers data from well known protein interaction databases and deep merges the information Utilizing an identity function molecules that may have different identifiers but represent the same real world object are merged Thus MiMI allows the user to retrieve information from many different databases at once highlighting complementary and contradictory information There are several steps needed to create the final MiMI dataset They are 1 The original source datasets are obtained and transformed into the MiMI schema except KEGG NCBI Gene Uniprot Ensembl 2 Molecules that can be rolled into a gene are annotated to that gene record 3 Using all known identifiers of a merged molecule sources such as OrganelleDB or miBLAST are queried to annotate specific molecular fields 4 The resulting dataset is loaded into a relational database Because this is an automated process and no curation occurs any errors or misnomers in the original data sources will also exist in MiMI For example if a source indicates that the organism is unknown MiMI will as well 2 1 Rules and Assumptions MIMI is not merged by experts everything is done automatically When you look into genes of interest it is important to understand why your target gene contains the attributes and associated a
13. ne has The number of related articles Articles include those that have been curated and included in our merged databases as well as those retrieved through text mining The number of pathways in which this gene appears Table 4 1 Description of the Search Results Overview Fields 17 18
14. nnotations you also may want to know why conflicting data are displayed in the merged data Some of the assumptions and rules that MiMI uses in deep merging that may be relevant to understanding and being confident in its displays include the following Source differences in quality Not all sources are created equal While each source has a particular strength each also has its drawback Some important things to know about the curation processes in these different databases that might affect your interpretations and confidence include BIND Has a large number of interactions many based on high throughput data IntAct Lists molecules as interacting when they co locate Source content Not only do sources have different strengths and weaknesses they also organize content differently For example IntAct will associate publications with individual molecules while BIND associates publications with interactions only MiMI remains true to individual sources and how they assign publications to molecules or interactions Source data not used colocators etc In general MiMI uses all data from each source However there are some data from each source that are not incorporated into MiMI For instance sequence data is never stored within the MiMI dataset 2 2 Curation and Sources of the Displayed Data Because MiMI does not do any curation any errors or misnomers in the original data sources will also exist in MiMI For example if
15. number gt Interactions Quick View page Doc number gt Interactive Document Selection page Path number gt Pathway Quick View page A GO annotation gt EMBL EBI site for that term 2 Sort the table Click on any column headings to sort in ascending or descending order 3 Save and export Click on csv Excel or XML to save the entire Search Results table symbol to move GO annotations when available Search to details and One gene often has many vianctont interactions Frees OtherNames Descipton calls Components Biological Processes Polecular Functions Tint Dc Path PROVI Homo protein p pepa ose Sapiens coding dJITINIL2 can Click on any column heading to s rt UC28 UROC28 overexpress IGM4 Homo protein TGM4 hTGP transglutaminase 4 cellular component peptide cross linking acyltransferase activity G0 0008415 j e sapien coding TGP prostate 69 0005575 i protein Salcium ion binding G10005509 protein amino acid polyamination glutamine qgamma alutamyltransferase 60 0018184 activity 60 0003810 transferase activity 0 0016740 ASPP Homo protein ACPP ACP3 acid phosphatase extracellular region acid phosphatase activity GO 0003993 44 33 2 sapiens coding ACP 3 PAP prostate G0 0005576 hydrolase activi 10016787 protein tyrosine phosphatase activity 6010004725 Export options CSV Excel XML Click on these numbers to move respectively to associated Inter
16. ols and Gene IDs To get results on all interactors with the products of a specific gene Type a gene symbol or ID into the Gene 1 box Leave the Gene 2 box blank Filter by an Organism from the pull down list or choose All organisms You can choose only one organism in this version of MiMI The default is Homo Sapiens Filter by Interaction type from the pull down list or choose All Interaction Types the default is All Interaction Types Click on the MiMI Interaction Query button to submit your search A summary of Interactions appears See Figure 6 Details include when available GO annotations and Interaction Type 14 If no records meet your search criteria or if the search does not meet Lucene rules MiMI provides a message 5 Click on View hyperlinked to see more details for any of the interactions g Michigan Molecular Interactions MMI NCiBI Integrating Gene and Molecule Interactions Search Results Interactions Search Results Figure X6 Summary of Interactions Results Screen 3 4 Strategies for Changing Results After Searching If no search results appear after your query or the results do not contain an entry of interest to you reformulating your search may be of use Understanding how MiMI merges data may also be helpful in reformulating your search strategy or explaining your search results Please refer to the How MiMI Merges Data in the Licensing and Background section Relaxing c
17. one organism in this version of MiMI the default is Homo Sapiens Click on the MiMI Search button to submit your search The Query Results Overview screen appears MiMI treats the list as ORs providing all records that have a match to any the names or IDs See Figure 4 Overview details summarize aliases Description text and GO annotations and they indicate the number of interactors the gene has the number of articles associated with the gene and the number of pathways containing it If no records meet your search criteria or if the search does not meet Lucene rules MiMI provides a message Click on a gene name hyperlinked to view more details for that gene Figure 3 g Michigan Molecular Interactions i MIMI NC BI Integrating Gene and Molecule Interactions oe bromo samens Search Results i SS ee ee OE Eee eee LES LOSS L Eata EROUL Mams protam ae cgale t A TEST peatee Figure 3 4 Query Results Overview for List of Gene Search srecallaler e EIAM 3 3 Query Interactions Search Entering a gene list search and MiMI s search for results The Query Interactions search has its own entry boxes Click Query Interactions next to the free text search box to get to this display see Figure 5 13 s Michigan Molecular Interactions MMI NCIBI Integrating Gene and Molecule Interactions Figure 3 5 Query Interaction Search entry form By typing in the gene s
18. onstraints Your query may be too specific If you searched for insulin receptor AND cellularComponent nucleus AND molecularFunction transcription AND organism homo OR organism dro then your search may be too specific Try relaxing some constraints Remember MiMI does not populate every field If you are only interested in something that occurs in the nucleus a protein may exist in the nucleus but MiMI does not contain that information Drop search terms until you have a good result set Dealing with Unknowns If your search does not contain the entries you sought consider broadening your search by eliminating unknowns For instance some proteins have dozens of names However MiMI may not be aware of the exact name you specified Try typing in the base name and using a wildcard to fill in the rest For example if you were looking for HNF4 alpha and typed hnf4_alpha no results are returned However by typing hnf4 several versions of HNF4 alpha are returned 15 4 Scanning the Search Results Overview 4 1 Interacting with the Search Results Screen A successful free text or gene list search produces results displayed in a tabular format below your query entry figure Y1 Results are displayed in groups of twenty Step by step procedures You can interact with this screen in numerous ways as follows 1 Goto more details Click hyperlinks to move to specific results pages as follows Gene name gt Gene details page Int
19. processes that you can test through further experimentation Specifically with MiMI you can conduct the following analytical tasks Search Specifiy target genes or keywords and move directly to information about them and link out to other sources e g to PubMed articles PFam Streamline your search process to find confirmatory articles that you can cite in a manuscripts proposals or presentations Browse Enter queries and explore results to confirm your expectations prior knowledge or findings from other bioinformatics methodologies Uncover previously unknown information that pertain to your research e g pairwise protein interactions that are new to you Locate skim and download potentially relevant articles quickly Scan NLP extracted passages relevant to formulating an hypothesis Distinguish and validate relationships of interest Find multidimensional relationships between genes or gene products e g genes with similar molecular functions and or shared pathways other organisms in which genes of interest are found Gain confidence in potentially interesting relationships by seeing number of interactions types and counts of experiments identifying an interaction articles discussing a relationship or interaction Filter to adjust the relationships of interest and either export or further explore that information Link out for additional details about the molecules and interactions relevant to your research e g go to BLAST
20. rotein interaction data exists in a number of repositories Each repository has its own data format molecule identifier and supplementary information Michigan Molecular Interactions MIMI assists scientists searching through this overwhelming amount of protein interaction data MiMI gathers data from well known protein interaction databases and deep merges the information Utilizing an identity function molecules that may have different identifiers but represent the same real world object are merged Thus MiMI allows the users to retrieve information from many different databases at once highlighting complementary and contradictory information To help scientists judge the usefulness of a piece of data MiMI tracks the provenance of all data Finally a simple yet powerful user interface aids users in their queries and frees them from the onerous task of knowing the data format or learning a query language MiMI allows scientists to query all data whether corroborative or contradictory and specify which sources to utilize MiMI is part of the National Center for Integrative Biomedical Informatics NCIBI and is publicly available at http mimi ncibi org 1 Background on MiMI 1 1 What is MiMI MIMI Michigan Molecular Interactions is part of the NIH s National Center for Integrative Biomedical Informatics NCIBI It provides access to the knowledge and data merged and integrated from numerous protein interactions databases It augments
21. tation the implied warranties of merchantability and fitness for a particular purpose The Regents of the University of Michigan shall not be liable for any damages including special indirect incidental or consequential damages with respect to any claim arising out of or in connection with the use of this website or data even if it has been or is hereafter advised of the possibility of such damages The data integration service is supplied under the conditions of the original data sources and the specific terms of use for MiMI Access to this website is provided free of charge Permission is granted to use this software and data internally only so long as no fee is charged usage of this website is cited in any resulting publications involving results from such use and so long as the name of the University of Michigan is not used in any advertising or publicity pertaining to such use without specific written prior authorization Permission to redistribute this data in any form is specifically not granted Software Products Used MiMI and the MiMI Web Site are built on a number of standard open source software tools 1 Timber http www eecs umich edu db timber In the TIMBER project we are exploring the issues involved in storing XML in native format We recognize XML documents to be trees and built a system to manipulate collections of trees In doing so we attempt to avoid the pitfall of instance at a time navigational access Ra
22. ther we attempt to bring to bear the core ideas of database technology such as declarative querying a bulk algebra and cost based query optimization 2 Tomcat http tomcat apache org Apache Tomcat is the servlet container that is used in the official Reference Implementation for the Java Servlet and JavaServer Pages technologies The Java Servlet and JavaServer Pages specifications are developed by Sun under the Java Community Process 3 Lucene http lucene apache org java docs Apache Lucene is a high performance full featured text search engine library written entirely in Java It is a technology suitable for nearly any application that requires full text search especially cross platform 4 Cytoscape http www cytoscape org Cytoscape is an open source bioinformatics software platform for visualizing molecular interaction networks and integrating these interactions with gene expression profiles and other state data How to Cite MiMI Please use the following citation for this web site the PubMed Citation Magesh Jayapandian Adriane Chapman V Glenn Tarcea Cong Yu Aaron Elkiss Angela lanni Bin Liu Arnab Nandi Carlos Santos Philip Andrews Brian Athey David States H V Jagadish Michigan Molecular Interactions MiMl Putting the Jigsaw Puzzle Together Nucleic Acids Research 2007 Vol 35 Database issue D566 D571 The URL http nar oxfordjournals org cgi content full 35 suppl_1 D566 The abstract P
23. ymbol Gene name from Entrez Gene pubcount The number of documents related to a given gene or pairwise interaction genetype Distinctions such as protein DNA scitaxname Interactioncount The number of interactions associated with a gene s products taxid The numeric ID of an organism taxname Table 3 1 Gene related fields on which MiMI searches to retrieve results from free text searches Entering multiple terms search logics and filters Free text search lets you do the following e Enter multiple terms e Specify search logic with Boolean operators nesting parentheses or quotation marks e Narrow searches to just one field by specifying a field name for the given term e Run a wildcard search using using only part of the spelling of a term e Filter through a pull down list to any one organism type Constraints Certain rules constrain your searches Boolean operators must be capitalized The Boolean operator NOT is not available for use in this version of MiMI search terms themselves are not case sensitive The free text search treats commas as an AND The pull down Organism filter permits only one choice If desired search on multiple terms using Lucene logics and get the following results For more on Lucene queries see http lucene apache org java docs queryparsersyntax html You enter You get AND e g insulin AND receptor Records that contain all of the terms
24. ymbols of two genes you can quickly see results in the form of detailed information about the interaction if MiMI records in fact show that the two genes interact If no interactions are recorded MIMI gives a message that nothing is found to display Use this search method as well if you want results showing detailed information about all the interactors associated with any one gene If you leave the second interactor text box blank MiMi treats it as a wildcard and finds and displays all interactors with the gene products for the gene symbol or ID you entered Constraints You must enter a Gene Symbol Any other entry results in an error null result set MIMI only searches the Gene Name field for the entries you submit This version does not search the Other Gene Name field so it is important to type in the gene symbol that MIMI recognizes as the main name No wildcard entries are permitted Unlike other search modes this one is not Lucene You can filter by Organism Interaction type or both by using the pull down lists to the right of the text boxes This version of MilMI allows only one filter term at a time in each of these fields You cannot filter on any other fields Step by step procedures 1 Move to the Query Interaction display from MiMI home by clicking Query Interactions To get results on a specific pairwise interaction Type a gene symbol or ID into the Gene 1 and Gene 2 box You cannot mix Gene symb
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