micrornas are small endogenous rna molecules that affect many biological processes by regulating gene expression in a post - transcriptional way . they are 2122  nt in length whose primary role is to regulate gene expression through translational repression and/or mrna degradation ( 1 ) . the first mirna molecules and mirna targets were identified in 1993 via classical genetic techniques in caenorhabditis elegans ( 2 ) . since then , there has been a dramatic increase in the number of mirnas registered in mirbase ( 3 ) . in parallel , the development of the first computational target prediction programs ( 47 ) led to the experimental identification of dozens of mirna targets ( 8) , and emphasized the need to provide mirna target predictions in an efficient way to assist biologists in experimental design . the previous version of the diana - microt web server ( 9 ) presented extensive information for predicted mirna target gene interactions in a user - friendly interface . it offers links to nomenclature , sequence and protein databases , information for experimentally verified targets through tarbase ( 8) and targets predicted by pictar ( 6 ) or targetscan ( 10 ) . also , users are facilitated by being able to search for targeted genes using different names or functional features . here , we describe an extensive update of this web server with several important improvements : ( i ) an advanced bibliographic analysis which correlates mirnas to diseases , ( ii ) support for two additional species , ( iii ) a graphical display with all relevant functional information from the ucsc genome browser , ( iv ) tracking of changes in mirna nomenclature and ( v ) user personalized sessions allowing personal query history and bookmarks . diana microt web server provides functional analysis of mirnas that reaches beyond a simple listing of mirna targets through integration of knowledge extracted from bibliography and known biological pathways . in the previous version of the web server , bibliographic integration considered automated searches in pubmed providing publications related to a mirna , each target gene or combination of the two . related diseases has been added that directly associates a mirna to publications connected to one or several diseases . this feature is based on information included in the title or the abstract of publications found in pubmed . all abstracts associated with a mirna are retrieved from pubmed , based on the presence of the name of the mirna or a member of its family , as defined by mirbase , in the title or abstract of the publication . the retrieved publications are associated with medical subject headings ( mesh ) , the national library of medicine 's controlled vocabulary thesaurus , through their metadata . all disease associated mesh terms for a mirna are counted and visualized through a tag cloud ( figure 1 ) , where mesh terms appear in a size proportional to the number of publications reporting this mirna - disease association . the mesh terms of the tag cloud also serve as hyperlinks to the relevant publications . for example , in figure 2 mir-455-star ( mir-455 * ) has been associated with a publication indicating that lower expression of this mirna correlates with poor overall survival in endometrial serous adenocarcinoma ( 11 ) . figure 1.an example of a tag cloud for hsa - mir-1 showing relevant disease associated mesh terms . 
 figure 2.example of a diana - microt web server results page . related diseases tag cloud contains links to pubmed and specifies all papers which associate the particular disease with the corresponding mirna . pubmed links provides automated bibliography searches based only on the name of mirnas , protein coding genes or the combination of both . ucsc graphic link presents the predicted binding sites in a ucsc genome browser window along with tracks such as snps and repeat elements . the left side of the page is devoted to the administration of the user personal space and reports their latest searches and bookmarks . an example of a tag cloud for hsa - mir-1 showing relevant disease associated mesh terms . related diseases tag cloud contains links to pubmed and specifies all papers which associate the particular disease with the corresponding mirna . pubmed links provides automated bibliography searches based only on the name of mirnas , protein coding genes or the combination of both . ucsc graphic link presents the predicted binding sites in a ucsc genome browser window along with tracks such as snps and repeat elements . the left side of the page is devoted to the administration of the user personal space and reports their latest searches and bookmarks . the feature that allowed the user to filter the targets of a mirna based on kegg pathways ( 12 ) is now integrated in the initial input query form . the user has now the option to enter a mirna together with names of pathways of interest and provided immediately with only the mirna target genes found in the pathways of interest . for example , a query for hsa - mir-221 would return 113 predicted targets at a score threshold of 0.5 while the combined search of the mirna with the term  mapk - signaling - pathway would filter the results to 21 relevant targets . in addition , the positions of the binding sites on the mrna of the target gene are graphically presented through the ucsc genome browser . this automatic upload can be used to provide information in comparison to other tracks of interest such as single nucleotide polymorphisms ( snps ) , repeat elements and alternative 3-utr splice forms . the relation of mirnas to function and diseases described above is based on mirna nomenclature . since mirna biology is still a field in flux , it can occur that a mirna may change name between two successive versions of mirbase . due to such changes , researchers may lose track of a mirna full history and related literature searches will remain incomplete . to address this issue , an extended analysis on 13 versions of mirbase ( versions 7.1 . to 14 ) is performed , and the nomenclature history of each mirna is extracted . this version includes 1884 mature mirnas for the four species supported in the web server . mimat id and one associated mirna specific name . among versions , changes are found in 77 mimat ids ( 38 in human , 37 in mouse and 2 in drosophila ) and 151 mirna names ( 76 in human , 71 in mouse and 4 in drosophila ) . this indicates that name changes are more frequent than changes in mimat ids . to keep track of these changes , its name was later changed to mmu - mir-455 - 5  p in version 8.2 and later appeared as mmu - mir-455 * in version 10.0 ( figure 3 ) . this information can be retrieved from the mirna history , but is also used to extend the association of mmu - mir-455 * with endometrial serous adenocarcinoma in the publication where it is referred to as mir-455 - 5  p ( figure 2 ) . figure 3.graphic presentation of the changes involved in the history of mirna mmu - mir-455 . initially , mimat0003485 was presented in version 8.1 as mmu - mir-455 but its name changed consecutively to mmu - mir-455 - 5  p in version 8.2 and mmu - mir-455-star ( mmu - mir-455 * ) in version 10.0 . similarly , mimat0003742 was first presented in version 8.2 as mmu - mir-455 - 3  p , while in version 10.0 , its sequence changed and it was renamed to mmu - mir-455 . initially , mimat0003485 was presented in version 8.1 as mmu - mir-455 but its name changed consecutively to mmu - mir-455 - 5  p in version 8.2 and mmu - mir-455-star ( mmu - mir-455 * ) in version 10.0 . similarly , mimat0003742 was first presented in version 8.2 as mmu - mir-455 - 3  p , while in version 10.0 , its sequence changed and it was renamed to mmu - mir-455 . the first version of diana - microt web server was designed to support the functional analysis of human and mouse mirnas . now the server has been updated with predictions for two additional species and newer versions of mirbase ( mirbase 13 ) and ensembl ( ensembl 54 ) ( 13 ) . in total predictions for 723 new mirnas have been added , out of which 147 correspond to drosophila melanogaster , 154 to c. elegans and the rest being new homo sapiens and mus musculus mirnas . this results in an approximately doubled number of predicted targets in comparison to the previous version , totaling to more than six million predicted target genes . the web server can support different prediction algorithms and currently provides the targets of an updated version of the previously used algorithm ( 14 ) . while microt - v3.0 is based on features separating real and mock ( shuffled ) mirnas the current version , microt - v4.0 , uses high throughput experimental data for the same purpose ( 15 ) . to allow users to take full advantage of the web server 's functions , the most important is an integrated personal user space in which users can easily save important searches and results that they wish to keep for future analysis . in particular , the system keeps the most recent user searches , giving the opportunity to repeat searches . a bookmarking mechanism provides the opportunity to save interesting results along with user comments . the personal space provides usage statistics regarding the most recent searches , thus , enabling them to keep track of their latest findings . it is noted that researchers may use any feature of the web server irrespectively of the personal user space feature . finally , special attention has been given to the web server documentation introducing hovering help notes for important fields . diana microt web server provides functional analysis of mirnas that reaches beyond a simple listing of mirna targets through integration of knowledge extracted from bibliography and known biological pathways . in the previous version of the web server , bibliographic integration considered automated searches in pubmed providing publications related to a mirna , each target gene or combination of the two . related diseases has been added that directly associates a mirna to publications connected to one or several diseases . this feature is based on information included in the title or the abstract of publications found in pubmed . all abstracts associated with a mirna are retrieved from pubmed , based on the presence of the name of the mirna or a member of its family , as defined by mirbase , in the title or abstract of the publication . the retrieved publications are associated with medical subject headings ( mesh ) , the national library of medicine 's controlled vocabulary thesaurus , through their metadata . all disease associated mesh terms for a mirna are counted and visualized through a tag cloud ( figure 1 ) , where mesh terms appear in a size proportional to the number of publications reporting this mirna - disease association . the mesh terms of the tag cloud also serve as hyperlinks to the relevant publications . for example , in figure 2 mir-455-star ( mir-455 * ) has been associated with a publication indicating that lower expression of this mirna correlates with poor overall survival in endometrial serous adenocarcinoma ( 11 ) . figure 1.an example of a tag cloud for hsa - mir-1 showing relevant disease associated mesh terms . 
 figure 2.example of a diana - microt web server results page . related diseases tag cloud contains links to pubmed and specifies all papers which associate the particular disease with the corresponding mirna . pubmed links provides automated bibliography searches based only on the name of mirnas , protein coding genes or the combination of both . ucsc graphic link presents the predicted binding sites in a ucsc genome browser window along with tracks such as snps and repeat elements . the left side of the page is devoted to the administration of the user personal space and reports their latest searches and bookmarks . an example of a tag cloud for hsa - mir-1 showing relevant disease associated mesh terms . related diseases tag cloud contains links to pubmed and specifies all papers which associate the particular disease with the corresponding mirna . pubmed links provides automated bibliography searches based only on the name of mirnas , protein coding genes or the combination of both . ucsc graphic link presents the predicted binding sites in a ucsc genome browser window along with tracks such as snps and repeat elements . the left side of the page is devoted to the administration of the user personal space and reports their latest searches and bookmarks . the feature that allowed the user to filter the targets of a mirna based on kegg pathways ( 12 ) is now integrated in the initial input query form . the user has now the option to enter a mirna together with names of pathways of interest and provided immediately with only the mirna target genes found in the pathways of interest . for example , a query for hsa - mir-221 would return 113 predicted targets at a score threshold of 0.5 while the combined search of the mirna with the term  mapk - signaling - pathway would filter the results to 21 relevant targets . in addition , the positions of the binding sites on the mrna of the target gene are graphically presented through the ucsc genome browser . this automatic upload can be used to provide information in comparison to other tracks of interest such as single nucleotide polymorphisms ( snps ) , repeat elements and alternative 3-utr splice forms . the relation of mirnas to function and diseases described above is based on mirna nomenclature . since mirna biology is still a field in flux , it can occur that a mirna may change name between two successive versions of mirbase . due to such changes , researchers may lose track of a mirna full history and related literature searches will remain incomplete . to address this issue , an extended analysis on 13 versions of mirbase ( versions 7.1 . to 14 ) this version includes 1884 mature mirnas for the four species supported in the web server . mimat id and one associated mirna specific name . among versions , changes are found in 77 mimat ids ( 38 in human , 37 in mouse and 2 in drosophila ) and 151 mirna names ( 76 in human , 71 in mouse and 4 in drosophila ) . this indicates that name changes are more frequent than changes in mimat ids . to keep track of these changes , its name was later changed to mmu - mir-455 - 5  p in version 8.2 and later appeared as mmu - mir-455 * in version 10.0 ( figure 3 ) . this information can be retrieved from the mirna history , but is also used to extend the association of mmu - mir-455 * with endometrial serous adenocarcinoma in the publication where it is referred to as mir-455 - 5  p ( figure 2 ) . figure 3.graphic presentation of the changes involved in the history of mirna mmu - mir-455 . initially , mimat0003485 was presented in version 8.1 as mmu - mir-455 but its name changed consecutively to mmu - mir-455 - 5  p in version 8.2 and mmu - mir-455-star ( mmu - mir-455 * ) in version 10.0 . similarly , mimat0003742 was first presented in version 8.2 as mmu - mir-455 - 3  p , while in version 10.0 , its sequence changed and it was renamed to mmu - mir-455 . initially , mimat0003485 was presented in version 8.1 as mmu - mir-455 but its name changed consecutively to mmu - mir-455 - 5  p in version 8.2 and mmu - mir-455-star ( mmu - mir-455 * ) in version 10.0 . similarly , mimat0003742 was first presented in version 8.2 as mmu - mir-455 - 3  p , while in version 10.0 , its sequence changed and it was renamed to mmu - mir-455 . the first version of diana - microt web server was designed to support the functional analysis of human and mouse mirnas . now the server has been updated with predictions for two additional species and newer versions of mirbase ( mirbase 13 ) and ensembl ( ensembl 54 ) ( 13 ) . in total predictions for 723 new mirnas have been added , out of which 147 correspond to drosophila melanogaster , 154 to c. elegans and the rest being new homo sapiens and mus musculus mirnas . this results in an approximately doubled number of predicted targets in comparison to the previous version , totaling to more than six million predicted target genes . the web server can support different prediction algorithms and currently provides the targets of an updated version of the previously used algorithm ( 14 ) . while microt - v3.0 is based on features separating real and mock ( shuffled ) mirnas the current version , microt - v4.0 , uses high throughput experimental data for the same purpose ( 15 ) . to allow users to take full advantage of the web server 's functions , several functional improvements have been implemented ( figure 2 ) . the most important is an integrated personal user space in which users can easily save important searches and results that they wish to keep for future analysis . in particular , the system keeps the most recent user searches , giving the opportunity to repeat searches . a bookmarking mechanism provides the opportunity to save interesting results along with user comments . the personal space provides usage statistics regarding the most recent searches , thus , enabling them to keep track of their latest findings . it is noted that researchers may use any feature of the web server irrespectively of the personal user space feature . finally , special attention has been given to the web server documentation introducing hovering help notes for important fields . in recent years it has become apparent that web applications are an essential tool for researchers to decipher complex biological processes . as one of these , the diana microt web server has been updated to integrate different additional resources in order to offer insight for putative mirna involvement in biological processes , and to allow researchers to supplement their knowledge with already published scientific material . performing an extended analysis on the versioning pattern of mirbase the history of each mirna has been extracted , offering a unique feature in computational mirna analysis . we believe that the current web server update provides important tools for biological analysis and improves interaction with the complicated interconnections regarding mirna functionality . the hellenic republic , general secretariat for research and technology ( 09syn-13 - 1055 ) . funding for open access charge : 09syn-13 - 1055 .