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1. Gene List Genomatix Knowledge Base Complete Gene Relation Network 2007 Genomatix Software GmbH 9 Introduction to BiblioSphere PathwayEdition Genomatix understanding gene regulation BiblioSphere PathwayEdition BSPE provides different kinds of views to the large amount of information that is included in the gene regulation networks 2D view Application of shortest path algorithm allows focusing on different genes and their shortest path to the genes within the network The Genomatix Knowledge base is continually updated to provide the most current data from literature and sequence analysis 3D view Quick identification of closely related gene groups The distance between the entities in the 3D view reflects the number of abstracts in which the two genes are co cited Biological Scoring Networks are scored according to overrepresentation of genes in biological categories such as biological process disease tissue etc A total of 10 different categories is available 2007 Genomatix Software GmbH Genomatix lyses left unlimited Fie View Filter Extras Data BiblioSphere search BiblioSpheres intersection 1 FreeTextFilter CoCitationFilter UserDataFilter B Cocitation Browser FF Genes E Documents s TF Analysis af Gene gene connections BiblioSphere 3D BiblioSphere Pathway View show n 8 KE EE nemen DR S 2 input genes F
2. k Analysis Results Hernia H sapiens MeSH term search 107 abstract s containing cocitations found Cluster Centered BiblioSpheres CCBS A CCBS shows all genes classifiers connected with at least one member of your input set of genes classifiers View Cluster Centered BiblioSphere Example SGBS list Analysis Results Analysis_GeneNameSearch Single Gene Centered BiblioSphere A SGBS shows all genes classifiers connected with your input gene All second level connections are computed only when your input gene is involved TOM1 of Homo sapiens 77 genes classifiers fullname target of myb1 chicken locusid 10043 synonyms TOM1 News of Homo sapiens 11 genes classifiers fullname target of myb1 like 2 chicken locusid 146691 synonyms TOM1L2 FLI32746 Nam of Homo sapiens 14 genes classifiers fullname target of myb1 like 1 chicken locusid 10040 synonyms TOM1L1 SRCASM Both a CCBS and an SGBS list are available if the gene identifiers were provided by file upload or if group of genes was selected in a gene name based search If any of the input gene identifiers were not recognized by BiblioSphere they are listed in an extra table You can switch between these different views Example CCBS view a Analysis Results Analysis_FileUpload3 3 identifiers could be mapped to a gene Cluster Centered BiblioSpheres CCBS A CCBS shows all genes classifiers connected with at least one memb
3. the customize option All changes you make will apply to the selected node only You can set the following attributes Background Clicking the color bar opens a dialog for selecting the background color Border Un checking this option removes the border from the node box default is on Filled This checkbox toggles the background on off default is on Font You can change the font font size and markup of the displayed text Icon Allows you to change the icon displayed in the node box Shadow Toggles the node box s shadow on off default is on Text Changes the text displayed in the node 3D View Overview The BiblioSphere 3D view lets you navigate the literature in a unique but intuitive way Animated 3D graphs allow the identification of complex gene relation structures at first sight The 3D View reflects the co citation frequency as the distance between two genes The more often two genes occur in the same abstract or sentence the closer they are in the Literature Molecule You can get the information on how often two genes are co cited by simply moving your mouse pointer over the connecting lines between the spheres that represent these genes For the lines connecting a gene to become visible you move the pointer over the gene of interest while the Show gene connections option is active Placing the pointer over a gene displays its full name and Locus ID To turn the graph you can click and drag anywhere in the view pane Alt
4. Help A description for the project used in the BSPE manual 2006 03 01 Project folder B 3 s launch bibliosphere LS edit analysis project La new analysis delete analysis project If you encounter any problems please contact support genomatix de Genomatix Software GmbH 1998 2006 All rights reserved Create a New Analysis You can add a new analysis to a project by clicking on the new analysis symbol in a project row this will create a gene name search based analysis Alternatively you can select an analysis from the Project Manager menu There are five different ways to provide the data you want to analyze e Input a list of gene names or Gene IDs e Upload an Excel file containing the gene names or IDs e Enter free text search terms e Enter a list of MeSH terms e Input a list of PMIDs Common to all of them you enter a title and an optional description for your analysis and select the project you want to link it to Also you select the species in which you are going to search for genes connected to your input data At present available species are human mouse chicken rat zebrafish chimpanzee dog cow rhesus monkey and C elegans Entering Gene Identifiers comprised of more than one word necessitates the use of quotation marks 2007 Genomatix Software GmbH 34 Starting an Analysis Genomatix BiblioSphere PathwayEdition understanding gene regulation Input Data BSPE searches
5. If you should run into trouble logging onto our serwer please first read http portall O genomatizx de online help help techtag html After that do not hesitate to contact us in case of any problems or questions Best regards Your Genomatix support team Vu EN dd a a a a a a a dd dv d V EN del dv d V EN del dv d V oo oo Cd dw dx Eu Cd oo Eu Cd dw dv Ex Cd dw dv EN Cd dw dv xd Cd dw du Ed dd dw For comments ar suggestions please contact Genomatix Software at supporthgenomatix de ee ee eee eee ee The login and password is not only valid for BiblioSphere PathwayEdition but for all Genomatix products Change Password Open your internet Browser and switch to www genomatix de Click on Login in the upper right corner of the webpage see above Enter your login and password which was sent to you via e mail E Genomatix Login Page Mozilla File Edit View Go Bookmarks Tools Window Help S a A ee me a AL http portall 0 genomatix de cgi bin sessions l e CA a Back Reload 4 pill g K ch 2 Print r i Zh Home WE Bookmarks L mozilla org L mozillaZine L mozdey org Genomatix GenomatixPortal Switch to encrypted login page Please log in Username bmustermann Password Register fora free of charge evaluation account if you haven t done so yet Lost your password Click here to retrieve your account info if you lost your username and or password For comments questions or bug reports pl
6. gt TP53 promoter 12625370 E2F1 gt E2F1 activated the p53 gt TP53 promoter through E2F1 gt E2F 1 binding site When E2F1 gt E2F1 was cotransfected with HBx E2F1 gt E2F1 overcame the repressive effect of HBx on the p53 gt TP53 promoter through the E2F1 gt E2F 1 site Expert level Hand annotated co citation of E2F1 and TP53 15255934 Overexpression of E2F 1 gt E2F 1 in PC12 cells was sufficient to induce p53 gt TP43 and Bax protems as well as nuclear fragmentation Signal transduction associations E2F1 and TP53 are co cited in a sentence containing a pathway associated term ochre background at least one of the co cited genes bears a Genomatix signal transduction pathway annotation 16582589 Myc and E2F1 gt E2F 1 engage the AT eto d ing pathway to activate p53 gt TP53 and induce apoptosis Implications The Abstract level comprises all gene gene co citations available from the literature without ignoring any information The advantage of this level is the broad statistical basis The advantage of the other filter levels is the increasing specificity 2007 Genomatix Software GmbH 64 Network Filtering Genomatix BiblioSphere understanding gene regulation PathwayEdition Free Text Filter The Free Text Filter filters the documents that make up your BiblioSphere by a full text search with your query terms Use prefixes separated by a colon fro
7. understanding gene regulation 2007 Genomatix Software GmbH For more information please contact Genomatix Software GmbH Bayerstr 85a 80335 Munich Germany Phone 49 89 599766 0 Fax 49 89 599766 55 Email info genomatix de WWW http www genomatix de Genomatix BiblioSphere understanding gene regulation Path wayE dition Table of Contents Kiel CONN E 2 Introduction to BiblioSpnere FatbwawbgltIoft euserEeSENENEVENENENENESENENENENENEVENENENENESENESENENEENENEKENENEEENENENENENEeH 4 Knowledge Database s ssassnnnnnnnsnnnnnnnnnnnnnnnnnnnnnnnnsnnnnnnnnnnsnnnnnnnnnnsannnnnnnnnnannnnnnnnnsnnnnnnnnnnnnnnnnnnnnnnnn 5 What Data iS BSPE EE 5 Memos anad DIa SO CSS acces sce te te eeepc eee eens nce eae ceee gece oan cee gee avec araeeesecccencaces 6 Network Generation and Analysis NNN 8 Data Input Network Calculation and Biological Ranking NENNEN 8 User Controlled Network Construction and Analysis uk 9 Rain le Fe SCM STS TNS age ese se EE 12 aparand SV Tu e 12 Java Runtime ENVIFOMIMGN eege ege EE RER AEERK DEENEN REEERE ENEKEN SERA EEEREEAEEEAEERE ER AEEE RER AER LEEEE ERR EEEEEE ERR 12 COmmmeCtiOnn EO Tine Ter NG E 14 Installation OF BSP E 14 DOs eT Te Sr er er cr rc rrr re 14 Gar Ladin ana PAS SAO eee etree cece ee eee te ster tr ser ee cere tee ere eee ee ere te 16 eege GIO M E 16 Change Password ee 18 Kee elle ATTE E E A 19 ee WE Le E 20 Configuration OF BSPE E 22 Beer aol ie le E 24 CR gen te UO 25 Bei Ver
8. 10 3 or higher Linux Unix DOWNLOAD 64 MB T use Manual Domm 1 8 MB 2007 Genomatix Software GmbH 14 Technical Requirements Genomatix BiblioSphere understanding gene regulation PathwayEdition Clicking on the download icon will result in the following screen Opening InstallbenomatxA pplications exe The file Installsenomatix4pplications exe is of opge a application msdos program 4anwendung and Mozilla does nok know how to handle this File type This File is located at ARES waat genomatix de What should Mozilla do with this File O openitwith OO Save it to disk Always perform this action when handling Files of this type Choose the option save to disk and click ok A window will show up where you can choose a folder to save the file Choose the folder where you would like to save the installer and press ok If the installer is successfully downloaded Windows users should see the following icon with the subtitle InstallGenomatixApplication exe Installaenomatixapplic Mac users will find a folder named GenomatixApplications on their desktop or in their designated download folder It contains an installer package a ReadMe and the license file Double clicking the GenomatixApplications installer package will start the installation of the software L GenomatixApplicatio A _ GenomatixApplications Ki GenomatixApplications _ Rea
9. B Cocitation Browser Genes E Documents sa TF Analysis af Gene gene connections BiblioSphere 3D SE BiblioSphere Pathway View E undock RA e x ER SVG Legend ACADYL v help Relationship between ALDH3A1 and HBB l abstract s with cocitations BO No cocitation s on sentence level B1 No cocitation s on function word level B2 No cocitation s on gene function word gene level B3 Node Info Unconnected Nodes Gene symbol ALDH3A1 id 218 a Full Name aldehyde dehydrogenase 3 family member 1 Analyze Promoter s of ALDH3A1 show BiblioSphere for ALDH3A1 Get FlDorado annotation for 218 show comparative Genomics for ALDH3A1 Remove ALDH3A1 from BiblioSphere TDieserintion Gildebazde dehudrocenaces ovidive A 2007 Genomatix Software GmbH 51 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Network Customization Gene focus Selecting a gene symbol from the gene selection list in the toolbar redraws the network graph centred on the selected gene Position of gene nodes You can drag a node to manually change its position Clicking the Layout Optimization button will reset the layout based on the graph optimization algorithm Gene node appearance You might want to customize the appearance of a node in the network graph e g to highlight a gene of interest Right clicking a node will open a context menu To open a customization dialog choose
10. Full Name v myc myelocytomatosis viral oncogene homolog avian Analyze Promoter s of MYC show BiblioSphere for MYC Get ElDorado annotation for MYC Show matrix info for VSEBOX Sa E raner show comparative Genomics for MYC Ba Remove MYC from BiblioSphere a staca Description The protein encoded by this gene is a multifunctional nuclear Esebur phosphoprotein that plays a role in cell cycle progression apoptosis and cellular transformation It functions as a transcription factor that regulates transcription of specific farget genes Mutations overexpressiqn gt rearrangement and transipcation of this z NR3C1 Pathway Panel Node Info Panel Display symbols for input genes are highlighted blue currently selected genes dark blue Different symbols are used to mark special properties Gene product is a transcription factor ST Gene product is part of a Genomatix signal transduction pathway IN Input gene only in CCBS M Gene product is part of a metabolic pathway U User annotated gene Position the mouse pointer over a gene symbol to display the gene s full name and Gene ID 2007 Genomatix Software GmbH 42 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Connection Modes Functional relationships between co cited genes are visualized by the connection lines between the genes Connection with no expert curated annotations Open arrowhead indicates reg
11. Inputting your Data Sign In Clicking the green arrow symbol on the BSPE start screen opens a dialog where you enter your username and password to connect to your BiblioSphere server Authentication request Host requests Authentication wua genomatix de Realm online account Protocol http Username Password Cancel 2007 Genomatix Software GmbH 32 Starting an Analysis Genomatix BiblioSphere understanding gene regulation Path wayE dition Project Management You start off with your analyses in the Project Manager panel Projects group your analyses for easier identification and retrieval of results E Genomatix Bibliosphere ile View Extras Data Analyses left unlimited EES BiblioSphere search E undock 4 back gt reload home BI save p amp print e BiblioSphere Genomatix eile donde a Version 7 20 e Project Manager Project Manager 2 Personal Page E New Project Name Description Created Type Action Help launch bibliosphere L edit analysis project La new analysis delete analysis project If you encounter any problems please contact support qgenomatix de Genomatix Software GmbH 1998 2006 All rights reserved Create a New Project Clicking New Project opens a panel where you can enter a name for your project and an optional description The new project is added to the project list in the Project Manager panel OGenomatix Bibliosphere Fil
12. and network views as well 2007 Genomatix Software GmbH 70 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation Statistical Analysis Statistical Rating Every hierarchical filter added to a BiblioSphere is statistically analyzed for over and underrepresented terms based on the number of observed and expected annotations for each term The z score of a term indicates whether a certain annotation or group of annotations is over or underrepresented in the treated set This helps you to determine whether the accumulation of annotations in a certain branch of the tree is meaningful To simplify the inspection of the results of this analysis a spreadsheet view is displayed The spreadsheet data can be exported easily to other applications such as MS Excel for further analysis Select Term in Corresponding Filter EE Annotations observed Observed value for Term Z Score of Term Dock Undock Upper threshold for Annotations expected Button Data Export ID of Term Observed value for Term Help Button Button Total number of Analyzed Term annotations for Term Sees 50Filter biological process ES dock rr Ste export data Minimum Observed 4 Maximum bserved 211 help C C om e el o J HE apoptosis Ao 0006915 6 1 11 vol 3 66 e response to DNA damage stimulus emeng 261 6o 0 51 response to endogenous stimulus amp 0 0009719 298 0 58 positive regulation of apo
13. annotation set and choose an icon that identifies genes with an annotation Data Import Assistant Steps Set display options W Select Excel sheet Your set of annotations will be made available in BiblioSpheres pathway view whenever there are gene ids y Select import columns matching your set in your current BiblioSpheres gene list You can enter a name and an icon of up to 16 x 16 f pixels 8 8 pixel images will look best For your annotation set or use the default values defined here gt Customize your annotation set Choose a name For your annotation set kmoking induc Upload image file or drag it to the preview area Icon preview Find File Muster HSB RGB LL eee BRETT BREET LISER TT TT ae V pp ERATAN LISER BREET BREET BREET BRELL LTL BREET BREET LIESER DREI TL hae TT hee Vorschau m g e E Seiten Beispieltext E E EEA Beispieltext Beispieltext If the selected file is a text file the Data Import Assistant will look like this Data Import Assistant Steps The Data Import Assistant tries to recognize the data Format of your imported file Please make sure gt Select data import Format that the file format was recognized correctly before you continue Original Format See the description that Fits best for the type of File you want to BS O Fixed Width Fields have a fixed length filled with blanks Begin import at line 1 y Preview of import file
14. configure the BSPE concerning Proxy configuration for internet access Security configuration for secure information transfer over the internet Application update to get the latest version of BSPE online BSPE offers a form for configuration which can be accessed as follows Start BSPE application Go to menu Extras and select Proxy settings to launch a preferences configuration dialog Genomatix Bibliosphere File View Extras BiblioSphere searct Login Analyses left snot connected pelle Proxy settings eS o 7 undoc reloa ome e Check for updates z Ge E print Preferences BiblioSphere PathwayEdition 2007 Genomatix Software GmbH 22 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation You will get the following dialog which consists of four forms for the different configurations G Preferences Proxy Configuration Update Frequency SSL Configuration Server Configuration Direct connection to the Internet Server HTTP Proxy Port SSL Proxy Port SOCKS Host Port Automatic proxy Configuration URL aaa Automatic search for proxy configuration OK Cancel Help 2007 Genomatix Software GmbH 23 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Proxy Configuration Many companies and institutions use proxies and firewa
15. connections Various tools facilitate focusing on the most relevant biological context BSPE is based on a client server architecture which includes the BiblioSphere PathwayEdition Knowledge Database BSPEKD on the server side and a retrieval visualization and analysis system for Network Generation and Analysis which is installed as a stand alone tool on the user s computer client side Server located at Genomatix or In House Genomatix _Knowledge Base Client Client 2007 Genomatix Software GmbH 4 Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation Knowledge Database The BiblioSphere Pathway Knowledge Database BSPEKD is a one of a kind structured resource of gene identifiers and relationships between biological entities Relationships are created from more than 15 million PubMed abstracts plus the analysis of Genomatix s world s largest quality checked promoter database for transcription factor binding sites with MatInspector Ontologies taxonomies and thesauri allow for dynamic superimposition to focus on the biological context relevant for your research What Data is BSPE Based on The primary source of BSPE data is NCBI PubMed This collection of over 16 million scientific abstracts is analyzed for co citations of quality checked gene names synonyms amp relation concepts The Genomatix collection of gene names and synonyms is composed of
16. input transcription factors tf A Relationship between CDK6 and DNTT Labstract s with cocitations BO EES ena No cocitation s on sentence level B1 EE No cocitation s on function word level B2 penes are coc S lee H No cocitation s on gene function 7 Sk min 1 max 13 word gene level B3 input genes genes are at least 16 1 1885 times cocited with one input gene Ee Abstract level BO Two genes are co cited within an abstract Sentence level B1 Two genes are co cited Function word level B2 Level B1 restricted to sentences with a function word Examples for function word regulation inhibit Node Info Unconnected Nodes Gene symbol CDK6 id 1021 AI Full Name cyclin dependent kinase 6 Analyze Promoter s of CDK6 Show BiblioSphere for CDK6 Get ElDorado annotation for CDK6 Show comparative Genomics for CDK6 Remove CDK6 from BiblioSphere Description The protein encoded by this gene is a member of the cyclin dependent protein kinase CDK family CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28 and Schizosaccharomyces pombe cdc2 and are known to be important regulators of cell cycle progression This kinase is a al Lombotartioartormndt afiha mentain Lit 0 m GFG level B3 gt Level B2 restricted to sentences with order gene function word gene Expert level B4 gt L
17. level B3 evel B2 restricted to sentences with order gene function word gene MYOD1 Expert level B4 J Level B4 restricted to CEBPA j sentences with expert 4 curated information lt gt v Filter settings CoCitationFilter Current BiblioSphere level is Sentence level plus function word This BiblioSphere is restricted to input and transcription factor genes Visible genes must be cocited with at least 10 of your input genes and cocited at least 5 time s with an input gene number of genes passing the filter 40 fe Genomatix Bibliosphere File View Filter Extras Data Analyses unlimited BiblioSphere search E 24vs0_test FreeTextFilter___ _CoCitationFilter__ Cocitation Browser ES Genes E Documents w TF Analysis af Gene gene connections BiblioSphere 3D 28 BiblioSphere Pathway view E GOFilter biological process UserDataFilter GOFilter biological process Po export data Minimum Observed 4 Maximum Observed 15606 help messe F Term ID I Total Observed Expected Z25core D Fy G0spbiologieal_process mitotic cell cycle G0 0000278 247 69 8 88 A 15 reproduction cell cycle GO 0007049 773 132 27 79 E 7 cell killing 73 cell cycle process GO 0022402 659 116 23 69 E 3 immune system process iA cell c
18. localization Gene symbols are subgrouped further according to sub compartmentalization Basic Navigation Nodes can be dragged with the mouse pointer to customize the layout A single click on a gene node displays summary info in the Node Info Panel which shows detailed information on the selected gene and provides links for further analysis The shortest path for each gene can be brought up by a double click on it in the Cellular Component View Panel Zoom In Out unknown Optimize Layout Localization membrane bound cytoplasmic Shortest Path On Off extracellular nuclear Export Image Help Button Gene Info Panel ranpformida Growth Fact F beta Pathway EH TissueFilter ZS Cellular Component View E GOFilfer cellfar component E GoOFilter biological process e o K ES Te hep CTGF 4FTH1 SC D growth factors STAT family members are phosphorylated TEGT CD44 by the feceptor associated kinases and then form homo or dcer and activator of transcription 3 ctor Mrs ec D STAT3 fro auoo Yeate sasr STAT3 Wank We EiDorado dnnotafion for STAT3 JN e for matrix fafo fof VESTAT YEN SS SSS been KA SCH Ch R J Jom BiblioSphere N iptign The protein encoded by this gene is a member ein family In response to cytokines and V N hat translocate to the cell nucleus where they act gs transcmption activators This prot
19. matrices of our matrix library have been improved D promoter module library For more information see the Release Notes For consistency and a smooth transition for the next few months you will be able to choose between GenomatixPortal keng Genomatix Suite Current Release December 05 Previous Release April 05 Account upgrades If you have purchased an account upgrade in our online shop and received a voucher code or if you received a voucher during a conference you can enter the voucher code here including the dashes Click Continue and a confirmation page will open stating that your account has been upgraded Users will not receive a voucher code if their account has already been upgraded during the online shop purchase or if the Genomatix staff did the upgrade manually For comments questions or bug reports please contact support genomatix de Genomatix Software GmbH 1998 2006 AH rights reserved License Agreement COCO Fa ict Be EN ei Fill in the form and click on Change Password to change your password Datei Bearbeiten Ansicht Chronik Lesezeichen Extras Hilfe 7 v T Gt Ss http www genomatix de cgi bin password password pl s d2e289ate vy gt Cl ZS Getting Started A Latest Headlines Genomatix tix e Deh eres KR GenomatixPortal Change password for your Genomatix online account Your username is bmustermann Please enter your old pass
20. node in the tree displays the term name and the number of genes annotated with this tissue term for your active BiblioSphere In the example above 406 genes are annotated with UniGene tissue names assigned to the leukocyte branch of the hierarchy 2007 Genomatix Software GmbH 69 Network Filtering Genomatix BiblioSphere understanding gene regulation PathwayEdition User Data Filter The User Data Filter is available if expression values were provided in the data file that was uploaded for analysis It allows you to define an exclusion range for these values so that only genes with an expression value below or above that range will be displayed If expression values from a multi class analysis were provided you can set the range for each experimental class separately Help Button Reset Button Freele CoCitationFilter UserDataFilber Filter nodes Column 1 Set exclusion range SE J Lower Exclusion Range Boundary 0 94 0 4 0 72 ES E Upper Exclusion Range Boundary 0 3 DA D Set enabled Toggle Filter for this Class on off Column 2 From 0 94 0 6 0 72 Fo 0 9 DS Me Set enabled Column 3 Set exclusion range m From RB 0 94 0 0 KE bo d 0 9 Da Of Set enabled L gt Sub Network Filter You can focus on gene subnets clusters by activating the Cluster View option in the BiblioSphere 3D View This will affect other tabular
21. to locate matches in sequences of unlimited length A large library of predefined matrix descriptions for protein binding sites exists and has been tested for accuracy and suitability Similar and or related matrices have been grouped into matrix families MatlInspector is almost as fast as a search for IUPAC strings but has been shown to produce superior results It assigns a quality rating to matches called matrix similarity and thus allows quality based filtering and selection of matches Individually optimized thresholds for the matrix similarity are available for all matrices Matlnspector has been described first by Quandt et al 1995 and more recently by Cartharius et al 2005 2007 Genomatix Software GmbH T Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation Shortest path calculation BSPE views use shortest path algorithms to calculate the optimal sub networks for all genes All pairs shortest paths Gene networks in BiblioSphere contain very large numbers of connections between genes Displaying all these connections in the pathway view would render it unreadable Therefore a strategy is needed to reduce the number of displayed edges without losing relevant information To achieve this BiblioSphere PathwayEdition always displays only the shortest paths from the focused gene to all other genes in the pathway view All other connections remain hidden unt
22. your username and or password For comments questions or bug reports please contact support qenomatix de Genomatizx Software GmbH 1998 2006 AN rights reserved License Agreement Fill in the form please enter your e mail correctly 2007 Genomatix Software GmbH 16 Installation of BSPE GenomatixX BiblioSphere understanding gene regulation Path wayE dition EE Genomatix GenomatixPortal Registration Mozilla z Fie Edit wiew Go Bookmarks Tools Window Help w v a Ei http fportall 0 genomatix de icgi binjUMappsiregister pl v CA ef KG HE httpsiip g icgi bin UMappsjregister p A Wei i Ah Home we Bookmarks mozilla org mozillaZine L mozdev org conditions ACADEMIC USERS get the following number of analyses for FREE every month 20 ElDorado analyses 5 Gene2Promoter analyses with at most 5 accession numbers each 20 BiblioSphere analyses 20 GEMS Launcher MatInspector analyses and the following number of analyses once e 2 ChipInspector analyses COMMERCIAL USERS get these analyses for FREE only once For free accounts some limitations apply For online demonstrations and unlimited access please contact sales genomatix de First name Last name Company Organization Department Affiliation academic commercial Address P O Box ZIP Postal code City State Province Country Please select your country Phone number Email address The f
23. 2 11 7 0 4 microtubule based process G0O 0007017 153 30 55 response to DNA damage stimulus GO 0006974 261 41 9 38 i mitotic spindle checkpoint coooa e 5 Oa macromolecule metabolic process G60 0043170 5162 300 185 56 chromnsome ornanization and biogenesis ENEE 331 46 14 9 Filter settings CoCitationFilter This BiblioSphere is restricted to input genes number of genes passing the filter 561 LICA 10 Introduction to BiblioSphere PathwayEdition bere Genomatix BiblioS PathwayEdition understanding gene regulation Gene Info An exhaustive summary provides Q Se Datei Bearbeiten Ansicht Chronik Lesezeichen Extras Hilfe q u i ck ove rvi ew a b O ut a g e n e of i n te re st b H tit http jftest genomatix defegi bin eldorado eldorado pl s dc9956431554a9854ed218 93225906c PMS_HEAD 0 ELDORADO_VERSION E16R0702 GEn gt Gl Q Getting Started HY Latest Headlines G ms f ional d ipti aa a ene synon s functional description e amp a 7 y y 7 p 7 enomat Personal Password Messages Logout ElDorado D A transcript variants etc are included GenomatixPortal GEMS Launcher Seng Gene2Promoter ___MatBace FAQ Projects Protocol Help Currently selected ElDorado data
24. All rights reserved CHEM Running your Analysis Ambiguities It is possible that BSPE returns a list of proposed genes if the input identifier is ambiguous In this case a list similar to the following one appears asking you to enter the correct correspondence The official preferred symbol is the default choice some of your query terms have lead to ambiguous results Please select your genes of interest for each query term for your query term ARDI the following genes were found please select one e V tripartite motif containing 23 official preferred symbol TRIM23 ARD1 ARFD1 RNF46 LOC373 s i N acetyltransferase 5 ARD1 homolog cerevisiae official preferred symbol NATS ARD1 dJ1002M8 1 LOC51126 protein phosphatase 1 regulatory inhibitor subunit 8 official preferred symbol PPP1R8 ARD1 NIPP 1 NIPP1 PRO2047 LOC5511 2 i ARD1 homolog N acetyltransferase S cerevisiae official preferred symbol ARD1 dm DX5707 TE2 LOC8260 This can happen if ambiguous gene descriptions symbols are used or if one name is used for different genes homonym It is always recommended to use the unambiguous Locus ID for the input genes 2007 Genomatix Software GmbH 38 Starting an Analysis Genomatix BiblioSphere PathwayEdition understanding gene regulation Hit List Depending on the type of analysis performed BSPE displays either information on the generated CCBS or an SGBS list or both Example CCBS info
25. CMeMIS e EE 46 EXp rt 1d 0 9 lt n eeerer Serer er errr es rrerreer eres rere rrr rer err er ertr eer rere rier rrr rrr Terre errr rrr eer errr eer 47 Metabolic amp Signal Transduction Pathways ek 47 2007 Genomatix Software GmbH 2 Genomatix BiblioSphere understanding gene regulation Path wayE dition Importing your OWN Annotations NENNEN 48 Network Customization cecccrescvcececereccoecece cede cenvcacece deco euecducate code cnducadecetecesvenercadececocedicedivadecesreneeds 52 ER 52 Ola cl eee ee ene ee ee 52 Information about Genes ANd CONNECTIONS ANNER 54 Focus on Gene Subnets CIUSLCNS E 54 Co Citation Bi OW E 55 LINK to PUDME ccceccccueeccucuseecueuseeaueusevaueusevaueusavaueusevaueusevaueusavaueusaeaueusavaueusavaueusavaususavausenavante 55 tagged ONEN aeeeeerrtrr ere tre ET 55 MAS E 56 BEE 56 Documents TA bl ccccccceccueuseccueueeeaueueevaueusevaueusevaueusavaueusavaueusevaueusavaueusavaueusavaueusavausueavausenavenss 56 ET 57 EE 58 Gene Gene CONNECTIONS cccccececevcvcveueueueeeeeavavaveueusueueaeavavavaueueusauaeavavavaueusunauauavavavaueueunenavavavavans 59 Cellular Component TEE 60 PROUOCO PANNE E 61 SEIL EE 61 KE ielg FILEP O D 62 BEE 62 PE PANEL a 62 Literature Analysis Filter n nnnnennnnnnnnnnnnnnnnnnnnrsrnnnnnrnnrnrrnnnnnnnrnnnnnnnnnnrnnrnnnnnnnrnnnnnnnnnnnnnnnnnnnnnnn nnn nnnnn 62 COCO e 62 Free Ext FIle E 65 BIOOGK A ENUO t 65 GUTE 65 CANE ln re 0 6 A TE 66 MeSH Ra E 67 Ti
26. COM CUNO sere eevee ri yee re eee eee rece ee 26 Check EE 27 Turning on Automatic Update Notification kk 28 Updating your liegen E E 29 ROW TO Prepare your DUE RER 31 CGA e lc er TT Te eT ec Tr rr er ce rrr rr 31 Cega Ec ee eee cere eee E cere ee cree ee re ee eee re eee ere cre 31 BE SFr UN ACS asec vet eed ee eee se es T 31 EXC Cl WE 32 aN GING lt I PAD ANY SIS E E E O 32 PPUECING VOU Wale tiierisctias renronneniaevits brad raneronne nga nens iad rene onne iio renL bred eae ehnE iN TEr bee ar einenoRers nice rueeat 32 E pIE 0 eeeeeere rere rer rer rer err eer rrr rere reer rer rere reer rrr rrr erreer rrr rr rr err eer rrr rrr rerreer rrr srr eer ee 32 Project MAMAGCINGIN T earnan 33 KEE ENEE a sec enc ate sess tc se ccng cans sea tcce conan ans este ecctanaesie sce csteeasaes ee secesecaa 33 EOC At ln e E 34 Create a New Analysis nnnnnnannannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnsnnnnnnnnnnnnnnnnnnnnnnnnennnnnnnsnnennnnnnnnnnennnnnnnnnnnn 34 ail Tt ap PEPEE T E T I I A I I 35 EINEN aan sees sage gene cane gte pee ena coee ceeencneccne sees seeccan een anee seaeeaoeeccee 38 Running aile E WE 38 nie elt Te 38 gh Ss ee ee ee ee ee ee eee eee 39 PTOI e 41 POU NWA Ee 41 KEE eege 41 elei eg ei A el 43 Relation Info WEIEN 43 Node TG E 44 Dove die get UNGOCK IA eee eee cere eter ee ers ee er cece eee eee ee eT 46 ee eerie hirer tree ets eee ers eee 46 SONGS EPA rere tees eect rescence ees tee eee eee eee ee 46 Pee OU ODUM Ei de WE 46 coor S
27. GNALING View BioCarta pathway diagram in external browser View KEGG pathway diagram in external browser View o TEE pathway diagram in external browser View o TEE pathway diagram in external browser 2007 Genomatix Software GmbH 45 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Unconnected Nodes Tab The Unconnected Nodes tab displays all input genes that are not part of the generated network Docking and Undocking You can move the Pathway View to a dedicated window by clicking the undock button Clicking the dock button in that window or closing the window will re dock the Pathway View Zoom You can zoom in and out of the displayed network by clicking repeatedly on the zoom buttons in the toolbar Shortest Path If the Shortest Path option is activated display of edges is restricted to those that constitute the shortest path from the node that was double clicked last to all other displayed genes Otherwise all direct connections are displayed Double clicking another node recalculates the shortest path with that node as the starting point and redisplays the graph To optimize the layout after recalculating click the Layout Optimization button Layout Optimization Clicking the Layout Optimization button redraws the network graph so that overlapping of connections and overall connection length are minimized and relative connection lengths reflect the strengths o
28. Genomatix releases new versions of America Get a free evaluation ChipInspector and BiblioSphere SEW i s read manisa otua account 4 new subsidiary and training academy have Se Genomatix has released Chipitspector 1 3 5 been incorporated in nn Arbor Michigan book a training seminar Buy a license online with updated probe annotation and a new Currently we offer courses on promoter and N nosition based analysis feature which allows re eg Vert Eder Si to export significant regions BibloSphere Ae Al ia Ale Er PathwayEdition 7 0 now contains data from contact us at seminars genomatix de R Search our site MolecularConnection s NetPro database providing an additional line of expert curated E evidence and a new filter method Both applictions are available from our download area If you do not have an account yet please click on Register ES Genomatix Login Page Mozilla File Edit view Go Bookmarks Tools Window Help be lt 4 RECH E KS E en 2 i SS portal 0 genomatix de cgi bin sessions login pl s 789019cS Y og Search Back Dee HE httpiiip g icgi bin flogin p aie i Fh Home ab Bookmarks L mozilla org L mozillaZine L mozdey org Genomatix GenomatixPortal Switch to encrypted login page Please log in Username Password Register for a free of charge evaluation account if you haven t done so yet Lost your password Click here to retrieve your account info if you lost
29. HD SPDEF v ETSF cone syi am HTATIP2 unspecific KLF4 V GKLF al Ps 2007 Genomatix Software GmbH 57 Network View BiblioSphere PathwayEdition Genomatix understanding gene regulation Genes The Genes spreadsheet displays all the genes in your current selection of BiblioSphere data You can jump directly to a gene of interest in the list by selecting a gene symbol in the Gene Selection List in the toolbar A click on the row header of a gene dataset opens the Cocitation Browser displaying the citations for this gene Table Content Column Name Row Header Regulatory Function Content The row header as a specialized column links directly to co citations of the gene in this row Shows Genomatix annotation for genes with a known regulatory function Currently only transcription factors are annotated Gene Symbol The official or preferred symbol of this gene Gene Name The official or preferred name of this gene Identifier The gene identifier Gene ID User Input Shows the original query term entered by the user to find this gene Filter Indicates whether the gene has passed the filter or has been blocked Blocked genes are not displayed in the network views Matrix Family For transcription factors matrix families from the Matlnspector library are displayed here Description A description of the gene as provided by NCBI User Data Expression value for each gene if
30. It is not necessary that the annotated gene be displayed with the current filter settings i e if you restricted the view on the genes you might not see any pathway annotation of a certain type even though you enabled their display Pathway annotations appear in the graph as nodes that are linked to the annotated gene GE undock S REESE ELecend Genomatix Signal Transduction f MEREMEES o2 v help WS i PPARA ii SMARGAA Clicking an annotation node will display information in the Node Info tab 2007 Genomatix Software GmbH 47 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Importing your Own Annotations You can add your own sets of annotations to BSPE they will appear in the Pathway view To this end select Data Import Annotations from the main menu a file dialog will be displayed ffnen Suchen in Import v oF SS Zuletzt verwendete Dokumente T Dateiname import _example_excel xls Netzwerkumoeby Dateityp ais TEN Ge 2007 Genomatix Software GmbH 48 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Your annotation file should be either an Excel file or a plain text file containing Gene IDs and the labels for each gene in the same row Selecting a file will launch the Data Import Assistant Depending on the format of your file the assistant will guide you through the import pr
31. K19 and vimentin The whole mesenchymal component was positive for vimentin negative for cytokeratins and focal cells were positive for smooth muscle actin 17321453 Both components were strongly positive for P53 gt TP53 and Cyclin D1 and focally positive for MDM2 Rare multinucleated giant cells showed expression of CD68 and focal dendritical cells on carcinomatous nests were positive for 5 100 The CK7 CK Factor XIIIa c erbB 2 P16 CDK 4 Rb1 and E2F 1 gt E2F 1 were not detected in these 2 groups of malignant cell populations Sentence level E2F1 and TP53 are co cited within the same sentence In addition KS Myc and K5 E2F1 gt E2F 1 transgenic mice both display aberrant p53 gt TP453 dependent apoptosis in the epidermis 11536046 H Sentence level plus function word E2F1 and TP53 are co cited in the same sentence and the sentence also contains a function word colored in light pink Examples of function words are regulation inhibit modulate enhance 9519869 Deregulation of the S phase promoting E2F 1 gt E2F 1 transcription factor has been shown to cooperate with p53 gt TP53 to induce apoptosis Sentence level plus gene function word gene E2F1 and TP53 are co cited in one sentence and connected via a function word E2F1 gt E2F 1 activates the human p53 gt TP453 promoter and overcomes the repressive effect of hepatitis B viral X protein Hbx on the p53
32. PS3F how comparative Genomics for TH Remove TP534 from Bibhosphere Description Tumor protein p53 a nuclear protein plays an essential role in the regulation of cell cycle specifically in the transition from GU to G1 Itis found in very low levels in normal cells however in a variety of transformed cell lines itis expressed in high amounts and believed to contribute to transformation and malignancy p53 is a DNA binding protein containing DNA binding oligomerization and transcription activation domains It is postulated to bind as a tetramer to a p53 binding site and activate expression of downstream genes that inhibit growth anchor invasion and thus function as a tumor suppressor Mutants of p53 that frequently occur ina number of different human cancers fail to bind the consensus DNA binding site and hence cause the loss of tumor suppressor activity Alterations of the TP53 gene occur not only as somatic mutations in human malignancies but also as germline mutations in some cancer prone families with Li Fraumeni Syridr ome Pathway annotation node For pathway annotations the annotation is displayed Genomatix signal transduction pathway annotations can have outbound links to BioCarta KEGG and or STKE pathway diagrams Clicking a pathway link opens the according pathway graph on the content provider s web page in a browser window Mode Info Unconnected Modes Pathway annotation WITOGEN ACTIVATED PROTEIN EINASE SI
33. Standard Edition Chuild 1 5 6_H6 bH5 gt 5 Java HotSpottTMN Client UM Chuild 1 5 6_66 bH5 mixed mode sharing If Java is not yet installed on your computer or if you have a Java version older than 1 5 please follow the link http www java com to download and install the newest version of Java at least version 1 5 2007 Genomatix Software GmbH 13 Technical Requirements Genomatix BiblioSphere understanding gene regulation PathwayE dition Connection to the Internet BSPE retrieves information from the BSPEKD Database which is hosted by Genomatix Therefore an internet connection is needed to run BSPE Alternatively BSPEKD can be installed on a server at your site please contact support genomatix de for details on in house installations In this case an intranet connection to your server would be required Installation of BSPE BSPE is a Java program which must be installed locally on your computer Please proceed for download and installation as follows Download To download BSPE please follow the following steps Create a folder on you hard disk where you want to store the installer Switch to http www genomatix de products BiblioSphere BiblioSpherePE5 html Choose your operating system from the download Click on the download button next to your operating system aa Een download File size Windows Ox 2000 xP Please contact suppor genomatix de for installation on sP 64bit MacOs x
34. ain panel click the General Options button a Preferences Proxy Configuration Update Frequency 55L Configuration Statistical Analysis Data Storage Select an Update server munich tokyo General Options 2007 Genomatix Software GmbH 30 Installation of BSPE Genomatix understanding gene regulation How to Prepare your Input Data BSPE expects a list of genes required with a signal value assigned to every gene optional A gene list query only contains terms to identify genes If signal values for the genes should be added for analysis you have to create an excel file see below Gene Identifiers Gene identifiers can be entered as a list separated by white spaces commas or semicolons The following gene identifiers are accepted by BSPE Gene symbols e g icam3 Gene description e g mitogen activated protein kinase 1 Entrez gene identifier or GenelD e g LOC5166 or 5166 RefSeq ID e g NM_02044 GenBank oligo capped mRNAs e g AKO00539 UniGene ID e g Hs 202453 oe a a BSPE allows using different gene identifiers in the same list If you do not remember the exact gene name or gene description you want to retrieve you can use an asterisk in your search term The asterisk represents a wildcard meaning a placeholder for zero or more unknown characters Example mapk retrieves mapk1 mapk2 mapk12 mapk13 but also MAPK ERK and putative mapk Gene List There ar
35. alysis results Data Input Network Calculation and Biological Ranking Depending on the application strategy the user can access the system with the following input formats e Single gene e List of genes e List of genes plus numerical attribute for every gene e g derived from o Expression microarray e g as provided by Genomatix s Chiplnspector o Protein microarray o Gel electrophoresis o Protein mass spectrometry BSPE accepts the following gene identifiers as input gene symbols gene names keywords locus link IDs and mRNA accession numbers e g from RefSeq Moreover PubMed IDs MeSH terms and free text can be supplied to indirectly retrieve the genes cited in the according journal abstracts As to details please refer to chapter How to prepare your input data BSPE calculates the complete gene relation network from the list of input genes and validates and ranks pathway interactions by z scoring on basis of the Genomatix knowledge Base Nodes which represent input genes in the network are colour coded if expression ratios or any other numerical attribute in the input file are provided 2007 Genomatix Software GmbH 8 Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation User Controlled Network Construction and Analysis Starting from the complete gene relation network the user has full control to analyse focus and extend the network accordi
36. ant Steps Choose Data Separator Select data import Format This Dialog allows you to specify the delimiter used in your imported file The preview shows you how your gt Choose Data Separator file will be processed Delimiter Semicolon Comma Space Other Text Qualifier ze C Use first line as column headers Preview of import file 1 spermidine spermine N1 acetyltransferase lhomogentisate 1 2 dioxyqenase homogentisa isocitrate dehydrogenase 1 NADP soluble Ferritin light polypeptide mucin 4 tracheobronchial 5100 calcium binding protein 414 5100 calcium binding protein P ferritin heavy polypeptide 1 transaldolase 1 transmembrane 4 superfamily member 13 serine protease inhibitor Kunitz type 2 Kruppel like Factor 4 out NAD PIH dehydrogenase quinone 1 anterior gradient 2 homolog Xenopus laevis aldo keto reductase family 1 member C3 3 al signal sequence receptor delta translocon as carcinoembryonic antigen related cell adhesion The following steps are identical with the import of an Excel file The annotations are made available in the Pathway view of BiblioSphere just like the metabolic and signal transduction pathways Whenever one of the genes in BiblioSphere has an annotation a checkbox will be displayed in the menu bar of this view All genes that have an annotation in your set carry the icon you selected
37. arta pathway graphs on the web Filter statistics BSPE s hierarchical filters use statistical analysis to check for over or underrepresented groups of genes and abstracts Statistical Rating For each term in a hierarchical filter a statistical analysis is performed based on the number of observed and expected annotations for terms The z score of this item shows whether a certain annotation or group of annotations is over or underrepresented in your set of genes This can help you to determine if an accumulation of annotations in a branch of the tree is meaningful or not Z Score The z score of a term indicates how far and in what direction that term deviates from its distribution s mean expressed in units of its distribution s standard deviation The general equation for the calculation of z is 7 observed expected std deviation observed For filter statistics in BiblioSphere the z score is calculated as follows as z N n 1l N 1 P R EES where N is the total number of annotated genes R the number of genes meeting the filter criterion n the total number of genes in the analysed set and r the number of genes meeting the filter criterion in the analysed set Promoter analysis Promoter Analysis in BSPE is performed with Genomatix Matlnspector on the Genomatix Promoter Database GPD Matlnspector is a tool that utilizes a library of matrix descriptions for transcription factor binding sites
38. ased analysis creates a CCBS comprised of the genes mentioned in the articles abstracts that were found using the search terms Data Organism Homo sapiens K Enter your query term s bere 2 Start analysis Reset 2007 Genomatix Software GmbH 36 Starting an Analysis Genomatix BiblioSphere PathwayEdition understanding gene regulation MeSH term search You can search by one or more valid MeSH terms a link for browsing available MeSH terms is provided As to use of Boolean operators the same rules as in the free text search apply The genes displayed in the resulting CCBS will be those that appear in the articles found with the selected MeSH search terms Data D rgan ism Homo sapiens k Enter your Mech term s Browse available MeSH terms here Be E Start analysis Reset PMID list search Here you can enter a list of PubMed IDs to search based on the genes covered in the pertaining articles abstracts The genes that appear in the articles with the selected PMIDs will be displayed in a CCBS Data Organism Homo sapiens El Enter a list of pmids 4 gt aoe Start analysis Reset 2007 Genomatix Software GmbH 3 Starting an Analysis Genomatix BiblioSphere understanding gene regulation PathwayEdition Accessing your Analyses Any new analysis will appear in the Project Manager panel under the project it has been associated to If a CCBS was generated dur
39. ature analysis Tagged sentences allow a quick Maei ms er BiblioSphere search BiblioSpheres overview of the relevant sentences of an UserDataFilter GOFilter biologicaLorocess E Cocitation Browser ER Genes E Documents TF Analysis g Gene gene connections BiblioSphere 3D E BiblioSphere Pathway View ES GOFilter biological process FreeTextFilter CoCitationFilter a b stra ct es undock q back forward p cance reload ff home a save CG open 5 print a H input genes input transcription factors tf All citations of CCNA2 View next page Color legend Disease Transcription Factor Pathway Gene Function Tissue The anti inflammatory properties of SM933 were characterized by inhibition of encephalitogenic Tcell responses that were altered to exhibit a Th2 immune deviation and reduced activity and concentration of NO and Abstract level BO Two genes are co cited The observed effect of SM933 was mediated through regulatory mechanisms involving the NFkappaB and the Rig G JAB1 signaling pathways within an abstract Sentence level B1 M933 was found to inhibit the activity of NFkappaB by up regulating IkappaB which accounted for various down stream anti inflammatory actions o eriak See Furthermore it up regulated Rig G through the action of and prevented JABL a master cell cycle regulator from entering the nucleus to promote p27 degradation resulting in down regulati
40. base is ElDorado 05 2007 change here GXL_98518 found on chromosome 16 of Homo sapiens NCBI_build36 ElDorado 05 2007 LocusID GXL 98518 Name integrin alpha M complement component 3 receptor 3 subunit integrin alpha M antigen CD11b p170 integrin alpha M precursor macrophage antigen alpha polypeptide complement component receptor 3 alpha neutrophil adherence Protein Name receptor alpha M subunit Integrin alpha M complement component receptor 3 alpha antigen CD118 p170 macrophage antigen alpha polypeptide integrin alpha M complement component receptor 3 alpha also known as CD11b p170 macrophage antigen alpha polypeptide Symbol ITGAM Synonyms CD11B CR3A4 ITGAM MAC 1 MAC14 MGC117044 MO14 Organism Homo sapiens human Chromosomal Location 16pil2 GeneID 3684 Unigene Cluster Hs 172631 This gene encodes the integrin alpha M chain Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain This I domain containing alpha integrin combines with the beta 2 chain ITGB2 to form a leukocyte specific integrin referred to as macrophage receptor 1 Mac 1 or inactivated C3b iC3b receptor 3 CR3 The alpha M beta 2 integrin is important in the adherence of neutrophils and monocytes to stimulated endothelium and also in the phagocytosis of complement coated particles Some integrin alpha M proteins contain an inserted amino acid Q between AA positions 499 and 500 resulting from a 3bp shi
41. beyond promoter analysis based on transcription factor binding sites Bioinformatics 21 2933 42 PUBMED 15860560 Seifert M Scherf M Epple A Werner T 2005 Multievidence microarray mining Trends in Genetics 21 553 8 PUBMED 16098629 Scherf M Epple A Werner T 2005 The next generation of literature analysis Integration of genomic analysis into text mining Brief Bioinform 6 287 97 2007 Genomatix Software GmbH 72 BiblioSphere PathwayEdition Help
42. citations on Cocitations on Link to Sentence Level GFG Level Cocitations aT Connected Genes C0Citations on Cocitations on Abstract Level Function Word Level Dock Undock Customize Data Export Button Button BURON Help Button Gene gene connections FH dock cl ou customize ze ES Ej SE data Eech mm mo S o e Bi mp We asooo mm a Kee EE i Ge TH ao et EE BS jceacams Par im oyoo o a d Bs mees mm e o s a Gees fea at a E SI mp Pt at Im kb Lu LA Del J E ea pee S SR GA MUCSB 160 SEN Ip 3 2007 Genomatix Software GmbH 59 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Cellular Component View The Cellular Component View helps you to identify the subcellular compartments relevant to your set of genes The hierarchical Gene Ontology filter assigns genes to their subcellular compartment Based on these annotations the Cellular Component View builds a diagrammed cell layout Therefore the Cellular Component View is only available if the GO filter Cellular Component has been activated Network genes are displayed in their subcellular location helping to reconstruct the way a signal takes through the cell compartments during a regulatory event The basic localizations are color coded with blue denoting extra cellular orange membrane bound yellow cytoplasmic pink nuclear and white unknown
43. dMe rtf 2007 Genomatix Software GmbH 15 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Get Login and Password To apply the BSPE application you need a login and a password Registration is free of charge An e mail with your personal username and password will be sent to you right away Registration Open your internet browser and switch to www genomatix de Click on Login in the navigation panel of the webpage aa Genomatix Home e Sitemap e Contact understanding gene regulation F Software Software Training Use our tools to understand the molecular To help you get the most from our products Collaborative Research mechanisms of gene regulation as a central part Genomatix offers various training options Pen of systems biology Our programs w including step b p tutorials and online Training comprehensive reliable results based on scientific webmeetings a sible directly from your algorithms workplace ell as tutored seminars at our Customers headquarters in Munich or even at your site About us Downloads Collaborative amp Contract Research News amp Events More than ten years of scientific experience make Careers Ss microarray analysis Learn more about our recent collaborations from our project list or contact us at research genomatix de Login Genomatix Expands Operations in North Training Resources
44. de Reset Cancel Help 2007 Genomatix Software GmbH 26 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Check for Updates Periodically Genomatix provides important BSPE updates The Genomatix Update Service helps you to keep your application current Click on Update Frequency in the Configuration dialog Gs Preferences EELER Proxy Configuration Update Frequency 55L Configuration Server Configuration Get the latest version of bibliosphere Automatically check For updates Checking For updates requires an active Internet connection Manually check for updates Current version 6 31 Last check For updates 09 05 07 18 There are two modes for update Automatically check for updates and Manually check for updates 2007 Genomatix Software GmbH 27 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Turning on Automatic Update Notification The Automatic Update Service checks for updates at regular intervals Any time a product update becomes available you receive a notification Once you receive the notification the Update Service guides you toward the download and installation of the updates you need The Automatic Update Service is activated as follows Select automatically check for updates and choose your preferred update frequency choices are daily weekly and mon
45. e View Extras Data Analyses left unlimited BiblioSphere search d undock d back o gt reload f home BI save pe print Genomatix BiblioSphere PathwayEdition Version 7 20 LS tap Project Manager t Personal Page fs New Project New Analysis _ Gene name search Edit project Ld File upload Title Ld Free text search New Project MeSH term search Description _ PMID list search EN Help v L i Si If you encounter any problems please contact support qenomatix de Genomatix Software GmbH 1998 2006 All rights reserved 2007 Genomatix Software GmbH 33 Starting an Analysis Genomatix BiblioSphere understanding gene regulation PathwayEdition Edit an Existing Project You can edit an existing project i e change its name or description anytime To open the editing panel click the edit analysis project symbol in the respective row To delete a project including all its associated analyses click on the respective delete analysis project symbol File view Extras Data Analyses left unlimited BiblioSphere search 2 undock 4 back reload ff home RB save pee A print Genomatix BiblioSphere PathwayEdition Version 7 20 a 7 Project Manager Project Ma nager 2 Personal Page 3 New Project Name Description Created Type Action New Analysis Ld Gene name search wech Demo_Manual _d File upload E Free text search Ld MeSH term search _d PMID list search
46. e default location is C Program Files GenomatixApplications apps bibliosphere conf bibliosphere bat Double click on the file in your windows explorer or in the Windows start menu choose Execute type in the complete file name including the path and click OK 4 Start BSPE from the Genomatix Portal see below Genomatix B sse SE SE Oa GenomatixPortal PET a Release Notes Chipinspector g EIiDorado Genomatix Microarray Analysis Extended Genome Annotation wna xana a a Gene2Promoter Literature Network Mining Sequences Retrieve amp Analyze Promoters GEMS Launcher R GPD Sequence Analysis amp Modeling Software _Protocoi_ Genomatix Promoter Database Matinspector MatBase Search Transcription Factor Binding Sites Transcription Factor Database For comments questions or bug reports please contact support genomatix de Genomatizx Software GmbH 1998 2006 Al rights reserved License Agreemen 2007 Genomatix Software GmbH 21 Installation of BSPE Genomatix BiblioSphere PathwayEdition After successful launch of the BSPE application you will see the following screen Genomatix Bibliosphere File View Extras Analyses left not connected reload fs home EI BiblioSphere PathwayEdition D gt V 2003 2005 Genomatix Software GmbH Configuration of BSPE Before you start working with BSPE you should
47. e two different ways to enter a list of genes for analysis with BSPE e Gene list query which is directly entered in the BSPE user interface without assigned value e Excel file which can be uploaded with and without assigned value e g as provided by Genomatix s microarray analysis software ChipInspector User Interface You can enter a comma semicolon or space separated gene list directly in the interface 2007 Genomatix Software GmbH How to prepare your input data Genomatix BiblioSphere understanding gene regulation PathwayEdition Excel Files An Excel file requires one column with gene identifiers Valid identifiers are Entrez GenelDs e g 5166 Affymetrix probe set IDs e g 202275 at and Genomatix Transcript IDs e g GXT_2740761 Optionally you can place one or more columns containing any kind of numerical values after the identifier column e g expression values of a microarray experiment leh So A Ba EI hi fe A B C L 1 20014 0 261116 0 81731 22664 2 71853 0 3330626 0 56562 0 121202 3 107503 0 69406 0 277214 0 03302 4 107566 0603165 0 215691 02207342 5 20737 039421 0 170641 0015294 6 107503 0 69466 0 277214 0 053502 7 20737 0 39421 0 170641 0 015294 D 71653 0333020 050562 0 121202 9 15081 0 217975 0 56277 0 15059 10 22626 0 46330 0 233547 0 202451 11 122626 040330 U 233527 0 202451 12 19046 0227505 0 55705 0 54602 13 Manas 0717075 nae VF 012000 Starting an Analysis
48. ease contact support qenomatix de Genomatix Software GmbH 1998 2006 AN rights reserved License Agreement te Gb EI ep _ 2 a 2007 Genomatix Software GmbH 18 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation After login you will see the following page Click on Password E Genomatix Welcome to Genomatix Suite Bernd Mustermann Mozilla R File Edit View Go Bookmarks Tools Window Help X ee P E E Z Hs amp http portall 0 genomatix de cgi bin welcome welcome pl s f87ee8bd4236dd7e87F1c2d583dd6cd3 v A F rint Back Reload ii 44 Home d Bookmarks L mozilla org L mozillaZine L mozdev org Genoma tix R D New Sol ee MeN GenomatixPortal EIDorado Gene2Promoter BiblioSphere Results Sequences Protocol GenomatixPortal GEMS Launche Login information 2006 03 17 Welcome to Genomatix Suite Bernd Mustermann 6 new messages Our database contains no records about your former logins Our commitment is to offer the best quality and most accurate data based on state of the art science The new GenomatixPortal is the result of more than a year of intensive research and development Improvements and scientific progress have consequences for e ElDorado genome annotation e Homology groups e Affymetrix probe set annotation es transcription factor matrix database more than 200
49. ein is activated N ES N AA f pugh phofphorylation in response to various cytokines SS Vaso mea eeng e hni growth factors including IFNs EGF IL5 IL6 HGF i LES EE j F and DD This protein mediates the expression ofa l zs ariety of genes in response to cell stimuli and thus plays a KCL o Si in many cellular processes such as cell growth and E The small GTPase Racl has been shown to bind W d Pearce BOS e e ipt variants encoding distinct isoforms have been v Aa e STATI lee TC fn eh a L2KE f 2007 Genomatix Software GmbH 60 Network View Genomatix BiblioSphere understanding gene regulation Path way Edition Toolbar Controls and Actions B Zoom In Zoom in to the view Gi Zoom Out Zoom out G Optimize Layout Recalculate the layout depending on the gene in focus Ke Shortest Path Shortest path for the gene in focus ON OFF SVG Save SVG Save an image of the Network as Scalable Vector Graphic SVG IPG Save JPEG Save a bitmap image of the Network in JPEG format Protocol Panel The Protocol Panel displays the current filter settings and the number of genes passing the filter Filter settings ClusterFilter The current cluster center is TP53 MeSHFilter Disease The current filter values are Neoplastic Syndromes Hereditary C16 320 700 OR Abnormalities C16 131 CoCitationFilter Current BiblioSphere level is Sentence level plus gene function word gene Visible genes
50. ences dialog for proxy configuration Click on SSL Configuration Gs Preferences Proxy Configuration Update Frequency SSL Configuration Server Configuration SSL SSL short for Secure Sockets Layer is a protocol for transmitting private documents via the Internet A private key is used to encrypt information that can otherwise easily be intercepted by a third party Wwe strongly recommend to enable encryption for sensitive data Check the box next to Use encrypted connection to Genomatix server and then click ok If you have chosen a secure connection to the internet a little icon will show up at the bottom of the BSPE 2007 Genomatix Software GmbH 25 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Server Configuration If the BSPEKD is installed in house you will have to enter the correct server name Please contact your system administrator As default the BSPEKD installed on the Genomatix server is used You can change the BSPEKD server as follows Start BSPE see above Go to menu Extras and select Proxy settings to launch a preferences dialog for proxy configuration Click on the Server Configuration E Preferences Proxy Configuration Update Frequency SSL Configuration Server Configuration Biblio Sphere Server Your detaut BiblioSphere host is was genomatiz de Change to alternate server hana genomatix
51. er directly annotated with the selected term signal transducer activity or with one of its more specific terms in the subcategories of this branch 2007 Genomatix Software GmbH 66 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation MeSH Filter BiblioSphere s MeSH Filter enables you to group and filter the PubMed abstracts and genes in your BiblioSphere by MeSH Annotations MeSH Filter Structure Separate MeSH Filters are available for selected categories of MeSH hierarchy e Disease e Chemicals and Drugs e Anatomy e Biological Sciences Analytical Diagnostic and Therapeutic Techniques and Equipment Each MeSH Filter consists of a hierarchy of terms and the corresponding annotations for your BiblioSphere While GO Filters and Tissue Filters contain annotations for genes the MeSH Filters contains this information for PubMed articles Filtering is performed on documents Thus genes are filtered indirectly as only genes co cited in the filtered documents are displayed Clicking the Filter nodes button will apply the MeSH Filter to articles that just cite one of the genes using the selected terms Consequently a connection between two genes that are co cited in an abstract that is not annotated with the selected MeSH filter term will be displayed if both genes appear in other accordingly annotated abstracts In contrast the Filter nodes and connections button filters for ar
52. er of your input set of genes classifiers View Cluster Centered BiblioSphere 2007 Genomatix Software GmbH 39 Starting an Analysis Genomatix BiblioSphere understanding gene regulation PathwayEdition Example SGBS view Analysis Results Analysis_FileUpload3 3 identifiers could be mapped to a gene Search Term Locusid Symbol Gene Name Action LOC13195 13195 Ddc dopa decarboxylase A 9 Single Gene BiblioSphere single Gene BIDNOSpNhere LOC16956 16956 Lpl lipoprotein lipase RM Single Gene BiblioSphere singie Gene bIDIOSpnere LOC93695 93695 Gpnmb glycoprotein transmembrane nmb be Sinale Gene BiblioSphere Single Gene Biblospnere Example Unidentified Search Term view Analysis Results Analysis_FileUpload3 EE EE d ue 1 query term s could not be mapped to a gene Search Term Locusid Symbol Gene Name LOCOOO01 2007 Genomatix Software GmbH 40 Starting an Analysis Genomatix BiblioSphere PathwayEdition understanding gene regulation Network View Pathway View Overview A BiblioSphere represents your input gene s bibliographical environment It contains your input gene s genes co cited with the input genes and various information pertaining to the genes the relationships between them and their literature context Various filter settings allow you to restrict the view to elements of your interest You open a BiblioSphere view by clicking on the respective link in the BiblioSphere search v
53. ernatively you can select a gene from the Gene Selection List to highlight its cluster and bring it to the fore this is especially handy if you want to get a better look at the environment of a gene in a BiblioSphere containing many elements For zooming you click the zoom button which will drop down a slider that you can move up and down to zoom in and out 2007 Genomatix Software GmbH 52 Network View BiblioSphere PathwayEdition GenomatiX understanding gene regulation In the 3D view s upper right hand corner you see a miniaturized outline of your BiblioSphere graph The green area represents the section of the 3D graph that is currently visible to you on the screen while the black rectangle encloses all spheres in the graph which are represented as pixel sized red dots When you open a BiblioSphere the rectangle is well within the borders of the green area Zooming into the graph however will enlarge the size of the graph the rectangle then gives you an idea which part of the graph you are currently looking at and of how to bring spheres that are currently outside of the visible area into focus Cluster Mode Edge Mode Reset View Node Info Panel Legend Relation Info Panel Export Image Help Button Gene Selection List Graph Outline Cokitation Browser E9 genes E Document sw TF Analysis a Gene gene connections BiblioSphere 3D ae BiblioSphere Pathway view ES MeSHAilter Disease o CH 2 2 To
54. ert level B4 ro Level B4 restricted to sentences with expert PDESB curated information BIRCS Signal transduction associations ST LCN2 CO Level ST restricted to sentences with signal transduction information 510049 CUGBP2 CCNAZ Filter settings CoCitationFilter This BibliaSphere is restricted to input genes number of genes passing the filter 561 cs 2007 Genomatix Software GmbH 11 Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation Technical Requirements The following chapter explains the technical requirements to install the BiblioSphere PathwayEdition client application on your computer Operating Systems The application is certified to run under the following operation systems Windows systems e Windows 98 SE 2000 ME XP e 80 MB hard disc space e 512 MB RAM recommended Macintosh systems e Atleast MacOS 10 3 e 80 MB hard disc space e 512 MB RAM recommended Linux Unix systems e 80 MB hard disc space e 512 MB RAM recommended If you do not have any of these operation systems or if you are not sure about your operation system please contact the Genomatix customer support Support genomatix de Java Runtime Environment In order to run the BSPE application you will need Java 1 5 or higher To test if you have an appropriate Java version already installed on your system type java ve
55. est BSPE offers a potent system of filters to customize the analysis output according to your needs This includes filters based on the content of the literature itself as well as on functional analysis using hierarchical annotation terms A statistical evaluation of the results of the functional analysis is available to facilitate focussing on the most relevant findings Filter Panel The Filter Panel contains all active filters for a BiblioSphere The Free Text and Co Citation Filters are always available Additionally you can load biological entity filters based on MeSH or Gene Ontology terms or on UniGene tissue names To this end you select the desired filter from the Filter menu Loaded filters are check marked in the menu To unload and thus deactivate a filter uncheck the according menu item Filters act additively you can load and activate any number of them in parallel Changes in the filter settings will affect the content of the following views e Gene List Documents List TF Analysis Gene gene Connection List 3D View Pathway View Literature Analysis Filter Co Citation Filter The Co Citation Filter filters your BiblioSphere data based on co citation frequency and semantic specificity levels BiblioSpheres from free text MeSH term or PMID list search analyses contain all genes found in the search However if your BiblioSphere was generated in an analysis based on gene identifiers that you provided by manual input or fi
56. evel B4 restricted to M sentences with expert curated information Signal transduction associations ST Level ST restricted to sentences with signal transduction information a lv la lv Filter settings CoCitationFilter Current BiblioSphere level is Sentence level plus function word This BibliaSphere is restricted to input and transcription factor genes Visible genes must be cocited with at least 7 of your input genes and cocited at least 1 time s with an input gene number of genes passing the filter 45 Genomatix Analyses left unlimited File View Filter Extras Data BiblioSphere search BiblioSpheres newmanualex FreeTextFilter CoCitationFilter B Cocitation Browser E Genes E Documents s TF Analysis Gene gene connections gt BiblioSphere 3D zg BiblioSphere Pathway View Show DNA Q 2 He RE pau v input transcription factors tf input tf and all other genes genes are cocited with at least LILRB3 10 min 1 max 23 input genes genes are at least P 52 1 6102 FI times cocited with one input gene vw M Abstract level B0 PRERC Two genes are co cited within an abstract Sentence level B1 Two genes are co cited in the same sentence REBBP Function word level B2 Level B1 restricted to entences with a function word xamples for function word regulation inhibit GFG
57. f the connections optimally Color Scheme Chooser The Color Scheme chooser can be used to activate and adjust the color coding for over and under expression of the genes in the BiblioSphere if expression level information has been provided in the Excel file uploaded for analysis Nodes for overexpressed genes are colored red those for underexpressed genes blue If expression values from a multi class analysis were provided the gene nodes will appear striped displaying one color per experimental class Moving the slider will change the color threshold for over underrepresented genes Choose color scheme zg Choose a threshold to adjust the node coloring scheme wel o e2 E Poa d Nfkb 1 P Sal Sfpit V Use node coloring A Cancel al pama 2007 Genomatix Software GmbH 46 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Export Networks Clicking the Save SVG or Save JPEG button lets you save the network graph in the respective format In the dialog please enter the file name including the extension Metabolic amp Signal Transduction Pathways BSPE offers pathway annotations for the genes in the BiblioSphere You can select to display the following annotations e Genomatix Signal Transduction pathway database e BioCyc Metabolic Pathways database Each option is available if at least one of the genes in the selected BiblioSphere has a pathway annotation of the respective type
58. f Identified Genes Button Button Button Help Button Documents Swe P help ER mem Em SH Seege 11 Jerhuc Mee E D sen we TI SE _ 15151204 uci wes TI ce eech weex LI D ss eech mucsac wES E __ SCC Een SE ES ES Bi egshuco wg B5 11420467 5MAD4 WC MUCSE Bie 9737246 PGR a TFF3 2007 Genomatix Software GmbH 56 M TERT LLL LUUT B FF i Genomatix BiblioSphere PathwayEdition understanding gene regulation TF Analysis The TF Analysis component displays the results of Matlnspector analysis for transcription factor binding sites in the promoters of co cited genes in your current selection of BiblioSphere data and provides links to promoter analysis with GEMS Launcher Promoters are checked for binding sites of transcription factors present in the BiblioSphere if a MatInspector matrix is available Each row in the table represents one gene promoter analysis result Each column represents the results for one transcription factor The meanings of the cell entries are as follows Clicking the Analyse Promoter button of a gene displays the analysis of its promoter with GEMS Launcher in an external browser Input genes are marked with the symbol transcription factors with the TEE Transcription Factors and Binding Sites Analyse Promoter Genes Dock Undock Data Export Help Button Button Button DAR CH export data FOXAZ Y FE
59. for co citations between your input genes If you perform an analysis that requires you to specify gene identifiers as input i e a gene name search or a file upload analysis by default only those genes in your input set that are either co cited with another gene in the input set or with any transcription factor are included in the resulting gene network Gene name search If you provide gene names you can choose between two different types of analysis single gene and group of genes A single gene analysis will retrieve a Single Gene Centred BiblioSphere SGBS for each of your input genes from the database while a group centred analysis additionally will generate a Cluster Centred BiblioSphere CCBS based on all your input genes You can switch between cluster and gene centred views in an analysis of the latter type If you keep the Show only co cited transcription factor genes option checked which is the default setting the input genes that are either co cited with another input gene or with any transcription factor which is not necessarily among the input genes as well as the co cited transcription factors will be included in the CCBS Other genes that are co cited with an input gene but do not code for transcription factors will not be included nor will input genes for which there is no co citation with another input gene or with a transcription factor Deselecting the Show only co cited transcription factor genes option
60. formation e The number of abstracts containing co citations of the connected genes Clicking this number opens the Cocitation Browser which provides links to the abstracts and which will display every sentence in the abstracts that cites at least one of the co cited genes e For each co citation level above Abstract the number of co citing sentences that conform to that level Clicking on a number will open the Cocitation Browser displaying the relevant sentences e Expert curated annotations with links that will display the pertaining sentences in the Cocitation Browser e If one of the connected genes codes for a transcription factor matching binding sites in the promoter of the other gene including the binding site s matrix family name 2007 Genomatix Software GmbH 43 Network View Genomatix understanding gene regulation Example Relation Info Panel contents Relationship between HK 21 and TPS4 oe abstracts with cocitations BO 23 cocttation s on sentence level BL 18 cocitation s on function word level B2 amp cocitation s on gene function word gene level BS T Genomatix expert curated annotations TP53 regulates NRSCIC1 NRSC activates TPSai 1h NRSC 1 interacts with TPS 32 TP53 inhibits MRSC IC MRSC lL regulates TPS 1 3 NetPro expert curated annotations NRSC 1 directly inhibits activity of THAI NRSC directly binds TPS3 2 MatInspector has found evidence for transcriptional regula
61. ft in a splice acceptor that inserts the codon CAG receptors with or without the extra amino acid are functionally indistinguishable Mac 1 molecules mediated cell adhesion predominantly to fibrinogen and its early degradation products fragments X and Y PubMed CD11b mediated adhesion of myeloid leukemia cells in the course of induced monocytic differentiation is crucial for cell attachment development of a monocytic phenotype and PubMed subsequent survival Respiratory syncytial virus enhances the expression of CD11b molecules by human eosinophils primed with platelet activating factor PubMed CD11b may play an important role in pathogenic process in COPD PubMed fibroblasts prostaglandin E2 is elevated in Alzheimer s disease prostaglandin E2 PGE2 PubMed Identification of integrin alpha M beta 2 as an adhesion receptor on human peripheral blood monocytes for Cyr61 and connective tissue growth factor immediate early gene PubMed products expressed in atherosclerotic lesions integrin alpha M beta 2 Impaired neutrophil actin assembly causes persistent expression and reduced primary granule exocytosis in Type II diabetes PubMed Increased expression of CD11b CD18 adhesion molecules was obtained in PV and ET patients which could be associated with increased leukocyte adehesiveness contributing PubMed Ito the hypercoagulable state mediates type I phagocytosis under nonopsonic conditions and type II under opsonic conditions PubMed Vv i r Fertig Liter
62. gene names and synonyms supplied by NCBI Entrez Gene checked for ambiguities by automated computational analysis and enhanced amended and filtered by manual curation Co cited genes are additionally analyzed with Genomatix MatInspector for transcription factor binding sites in their promoters This compilation of gene gene connections can be filtered for gene or document based annotations and checked for overrepresented features by statistical analysis Gene based annotations include Gene Ontology analysis from Entrez Gene and information on tissue specific expression from UniGene Document based annotations utilize MeSH annotations of abstracts supplied by PubMed and a full text index of the abstracts that make up your BSPE The available hand annotated information on gene gene connections has been assembled by Genomatix experts or is based on interaction information in Molecular Connections NetPro databse Genes that are known to belong to a certain metabolic or signal transduction pathway are labelled in the Pathway View The pathways are the Genomatix signal transduction pathways and metabolic pathway associations from BioCyc 2007 Genomatix Software GmbH 5 Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation Methods and Data Sources PubMed PubMed is a service of the National Library of Medicine It includes over 15 million citations for biomedical articles T
63. has two effects Firstly any gene that is co cited with one of your input genes will be included in the network regardless of its coding for a transcription factor and secondly any co citation of an input gene is sufficient qualification for inclusion of that gene in the CCBS The SGBS remain unaffected by this setting E Edit analysis Gene name search Description Title New Analysis Description b Link with project Demo Manual ze Data Organism Analysis type jHome sapiens Bie group of genes Gi Show only cocited transcription factor genes Enter your gene id s here Pa 4 gt Start analysis Reset 2007 Genomatix Software GmbH 35 Starting an Analysis Genomatix BiblioSphere PathwayEdition understanding gene regulation File upload You can let BSPE read a gene list from an Excel file whose path and name you can enter here As to the accepted format see How to prepare your input data Excel Files The analysis includes both CCBS and SGBS based on the input genes Data Organism Homo sapiens k Upload correctly formatted data file optional d Durchsuchen Start analysis Reset Free text search You can enter one or more search terms that will be combined using the OR operator by default However you may also explicitly specify the logical operators Accepted operators are AND OR NOT and use of parentheses is possible A free text search b
64. hese citations are from MEDLINE and additional life science journals The database is filtered in regard to the species of interest in the analysis and then mined for gene gene co citations to create the BiblioSphere GeneOntology The Gene Ontology controlled vocabulary is produced and maintained by the Gene Ontology GO Consortium GO provides three structured networks of defined terms to describe gene product attributes It is widely used for the annotation of genes and gene products Gene Ontology annotations for the BiblioSphere are supplied by NCBI Entrez Gene MeSH The Medical Subject Headings MeSH thesaurus is a controlled vocabulary used for indexing cataloguing and searching for biomedical and health related information and documents This indexing technique was introduced by the National Library of Medicine to classify and thus easily retrieve the scientific publications in medical subjects published around the world Today MeSH contains millions of documents in fifteen main categories of which BSPE integrates five e Chemicals an Drugs e Anatomy e Disease e Analytical Diagnostic and Therapeutic Techniques and Equipment e Biological Sciences UniGene UniGene is an experimental system for automatically partitioning GenBank sequences into a non redundant set of gene oriented clusters Each UniGene cluster contains sequences that represent a unique gene as well as related information such as the tissue types in which the gene
65. ields marked with are required fields Please provide your full First name and Last name We allow for one free account per user Please fill in your full and correct details above We offer free of charge special arrangements for academic teaching courses Any account with wrong or incomplete registration details will be cancelled without pre notice Your IP address is being monitored After the registration you will immediately receives wi r evaluation account information and password ES For comments questions or bug reports please contact support qenomatix de Genomatix Software GmbH 1998 2006 AN rights reserved License Agreement 8 EZ ES ef egie Check your e mail A mail with you login data should be sent to you right away 2007 Genomatix Software GmbH 17 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Dear Bernd Mustermann your registration for a Genomatix evaluation account was successful Here are your account details login name bmustermann password nUDbIPnW Please note that username AND password are case sensitive You will find the GenomatixSuite at http portall O qgenomatix de cqi bin feldorado main pl You can change your password using the change password link at the top of the program page or on your Personal profile page You can also subscribe to unlimited Mat Inspector access on your Personal profile page
66. iew Several BiblioSpheres can be open in parallel You can switch between them by clicking the appropriate tab SGBS tabs are labelled with the input gene ID CCBS tabs with the name of the analysis they were created for An icon denotes the species selected in the analysis The workspace area of a BiblioSphere view consist of three panels a filter panel on the left hand side a protocol panel at the bottom and the main panel which occupies the rest of the available space The main panel itself contains several different views on the data organized in tabbed panes The BiblioSphere Pathway View pane is displayed in the foreground when you open a BiblioSphere It shows a graphical network representation of the BiblioSphere in the Pathway Panel Genes are displayed as network nodes whereas the relationships between them make up the edges If you click on a relationship information on it is shown in the upper right hand corner Relation Info panel Below that details on the gene that currently has the focus in the network view are displayed in the Node Info tab of the Node Info Panel In the Unconnected Nodes tab all input genes that could not be integrated into the network are listed Toolbar Controls and Actions Gi Zoom In Zoom in to the Pathway View ka H Zoom Out Zoom out Optimize Layout Recalculate the layout depending on the gene in focus Shortest Path Shortest path for the gene in focus ON OFF Launch the Color Scheme Chooser onl
67. il the user changes the focus by double clicking a different gene in the graph To calculate the shortest path between gene pairs Dijkstra s algorithm is used a graph search algorithm that solves the single source shortest path problem for a directed graph with non negative edge path costs As some edges in BiblioSphere s Gene Networks are undirected they are treated as two directed edges In BiblioSphere the length of an edge between two genes is determined by the weighted lines of evidence e g number of co citations supporting the connection the more evidence the shorter the connection However as opposed to the road map example it makes a difference whether a relation is direct or indirect in biological networks As the number of hops between two nodes is not taken into account by the algorithm we needed to find a way to make use of this information to make sure that direct relations between two genes are always preferred over indirect connections To achieve this we defined minimum min and maximum max edge lengths so that two minimum length edges are longer than one maximum length edge min max 2 1 This guarantees that regardless of the number of co citations a direct connection is always shorter than an indirect connection Network Generation and Analysis BSPE can be applied for various research strategies ranging from information retrieval about a single gene of interest up to the evaluation of microarray an
68. import data 1 6303 spermidine spermine N1 acetyltransferase 2 3081 homogentisate 1 2 dioxygenase homogentisate oxidase 3 B417 isocitrate dehydrogenase 1 NADP soluble 4 2512 ferritin light polypeptide 5H 585 mucin 4 tracheobronchial ek 7402 100 calcium binding protein 414 286 5100 calcium binding protein P 2495 ferritin heavy polypeptide 1 8 9 6888 transaldolase 1 10 11 27075 transmembrane 4 superfamily member 13 10653 serine protease inhibitor Kunitz type 2 314 Kruppel like Factor 4 out 13 1728 NAD P H dehydrogenase quinone 1 14110551 anterior gradient 2 homolog xenopus laevis H 644 aldo keto reductase family 1 member C3 3 alpha hydroxysteroid dehydrogenase type IT 16 6748 signal sequence receptor delta translocon associated protein delta 17 1048 carcinoembryonic antigen related cell adhesion molecule 5 Cosi Uess 2007 Genomatix Software GmbH 50 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation In the first step the data format of the file can be selected The Data Import Assistant will guess the format based on a data sample and pre select the values In the subsequent step you can set data separators and text qualifiers Again the Data Import Assistant will make the pre selection based on the analysis of a sample Data Import Assist
69. ing the analysis you will be able to retrieve it anytime by clicking the launch bibliosphere icon in the respective row If a list of SGBSs exists it is accessible via the Analysis results hyperlink in the row below the analysis If you want to update or delete an analysis click the according symbol in the appropriate row Genomatix Bibliosphere ile View Filter Extras Data Analyses left unlimited BiblioSphere search BiblioSpheres El undock 4 back gt reload 3 home BH save pe amp print Rah Genomatix BiblioSphere PathwayEdition Version 7 20 e Project Manager Project Manager Personal Page New Project Name Description Created Type Action New Analysis _d Gene name search a Demo_Manual A description for the project used in the 2006 03 0 Project folder BE 3 d File upload BSPE manual d Free text search i 03 dae Sean eearch ow Analysis_GeneNameSearch SC 03 0 SE VG 3 2 PMID list search S Help A Analysis results Analysis Results C Analysis_FileUpload 2006 03 0 File upload CG 3 2 Analysis_FreeText 2006 03 0 Free text gf 3 2 search Gell Analysis_MeSHTerm 2006 03 0 MeSH term e LG 3 Search Gell Analysis_PMIDList 2006 03 0 PMID list search SG 3 2 launch bibliosphere LS edit analysis project a new analysis delete analysis project If you encounter any problems please contact support genomatix de Genomatix Software GmbH 1998 2006
70. ings Ch Zoom Zoom in and out the 3D view Clicking the button will drop down a slider that lets you zoom continuously W Optimize Layout Recalculate the 3D layout Ke Legend Display a legend explaining what the different spheres represent JPG Save JPEG Save a bitmap image of the network in JPEG format SVG Save SVG Save an image of the network as Scalable Vector Graphic SVG The different types of colored spheres represent functions of genes and the relations between them input gene input transcription factor gene input gene filtered out input transcription factor gene filtered out co cited gene co cited transcription factor gene gene is co cited with focused gene OOGA transcription factor gene is co cited with focused gene Information about Genes and Connections Additional information on focused genes and their relationships is displayed in the Info Panels next to the 3D view see Relation Info Panel and Node Info Panel for details in contrast to the BiblioSphere Pathway View the Node Info Panel here is not subdivided into tabs as there is no list of unconnected nodes If one of these genes is a transcription factor you can additionally gain information on potential binding sites in the promoters of its cocited neighbours Connections affirmed by this promoter analysis are displayed in green Focus on Gene Subnets Clusters Activating the Expand Collapse Gene Cluster option adds yet another level of dynamic fi
71. ions Each node in the tree displays the term name and the number of abstracts annotated with this term for your active BiblioSphere In the example above 609 PubMed articles are either directly annotated with the selected term Gastrointestinal Diseases or with one of its more specific terms in the subcategories of this branch 2007 Genomatix Software GmbH 68 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation Tissue Filter The Tissue Filter allows you to identify clusters of genes that share a common expression profile Tissue Filter Structure Genomatix has assigned UniGene tissue names to a hierarchical tissue ontology Thus the Genomatix hierarchical filter concept can be applied to UniGene expression data and groups of genes with significant coexpression profiles can be identified Help Button Query Field Reset Button Selected Terms FreeTextFilter CoCitationFilke TissueFilter K i B ooo Pamies hl S O El 1 GO muschke 5 J 7 12 organ system i E 65 adipose tissue Se f4460cardiovascular system E i377 endocrine system 2 546 haemolymphoid syste ER Kee D 5 L 2 406 leukocyte Clay gt P ewes mi E 799 Junig vee PR 24 unig ie ya Ge blood mph eukocyte ene ly ene E Hierarchical Annotations Each
72. is expressed BSPE utilizes the tissue information assigned to a gene by UniGene and integrates it into its unique hierarchical Tissue Filter NetPro NetPro is Molecular Connections comprehensive fully hand curated knowledgebase of Protein Protein Protein Small molecules DNA and RNA interactions consisting of more than 200 000 interactions captured from approximately 1 400 published journals covering more than 31 000 references BiblioSphere integrates NetPro in its network graphs and connection info STKE STKE is an online resource devoted to the understanding of cell signalling developed by the American Association for the Advancement of Science AAAS and hosted by Stanford University s HighWire Press BiblioSphere provides links to STKE s connections maps on the web KEGG Pathway KEGG Kyoto Encyclopedia of Genes and Genomes provides among other bioinformatic data manually drawn pathway maps KEGG is maintained by the Kanehisa Laboratories in the Bioinformatics Center of Kyoto University and the Human Genome Center of the University of Tokyo BiblioSphere provides links to KEGG pathway maps on the web BioCarta 2007 Genomatix Software GmbH 6 Introduction to BiblioSphere PathwayEdition Genomatix BiblioSphere PathwayEdition understanding gene regulation BioCarta provides interactive graphic models of molecular and cellular pathways as part of an open source project BiblioSphere provides links to BioC
73. k 4 back forward p cancel reload home BI save GS open amp pri All citations of CDK6 Honokiol causes GO G1 phase cell cycle arrest in human prostate cancer cells in associatio transcriptional activity dasste ie Cdk4 Cdk6 gt CDK6 and or cyclin E and suppression body follo Ge immunoblotting for Cdk4 protein astoma protein Rb which correlated with the suppression of kin expresfion LNCaP GI ed to confer any protection against honokiol induced cell cycle 17938262 Exposure of PC 3 and LNCaP cells to honokiol resulted in the induction of p21 PC 3 and LNCaP and p53 pro However small interfering RNA siRNA mediated knockdown of either p21 PC 3 and LNCaP or p53 LNCaP arrest In leiere the present study reveals that the honoliol mediated G 0 G 1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein osphorylation of Rb leading to inhibition of transcriptional activity of E2F1 Association study of 69 genes in the ret pathway identifies low penetrance loci in sporadic medullary thyroid carcinoma We selected 417 single nucleotide polymorphisms SNP belonging to 69 genes either related to RET signaling pathway functions or involved in key processes for cancer development 17909067 This strategy allowed us to identify seven low penetrance genes six of them STATI AURKA BCL2 CDKN2B CDK6 gt CDK6 a
74. le upload you can specify what kinds of genes you want to see e Only your input genes e Your input genes and the transcription factor genes connected to them e Your input genes and all connected genes The last option is available if you entered the gene identifiers manually and unchecked the Show only co cited transcription factor genes option in the analysis An analysis based on uploaded data is restricted to finding co cited transcription factors 2007 Genomatix Software GmbH 62 Network Filtering Genomatix understanding gene regulation BiblioSphere PathwayEdition If you choose the second or third option further filtering options pertaining to the non input genes become available e In aCCBS you can select the number of input genes another gene has to be connected to in order to be displayed in an SGBS this number will always be 1 the maximum is the total number of input genes e You can choose the number of times a gene has to be co cited with one input gene the maximum is the largest number of co citations for a non input gene with an input gene in your BiblioSphere The specificity level options are always available FreeTextFilter CcoCitationFilter Show f input genes C input transcription Factors th Ce input tF and all other genes genes are cociked with ak least 1 i min 1 max 20 nput genes genes are at least j 1 3117 imes cocited with one input gene Ab
75. lioSphere a Filter Statistics table is available in the View Panel This view component is interlinked with the corresponding filter and allows for sorting and export of data 2007 Genomatix Software GmbH 65 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation Gene Ontology Filter Filters for each category of Gene Ontology are available Integrated statistical rating allows for the identification and selection of clusters of functionally related genes Each GO Filter consists of a hierarchy of terms and the corresponding annotations for your BiblioSphere This hierarchy is originally a directed acyclic graph DAG but for easier navigation it has been converted to a tree for the GO Filter To activate the GO Filter using the selected terms click the Filter nodes button Clicking the Reset Button will deactivate the GO Filter Help Button Reset Button Query Field Apply Filter Selection to Nodes Led D ao 20h signal transducer ah ky _ EE Galecied Tenn 9 11 9 receptor binding Statistical Analysis Expected Evaluated Observed Variance Standard deviation focore eeeeeeese Ssicytokine activity Hierarchical Annotations Each node in the tree displays the term name and the number of nodes annotated with this term for your active BiblioSphere In the example above 294 genes are eith
76. lls for secure and fast access to the Web Thus you need to configure the BSPE application to get through your proxy or firewall Please proceed as follows Get the proxy settings from your internet browser If you use internet explorer Go to Tools gt Internet Options gt Connections gt LAN settings If you use Netscape or Mozilla Go to Edit gt Preferences gt Advanced gt Proxies Below you see an example for the Mozilla browser Preferences Category Languages Helper Applicat Configure Proxies to Access the Internet Smart Browsing T EE Direct connection to the Internet Tabbed Browsing Downloads HTTP Proxy proxy your org Port 3126 PUE Lise these settings For 55L FTP and Gopher Mail amp Newsgroups Privacy amp Security lt Chat7illa ETF Proxy proxy your org Pork 3128 SSL Proxy proxy your org Port 3128 H Advanced Gopher Proxy proxy your org Port 3128 Scripts amp Plug ins SOCKS Host Port o keyboard Navi O SOCKS v4 SOCKS v5 Cache No Proxy For localhost 127 0 0 1 Proxies z i il sample mozilla org net nz HTTP Networking S 2l Software Insta Mouse Wheel DOM Inspector System Automatic proxy configuration URL Configure the settings according to the configuration of your browser and press ok Below you see an example for manual proxy configuration Preferences REES s Proxy Configuration Update Frequency SSL Configuratio
77. ltering to your BiblioSphere By clicking on a sphere you hide all elements that are not directly connected to it from view leaving only the cluster around the selected gene visible The graph s zoom factor is adjusted automatically to provide an optimized view on the region of interest Clicking anywhere between the displayed elements lets you see the whole graph again Furthermore you can activate the Show Ghosts option which will show faded those input gene spheres that are blocked from view by the current combination of filters 2007 Genomatix Software GmbH 54 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Co Citation Browser The Co citation Browser provides access to the citations of a gene in the literature You display citations of a gene in the browser by clicking on the row header of a gene dataset in the Genes View table all citations of that gene will be shown Alternatively you can view co citations of two genes To that aim click on the appropriate co citation link in the Relation Info Panel of the Pathway View or the 3D View Identified pathway word Identified function word Hyperlink to PubMed abstract Hyperlink to EIDorado gene info Identified transcription factor Identified tissue Identified disease Identified gene B Cocitation Browser Eg Genes bes Documents wt TF Analysis a Gene gene connections gt NiblioSphere 30 BiblioSphere Pathway view Gal undof
78. m your search term to specify the document fields you want to search in Available document fields and prefixes are listed in the fields table FreeTextFiter CoCitationFilter Lise on Reset Button FO 1999 finds articles containing the te complement published in 1999 Submit Button GE Es Query Field ArticleTitle TI Fields Table Abstract AbstractT ext an Author au PMID mat PublisherMame um Journal Title Ba MESH chemical subheading Affiliation d Biological Entity Filter Overview Filtering In any of the hierarchical filters you can enter a term in the Query Field and press return This will expand the tree to show the first matching term or you can select your filter term by clicking on it Pressing the control key during selection enables you to use a combination of terms for filtering These filter terms are combined using the OR operator The current combination of filters is displayed in the Protocol Panel Statistical information is displayed in several ways Mouseover Text Placing the mouse pointer over a term of interest will display a small table with the results of statistical analysis Color Code each term is colored according to its z score The more an item deviates from its distributions mean the deeper the color Green color indicates overrepresented items while underrepresented terms are colored in red Filter Statistics For each active hierarchical filter in Bib
79. must be cocited at least 1 time s with an input gene number of genes passing the filter 13 Status Bar The Status Bar keeps you informed about your internet connection settings and state Function wa im ara SR2 SSS oes E i Level B1 restric EA Ca CHP O sentences with APOE Examples for A AC D i d VMEIL1 a Filter settings CoCitationFilter Current Bibliosphere level is Sentence level plus gene function word gene This Riblin nhere ic restricted ro Innit ana teancerintinn factar oaeneg S YT if Message Area k Status Bar roxy State Encryption State Connection State Status Bar Items Message Area Information on the state of the application is displayed here Proxy State a The colored icon indicates that a proxy server is used to connect to the internet The icon is greyed out when no proxy server is used Encryption State GN Connection encrypted SSL mk No encryption is used Connection State lio The client is not connected to a BiblioSphere server on the internet K Trying to connect le Connected to a BiblioSphere server 2007 Genomatix Software GmbH 61 Protocol Panel Genomatix BiblioSphere PathwayEdition understanding gene regulation Network Filtering Overview The unfiltered output of any literature mining tool often includes large portions of data that may be only marginally relevant to the user s focus of inter
80. n Server Configuration l Navigator Configure Proxies to Access the Internet History EE bo tiie Inteniet Direct connection to the Internet Languages EE Mena Rahs RSE ON RO NaS ORES LE ARETE SPER ETE ERTL REN OI LE A Helper Applicat Manual proxy configuration O Manual Proxy Configuration Smart Browsing HTTP Proxy proxy your org Port 3128 Server Internet Search Use these settings for SSL FTP and Gopher Tabbed Browsing Downloads SSL Proxy proxy your org Port 3128 HTTP Proxy Composer FTP Proxy proxy your org Port 3128 Mail amp Newsgroups Gopher Proxy proxy your org Port 3128 Privacy amp Security SOCKS Host Port 0 ChatzZilla Advanced SOCKS vd SOCKS v5 No Proxy for localhost 127 0 0 1 Automatic proxy Configuration URL Scripts amp Plug ins 5 i 7 Rerberet Navi xample mozilla org net nz Cache Proxies l l i HTTP Networking Automatic search for proxy configuration Sots etal Automatic proxy configuration URL 2007 Genomatix Software GmbH 24 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation SSL Configuration BSPE allows for encrypted communication with the server via internet via Secure Socket Layer SSL If you would like to use the encrypted protocol proceed as follows Start BSPE see above Go to menu Extras and select Proxy settings to launch a prefer
81. nd COMT consistently associated with sMTC risk in the two case control series and a seventh HRAS with individual SNPs and haplotypes associated with sMTC in the Spanish data set The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP rs7044859 in the promoter region in altering the binding of the transcription factor HNF1 A CDKN2A mutation in familial melanoma that abrogates binding of pl6INK4a to CDK4 but not CDK6 gt CDK6 The CDKN2A locus encodes two distinct proteins pl6INK4a and pl4ARF both of which are implicated in replicative senescence and tumor suppression in different contexts Here we describe the characterization of a novel strain of human diploid fibroblasts designated Milan HDF s from an individual who is homozygous for the R24P mutation in pl6INK4a As this mutation occurs in the first exon of INK4a exon lalpha it has no effect on the primary sequence of pl4 ARF 17909018 Based on both in vitro and in vivo analyses the R24P variant is specifically defective for binding to CDK4 but remains able to associate with CDK6 gt CDK6 x Link to PubMed The browser displays the PubMed IDs of the relevant articles as links to the PubMed abstracts which will be displayed in an external browser if you click on the link Tagged Sentences Every sentence in the abstract that cites the gene or in the case of co citation abstracts one of the co cited genes is displayed for a quick over
82. ng to a biological context of interest For this purpose BiblioSphere PathwayEdition offers a number of powerful tools and methods e Focus network on specific biological experimental context o Unsupervised purely data driven by following the green path via z scoring o Supervised by filter settings according to specific area of interest e Dynamic shortest path calculation and display by double clicking of central gene of interest e Automatic integration of pathway network relevant transcription factors even if those are not elements of the input set Optional expansion by all other genes in the network beyond input list and transcription factors e Superimposition of additional evidence based on promoter sequence analysis e Superimposition of additional evidence based on expert curated transcriptional regulation knowledge The picture below shows the basic principle of the BSPE application After an initialization step 1 which collects all information for the given set of input genes and their association to other genes the analysis step 2 takes place fully under control of the user and under control of a permanent biological scoring and ranking of the gene relation network Biological Filter e g Disease Tissue GO Text Filter e g Free Text Co Citation User Specific Biological Gene Relation Network Network Scoring Biological Network Scores Literature In silico Sequence analysis In depth information ete
83. ocess If the selected file is an Excel file you select the data sheet you would like to import Data Import Assistant Steps Select Excel sheet gt Select Excel sheet You can only import one datasheet at a time Please select the tab with the data you want to import before you continue 4 B 6303 spermidine spe 3081 homogentisate 3417 isocitrate 2512 ferritin light 4635 mucin 4 57402 5100 6286 5100 2495 ferritin 6888 transaldolase 27075 transmembran 10653 serine 9314 Kruppel like 1723 NAD P3H 10551 anterior 8644 aldo keto 6748 signal sequen 1048 carcinoembrys 2934 gelsolin 1646 aldo keto 1645 aldo keto 7296 thioredoxin 7295 thioredoxin 2877 glutathione 8544 pirin 4070 tumor associat 1545 cytochrome 1543 cytochrome 4680 carcinoembrys 9071 claudin 10 84790 tubulin connective EZTI In the next step you can identify the column containing the Gene IDs and the column holding the associated annotations by selecting the appropriate label in the column header All other columns will be ignored Data Import Assistant Steps Data Selection Select Excel sheet Please identify the column containing the gene ids only Entrez Gene or Locusid identifiers are supported and the column that holds the corresponding Label All other columns will be ignored Geneld w Label 6303 s
84. on of and cyclin A gt CCNA and cell cycle progression Function word level B2 Level B1 restricted to Regulation of the Rig Gi pathway by 5M933 led to altered cell cycle activity of encephalitogenic T cells as a result of its selective effect on O sentences with a function word activated but not resting T cells Examples for function word regulation inhibit GFG level B3 At 1 0 mg ml NGRE inhibited cell growth by 85 8 P lt 0 01 probably linked to the higher concentration of ginsenosides Rbl and Hei Level B2 restricted t aih ode The pharmacologic activities of notoginsenoside R1 and ginsenosides Rg and Rbl on the cells were antiproliferative gene function word gene Expert level B4 Two day treatment with 300 microM of notoginsenoside R1 ginsenosides Rg and Rbl increased cell apoptosis significantly CO pale pala Cell cycle and cyclin A gt CCNA2 assay showed that NGRE arrested cells in the synthesis phase and increased the expression of cyclin A gt CCNA curated information remarkably o Signal transduction associations ST Level ST restricted to ech S PCS 7 S sentences with signal transduction information The mean reduction in the expression of keratinocyte proliferation markers after NBUVB was 62 68 and 81 for Ke cyclin A gt CCNA2 and 17880582 cyclin B respectively Expression of suprabasal keratin 16 and filaggrin was almost normalized in most cases We have shown previ
85. ons Setup aH Welcome to the Genomatix Applications Setup Wizard This wizard will guide you through the installation of Genomatizx Applications It is recommended that you close all other applications before starting Setup This will make it possible to update relevant system Files without having to reboot your computer Click Next bo continue Click Next gt and follow the instructions 2007 Genomatix Software GmbH 20 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation After BSPE is installed successfully you can start the application in different ways 1 Start BSPE from the program group After successful installation windows users should have a new Program Group Genomatix Applications with an executable BiblioSphere Click Start All Programs GenomatixApplications BiblioSphere ken GenomatixApplications gt CG BiblioSphere o UninstallGenomatixApplications E Paint Alle Programme Chipinspector 2 Start BSPE from desktop After installation you should find an Icon on your desktop BiblioS phere A double click on the icon will launch the BSPE application 3 Start BSPE per batch file MS Windows only On Windows systems if BSPE does not start when you double click the desktop icon you can use a batch file that you find the in a subdirectory of your Genomatix installation directory Th
86. ously that one of the TPR subunits of the Drosophila APC C Apc3 also known as Cde27 or Makos is essential for development and perturbation of its function results in mitotic cyclin accumulation and metaphase like arrest Filter settings CoCitationFilter This BiblioSphere is restricted to input genes number of genes passing the filter 561 LIAE Promoter analysis Quick identification of transcription factor emmma gene relations defined by binding UserDataFilter GOFilter biologii B Cocitation Browser ES Genes E Documents TF Analysis a Gene gene connections gt BiblioSphere 3D a BiblioSphere Pathway view ES GOFilter biological process sites on promoter level e ek z zl Show P Gene TP53 W PS3F CEBPD V CEBP TGIFI V TALE TI mettes TFAM M TFAM coca mvc v EB0x CO z JUN a input genes Y Genomatix Bibliosphere input transcription factors tf SERPINE1 IPO 1 HSP90441 C16orf80 PCNA ITGA4 Abstract level B0 mee Two genes are co cited e within an abstract IL16 Sentence level B1 G Two genes are co cited RUNX1 in the same sentence STATI Function word level B2 BRCAL Level B1 restricted to O sentences with a function word E Examples for function word BCL2AL regulation inhibit MBNL1 GFG level B3 Level B2 restricted to sentences with order gene function word gene Exp
87. permidine spermine Ni acetyltransferase 3081 lhomogentisate 1 2 dioxygenase homogentisate oxidase 3417 lisocitrate dehydrogenase 1 NADP soluble 2512 Ferritin light polypeptide 4585 much 4 tracheobronchial 57402 5100 calcium binding protein 414 6286 5100 calcium binding protein P 2495 Ferritin heavy polypeptide 1 6388 transaldolase 1 27075 transmembrane 4 superfamily member 13 10653 serine protease inhibitor Kunitz type 2 9314 Kruppel like Factor 4 out 1728 INAD PIH dehydrogenase quinone 1 10551 lanterior gradient 2 homolog Xenopus laevis 8644 laldo keto reductase Family 1 member C3 3 alpha hydr 6748 sonal sequence receptor delta translocon associated 1048 carcinoembryonic antigen related cell adhesion molecule 5 2934 gelsolin amyloidosis Finnish type 1646 laldo keto reductase family 1 member C2 dihydrodiol d 1645 laldo keto reductase Family 1 member C1 dihydrodiol d 7296 thioredoxin reductase 1 7295 thioredoxin 2877 glutathione peroxidase 2 gastrointestinal 8544 pirin iron binding nuclear protein 4070 tumor associated calcium signal transducer 2 1545 lcytochrome P450 Family 1 subfamily B polypeptide 1 gt Select import columns 2007 Genomatix Software GmbH 49 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation The last step allows you to name your
88. provided for analysis by the user Show Citations for this Gene Dock Undock Button Customize Data Export Button Help Button Gene Selection List Chcitation Browse EE ges E Documen e bes 2 BiblioSphere 3D TZE BiblioSphere Pathway View E GoFilter biological process E uhdock EA ftom Ea eot a find BCL2A1 DN Y help ee et Lee Less Lem Lem ite Lee Lee Let LU Did F umor protein p53 Li F 7157 passed P53F Tumor protein p53 a nuclear protein plays an essential r 0 315 A meeps CL2L11 BCL2 like 11 EE 10018 10018 a EG he See encoded by this gene Geck to the BCL 2 pro 0 354 US SS signal transducer and Poo o o STAT he protein encoded by this gene is a member of the STAT SC E RECS X ray repair EE e E E EE he protein encoded ad this gene is the 80 kilodalton subu 0 317 i SE a E E e ES SE EE Ee DEE DEE SES EE e ES Jr ii E f 2007 Genomatix Software GmbH 58 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Gene Gene Connections The spreadsheet view of co citations contained in a BiblioSphere contains direct links to the Cocitation Browser and supplies the functionality to export data for further analysis with external applications While the BiblioSphere 3D view displays the edges of one gene at a time the Gen Gene Connections spreadsheet holds all literature based relations in your current selection of BiblioSphere data Co
89. ptosis 0 44 470 Z 0 1 kuch E D LA 1 Z 3 sad He i 6 E 5 J E CH Fi CD CD VC E Du CT CH a el CH E CH CH bes Du 3 z CD CL CO T CL CD Du H St oi CH CH CH Ka LA CH CN DI Dm om go Awol oye we aS Cu Go E Go ee oy oe response to stress 1 73 regulation of apoptosis Goons 70 0 92 Cell development 2 08 regulation of programmed cell death 0 93 induction of apoptosis 0 37 induction of programmed cell death 0 37 cellular developmental process 3 01 CP GO on on om 9 dead E 5 co Eech fa WM Total The number of genes annotated with this term Observed The number of genes in your BiblioSphere meeting the criterion Minimum Observed Lower threshold for Observed value by default 4 to avoid spurious statistical results based on small numbers Maximum Observed Upper threshold for Observed value by default Observed value for root term in the filter decrease to exclude the more general terms in the filter from the table Expected The number of genes expected to meet the criterion based on observed values for all co cited genes in PubMed and your input set size ZScore Over or underrepresentation of the criterion expressed in multiples of the standard deviation Superimposition of Filters You can activate any number of filters in parallel to make your selection more specific the filter terms
90. resulting from your selection in each single filter will be combined using the AND operator 2007 Genomatix Software GmbH N 1 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation BiblioSphere PathwayEdition Help Online Resources To access the online help click on in the BSPE main menu and select Help or click on the help button in any of the BiblioSphere views Contacting Genomatix If you encounter any problems please contact support genomatix de Glossary Cluster Centred BiblioSphere CCBS A CCBS shows all genes connected with at least one member of your input set of genes All second level connections in between all genes are computed regardless of whether an input gene is involved or not This type of BiblioSphere is calculated when an analysis is performed Single Gene Centred BiblioSphere SGBS A SGBS is based upon one input gene this and all genes connected with it are shown This type of BiblioSphere is pre calculated and will be retrieved from the database when requested in an analysis Literature Quandt K Frech K Karas H Wingender E Werner T 1995 MatiInd and Matlinspector new fast and versatile tools for detection of consensus matches in nucleotide sequence data Nucleic Acids Res 23 4878 84 PUBMED 96128303 Cartharius K Frech K Grote K Klocke B Haltmeier M Klingenhoff A Frisch M Bayerlein M Werner T 2005 Matinspector and
91. rsion on command line 2007 Genomatix Software GmbH 12 Technical Requirements Genomatix BiblioSphere PathwayEdition understanding gene regulation Here is an example for windows users how to check the installed java version Click on Start All Programs Accessories Command Prompt see screenshot below i gt ia Accessories d H Accessibdity gt e E mail dt s x 1 EH Games gt tm Communications gt CH Microsoft Office Tools K H Entertainment gt Internet Explorer var o T En em EH Startup K H System Tools gt Fy Internet Explorer UJ Address Boot Microsoft Access S Calculator e 28 Microsoft Excel e Command Prompt 5 Microsoft FrontPage ze Notepad 3 G Microsoft Outloot g y Paint i Microsoft PowerPoint 3 Program Compatibiity Wizard Burning Rom p g E e q Microsoft Word i SA Synchronize 1 m MSN Explorer l O Tou Windows xP l R er ats sk on i KA Anpe E Le 2 Outos Express iw Windows Explorer erver Maneoe gt Remote Assistance GG Windows Movie Maker j Windows Media Player A WordPad Se V A ALE IOUS 2 0 i Evert Viewer i gt WGs E f pke er 2 d ei Download Accelerator gt AllPrograms P T 7 HP RecordNow gt A command window will pop up e C WINDOWSystem3 7 cmd exe iC gt SUTNDOWS gt Type in java version and press Enter If Java is installed you will get an output like i gt java version java version 1 5 6_H6 JavatIM 2 Runtime Environment
92. ssue e ICT 69 Uer eae et MS acre ace a wets cee cere ccc ce te eee ee eet ee ee oe ee ee ee eee eee 70 Sub Network IT 70 de AN a E 71 Se de RAUNO sirisser nanak EAE EEEa 7i SUDEHM POSITION OF FIGG S esiri ninni A 7i Sleeve Selen E 72 Online ReSOuUrCeS cccececcueecevcueusevaueusevaueusevaueusevaueusevaueuseeaueuseeaueusevaveuseeaueusueaueususavausuvavaususavausenanants 72 eine cono GENOMA E rE ET E re rr rr rr rc rc rr rr cr tT 72 lo Te eee ee ee ee 72 Keen le EN 72 2007 Genomatix Software GmbH 3 GenomatiX BiblioSphere PathwayEdition understanding gene regulation Introduction to BiblioSphere PathwayEdition BiblioSphere PathwayEdition BSPE is a next generation software system for dynamic data driven retrieval and analysis of gene relation networks BSPE is the only system available which combines literature analysis with proprietary genome annotation and promoter analysis Relations between biological entities are based on independent information sources multiple lines of evidence which provides insights beyond current literature knowledge National kal Library Pub Aed of Medicine Proprietary literature analysis D Ns MatInspector sos EiDorado Expert curated knowledge BiblioSphere Analysis of quality checked promoters PathwayEdition External data resources BSPE is the only application where the user starts his analysis on base of the entire network of input genes correlated genes and their biological
93. stract level 60 e Two genes are co cited within an abstract Sentence level B1 T Two genes are co cited in the same sentence Function word level 62 Level B1 restricted to C sentences with a Function word Examples For function word regulation inhibit GFG level B3 La Level B2 restricted ta sentences with order gene a Function word gene Expert level 64 e Level E4 restricted to sentences with expert curated information Show hide co cited transcription factors and other genes Filter genes by number of connections to input genes Filter connections by co citation frequency Switch specificity level Signal transduction associations ST C Level ST restricted to centences with signal transduction information 2007 Genomatix Software GmbH 63 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation Specificity Levels Genomatix BiblioSphere includes six different filter levels for gene gene co citations As an example co citations of the transcription factors E2F1 and TP53 are shown for each of the six levels Transcription factor names are printed in indigo other gene names in green tissues in cyan and function words in pink Abstract level E2F1 and TP53 are co cited somewhere within an abstract of a publication The epithelial component was strongly positive for CK13 CK14 and AF1 AE and groups of positive cells were seen for C
94. svc AKRIBI v 0 oO CC Optimize Layout Zoom Gei a FOXO1A 3100F Show Hide S Ghosts A HFE GSPT1 FOXF1 V FKHD binding sites found in A d promoter s of FOKA GTF3c1 FOXES 2 SLPI li cau SZ CA4 a a F a APP ame F amp UGT1A10 DICER1 ETV6 UGT1A4 A TALDO1 2007 Genomatix Software GmbH 53 Gene symbol FOXA2 1d 3170 Full Name forkhead box A2 Analyze Promoter s of FOXA2 show BiblioSphere for FOXA Get ElDorado annotation for FOXA2 Show matrix info for V FKHD show comparative Genomics for FOXA2 Remove FOXA from BiblioSphere Description This gene encodes a member of the forkhead class of DNA binding proteins These hepatocyte nuclear factors are transcriptional activators for liver specific transcripts such as albumin and transthyretin and they also interact with chromatin Network View Genomatix BiblioSphere understanding gene regulation Path wayE dition Toolbar controls and actions Oh Cluster Mode Allows you to switch to a sub cluster when active by simply clicking on your cluster centre of choice Click anywhere in the space between the spheres and connections to switch back to the total survey e Edge Mode Displays edges for a gene when you position the mouse pointer over its sphere ei Reset View Resets all filters of your BiblioSphere Oh Show Hide Ghosts Ghosts are input genes that do not pass the filter with the current sett
95. thly Then press the ok button E Preferences Proxy Configuration Update Frequency 55L Configuration Server Configuration Get the latest version of bibliosphere Gei daily Checking For updates requires an active Internet connection O Manually check for updates Current version 6 31 Last check For updates 09 05 07 18 2007 Genomatix Software GmbH 28 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Updating your Application Manually In some situations you might want to update your application manually Select Manually check for updates This will activate the Check now button Press the Check now button If an update is available the Update Service will guide you through the update process E Preferences EELER Proxy Configuration Update Frequency 55L Configuration Server Configuration Get the latest wersion of bibliosphere Automatically check for updates Checking For updates requires an active Internet connection Manually check for updates Current version 6 31 Last check For updates 09 05 07 18 2007 Genomatix Software GmbH 29 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Selecting an Update Server If update speed is slow click the Advanced button in the Update Frequency panel and select a different update server from the list To go back to the m
96. ticles that contain the co citation and are annotated with the selected term which is more stringent The number of abstracts can exceed the number of genes in the network due to multiple citations of the same gene Clicking the Reset Button will deactivate the GO Filter 2007 Genomatix Software GmbH 67 Network Filtering Genomatix BiblioSphere PathwayEdition understanding gene regulation Help Button Query Field Reset Button FreeTextFilter CoCitationFilker MeSHFilter Disease Se aN nu 1 S Joint Diseases CO5 550 Se Muscular Diseases 005 651 Sy 2iMusculoskeletal Abnormalities 705 660 S Rheumatic Diseases 205 799 een pA System Diseases CO5 Apply Filter Selection to Nodes and a 7 C105Biliary Tract Diseases CO6 130 Connections ay SUDigestive System Abnormalities 206 198 Se GG Digoestive System Fistula 206 267 Ce S02 Digestive System Neoplasms 706 301 Sa Selected Term ia 6JEsophageal Diseases C06 405 L E Apply Filter Selection to Nodes ma m Expected 173 73 Statistical Analysis l d D Evaluated 4315 9 70 Colitis 006 405 205 265 Observed 609 e 1 Colitis Ischemic 006 40 variance 119 04 Er Pi Standard deviation 10 91 A5COre 44 46 ge SF 1Colitis Ulcerative C06 405 205 265 231 wi lt gt Hierarchical Annotat
97. tion TPS3 V PS3F binding site s found in promoter si of NRSCl Node Info Panel BiblioSphere PathwayEdition In the BiblioSphere Pathway View the information displayed in the Node Info Panel is distributed to two tabs whereas in the BiblioSphere 3D View the Node Info Panel displays only Gene node see below information and is therefore not tabbed Node Info Tab The Node Info tab shows information for the currently selected node in the BiblioSphere graph Nodes can represent either a gene or a pathway annotation for a gene Gene node The gene s locus ID full name organism and description are displayed Clicking on the gene symbol hyperlink opens a browser window with detailed gene information Moreover links to other components of the Genomatix Suite are provided that offer further analysis of the gene e Promoter analysis with MatlInspector e Single Gene Centred BiblioSphere s ElDorado annotation e Comparative genomics with ElDorado s TF binding site matrix for transcription factors Another link allows you to remove the gene from the BiblioSphere 2007 Genomatix Software GmbH Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Example gene node information ene symbol TE53 id 7157 Full Name tumor protem p53 Li Fraumeni syndrome Analyze Promoterts of TPS3 show Bibliosphere for Hi Get El Dorado annotation for Hi mow matrix info for Vo
98. ulation Filled arrowhead indicates activation Blocked arrowhead indicates inhibition Lidl Red color indicates enzymatic modification Green line indicates transcription Factor binding site match in target promoter B Connection annotated by Molecular Connections experts _ Connection annotated by Genormatix experts B Connection annotated by Genomatix and Molecular Connections experts Arrowheads at the ends of a connecting line symbolize the type of functional relationship between the connected genes If a gene that codes for a transcription factor is connected to a gene that is known to contain a binding site for this transcription factor in its promoter the connecting line is colored green over half of its length near the gene containing the binding site Hand annotated gene gene relationships are indicated by a circle in the centre of the connection line Relation Info Panel The Relation Info Panel shows information on the currently selected connection between two genes particularly on the numbers of co citations of these genes on different levels Available levels are Abstract Sentence Function Word Gene Function Word Gene GFG and Expert For detailed information on co citation levels see the chapter Co citation Filter The information provided in detail S e Genes that are linked by the currently selected connection Clicking on a gene symbol hyperlink opens a browser window with detailed gene in
99. view Expressions identified as denoting a transcription factor a gene a tissue a disease a function word or a pathway associated term are color tagged to facilitate assessment of the context For co citations on abstract level every sentence in the abstract citing any gene is displayed 2007 Genomatix Software GmbH 55 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Table Views Overview BSPE offers tabular views to the data in your BiblioSphere specifically to genes gene gene connections documents containing references to the genes and transcription factor analysis You can sort any table by any column select deselect display of individual columns and export the data to an Excel file Toolbar controls and actions iss Dock Undock Open table in a separate window return table to BiblioSphere window E Customize Hide show individual columns in the table LSC Export Data Save the table in Excel format 7 Help Display the BiblioSphere help Documents Table The Documents view component displays information for the PubMed abstracts compiled into your BiblioSphere which pass the filter at the current settings and links directly to PubMed For each document the PMID the identified genes and their number are displayed Clicking the row number opens the relevant PubMed article in an external browser Link to PubMed Document PMID Identified Genes Dock Undock Customize Data Export Number o
100. word E Please enter your new password Please re type your new password rr Change Password Beset Form Please note e password length must be at least 6 characters e password must contain at least one non alpahabetic or capital character e password must not contain blanks or tabs For comments questions or bug reports please contact support qenomatix de Genomatix Software GmbH 1998 2007 AN rights reserved License Agreement Fertig Password Policy Genomatix s password policy requires all passwords to be at least 6 characters long and must contain at least one non alphabetic or capital character No blanks or tabs are allowed 2007 Genomatix Software GmbH 19 Installation of BSPE Genomatix BiblioSphere PathwayEdition understanding gene regulation Installation Switch to the folder on your hard disk where the installer was saved Execute the installer see below and follow the instructions The installer will install both BSPE and ChipInspector install E windows 9x 2000 P doubleclick on the Genomatix install icon in the folder requires administrator privileges i MacOS 10 3 orirun the Genomatiz4pplications installer from the downloaded disk image falder requires administrator M higher privileges Sp CH A kinusunis type java jar InstallGenomatizApplications jar If you run a windows system the following screen will pop up Genomatix Applicati
101. y enabled when expression ranking Color Scheme Chooser data is available Save SVG Save an image of the network as Scalable Vector Graphic SVG Save JPG Save a bitmap image of the network in JPEG format Legend Display Legend Display a legend for gene gene connections as Se Display signal transduction pathway associations of visible genes Check j I I SC Bom Metabolic Pathways Display BioCyc metabolic pathway associations of visible genes Pull down Gene Selection List Sorted list of network genes Focus gene by selecting it from the list menu 2007 Genomatix Software GmbH 41 Network View Genomatix BiblioSphere PathwayEdition understanding gene regulation Optimize Layout Shortest Path on off Zoom in out Color Nodes Export Image Relation Info Panel Show Legend Display Pathway Associations Gene Selection List Help Button salt TF Analysis a Gepegene connections BiblioSpifiere 3D TE BiblioSpber Pathway View Relationship between ACTL6A and MYC 2 abstract s with cocitations BO 4 cocitation s on sentence level B1 4 cocitation s on function word level B2 1 cocitation s on gene function word gene level B3 4 Genomatix expert curated annotations ACTL6A interacts with MYCr4 MatInspector has found evidence for transcriptional regulation MYC V EBOX binding site s found in promoter s of ACTL6A Node Info Unconnected Nodes Gene symbol MYC id 4609
102. ycle phase G0 0022403 278 70 9 99 P SE mitosis so ooo7067 mm 54 636 Wiral reproduction F M phase of mitotic cell cycle GO 0000087 178 54 6 4 7 reproductive process M phase Go 0000279 225 61 8 09 biological adhesion SS Bell DNA replication Go 0006260 je 49 6 08 p m Es cell division GO 0051301 138 52 7 12 aE 11 growth S DNA metabolic process GO 0006259 626 97 22 5 E Wlocomation 711 spindle organization and biogenesis GO 0007051 21 14 0 75 E 2 pigmentation o J chromosome segregation Go 0007059 56 22 zm 2 SC Se i regulation of cell cycle G0 0051726 aen 75 17 61 bt regulation of progression through cell cycle so oo00074 ae 74 rs E 82 establishment of localization 215 fudeobase nucleoside nucleotide and nucleic acid metabolic G0 0006139 2865 221 102 99 E 2 maintenance of localization S mitotic sister chromatid segregation Go 0000070 26 13 0 93 omg Green sister chromatid segregation G0 0000819 27 13 0 97 cell cycle checkpoint G0 0000075 47 17 1 69 regulation of mitosis f G0 0007088 48 TI 17 173 spindle checkpoint GO 0031577 7 6 0 25 cellular process G0O 0009987 9530 474 342 58 cellular metabolic process Go 0044237 5969 344 214 57 mitotic checkpoint G0 0007093 16 i 9 0 58 biopolymer metabolic process GO 0043283 3860 252 138 76 primary metabolic process GO 0044233 5987 339 215 22 DNA repair GO 0006281 214 37 7 69 mitotic spindle organization and biogenesis GO 000705

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