Pentti Riikonen

MUTbase: maintenance and analysis of distributed mutation databases.

MOTIVATION To develop tools for the submission of mutations to databases and maintenance of locus-specific mutation databases. Advanced, integrated computer systems are needed to store and organize the increasing mutation information. RESULTS The MUTbase program suite provides an easy, interactive and quality-controlled submission of information to mutation databases. For further study of the databases on the World Wide Web, a number of tools are provided. The program package also writes and updates a large number of Web pages, e.g. about the distribution and statistics of disease-causing mutations, and changes in restriction patterns.

KinMutBase, a database of human disease-causing protein kinase mutations

KinMutBase (http://www.uta.fi/laitokset/imt/KinMut Base.html) is a registry of mutations in human protein kinases related to disorders. Kinases are essential cellular signalling molecules, in which mutations can lead into diseases including, e.g., immunodeficiencies, cancers and endocrine disorders. The first release of KinMutBase contains information for nine protein tyrosine kinases. There are altogether 170 entries representing 273 families and 403 patients. Mutations appear both in conserved hallmark residues of the kinases as well as in non-homologous sites. The KinMutBase WWW pages provide plenty of information, namely mutation statistics and display, clickable sequences with mutations, restriction enzyme patterns and online submission.

Novel immunodeficiency data servers

The Internet contains scientific information in increasing amounts. It is possible to obtain the latest information, and Web services can easily be maintained and updated. We have set up three Internet services on immunodeficiencies. Immunodeficiency-related mutation infor mation is available in immunodeficiency mutation databases (IDbases). Currently 14 registries are distributed, including information about Bloom syndrome (BLMbase), X-linked agammaglobulinemia (BTKbase), X-linked and autosomal recessive chronic granulomatous diseases (CYBBbase for X-linked CGD, CYBAbase for p22(phox) deficiency, NCF1base for p47(phox) deficiency, NCF2base for p67(phox) deficiency), CD3gamma and CD3epsilon deficiencies (CD3Gbase, CD3Ebase), X-linked hyper-IgM syndrome (CD40Lbase), T-B+ severe combined immunodeficiency (JAK3base), V(D)J recombination defects (RAG1base, RAG2base), X-linked lymphoproliferative syndrome (SH2D1Abase), and ZAP-70 deficiency (ZAP70base). Information on laboratories analysing the genetic defects is collected to IDdiagnostics registry. Due to the rareness of immunodeficiencies there are very few laboratories performing genetic diagnostics. Such laboratories are listed in IDdiagnostics and physicians can use the registry to find a suitable laboratory for their diagnostic needs. Immunodeficiency Resource (IDR) is a comprehensive integrated knowledge base for all the information on immunode ficiencies, including clinical, biochemical, genetic, structural and computational data and analyses. All three services are available at http: //www.uta.fi/imt/bioinfo/.

National research contributions: A case study on Finnish biomedical research

The long-term influence and contribution of research can be evaluated relatively reliably by bibliometric citation analysis. Previously, productivity of nations has been estimated by using either the number of published articles or journal impact factors and/or citation data. These studies show certain trends, but detailed analysis is not possible due to the assumption that all articles in a journal were equally cited. Here we describe the first comprehensive, longterm, nationwide analysis of scientific performance. We studied the lifetime research output of 748 Finnish principal investigators in biomedicine during the years 1966–2000, analysed national trends, and made a comparison with international research production. Our results indicate that analyses of the scientific contribution of persons, disciplines, or nations should be based on actual publication and citation counts rather than on derived information like impact factors. 51% of the principal investigators have published altogether 75% of the articles; however, the whole scientific community has contributed to the growth of biomedical research in Finland since the Second World War.

Mobile access to biological databases on the Internet

We have developed a new way of accessing biological databases and bioinformatics applications on the Internet. This new service, bioinformatics wireless application protocol (BioWAP) service, which is accessible by mobile devices makes it possible to access bioinformatics services, where normal PC or personal digital assistant (PDA) connections are not feasible. The BioWAP service includes major biological databases and applications demonstrating a simple method of implementing WAP interfaces to uncompliant applications, i.e. the applications that are not WAP or Internet based. The BioWAP service can be browsed with any WAP terminal.

Distribution of immunodeficiency fact files with XML – from Web to WAP

BackgroundAlthough biomedical information is growing rapidly, it is difficult to find and retrieve validated data especially for rare hereditary diseases. There is an increased need for services capable of integrating and validating information as well as proving it in a logically organized structure. A XML-based language enables creation of open source databases for storage, maintenance and delivery for different platforms.MethodsHere we present a new data model called fact file and an XML-based specification Inherited Disease Markup Language (IDML), that were developed to facilitate disease information integration, storage and exchange. The data model was applied to primary immunodeficiencies, but it can be used for any hereditary disease. Fact files integrate biomedical, genetic and clinical information related to hereditary diseases.ResultsIDML and fact files were used to build a comprehensive Web and WAP accessible knowledge base ImmunoDeficiency Resource (IDR) available at http://bioinf.uta.fi/idr/. A fact file is a user oriented user interface, which serves as a starting point to explore information on hereditary diseases.ConclusionThe IDML enables the seamless integration and presentation of genetic and disease information resources in the Internet. IDML can be used to build information services for all kinds of inherited diseases. The open source specification and related programs are available at http://bioinf.uta.fi/idml/.

BioWAP, mobile Internet service for bioinformatics

UNLABELLED We have developed a new Internet service, which provides mobile access to bioinformatics databases and software tools. The BioWAP service facilitates access to basic bioinformatics databases and analysis tools from everywhere without a PC or a laptop computer. Both open source bioinformatics program suites and Internet services, which are not designed for mobile Internet access, were utilized in the BioWAP service. AVAILABILITY The BioWAP service starting page can be browsed with any WAP terminal from http://bioinf.uta.fi/wml/welcome.wml.

Evaluation of Protein Hydropathy Scales

Hydropathy is a dominant force in protein folding and has been measured with numerous methods. Several hydropathy scales are widely used in sequence-based predictions, however, without knowledge about their reliability. We investigated the prediction accuracy of 56 hydropathy scales by correlating predicted values with the accessible surface area in known 3-D structures of proteins. The correlations for the best scales are in the order of - 0.26, whereas the weakest have on average merely - 0.11. Results for different amino acids vary greatly within the scales, but are more consistent between the scales. One of the most common applications of hydropathy scales is to predict antigenic regions. Our analysis indicated that some epitopes are located among the most exposed regions. Despite poor overall correlation, hydropathy predictions can still be used in certain applications where qualitative analysis is sufficient.

Accuracy of protein hydropathy predictions

Hydropathy is a dominant force in protein folding. Sequence-based hydropathy predictions are widely used, without knowledge about their accuracy and reliability. We investigated the prediction accuracy of 56 hydropathy scales by correlating predicted values with the accessible surface area in known protein structures. Results for different amino acids vary greatly within each scale. We also investigated prediction accuracies of amino acids separately in secondary structural elements and in protein fold families. Despite very low overall correlation, hydropathy predictions can still be used if the shape of the plot is important instead of the prediction values.

Detecting biological associations between genes based on the theory of phase synchronization.

This study presents a novel approach to detect biological associations for gene pairs with cell cycle-specific expression profiles. Previous studies have shown that periodic transcription is commonly regulated by transcription factors that are also periodically transcribed, and there is a growing number of examples where cell cycle regulated genes are conserved in yeast and mammalian cells. Some genes have periodicity for their oscillatory activity throughout cell division. These cell cycle-specific oscillatory activities could be explained by a biological phenomenon in terms of efficiency and logical order. In the yeast data used in this study, about 13% of genes behave in this manner based on a previous yeast study. Microarrays have been applied to determine genome-wide expression patterns during the cell cycle of a number of different cells. Moreover, several previous studies have shown that many pairs of genes, which have linearly correlated expression profiles, have similar cellular roles or physical interactions. Based on this point of view, the traditional clustering methods have focused on similar expression profiles based on the premise that genes with similar expression profiles have similar biological functions or relevant biological interactions. However, there are a number of previous studies indicating that the expression of some genes may be delayed compared to others due to a time lag in their transcriptional control. Therefore, we propose a novel clustering method, named as phase-synchronization clustering, based on the theory of phase synchronization for detecting biological associations using cell cycle-specific expression profiles. We evaluate phase-synchronization clustering here using Saccharomyces cerevisiae microarray data. Phase-synchronization clustering is able to detect biologically associated gene pairs that have linearly correlated (simultaneous and inverted) as well as time-delayed expression profiles. The performance of phase-synchronization clustering is compared with other conventional clustering methods. The likelihood of finding relevant biological associations by phase-synchronization clustering is significantly higher than other clustering methods. Therefore, phase-synchronization clustering is more efficient for detecting known biological interactions for gene pairs than other conventional clustering methods for analyzing cell cycle-specific expression data. The evaluation analysis of the results by phase-synchronization clustering also suggests that the cellular activities during the cell division process could be understood as a phenomenon of collective synchronization.