Biomedical subjects

Alexander Kel

Publications and source records attributed to Alexander Kel.

8 recordsLinked to original sources

PubMed2007

CYCLONET--an integrated database on cell cycle regulation and carcinogenesis.

Computational modelling of mammalian cell cycle regulation is a challenging task, which requires comprehensive knowledge on many interrelated processes in the cell. We have developed a web-based integrated database on cell cycle regulation in mammals in normal and pathological states (Cyclonet database). It integrates data obtained by 'omics' sciences and chemoinformatics on the basis of systems biology approach. Cyclonet is a specialized resource, which enables researchers working in the field of anticancer drug discovery to analyze the wealth of currently available information in a systematic way. Cyclonet contains information on relevant genes and molecules; diagrams and models of cell cycle regulation and results of their simulation; microarray data on cell cycle and on various types of cancer, information on drug targets and their ligands, as well as extensive bibliography on modelling of cell cycle and cancer-related gene expression data. The Cyclonet database is also accessible through the BioUML workbench, which allows flexible querying, analyzing and editing the data by means of visual modelling. Cyclonet aims to predict promising anticancer targets and their agents by application of Prediction of Activity Spectra for Substances. The Cyclonet database is available at http://cyclonet.biouml.org.

Animals↗

PubMed2006

Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease.

Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelial barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant downregulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappaB (NFkappaB) binding sites in each promoter. Furthermore, NFkappaB was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-alpha and transforming growth factor-beta, which could be blocked by NFkappaB signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P = 0.003) polymorphism with CD and for MUC4-A585S (P = 0.025), as well as MUC13-R502S (P = 0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NFkappaB pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.

Adult↗

PubMed2006

TRANSPATH: an information resource for storing and visualizing signaling pathways and their pathological aberrations.

TRANSPATH is a database about signal transduction events. It provides information about signaling molecules, their reactions and the pathways these reactions constitute. The representation of signaling molecules is organized in a number of orthogonal hierarchies reflecting the classification of the molecules, their species-specific or generic features, and their post-translational modifications. Reactions are similarly hierarchically organized in a three-layer architecture, differentiating between reactions that are evidenced by individual publications, generalizations of these reactions to construct species-independent 'reference pathways' and the 'semantic projections' of these pathways. A number of search and browse options allow easy access to the database contents, which can be visualized with the tool PathwayBuildertrade mark. The module PathoSign adds data about pathologically relevant mutations in signaling components, including their genotypes and phenotypes. TRANSPATH and PathoSign can be used as encyclopaedia, in the educational process, for vizualization and modeling of signal transduction networks and for the analysis of gene expression data. TRANSPATH Public 6.0 is freely accessible for users from non-profit organizations under http://www.gene-regulation.com/pub/databases.html.

Computer Graphics↗

PubMed2006

TiProD: the Tissue-specific Promoter Database.

TiProD is a database of human promoter sequences for which some functional features are known. It allows a user to query individual promoters and the expression pattern they mediate, gene expression signatures of individual tissues, and to retrieve sets of promoters according to their tissue-specific activity or according to individual Gene Ontology terms the corresponding genes are assigned to. We have defined a measure for tissue-specificity that allows the user to discriminate between ubiquitously and specifically expressed genes. The database is accessible at http://tiprod.cbi.pku.edu.cn:8080/index.html.

Databases, Nucleic Acid↗

PubMed2004

A novel computational approach for the prediction of networked transcription factors of aryl hydrocarbon-receptor-regulated genes.

A novel computational method based on a genetic algorithm was developed to study composite structure of promoters of coexpressed genes. Our method enabled an identification of combinations of multiple transcription factor binding sites regulating the concerted expression of genes. In this article, we study genes whose expression is regulated by a ligand-activated transcription factor, aryl hydrocarbon receptor (AhR), that mediates responses to a variety of toxins. AhR-mediated change in expression of AhR target genes was measured by oligonucleotide microarrays and by reverse transcription-polymerase chain reaction in human and rat hepatocytes. Promoters and long-distance regulatory regions (>10 kb) of AhR-responsive genes were analyzed by the genetic algorithm and a variety of other computational methods. Rules were established on the local oligonucleotide context in the flanks of the AhR binding sites, on the occurrence of clusters of AhR recognition elements, and on the presence in the promoters of specific combinations of multiple binding sites for the transcription factors cooperating in the AhR regulatory network. Our rules were applied to search for yet unknown Ah-receptor target genes. Experimental evidence is presented to demonstrate high fidelity of this novel in silico approach.

Algorithms↗

PubMed2004

Bifurcation analysis of the regulatory modules of the mammalian G1/S transition.

MOTIVATION: Mathematical models of the cell cycle can contribute to an understanding of its basic mechanisms. Modern simulation tools make the analysis of key components and their interactions very effective. This paper focuses on the role of small modules and feedbacks in the gene-protein network governing the G1/S transition in mammalian cells. Mutations in this network may lead to uncontrolled cell proliferation. Bifurcation analysis helps to identify the key components of this extremely complex interaction network. RESULTS: We identify various positive and negative feedback loops in the network controlling the G1/S transition. It is shown that the positive feedback regulation of E2F1 and a double activator-inhibitor module can lead to bistability. Extensions of the core module preserve the essential features such as bistability. The complete model exhibits a transcritical bifurcation in addition to bistability. We relate these bifurcations to the cell cycle checkpoint and the G1/S phase transition point. Thus, core modules can explain major features of the complex G1/S network and have a robust decision taking function.

Animals↗

PubMed2004

Consistent re-modeling of signaling pathways and its implementation in the TRANSPATH database.

The data model of the signaling pathways database TRANSPATH has been re-engineered to a three-layer model comprising experimental evidences and summarized pathway information, both in a mechanistically detailed manner, and a "semantic" projection for the abstract overview. Each molecule is described in the context of a certain reaction in the multidimensional space of posttranslational modification, molecular family relationships, and the biological species of its origin. The new model makes the data better suitable for reconstructing signaling pathways and networks and mapping expression data, for instance from microarray experiments, onto regulatory networks.

Algorithms↗

PubMed2003

From transcriptional regulation to aggressive behavior.

Gene expression in higher organisms, is, to a large degree, controlled at the level of transcription, where DNA-binding proteins (transcription factors) play an influential role in gene regulation. This is achieved through various mechanisms, including those that involve silencer and enhancer regions. Variation in those regulatory regions, as well as in the genes encoding the transcription factors, has been shown to generate functional effects at the molecular, cellular, and neurobehavioral levels. The aim of the present paper is two-fold. First, for the sake of clarity and to reintroduce the terminology to Behavior Genetics readers, we review the concepts of gene structure, gene expression, and gene regulation. Second, using distinct bioinformatic tools, we set out to identify transcription factors that could be involved in the transcriptional regulation of genes known to be associated with aggressive behavior in mice. The results of this in silico study reveal common putative transcription factor binding sites among the set of genes investigated (especially for SRY), suggesting similar molecular transcriptional mechanisms.

Aggression↗