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    Keywords: CELLS ; EXPRESSION ; Germany ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; COMPLEX ; COMPLEXES ; SEQUENCE ; METABOLITES ; gene expression ; ESCHERICHIA-COLI ; DATABASE ; OXYGEN ; CLUSTER ; MATRIX ; SYNTHETASE ; EXTRACTION ; LEVEL ; ENZYME ; TECHNOLOGY ; EXPRESSION PATTERNS ; CHAIN AMINO-ACIDS ; K-12
    Abstract: Background: Microarray technology produces gene expression data on a genomic scale for an endless variety of organisms and conditions. However, this vast amount of information needs to be extracted in a reasonable way and funneled into manageable and functionally meaningful patterns. Genes may be reasonably combined using knowledge about their interaction behaviour. On a proteomic level, biochemical research has elucidated an increasingly complete image of the metabolic architecture, especially for less complex organisms like the well studied bacterium Escherichia coli. Results: We sought to discover central components of the metabolic network, regulated by the expression of associated genes under changing conditions. We mapped gene expression data from E. coli under aerobic and anaerobic conditions onto the enzymatic reaction nodes of its metabolic network. An adjacency matrix of the metabolites was created from this graph. A consecutive ones clustering method was used to obtain network clusters in the matrix. The wavelet method was applied on the adjacency matrices of these clusters to collect features for the classifier. With a feature extraction method the most discriminating features were selected. We yielded network sub-graphs from these top ranking features representing formate fermentation, in good agreement with the anaerobic response of heterofermentative bacteria. Furthermore, we found a switch in the starting point for NAD biosynthesis, and an adaptation of the l-aspartate metabolism, in accordance with its higher abundance under anaerobic conditions. Conclusion: We developed and tested a novel method, based on a combination of rationally chosen machine learning methods, to analyse gene expression data on the basis of interaction data, using a metabolic network of enzymes. As a case study, we applied our method to E. coli under oxygen deprived conditions and extracted physiologically relevant patterns that represent an adaptation of the cells to changing environmental conditions. In general, our concept may be transferred to network analyses on biological interaction data, when data for two comparable states of the associated nodes are made available
    Type of Publication: Journal article published
    PubMed ID: 16524469
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  • 3
    Keywords: CANCER ; EXPRESSION ; GROWTH ; tumor ; Germany ; PATHWAY ; PATHWAYS ; THERAPY ; CLASSIFICATION ; NETWORK ; NETWORKS ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; DRUG ; METABOLISM ; TUMORS ; validation ; BIOLOGY ; RECOGNITION ; PATTERNS ; gene expression ; microarrays ; neuroblastoma ; INHIBITORS ; REGRESSION ; PATTERN ; SCIENCE ; methods ; DRUGS ; glutamine ; outcome ; PROBABILITIES ; SHIFT ; motivation
    Abstract: Motivation: Gene expression pro. ling by microarrays or transcript sequencing enables observing the pathogenic function of tumors on a mesoscopic level. Results: We investigated neuroblastoma tumors that clinically exhibit a very heterogeneous course ranging from rapid growth with fatal outcome to spontaneous regression and detected regulatory oncogenetic shifts in their metabolic networks. In contrast to common enrichment tests, we took network topology into account by applying adjusted wavelet transforms on an elaborated and new 2D grid representation of curated pathway maps from the Kyoto Enzyclopedia of Genes and Genomes. The aggressive form of the tumors showed regulatory shifts for purine and pyrimidine biosynthesis as well as folate-mediated metabolism of the one-carbon pool in respect to increased nucleotide production. We spotted an oncogentic regulatory switch in glutamate metabolism for which we provided experimental validation, being the first steps towards new possible drug therapy. The pattern recognition method we used complements normal enrichment tests to detect such functionally related regulation patterns
    Type of Publication: Journal article published
    PubMed ID: 20335275
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  • 4
    Keywords: CELLS ; EXPRESSION ; INHIBITION ; CLASSIFICATION ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; gene expression ; AGE ; genetics ; leukemia ; genomics ; ACID-INDUCED APOPTOSIS ; GENDER ; SIGNATURE ; GLYCOLYSIS ; tumor therapy ; BILE-ACIDS
    Abstract: Background: Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. Methods: For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. Results: Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. Conclusion: We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment
    Type of Publication: Journal article published
    PubMed ID: 20831783
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  • 5
    Keywords: CANCER ; PATHWAYS ; AGE ; LIFE-SPAN ; RESOURCES
    Abstract: BACKGROUND: Common approaches to pathway analysis treat pathways merely as lists of genes disregarding their topological structures, that is, ignoring the genes' interactions on which a pathway's cellular function depends. In contrast, PathWave has been developed for the analysis of high-throughput gene expression data that explicitly takes the topology of networks into account to identify both global dysregulation of and localized (switch-like) regulatory shifts within metabolic and signaling pathways. For this purpose, it applies adjusted wavelet transforms on optimized 2D grid representations of curated pathway maps. RESULTS: Here, we present the new version of PathWave with several substantial improvements including a new method for optimally mapping pathway networks unto compact 2D lattice grids, a more flexible and user-friendly interface, and pre-arranged 2D grid representations. These pathway representations are assembled for several species now comprising H. sapiens, M. musculus, D. melanogaster, D. rerio, C. elegans, and E. coli. We show that PathWave is more sensitive than common approaches and apply it to RNA-seq expression data, identifying crucial metabolic pathways in lung adenocarcinoma, as well as microarray expression data, identifying pathways involved in longevity of Drosophila. CONCLUSIONS: PathWave is a generic method for pathway analysis complementing established tools like GSEA, and the update comprises efficient new features. In contrast to the tested commonly applied approaches which do not take network topology into account, PathWave enables identifying pathways that are either known be involved in or very likely associated with such diverse conditions as human lung cancer or aging of D. melanogaster. The PathWave R package is freely available at http://www.ichip.de/software/pathwave.html.
    Type of Publication: Journal article published
    PubMed ID: 24886210
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  • 6
    ISSN: 1432-5217
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-5217
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1432-5217
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Computing 47 (1991), S. 43-49 
    ISSN: 1436-5057
    Keywords: 51-04 ; 68Q25 ; 68R10 ; Computational geometry ; Voronoi diagram ; Delaunay triangulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Description / Table of Contents: Zusammenfassung In den letzten Jahren hat die praktische Berechnung von Delaunay-Triangulationen bzw. Voronoi-Diagrammen große Aufmerksamkeit erfahren, da sie wichtige grundlegende Konzepte für geometrische Algorithmen darstellen. In dieser technischen Notiz betrachten wir das Problem ihrer numerisch stabilen Berechnung. Hierzu nehmen wir an, daß die generierenden Punkte Gitterpunkte eines quadratischenM×M-Gitters in der Ebene sind. Abhängig vonM bestimmen wir die notwendige Wortlänge zur Durchführung ganzzahliger Arithmetik, die es erlaubt, Delaunay-Triangulationen exakt zu berechnen. Die Analyse wird für dieL 1-,L 2- undL ∞-Metrik durchgeführt.
    Notes: Abstract In recent years the practical computation of Delaunay triangulations, resp. Voronoi diagrams has received a lot of attention in the literature. While the Delaunay triangulation is an important basic tool in geometric optimization algorithms, it is nontrivial to achieve a numerically stable computer implementation. In this technical note we assume that all generating points are grid points of a regularM byM lattice in the plane. Depending onM we derive the necessary word length a binary computer must have for integer representation in order to obtain exact Delaunay triangulations. This analysis is carried out for theL 1-,L 2- andL ∞-metric.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1572-9613
    Keywords: Branch and cut ; Ising spin glasses ; exact ground states
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract In this paper we study the problem of finding an exact ground state of a two-dimensional ±J Ising spin glass on a square lattice with nearest neighbor interactions and periodic boundary conditions when there is a concentrationp of negative bonds, withp ranging between 0.1 and 0.9. With our exact algorithm we can determine ground states of grids of sizes up to 50×50 in a moderate amount of computation time (up to 1 hr each) for several values ofp. For the ground-state energy of an infinite spin-glass system withp=0.5 we estimateE 0.5 ∞ =−1.4015±0.0008. We report on extensive computational tests based on more than 22,000 experiments.
    Type of Medium: Electronic Resource
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