研究者詳細 - 冨田　勝

論文 - 冨田　勝

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Proteins as networks: Usefulness of graph theory in protein science

Krishnan, A., Zbilut, P.J., Tomita, M. and Giuliani, A.

Current Protein and Peptide Science 9 （ 1 ） 28-38 - 38 2008年

研究論文（学術雑誌）, 共著, ISSN 13892037

The network paradigm is based on the derivation of emerging properties of studied systems by their representation as oriented graphs: any system is traced back to a set of nodes (its constituent elements) linked by edges (arcs) correspondent to the relations existing between the nodes. This allows for a straightforward quantitative formalization of systems by means of the computation of mathematical descriptors of such graphs (graph theory). The network paradigm is particularly useful when it is clear which elements of the modelled system must play the role of nodes and arcs respectively, and when topological constraints have a major role with respect to kinetic ones. In this review we demonstrate how nodes and arcs of protein topology are characterized at different levels of definition: 1. Recurrence matrix of hydrophobicity patterns along the sequence 2. Contact matrix of alpha carbons of 3D structures 3. Correlation matrix of motions of different portion of the molecule in molecular dynamics. These three conditions represent different but potentially correlated reticular systems that can be profitably analysed by means of network analysis tools. © 2008 Bentham Science Publishers Ltd.

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Sequence evidence in the archaeal genomes that tRNAs emerged through the combination of ancestral genes as 5′ and 3′ tRNA halves

Fujishima, K., Sugahara, J., Tomita, M. and Kanai, A.

PLoS ONE 3 （ 2 ） e1622 2008年

研究論文（学術雑誌）, 共著

The discovery of separate 5′ and 3′ halves of transfer RNA (tRNA) molecules - so called split tRNA - in the archaeal parasite Nanoarchaeum equitans made us wonder whether ancestral tRNA was encoded on 1 or 2 genes. We performed a comprehensive phylogenetic analysis of tRNAs in 45 archaal species to explore the relationship between the three types of tRNAs (nonintronic, intronic and split). We classified 1953 mature tRNA sequences into 22 clusters. All split tRNAs have shown phylogenetic relationships with other tRNAs possessing the same anticodon. We also mimicked split tRNA by artificially separating the tRNA sequences of 7 primitive archaeal species at the anticodon and analyzed the sequence similarity and diversity of the 5′ and 3′ tRNA halves. Network analysis revealed specific characteristics of and topological differences between the 5′ and 3′ tRNA halves: the 5′ half sequences were categorized into 6 distinct groups with a sequence similarity of > 80%, while the 3′ half sequences were categorized into 9 groups with a higher sequence similarity of > 88%, suggesting different evolutionary backgrounds of the 2 halves. Furthermore, the combinations of 5′ and 3′ halves coresponded with the variation of amino acids in the codon table. We found not only universally conserved combinations of 5′-3′ tRNA halves in tRNS Imet, tRNA Thr, tRNAIle, tRNAGly, tRNAGin, tRNAGlu, tRNAAsp, tRNALys, tRNA Arg and tRNA but also phylum-specific combinations in tRNAPro, tRNAAla, and tRNATrp. Our results support the idea that tRNA emerged through the combination of separate genes and explain the sequence diversity that arose during archaeal tRNA evolution. © 2008 Fujishima et al.

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Comparative expression analysis uncovers novel features of endogenous antisense transcription

Yuki Okada, Chiaki Tashiro, Koji Numata, Kazufumi Watanabe, Hajime Nakaoka, Naoyuki Yamamoto, Kazue Okubo, Rieko Ikeda, Rintaro Saito, Akio Kanai, Kuniya Abe, Masaru Tomita, and Hidenori Kiyosawa

Human Molecular Genetics 17 （ 11 ） 1631-1640 - 1640 2008年

研究論文（学術雑誌）, 共著, ISSN 09646906

Increasing numbers of sense - antisense transcripts (SATs), which are transcribed from the same chromosomal location but in opposite directions, have been identified in various eukaryotic species, but the biological meanings of most SATs remain unclear. To improve understanding of natural sense - antisense transcription, we performed comparative expression profiling of SATs conserved among humans and mice. Using custom oligo-arrays loaded with probes that represented SATs with both protein-coding and non-protein-coding transcripts, we showed that 33% of the 291 conserved SATs displayed identical expression patterns in the two species. Among these SATs, expressional balance inversion of sense - antisense genes was mostly observed in testis at a tissue-specific manner. Northern analyses of the individual conserved SAT loci revealed that: (i) a smeary hybridization pattern was present in mice, but not in humans, and (2) small RNAs (about 60 to 80 nt) were detected from the exon-overlapping regions of SAT loci. In addition, further analyses showed marked alteration of sense - antisense expression balance throughout spermatogenesis in testis. These results suggest that conserved SAT loci are rich in potential regulatory roles that will help us understand this new class of transcripts underlying the mammalian genome. © The Author 2008. Published by Oxford University Press. All rights reserved.

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Implications from a network-based topological analysis of ubiquitin unfolding simulations

Arun Krishnan, Alessandro Giuliani, Joseph P. Zbilut, Masaru Tomita

PLoS ONE 3 （ 5 ） e2149 2008年

研究論文（学術雑誌）, 共著

Background: The architectural organization of protein structures has been the focus of intense research since it can hopefully lead to an understanding of how proteins fold. In earlier works we had attempted to identify the inherent structural organization in proteins through a study of protein topology. We obtained a modular partitioning of protein structures with the modules correlating well with experimental evidence of early folding units or "foldons". Residues that connect different modules were shown to be those that were protected during the transition phase of folding. Methodology/Principal Findings: In this work, we follow the topological path of ubiquitin through molecular dynamics unfolding simulations. We observed that the use of recurrence quantification analysis (RQA) could lead to the identification of the transition state during unfolding. Additionally, our earlier contention that the modules uncovered through our graph partitioning approach correlated well with early folding units was vindicated through our simulations. Moreover, residues identified from native structure as connector hubs and which had been shown to be those that were protected during the transition phase of folding were indeed more stable (less flexible) well beyond the transition state. Further analysis of the topological pathway suggests that the all pairs shortest path in a protein is minimized during folding. Conclusions: We observed that treating a protein native structure as a network by having amino acid residues as nodes and the non-covalent interactions among them as links allows for the rationalization of many aspects of the folding process. The possibility to derive this information directly from 3D structure opens the way to the prediction of important residues in proteins, while the confirmation of the minimization of APSP for folding allows for the establishment of a potentially useful proxy for kinetic optimality in the validation of sequence-structure predictions. © 2008 Krishnan et al.

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Time-resolved metabolomics reveals metabolic modulation in rice foliage

Shigeru Sato , Masanori Arita , Tomoyoshi Soga , Takaaki Nishioka and Masaru Tomita

BMC Systems Biology 2 51 2008年

研究論文（学術雑誌）, 共著

Background: To elucidate the interaction of dynamics among modules that constitute biological systems, comprehensive datasets obtained from "omics" technologies have been used. In recent plant metabolomics approaches, the reconstruction of metabolic correlation networks has been attempted using statistical techniques. However, the results were unsatisfactory and effective data-mining techniques that apply appropriate comprehensive datasets are needed. Results: Using capillary electrophoresis mass spectrometry (CE-MS) and capillary electrophoresis diode-array detection (CE-DAD), we analyzed the dynamic changes in the level of 56 basic metabolites in plant foliage (Oryza sativa L. ssp. japonica) at hourly intervals over a 24-hr period. Unsupervised clustering of comprehensive metabolic profiles using Kohonen's self-organizing map (SOM) allowed classification of the biochemical pathways activated by the light and dark cycle. The carbon and nitrogen (C/N) metabolism in both periods was also visualized as a phenotypic linkage map that connects network modules on the basis of traditional metabolic pathways rather than pairwise correlations among metabolites. The regulatory networks of C/N assimilation/dissimilation at each time point were consistent with previous works on plant metabolism. In response to environmental stress, glutathione and spermidine fluctuated synchronously with their regulatory targets. Adenine nucleosides and nicotinamide coenzymes were regulated by phosphorylation and dephosphorylation. We also demonstrated that SOM analysis was applicable to the estimation of unidentifiable metabolites in metabolome analysis. Hierarchical clustering of a correlation coefficient matrix could help identify the bottleneck enzymes that regulate metabolic networks. Conclusion: Our results showed that our SOM analysis with appropriate metabolic time-courses effectively revealed the synchronous dynamics among metabolic modules and elucidated the underlying biochemical functions. The application of discrimination of unidentified metabolites and the identification of bottleneck enzymatic steps even to non-targeted comprehensive analysis promise to facilitate an understanding of large-scale interactions among components in biological systems. © 2008 Sato et al; licensee BioMed Central Ltd.

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Successive and selective release of phosphorylated peptides captured by hydroxy acid-modified metal oxide chromatography

Kyono, Y.,Sugiyama, N., Imami, K., Tomita, M. and Ishihama, Y.

Journal of Proteome Research 7 （ 10 ） 4585-4593 - 4593 2008年

研究論文（学術雑誌）, 共著, ISSN 15353893

We developed a novel approach to enlarge phosphoproteome coverage using successive elution of phosphopeptides with various buffers in series from a single microcolumn packed with hydroxy acid-modified metal oxides, such as titania and zirconia. Elution conditions were investigated to maximize the recovery of phosphopeptides from three standard phosphoproteins. Secondary amines, such as piperidine and pyrrolidine, provided better efficiency than the conventional conditions using ammonium hydroxide and phosphate buffers. Furthermore, elution with these secondary amines provided unique phosphopeptides that were not eluted under the conventional conditions in the analysis of HeLa cell lysates. On the basis of these results, we fractionated phosphopeptides captured by a single metal oxide microcolumn using successive elution with 5% ammonium hydroxide solution, 5% piperidine solution and 5% pyrrolidine solution in series. We identified 1803 nonredun- dant phosphopeptides from 100 μg of HeLa cells, which represented a 1.6-fold increase in phosphopeptide number and a 1.9-fold increase in total peak area of phosphopeptides in comparison with the results obtained under the conventional conditions. Since this approach is applicable to any single tip-based protocol without coupling with other enrichment methods, this simple strategy can be easily incorporated as an option into existing protocols for phosphopeptide enrichment, and would be suitable for high-throughput analysis in a parallel format. © 2008 American Chemical Society.

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Computational Genome Analysis Using The G-language System

Arakawa,K., Suzuki,H. and Tomita,M.

Genges,Genomes and Genomics 2 1-13 2008年

研究論文（学術雑誌）, 共著

Visualizing Conplex Omics Information-Scientific Visualization for Genomics and Systems Biology

Arakawa, K., Yachie, N. and Tomita M.

BIOforum Europe 6 27-29 2008年

研究論文（学術雑誌）, 共著

Junction ribonuclease activity specified in RNases HII/2

Ohtani, N., Tomita, M. and Itaya, M.

FEBS Journal 275 （ 21 ） 5444-55 - 5455 2008年

研究論文（学術雑誌）, 共著, ISSN 1742464X

Junction ribonuclease (JRNase) recognizes the transition from RNA to DNA of an RNA-DNA/DNA hybrid, such as an Okazaki fragment, and cleaves it, leaving a mono-ribonucleotide at the 5′ terminus of the RNA-DNA junction. Although this JRNase activity was originally reported in calf RNase H2, some other RNases H have recently been suggested to possess it. This paper shows that these enzymes can also cleave an RNA-DNA/RNA heteroduplex in a manner similar to the RNA-DNA/DNA substrate. The cleavage site of the RNA-DNA/RNA substrate corresponds to the RNA//RNA duplex region, indicating that the cleavage activity cannot be categorized as RNase H activity, which specifically cleaves an RNA strand of an RNA/DNA hybrid. Examination of several RNases H with respect to JRNase activity suggested that the activity is only found in RNase HII orthologs. Therefore, RNases HIII, which are RNase HII paralogs, are distinguished from RNases HII by the absence of JRNase activity. Whether a substrate can be targeted by JRNase activity would depend only on whether or not an RNA-DNA junction consisting of one ribonucleotide and one deoxyribonucleotide is included in the duplex. In addition, although the activity has been reported not to occur on completely single-stranded RNA-DNA, it can recognize a single-stranded RNA-DNA junction if a double-stranded region is located adjacent to the junction. © 2008 The Authors.

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Versatile architecture of a bacterial aconitase B and its catalytic performance in the sequential reaction coupled with isocitrate dehydrogenase

Tsuchiya D., Shimizu N., and Tomita M.

Biochimica et Biophysica Acta - Proteins and Proteomics 1784 （ 11 ） 1847-56. - 1856 2008年

研究論文（学術雑誌）, 共著, ISSN 15709639

Aconitase B (AcnB) and isocitrate dehydrogenase (ICDH) catalyze the sequential reaction in the Krebs cycle. Since each enzyme was characterized as an independent protein in a diluted condition, the catalytic performance within the cellular metabolism remains unclear. In particular, high macromolecular concentration in the cytosol promotes weak interactions, which affects structure and function of the proteins. We found that the two bacterial enzymes exhibit variable catalytic performance of the sequential reaction, depending on the oligomerization state. The small-angle solution X-ray scattering and the chemical crosslinking analyses revealed that not only the two enzymes but also the fusion protein of the two enzymes assume homodimers in solution. Interestingly, the fusion protein maintains the homodimeric architecture of ICDH, but not AcnB. Instead, one of the two monomeric AcnB regions associates with the homodimeric ICDH region. The fusion protein displayed different catalytic performance of the sequential reaction from that observed in the mixture of the AcnB and ICDH proteins in an equimolar ratio. Connecting the two proteins by a flexible linker yielded a locally high concentration to promote the weak protein-protein interaction. The versatile architecture of AcnB may alter the metabolic process involving the Krebs cycle. © 2008 Elsevier B.V. All rights reserved.

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Aligning LC peaks by converting gradient retention times to retention index of peptides in proteomic experiments

Shinoda, K., Tomita, M., Ishihama, Y.

Bioinformatics 24 （ 14 ） 1590-5 - 1595 2008年

研究論文（学術雑誌）, 共著, ISSN 13674803

Motivation: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful tool in proteomics studies, but when peptide retention information is used for identification purposes, it remains challenging to compare multiple LC-MS/MS runs or to match observed and predicted retention times, because small changes of LC conditions unavoidably lead to variability in retention times. In addition, non-contiguous retention data obtained with different LC-MS instruments or in different laboratories must be aligned to confirm and utilize rapidly accumulating published proteomics data. Results: We have developed a new alignment method for peptide retention times based on linear solvent strength (LSS) theory. We found that log k0 (logarithm of retention factor for a given organic solvent) in the LSS theory can be utilized as a 'universal' retention index of peptides (RIP) that is independent of LC gradients, and depends solely on the constituents of the mobile phase and the stationary phases. We introduced a machine learning-based scheme to optimize the conversion function of gradient retention times (tg) to log k0. Using the optimized function, tg values obtained with different LC-MS systems can be directly compared with each other on the RIP scale. In an examination of Arabidopsis proteomic data, the vast majority of retention time variability was removed, and five datasets obtained with various LC-MS systems were successfully aligned on the RIP scale. © The Author 2008. Published by Oxford University Press. All rights reserved.

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Restriction on conjugational transfer of pLS20 in Bacillus subtilis 168

Ohtani, N., Sato, M., Tomita, M. and Itaya, M ,

Bioscience, Biotechnology and Biochemistry 72 （ 9 ） 2472-5 - 2475 2008年

研究論文（学術雑誌）, 共著, ISSN 09168451

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Junction ribonuclease: A ribonuclease HII orthologue from Thermus thermophilus HB8 prefers the RNA-DNA junction to the RNA/DNA heteroduplex

Ohtani, N., Tomita, M. and Itaya, M.

Biochemical Journal 412 （ 3 ） 517-26 - 526 2008年

研究論文（学術雑誌）, 共著, ISSN 02646021

The genome of an extremely thermophilic bacterium, Thermus thermophilus HB8, contains a single ORF (open reading frame) encoding an RNase-HII-like sequence. Despite the presence of significant amino acid sequence identities with RNase (ribonuclease) HII enzymes, the ORF TTHA0198 could not suppress the temperature-sensitive growth defect of an RNase-H-deficient Escherichia coli mutant and the purified recombinant protein could not cleave an RNA strand of an RNA/DNA heteroduplex, suggesting that the TTHA0198 exhibited no RNase H activity both in vivo and in vitro. When oligomeric RNA-DNA/DNAs were used as a mimic substrate for Okazaki fragments, however, the protein cleaved them only at the 5′ side of the last ribonucleotide at the RNA-DNA junction. In fact, the TTHA0198 protein prefers the RNA-DNA junction to the RNA/DNA hybrid. We have referred to this activity as JRNase (junction RNase) activity, which recognizes an RNA-DNA junction of the RNA-DNA/DNA heteroduplex and cleaves it leaving a mono-ribonucleotide at the 5′ terminus of the RNA-DNA junction. E. coli and Deinococcus radiodurans RNases HII also cleaved the RNA-DNA/DNA substrates at the same site with a different metal-ion preference from that for RNase H activity, implying that the enzymes have JRNase activity as well as RNase H activity. The specialization in the JRNase activity of the RNase HII orthologue from T. thermophilus HB8 (Tth-JRNase) suggests that the JRNase activity of RNase HII enzymes might be independent of the RNase H activity. © The Authors.

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GeNESiS: Gene network evolution simulation software

Anton Kratz, Masaru Tomita and Arun Krishnan

BMC Bioinformatics 9 541 2008年

研究論文（学術雑誌）, 共著

Background: There has been a lot of interest in recent years focusing on the modeling and simulation of Gene Regulatory Networks (GRNs). However, the evolutionary mechanisms that give rise to GRNs in the first place are still largely unknown. In an earlier work, we developed a framework to analyze the effect of objective functions, input types and starting populations on the evolution of GRNs with a specific emphasis on the robustness of evolved GRNs. Results: In this work, we present a parallel software package, GeNESiS for the modeling and simulation of the evolution of gene regulatory networks (GRNs). The software models the process of gene regulation through a combination of finite-state and stochastic models. The evolution of GRNs is then simulated by means of a genetic algorithm with the network connections represented as binary strings. The software allows users to simulate the evolution under varying selective pressures and starting conditions. We believe that the software provides a way for researchers to understand the evolutionary behavior of populations of GRNs. Conclusion: We believe that GeNESiS will serve as a useful tool for scientists interested in understanding the evolution of gene regulatory networks under a range of different conditions and selective pressures. Such modeling efforts can lead to a greater understanding of the network characteristics of GRNs. © 2008 Kratz et al; licensee BioMed Central Ltd.

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E. coli metabolomics: Capturing the complexity of a "simple" model

Robert M., Soga T., Tomita M.

Topics in Current Genetics 18 189 - 234 2007年09月

ISSN 16106970

As the workhorse of early studies on metabolism, the metabolic pathways of E. coli are arguably the best characterized. The richness of information available about its pathways is broader than for any other model. However, in spite of decades of descriptive work, only recently can a significant number of E. coli metabolic network constituents be analyzed simultaneously. The advent of metabolomic methods that allow to capture qualitative as well as quantitative information about the intracellular and extracellular metabolite profiles is starting to shed light on the remaining complexity of this simpler model. Here we describe important findings about the physiology of E. coli resulting from emerging metabolomic studies. While a vast number of intracellular metabolites in E. coli still remain to be characterized, the information obtained from those studies can provide an unprecedented amount of information about metabolic pathways including their functional elucidation, enzyme activity, metabolic fluxes, network robustness, or even the discovery of completely novel reactions or pathways. These results are also being used to populate rich databases and to develop computational models of E. coli metabolism that have already proven effective to predict cellular states and will shed light on complex and until now still elusive regulatory principles. © 2007 Springer-Verlag Berlin Heidelberg.

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Bioinformatic analysis of post-transcriptional regulation by uORF in human and mouse

Matsui M., Yachie N., Okada Y., Saito R., Tomita M.

FEBS Letters 581 （ 22 ） 4184 - 4188 2007年09月

ISSN 00145793

RNA decay is thought to exert an important influence on gene expression by maintaining a steady-state level of transcripts and/or by eliminating aberrant transcripts. However, the sequence elements which control such processes have not been determined. Upstream open reading frames (uORFs) in the transcripts of several genes are reported to control translational initiation by stalling ribosomes and thereby promote RNA decay. We therefore performed bioinformatic analysis of the tissue-wide expression profiles and mRNA half-life of transcripts containing uORFs in humans and mice to assess the relationship between RNA decay and the presence of uORFs in transcripts. The expression levels of transcripts containing uORF were markedly lower than those not containing uORF. Moreover, the half-life of the uORF-containing transcripts was also shorter. These results suggest that uORFs are sequence elements that down-regulate RNA transcripts via RNA decay mechanisms. © 2007 Federation of European Biochemical Societies.

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Sequential logic model deciphers dynamic transciptional control of gene expressions

Yeo Z., Wong S., Vel Arjunan S., Piras V., Tomita M., Selvarajoo K., Giuliani A., Tsuchiya M.

PLoS ONE 2 （ 8 ） 2007年08月

Background. Cellular signaling involves a sequence of events from ligand binding to membrane receptors through transcription factors activation and the induction of mRNA expression. The transcriptional-regulatory system plays a pivotal role in the control of gene expression. A novel computational approach to the study of gene regulation circuits is presented, here. Methodology. Based on the concept of finite state machine, which provides a discrete view of gene regulation, a novel sequential logic model (SLM) is developed to decipher control mechanisms of-dynamic transcriptional regulation of gene expressions. The SLM technique is also used to systematically analyze the dynamic function of transcriptional inputs, the dependency and cooperativity, such as synergy effect, among the binding sites with respect to when, how much and how fast the gene of interest is expressed. Principal Findings. SLM is verified by a set of well studied expression data on endo 16 of Strongylocentrotus purpuratus (sea urchin) during the embryonic midgut development. A dynamic regulatory mechanism for endo 16 expression controlled by three binding sites, UI, R and Otx is identified and demonstrated to be consistent with experimental findings. Furthermore, we show that during transition from specification to differentiation in wild type endo16 expression profile, SLM reveals three binary activities are not sufficient to explain the transcriptional regulation of endo16 expression and additional activities of binding sites are required. Further analyses suggest detailed mechanism of R switch activity where indirect dependency occurs in between UI activity and R switch during specification to differentiation stage. Conclusions/Significatwe. The sequential logic formalism allows for a simplification of regulation network dynamics going from a continuous to a discrete representation of gene activation in time. In effect our SLM is non-parametric and model-independent, yet providing rich biological insight. The demonstration of the efficacy of this approach in endo 16 is a promising step for further application of the proposed method. © 2007 Yeo et al.

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P-BOSS: A new filtering method for treasure hunting in metabolomics

Morohashi M., Shimizu K., Ohashi Y., Abe J., Mori H., Tomita M., Soga T.

Journal of Chromatography A 1159 （ 1-2 ） 142 - 148 2007年08月

ISSN 00219673

Metabolomics is expected to boost data driven research. In biomarker discovery, powerful filtering methods to remove noise and outliers are essential for screening significant candidates from the huge volume of omic data. Here we propose a post-measurement peak filtering method (named P-BOSS) for CE electrospray ionization-time-of-flight MS (CE-TOFMS) data. Combining outlier detection method functions in parallel, we applied P-BOSS to the data using Escherichia coli knockout mutants of the tryptophan and purine biosynthesis pathways. As the result, P-BOSS showed remarkably superior performance, reducing 65% of all peaks, while leaving significant peaks. © 2007 Elsevier B.V. All rights reserved.

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Distinguishing enzymes using metabolome data for the hybrid dynamic/static method

Ishii N., Nakayama Y., Tomita M.

Theoretical Biology and Medical Modelling 4 2007年06月

Background. In the process of constructing a dynamic model of a metabolic pathway, a large number of parameters such as kinetic constants and initial metabolite concentrations are required. However, in many cases, experimental determination of these parameters is time-consuming. Therefore, for large-scale modelling, it is essential to develop a method that requires few experimental parameters. The hybrid dynamic/static (HDS) method is a combination of the conventional kinetic representation and metabolic flux analysis (MFA). Since no kinetic information is required in the static module, which consists of MFA, the HDS method may dramatically reduce the number of required parameters. However, no adequate method for developing a hybrid model from experimental data has been proposed. Results. In this study, we develop a method for constructing hybrid models based on metabolome data. The method discriminates enzymes into static modules and dynamic modules using metabolite concentration time series data. Enzyme reaction rate time series were estimated from the metabolite concentration time series data and used to distinguish enzymes optimally for the dynamic and static modules. The method was applied to build hybrid models of two microbial central-carbon metabolism systems using simulation results from their dynamic models. Conclusion. A protocol to build a hybrid model using metabolome data and a minimal number of kinetic parameters has been developed. The proposed method was successfully applied to the strictly regulated central-carbon metabolism system, demonstrating the practical use of the HDS method, which is designed for computer modelling of metabolic systems. © 2007 Ishii et al; licensee BioMed Central Ltd.

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Gene expression waves: Cell cycle independent collective dynamics in cultured cells

Tsuchyia M., Wong S., Yeo Z., Colosimo A., Palumbo M., Farina L., Crescenzi M., Mazzola A., Negri R., Bianchi M., Selvarajoo K., Tomita M., Giuliani A.

FEBS Journal 274 （ 11 ） 2878 - 2886 2007年06月

ISSN 1742464X

The ergodic hypothesis, which assumes the independence of each cell of the ensemble from all the others, is a necessary prerequisite to attach single cell based explanations to the grand averages taken from population data. This was the prevailing view about the interpretation of cellular biology experiments that typically are performed on colonies of billions of cells. By analysing gene expression data of different cells going from yeast to mammalian cell cultures, we demonstrate that cell cultures display a sort of 'ecology-in-a-plate' giving rise to a rich dynamics of gene expression that are independent from reproductive cycles, hence contradicting simple ergodic assumptions The aspecific character of the observed coordinated gene expression activity inhibits any simple mechanistic hypothesis and highlights the need to consider population effects in the interpretation of data coming from cell cultures. © 2007 The Authors.

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