Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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Comparison and characterization of proteomes in the three domains of life using 2D correlation analysis

Fujishima K., Komasa M., Kitamura S., Tomita M., Kanai A.

Progress of Theoretical Physics Supplement ( 173 ) 206 - 218 2008

ISSN 03759687

Proteins are a major regulatory component in complex biological systems. Among them, DNA/RNA-binding proteins, the key components of the central dogma of molecular biology, and membrane proteins, which are necessary for both signal transduction and metabolite transport, are suggested to be the most important protein families that arose in the early stage of life. In this study, we computationally analyzed the whole proteome data of six model species to overview the protein diversity in the three domains of life (Bacteria, Archaea and Eukaryota), especially focusing on the above two protein families. To compare the protein distribution among the six model species, we calculated various protein profiles: hydropathy, molecular weight, amino acid composition and periodicity for each protein. We found a domain-specific distribution of the proteome based on 2D correlation analysis of hydropathy and molecular weight. Further, the merged protein distribution of Archaea and other domains revealed many membrane proteins localized in Bacteria-specific regions with a high ratio of hydropathy and many DNA/RNA-binding proteins localized in Eukaryota-specific regions with a low ratio of hydropathy. Since about half of the proteins encoded in the genome are still functionally unknown, we further conducted Support Vector Machine (SVM)-based functional prediction using amino acid composition (CO score) and periodicity (PD score) as feature vectors to predict the overall number of DNA/RNA-binding proteins and membrane proteins in the proteome. Our estimation indicated that two functional categories occupy approximately 60% to 80% of the proteome, and further, the proportion of the two categories varied among the three domains of life, suggesting that the proteome has gone through different selective pressure during evolution.

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Construction of a Biological Tissue Model Based on a Single-Cell Model: A Computer Simulation of Metabolic Heterogeneity in the Liver Lobule

Ohno, H., Naito, Y., Nakajima, H. and Tomita, M.

Artificial Life 14 ( 1 ) 3-28 - 28 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

An enormous body of information has been obtained by molecular and cellular biology in the last half century, However, even these powerful approaches are not adequate when it comes to higher-level biological structures, such as tissues, organs, and individual organisms, because of the complexities involved. Thus, accumulation of data at the higher levels supports and broadens the context for that obtained on the molecular and cellular levels. Under such auspices, an attempt to clucidate mesoscopic and macroscopic subjects based on plentiful nanoscopic and microscopic data is ot great potential value. On the other hand, fully realistic simulation is impracticable because of the extensive cost entailed and enormous amount of data required. Abstraction and modeling that balance the dual requirements of prediction accuracy and manageable calculation cost are of great importance for systems biology. We have constructed an ammonia metabolism model of the hepatic lobule, a histological component of the liver, based on a single-hepatocyte model that consists of the biochemical kinetics of enzymes and transporters. To bring the calculation cost within reason, the porto-central axis, which is an elemental structure of the lobule, is defined as the systems biological unit of the liver, and is accordingly modeled. A model including both histological structure and position-specific gene expression of major enzymes largely represents the physiological dynamics of the hepatic lobule in nature. In addition, heterogeneous gene expression is suggested to have evolved to optimize the energy efficiency of ammonia detoxificattion at the macroscopic level, implying that approaches like this may elucidate how properties at the molecular and cellular levels, such as regulated gene expression, modify higher-level phenomena of multicellular tissue, organs, and organisms. © 2008 Massachusetts Institute of Technology.

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Comparative Study of Circadian Oscillatory Network Models of Drosophila

Ogawa, Y., Arakawa, K., Kaizu, K., Miyoshi, F., Nakayama, Y. and Tomita, M.

Artificial Life 14 ( 1 ) 29-48 - 48 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

The circadian clock of Drosophila is a model pathway for research in biological dock mechanisms, both with traditional experimental approaches and with emerging systems biology approaches utilizing mathematical modeling and in silico computer simulation. Dynamic diurnal oscillations are achieved by the complex interaction of components as a system, and mathematical reconstruction his proven to be an invaluable means of understanding such systematic behavior. In this study, we implemented eight published models of the Drosqpbila circadian clock in Systems Biology Markup Language (SBML) for comparative systems biology studies using E-Cell Simulation Environment version 3, to examine the system-level requirements for the clock mechanism to be robust, by calculating the period and amplitude sensitivity coefficients with simulation experiments. While all models were generally robust as determined by the network topology of the oscillatory feedback loop structure, existing models place relatively strong emphasis on transcription regulation, although this is a limitation on robustness. We suggest that more comprehensive modeling including protein phosphorylation, polymerization, and nuclear transport with regard to amplitude sensitivity will be necessary for understanding the light entrainment and temperature compensation of circadian clocks. © 2008 Massachusetts Institute of Technology.

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Algebraic Method for the Analysis of Signaling Crosstalk

Matsubara, Y., Kikuchi, S., Sugimoto, M., Oka, K. and Tomita, M.

Artificial Life 14 ( 1 ) 81-94 - 94 2008

Research paper (scientific journal), Joint Work, ISSN 10645462

A unified mathematical description that expresses the characteristics of whole systems is necessary for an understanding of signal transduction cascades. In this study we explore an algebraic method, named extreme signaling flow, enhanced from the concept of extreme pathway, to analyze signal transduction systems. This method enables us to represent the long-term potentiation (LTP) and the long-term depression (LTD) of hippocampal neuronal plasticity in an integrated simulation model. The model is validated by comparing the results of redundancy, reaction participation, and in silico knockout analysis with biological knowledge available from the literature. The following properties are assumed in these computational analyses: (1) LTP is fault-tolerant under network modification, (2) protein kinase C and MAPK have numerous routes to LTP induction, (3) calcium-calmodulin kinase II has a few routes to LTP induction, and (4) calcineurin has many routes to LTD induction. These results demonstrate that our approach produces an integrated framework for analyzing properties of large-scale systems with complicated signal transduction. © 2008 Massachusetts Institute of Technology.

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Automated Phosphoproteome Analysis for Cultured Cancer Cells by Two-Dimensional NanoLC-MS Using a Calcined Titania/C18 Biphasic Column

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

Innovations in Analytical Sciences 24 ( 1 ) 161 - 166 2008

Research paper (scientific journal), Joint Work, ISSN 09106340

We have developed an on-line automated system for phosphoproteome analysis using titania-based phosphopeptide enrichment followed by nanoLC-MS/MS. Titania beads were prepared by calcination of commercial chromatographic titania beads at 800°C to convert the crystalline structure. The obtained rutile-form titania exhibited higher selectivity in phosphopeptide enrichment than commercial titania, even in the absence of a competitive chelating reagent for non-phosphopeptides. For phosphoproteome analysis of human cervical cancer HeLa cells, tryptic digests of the cell extracts were directly injected into this on-line system, and 696 non-redundant phosphopeptides with 671 unambiguously determined phosphorylation sites, derived from 512 phosphoproteins, were successfully identified. This is the first successful application of an on-line automated phosphoproteome analysis system to complex biological samples. 2008 © The Japan Society for Analytical Chemistry.

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Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS

Ohashi,Y.,Hirayama,A.,Ishikawa,T.,Nakamura,S.,Shimizu,K.,Ueno,Y.,Tomita,M.and Soga,T.

Mol.BioSyst 4 ( 2 ) 135-147 - 147 2008

Research paper (scientific journal), Joint Work, ISSN 1742206X

Metabolic changes in response to histidine starvation were observed in histidine-auxotrophic Escherichia coli using a capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolomics technique. Prior to the analysis, we prepared an E. coli metabolome list of 727 metabolites reported in the literature. An improved method for metabolite extraction was developed, which resulted in higher extraction efficiency in phosphate-rich metabolites, e.g., ATP and GTP. Based on the results, 375 charged, hydrophilic intermediates in primary metabolisms were analysed simultaneously, providing quantitative data of 198 metabolites. We confirmed that the intracellular levels of intermediates in histidine biosynthesis are rapidly accumulated in response to a drop in histidine level under histidine-starved conditions. Simultaneously, disciplined responses were observed in the glycolysis, tricarboxylic acid cycle, and amino acid and nucleotide biosynthesis pathways as regulated by amino acid starvation. © The Royal Society of Chemistry.

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Evolution of gene regulatory networks:Robustness as an emergent property of evolution

Krishnan,A.,Tomita,M.and Giuliani,A.

Physica A:Statistical Mechanics nad its Applications 387 ( 8-9 ) 2170-2186 - 2186 2008

Research paper (scientific journal), Joint Work, ISSN 03784371

Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Although much work has been done in elucidating the transcriptional regulatory network, the underlying mechanisms that have possibly influenced the evolution of these GRNs are still debatable. We have 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. We observed that robustness evolves along with the networks as an emergent property even in the absence of specific selective pressure towards more robust systems. In addition, robustness was independent of the selective pressure, input types or the initial starting populations. We also observed the existence of multiple genotypes giving rise to the same phenotype in accordance with the theoretical view that natural selection operates on phenotypes thereby accommodating variation in the genotype by fixing those changes that are phenotype-neutral. This study gives a proof-of-concept of the fact that robustness is an emergent property of GRNs as well as of the degeneracy of the network topology/function relationship analogous to the sequence/structure problem in proteins. © 2007 Elsevier Ltd. All rights reserved.

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Reshuffling of the Bacillus subtilis 168 genome by multifold inversion

Kuroki,A.,TOda,T.,Matsui,K.,Uotsu-Tomita,R.,Tomita,M.and Itaya,M.

Journal of Biochemistry 143 ( 1 ) 97-105 - 105 2008

Research paper (scientific journal), Joint Work, ISSN 0021924X

The genome of Bacillus subtilis 168 was modified to yield a genome vector for the cloning of DNA several Mb in size. Unlike contemporary plasmid-based vectors, this 4.2 Mb genome vector requires specific in vivo handling protocols because of its large size. Inversion mutagenesis, a method to modify local genome structure without gain or loss of genes, was applied intensively to the B. subtilis genome; this technique made possible both exchange and translocation of designated regions of the genome. This method not only reshuffles the genome of B. subtilis, but can provide insight into the biologic principles underlying genome plasticity. © 2007 The Japanese Biochemical Society.

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Informatics for Peptide Retention Properties in Proteomic LC-MS

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

Proteomics 8 ( 4 ) 787-98 - 798 2008

Research paper (scientific journal), Joint Work, ISSN 16159853

Retention times in HPLC yield valuable information for the identification of various analytes and the prediction of peptide retention is useful for the identification of peptides/proteins in LC-MS-based proteomics. Informatics methods such as artificial neural networks and support vector machines capable of solving nonlinear problems made possible the accurate modeling of quantitative structure-retention relationships of peptides (including large polymers) up to 5 kDa to which classical linear models cannot be applied, as well as the proteome-wide prediction of peptide retention. Proteome-wide retention prediction and accurate mass-information facilitate the identification of peptides in complex proteomic samples. In this review, we address recent developments in solid informatics methods and their application to peptide-retention properties in 'bottom-up' shotgun proteomics. We also describe future prospects for the standardization and application of retention times. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

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Proteins as Networks: Usefulness of Graph Theory in Protein Science

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

Currents in Protein and Peptide Science 9 ( 1 ) 28-38 - 38 2008

Research paper (scientific journal), Joint Work, 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 journal 3 ( 2 ) e1622 2008

Research paper (scientific journal), Joint Work

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

Hum. Mol. Genet. 17 ( 11 ) 1631-1640 - 1640 2008

Research paper (scientific journal), Joint Work, 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

Research paper (scientific journal), Joint Work

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

Research paper (scientific journal), Joint Work

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

Robert M., Soga T., Tomita M.

Topics in Current Genetics 18 189 - 234 2007.09

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 2007.09

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 ) 2007.08

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 2007.08

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 2007.06

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 2007.06

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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