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Sample records for metabolic complexity analysis

  1. Differential network analysis reveals evolutionary complexity in secondary metabolism of Rauvolfia serpentina over Catharanthus roseus

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    Shivalika Pathania

    2016-08-01

    Full Text Available Comparative co-expression analysis of multiple species using high-throughput data is an integrative approach to determine the uniformity as well as diversification in biological processes. Rauvolfia serpentina and Catharanthus roseus, both members of Apocyanacae family, are reported to have remedial properties against multiple diseases. Despite of sharing upstream of terpenoid indole alkaloid pathway, there is significant diversity in tissue-specific synthesis and accumulation of specialized metabolites in these plants. This led us to implement comparative co-expression network analysis to investigate the modules and genes responsible for differential tissue-specific expression as well as species-specific synthesis of metabolites. Towards these goals differential network analysis was implemented to identify candidate genes responsible for diversification of metabolites profile. Three genes were identified with significant difference in connectivity leading to differential regulatory behavior between these plants. These mechanisms may be responsible for diversification of secondary metabolism, and thereby for species-specific metabolite synthesis. The network robustness of R. serpentina, determined based on topological properties, was also complemented by comparison of gene-metabolite networks of both plants, and may have evolved to have complex metabolic mechanisms as compared to C. roseus under the influence of various stimuli. This study reveals evolution of complexity in secondary metabolism of Rauvolfia serpentina, and key genes that contribute towards diversification of specific metabolites.

  2. Differential Network Analysis Reveals Evolutionary Complexity in Secondary Metabolism of Rauvolfia serpentina over Catharanthus roseus.

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    Pathania, Shivalika; Bagler, Ganesh; Ahuja, Paramvir S

    2016-01-01

    Comparative co-expression analysis of multiple species using high-throughput data is an integrative approach to determine the uniformity as well as diversification in biological processes. Rauvolfia serpentina and Catharanthus roseus, both members of Apocyanacae family, are reported to have remedial properties against multiple diseases. Despite of sharing upstream of terpenoid indole alkaloid pathway, there is significant diversity in tissue-specific synthesis and accumulation of specialized metabolites in these plants. This led us to implement comparative co-expression network analysis to investigate the modules and genes responsible for differential tissue-specific expression as well as species-specific synthesis of metabolites. Toward these goals differential network analysis was implemented to identify candidate genes responsible for diversification of metabolites profile. Three genes were identified with significant difference in connectivity leading to differential regulatory behavior between these plants. These genes may be responsible for diversification of secondary metabolism, and thereby for species-specific metabolite synthesis. The network robustness of R. serpentina, determined based on topological properties, was also complemented by comparison of gene-metabolite networks of both plants, and may have evolved to have complex metabolic mechanisms as compared to C. roseus under the influence of various stimuli. This study reveals evolution of complexity in secondary metabolism of R. serpentina, and key genes that contribute toward diversification of specific metabolites.

  3. Quantifying complexity in metabolic engineering using the LASER database

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    James D. Winkler

    2016-12-01

    Full Text Available We previously introduced the LASER database (Learning Assisted Strain EngineeRing, https://bitbucket.org/jdwinkler/laser_release (Winkler et al. 2015 to serve as a platform for understanding past and present metabolic engineering practices. Over the past year, LASER has been expanded by 50% to include over 600 engineered strains from 450 papers, including their growth conditions, genetic modifications, and other information in an easily searchable format. Here, we present the results of our efforts to use LASER as a means for defining the complexity of a metabolic engineering “design”. We evaluate two complexity metrics based on the concepts of construction difficulty and novelty. No correlation is observed between expected product yield and complexity, allowing minimization of complexity without a performance trade-off. We envision the use of such complexity metrics to filter and prioritize designs prior to implementation of metabolic engineering efforts, thereby potentially reducing the time, labor, and expenses of large-scale projects. Possible future developments based on an expanding LASER database are then discussed. Keywords: Metabolic engineering, Synthetic biology, Standardization, Design tools

  4. Gene Coexpression Analysis Reveals Complex Metabolism of the Monoterpene Alcohol Linalool in Arabidopsis Flowers[W][OPEN

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    Ginglinger, Jean-François; Boachon, Benoit; Höfer, René; Paetz, Christian; Köllner, Tobias G.; Miesch, Laurence; Lugan, Raphael; Baltenweck, Raymonde; Mutterer, Jérôme; Ullmann, Pascaline; Beran, Franziska; Claudel, Patricia; Verstappen, Francel; Fischer, Marc J.C.; Karst, Francis; Bouwmeester, Harro; Miesch, Michel; Schneider, Bernd; Gershenzon, Jonathan; Ehlting, Jürgen; Werck-Reichhart, Danièle

    2013-01-01

    The cytochrome P450 family encompasses the largest family of enzymes in plant metabolism, and the functions of many of its members in Arabidopsis thaliana are still unknown. Gene coexpression analysis pointed to two P450s that were coexpressed with two monoterpene synthases in flowers and were thus predicted to be involved in monoterpenoid metabolism. We show that all four selected genes, the two terpene synthases (TPS10 and TPS14) and the two cytochrome P450s (CYP71B31 and CYP76C3), are simultaneously expressed at anthesis, mainly in upper anther filaments and in petals. Upon transient expression in Nicotiana benthamiana, the TPS enzymes colocalize in vesicular structures associated with the plastid surface, whereas the P450 proteins were detected in the endoplasmic reticulum. Whether they were expressed in Saccharomyces cerevisiae or in N. benthamiana, the TPS enzymes formed two different enantiomers of linalool: (−)-(R)-linalool for TPS10 and (+)-(S)-linalool for TPS14. Both P450 enzymes metabolize the two linalool enantiomers to form different but overlapping sets of hydroxylated or epoxidized products. These oxygenated products are not emitted into the floral headspace, but accumulate in floral tissues as further converted or conjugated metabolites. This work reveals complex linalool metabolism in Arabidopsis flowers, the ecological role of which remains to be determined. PMID:24285789

  5. Machine Learning Methods for Analysis of Metabolic Data and Metabolic Pathway Modeling.

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    Cuperlovic-Culf, Miroslava

    2018-01-11

    Machine learning uses experimental data to optimize clustering or classification of samples or features, or to develop, augment or verify models that can be used to predict behavior or properties of systems. It is expected that machine learning will help provide actionable knowledge from a variety of big data including metabolomics data, as well as results of metabolism models. A variety of machine learning methods has been applied in bioinformatics and metabolism analyses including self-organizing maps, support vector machines, the kernel machine, Bayesian networks or fuzzy logic. To a lesser extent, machine learning has also been utilized to take advantage of the increasing availability of genomics and metabolomics data for the optimization of metabolic network models and their analysis. In this context, machine learning has aided the development of metabolic networks, the calculation of parameters for stoichiometric and kinetic models, as well as the analysis of major features in the model for the optimal application of bioreactors. Examples of this very interesting, albeit highly complex, application of machine learning for metabolism modeling will be the primary focus of this review presenting several different types of applications for model optimization, parameter determination or system analysis using models, as well as the utilization of several different types of machine learning technologies.

  6. Machine Learning Methods for Analysis of Metabolic Data and Metabolic Pathway Modeling

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    Cuperlovic-Culf, Miroslava

    2018-01-01

    Machine learning uses experimental data to optimize clustering or classification of samples or features, or to develop, augment or verify models that can be used to predict behavior or properties of systems. It is expected that machine learning will help provide actionable knowledge from a variety of big data including metabolomics data, as well as results of metabolism models. A variety of machine learning methods has been applied in bioinformatics and metabolism analyses including self-organizing maps, support vector machines, the kernel machine, Bayesian networks or fuzzy logic. To a lesser extent, machine learning has also been utilized to take advantage of the increasing availability of genomics and metabolomics data for the optimization of metabolic network models and their analysis. In this context, machine learning has aided the development of metabolic networks, the calculation of parameters for stoichiometric and kinetic models, as well as the analysis of major features in the model for the optimal application of bioreactors. Examples of this very interesting, albeit highly complex, application of machine learning for metabolism modeling will be the primary focus of this review presenting several different types of applications for model optimization, parameter determination or system analysis using models, as well as the utilization of several different types of machine learning technologies. PMID:29324649

  7. Temporal expression-based analysis of metabolism.

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    Sara B Collins

    Full Text Available Metabolic flux is frequently rerouted through cellular metabolism in response to dynamic changes in the intra- and extra-cellular environment. Capturing the mechanisms underlying these metabolic transitions in quantitative and predictive models is a prominent challenge in systems biology. Progress in this regard has been made by integrating high-throughput gene expression data into genome-scale stoichiometric models of metabolism. Here, we extend previous approaches to perform a Temporal Expression-based Analysis of Metabolism (TEAM. We apply TEAM to understanding the complex metabolic dynamics of the respiratorily versatile bacterium Shewanella oneidensis grown under aerobic, lactate-limited conditions. TEAM predicts temporal metabolic flux distributions using time-series gene expression data. Increased predictive power is achieved by supplementing these data with a large reference compendium of gene expression, which allows us to take into account the unique character of the distribution of expression of each individual gene. We further propose a straightforward method for studying the sensitivity of TEAM to changes in its fundamental free threshold parameter θ, and reveal that discrete zones of distinct metabolic behavior arise as this parameter is changed. By comparing the qualitative characteristics of these zones to additional experimental data, we are able to constrain the range of θ to a small, well-defined interval. In parallel, the sensitivity analysis reveals the inherently difficult nature of dynamic metabolic flux modeling: small errors early in the simulation propagate to relatively large changes later in the simulation. We expect that handling such "history-dependent" sensitivities will be a major challenge in the future development of dynamic metabolic-modeling techniques.

  8. Identification of the Mitochondrial Heme Metabolism Complex.

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    Medlock, Amy E; Shiferaw, Mesafint T; Marcero, Jason R; Vashisht, Ajay A; Wohlschlegel, James A; Phillips, John D; Dailey, Harry A

    2015-01-01

    Heme is an essential cofactor for most organisms and all metazoans. While the individual enzymes involved in synthesis and utilization of heme are fairly well known, less is known about the intracellular trafficking of porphyrins and heme, or regulation of heme biosynthesis via protein complexes. To better understand this process we have undertaken a study of macromolecular assemblies associated with heme synthesis. Herein we have utilized mass spectrometry with coimmunoprecipitation of tagged enzymes of the heme biosynthetic pathway in a developing erythroid cell culture model to identify putative protein partners. The validity of these data obtained in the tagged protein system is confirmed by normal porphyrin/heme production by the engineered cells. Data obtained are consistent with the presence of a mitochondrial heme metabolism complex which minimally consists of ferrochelatase, protoporphyrinogen oxidase and aminolevulinic acid synthase-2. Additional proteins involved in iron and intermediary metabolism as well as mitochondrial transporters were identified as potential partners in this complex. The data are consistent with the known location of protein components and support a model of transient protein-protein interactions within a dynamic protein complex.

  9. Therapeutic potential of Mediator complex subunits in metabolic diseases.

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    Ranjan, Amol; Ansari, Suraiya A

    2018-01-01

    The multisubunit Mediator is an evolutionary conserved transcriptional coregulatory complex in eukaryotes. It is needed for the transcriptional regulation of gene expression in general as well as in a gene specific manner. Mediator complex subunits interact with different transcription factors as well as components of RNA Pol II transcription initiation complex and in doing so act as a bridge between gene specific transcription factors and general Pol II transcription machinery. Specific interaction of various Mediator subunits with nuclear receptors (NRs) and other transcription factors involved in metabolism has been reported in different studies. Evidences indicate that ligand-activated NRs recruit Mediator complex for RNA Pol II-dependent gene transcription. These NRs have been explored as therapeutic targets in different metabolic diseases; however, they show side-effects as targets due to their overlapping involvement in different signaling pathways. Here we discuss the interaction of various Mediator subunits with transcription factors involved in metabolism and whether specific interaction of these transcription factors with Mediator subunits could be potentially utilized as therapeutic strategy in a variety of metabolic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  10. The Mediator Complex and Lipid Metabolism.

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    Zhang, Yi; Xiaoli; Zhao, Xiaoping; Yang, Fajun

    2013-03-01

    The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and sterol regulatory element-binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism.

  11. Integrative Analysis of Metabolic Models – from Structure to Dynamics

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    Hartmann, Anja, E-mail: hartmann@ipk-gatersleben.de [Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben (Germany); Schreiber, Falk [Monash University, Melbourne, VIC (Australia); Martin-Luther-University Halle-Wittenberg, Halle (Germany)

    2015-01-26

    The characterization of biological systems with respect to their behavior and functionality based on versatile biochemical interactions is a major challenge. To understand these complex mechanisms at systems level modeling approaches are investigated. Different modeling formalisms allow metabolic models to be analyzed depending on the question to be solved, the biochemical knowledge and the availability of experimental data. Here, we describe a method for an integrative analysis of the structure and dynamics represented by qualitative and quantitative metabolic models. Using various formalisms, the metabolic model is analyzed from different perspectives. Determined structural and dynamic properties are visualized in the context of the metabolic model. Interaction techniques allow the exploration and visual analysis thereby leading to a broader understanding of the behavior and functionality of the underlying biological system. The System Biology Metabolic Model Framework (SBM{sup 2} – Framework) implements the developed method and, as an example, is applied for the integrative analysis of the crop plant potato.

  12. Proteolytic regulation of metabolic enzymes by E3 ubiquitin ligase complexes: lessons from yeast.

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    Nakatsukasa, Kunio; Okumura, Fumihiko; Kamura, Takumi

    2015-01-01

    Eukaryotic organisms use diverse mechanisms to control metabolic rates in response to changes in the internal and/or external environment. Fine metabolic control is a highly responsive, energy-saving process that is mediated by allosteric inhibition/activation and/or reversible modification of preexisting metabolic enzymes. In contrast, coarse metabolic control is a relatively long-term and expensive process that involves modulating the level of metabolic enzymes. Coarse metabolic control can be achieved through the degradation of metabolic enzymes by the ubiquitin-proteasome system (UPS), in which substrates are specifically ubiquitinated by an E3 ubiquitin ligase and targeted for proteasomal degradation. Here, we review select multi-protein E3 ligase complexes that directly regulate metabolic enzymes in Saccharomyces cerevisiae. The first part of the review focuses on the endoplasmic reticulum (ER) membrane-associated Hrd1 and Doa10 E3 ligase complexes. In addition to their primary roles in the ER-associated degradation pathway that eliminates misfolded proteins, recent quantitative proteomic analyses identified native substrates of Hrd1 and Doa10 in the sterol synthesis pathway. The second part focuses on the SCF (Skp1-Cul1-F-box protein) complex, an abundant prototypical multi-protein E3 ligase complex. While the best-known roles of the SCF complex are in the regulation of the cell cycle and transcription, accumulating evidence indicates that the SCF complex also modulates carbon metabolism pathways. The increasing number of metabolic enzymes whose stability is directly regulated by the UPS underscores the importance of the proteolytic regulation of metabolic processes for the acclimation of cells to environmental changes.

  13. Metabolic profiling of residents in the vicinity of a petrochemical complex

    International Nuclear Information System (INIS)

    Yuan, Tzu-Hsuen; Chung, Ming-Kei; Lin, Ching-Yu; Chen, Shu-Ting; Wu, Kuen-Yuh; Chan, Chang-Chuan

    2016-01-01

    No previous studies have simultaneously measured the biomarkers of environmental exposure and metabolome perturbation in residents affected by industrial pollutants. This study aimed to investigate the metabolic effects of environmental pollutants such as vanadium and polycyclic aromatic hydrocarbons (PAHs) on residents in the vicinity of a petrochemical complex. The study subjects were 160 residents, including 80 high-exposure subjects exposed to high levels of vanadium and PAHs and 80 age- and gender-matched low-exposure subjects living within a 40-km radius of a petrochemical complex. The exposure biomarkers vanadium and 1-hydroxypyrene and four oxidative/nitrosative stress biomarkers were measured in these subjects. Plasma samples from the study subjects were also analyzed using "1H NMR spectroscopy for metabolic profiling. The results showed that the urinary levels of vanadium and 1-hydroxypyrene in the high-exposure subjects were 40- and 20-fold higher, respectively, than those in the low-exposure subjects. Higher urinary levels of stress biomarkers, including 8-OHdG, HNE-MA, 8-isoPF2α, and 8-NO_2Gua, were also observed among the high-exposure subjects compared with the low-exposure subjects. Partial least squares discriminant analysis of the plasma metabolome demonstrated a clear separation between the high- and low-exposure subjects; the intensities of amino acids and carbohydrate metabolites were lower in the high-exposure subjects compared with the low-exposure subjects. The exposure to vanadium and PAHs may cause a reduction in the levels of amino acids and carbohydrates by elevating PPAR and insulin signaling, as well as oxidative/nitrosative stress. - Highlights: • Metabolic effects when exposure to pollutants near a petrochemical complex • V and PAHs exposure associated with elevated oxidative/nitrosative stress responses • V and PAHs exposure related to reduced amino acid and carbohydrate levels • V and PAHs affect metabolic profiling by

  14. Metabolic profiling of residents in the vicinity of a petrochemical complex

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Tzu-Hsuen; Chung, Ming-Kei [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Lin, Ching-Yu [Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Chen, Shu-Ting; Wu, Kuen-Yuh [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China); Chan, Chang-Chuan, E-mail: ccchan@ntu.edu.tw [Institute of Occupational Medicine and Industrial Hygiene, College of Public Health, National Taiwan University, Taipei, Taiwan (China)

    2016-04-01

    No previous studies have simultaneously measured the biomarkers of environmental exposure and metabolome perturbation in residents affected by industrial pollutants. This study aimed to investigate the metabolic effects of environmental pollutants such as vanadium and polycyclic aromatic hydrocarbons (PAHs) on residents in the vicinity of a petrochemical complex. The study subjects were 160 residents, including 80 high-exposure subjects exposed to high levels of vanadium and PAHs and 80 age- and gender-matched low-exposure subjects living within a 40-km radius of a petrochemical complex. The exposure biomarkers vanadium and 1-hydroxypyrene and four oxidative/nitrosative stress biomarkers were measured in these subjects. Plasma samples from the study subjects were also analyzed using {sup 1}H NMR spectroscopy for metabolic profiling. The results showed that the urinary levels of vanadium and 1-hydroxypyrene in the high-exposure subjects were 40- and 20-fold higher, respectively, than those in the low-exposure subjects. Higher urinary levels of stress biomarkers, including 8-OHdG, HNE-MA, 8-isoPF2α, and 8-NO{sub 2}Gua, were also observed among the high-exposure subjects compared with the low-exposure subjects. Partial least squares discriminant analysis of the plasma metabolome demonstrated a clear separation between the high- and low-exposure subjects; the intensities of amino acids and carbohydrate metabolites were lower in the high-exposure subjects compared with the low-exposure subjects. The exposure to vanadium and PAHs may cause a reduction in the levels of amino acids and carbohydrates by elevating PPAR and insulin signaling, as well as oxidative/nitrosative stress. - Highlights: • Metabolic effects when exposure to pollutants near a petrochemical complex • V and PAHs exposure associated with elevated oxidative/nitrosative stress responses • V and PAHs exposure related to reduced amino acid and carbohydrate levels • V and PAHs affect metabolic

  15. Metabolic responses in Candida tropicalis to complex inhibitors during xylitol bioconversion.

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    Wang, Shizeng; Li, Hao; Fan, Xiaoguang; Zhang, Jingkun; Tang, Pingwah; Yuan, Qipeng

    2015-09-01

    During xylitol fermentation, Candida tropicalis is often inhibited by inhibitors in hemicellulose hydrolysate. The mechanisms involved in the metabolic responses to inhibitor stress and the resistances to inhibitors are still not clear. To understand the inhibition mechanisms and the metabolic responses to inhibitors, a GC/MS-based metabolomics approach was performed on C. tropicalis treated with and without complex inhibitors (CI, including furfural, phenol and acetic acid). Partial least squares discriminant analysis was used to determine the metabolic variability between CI-treated groups and control groups, and 25 metabolites were identified as possible entities responsible for the discrimination caused by inhibitors. We found that xylose uptake rate and xylitol oxidation rate were promoted by CI treatment. Metabolomics analysis showed that the flux from xylulose to pentose phosphate pathway increased, and tricarboxylic acid cycle was disturbed by CI. Moreover, the changes in levels of 1,3-propanediol, trehalose, saturated fatty acids and amino acids showed different mechanisms involved in metabolic responses to inhibitor stress. The increase of 1,3-propanediol was considered to be correlated with regulating redox balance and osmoregulation. The increase of trehalose might play a role in protein stabilization and cellular membranes protection. Saturated fatty acids could cause the decrease of membrane fluidity and make the plasma membrane rigid to maintain the integrity of plasma membrane. The deeper understanding of the inhibition mechanisms and the metabolic responses to inhibitors will provide us with more information on the metabolism regulation during xylitol bioconversion and the construction of industrial strains with inhibitor tolerance for better utilization of bioresource. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Plant metabolic modeling: achieving new insight into metabolism and metabolic engineering.

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    Baghalian, Kambiz; Hajirezaei, Mohammad-Reza; Schreiber, Falk

    2014-10-01

    Models are used to represent aspects of the real world for specific purposes, and mathematical models have opened up new approaches in studying the behavior and complexity of biological systems. However, modeling is often time-consuming and requires significant computational resources for data development, data analysis, and simulation. Computational modeling has been successfully applied as an aid for metabolic engineering in microorganisms. But such model-based approaches have only recently been extended to plant metabolic engineering, mainly due to greater pathway complexity in plants and their highly compartmentalized cellular structure. Recent progress in plant systems biology and bioinformatics has begun to disentangle this complexity and facilitate the creation of efficient plant metabolic models. This review highlights several aspects of plant metabolic modeling in the context of understanding, predicting and modifying complex plant metabolism. We discuss opportunities for engineering photosynthetic carbon metabolism, sucrose synthesis, and the tricarboxylic acid cycle in leaves and oil synthesis in seeds and the application of metabolic modeling to the study of plant acclimation to the environment. The aim of the review is to offer a current perspective for plant biologists without requiring specialized knowledge of bioinformatics or systems biology. © 2014 American Society of Plant Biologists. All rights reserved.

  17. Regulation of metabolism by the Mediator complex.

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    Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

    2016-01-01

    The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

  18. Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions

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    Edwards Jeremy S

    2000-07-01

    Full Text Available Abstract Background Genome sequencing and bioinformatics are producing detailed lists of the molecular components contained in many prokaryotic organisms. From this 'parts catalogue' of a microbial cell, in silico representations of integrated metabolic functions can be constructed and analyzed using flux balance analysis (FBA. FBA is particularly well-suited to study metabolic networks based on genomic, biochemical, and strain specific information. Results Herein, we have utilized FBA to interpret and analyze the metabolic capabilities of Escherichia coli. We have computationally mapped the metabolic capabilities of E. coli using FBA and examined the optimal utilization of the E. coli metabolic pathways as a function of environmental variables. We have used an in silico analysis to identify seven gene products of central metabolism (glycolysis, pentose phosphate pathway, TCA cycle, electron transport system essential for aerobic growth of E. coli on glucose minimal media, and 15 gene products essential for anaerobic growth on glucose minimal media. The in silico tpi-, zwf, and pta- mutant strains were examined in more detail by mapping the capabilities of these in silico isogenic strains. Conclusions We found that computational models of E. coli metabolism based on physicochemical constraints can be used to interpret mutant behavior. These in silica results lead to a further understanding of the complex genotype-phenotype relation. Supplementary information: http://gcrg.ucsd.edu/supplementary_data/DeletionAnalysis/main.htm

  19. Stoichiometric Correlation Analysis: Principles of Metabolic Functionality from Metabolomics Data

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    Kevin Schwahn

    2017-12-01

    Full Text Available Recent advances in metabolomics technologies have resulted in high-quality (time-resolved metabolic profiles with an increasing coverage of metabolic pathways. These data profiles represent read-outs from often non-linear dynamics of metabolic networks. Yet, metabolic profiles have largely been explored with regression-based approaches that only capture linear relationships, rendering it difficult to determine the extent to which the data reflect the underlying reaction rates and their couplings. Here we propose an approach termed Stoichiometric Correlation Analysis (SCA based on correlation between positive linear combinations of log-transformed metabolic profiles. The log-transformation is due to the evidence that metabolic networks can be modeled by mass action law and kinetics derived from it. Unlike the existing approaches which establish a relation between pairs of metabolites, SCA facilitates the discovery of higher-order dependence between more than two metabolites. By using a paradigmatic model of the tricarboxylic acid cycle we show that the higher-order dependence reflects the coupling of concentration of reactant complexes, capturing the subtle difference between the employed enzyme kinetics. Using time-resolved metabolic profiles from Arabidopsis thaliana and Escherichia coli, we show that SCA can be used to quantify the difference in coupling of reactant complexes, and hence, reaction rates, underlying the stringent response in these model organisms. By using SCA with data from natural variation of wild and domesticated wheat and tomato accession, we demonstrate that the domestication is accompanied by loss of such couplings, in these species. Therefore, application of SCA to metabolomics data from natural variation in wild and domesticated populations provides a mechanistic way to understanding domestication and its relation to metabolic networks.

  20. Two-Scale 13C Metabolic Flux Analysis for Metabolic Engineering.

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    Ando, David; Garcia Martin, Hector

    2018-01-01

    Accelerating the Design-Build-Test-Learn (DBTL) cycle in synthetic biology is critical to achieving rapid and facile bioengineering of organisms for the production of, e.g., biofuels and other chemicals. The Learn phase involves using data obtained from the Test phase to inform the next Design phase. As part of the Learn phase, mathematical models of metabolic fluxes give a mechanistic level of comprehension to cellular metabolism, isolating the principle drivers of metabolic behavior from the peripheral ones, and directing future experimental designs and engineering methodologies. Furthermore, the measurement of intracellular metabolic fluxes is specifically noteworthy as providing a rapid and easy-to-understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis in the Learn phase of the DBTL cycle, where we show how one can take the isotope labeling data from a 13 C labeling experiment and immediately turn it into a determination of cellular fluxes that points in the direction of genetic engineering strategies that will advance the metabolic engineering process.For our modeling purposes we use the Joint BioEnergy Institute (JBEI) Quantitative Metabolic Modeling (jQMM) library, which provides an open-source, python-based framework for modeling internal metabolic fluxes and making actionable predictions on how to modify cellular metabolism for specific bioengineering goals. It presents a complete toolbox for performing different types of flux analysis such as Flux Balance Analysis, 13 C Metabolic Flux Analysis, and it introduces the capability to use 13 C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13 C Metabolic Flux Analysis (2S- 13 C MFA) [1]. In addition to several other capabilities, the jQMM is also able to predict the effects of knockouts using the MoMA and ROOM methodologies. The use of the jQMM library is

  1. Hemolymph Melanization in the Silkmoth Bombyx mori Involves Formation of a High Molecular Mass Complex That Metabolizes Tyrosine*

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    Clark, Kevin D.; Strand, Michael R.

    2013-01-01

    The phenoloxidase (PO) cascade regulates the melanization of blood (hemolymph) in insects and other arthropods. Most studies indicate that microbial elicitors activate the PO cascade, which results in processing of the zymogen PPO to PO. PO is then thought to oxidize tyrosine and o-diphenols to quinones, which leads to melanin. However, different lines of investigation raise questions as to whether these views are fully correct. Here we report that hemolymph from the silkmoth, Bombyx mori, rapidly melanizes after collection from a wound site. Prior studies indicated that in vitro activated PPO hydroxylates Tyr inefficiently. Measurement of in vivo substrate titers, however, suggested that Tyr was the only PO substrate initially present in B. mori plasma and that it is rapidly metabolized by PO. Fractionation of plasma by gel filtration chromatography followed by bioassays indicated that melanization activity was primarily associated with a high mass complex (∼670 kDa) that contained PO. The prophenoloxidase-activating protease inhibitor Egf1.0 blocked formation of this complex and Tyr metabolism, but the addition of phenylthiourea to plasma before fractionation enhanced complex formation and Tyr metabolism. Mass spectrometry analysis indicated that the complex contained PO plus other proteins. Taken together, our results indicate that wounding alone activates the PO cascade in B. mori. They also suggest that complex formation is required for efficient use of Tyr as a substrate. PMID:23553628

  2. Comparative analysis of taxonomic, functional, and metabolic patterns of microbiomes from 14 full-scale biogas reactors by metagenomic sequencing and radioisotopic analysis.

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    Luo, Gang; Fotidis, Ioannis A; Angelidaki, Irini

    2016-01-01

    Biogas production is a very complex process due to the high complexity in diversity and interactions of the microorganisms mediating it, and only limited and diffuse knowledge exists about the variation of taxonomic and functional patterns of microbiomes across different biogas reactors, and their relationships with the metabolic patterns. The present study used metagenomic sequencing and radioisotopic analysis to assess the taxonomic, functional, and metabolic patterns of microbiomes from 14 full-scale biogas reactors operated under various conditions treating either sludge or manure. The results from metagenomic analysis showed that the dominant methanogenic pathway revealed by radioisotopic analysis was not always correlated with the taxonomic and functional compositions. It was found by radioisotopic experiments that the aceticlastic methanogenic pathway was dominant, while metagenomics analysis showed higher relative abundance of hydrogenotrophic methanogens. Principal coordinates analysis showed the sludge-based samples were clearly distinct from the manure-based samples for both taxonomic and functional patterns, and canonical correspondence analysis showed that the both temperature and free ammonia were crucial environmental variables shaping the taxonomic and functional patterns. The study further the overall patterns of functional genes were strongly correlated with overall patterns of taxonomic composition across different biogas reactors. The discrepancy between the metabolic patterns determined by metagenomic analysis and metabolic pathways determined by radioisotopic analysis was found. Besides, a clear correlation between taxonomic and functional patterns was demonstrated for biogas reactors, and also the environmental factors that shaping both taxonomic and functional genes patterns were identified.

  3. SUMOFLUX: A Generalized Method for Targeted 13C Metabolic Flux Ratio Analysis

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    Kogadeeva, Maria

    2016-01-01

    Metabolic fluxes are a cornerstone of cellular physiology that emerge from a complex interplay of enzymes, carriers, and nutrients. The experimental assessment of in vivo intracellular fluxes using stable isotopic tracers is essential if we are to understand metabolic function and regulation. Flux estimation based on 13C or 2H labeling relies on complex simulation and iterative fitting; processes that necessitate a level of expertise that ordinarily preclude the non-expert user. To overcome this, we have developed SUMOFLUX, a methodology that is broadly applicable to the targeted analysis of 13C-metabolic fluxes. By combining surrogate modeling and machine learning, we trained a predictor to specialize in estimating flux ratios from measurable 13C-data. SUMOFLUX targets specific flux features individually, which makes it fast, user-friendly, applicable to experimental design and robust in terms of experimental noise and exchange flux magnitude. Collectively, we predict that SUMOFLUX's properties realistically pave the way to high-throughput flux analyses. PMID:27626798

  4. The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture.

    Science.gov (United States)

    Caetano-Anollés, Gustavo; Kim, Hee Shin; Mittenthal, Jay E

    2007-05-29

    Metabolism represents a complex collection of enzymatic reactions and transport processes that convert metabolites into molecules capable of supporting cellular life. Here we explore the origins and evolution of modern metabolism. Using phylogenomic information linked to the structure of metabolic enzymes, we sort out recruitment processes and discover that most enzymatic activities were associated with the nine most ancient and widely distributed protein fold architectures. An analysis of newly discovered functions showed enzymatic diversification occurred early, during the onset of the modern protein world. Most importantly, phylogenetic reconstruction exercises and other evidence suggest strongly that metabolism originated in enzymes with the P-loop hydrolase fold in nucleotide metabolism, probably in pathways linked to the purine metabolic subnetwork. Consequently, the first enzymatic takeover of an ancient biochemistry or prebiotic chemistry was related to the synthesis of nucleotides for the RNA world.

  5. Complex chloroplast RNA metabolism: just debugging the genetic programme?

    Directory of Open Access Journals (Sweden)

    Schmitz-Linneweber Christian

    2008-08-01

    Full Text Available Abstract Background The gene expression system of chloroplasts is far more complex than that of their cyanobacterial progenitor. This gain in complexity affects in particular RNA metabolism, specifically the transcription and maturation of RNA. Mature chloroplast RNA is generated by a plethora of nuclear-encoded proteins acquired or recruited during plant evolution, comprising additional RNA polymerases and sigma factors, and sequence-specific RNA maturation factors promoting RNA splicing, editing, end formation and translatability. Despite years of intensive research, we still lack a comprehensive explanation for this complexity. Results We inspected the available literature and genome databases for information on components of RNA metabolism in land plant chloroplasts. In particular, new inventions of chloroplast-specific mechanisms and the expansion of some gene/protein families detected in land plants lead us to suggest that the primary function of the additional nuclear-encoded components found in chloroplasts is the transgenomic suppression of point mutations, fixation of which occurred due to an enhanced genetic drift exhibited by chloroplast genomes. We further speculate that a fast evolution of transgenomic suppressors occurred after the water-to-land transition of plants. Conclusion Our inspections indicate that several chloroplast-specific mechanisms evolved in land plants to remedy point mutations that occurred after the water-to-land transition. Thus, the complexity of chloroplast gene expression evolved to guarantee the functionality of chloroplast genetic information and may not, with some exceptions, be involved in regulatory functions.

  6. Synergy between 13C-metabolic flux analysis and flux balance analysis for understanding metabolic adaption to anaerobiosis in e. coli

    Science.gov (United States)

    Genome-based Flux Balance Analysis (FBA, constraints based flux analysis) and steady state isotopic-labeling-based Metabolic Flux Analysis (MFA) are complimentary approaches to predicting and measuring the operation and regulation of metabolic networks. Here a genome-derived model of E. coli metabol...

  7. Gene Coexpression Analysis Reveals Complex Metabolism of the Monoterpene Alcohol Linalool in Arabidopsis FlowersW

    NARCIS (Netherlands)

    Ginglinger, J.F.; Boachon, B.; Hofer, R.; Paetz, C.; Kollner, T.G.; Miesch, L.; Lugan, R.; Baltenweck, R.; Mutterer, J.; Ullman, P.; Verstappen, F.W.A.; Bouwmeester, H.J.

    2013-01-01

    The cytochrome P450 family encompasses the largest family of enzymes in plant metabolism, and the functions of many of its members in Arabidopsis thaliana are still unknown. Gene coexpression analysis pointed to two P450s that were coexpressed with two monoterpene synthases in flowers and were thus

  8. Complex partial seizures: cerebellar metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Theodore, W.H.; Fishbein, D.; Deitz, M.; Baldwin, P.

    1987-07-01

    We used positron emission tomography (PET) with (/sup 18/F)2-deoxyglucose to study cerebellar glucose metabolism (LCMRglu) and the effect of phenytoin (PHT) in 42 patients with complex partial seizures (CPS), and 12 normal controls. Mean +/- SD patient LCMRglu was 6.9 +/- 1.8 mg glucose/100 g/min (left = right), significantly lower than control values of 8.5 +/- 1.8 (left, p less than 0.006), and 8.3 +/- 1.6 (right, p less than 0.02). Only four patients had cerebellar atrophy on CT/MRI; cerebellar LCMRglu in these was 5.5 +/- 1.5 (p = 0.054 vs. total patient sample). Patients with unilateral temporal hypometabolism or EEG foci did not have lateralized cerebellar hypometabolism. Patients receiving phenytoin (PHT) at the time of scan and patients with less than 5 years total PHT exposure had lower LCMRglu, but the differences were not significant. There were weak inverse correlations between PHT level and cerebellar LCMRglu in patients receiving PHT (r = -0.36; 0.05 less than p less than 0.1), as well as between length of illness and LCMRglu (r = -0.22; 0.05 less than p less than 0.1). Patients with complex partial seizures have cerebellar hypometabolism that is bilateral and due only in part to the effect of PHT.

  9. Pareto optimality in organelle energy metabolism analysis.

    Science.gov (United States)

    Angione, Claudio; Carapezza, Giovanni; Costanza, Jole; Lió, Pietro; Nicosia, Giuseppe

    2013-01-01

    In low and high eukaryotes, energy is collected or transformed in compartments, the organelles. The rich variety of size, characteristics, and density of the organelles makes it difficult to build a general picture. In this paper, we make use of the Pareto-front analysis to investigate the optimization of energy metabolism in mitochondria and chloroplasts. Using the Pareto optimality principle, we compare models of organelle metabolism on the basis of single- and multiobjective optimization, approximation techniques (the Bayesian Automatic Relevance Determination), robustness, and pathway sensitivity analysis. Finally, we report the first analysis of the metabolic model for the hydrogenosome of Trichomonas vaginalis, which is found in several protozoan parasites. Our analysis has shown the importance of the Pareto optimality for such comparison and for insights into the evolution of the metabolism from cytoplasmic to organelle bound, involving a model order reduction. We report that Pareto fronts represent an asymptotic analysis useful to describe the metabolism of an organism aimed at maximizing concurrently two or more metabolite concentrations.

  10. Metatranscriptomic analysis of diverse microbial communities reveals core metabolic pathways and microbiome-specific functionality.

    Science.gov (United States)

    Jiang, Yue; Xiong, Xuejian; Danska, Jayne; Parkinson, John

    2016-01-12

    Metatranscriptomics is emerging as a powerful technology for the functional characterization of complex microbial communities (microbiomes). Use of unbiased RNA-sequencing can reveal both the taxonomic composition and active biochemical functions of a complex microbial community. However, the lack of established reference genomes, computational tools and pipelines make analysis and interpretation of these datasets challenging. Systematic studies that compare data across microbiomes are needed to demonstrate the ability of such pipelines to deliver biologically meaningful insights on microbiome function. Here, we apply a standardized analytical pipeline to perform a comparative analysis of metatranscriptomic data from diverse microbial communities derived from mouse large intestine, cow rumen, kimchi culture, deep-sea thermal vent and permafrost. Sequence similarity searches allowed annotation of 19 to 76% of putative messenger RNA (mRNA) reads, with the highest frequency in the kimchi dataset due to its relatively low complexity and availability of closely related reference genomes. Metatranscriptomic datasets exhibited distinct taxonomic and functional signatures. From a metabolic perspective, we identified a common core of enzymes involved in amino acid, energy and nucleotide metabolism and also identified microbiome-specific pathways such as phosphonate metabolism (deep sea) and glycan degradation pathways (cow rumen). Integrating taxonomic and functional annotations within a novel visualization framework revealed the contribution of different taxa to metabolic pathways, allowing the identification of taxa that contribute unique functions. The application of a single, standard pipeline confirms that the rich taxonomic and functional diversity observed across microbiomes is not simply an artefact of different analysis pipelines but instead reflects distinct environmental influences. At the same time, our findings show how microbiome complexity and availability of

  11. Nonlinear temperature effects on multifractal complexity of metabolic rate of mice

    Directory of Open Access Journals (Sweden)

    Fabio A. Labra

    2016-10-01

    Full Text Available Complex physiological dynamics have been argued to be a signature of healthy physiological function. Here we test whether the complexity of metabolic rate fluctuations in small endotherms decreases with lower environmental temperatures. To do so, we examine the multifractal temporal scaling properties of the rate of change in oxygen consumption r(VO2, in the laboratory mouse Mus musculus, assessing their long range correlation properties across seven different environmental temperatures, ranging from 0 °C to 30 °C. To do so, we applied multifractal detrended fluctuation analysis (MF-DFA, finding that r(VO2 fluctuations show two scaling regimes. For small time scales below the crossover time (approximately 102 s, either monofractal or weak multifractal dynamics are observed depending on whether Ta  15 °C respectively. For larger time scales, r(VO2 fluctuations are characterized by an asymptotic scaling exponent that indicates multifractal anti-persistent or uncorrelated dynamics. For both scaling regimes, a generalization of the multiplicative cascade model provides very good fits for the Renyi exponents τ(q, showing that the infinite number of exponents h(q can be described by only two independent parameters, a and b. We also show that the long-range correlation structure of r(VO2 time series differs from randomly shuffled series, and may not be explained as an artifact of stochastic sampling of a linear frequency spectrum. These results show that metabolic rate dynamics in a well studied micro-endotherm are consistent with a highly non-linear feedback control system.

  12. Complex exercise rehabilitation program for women of the II period of age with metabolic syndrome

    OpenAIRE

    Lee, Eun-Ok; Olga, Kozyreva

    2013-01-01

    The purpose of this study was to develop a complex exercise program integrating Eastern and Western complex exercise rehabilitation programs in order to examine the effects of it on the human body with the subjects for women of the II period of mature age with metabolic syndrome. The subjects of this study are 60 II period of mature aged women with metabolic syndrome living in G City, and the experimental group conducted Taekwon-aerobic exercise, European rehabilitation gymnastics, gym ball e...

  13. Understanding Regulation of Metabolism through Feasibility Analysis

    NARCIS (Netherlands)

    Nikerel, I.E.; Berkhout, J.; Hu, F.; Teusink, B.; Reinders, M.J.T.; De Ridder, D.

    2012-01-01

    Understanding cellular regulation of metabolism is a major challenge in systems biology. Thus far, the main assumption was that enzyme levels are key regulators in metabolic networks. However, regulation analysis recently showed that metabolism is rarely controlled via enzyme levels only, but

  14. Metabolic cartography: experimental quantification of metabolic fluxes from isotopic labelling studies.

    Science.gov (United States)

    O'Grady, John; Schwender, Jörg; Shachar-Hill, Yair; Morgan, John A

    2012-03-01

    For the past decade, flux maps have provided researchers with an in-depth perspective on plant metabolism. As a rapidly developing field, significant headway has been made recently in computation, experimentation, and overall understanding of metabolic flux analysis. These advances are particularly applicable to the study of plant metabolism. New dynamic computational methods such as non-stationary metabolic flux analysis are finding their place in the toolbox of metabolic engineering, allowing more organisms to be studied and decreasing the time necessary for experimentation, thereby opening new avenues by which to explore the vast diversity of plant metabolism. Also, improved methods of metabolite detection and measurement have been developed, enabling increasingly greater resolution of flux measurements and the analysis of a greater number of the multitude of plant metabolic pathways. Methods to deconvolute organelle-specific metabolism are employed with increasing effectiveness, elucidating the compartmental specificity inherent in plant metabolism. Advances in metabolite measurements have also enabled new types of experiments, such as the calculation of metabolic fluxes based on (13)CO(2) dynamic labelling data, and will continue to direct plant metabolic engineering. Newly calculated metabolic flux maps reveal surprising and useful information about plant metabolism, guiding future genetic engineering of crops to higher yields. Due to the significant level of complexity in plants, these methods in combination with other systems biology measurements are necessary to guide plant metabolic engineering in the future.

  15. Metabolic imaging for breast cancer detection and treatment: a role for mitochondrial Complex I function

    Science.gov (United States)

    Ramanujan, V. Krishnan

    2018-02-01

    Cancer cells are known to display a variety of metabolic reprogramming strategies to fulfill their own growth and proliferative agenda. With the advent of high resolution imaging strategies, metabolomics techniques etc., there is an increasing appreciation of critical role that tumor cell metabolism plays in the overall breast cancer (BC) growth. A recent study from our laboratory demonstrated that the development of invasive cancers could be causally connected to deficits in mitochondrial function. Using this study as a rationale, we hypothesize that the widely accepted multistep tumor growth model might have a strong metabolic component as well. In this study, we explore the possibility of targeting mitochondrial Complex I enzyme system for not only metabolic detection of cancer-associated redox changes but also for modulating breast cancer cell growth characteristics. As a proof-of-principle, we demonstrate two approaches (pharmacological and genetic) for modulating mitochondrial Complex I function so as to achieve breast cancer control.

  16. Metabolic analysis of the soil microbe Dechloromonas aromatica str. RCB: indications of a surprisingly complex life-style and cryptic anaerobic pathways for aromatic degradation

    Energy Technology Data Exchange (ETDEWEB)

    Salinero, Kennan Kellaris; Keller, Keith; Feil, William S.; Feil, Helene; Trong, Stephan; Di Bartolo, Genevieve; Lapidus, Alla

    2008-11-17

    Initial interest in Dechloromonas aromatica strain RCB arose from its ability to anaerobically degrade benzene. It is also able to reduce perchlorate and oxidize chlorobenzoate, toluene, and xylene, creating interest in using this organism for bioremediation. Little physiological data has been published for this microbe. It is considered to be a free-living organism. The a priori prediction that the D. aromatica genome would contain previously characterized 'central' enzymes involved in anaerobic aromatic degradation proved to be false, suggesting the presence of novel anaerobic aromatic degradation pathways in this species. These missing pathways include the benzyl succinyl synthase (bssABC) genes (responsible for formate addition to toluene) and the central benzoylCoA pathway for monoaromatics. In depth analyses using existing TIGRfam, COG, and InterPro models, and the creation of de novo HMM models, indicate a highly complex lifestyle with a large number of environmental sensors and signaling pathways, including a relatively large number of GGDEF domain signal receptors and multiple quorum sensors. A number of proteins indicate interactions with an as yet unknown host, as indicated by the presence of predicted cell host remodeling enzymes, effector enzymes, hemolysin-like proteins, adhesins, NO reductase, and both type III and type VI secretory complexes. Evidence of biofilm formation including a proposed exopolysaccharide complex with the somewhat rare exosortase (epsH), is also present. Annotation described in this paper also reveals evidence for several metabolic pathways that have yet to be observed experimentally, including a sulphur oxidation (soxFCDYZAXB) gene cluster, Calvin cycle enzymes, and nitrogen fixation (including RubisCo, ribulose-phosphate 3-epimerase, and nif gene families, respectively). Analysis of the D. aromatica genome indicates there is much to be learned regarding the metabolic capabilities, and life-style, for this microbial

  17. Metabolic analysis of the soil microbe Dechloromonas aromatica str. RCB: indications of a surprisingly complex life-style and cryptic anaerobic pathways for aromatic degradation

    Directory of Open Access Journals (Sweden)

    Feil Helene

    2009-08-01

    Full Text Available Abstract Background Initial interest in Dechloromonas aromatica strain RCB arose from its ability to anaerobically degrade benzene. It is also able to reduce perchlorate and oxidize chlorobenzoate, toluene, and xylene, creating interest in using this organism for bioremediation. Little physiological data has been published for this microbe. It is considered to be a free-living organism. Results The a priori prediction that the D. aromatica genome would contain previously characterized "central" enzymes to support anaerobic aromatic degradation of benzene proved to be false, suggesting the presence of novel anaerobic aromatic degradation pathways in this species. These missing pathways include the benzylsuccinate synthase (bssABC genes (responsible for fumarate addition to toluene and the central benzoyl-CoA pathway for monoaromatics. In depth analyses using existing TIGRfam, COG, and InterPro models, and the creation of de novo HMM models, indicate a highly complex lifestyle with a large number of environmental sensors and signaling pathways, including a relatively large number of GGDEF domain signal receptors and multiple quorum sensors. A number of proteins indicate interactions with an as yet unknown host, as indicated by the presence of predicted cell host remodeling enzymes, effector enzymes, hemolysin-like proteins, adhesins, NO reductase, and both type III and type VI secretory complexes. Evidence of biofilm formation including a proposed exopolysaccharide complex and exosortase (epsH are also present. Annotation described in this paper also reveals evidence for several metabolic pathways that have yet to be observed experimentally, including a sulphur oxidation (soxFCDYZAXB gene cluster, Calvin cycle enzymes, and proteins involved in nitrogen fixation in other species (including RubisCo, ribulose-phosphate 3-epimerase, and nif gene families, respectively. Conclusion Analysis of the D. aromatica genome indicates there is much to be

  18. Proteomic Analysis of the Mediator Complex Interactome in Saccharomyces cerevisiae.

    Science.gov (United States)

    Uthe, Henriette; Vanselow, Jens T; Schlosser, Andreas

    2017-02-27

    Here we present the most comprehensive analysis of the yeast Mediator complex interactome to date. Particularly gentle cell lysis and co-immunopurification conditions allowed us to preserve even transient protein-protein interactions and to comprehensively probe the molecular environment of the Mediator complex in the cell. Metabolic 15 N-labeling thereby enabled stringent discrimination between bona fide interaction partners and nonspecifically captured proteins. Our data indicates a functional role for Mediator beyond transcription initiation. We identified a large number of Mediator-interacting proteins and protein complexes, such as RNA polymerase II, general transcription factors, a large number of transcriptional activators, the SAGA complex, chromatin remodeling complexes, histone chaperones, highly acetylated histones, as well as proteins playing a role in co-transcriptional processes, such as splicing, mRNA decapping and mRNA decay. Moreover, our data provides clear evidence, that the Mediator complex interacts not only with RNA polymerase II, but also with RNA polymerases I and III, and indicates a functional role of the Mediator complex in rRNA processing and ribosome biogenesis.

  19. Understanding Regulation of Metabolism through Feasibility Analysis

    Science.gov (United States)

    Nikerel, Emrah; Berkhout, Jan; Hu, Fengyuan; Teusink, Bas; Reinders, Marcel J. T.; de Ridder, Dick

    2012-01-01

    Understanding cellular regulation of metabolism is a major challenge in systems biology. Thus far, the main assumption was that enzyme levels are key regulators in metabolic networks. However, regulation analysis recently showed that metabolism is rarely controlled via enzyme levels only, but through non-obvious combinations of hierarchical (gene and enzyme levels) and metabolic regulation (mass action and allosteric interaction). Quantitative analyses relating changes in metabolic fluxes to changes in transcript or protein levels have revealed a remarkable lack of understanding of the regulation of these networks. We study metabolic regulation via feasibility analysis (FA). Inspired by the constraint-based approach of Flux Balance Analysis, FA incorporates a model describing kinetic interactions between molecules. We enlarge the portfolio of objectives for the cell by defining three main physiologically relevant objectives for the cell: function, robustness and temporal responsiveness. We postulate that the cell assumes one or a combination of these objectives and search for enzyme levels necessary to achieve this. We call the subspace of feasible enzyme levels the feasible enzyme space. Once this space is constructed, we can study how different objectives may (if possible) be combined, or evaluate the conditions at which the cells are faced with a trade-off among those. We apply FA to the experimental scenario of long-term carbon limited chemostat cultivation of yeast cells, studying how metabolism evolves optimally. Cells employ a mixed strategy composed of increasing enzyme levels for glucose uptake and hexokinase and decreasing levels of the remaining enzymes. This trade-off renders the cells specialized in this low-carbon flux state to compete for the available glucose and get rid of over-overcapacity. Overall, we show that FA is a powerful tool for systems biologists to study regulation of metabolism, interpret experimental data and evaluate hypotheses. PMID

  20. Metabolic Flux Analysis in Isotope Labeling Experiments Using the Adjoint Approach.

    Science.gov (United States)

    Mottelet, Stephane; Gaullier, Gil; Sadaka, Georges

    2017-01-01

    Comprehension of metabolic pathways is considerably enhanced by metabolic flux analysis (MFA-ILE) in isotope labeling experiments. The balance equations are given by hundreds of algebraic (stationary MFA) or ordinary differential equations (nonstationary MFA), and reducing the number of operations is therefore a crucial part of reducing the computation cost. The main bottleneck for deterministic algorithms is the computation of derivatives, particularly for nonstationary MFA. In this article, we explain how the overall identification process may be speeded up by using the adjoint approach to compute the gradient of the residual sum of squares. The proposed approach shows significant improvements in terms of complexity and computation time when it is compared with the usual (direct) approach. Numerical results are obtained for the central metabolic pathways of Escherichia coli and are validated against reference software in the stationary case. The methods and algorithms described in this paper are included in the sysmetab software package distributed under an Open Source license at http://forge.scilab.org/index.php/p/sysmetab/.

  1. Familial aggregation and linkage analysis with covariates for metabolic syndrome risk factors.

    Science.gov (United States)

    Naseri, Parisa; Khodakarim, Soheila; Guity, Kamran; Daneshpour, Maryam S

    2018-06-15

    Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates. Copyright © 2018. Published by Elsevier B.V.

  2. Urban water metabolism efficiency assessment: integrated analysis of available and virtual water.

    Science.gov (United States)

    Huang, Chu-Long; Vause, Jonathan; Ma, Hwong-Wen; Yu, Chang-Ping

    2013-05-01

    Resolving the complex environmental problems of water pollution and shortage which occur during urbanization requires the systematic assessment of urban water metabolism efficiency (WME). While previous research has tended to focus on either available or virtual water metabolism, here we argue that the systematic problems arising during urbanization require an integrated assessment of available and virtual WME, using an indicator system based on material flow analysis (MFA) results. Future research should focus on the following areas: 1) analysis of available and virtual water flow patterns and processes through urban districts in different urbanization phases in years with varying amounts of rainfall, and their environmental effects; 2) based on the optimization of social, economic and environmental benefits, establishment of an indicator system for urban WME assessment using MFA results; 3) integrated assessment of available and virtual WME in districts with different urbanization levels, to facilitate study of the interactions between the natural and social water cycles; 4) analysis of mechanisms driving differences in WME between districts with different urbanization levels, and the selection of dominant social and economic driving indicators, especially those impacting water resource consumption. Combinations of these driving indicators could then be used to design efficient water resource metabolism solutions, and integrated management policies for reduced water consumption. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  4. Topological analysis of metabolic control.

    Science.gov (United States)

    Sen, A K

    1990-12-01

    A topological approach is presented for the analysis of control and regulation in metabolic pathways. In this approach, the control structure of a metabolic pathway is represented by a weighted directed graph. From an inspection of the topology of the graph, the control coefficients of the enzymes are evaluated in a heuristic manner in terms of the enzyme elasticities. The major advantage of the topological approach is that it provides a visual framework for (1) calculating the control coefficients of the enzymes, (2) analyzing the cause-effect relationships of the individual enzymes, (3) assessing the relative importance of the enzymes in metabolic regulation, and (4) simplifying the structure of a given pathway, from a regulatory viewpoint. Results are obtained for (a) an unbranched pathway in the absence of feedback the feedforward regulation and (b) an unbranched pathway with feedback inhibition. Our formulation is based on the metabolic control theory of Kacser and Burns (1973) and Heinrich and Rapoport (1974).

  5. Capturing the essence of a metabolic network: a flux balance analysis approach.

    Science.gov (United States)

    Murabito, Ettore; Simeonidis, Evangelos; Smallbone, Kieran; Swinton, Jonathan

    2009-10-07

    As genome-scale metabolic reconstructions emerge, tools to manage their size and complexity will be increasingly important. Flux balance analysis (FBA) is a constraint-based approach widely used to study the metabolic capabilities of cellular or subcellular systems. FBA problems are highly underdetermined and many different phenotypes can satisfy any set of constraints through which the metabolic system is represented. Two of the main concerns in FBA are exploring the space of solutions for a given metabolic network and finding a specific phenotype which is representative for a given task such as maximal growth rate. Here, we introduce a recursive algorithm suitable for overcoming both of these concerns. The method proposed is able to find the alternate optimal patterns of active reactions of an FBA problem and identify the minimal subnetwork able to perform a specific task as optimally as the whole. Our method represents an alternative to and an extension of other approaches conceived for exploring the space of solutions of an FBA problem. It may also be particularly helpful in defining a scaffold of reactions upon which to build up a dynamic model, when the important pathways of the system have not yet been well-defined.

  6. MetaFluxNet: the management of metabolic reaction information and quantitative metabolic flux analysis.

    Science.gov (United States)

    Lee, Dong-Yup; Yun, Hongsoek; Park, Sunwon; Lee, Sang Yup

    2003-11-01

    MetaFluxNet is a program package for managing information on the metabolic reaction network and for quantitatively analyzing metabolic fluxes in an interactive and customized way. It allows users to interpret and examine metabolic behavior in response to genetic and/or environmental modifications. As a result, quantitative in silico simulations of metabolic pathways can be carried out to understand the metabolic status and to design the metabolic engineering strategies. The main features of the program include a well-developed model construction environment, user-friendly interface for metabolic flux analysis (MFA), comparative MFA of strains having different genotypes under various environmental conditions, and automated pathway layout creation. http://mbel.kaist.ac.kr/ A manual for MetaFluxNet is available as PDF file.

  7. A rapid, simple method for the genetic discrimination of intact Arabidopsis thaliana mutant seeds using metabolic profiling by direct analysis in real-time mass spectrometry

    Directory of Open Access Journals (Sweden)

    Jang Young

    2011-06-01

    Full Text Available Abstract Background Efficient high throughput screening systems of useful mutants are prerequisite for study of plant functional genomics and lots of application fields. Advance in such screening tools, thanks to the development of analytic instruments. Direct analysis in real-time (DART-mass spectrometry (MS by ionization of complex materials at atmospheric pressure is a rapid, simple, high-resolution analytical technique. Here we describe a rapid, simple method for the genetic discrimination of intact Arabidopsis thaliana mutant seeds using metabolic profiling by DART-MS. Results To determine whether this DART-MS combined by multivariate analysis can perform genetic discrimination based on global metabolic profiling, intact Arabidopsis thaliana mutant seeds were subjected to DART-MS without any sample preparation. Partial least squares-discriminant analysis (PLS-DA of DART-MS spectral data from intact seeds classified 14 different lines of seeds into two distinct groups: Columbia (Col-0 and Landsberg erecta (Ler ecotype backgrounds. A hierarchical dendrogram based on partial least squares-discriminant analysis (PLS-DA subdivided the Col-0 ecotype into two groups: mutant lines harboring defects in the phenylpropanoid biosynthetic pathway and mutants without these defects. These results indicated that metabolic profiling with DART-MS could discriminate intact Arabidopsis seeds at least ecotype level and metabolic pathway level within same ecotype. Conclusion The described DART-MS combined by multivariate analysis allows for rapid screening and metabolic characterization of lots of Arabidopsis mutant seeds without complex metabolic preparation steps. Moreover, potential novel metabolic markers can be detected and used to clarify the genetic relationship between Arabidopsis cultivars. Furthermore this technique can be applied to predict the novel gene function of metabolic mutants regardless of morphological phenotypes.

  8. Systematic Sensitivity Analysis of Metabolic Controllers During Reductions in Skeletal Muscle Blood Flow

    Science.gov (United States)

    Radhakrishnan, Krishnan; Cabrera, Marco

    2000-01-01

    An acute reduction in oxygen delivery to skeletal muscle is generally associated with profound derangements in substrate metabolism. Given the complexity of the human bioenergetic system and its components, it is difficult to quantify the interaction of cellular metabolic processes to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in oxygen availability affect the pathways of ATP synthesis and their regulation. In this study, we apply a previously developed mathematical model of human bioenergetics to study effects of ischemia during periods of increased ATP turnover (e.g., exercise). By using systematic sensitivity analysis the oxidative phosphorylation rate was found to be the most important rate parameter affecting lactate production during ischemia under resting conditions. Here we examine whether mild exercise under ischemic conditions alters the relative importance of pathways and parameters previously obtained.

  9. Hierarchical multivariate covariance analysis of metabolic connectivity.

    Science.gov (United States)

    Carbonell, Felix; Charil, Arnaud; Zijdenbos, Alex P; Evans, Alan C; Bedell, Barry J

    2014-12-01

    Conventional brain connectivity analysis is typically based on the assessment of interregional correlations. Given that correlation coefficients are derived from both covariance and variance, group differences in covariance may be obscured by differences in the variance terms. To facilitate a comprehensive assessment of connectivity, we propose a unified statistical framework that interrogates the individual terms of the correlation coefficient. We have evaluated the utility of this method for metabolic connectivity analysis using [18F]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. As an illustrative example of the utility of this approach, we examined metabolic connectivity in angular gyrus and precuneus seed regions of mild cognitive impairment (MCI) subjects with low and high β-amyloid burdens. This new multivariate method allowed us to identify alterations in the metabolic connectome, which would not have been detected using classic seed-based correlation analysis. Ultimately, this novel approach should be extensible to brain network analysis and broadly applicable to other imaging modalities, such as functional magnetic resonance imaging (MRI).

  10. Thermodynamics-based Metabolite Sensitivity Analysis in metabolic networks.

    Science.gov (United States)

    Kiparissides, A; Hatzimanikatis, V

    2017-01-01

    The increasing availability of large metabolomics datasets enhances the need for computational methodologies that can organize the data in a way that can lead to the inference of meaningful relationships. Knowledge of the metabolic state of a cell and how it responds to various stimuli and extracellular conditions can offer significant insight in the regulatory functions and how to manipulate them. Constraint based methods, such as Flux Balance Analysis (FBA) and Thermodynamics-based flux analysis (TFA), are commonly used to estimate the flow of metabolites through genome-wide metabolic networks, making it possible to identify the ranges of flux values that are consistent with the studied physiological and thermodynamic conditions. However, unless key intracellular fluxes and metabolite concentrations are known, constraint-based models lead to underdetermined problem formulations. This lack of information propagates as uncertainty in the estimation of fluxes and basic reaction properties such as the determination of reaction directionalities. Therefore, knowledge of which metabolites, if measured, would contribute the most to reducing this uncertainty can significantly improve our ability to define the internal state of the cell. In the present work we combine constraint based modeling, Design of Experiments (DoE) and Global Sensitivity Analysis (GSA) into the Thermodynamics-based Metabolite Sensitivity Analysis (TMSA) method. TMSA ranks metabolites comprising a metabolic network based on their ability to constrain the gamut of possible solutions to a limited, thermodynamically consistent set of internal states. TMSA is modular and can be applied to a single reaction, a metabolic pathway or an entire metabolic network. This is, to our knowledge, the first attempt to use metabolic modeling in order to provide a significance ranking of metabolites to guide experimental measurements. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier

  11. Ecological relationship analysis of the urban metabolic system of Beijing, China

    International Nuclear Information System (INIS)

    Li Shengsheng; Zhang Yan; Yang Zhifeng; Liu Hong; Zhang Jinyun

    2012-01-01

    Cities can be modelled as giant organisms, with their own metabolic processes, and can therefore be studied using the same tools used for biological metabolic systems. The complicated distribution of compartments within these systems and the functional relationships among them define the system's network structure. Taking Beijing as an example, we divided the city's internal system into metabolic compartments, then used ecological network analysis to calculate a comprehensive utility matrix for the flows between compartments within Beijing's metabolic system from 1998 to 2007 and to identify the corresponding functional relationships among the system's compartments. Our results show how ecological network analysis, utility analysis, and relationship analysis can be used to discover the implied ecological relationships within a metabolic system, thereby providing insights into the system's internal metabolic processes. Such analyses provide scientific support for urban ecological management. - Highlights: ► Urban metabolic processes can be analyzed by treating cities as superorganisms. ► We developed an ecological network model for an urban system. ► We studied the system's network relationships using ecological network analysis. ► We developed indices for judging the system's synergism and degree of stability. - Using Beijing as an example of an urban superorganism, we used ecological network analysis to describe the ecological relationships among the urban metabolic system's compartments.

  12. Cerebral glucose metabolism change in patients with complex regional pain syndrome. A PET study

    International Nuclear Information System (INIS)

    Shiraishi, Satoe; Kobayashi, Hidetoshi; Nihashi, Takashi

    2006-01-01

    The aim of this study was to examine abnormalities of the central nervous system in patients with chronic pain who were diagnosed with complex regional pain syndrome (CRPS). Brain activity was assessed using 18 F-fluorodeoxyglucose positron emission tomography. The data collected from 18 patients were compared with data obtained from 13 normal age-matched controls. Our results showed that glucose metabolism was bilaterally increased in the secondary somatosensory cortex, mid-anterior cingulated cortex (ACC) or posterior cingulated cortex (PCC) (or both), parietal cortex, posterior parietal cortex (PPC), and cerebellum as well as in the right posterior insula and right thalamus in our patients. In contrast, glucose metabolism was reduced contralaterally in the dorsal prefrontal cortex and primary motor cortex. Glucose metabolism was bilaterally elevated in the mid-ACC/PCC and the PPC, which correlated with pain duration. These data suggested that glucose metabolism in the brains of patients with CRPS changes dramatically at each location. In particular, glucose metabolism was increased in the areas concerned with somatosensory perception, possibly due to continuous painful stimulation. (author)

  13. Quantifying the metabolic capabilities of engineered Zymomonas mobilis using linear programming analysis

    Directory of Open Access Journals (Sweden)

    Tsantili Ivi C

    2007-03-01

    needed to yield further conclusions for potential genetic targets that may lead to optimized Z. mobilis strains. Conclusion Applying LP to study the Z. mobilis physiology enabled the identification of the main factors influencing the accomplishment of certain biological objectives due to metabolic network connectivity only. This first-level metabolic analysis model forms the basis for the incorporation of more complex regulatory mechanisms and the formation of more realistic models for the accurate simulation of the in vivo Z. mobilis physiology.

  14. Complex analysis

    CERN Document Server

    Freitag, Eberhard

    2005-01-01

    The guiding principle of this presentation of ``Classical Complex Analysis'' is to proceed as quickly as possible to the central results while using a small number of notions and concepts from other fields. Thus the prerequisites for understanding this book are minimal; only elementary facts of calculus and algebra are required. The first four chapters cover the essential core of complex analysis: - differentiation in C (including elementary facts about conformal mappings) - integration in C (including complex line integrals, Cauchy's Integral Theorem, and the Integral Formulas) - sequences and series of analytic functions, (isolated) singularities, Laurent series, calculus of residues - construction of analytic functions: the gamma function, Weierstrass' Factorization Theorem, Mittag-Leffler Partial Fraction Decomposition, and -as a particular highlight- the Riemann Mapping Theorem, which characterizes the simply connected domains in C. Further topics included are: - the theory of elliptic functions based on...

  15. Emergy-Based Regional Socio-Economic Metabolism Analysis: An Application of Data Envelopment Analysis and Decomposition Analysis

    OpenAIRE

    Zilong Zhang; Xingpeng Chen; Peter Heck

    2014-01-01

    Integrated analysis on socio-economic metabolism could provide a basis for understanding and optimizing regional sustainability. The paper conducted socio-economic metabolism analysis by means of the emergy accounting method coupled with data envelopment analysis and decomposition analysis techniques to assess the sustainability of Qingyang city and its eight sub-region system, as well as to identify the major driving factors of performance change during 2000–2007, to serve as the basis for f...

  16. MetAssimulo:Simulation of Realistic NMR Metabolic Profiles

    Directory of Open Access Journals (Sweden)

    De Iorio Maria

    2010-10-01

    Full Text Available Abstract Background Probing the complex fusion of genetic and environmental interactions, metabolic profiling (or metabolomics/metabonomics, the study of small molecules involved in metabolic reactions, is a rapidly expanding 'omics' field. A major technique for capturing metabolite data is 1H-NMR spectroscopy and this yields highly complex profiles that require sophisticated statistical analysis methods. However, experimental data is difficult to control and expensive to obtain. Thus data simulation is a productive route to aid algorithm development. Results MetAssimulo is a MATLAB-based package that has been developed to simulate 1H-NMR spectra of complex mixtures such as metabolic profiles. Drawing data from a metabolite standard spectral database in conjunction with concentration information input by the user or constructed automatically from the Human Metabolome Database, MetAssimulo is able to create realistic metabolic profiles containing large numbers of metabolites with a range of user-defined properties. Current features include the simulation of two groups ('case' and 'control' specified by means and standard deviations of concentrations for each metabolite. The software enables addition of spectral noise with a realistic autocorrelation structure at user controllable levels. A crucial feature of the algorithm is its ability to simulate both intra- and inter-metabolite correlations, the analysis of which is fundamental to many techniques in the field. Further, MetAssimulo is able to simulate shifts in NMR peak positions that result from matrix effects such as pH differences which are often observed in metabolic NMR spectra and pose serious challenges for statistical algorithms. Conclusions No other software is currently able to simulate NMR metabolic profiles with such complexity and flexibility. This paper describes the algorithm behind MetAssimulo and demonstrates how it can be used to simulate realistic NMR metabolic profiles with

  17. Constraining genome-scale models to represent the bow tie structure of metabolism for 13C metabolic flux analysis

    DEFF Research Database (Denmark)

    Backman, Tyler W.H.; Ando, David; Singh, Jahnavi

    2018-01-01

    for a minimum of fluxes into core metabolism to satisfy these experimental constraints. Together, these methods accelerate and automate the identification of a biologically reasonable set of core reactions for use with 13C MFA or 2S- 13C MFA, as well as provide for a substantially lower set of flux bounds......Determination of internal metabolic fluxes is crucial for fundamental and applied biology because they map how carbon and electrons flow through metabolism to enable cell function. 13C Metabolic Flux Analysis (13C MFA) and Two-Scale 13C Metabolic Flux Analysis (2S-13C MFA) are two techniques used...

  18. Hydrogen production and metabolic flux analysis of metabolically engineered Escherichia coli strains

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Seohyoung; Seol, Eunhee; Park, Sunghoon [Department of Chemical and Biochemical Engineering, Pusan National University, Busan 609-735 (Korea); Oh, You-Kwan [Bioenergy Research Center, Korea Institute of Energy Research, Daejeon 305-543 (Korea); Wang, G.Y. [Department of Oceanography, University of Hawaii at Manoa Honolulu, HI 96822 (United States)

    2009-09-15

    Escherichia coli can produce H{sub 2} from glucose via formate hydrogen lyase (FHL). In order to improve the H{sub 2} production rate and yield, metabolically engineered E. coli strains, which included pathway alterations in their H{sub 2} production and central carbon metabolism, were developed and characterized by batch experiments and metabolic flux analysis. Deletion of hycA, a negative regulator for FHL, resulted in twofold increase of FHL activity. Deletion of two uptake hydrogenases (1 (hya) and hydrogenase 2 (hyb)) increased H{sub 2} production yield from 1.20 mol/mol glucose to 1.48 mol/mol glucose. Deletion of lactate dehydrogenase (ldhA) and fumarate reductase (frdAB) further improved the H{sub 2} yield; 1.80 mol/mol glucose under high H{sub 2} pressure or 2.11 mol/mol glucose under reduced H{sub 2} pressure. Several batch experiments at varying concentrations of glucose (2.5-10 g/L) and yeast extract (0.3 or 3.0 g/L) were conducted for the strain containing all these genetic alternations, and their carbon and energy balances were analyzed. The metabolic flux analysis revealed that deletion of ldhA and frdAB directed most of the carbons from glucose to the glycolytic pathway leading to H{sub 2} production by FHL, not to the pentose phosphate pathway. (author)

  19. Multiparameter rodent chronic model for complex evaluation of alcoholism-mediated metabolic violations.

    Science.gov (United States)

    Shayakhmetova, Ganna M; Bondarenko, Larysa B; Kovalenko, Valentina M; Kharchenko, Olga I; Bohun, Larisa I; Omelchenko, Yuliya O

    2015-01-01

    Despite of the wide spectrum of alcoholism experimental models, the majority of them are very specialized on the short list of investigated parameters and could not provide reproduction of complex metabolic changes in the rats. The aim of the present study was to estimate whether rats selected by high alcohol preference, allowed free access to 15% alcohol for 150 days, develop simultaneous multilevel disturbances of cell macromolecules structure, metabolism and oxidative/nitrosative stress. Wistar albino male rats were divided into groups: I - rats selected by preferences to alcohol were used for chronic alcoholism modeling by replacing water with 15% ethanol (150 days), II - control. Contents of amino acids in serum, liver mRNA CYP2E1 and CYP3A2 expression, DNA fragmentation and lipid peroxidation levels, the reduced glutathione content, superoxide dismutase, catalase, iNOS and cNOS activities were evaluated. In serum of ethanol-treated rats contents of aspartic acid, serine, glycine, alanine and valine were decreased whereas contents of histidine, methionine and phenylalanine were increased. Liver CYP2E1, CYP3A2 mRNA expression, DNA fragmentation levels significantly elevated. Level of cNOS in ethanol-treated rat's hepatocytes was within the normal limits, whereas iNOS activity was raised 1.6 times. Liver pro- and anti-oxidant system alterations were shown. Rats' chronic 15% alcohol consumption (150 days) led solely to complex metabolomic changes at different levels, which simultaneously characterized cell macromolecules structure, metabolism, and oxidative/nitrosative stress. Rodent model of chronic alcoholism in the proposed modification could be an adequate and reasonably priced tool for further preclinical development and testing of pharmacotherapeutic agents.

  20. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

    DEFF Research Database (Denmark)

    Volkov, Petr; Olsson, Anders H; Gillberg, Linn

    2016-01-01

    Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, w...... and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.......Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men......, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5...

  1. Revitalizing Complex Analysis: A Transition-to-Proof Course Centered on Complex Topics

    Science.gov (United States)

    Sachs, Robert

    2017-01-01

    A new transition course centered on complex topics would help in revitalizing complex analysis in two ways: first, provide early exposure to complex functions, sparking greater interest in the complex analysis course; second, create extra time in the complex analysis course by eliminating the "complex precalculus" part of the course. In…

  2. The influence of a selenium-chromium-lipid complex obtained from Chlorella vulgaris on the energy metabolism in rats with experimental diabetes

    Directory of Open Access Journals (Sweden)

    O. Y. Lukashiv

    2017-07-01

    Full Text Available One of the leading roles in treating diabetes mellitus belongs to chrome ions therapy (III, especially in the complex with selenium (IV. Currently selenium is obtained from unicellular algae, which contain biologically active substances and which are capable of accumulating exogenous microelements. By incubating unicellular algae Chlorella vulgaris Biej. in the conditions of aquaculture with sodium selenite (IV and chromium (III chloride, we obtained a biologically active lipid substance which contains selenium and chromium. The substance was tested for the impact on energy metabolism of animals exposed to experimentally induced diabetes mellitus. The diabetes was caused by modeling obesity of the animals with further injection of streptozotocin in the amount of 65 mg/kg and nicotinamide at the dose of 230 mg/kg. The rats were intragastrically injected with 1 ml of 1% starch solution which contained a selenium-chrome-lipid complex extracted from the Chlorella containing 0.6 µg of selenium, 1.05 µg of chrome and 0.5 mg of lipids for prophylactic, therapeutic and prophylactic-therapeutic purposes; the other group of rats for therapeutic purposes was injected with starch solution with the same composition of microelements in inorganic form – sodium selenite (IV and chromium chloride (III. This paper presents the results of our study of the impact of organic and inorganic compounds of chrome and selenium on the energetic metabolism of rats exposed to experimental diabetes mellitus. The analysis determined that in the rats’ organism, the selenium-chrome-lipid complex from the Chlorella improved the indicators of the energetic metabolism – in the group of rats which received it for therapeutic purposes, we observed an up to 7.5 fold increase in the activity of succinate dehydrogenase compared to the rats which did not receive therapeutic treatment. The increase in the activity of succinate dehydrogenase corresponded to the increase in the

  3. HUMAN CAPITAL, THE DIGITAL DIVIDE, AND THE POSSIBLE CONNECTION TO THE FLOW-FUND ANALYSIS OF SOCIOECONOMIC METABOLISM

    Directory of Open Access Journals (Sweden)

    RALUCA I. IORGULESCU

    2015-03-01

    Full Text Available Poverty and economic growth are interconnected research fields via the standard concept ‘human capital’ and in modern societies their analysis is intertwined. In the past decades, more and more research has considered modern economies as complex systems embedded in the biosystem. Under this assumption, scenario analysis based on the concept of socioeconomic metabolism is used to complement more traditional forecasting methods. Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MuSIASEM is developed on the framework of Georgescu-Roegen’s 'flow-fund' model of production and it characterizes socioeconomic systems as metabolic systems. In the context of this novel approach, concepts like bio-economic pressure enable scenario analysis for the evolution of the whole or partial socioeconomic system. The Human Activity Fund is a concept central to the socioeconomic metabolic flow-fund framework and it is related, besides human capital, to one of the newest sources of inequality, namely the ‘digital divide’. The digital divide is a result of the IT Revolution and recent research has associated it with the ‘rewiring of the human brain’. This paper introduces the concept of human capital and presents some of the measures employed in the literature. It also investigates the possible change, due to the digital divide, in the metabolic pattern of a society associated with ‘quality’ changes of the Human Activity Fund through demographic structure or poverty pattern alterations. The ‘internet illiteracy’ indicator is used as a first step to investigate the connection between the MuSIASEM concept Human Activity Fund and the standard concept Human Capital.

  4. Automated metabolic gas analysis systems: a review.

    Science.gov (United States)

    Macfarlane, D J

    2001-01-01

    The use of automated metabolic gas analysis systems or metabolic measurement carts (MMC) in exercise studies is common throughout the industrialised world. They have become essential tools for diagnosing many hospital patients, especially those with cardiorespiratory disease. Moreover, the measurement of maximal oxygen uptake (VO2max) is routine for many athletes in fitness laboratories and has become a defacto standard in spite of its limitations. The development of metabolic carts has also facilitated the noninvasive determination of the lactate threshold and cardiac output, respiratory gas exchange kinetics, as well as studies of outdoor activities via small portable systems that often use telemetry. Although the fundamental principles behind the measurement of oxygen uptake (VO2) and carbon dioxide production (VCO2) have not changed, the techniques used have, and indeed, some have almost turned through a full circle. Early scientists often employed a manual Douglas bag method together with separate chemical analyses, but the need for faster and more efficient techniques fuelled the development of semi- and full-automated systems by private and commercial institutions. Yet, recently some scientists are returning back to the traditional Douglas bag or Tissot-spirometer methods, or are using less complex automated systems to not only save capital costs, but also to have greater control over the measurement process. Over the last 40 years, a considerable number of automated systems have been developed, with over a dozen commercial manufacturers producing in excess of 20 different automated systems. The validity and reliability of all these different systems is not well known, with relatively few independent studies having been published in this area. For comparative studies to be possible and to facilitate greater consistency of measurements in test-retest or longitudinal studies of individuals, further knowledge about the performance characteristics of these

  5. Identification of Conserved Moieties in Metabolic Networks by Graph Theoretical Analysis of Atom Transition Networks

    Science.gov (United States)

    Haraldsdóttir, Hulda S.; Fleming, Ronan M. T.

    2016-01-01

    Conserved moieties are groups of atoms that remain intact in all reactions of a metabolic network. Identification of conserved moieties gives insight into the structure and function of metabolic networks and facilitates metabolic modelling. All moiety conservation relations can be represented as nonnegative integer vectors in the left null space of the stoichiometric matrix corresponding to a biochemical network. Algorithms exist to compute such vectors based only on reaction stoichiometry but their computational complexity has limited their application to relatively small metabolic networks. Moreover, the vectors returned by existing algorithms do not, in general, represent conservation of a specific moiety with a defined atomic structure. Here, we show that identification of conserved moieties requires data on reaction atom mappings in addition to stoichiometry. We present a novel method to identify conserved moieties in metabolic networks by graph theoretical analysis of their underlying atom transition networks. Our method returns the exact group of atoms belonging to each conserved moiety as well as the corresponding vector in the left null space of the stoichiometric matrix. It can be implemented as a pipeline of polynomial time algorithms. Our implementation completes in under five minutes on a metabolic network with more than 4,000 mass balanced reactions. The scalability of the method enables extension of existing applications for moiety conservation relations to genome-scale metabolic networks. We also give examples of new applications made possible by elucidating the atomic structure of conserved moieties. PMID:27870845

  6. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism.

    Directory of Open Access Journals (Sweden)

    Goran Lakisic

    2016-03-01

    Full Text Available BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi. In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases.

  7. [Efficacy of complex therapy with metformin and ramipril combination for patients with metabolic syndrome].

    Science.gov (United States)

    Kaĭdashev, I P; Savchenko, L H; Kaĭdasheva, E I; Kutsenko, N L; Kutsenko, L O; Solokhina, I L; Mamontova, T V

    2010-01-01

    We have studied efficiency of a complex therapy with metformin and ramipril combination (1000 mg and 5 mg per day) respectively in patients with metabolic syndrome (MS). The group of patients with MS which answered the basic criteria IDF (2005) was determined. Carbohydrate and Lipidic metabolism were studied. Patients were characterized with raised weight index (WI), arterial hypertension, increased concentration of triglycerides in blood serum, of glucose, of HbAlc level and S-peptide, and also high level of endotelin (1-38) and CD32+CD40+circulating particles of endothelium. Three months treatment lead to decrease in WI, arterial pressure, triglycerides concentration, HbAlc, glucose, except CD32+CD40+. Six months treatment lead to more expressed positive dynamics. Thus, metformin and ramipril combination in patients with MS leads to decrease in insulin resistancy, carbohydrate and lipid metabolism normalization, to restoration of endothelium functions that is possible to consider as prophylaxis of the development of type 2 diabetes melitus and its cardiovascular complications.

  8. Energy analysis for a sustainable future multi-scale integrated analysis of societal and ecosystem metabolism

    CERN Document Server

    Giampietro, Mario; Sorman, Alevgül H

    2013-01-01

    The vast majority of the countries of the world are now facing an imminent energy crisis, particularly the USA, China, India, Japan and EU countries, but also developing countries having to boost their economic growth precisely when more powerful economies will prevent them from using the limited supply of fossil energy. Despite this crisis, current protocols of energy accounting have been developed for dealing with fossil energy exclusively and are therefore not useful for the analysis of alternative energy sources. The first part of the book illustrates the weakness of existing analyses of energy problems: the science of energy was born and developed neglecting the issue of scale. The authors argue that it is necessary to adopt more complex protocols of accounting and analysis in order to generate robust energy scenarios and effective assessments of the quality of alternative energy sources. The second part of the book introduces the concept of energetic metabolism of modern societies and uses empirical res...

  9. Functional genomics tools applied to plant metabolism: a survey on plant respiration, its connections and the annotation of complex gene functions

    Directory of Open Access Journals (Sweden)

    Wagner L. Araújo

    2012-09-01

    Full Text Available The application of post-genomic techniques in plant respiration studies has greatly improved our ability to assign functions to gene products. In addition it has also revealed previously unappreciated interactions between distal elements of metabolism. Such results have reinforced the need to consider plant respiratory metabolism as part of a complex network and making sense of such interactions will ultimately require the construction of predictive and mechanistic models. Transcriptomics, proteomics, metabolomics and the quantification of metabolic flux will be of great value in creating such models both by facilitating the annotation of complex gene function, determining their structure and by furnishing the quantitative data required to test them. In this review we highlight how these experimental approaches have contributed to our current understanding of plant respiratory metabolism and its interplay with associated process (e.g. photosynthesis, photorespiration and nitrogen metabolism. We also discuss how data from these techniques may be integrated, with the ultimate aim of identifying mechanisms that control and regulate plant respiration and discovering novel gene functions with potential biotechnological implications.

  10. Framework for network modularization and Bayesian network analysis to investigate the perturbed metabolic network

    Directory of Open Access Journals (Sweden)

    Kim Hyun

    2011-12-01

    Full Text Available Abstract Background Genome-scale metabolic network models have contributed to elucidating biological phenomena, and predicting gene targets to engineer for biotechnological applications. With their increasing importance, their precise network characterization has also been crucial for better understanding of the cellular physiology. Results We herein introduce a framework for network modularization and Bayesian network analysis (FMB to investigate organism’s metabolism under perturbation. FMB reveals direction of influences among metabolic modules, in which reactions with similar or positively correlated flux variation patterns are clustered, in response to specific perturbation using metabolic flux data. With metabolic flux data calculated by constraints-based flux analysis under both control and perturbation conditions, FMB, in essence, reveals the effects of specific perturbations on the biological system through network modularization and Bayesian network analysis at metabolic modular level. As a demonstration, this framework was applied to the genetically perturbed Escherichia coli metabolism, which is a lpdA gene knockout mutant, using its genome-scale metabolic network model. Conclusions After all, it provides alternative scenarios of metabolic flux distributions in response to the perturbation, which are complementary to the data obtained from conventionally available genome-wide high-throughput techniques or metabolic flux analysis.

  11. Framework for network modularization and Bayesian network analysis to investigate the perturbed metabolic network.

    Science.gov (United States)

    Kim, Hyun Uk; Kim, Tae Yong; Lee, Sang Yup

    2011-01-01

    Genome-scale metabolic network models have contributed to elucidating biological phenomena, and predicting gene targets to engineer for biotechnological applications. With their increasing importance, their precise network characterization has also been crucial for better understanding of the cellular physiology. We herein introduce a framework for network modularization and Bayesian network analysis (FMB) to investigate organism's metabolism under perturbation. FMB reveals direction of influences among metabolic modules, in which reactions with similar or positively correlated flux variation patterns are clustered, in response to specific perturbation using metabolic flux data. With metabolic flux data calculated by constraints-based flux analysis under both control and perturbation conditions, FMB, in essence, reveals the effects of specific perturbations on the biological system through network modularization and Bayesian network analysis at metabolic modular level. As a demonstration, this framework was applied to the genetically perturbed Escherichia coli metabolism, which is a lpdA gene knockout mutant, using its genome-scale metabolic network model. After all, it provides alternative scenarios of metabolic flux distributions in response to the perturbation, which are complementary to the data obtained from conventionally available genome-wide high-throughput techniques or metabolic flux analysis.

  12. Between theory and quantification: An integrated analysis of metabolic patterns of informal urban settlements

    International Nuclear Information System (INIS)

    Kovacic, Zora; Giampietro, Mario

    2017-01-01

    As informal urban settlements grow in size and population across the developing world, the issue of how to design and implement effective policies to provide for the needs and the aspirations of dwellers becomes ever more pressing. This paper addresses the challenge of how to characterise in quantitative terms the complex and fast-changing phenomenon of informal urban settlements without falling into oversimplification and a narrow focus on the material deficits of informal settlements. Energy policies are taken as an example to illustrate the shortcomings of oversimplification in producing policy relevant information. We adopt a semantically open representation of informal settlements that can capture the diversity of adaptive strategies used by different settlement typologies, based on the societal metabolism approach. Results show that as settlements grow in size and complexity, they remain economically and politically marginalised and fail to integrate into the city. We argue that in the case of energy policy, the analysis must go beyond the definition of problems such as access to energy at the level of the individual, and focus on a multi-scale assessment including the household and community levels studying the capacity of the household to increase it energy throughput through exosomatic devices and infrastructure. - Highlights: • The policy challenges of fast changing informal urban settlements are assessed. • Metabolic patterns are used to assess and compare different typologies of slums. • Semantically open representations are used to capture the complexity of slums.

  13. Genome-enabled Modeling of Microbial Biogeochemistry using a Trait-based Approach. Does Increasing Metabolic Complexity Increase Predictive Capabilities?

    Science.gov (United States)

    King, E.; Karaoz, U.; Molins, S.; Bouskill, N.; Anantharaman, K.; Beller, H. R.; Banfield, J. F.; Steefel, C. I.; Brodie, E.

    2015-12-01

    The biogeochemical functioning of ecosystems is shaped in part by genomic information stored in the subsurface microbiome. Cultivation-independent approaches allow us to extract this information through reconstruction of thousands of genomes from a microbial community. Analysis of these genomes, in turn, gives an indication of the organisms present and their functional roles. However, metagenomic analyses can currently deliver thousands of different genomes that range in abundance/importance, requiring the identification and assimilation of key physiologies and metabolisms to be represented as traits for successful simulation of subsurface processes. Here we focus on incorporating -omics information into BioCrunch, a genome-informed trait-based model that represents the diversity of microbial functional processes within a reactive transport framework. This approach models the rate of nutrient uptake and the thermodynamics of coupled electron donors and acceptors for a range of microbial metabolisms including heterotrophs and chemolithotrophs. Metabolism of exogenous substrates fuels catabolic and anabolic processes, with the proportion of energy used for cellular maintenance, respiration, biomass development, and enzyme production based upon dynamic intracellular and environmental conditions. This internal resource partitioning represents a trade-off against biomass formation and results in microbial community emergence across a fitness landscape. Biocrunch was used here in simulations that included organisms and metabolic pathways derived from a dataset of ~1200 non-redundant genomes reflecting a microbial community in a floodplain aquifer. Metagenomic data was directly used to parameterize trait values related to growth and to identify trait linkages associated with respiration, fermentation, and key enzymatic functions such as plant polymer degradation. Simulations spanned a range of metabolic complexities and highlight benefits originating from simulations

  14. PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs.

    Science.gov (United States)

    Zhu, Zhexin; Li, Chunliang; Zeng, Yanwu; Ding, Jianyi; Qu, Zepeng; Gu, Junjie; Ge, Laixiang; Tang, Fan; Huang, Xin; Zhou, Chenlin; Wang, Ping; Zheng, Deyou; Jin, Ying

    2017-02-02

    The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of α-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Expanded flux variability analysis on metabolic network of Escherichia coli

    Institute of Scientific and Technical Information of China (English)

    CHEN Tong; XIE ZhengWei; OUYANG Qi

    2009-01-01

    Flux balance analysis,based on the mass conservation law in a cellular organism,has been extensively employed to study the interplay between structures and functions of cellular metabolic networks.Consequently,the phenotypes of the metabolism can be well elucidated.In this paper,we introduce the Expanded Flux Variability Analysis (EFVA) to characterize the intrinsic nature of metabolic reactions,such as flexibility,modularity and essentiality,by exploring the trend of the range,the maximum and the minimum flux of reactions.We took the metabolic network of Escherichia coli as an example and analyzed the variability of reaction fluxes under different growth rate constraints.The average variability of all reactions decreases dramatically when the growth rate increases.Consider the noise effect on the metabolic system,we thus argue that the microorganism may practically grow under a suboptimal state.Besides,under the EFVA framework,the reactions are easily to be grouped into catabolic and anabolic groups.And the anabolic groups can be further assigned to specific biomass constitute.We also discovered the growth rate dependent essentiality of reactions.

  16. Metabolic control analysis of xylose catabolism in Aspergillus

    NARCIS (Netherlands)

    Prathumpai, W.; Gabelgaard, J.B.; Wanchanthuek, P.; Vondervoort, van de P.J.I.; Groot, de M.J.L.; McIntyre, M.; Nielsen, J.

    2003-01-01

    A kinetic model for xylose catabolism in Aspergillus is proposed. From a thermodynamic analysis it was found that the intermediate xylitol will accumulate during xylose catabolism. Use of the kinetic model allowed metabolic control analysis (MCA) of the xylose catabolic pathway to be carried out,

  17. Constraining Genome-Scale Models to Represent the Bow Tie Structure of Metabolism for 13C Metabolic Flux Analysis

    Directory of Open Access Journals (Sweden)

    Tyler W. H. Backman

    2018-01-01

    Full Text Available Determination of internal metabolic fluxes is crucial for fundamental and applied biology because they map how carbon and electrons flow through metabolism to enable cell function. 13 C Metabolic Flux Analysis ( 13 C MFA and Two-Scale 13 C Metabolic Flux Analysis (2S- 13 C MFA are two techniques used to determine such fluxes. Both operate on the simplifying approximation that metabolic flux from peripheral metabolism into central “core” carbon metabolism is minimal, and can be omitted when modeling isotopic labeling in core metabolism. The validity of this “two-scale” or “bow tie” approximation is supported both by the ability to accurately model experimental isotopic labeling data, and by experimentally verified metabolic engineering predictions using these methods. However, the boundaries of core metabolism that satisfy this approximation can vary across species, and across cell culture conditions. Here, we present a set of algorithms that (1 systematically calculate flux bounds for any specified “core” of a genome-scale model so as to satisfy the bow tie approximation and (2 automatically identify an updated set of core reactions that can satisfy this approximation more efficiently. First, we leverage linear programming to simultaneously identify the lowest fluxes from peripheral metabolism into core metabolism compatible with the observed growth rate and extracellular metabolite exchange fluxes. Second, we use Simulated Annealing to identify an updated set of core reactions that allow for a minimum of fluxes into core metabolism to satisfy these experimental constraints. Together, these methods accelerate and automate the identification of a biologically reasonable set of core reactions for use with 13 C MFA or 2S- 13 C MFA, as well as provide for a substantially lower set of flux bounds for fluxes into the core as compared with previous methods. We provide an open source Python implementation of these algorithms at https://github.com/JBEI/limitfluxtocore.

  18. RAPID AND AUTOMATED PROCESSING OF MALDI-FTICR/MS DATA FOR N-METABOLIC LABELING IN A SHOTGUN PROTEOMICS ANALYSIS.

    Science.gov (United States)

    Jing, Li; Amster, I Jonathan

    2009-10-15

    Offline high performance liquid chromatography combined with matrix assisted laser desorption and Fourier transform ion cyclotron resonance mass spectrometry (HPLC-MALDI-FTICR/MS) provides the means to rapidly analyze complex mixtures of peptides, such as those produced by proteolytic digestion of a proteome. This method is particularly useful for making quantitative measurements of changes in protein expression by using (15)N-metabolic labeling. Proteolytic digestion of combined labeled and unlabeled proteomes produces complex mixtures that with many mass overlaps when analyzed by HPLC-MALDI-FTICR/MS. A significant challenge to data analysis is the matching of pairs of peaks which represent an unlabeled peptide and its labeled counterpart. We have developed an algorithm and incorporated it into a compute program which significantly accelerates the interpretation of (15)N metabolic labeling data by automating the process of identifying unlabeled/labeled peak pairs. The algorithm takes advantage of the high resolution and mass accuracy of FTICR mass spectrometry. The algorithm is shown to be able to successfully identify the (15)N/(14)N peptide pairs and calculate peptide relative abundance ratios in highly complex mixtures from the proteolytic digest of a whole organism protein extract.

  19. Non-stationary (13)C-metabolic flux ratio analysis.

    Science.gov (United States)

    Hörl, Manuel; Schnidder, Julian; Sauer, Uwe; Zamboni, Nicola

    2013-12-01

    (13)C-metabolic flux analysis ((13)C-MFA) has become a key method for metabolic engineering and systems biology. In the most common methodology, fluxes are calculated by global isotopomer balancing and iterative fitting to stationary (13)C-labeling data. This approach requires a closed carbon balance, long-lasting metabolic steady state, and the detection of (13)C-patterns in a large number of metabolites. These restrictions mostly reduced the application of (13)C-MFA to the central carbon metabolism of well-studied model organisms grown in minimal media with a single carbon source. Here we introduce non-stationary (13)C-metabolic flux ratio analysis as a novel method for (13)C-MFA to allow estimating local, relative fluxes from ultra-short (13)C-labeling experiments and without the need for global isotopomer balancing. The approach relies on the acquisition of non-stationary (13)C-labeling data exclusively for metabolites in the proximity of a node of converging fluxes and a local parameter estimation with a system of ordinary differential equations. We developed a generalized workflow that takes into account reaction types and the availability of mass spectrometric data on molecular ions or fragments for data processing, modeling, parameter and error estimation. We demonstrated the approach by analyzing three key nodes of converging fluxes in central metabolism of Bacillus subtilis. We obtained flux estimates that are in agreement with published results obtained from steady state experiments, but reduced the duration of the necessary (13)C-labeling experiment to less than a minute. These results show that our strategy enables to formally estimate relative pathway fluxes on extremely short time scale, neglecting cellular carbon balancing. Hence this approach paves the road to targeted (13)C-MFA in dynamic systems with multiple carbon sources and towards rich media. © 2013 Wiley Periodicals, Inc.

  20. Reversal of brain metabolic abnormalities following treatment of AIDS dementia complex with 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine): a PET-FDG study

    International Nuclear Information System (INIS)

    Brunetti, A.; Berg, G.; Di Chiro, G.

    1989-01-01

    Brain glucose metabolism was evaluated in four patients with acquired immunodeficiency syndrome (AIDS) dementia complex using [ 18 F]fluorodeoxyglucose (FDG) and positron emission tomography (PET) scans at the beginning of therapy with 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine), and later in the course of therapy. In two patients, baseline, large focal cortical abnormalities of glucose utilization were reversed during the course of therapy. In the other two patients, the initial PET study did not reveal pronounced focal alterations, while the post-treatment scans showed markedly increased cortical glucose metabolism. The improved cortical glucose utilization was accompanied in all patients by immunologic and neurologic improvement. PET-FDG studies can detect cortical metabolic abnormalities associated with AIDS dementia complex, and may be used to monitor the metabolic improvement in response to AZT treatment

  1. Reconstruction and Analysis of Human Kidney-Specific Metabolic Network Based on Omics Data

    Directory of Open Access Journals (Sweden)

    Ai-Di Zhang

    2013-01-01

    Full Text Available With the advent of the high-throughput data production, recent studies of tissue-specific metabolic networks have largely advanced our understanding of the metabolic basis of various physiological and pathological processes. However, for kidney, which plays an essential role in the body, the available kidney-specific model remains incomplete. This paper reports the reconstruction and characterization of the human kidney metabolic network based on transcriptome and proteome data. In silico simulations revealed that house-keeping genes were more essential than kidney-specific genes in maintaining kidney metabolism. Importantly, a total of 267 potential metabolic biomarkers for kidney-related diseases were successfully explored using this model. Furthermore, we found that the discrepancies in metabolic processes of different tissues are directly corresponding to tissue's functions. Finally, the phenotypes of the differentially expressed genes in diabetic kidney disease were characterized, suggesting that these genes may affect disease development through altering kidney metabolism. Thus, the human kidney-specific model constructed in this study may provide valuable information for the metabolism of kidney and offer excellent insights into complex kidney diseases.

  2. Effect of IgG subclasses on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lewis rats

    International Nuclear Information System (INIS)

    Arquilla, E.R.; Stenger, D.; McDougall, B.; Ulich, T.R.

    1987-01-01

    The bioavailability, distribution, and metabolic fate of 125 I-labeled insulin complexed to antibodies in guinea pig antiserum, purified guinea pig IgG1, IgG2, a mixture of IgG1 and IgG2, and homologous Lou/m rat antiserum were studied in inbred Lewis rats. 125 I-insulin complexed to purified guinea pig IgG2 antibodies was rapidly cleared from the blood and sequestered in increasing amounts with time in the liver. Large amounts of the 125 I-insulin complexed to guinea pig IgG1 antibodies remained in the blood for at least 30 min. The bioavailability of 125 I-insulin bound to IgG1 and IgG2 antibodies was inhibited for at least 30 min because significantly less was available for rapid binding to insulin receptors on hepatocytes and renal tubular cells and its subsequent rapid degradation. The bioavailability of 125 I-insulin was further decreased when bound to antibodies in native guinea pig antiserum or a mixture of IgG1 and IgG2 antibodies compared with the 125 I-insulin complexed to either purified IgG1 or IgG2 antibodies alone. The 125 I-insulin bound to antibodies in native guinea pig antiserum or a mixture of IgG1 and IgG2 antibodies was distributed in vivo in a manner reflecting the relative concentrations of the IgG1 and IgG2 antibodies present. The bioavailability, distribution, and metabolic fate of 125 I-insulin in immune complexes prepared with homologous Lou/m rat insulin antiserum was qualitatively similar to that observed with immune complexes prepared with guinea pig insulin antiserum. It appears that the Lewis rat can be used as an in vivo model to study the bioavailability,distribution,and metabolic fate of insulin bound to xenogenic or homologous insulin antibodies

  3. Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation

    Directory of Open Access Journals (Sweden)

    Marangoni Sérgio

    2009-04-01

    Full Text Available Abstract Background Schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. Methods We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area – BA22p identifying by mass spectrometry several protein expression alterations that could be related to the disease. Results Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6 and glial fibrillary acidic protein (GFAP were confirmed by western blot in schizophrenia prefrontal cortex. Conclusion Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease.

  4. OpenFLUX: efficient modelling software for 13C-based metabolic flux analysis

    Directory of Open Access Journals (Sweden)

    Nielsen Lars K

    2009-05-01

    Full Text Available Abstract Background The quantitative analysis of metabolic fluxes, i.e., in vivo activities of intracellular enzymes and pathways, provides key information on biological systems in systems biology and metabolic engineering. It is based on a comprehensive approach combining (i tracer cultivation on 13C substrates, (ii 13C labelling analysis by mass spectrometry and (iii mathematical modelling for experimental design, data processing, flux calculation and statistics. Whereas the cultivation and the analytical part is fairly advanced, a lack of appropriate modelling software solutions for all modelling aspects in flux studies is limiting the application of metabolic flux analysis. Results We have developed OpenFLUX as a user friendly, yet flexible software application for small and large scale 13C metabolic flux analysis. The application is based on the new Elementary Metabolite Unit (EMU framework, significantly enhancing computation speed for flux calculation. From simple notation of metabolic reaction networks defined in a spreadsheet, the OpenFLUX parser automatically generates MATLAB-readable metabolite and isotopomer balances, thus strongly facilitating model creation. The model can be used to perform experimental design, parameter estimation and sensitivity analysis either using the built-in gradient-based search or Monte Carlo algorithms or in user-defined algorithms. Exemplified for a microbial flux study with 71 reactions, 8 free flux parameters and mass isotopomer distribution of 10 metabolites, OpenFLUX allowed to automatically compile the EMU-based model from an Excel file containing metabolic reactions and carbon transfer mechanisms, showing it's user-friendliness. It reliably reproduced the published data and optimum flux distributions for the network under study were found quickly ( Conclusion We have developed a fast, accurate application to perform steady-state 13C metabolic flux analysis. OpenFLUX will strongly facilitate and

  5. Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice.

    Science.gov (United States)

    Huang, S-L; Yu, R-T; Gong, J; Feng, Y; Dai, Y-L; Hu, F; Hu, Y-H; Tao, Y-D; Leng, Y

    2012-05-01

    Arctigenin is a natural compound that had never been previously demonstrated to have a glucose-lowering effect. Here it was found to activate AMP-activated protein kinase (AMPK), and the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated. 2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and ob/ob mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system. Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in ob/ob mice. This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in ob/ob mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.

  6. Metabolic flux analysis of heterotrophic growth in Chlamydomonas reinhardtii.

    Directory of Open Access Journals (Sweden)

    Nanette R Boyle

    Full Text Available Despite the wealth of knowledge available for C. reinhardtii, the central metabolic fluxes of growth on acetate have not yet been determined. In this study, 13C-metabolic flux analysis (13C-MFA was used to determine and quantify the metabolic pathways of primary metabolism in C. reinhardtii cells grown under heterotrophic conditions with acetate as the sole carbon source. Isotopic labeling patterns of compartment specific biomass derived metabolites were used to calculate the fluxes. It was found that acetate is ligated with coenzyme A in the three subcellular compartments (cytosol, mitochondria and plastid included in the model. Two citrate synthases were found to potentially be involved in acetyl-coA metabolism; one localized in the mitochondria and the other acting outside the mitochondria. Labeling patterns demonstrate that Acetyl-coA synthesized in the plastid is directly incorporated in synthesis of fatty acids. Despite having a complete TCA cycle in the mitochondria, it was also found that a majority of the malate flux is shuttled to the cytosol and plastid where it is converted to oxaloacetate providing reducing equivalents to these compartments. When compared to predictions by flux balance analysis, fluxes measured with 13C-MFA were found to be suboptimal with respect to biomass yield; C. reinhardtii sacrifices biomass yield to produce ATP and reducing equivalents.

  7. Radio metal (169Yb) uptake in normal and tumour cells in vitro. Influence of metabolic cell activity and complex structure

    International Nuclear Information System (INIS)

    Franke, W.G.; Kampf, G.

    1996-01-01

    Trivalent radio metal tracers have been used for tumour imaging and metastatic pain palliation. For better understanding their tumour accumulation, basic model studies of uptake of different 169 Yb complexes into cultured normal and tumour cells were performed. Whereas the uptake of 169 Yb citrate is strongly dependent on the metabolic activity and is not tumour-cell pacific, the uptake of 169 Yb complexed with amino carbonic acid (NTA, EDTA, DTPA) does not correlate to the metabolic activities. These complexes are taken up to a greater amount by the tumour cells (by a factor of about 2). Uptake of both complex types leads to a stable association to cellular compounds, 169 Yb is not releasable by the strong complexing agent DTPA. Protein binding of the 169 Yb complexes shows great influence on their cellular uptake. The bound proportion is no more available,for cellular uptake. The results indicate that i 0 uptake of 169 Yb citrate is an active cellular transport process which i not tumor-specific, ii) the 169 Yb amino carbonic acid complexes show a weak favouring by the tumour cells, iii) different from earlier acceptions the Yb complexes studied are not taken up by the cells in protein-bound form. The structure of the Yb complex is decisive for its protein binding and cellular uptake. (author). 13 refs., 6 figs

  8. Multiobjective flux balancing using the NISE method for metabolic network analysis.

    Science.gov (United States)

    Oh, Young-Gyun; Lee, Dong-Yup; Lee, Sang Yup; Park, Sunwon

    2009-01-01

    Flux balance analysis (FBA) is well acknowledged as an analysis tool of metabolic networks in the framework of metabolic engineering. However, FBA has a limitation for solving a multiobjective optimization problem which considers multiple conflicting objectives. In this study, we propose a novel multiobjective flux balance analysis method, which adapts the noninferior set estimation (NISE) method (Solanki et al., 1993) for multiobjective linear programming (MOLP) problems. NISE method can generate an approximation of the Pareto curve for conflicting objectives without redundant iterations of single objective optimization. Furthermore, the flux distributions at each Pareto optimal solution can be obtained for understanding the internal flux changes in the metabolic network. The functionality of this approach is shown by applying it to a genome-scale in silico model of E. coli. Multiple objectives for the poly(3-hydroxybutyrate) [P(3HB)] production are considered simultaneously, and relationships among them are identified. The Pareto curve for maximizing succinic acid production vs. maximizing biomass production is used for the in silico analysis of various combinatorial knockout strains. This proposed method accelerates the strain improvement in the metabolic engineering by reducing computation time of obtaining the Pareto curve and analysis time of flux distribution at each Pareto optimal solution. (c) 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009.

  9. Sequential metabolism of secondary alkyl amines to metabolic-intermediate complexes: opposing roles for the secondary hydroxylamine and primary amine metabolites of desipramine, (s)-fluoxetine, and N-desmethyldiltiazem.

    Science.gov (United States)

    Hanson, Kelsey L; VandenBrink, Brooke M; Babu, Kantipudi N; Allen, Kyle E; Nelson, Wendel L; Kunze, Kent L

    2010-06-01

    Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N-desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N-desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic-intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine > primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d(3)-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation.

  10. Anion-exchange analysis of isotopically labelled nucleotides, nucleosides, and bases in metabolic disorders

    International Nuclear Information System (INIS)

    Nissinen, E.A.O.

    1987-01-01

    This paper on the importance of cellular purines and pyrimidines is evidenced by the multitude of diseases, such as hyperuricemia, orotic aciduria, gout, Lesch-Nyhan syndrome, immunodeficiencies with B- and T-cell dysfunctions, etc. which result from aberrant metabolism. In addition, the use of purine and pyrimidine analogs in chemotherapy is of growing interest. Purine metabolism consists of a complex network of biochemical pathway. These pathways are under complicated feedback regulation and there also exists a close relationship between purine and pyrimidine metabolism. In addition, these pathways interact with those of the carbohydrate, amino acid, and energy metabolism. Since metabolic pathways are closely interrelated, a change in the concentration of a particular metabolite may lead to many changes in the overall metabolic profiles. For instance, in the area of nucleotide metabolism, the inhibition of IMP dehydrogenase by mycophenolic acid leads to various changes in both purine and pyrimidine nucleotide pools. Inhibition of de nova purine biosynthesis by methotrexate leads to many changes in purine and pyrimidine ribonucleotides and deoxyribonucleotides. Thus, the simultaneous measurement of all cellular purine and pyrimidine metabolites from individuals whose metabolism is altered, either by a metabolic disease or by the action of drugs, may further our understanding of cellular metabolism

  11. Genome scale engineering techniques for metabolic engineering.

    Science.gov (United States)

    Liu, Rongming; Bassalo, Marcelo C; Zeitoun, Ramsey I; Gill, Ryan T

    2015-11-01

    Metabolic engineering has expanded from a focus on designs requiring a small number of genetic modifications to increasingly complex designs driven by advances in genome-scale engineering technologies. Metabolic engineering has been generally defined by the use of iterative cycles of rational genome modifications, strain analysis and characterization, and a synthesis step that fuels additional hypothesis generation. This cycle mirrors the Design-Build-Test-Learn cycle followed throughout various engineering fields that has recently become a defining aspect of synthetic biology. This review will attempt to summarize recent genome-scale design, build, test, and learn technologies and relate their use to a range of metabolic engineering applications. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  12. Primary Metabolic Pathways and Metabolic Flux Analysis

    DEFF Research Database (Denmark)

    Villadsen, John

    2015-01-01

    his chapter introduces the metabolic flux analysis (MFA) or stoichiometry-based MFA, and describes the quantitative basis for MFA. It discusses the catabolic pathways in which free energy is produced to drive the cell-building anabolic pathways. An overview of these primary pathways provides...... the reader who is primarily trained in the engineering sciences with atleast a preliminary introduction to biochemistry and also shows how carbon is drained off the catabolic pathways to provide precursors for cell mass building and sometimes for important industrial products. The primary pathways...... to be examined in the following are: glycolysis, primarily by the EMP pathway, but other glycolytic pathways is also mentioned; fermentative pathways in which the redox generated in the glycolytic reactions are consumed; reactions in the tricarboxylic acid (TCA) cycle, which produce biomass precursors and redox...

  13. Effects of Protein-Iron Complex Concentrate Supplementation on Iron Metabolism, Oxidative and Immune Status in Preweaning Calves

    Directory of Open Access Journals (Sweden)

    Robert Kupczyński

    2017-07-01

    Full Text Available The objective of this study was to determine the effects of feeding protein-iron complex (PIC on productive performance and indicators of iron metabolism, hematology parameters, antioxidant and immune status during first 35 days of a calf’s life. Preparation of the complex involved enzymatic hydrolysis of milk casein (serine protease from Yarrowia lipolytica yeast. Iron chloride was then added to the hydrolyzate and lyophilizate. Calves were divided into treated groups: LFe (low iron dose 10 g/day calf of protein-iron complex, HFe (height iron dose 20 g/day calf, and control group. Dietary supplements containing the lower dose of concentrate had a significant positive effect on iron metabolism, while the higher dose of concentrate resulted in increase of total iron binding capacity (TIBC, saturation of transferrin and decrease of and unsaturated iron binding capacity (UIBC, which suggest iron overload. Additionally, treatment with the lower dose of iron remarkably increased the antioxidant parameters, mainly total antioxidant (TAS and glutathione peroxidase activity (GPx. Higher doses of PIC were related to lower total antioxidant status. IgG, IgM, insulin, glucose, TNFα and IGF-1 concentration did not change significantly in either group after supplementation. In practice, the use of protein-iron complex concentrate requires taking into account the iron content in milk replacers and other feedstuffs.

  14. An introduction to complex analysis and geometry

    CERN Document Server

    D'Angelo, John P

    2010-01-01

    An Introduction to Complex Analysis and Geometry provides the reader with a deep appreciation of complex analysis and how this subject fits into mathematics. The book developed from courses given in the Campus Honors Program at the University of Illinois Urbana-Champaign. These courses aimed to share with students the way many mathematics and physics problems magically simplify when viewed from the perspective of complex analysis. The book begins at an elementary level but also contains advanced material. The first four chapters provide an introduction to complex analysis with many elementary

  15. Uncertainty quantification in flux balance analysis of spatially lumped and distributed models of neuron-astrocyte metabolism.

    Science.gov (United States)

    Calvetti, Daniela; Cheng, Yougan; Somersalo, Erkki

    2016-12-01

    Identifying feasible steady state solutions of a brain energy metabolism model is an inverse problem that allows infinitely many solutions. The characterization of the non-uniqueness, or the uncertainty quantification of the flux balance analysis, is tantamount to identifying the degrees of freedom of the solution. The degrees of freedom of multi-compartment mathematical models for energy metabolism of a neuron-astrocyte complex may offer a key to understand the different ways in which the energetic needs of the brain are met. In this paper we study the uncertainty in the solution, using techniques of linear algebra to identify the degrees of freedom in a lumped model, and Markov chain Monte Carlo methods in its extension to a spatially distributed case. The interpretation of the degrees of freedom in metabolic terms, more specifically, glucose and oxygen partitioning, is then leveraged to derive constraints on the free parameters to guarantee that the model is energetically feasible. We demonstrate how the model can be used to estimate the stoichiometric energy needs of the cells as well as the household energy based on the measured oxidative cerebral metabolic rate of glucose and glutamate cycling. Moreover, our analysis shows that in the lumped model the net direction of lactate dehydrogenase (LDH) in the cells can be deduced from the glucose partitioning between the compartments. The extension of the lumped model to a spatially distributed multi-compartment setting that includes diffusion fluxes from capillary to tissue increases the number of degrees of freedom, requiring the use of statistical sampling techniques. The analysis of the distributed model reveals that some of the conclusions valid for the spatially lumped model, e.g., concerning the LDH activity and glucose partitioning, may no longer hold.

  16. Evolution of amino acid metabolism inferred through cladistic analysis.

    Science.gov (United States)

    Cunchillos, Chomin; Lecointre, Guillaume

    2003-11-28

    Because free amino acids were most probably available in primitive abiotic environments, their metabolism is likely to have provided some of the very first metabolic pathways of life. What were the first enzymatic reactions to emerge? A cladistic analysis of metabolic pathways of the 16 aliphatic amino acids and 2 portions of the Krebs cycle was performed using four criteria of homology. The analysis is not based on sequence comparisons but, rather, on coding similarities in enzyme properties. The properties used are shared specific enzymatic activity, shared enzymatic function without substrate specificity, shared coenzymes, and shared functional family. The tree shows that the earliest pathways to emerge are not portions of the Krebs cycle but metabolisms of aspartate, asparagine, glutamate, and glutamine. The views of Horowitz (Horowitz, N. H. (1945) Proc. Natl. Acad. Sci. U. S. A. 31, 153-157) and Cordón (Cordón, F. (1990) Tratado Evolucionista de Biologia, Aguilar, Madrid, Spain), according to which the upstream reactions in the catabolic pathways and the downstream reactions in the anabolic pathways are the earliest in evolution, are globally corroborated; however, with some exceptions. These are due to later opportunistic connections of pathways (actually already suggested by these authors). Earliest enzymatic functions are mostly catabolic; they were deaminations, transaminations, and decarboxylations. From the consensus tree we extracted four time spans for amino acid metabolism development. For some amino acids catabolism and biosynthesis occurred at the same time (Asp, Glu, Lys, Leu, Ala, Val, Ile, Pro, Arg). For others ultimate reactions that use amino acids as a substrate or as a product are distinct in time, with catabolism preceding anabolism for Asn, Gln, and Cys and anabolism preceding catabolism for Ser, Met, and Thr. Cladistic analysis of the structure of biochemical pathways makes hypotheses in biochemical evolution explicit and parsimonious.

  17. Flux-Enabled Exploration of the Role of Sip1 in galactose yeast metabolism

    DEFF Research Database (Denmark)

    Shymansky, Christopher M.; Wang, George; Baidoo, Edward E. K.

    2017-01-01

    13C metabolic flux analysis (13C MFA) is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon kn...

  18. Interdisciplinary Pathways for Urban Metabolism Research

    Science.gov (United States)

    Newell, J. P.

    2011-12-01

    With its rapid rise as a metaphor to express coupled natural-human systems in cities, the concept of urban metabolism is evolving into a series of relatively distinct research frameworks amongst various disciplines, with varying definitions, theories, models, and emphases. In industrial ecology, housed primarily within the disciplinary domain of engineering, urban metabolism research has focused on quantifying material and energy flows into, within, and out of cities, using methodologies such as material flow analysis and life cycle assessment. In the field of urban ecology, which is strongly influenced by ecology and urban planning, research focus has been placed on understanding and modeling the complex patterns and processes of human-ecological systems within urban areas. Finally, in political ecology, closely aligned with human geography and anthropology, scholars theorize about the interwoven knots of social and natural processes, material flows, and spatial structures that form the urban metabolism. This paper offers three potential interdisciplinary urban metabolism research tracks that might integrate elements of these three "ecologies," thereby bridging engineering and the social and physical sciences. First, it presents the idea of infrastructure ecology, which explores the complex, emergent interdependencies between gray (water and wastewater, transportation, etc) and green (e.g. parks, greenways) infrastructure systems, as nested within a broader socio-economic context. For cities to be sustainable and resilient over time-space, the theory follows, these is a need to understand and redesign these infrastructure linkages. Second, there is the concept of an urban-scale carbon metabolism model which integrates consumption-based material flow analysis (including goods, water, and materials), with the carbon sink and source dynamics of the built environment (e.g. buildings, etc) and urban ecosystems. Finally, there is the political ecology of the material

  19. Construction and analysis of the model of energy metabolism in E. coli.

    Directory of Open Access Journals (Sweden)

    Zixiang Xu

    Full Text Available Genome-scale models of metabolism have only been analyzed with the constraint-based modelling philosophy and there have been several genome-scale gene-protein-reaction models. But research on the modelling for energy metabolism of organisms just began in recent years and research on metabolic weighted complex network are rare in literature. We have made three research based on the complete model of E. coli's energy metabolism. We first constructed a metabolic weighted network using the rates of free energy consumption within metabolic reactions as the weights. We then analyzed some structural characters of the metabolic weighted network that we constructed. We found that the distribution of the weight values was uneven, that most of the weight values were zero while reactions with abstract large weight values were rare and that the relationship between w (weight values and v (flux values was not of linear correlation. At last, we have done some research on the equilibrium of free energy for the energy metabolism system of E. coli. We found that E(out (free energy rate input from the environment can meet the demand of E(ch(in (free energy rate dissipated by chemical process and that chemical process plays a great role in the dissipation of free energy in cells. By these research and to a certain extend, we can understand more about the energy metabolism of E. coli.

  20. Harmonic and complex analysis in several variables

    CERN Document Server

    Krantz, Steven G

    2017-01-01

    Authored by a ranking authority in harmonic analysis of several complex variables, this book embodies a state-of-the-art entrée at the intersection of two important fields of research: complex analysis and harmonic analysis. Written with the graduate student in mind, it is assumed that the reader has familiarity with the basics of complex analysis of one and several complex variables as well as with real and functional analysis. The monograph is largely self-contained and develops the harmonic analysis of several complex variables from the first principles. The text includes copious examples, explanations, an exhaustive bibliography for further reading, and figures that illustrate the geometric nature of the subject. Each chapter ends with an exercise set. Additionally, each chapter begins with a prologue, introducing the reader to the subject matter that follows; capsules presented in each section give perspective and a spirited launch to the segment; preludes help put ideas into context. Mathematicians and...

  1. Advances in real and complex analysis with applications

    CERN Document Server

    Cho, Yeol; Agarwal, Praveen; Area, Iván

    2017-01-01

    This book discusses a variety of topics in mathematics and engineering as well as their applications, clearly explaining the mathematical concepts in the simplest possible way and illustrating them with a number of solved examples. The topics include real and complex analysis, special functions and analytic number theory, q-series, Ramanujan’s mathematics, fractional calculus, Clifford and harmonic analysis, graph theory, complex analysis, complex dynamical systems, complex function spaces and operator theory, geometric analysis of complex manifolds, geometric function theory, Riemannian surfaces, Teichmüller spaces and Kleinian groups, engineering applications of complex analytic methods, nonlinear analysis, inequality theory, potential theory, partial differential equations, numerical analysis , fixed-point theory, variational inequality, equilibrium problems, optimization problems, stability of functional equations, and mathematical physics.  It includes papers presented at the 24th International Confe...

  2. Analysis of Piscirickettsia salmonis Metabolism Using Genome-Scale Reconstruction, Modeling, and Testing

    Directory of Open Access Journals (Sweden)

    María P. Cortés

    2017-12-01

    Full Text Available Piscirickettsia salmonis is an intracellular bacterial fish pathogen that causes piscirickettsiosis, a disease with highly adverse impact in the Chilean salmon farming industry. The development of effective treatment and control methods for piscireckttsiosis is still a challenge. To meet it the number of studies on P. salmonis has grown in the last couple of years but many aspects of the pathogen’s biology are still poorly understood. Studies on its metabolism are scarce and only recently a metabolic model for reference strain LF-89 was developed. We present a new genome-scale model for P. salmonis LF-89 with more than twice as many genes as in the previous model and incorporating specific elements of the fish pathogen metabolism. Comparative analysis with models of different bacterial pathogens revealed a lower flexibility in P. salmonis metabolic network. Through constraint-based analysis, we determined essential metabolites required for its growth and showed that it can benefit from different carbon sources tested experimentally in new defined media. We also built an additional model for strain A1-15972, and together with an analysis of P. salmonis pangenome, we identified metabolic features that differentiate two main species clades. Both models constitute a knowledge-base for P. salmonis metabolism and can be used to guide the efficient culture of the pathogen and the identification of specific drug targets.

  3. PFA toolbox: a MATLAB tool for Metabolic Flux Analysis.

    Science.gov (United States)

    Morales, Yeimy; Bosque, Gabriel; Vehí, Josep; Picó, Jesús; Llaneras, Francisco

    2016-07-11

    Metabolic Flux Analysis (MFA) is a methodology that has been successfully applied to estimate metabolic fluxes in living cells. However, traditional frameworks based on this approach have some limitations, particularly when measurements are scarce and imprecise. This is very common in industrial environments. The PFA Toolbox can be used to face those scenarios. Here we present the PFA (Possibilistic Flux Analysis) Toolbox for MATLAB, which simplifies the use of Interval and Possibilistic Metabolic Flux Analysis. The main features of the PFA Toolbox are the following: (a) It provides reliable MFA estimations in scenarios where only a few fluxes can be measured or those available are imprecise. (b) It provides tools to easily plot the results as interval estimates or flux distributions. (c) It is composed of simple functions that MATLAB users can apply in flexible ways. (d) It includes a Graphical User Interface (GUI), which provides a visual representation of the measurements and their uncertainty. (e) It can use stoichiometric models in COBRA format. In addition, the PFA Toolbox includes a User's Guide with a thorough description of its functions and several examples. The PFA Toolbox for MATLAB is a freely available Toolbox that is able to perform Interval and Possibilistic MFA estimations.

  4. An update on psoriasis and metabolic syndrome: A meta-analysis of observational studies.

    Directory of Open Access Journals (Sweden)

    Sanminder Singh

    Full Text Available The relationship between psoriasis and metabolic syndrome is not well understood. Though multiple epidemiologic studies have suggested a link between psoriasis and metabolic syndrome, there is a lack of a comprehensive meta-analysis synthesizing the results of all available observational studies to date. In this meta-analysis, we examined global data on the relationship between psoriasis and odds of metabolic syndrome by searching for studies published between 1946-2016. Specifically, we analyzed the results from 35 observational studies from 20 countries with 1,450,188 total participants, of which 46,714 were psoriasis patients. The pooled odds ratio based on random effects analysis was 2.14 (95% CI 1.84-2.48. Publication bias was present, as evidenced by an Egger test and graphical visualization through a funnel plot (p = 0.001. Based on this comprehensive meta-analysis, psoriasis patients have higher odds of having metabolic syndrome when compared with the general population.

  5. Flux networks in metabolic graphs

    International Nuclear Information System (INIS)

    Warren, P B; Queiros, S M Duarte; Jones, J L

    2009-01-01

    A metabolic model can be represented as a bipartite graph comprising linked reaction and metabolite nodes. Here it is shown how a network of conserved fluxes can be assigned to the edges of such a graph by combining the reaction fluxes with a conserved metabolite property such as molecular weight. A similar flux network can be constructed by combining the primal and dual solutions to the linear programming problem that typically arises in constraint-based modelling. Such constructions may help with the visualization of flux distributions in complex metabolic networks. The analysis also explains the strong correlation observed between metabolite shadow prices (the dual linear programming variables) and conserved metabolite properties. The methods were applied to recent metabolic models for Escherichia coli, Saccharomyces cerevisiae and Methanosarcina barkeri. Detailed results are reported for E. coli; similar results were found for other organisms

  6. Second Law of Thermodynamics Applied to Metabolic Networks

    Science.gov (United States)

    Nigam, R.; Liang, S.

    2003-01-01

    We present a simple algorithm based on linear programming, that combines Kirchoff's flux and potential laws and applies them to metabolic networks to predict thermodynamically feasible reaction fluxes. These law's represent mass conservation and energy feasibility that are widely used in electrical circuit analysis. Formulating the Kirchoff's potential law around a reaction loop in terms of the null space of the stoichiometric matrix leads to a simple representation of the law of entropy that can be readily incorporated into the traditional flux balance analysis without resorting to non-linear optimization. Our technique is new as it can easily check the fluxes got by applying flux balance analysis for thermodynamic feasibility and modify them if they are infeasible so that they satisfy the law of entropy. We illustrate our method by applying it to the network dealing with the central metabolism of Escherichia coli. Due to its simplicity this algorithm will be useful in studying large scale complex metabolic networks in the cell of different organisms.

  7. Cell-selective metabolic labeling of biomolecules with bioorthogonal functionalities.

    Science.gov (United States)

    Xie, Ran; Hong, Senlian; Chen, Xing

    2013-10-01

    Metabolic labeling of biomolecules with bioorthogonal functionalities enables visualization, enrichment, and analysis of the biomolecules of interest in their physiological environments. This versatile strategy has found utility in probing various classes of biomolecules in a broad range of biological processes. On the other hand, metabolic labeling is nonselective with respect to cell type, which imposes limitations for studies performed in complex biological systems. Herein, we review the recent methodological developments aiming to endow metabolic labeling strategies with cell-type selectivity. The cell-selective metabolic labeling strategies have emerged from protein and glycan labeling. We envision that these strategies can be readily extended to labeling of other classes of biomolecules. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Genome-scale metabolic modeling of Mucor circinelloides and comparative analysis with other oleaginous species.

    Science.gov (United States)

    Vongsangnak, Wanwipa; Klanchui, Amornpan; Tawornsamretkit, Iyarest; Tatiyaborwornchai, Witthawin; Laoteng, Kobkul; Meechai, Asawin

    2016-06-01

    We present a novel genome-scale metabolic model iWV1213 of Mucor circinelloides, which is an oleaginous fungus for industrial applications. The model contains 1213 genes, 1413 metabolites and 1326 metabolic reactions across different compartments. We demonstrate that iWV1213 is able to accurately predict the growth rates of M. circinelloides on various nutrient sources and culture conditions using Flux Balance Analysis and Phenotypic Phase Plane analysis. Comparative analysis of three oleaginous genome-scale models, including M. circinelloides (iWV1213), Mortierella alpina (iCY1106) and Yarrowia lipolytica (iYL619_PCP) revealed that iWV1213 possesses a higher number of genes involved in carbohydrate, amino acid, and lipid metabolisms that might contribute to its versatility in nutrient utilization. Moreover, the identification of unique and common active reactions among the Zygomycetes oleaginous models using Flux Variability Analysis unveiled a set of gene/enzyme candidates as metabolic engineering targets for cellular improvement. Thus, iWV1213 offers a powerful metabolic engineering tool for multi-level omics analysis, enabling strain optimization as a cell factory platform of lipid-based production. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Large-scale transcriptome analysis reveals arabidopsis metabolic pathways are frequently influenced by different pathogens.

    Science.gov (United States)

    Jiang, Zhenhong; He, Fei; Zhang, Ziding

    2017-07-01

    Through large-scale transcriptional data analyses, we highlighted the importance of plant metabolism in plant immunity and identified 26 metabolic pathways that were frequently influenced by the infection of 14 different pathogens. Reprogramming of plant metabolism is a common phenomenon in plant defense responses. Currently, a large number of transcriptional profiles of infected tissues in Arabidopsis (Arabidopsis thaliana) have been deposited in public databases, which provides a great opportunity to understand the expression patterns of metabolic pathways during plant defense responses at the systems level. Here, we performed a large-scale transcriptome analysis based on 135 previously published expression samples, including 14 different pathogens, to explore the expression pattern of Arabidopsis metabolic pathways. Overall, metabolic genes are significantly changed in expression during plant defense responses. Upregulated metabolic genes are enriched on defense responses, and downregulated genes are enriched on photosynthesis, fatty acid and lipid metabolic processes. Gene set enrichment analysis (GSEA) identifies 26 frequently differentially expressed metabolic pathways (FreDE_Paths) that are differentially expressed in more than 60% of infected samples. These pathways are involved in the generation of energy, fatty acid and lipid metabolism as well as secondary metabolite biosynthesis. Clustering analysis based on the expression levels of these 26 metabolic pathways clearly distinguishes infected and control samples, further suggesting the importance of these metabolic pathways in plant defense responses. By comparing with FreDE_Paths from abiotic stresses, we find that the expression patterns of 26 FreDE_Paths from biotic stresses are more consistent across different infected samples. By investigating the expression correlation between transcriptional factors (TFs) and FreDE_Paths, we identify several notable relationships. Collectively, the current study

  10. Early detection of metabolic and energy disorders by thermal time series stochastic complexity analysis

    Energy Technology Data Exchange (ETDEWEB)

    Lutaif, N.A. [Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil); Palazzo, R. Jr [Departamento de Telemática, Faculdade de Engenharia Elétrica e Computação, Universidade Estadual de Campinas, Campinas, SP (Brazil); Gontijo, J.A.R. [Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP (Brazil)

    2014-01-17

    Maintenance of thermal homeostasis in rats fed a high-fat diet (HFD) is associated with changes in their thermal balance. The thermodynamic relationship between heat dissipation and energy storage is altered by the ingestion of high-energy diet content. Observation of thermal registers of core temperature behavior, in humans and rodents, permits identification of some characteristics of time series, such as autoreference and stationarity that fit adequately to a stochastic analysis. To identify this change, we used, for the first time, a stochastic autoregressive model, the concepts of which match those associated with physiological systems involved and applied in male HFD rats compared with their appropriate standard food intake age-matched male controls (n=7 per group). By analyzing a recorded temperature time series, we were able to identify when thermal homeostasis would be affected by a new diet. The autoregressive time series model (AR model) was used to predict the occurrence of thermal homeostasis, and this model proved to be very effective in distinguishing such a physiological disorder. Thus, we infer from the results of our study that maximum entropy distribution as a means for stochastic characterization of temperature time series registers may be established as an important and early tool to aid in the diagnosis and prevention of metabolic diseases due to their ability to detect small variations in thermal profile.

  11. Early detection of metabolic and energy disorders by thermal time series stochastic complexity analysis

    International Nuclear Information System (INIS)

    Lutaif, N.A.; Palazzo, R. Jr; Gontijo, J.A.R.

    2014-01-01

    Maintenance of thermal homeostasis in rats fed a high-fat diet (HFD) is associated with changes in their thermal balance. The thermodynamic relationship between heat dissipation and energy storage is altered by the ingestion of high-energy diet content. Observation of thermal registers of core temperature behavior, in humans and rodents, permits identification of some characteristics of time series, such as autoreference and stationarity that fit adequately to a stochastic analysis. To identify this change, we used, for the first time, a stochastic autoregressive model, the concepts of which match those associated with physiological systems involved and applied in male HFD rats compared with their appropriate standard food intake age-matched male controls (n=7 per group). By analyzing a recorded temperature time series, we were able to identify when thermal homeostasis would be affected by a new diet. The autoregressive time series model (AR model) was used to predict the occurrence of thermal homeostasis, and this model proved to be very effective in distinguishing such a physiological disorder. Thus, we infer from the results of our study that maximum entropy distribution as a means for stochastic characterization of temperature time series registers may be established as an important and early tool to aid in the diagnosis and prevention of metabolic diseases due to their ability to detect small variations in thermal profile

  12. Visualization of Metabolic Interaction Networks in Microbial Communities Using VisANT 5.0.

    Directory of Open Access Journals (Sweden)

    Brian R Granger

    2016-04-01

    Full Text Available The complexity of metabolic networks in microbial communities poses an unresolved visualization and interpretation challenge. We address this challenge in the newly expanded version of a software tool for the analysis of biological networks, VisANT 5.0. We focus in particular on facilitating the visual exploration of metabolic interaction between microbes in a community, e.g. as predicted by COMETS (Computation of Microbial Ecosystems in Time and Space, a dynamic stoichiometric modeling framework. Using VisANT's unique metagraph implementation, we show how one can use VisANT 5.0 to explore different time-dependent ecosystem-level metabolic networks. In particular, we analyze the metabolic interaction network between two bacteria previously shown to display an obligate cross-feeding interdependency. In addition, we illustrate how a putative minimal gut microbiome community could be represented in our framework, making it possible to highlight interactions across multiple coexisting species. We envisage that the "symbiotic layout" of VisANT can be employed as a general tool for the analysis of metabolism in complex microbial communities as well as heterogeneous human tissues. VisANT is freely available at: http://visant.bu.edu and COMETS at http://comets.bu.edu.

  13. Visualization of Metabolic Interaction Networks in Microbial Communities Using VisANT 5.0.

    Science.gov (United States)

    Granger, Brian R; Chang, Yi-Chien; Wang, Yan; DeLisi, Charles; Segrè, Daniel; Hu, Zhenjun

    2016-04-01

    The complexity of metabolic networks in microbial communities poses an unresolved visualization and interpretation challenge. We address this challenge in the newly expanded version of a software tool for the analysis of biological networks, VisANT 5.0. We focus in particular on facilitating the visual exploration of metabolic interaction between microbes in a community, e.g. as predicted by COMETS (Computation of Microbial Ecosystems in Time and Space), a dynamic stoichiometric modeling framework. Using VisANT's unique metagraph implementation, we show how one can use VisANT 5.0 to explore different time-dependent ecosystem-level metabolic networks. In particular, we analyze the metabolic interaction network between two bacteria previously shown to display an obligate cross-feeding interdependency. In addition, we illustrate how a putative minimal gut microbiome community could be represented in our framework, making it possible to highlight interactions across multiple coexisting species. We envisage that the "symbiotic layout" of VisANT can be employed as a general tool for the analysis of metabolism in complex microbial communities as well as heterogeneous human tissues. VisANT is freely available at: http://visant.bu.edu and COMETS at http://comets.bu.edu.

  14. Understanding Plant Nitrogen Metabolism through Metabolomics and Computational Approaches

    Directory of Open Access Journals (Sweden)

    Perrin H. Beatty

    2016-10-01

    Full Text Available A comprehensive understanding of plant metabolism could provide a direct mechanism for improving nitrogen use efficiency (NUE in crops. One of the major barriers to achieving this outcome is our poor understanding of the complex metabolic networks, physiological factors, and signaling mechanisms that affect NUE in agricultural settings. However, an exciting collection of computational and experimental approaches has begun to elucidate whole-plant nitrogen usage and provides an avenue for connecting nitrogen-related phenotypes to genes. Herein, we describe how metabolomics, computational models of metabolism, and flux balance analysis have been harnessed to advance our understanding of plant nitrogen metabolism. We introduce a model describing the complex flow of nitrogen through crops in a real-world agricultural setting and describe how experimental metabolomics data, such as isotope labeling rates and analyses of nutrient uptake, can be used to refine these models. In summary, the metabolomics/computational approach offers an exciting mechanism for understanding NUE that may ultimately lead to more effective crop management and engineered plants with higher yields.

  15. Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism.

    Directory of Open Access Journals (Sweden)

    Sebastiano Collino

    Full Text Available The aging phenotype in humans has been thoroughly studied but a detailed metabolic profiling capable of shading light on the underpinning biological processes of longevity is still missing. Here using a combined metabonomics approach compromising holistic (1H-NMR profiling and targeted MS approaches, we report for the first time the metabolic phenotype of longevity in a well characterized human aging cohort compromising mostly female centenarians, elderly, and young individuals. With increasing age, targeted MS profiling of blood serum displayed a marked decrease in tryptophan concentration, while an unique alteration of specific glycerophospholipids and sphingolipids are seen in the longevity phenotype. We hypothesized that the overall lipidome changes specific to longevity putatively reflect centenarians' unique capacity to adapt/respond to the accumulating oxidative and chronic inflammatory conditions characteristic of their extreme aging phenotype. Our data in centenarians support promotion of cellular detoxification mechanisms through specific modulation of the arachidonic acid metabolic cascade as we underpinned increased concentration of 8,9-EpETrE, suggesting enhanced cytochrome P450 (CYP enzyme activity. Such effective mechanism might result in the activation of an anti-oxidative response, as displayed by decreased circulating levels of 9-HODE and 9-oxoODE, markers of lipid peroxidation and oxidative products of linoleic acid. Lastly, we also revealed that the longevity process deeply affects the structure and composition of the human gut microbiota as shown by the increased extrection of phenylacetylglutamine (PAG and p-cresol sulfate (PCS in urine of centenarians. Together, our novel approach in this representative Italian longevity cohort support the hypothesis that a complex remodeling of lipid, amino acid metabolism, and of gut microbiota functionality are key regulatory processes marking exceptional longevity in humans.

  16. Analysis of requirements for teaching materials based on the course bioinformatics for plant metabolism

    Science.gov (United States)

    Balqis, Widodo, Lukiati, Betty; Amin, Mohamad

    2017-05-01

    A way to improve the quality of learning in the course of Plant Metabolism in the Department of Biology, State University of Malang, is to develop teaching materials. This research evaluates the needs of bioinformatics-based teaching material in the course Plant Metabolism by the Analyze, Design, Develop, Implement, and Evaluate (ADDIE) development model. Data were collected through questionnaires distributed to the students in the Plant Metabolism course of the Department of Biology, University of Malang, and analysis of the plan of lectures semester (RPS). Learning gains of this course show that it is not yet integrated into the field of bioinformatics. All respondents stated that plant metabolism books do not include bioinformatics and fail to explain the metabolism of a chemical compound of a local plant in Indonesia. Respondents thought that bioinformatics can explain examples and metabolism of a secondary metabolite analysis techniques and discuss potential medicinal compounds from local plants. As many as 65% of the respondents said that the existing metabolism book could not be used to understand secondary metabolism in lectures of plant metabolism. Therefore, the development of teaching materials including plant metabolism-based bioinformatics is important to improve the understanding of the lecture material in plant metabolism.

  17. Towards high resolution analysis of metabolic flux in cells and tissues.

    Science.gov (United States)

    Sims, James K; Manteiga, Sara; Lee, Kyongbum

    2013-10-01

    Metabolism extracts chemical energy from nutrients, uses this energy to form building blocks for biosynthesis, and interconverts between various small molecules that coordinate the activities of cellular pathways. The metabolic state of a cell is increasingly recognized to determine the phenotype of not only metabolically active cell types such as liver, muscle, and adipose, but also other specialized cell types such as neurons and immune cells. This review focuses on methods to quantify intracellular reaction flux as a measure of cellular metabolic activity, with emphasis on studies involving cells of mammalian tissue. Two key areas are highlighted for future development, single cell metabolomics and noninvasive imaging, which could enable spatiotemporally resolved analysis and thereby overcome issues of heterogeneity, a distinctive feature of tissue metabolism. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. In silico analysis of human metabolism: Reconstruction, contextualization and application of genome-scale models

    DEFF Research Database (Denmark)

    Geng, Jun; Nielsen, Jens

    2017-01-01

    The arising prevalence of metabolic diseases calls for a holistic approach for analysis of the underlying nature of abnormalities in cellular functions. Through mathematic representation and topological analysis of cellular metabolism, GEnome scale metabolic Models (GEMs) provide a promising fram...... that correctly describe interactions between cells or tissues, and we therefore discuss how GEMs can be integrated with blood circulation models. Finally, we end the review with proposing some possible future research directions....

  19. Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

    DEFF Research Database (Denmark)

    Zelezniak, Aleksej; Pers, Tune Hannes; Pinho Soares, Simao Pedro

    2010-01-01

    mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets...... with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment...... factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic...

  20. Thermodynamic analysis of regulation in metabolic networks using constraint-based modeling

    Directory of Open Access Journals (Sweden)

    Mahadevan Radhakrishnan

    2010-05-01

    Full Text Available Abstract Background Geobacter sulfurreducens is a member of the Geobacter species, which are capable of oxidation of organic waste coupled to the reduction of heavy metals and electrode with applications in bioremediation and bioenergy generation. While the metabolism of this organism has been studied through the development of a stoichiometry based genome-scale metabolic model, the associated regulatory network has not yet been well studied. In this manuscript, we report on the implementation of a thermodynamics based metabolic flux model for Geobacter sulfurreducens. We use this updated model to identify reactions that are subject to regulatory control in the metabolic network of G. sulfurreducens using thermodynamic variability analysis. Findings As a first step, we have validated the regulatory sites and bottleneck reactions predicted by the thermodynamic flux analysis in E. coli by evaluating the expression ranges of the corresponding genes. We then identified ten reactions in the metabolic network of G. sulfurreducens that are predicted to be candidates for regulation. We then compared the free energy ranges for these reactions with the corresponding gene expression fold changes under conditions of different environmental and genetic perturbations and show that the model predictions of regulation are consistent with data. In addition, we also identify reactions that operate close to equilibrium and show that the experimentally determined exchange coefficient (a measure of reversibility is significant for these reactions. Conclusions Application of the thermodynamic constraints resulted in identification of potential bottleneck reactions not only from the central metabolism but also from the nucleotide and amino acid subsystems, thereby showing the highly coupled nature of the thermodynamic constraints. In addition, thermodynamic variability analysis serves as a valuable tool in estimating the ranges of ΔrG' of every reaction in the model

  1. Optimization of a blueprint for in vitro glycolysis by metabolic real-time analysis

    NARCIS (Netherlands)

    Bujara, Matthias; Schümperli, Michael; Pellaux, René; Heinemann, Matthias; Panke, Sven

    Recruiting complex metabolic reaction networks for chemical synthesis has attracted considerable attention but frequently requires optimization of network composition and dynamics to reach sufficient productivity. As a design framework to predict optimal levels for all enzymes in the network is

  2. Metabolic pathway analysis using a nash equilibrium approach

    NARCIS (Netherlands)

    Lucia, Angelo; DiMaggio, Peter A.; Alonso-Martinez, Diego

    2018-01-01

    A novel approach to metabolic network analysis using a Nash Equilibrium (NE) formulation is proposed in which enzymes are considered players in a multi-player game. Each player has its own payoff function with the objective of minimizing the Gibbs free energy associated with the biochemical

  3. Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

    Science.gov (United States)

    Zielinski, Daniel C.; Jamshidi, Neema; Corbett, Austin J.; Bordbar, Aarash; Thomas, Alex; Palsson, Bernhard O.

    2017-01-01

    Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.

  4. Clinical and economic analysis of the modern strategies for treating metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Marina Fedorovna Kalashnikova

    2014-04-01

    Full Text Available ObjectiveThe objective of this study was to identify the ways to optimize therapy for metabolic syndrome through complex clinical and economic analysis.MethodsSixty patients with metabolic syndrome were included in the study. The study group (30 subjects with the mean age of 41.0±11 years, 23 females (76.7%, 7 males (23.3% received pharmacotherapy for obesity (orlistat and insulin resistance (metformin, lipid-lowering therapy and antihypertensive therapy, if needed. The control group (30 patients with the mean age of 43.4±9.5 years, 26 females (86.7%, 4 males (13.3% received lipid-lowering and antihypertensive therapy, if needed. All patients underwent clinical and laboratory examination, assessment of depression (Beck Depression Inventory and evaluation of the quality of life using the SF-36 questionnaire at admission to the study and after 6 months of therapy. Complex clinical and economic analyses, including cost-effectiveness and cost-utility analyses and calculation of such indices as “the incremental cost-effectiveness ratio” (ICER, LYG, QALY and “net monetary benefit” (NMB, were conducted based on the results obtained.ResultsImprovement of clinical and laboratory indicators and quality of life in the study group was more significant than that in the control group. The direct medical costs were 33,440.40 RUB for the study group and 18,878.50 RUB for the control group (for 6 months of therapy. The control group CER was 4,016.70, while the study group CER was 3,125.30; ICER was 2,430.90 RUB. LYG was equal to 0.7 and 2.3 years for the control and the study groups, respectively. The QALY measure for the control and study groups was 8.63 and 9.45, respectively. The weighted average total costs for the intended period of living was 498,745.00 RUB for the control group and 457,866.00 RUB for the study group. The control group CUR was 57,792.00 and 54,902.00 RUB/QALY without and with discounting, respectively, while in the study group

  5. Clinical and economic analysis of the modern strategies for treating metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Marina Fedorovna Kalashnikova

    2014-04-01

    Full Text Available Objective. The objective of this study was to identify the ways to optimize therapy for metabolic syndrome through complex clinical and economic analysis. Methods. Sixty patients with metabolic syndrome were included in the study. The study group (30 subjects with the mean age of 41.0?11 years, 23 females (76.7%, 7 males (23.3% received pharmacotherapy for obesity (orlistat and insulin resistance (metformin, lipid-lowering therapy and antihypertensive therapy, if needed. The control group (30 patients with the mean age of 43.4?9.5 years, 26 females (86.7%, 4 males (13.3% received lipid-lowering and antihypertensive therapy, if needed. All patients underwent clinical and laboratory examination, assessment of depression (Beck Depression Inventory and evaluation of the quality of life using the SF-36 questionnaire at admission to the study and after 6 months of therapy. Complex clinical and economic analyses, including cost-effectiveness and cost-utility analyses and calculation of such indices as ?the incremental cost-effectiveness ratio? (ICER, LYG, QALY and ?net monetary benefit? (NMB, were conducted based on the results obtained. Results. Improvement of clinical and laboratory indicators and quality of life in the study group was more significant than that in the control group. The direct medical costs were 33,440.40 RUB for the study group and 18,878.50 RUB for the control group (for 6 months of therapy. The control group CER was 4,016.70, while the study group CER was 3,125.30; ICER was 2,430.90 RUB. LYG was equal to 0.7 and 2.3 years for the control and the study groups, respectively. The QALY measure for the control and study groups was 8.63 and 9.45, respectively. The weighted average total costs for the intended period of living was 498,745.00 RUB for the control group and 457,866.00 RUB for the study group. The control group CUR was 57,792.00 and 54,902.00 RUB/QALY without and with discounting, respectively, while in the study group they

  6. Linking metabolomics data to underlying metabolic regulation

    Directory of Open Access Journals (Sweden)

    Thomas eNägele

    2014-11-01

    Full Text Available The comprehensive experimental analysis of a metabolic constitution plays a central role in approaches of organismal systems biology.Quantifying the impact of a changing environment on the homeostasis of cellular metabolism has been the focus of numerous studies applying various metabolomics techniques. It has been proven that approaches which integrate different analytical techniques, e.g. LC-MS, GC-MS, CE-MS and H-NMR, can provide a comprehensive picture of a certain metabolic homeostasis. Identification of metabolic compounds and quantification of metabolite levels represent the groundwork for the analysis of regulatory strategies in cellular metabolism. This significantly promotes our current understanding of the molecular organization and regulation of cells, tissues and whole organisms.Nevertheless, it is demanding to elicit the pertinent information which is contained in metabolomics data sets.Based on the central dogma of molecular biology, metabolite levels and their fluctuations are the result of a directed flux of information from gene activation over transcription to translation and posttranslational modification.Hence, metabolomics data represent the summed output of a metabolic system comprising various levels of molecular organization.As a consequence, the inverse assignment of metabolomics data to underlying regulatory processes should yield information which-if deciphered correctly-provides comprehensive insight into a metabolic system.Yet, the deduction of regulatory principles is complex not only due to the high number of metabolic compounds, but also because of a high level of cellular compartmentalization and differentiation.Motivated by the question how metabolomics approaches can provide a representative view on regulatory biochemical processes, this article intends to present and discuss current metabolomics applications, strategies of data analysis and their limitations with respect to the interpretability in context of

  7. Modeling complex metabolic reactions, ecological systems, and financial and legal networks with MIANN models based on Markov-Wiener node descriptors.

    Science.gov (United States)

    Duardo-Sánchez, Aliuska; Munteanu, Cristian R; Riera-Fernández, Pablo; López-Díaz, Antonio; Pazos, Alejandro; González-Díaz, Humberto

    2014-01-27

    The use of numerical parameters in Complex Network analysis is expanding to new fields of application. At a molecular level, we can use them to describe the molecular structure of chemical entities, protein interactions, or metabolic networks. However, the applications are not restricted to the world of molecules and can be extended to the study of macroscopic nonliving systems, organisms, or even legal or social networks. On the other hand, the development of the field of Artificial Intelligence has led to the formulation of computational algorithms whose design is based on the structure and functioning of networks of biological neurons. These algorithms, called Artificial Neural Networks (ANNs), can be useful for the study of complex networks, since the numerical parameters that encode information of the network (for example centralities/node descriptors) can be used as inputs for the ANNs. The Wiener index (W) is a graph invariant widely used in chemoinformatics to quantify the molecular structure of drugs and to study complex networks. In this work, we explore for the first time the possibility of using Markov chains to calculate analogues of node distance numbers/W to describe complex networks from the point of view of their nodes. These parameters are called Markov-Wiener node descriptors of order k(th) (W(k)). Please, note that these descriptors are not related to Markov-Wiener stochastic processes. Here, we calculated the W(k)(i) values for a very high number of nodes (>100,000) in more than 100 different complex networks using the software MI-NODES. These networks were grouped according to the field of application. Molecular networks include the Metabolic Reaction Networks (MRNs) of 40 different organisms. In addition, we analyzed other biological and legal and social networks. These include the Interaction Web Database Biological Networks (IWDBNs), with 75 food webs or ecological systems and the Spanish Financial Law Network (SFLN). The calculated W

  8. Plasma metabolic profiling analysis of toxicity induced by brodifacoum using metabonomics coupled with multivariate data analysis.

    Science.gov (United States)

    Yan, Hui; Qiao, Zheng; Shen, Baohua; Xiang, Ping; Shen, Min

    2016-10-01

    Brodifacoum is one of the most widely used rodenticides for rodent control and eradication; however, human and animal poisoning due to primary and secondary exposure has been reported since its development. Although numerous studies have described brodifacoum induced toxicity, the precise mechanism still needs to be explored. Gas chromatography mass spectrometry (GC-MS) coupled with an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to characterize the metabolic profile of brodifacoum induced toxicity and discover potential biomarkers in rat plasma. The toxicity of brodifacoum was dose-dependent, and the high-dose group obviously manifested toxicity with subcutaneous hemorrhage. The blood brodifacoum concentration showed a positive relation to the ingestion dose in toxicological analysis. Significant changes of twenty-four metabolites were identified and considered as potential toxicity biomarkers, primarily involving glucose metabolism, lipid metabolism and amino acid metabolism associated with anticoagulant activity, nephrotoxicity and hepatic damage. MS-based metabonomics analysis in plasma samples is helpful to search for potential poisoning biomarkers and to understand the underlying mechanisms of brodifacoum induced toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Construction of phylogenetic trees by kernel-based comparative analysis of metabolic networks.

    Science.gov (United States)

    Oh, S June; Joung, Je-Gun; Chang, Jeong-Ho; Zhang, Byoung-Tak

    2006-06-06

    To infer the tree of life requires knowledge of the common characteristics of each species descended from a common ancestor as the measuring criteria and a method to calculate the distance between the resulting values of each measure. Conventional phylogenetic analysis based on genomic sequences provides information about the genetic relationships between different organisms. In contrast, comparative analysis of metabolic pathways in different organisms can yield insights into their functional relationships under different physiological conditions. However, evaluating the similarities or differences between metabolic networks is a computationally challenging problem, and systematic methods of doing this are desirable. Here we introduce a graph-kernel method for computing the similarity between metabolic networks in polynomial time, and use it to profile metabolic pathways and to construct phylogenetic trees. To compare the structures of metabolic networks in organisms, we adopted the exponential graph kernel, which is a kernel-based approach with a labeled graph that includes a label matrix and an adjacency matrix. To construct the phylogenetic trees, we used an unweighted pair-group method with arithmetic mean, i.e., a hierarchical clustering algorithm. We applied the kernel-based network profiling method in a comparative analysis of nine carbohydrate metabolic networks from 81 biological species encompassing Archaea, Eukaryota, and Eubacteria. The resulting phylogenetic hierarchies generally support the tripartite scheme of three domains rather than the two domains of prokaryotes and eukaryotes. By combining the kernel machines with metabolic information, the method infers the context of biosphere development that covers physiological events required for adaptation by genetic reconstruction. The results show that one may obtain a global view of the tree of life by comparing the metabolic pathway structures using meta-level information rather than sequence

  10. Construction of phylogenetic trees by kernel-based comparative analysis of metabolic networks

    Directory of Open Access Journals (Sweden)

    Chang Jeong-Ho

    2006-06-01

    Full Text Available Abstract Background To infer the tree of life requires knowledge of the common characteristics of each species descended from a common ancestor as the measuring criteria and a method to calculate the distance between the resulting values of each measure. Conventional phylogenetic analysis based on genomic sequences provides information about the genetic relationships between different organisms. In contrast, comparative analysis of metabolic pathways in different organisms can yield insights into their functional relationships under different physiological conditions. However, evaluating the similarities or differences between metabolic networks is a computationally challenging problem, and systematic methods of doing this are desirable. Here we introduce a graph-kernel method for computing the similarity between metabolic networks in polynomial time, and use it to profile metabolic pathways and to construct phylogenetic trees. Results To compare the structures of metabolic networks in organisms, we adopted the exponential graph kernel, which is a kernel-based approach with a labeled graph that includes a label matrix and an adjacency matrix. To construct the phylogenetic trees, we used an unweighted pair-group method with arithmetic mean, i.e., a hierarchical clustering algorithm. We applied the kernel-based network profiling method in a comparative analysis of nine carbohydrate metabolic networks from 81 biological species encompassing Archaea, Eukaryota, and Eubacteria. The resulting phylogenetic hierarchies generally support the tripartite scheme of three domains rather than the two domains of prokaryotes and eukaryotes. Conclusion By combining the kernel machines with metabolic information, the method infers the context of biosphere development that covers physiological events required for adaptation by genetic reconstruction. The results show that one may obtain a global view of the tree of life by comparing the metabolic pathway

  11. Evolution of metabolic network organization

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    Bonchev Danail

    2010-05-01

    Full Text Available Abstract Background Comparison of metabolic networks across species is a key to understanding how evolutionary pressures shape these networks. By selecting taxa representative of different lineages or lifestyles and using a comprehensive set of descriptors of the structure and complexity of their metabolic networks, one can highlight both qualitative and quantitative differences in the metabolic organization of species subject to distinct evolutionary paths or environmental constraints. Results We used a novel representation of metabolic networks, termed network of interacting pathways or NIP, to focus on the modular, high-level organization of the metabolic capabilities of the cell. Using machine learning techniques we identified the most relevant aspects of cellular organization that change under evolutionary pressures. We considered the transitions from prokarya to eukarya (with a focus on the transitions among the archaea, bacteria and eukarya, from unicellular to multicellular eukarya, from free living to host-associated bacteria, from anaerobic to aerobic, as well as the acquisition of cell motility or growth in an environment of various levels of salinity or temperature. Intuitively, we expect organisms with more complex lifestyles to have more complex and robust metabolic networks. Here we demonstrate for the first time that such organisms are not only characterized by larger, denser networks of metabolic pathways but also have more efficiently organized cross communications, as revealed by subtle changes in network topology. These changes are unevenly distributed among metabolic pathways, with specific categories of pathways being promoted to more central locations as an answer to environmental constraints. Conclusions Combining methods from graph theory and machine learning, we have shown here that evolutionary pressures not only affects gene and protein sequences, but also specific details of the complex wiring of functional modules

  12. Genome-centric resolution of microbial diversity, metabolism and interactions in anaerobic digestion.

    Science.gov (United States)

    Vanwonterghem, Inka; Jensen, Paul D; Rabaey, Korneel; Tyson, Gene W

    2016-09-01

    Our understanding of the complex interconnected processes performed by microbial communities is hindered by our inability to culture the vast majority of microorganisms. Metagenomics provides a way to bypass this cultivation bottleneck and recent advances in this field now allow us to recover a growing number of genomes representing previously uncultured populations from increasingly complex environments. In this study, a temporal genome-centric metagenomic analysis was performed of lab-scale anaerobic digesters that host complex microbial communities fulfilling a series of interlinked metabolic processes to enable the conversion of cellulose to methane. In total, 101 population genomes that were moderate to near-complete were recovered based primarily on differential coverage binning. These populations span 19 phyla, represent mostly novel species and expand the genomic coverage of several rare phyla. Classification into functional guilds based on their metabolic potential revealed metabolic networks with a high level of functional redundancy as well as niche specialization, and allowed us to identify potential roles such as hydrolytic specialists for several rare, uncultured populations. Genome-centric analyses of complex microbial communities across diverse environments provide the key to understanding the phylogenetic and metabolic diversity of these interactive communities. © 2016 Society for Applied Microbiology and John Wiley & Sons Ltd.

  13. Communication Analysis of Information Complexes.

    Science.gov (United States)

    Malik, M. F.

    Communication analysis is a tool for perceptual assessment of existing or projected information complexes, i.e., an established reality perceived by one or many humans. An information complex could be of a physical nature, such as a building, landscape, city street; or of a pure informational nature, such as a film, television program,…

  14. Systematic analysis of stability patterns in plant primary metabolism.

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    Dorothee Girbig

    Full Text Available Metabolic networks are characterized by complex interactions and regulatory mechanisms between many individual components. These interactions determine whether a steady state is stable to perturbations. Structural kinetic modeling (SKM is a framework to analyze the stability of metabolic steady states that allows the study of the system Jacobian without requiring detailed knowledge about individual rate equations. Stability criteria can be derived by generating a large number of structural kinetic models (SK-models with randomly sampled parameter sets and evaluating the resulting Jacobian matrices. Until now, SKM experiments applied univariate tests to detect the network components with the largest influence on stability. In this work, we present an extended SKM approach relying on supervised machine learning to detect patterns of enzyme-metabolite interactions that act together in an orchestrated manner to ensure stability. We demonstrate its application on a detailed SK-model of the Calvin-Benson cycle and connected pathways. The identified stability patterns are highly complex reflecting that changes in dynamic properties depend on concerted interactions between several network components. In total, we find more patterns that reliably ensure stability than patterns ensuring instability. This shows that the design of this system is strongly targeted towards maintaining stability. We also investigate the effect of allosteric regulators revealing that the tendency to stability is significantly increased by including experimentally determined regulatory mechanisms that have not yet been integrated into existing kinetic models.

  15. Complex analysis conformal inequalities and the Bieberbach conjecture

    CERN Document Server

    Kythe, Prem K

    2015-01-01

    Complex Analysis: Conformal Inequalities and the Bieberbach Conjecture discusses the mathematical analysis created around the Bieberbach conjecture, which is responsible for the development of many beautiful aspects of complex analysis, especially in the geometric-function theory of univalent functions. Assuming basic knowledge of complex analysis and differential equations, the book is suitable for graduate students engaged in analytical research on the topics and researchers working on related areas of complex analysis in one or more complex variables. The author first reviews the theory of analytic functions, univalent functions, and conformal mapping before covering various theorems related to the area principle and discussing Löwner theory. He then presents Schiffer’s variation method, the bounds for the fourth and higher-order coefficients, various subclasses of univalent functions, generalized convexity and the class of a-convex functions, and numerical estimates of the coefficient problem. The boo...

  16. Dynamic metabolic flux analysis using B-splines to study the effects of temperature shift on CHO cell metabolism

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    Verónica S. Martínez

    2015-12-01

    Full Text Available Metabolic flux analysis (MFA is widely used to estimate intracellular fluxes. Conventional MFA, however, is limited to continuous cultures and the mid-exponential growth phase of batch cultures. Dynamic MFA (DMFA has emerged to characterize time-resolved metabolic fluxes for the entire culture period. Here, the linear DMFA approach was extended using B-spline fitting (B-DMFA to estimate mass balanced fluxes. Smoother fits were achieved using reduced number of knots and parameters. Additionally, computation time was greatly reduced using a new heuristic algorithm for knot placement. B-DMFA revealed that Chinese hamster ovary cells shifted from 37 °C to 32 °C maintained a constant IgG volume-specific productivity, whereas the productivity for the controls peaked during mid-exponential growth phase and declined afterward. The observed 42% increase in product titer at 32 °C was explained by a prolonged cell growth with high cell viability, a larger cell volume and a more stable volume-specific productivity. Keywords: Dynamic, Metabolism, Flux analysis, CHO cells, Temperature shift, B-spline curve fitting

  17. Effect of isologous and autologous insulin antibodies on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lou/M rats

    International Nuclear Information System (INIS)

    Arquilla, E.R.; McDougall, B.R.; Stenger, D.P.

    1989-01-01

    The in vivo bioavailability, distribution, and metabolic fate of 125I-labeled insulin complexed to isologous and autologous antibodies were studied in inbred Lou/M rats. There was an impaired bioavailability of the 125I-insulin bound to the isologous and autologous antibodies. Very little of the 125I-insulin in these immune complexes could bind to insulin receptors on hepatocytes or renal tubular cells and be degraded, because the amounts of 125I from degraded 125I-insulin in the blood or secreted into the stomach were markedly attenuated in both cases for at least 30 min after injection. There was a simultaneous accumulation of 125I-insulin immune complexes in the liver and the kidneys of Lou/M rats injected with 125I-insulin complexed with isologous antibodies or when insulin-immunized Lou/M rats were injected with 125I-insulin during the same interval. The impaired bioavailability of immune-complexed insulin and altered distribution of radioactivity due to the accumulation of immune complexes in the liver and kidney were also observed in previous experiments in which Lewis rats were injected with xenogenic guinea pig and homologous insulin antibodies. These observations are therefore submitted as evidence that the Lou/M rat is a valid model in which to study the bioavailability of insulin immune complexed to isologous, homologous, and xenogenic antibodies and the metabolic fate of the respective insulin-antibody immune complexes

  18. Common cause failure analysis methodology for complex systems

    International Nuclear Information System (INIS)

    Wagner, D.P.; Cate, C.L.; Fussell, J.B.

    1977-01-01

    Common cause failure analysis, also called common mode failure analysis, is an integral part of a complex system reliability analysis. This paper extends existing methods of computer aided common cause failure analysis by allowing analysis of the complex systems often encountered in practice. The methods presented here aid in identifying potential common cause failures and also address quantitative common cause failure analysis

  19. Metaproteome analysis to determine the metabolically active part of a thermophilic microbial community producing biogas from agricultural biomass.

    Science.gov (United States)

    Hanreich, Angelika; Heyer, Robert; Benndorf, Dirk; Rapp, Erdmann; Pioch, Markus; Reichl, Udo; Klocke, Michael

    2012-07-01

    Complex consortia of microorganisms are responsible for biogas production. A lot of information about the taxonomic structure and enzymatic potential of such communities has been collected by a variety of gene-based approaches, yet little is known about which of all the assumable metabolic pathways are active throughout the process of biogas formation. To tackle this problem, we established a protocol for the metaproteomic analysis of samples taken from biogas reactors fed with agricultural biomass. In contrast to previous studies where an anaerobic digester was fed with synthetic wastewater, the complex matrix in this study required the extraction of proteins with liquid phenol and the application of paper bridge loading for 2-dimensional gel electrophoresis. Proteins were subjected to nanoHPLC (high-performance liquid chromatography) coupled to tandem mass spectrometry for characterization. Several housekeeping proteins as well as methanogenesis-related enzymes were identified by a MASCOT search and de novo sequencing, which proved the feasibility of our approach. The establishment of such an approach is the basis for further metaproteomic studies of biogas-producing communities. In particular, the apparent status of metabolic activities within the communities can be monitored. The knowledge collected from such experiments could lead to further improvements of biogas production.

  20. INTEGRATED QUANTITATIVE ASSESSMENT OF CHANGES IN NEURO-ENDOCRINE-IMMUNE COMPLEX AND METABOLISM IN RATS EXPOSED TO ACUTE COLD-IMMOBILIZATION STRESS

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    Sydoruk O Sydoruk

    2016-09-01

        Abstracts Background. It is known that the reaction of the neuroendocrine-immune complex to acute and chronic stress are different. It is also known about sex differences in stress reactions. Previously we have been carry out integrated quantitative estimation of neuroendocrine and immune responses to chronic restraint stress at male rats. The purpose of this study - to carry out integrated quantitative estimation of neuroendocrine, immune and metabolic responses to acute stress at male and female rats. Material and research methods. The experiment is at 58 (28 male and 30 female white rats Wistar line weighing 170-280 g (Mean=220 g; SD=28 g. The day after acute (water immersion restraint stress determined HRV, endocrine, immune and metabolic parameters as well as gastric mucosa injuries and comparing them with parameters of intact animals. Results. Acute cold-immobilization stress caused moderate injuries the stomach mucosa as erosions and ulcers. Among the metabolic parameters revealed increased activity Acid Phosphatase, Asparagine and Alanine Aminotranspherase as well as Creatinephosphokinase. It was also found to reduce plasma Testosterone as well as serum Potassium and Phosphate probably due to increased Parathyrine and Mineralocorticoid activity and Sympathotonic shift of sympatho-vagal balance. Integrated quantitative measure manifestations of Acute Stress as mean of modules of Z-Scores makes for 10 metabolic parameters 0,75±0,10 σ and for 8 neuro-endocrine parameters 0,40±0,07 σ. Among immune parameters some proved resistant to acute stress factors, while 10 significant suppressed and 12 activated. Integrated quantitative measure poststressory changes makes 0,73±0,08 σ. Found significant differences integrated status intact males and females, whereas after stress differences are insignificant. Conclusion. The approach to integrated quantitative assessment of neuroendocrine-immune complex and metabolism may be useful for testing the

  1. Analysis of Subclinical Hyperthyroidism Influence on Parameters of Bone Metabolism

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    I.V. Pankiv

    2016-03-01

    Full Text Available State of subclinical hypothyroidism can be considered as the optimal model for assessing the significance of thyroid stimulating hormone (TSH for bone tissue in clinical practice. Objective: to make a comparative analysis of the impact of subclinical hyperthyroidism of various origins on the performance of bone mineral density (BMD and bone metabolism parameters. Materials and methods. The study in an outpatient setting included 112 women with a diagnosis of subclinical hyperthyroidism and duration of menopause for at least 5 years. Among the examinees, endogenous subclinical hyperthyroidism has been detected in 78 women (group I, exogenous subclinical hyperthyroidism on the background of suppressive levothyroxine therapy (group II — in 34. The control group (group III included 20 women without thyroid dysfunction. Results. The study first conducted a comparative analysis of bone metabolism, BMD indicators, as well as parameters of phosphorus and calcium, blood lipids in women with subclinical hyperthyroidism of various origins. A positive correlation between markers of bone metabolism and free triiodothyronine (fT3 as hormones necessary for the development of the skeleton and to maintain its homeostasis indicates a physiological effect of parathyroid hormone and fT3 on bone tissue. It is shown that the bone metabolism and BMD depend not only on the content of TSH, but also on the causes of subclinical hyperthyroidism.Conclusions. In postmenopausal women with endogenous subclinical hyperthyroidism, there is a significant decline in BMD indices, more pronounced in the bones with the cortical structure. A negative correlation between markers of bone metabolism and TSH has been observed among all patients included in the study.

  2. Metabolic pathways for the whole community.

    Science.gov (United States)

    Hanson, Niels W; Konwar, Kishori M; Hawley, Alyse K; Altman, Tomer; Karp, Peter D; Hallam, Steven J

    2014-07-22

    A convergence of high-throughput sequencing and computational power is transforming biology into information science. Despite these technological advances, converting bits and bytes of sequence information into meaningful insights remains a challenging enterprise. Biological systems operate on multiple hierarchical levels from genomes to biomes. Holistic understanding of biological systems requires agile software tools that permit comparative analyses across multiple information levels (DNA, RNA, protein, and metabolites) to identify emergent properties, diagnose system states, or predict responses to environmental change. Here we adopt the MetaPathways annotation and analysis pipeline and Pathway Tools to construct environmental pathway/genome databases (ePGDBs) that describe microbial community metabolism using MetaCyc, a highly curated database of metabolic pathways and components covering all domains of life. We evaluate Pathway Tools' performance on three datasets with different complexity and coding potential, including simulated metagenomes, a symbiotic system, and the Hawaii Ocean Time-series. We define accuracy and sensitivity relationships between read length, coverage and pathway recovery and evaluate the impact of taxonomic pruning on ePGDB construction and interpretation. Resulting ePGDBs provide interactive metabolic maps, predict emergent metabolic pathways associated with biosynthesis and energy production and differentiate between genomic potential and phenotypic expression across defined environmental gradients. This multi-tiered analysis provides the user community with specific operating guidelines, performance metrics and prediction hazards for more reliable ePGDB construction and interpretation. Moreover, it demonstrates the power of Pathway Tools in predicting metabolic interactions in natural and engineered ecosystems.

  3. From real to complex analysis

    CERN Document Server

    Dyer, R H

    2014-01-01

    The purpose of this book is to provide an integrated course in real and complex analysis for those who have already taken a preliminary course in real analysis. It particularly emphasises the interplay between analysis and topology. Beginning with the theory of the Riemann integral (and its improper extension) on the real line, the fundamentals of metric spaces are then developed, with special attention being paid to connectedness, simple connectedness and various forms of homotopy. The final chapter develops the theory of complex analysis, in which emphasis is placed on the argument, the winding number, and a general (homology) version of Cauchy's theorem which is proved using the approach due to Dixon. Special features are the inclusion of proofs of Montel's theorem, the Riemann mapping theorem and the Jordan curve theorem that arise naturally from the earlier development. Extensive exercises are included in each of the chapters, detailed solutions of the majority of which are given at the end. From Real to...

  4. Association of sedentary behaviour with metabolic syndrome: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Charlotte L Edwardson

    Full Text Available In recent years there has been a growing interest in the relationship between sedentary behaviour (sitting and health outcomes. Only recently have there been studies assessing the association between time spent in sedentary behaviour and the metabolic syndrome. The aim of this study is to quantify the association between sedentary behaviour and the metabolic syndrome in adults using meta-analysis.Medline, Embase and the Cochrane Library were searched using medical subject headings and key words related to sedentary behaviours and the metabolic syndrome. Reference lists of relevant articles and personal databases were hand searched. Inclusion criteria were: (1 cross sectional or prospective design; (2 include adults ≥ 18 years of age; (3 self-reported or objectively measured sedentary time; and (4 an outcome measure of metabolic syndrome. Odds Ratio (OR and 95% confidence intervals for metabolic syndrome comparing the highest level of sedentary behaviour to the lowest were extracted for each study. Data were pooled using random effects models to take into account heterogeneity between studies. Ten cross-sectional studies (n = 21393 participants, one high, four moderate and five poor quality, were identified. Greater time spent sedentary increased the odds of metabolic syndrome by 73% (OR 1.73, 95% CI 1.55-1.94, p<0.0001. There were no differences for subgroups of sex, sedentary behaviour measure, metabolic syndrome definition, study quality or country income. There was no evidence of statistical heterogeneity (I(2 = 0.0%, p = 0.61 or publication bias (Eggers test t = 1.05, p = 0.32.People who spend higher amounts of time in sedentary behaviours have greater odds of having metabolic syndrome. Reducing sedentary behaviours is potentially important for the prevention of metabolic syndrome.

  5. Isotopically nonstationary metabolic flux analysis (INST-MFA) of photosynthesis and photorespiration in plants

    Science.gov (United States)

    Photorespiration is a central component of photosynthesis; however to better understand its role it should be viewed in the context of an integrated metabolic network rather than a series of individual reactions that operate independently. Isotopically nonstationary 13C metabolic flux analysis (INST...

  6. Plasma metabolic profiling analysis of nephrotoxicity induced by acyclovir using metabonomics coupled with multivariate data analysis.

    Science.gov (United States)

    Zhang, Xiuxiu; Li, Yubo; Zhou, Huifang; Fan, Simiao; Zhang, Zhenzhu; Wang, Lei; Zhang, Yanjun

    2014-08-01

    Acyclovir (ACV) is an antiviral agent. However, its use is limited by adverse side effect, particularly by its nephrotoxicity. Metabonomics technology can provide essential information on the metabolic profiles of biofluids and organs upon drug administration. Therefore, in this study, mass spectrometry-based metabonomics coupled with multivariate data analysis was used to identify the plasma metabolites and metabolic pathways related to nephrotoxicity caused by intraperitoneal injection of low (50mg/kg) and high (100mg/kg) doses of acyclovir. Sixteen biomarkers were identified by metabonomics and nephrotoxicity results revealed the dose-dependent effect of acyclovir on kidney tissues. The present study showed that the top four metabolic pathways interrupted by acyclovir included the metabolisms of arachidonic acid, tryptophan, arginine and proline, and glycerophospholipid. This research proves the established metabonomic approach can provide information on changes in metabolites and metabolic pathways, which can be applied to in-depth research on the mechanism of acyclovir-induced kidney injury. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Metabolic-flux analysis of hydrogen production pathway in Citrobacter amalonaticus Y19

    Energy Technology Data Exchange (ETDEWEB)

    Oh, You-Kwan; Kim, Mi-Sun [Bioenergy Research Center, Korea Institute of Energy Research, Daejeon 305-343 (Korea); Kim, Heung-Joo; Park, Sunghoon [Department of Chemical and Biochemical Engineering and Institute for Environmental Technology and Industry, Pusan National University, Busan 609-735 (Korea); Ryu, Dewey D.Y. [Biochemical Engineering Program, Department of Chemical Engineering and Material Science, University of California, Davis, CA 95616 (United States)

    2008-03-15

    For the newly isolated chemoheterotrophic bacterium Citrobacter amalonaticus Y19, anaerobic glucose metabolism and hydrogen (H{sub 2}) production pathway were studied using batch cultivation and an in silico metabolic-flux analysis. Batch cultivation was conducted under varying initial glucose concentration between 1.5 and 9.5 g/L with quantitative measurement of major metabolites to obtain accurate carbon material balance. The metabolic flux of Y19 was analyzed using a metabolic-pathway model which was constructed from 81 biochemical reactions. The linear optimization program MetaFluxNet was employed for the analysis. When the specific growth rate of cells was chosen as an objective function, the model described the batch culture characteristics of Ci. amalonaticus Y19 reasonably well. When the specific H{sub 2} production rate was selected as an objective function, on the other hand, the achievable maximal H{sub 2} production yield (8.7molH{sub 2}/mol glucose) and the metabolic pathway enabling the high H{sub 2} yield were identified. The pathway involved non-native NAD(P)-linked hydrogenase and H{sub 2} production from NAD(P)H which were supplied at a high rate from glucose degradation through the pentose phosphate pathway. (author)

  8. Analysis and control of complex dynamical systems robust bifurcation, dynamic attractors, and network complexity

    CERN Document Server

    Imura, Jun-ichi; Ueta, Tetsushi

    2015-01-01

    This book is the first to report on theoretical breakthroughs on control of complex dynamical systems developed by collaborative researchers in the two fields of dynamical systems theory and control theory. As well, its basic point of view is of three kinds of complexity: bifurcation phenomena subject to model uncertainty, complex behavior including periodic/quasi-periodic orbits as well as chaotic orbits, and network complexity emerging from dynamical interactions between subsystems. Analysis and Control of Complex Dynamical Systems offers a valuable resource for mathematicians, physicists, and biophysicists, as well as for researchers in nonlinear science and control engineering, allowing them to develop a better fundamental understanding of the analysis and control synthesis of such complex systems.

  9. Dithiobiuret metabolism in the rat

    International Nuclear Information System (INIS)

    Williams, K.D.; Porter, W.R.; Peterson, R.E.

    1982-01-01

    Our main objective was to describe the metabolism of dithiobiuret (DTB) in the adult, male rat. Based on the thin-layer chromatographic analysis of urine from animals treated with [ 14 C] or [ 35 S] labeled DTB, two pathways for metabolism are proposed. One pathway is reversible and involves the oxidation of DTB to thiuret and the reduction of thiuret back to DTB. The other pathway consists of the desulfurization of DTB to monothiobiuret. The liver appears to desulfurate DTB because DTB-derived [35S] was eliminated from the liver more rapidly than [ 14 C]. The liver was the only tissue where the elimination kinetics of [ 35 S] and [ 14 C] DTB were different. DTB-derived radioactivity in urine that co-chromatographed with DTB, monothiobiuret, thiuret and sulfate was quantitated along with that of three uncharacterized metabolites. The presence of these unknown metabolites suggests that DTB metabolism is complex. The present study is the first description of the metabolic fate of DTB in the rat and serves as a starting point for determining whether DTB neurotoxicity is caused by the parent compound or a metabolite

  10. Dynamics of a lipid and metabolic imbalance on the background of a complex programs of rehabilitation at metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Kotenko К.V.

    2013-12-01

    Full Text Available The study aimed the development and assessment of features of corrective action of a medical complex on a lipid imbalance at patients with obesity. Material and methods. For an assessment of features of corrective action of a medical complex on a lipid imbalance at patients with obesity in research I was 50 male patients with obesity and frustration of the reproductive sphere aged from 24 to 68 years were included, middle age was 38,5±6,1 years and 7 healthy persons, men of comparable age without any pathological states, results of which all researches were accepted to values of norm. To all patients included in research, except all-clinical inspection calculation of an index of body weight and the relation of a circle of a waist to a circle of hips, measurement of arterial pressure were applied questioning concerning food and food behavior, anthropometry (growth the body weight, a circle of a waist and hips. Besides all patients conducted laboratory methods the researches including definition of atherogenic fractions of lipids (the general cholesterol, triglycerides, LPNPand LPVP. Researches were conducted before treatment and after a course of treatment. Results. The effective complex program for restoration of reproductive function at patients with obesity is developed. Conclusion. Application of the developed comprehensive program more than its separate components caused the expressed reduction of body weight, mainly due to reduction of fatty tissue and manifestations of visceral obesity in patients with obesity and violation of reproductive function, including due to elimination of metabolic imbalance.

  11. Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.

    Directory of Open Access Journals (Sweden)

    Christine T Ferrara

    2008-03-01

    Full Text Available Although numerous quantitative trait loci (QTL influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptin(ob/ob and the diabetes-susceptible BTBR leptin(ob/ob mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines. We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes.

  12. Reconstruction and analysis of a genome-scale metabolic model for Scheffersomyces stipitis

    Directory of Open Access Journals (Sweden)

    Balagurunathan Balaji

    2012-02-01

    Full Text Available Abstract Background Fermentation of xylose, the major component in hemicellulose, is essential for economic conversion of lignocellulosic biomass to fuels and chemicals. The yeast Scheffersomyces stipitis (formerly known as Pichia stipitis has the highest known native capacity for xylose fermentation and possesses several genes for lignocellulose bioconversion in its genome. Understanding the metabolism of this yeast at a global scale, by reconstructing the genome scale metabolic model, is essential for manipulating its metabolic capabilities and for successful transfer of its capabilities to other industrial microbes. Results We present a genome-scale metabolic model for Scheffersomyces stipitis, a native xylose utilizing yeast. The model was reconstructed based on genome sequence annotation, detailed experimental investigation and known yeast physiology. Macromolecular composition of Scheffersomyces stipitis biomass was estimated experimentally and its ability to grow on different carbon, nitrogen, sulphur and phosphorus sources was determined by phenotype microarrays. The compartmentalized model, developed based on an iterative procedure, accounted for 814 genes, 1371 reactions, and 971 metabolites. In silico computed growth rates were compared with high-throughput phenotyping data and the model could predict the qualitative outcomes in 74% of substrates investigated. Model simulations were used to identify the biosynthetic requirements for anaerobic growth of Scheffersomyces stipitis on glucose and the results were validated with published literature. The bottlenecks in Scheffersomyces stipitis metabolic network for xylose uptake and nucleotide cofactor recycling were identified by in silico flux variability analysis. The scope of the model in enhancing the mechanistic understanding of microbial metabolism is demonstrated by identifying a mechanism for mitochondrial respiration and oxidative phosphorylation. Conclusion The genome

  13. Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

    Science.gov (United States)

    Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

    2017-05-08

    Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS. Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and

  14. Effects of dietary supplementation of arginine-silicate-inositol complex on absorption and metabolism of calcium of laying hens.

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    Kazim Sahin

    Full Text Available The effects of supplementation of arginine-silicate-inositol complex (ASI; 49.5-8.2-25 g/kg, respectively to laying hens were investigated with respect to eggshell quality, calcium (Ca balance, and expression of duodenal proteins related to Ca metabolism (calbindin and tight junction proteins. A total of 360 laying hens, 25 weeks old, were divided into 3 groups consisting of 6 replicate of cages, 20 birds per cage. The groups were fed a basal diet and the basal diet supplemented with 500 or 1000 mg ASI complex per kilogram for 90 days. Data were analyzed by ANCOVA using data during the first week of the adaptation period as covariates. As the ASI complex supplementation level increased, there were increases in feed intake (P < 0.0001, egg production (P < 0.001, egg weight (P < 0.0001 and eggshell weight (P < 0.001 weight, and shell thickness (P < 0.001 and decreases in feed conversion ratio and cracked egg percentage (P < 0.0001 for both. Concentrations of serum osteocalcin (P < 0.0001, vitamin D (P < 0.0001, calcium (P < 0.001, phosphorus (P < 0.001, and alkaline phosphatase (P < 0.008 as well as amounts of calcium retention (P < 0.0001 and eggshell calcium deposition (P < 0.001, and Ca balance (P < 0.0001 increased, whereas amount of calcium excretion (P < 0.001 decreased linearly in a dose-dependent manner. The ASI complex supplementation increased expressions of calcium transporters (calbindin-D28k, N sodium-calcium exchanger, plasma membrane calcium ATPase, and vitamin D receptor and tight junction proteins (zonula occludens-1 and occludin in the duodenum in a linear fashion (P < 0.0001 for all. In conclusion, provision of dietary ASI complex to laying hens during the peak laying period improved eggshell quality through improving calcium utilization as reflected by upregulation of genes related to the calcium metabolism. Further studies are needed to elucidate the contribution of each of the ASI complex ingredients.

  15. Energy metabolism in Desulfovibrio vulgaris Hildenborough: insights from transcriptome analysis

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Patricia M.; He, Qiang; Valente, Filipa M.A.; Xavier, Antonio V.; Zhou, Jizhong; Pereira, Ines A.C.; Louro, Ricardo O.

    2007-11-01

    Sulphate-reducing bacteria are important players in the global sulphur and carbon cycles, with considerable economical and ecological impact. However, the process of sulphate respiration is still incompletely understood. Several mechanisms of energy conservation have been proposed, but it is unclear how the different strategies contribute to the overall process. In order to obtain a deeper insight into the energy metabolism of sulphate-reducers whole-genome microarrays were used to compare the transcriptional response of Desulfovibrio vulgaris Hildenborough grown with hydrogen/sulphate, pyruvate/sulphate, pyruvate with limiting sulphate, and lactate/thiosulphate, relative to growth in lactate/sulphate. Growth with hydrogen/sulphate showed the largest number of differentially expressed genes and the largest changes in transcript levels. In this condition the most up-regulated energy metabolism genes were those coding for the periplasmic [NiFeSe]hydrogenase, followed by the Ech hydrogenase. The results also provide evidence for the involvement of formate cycling and the recently proposed ethanol pathway during growth in hydrogen. The pathway involving CO cycling is relevant during growth on lactate and pyruvate, but not during growth in hydrogen as the most down-regulated genes were those coding for the CO-induced hydrogenase. Growth on lactate/thiosulphate reveals a down-regulation of several energymetabolism genes similar to what was observed in the presence of nitrite. This study identifies the role of several proteins involved in the energy metabolism of D. vulgaris and highlights several novel genes related to this process, revealing a more complex bioenergetic metabolism than previously considered.

  16. Metabolic flux analysis of Cyanothece sp. ATCC 51142 under mixotrophic conditions.

    Science.gov (United States)

    Alagesan, Swathi; Gaudana, Sandeep B; Sinha, Avinash; Wangikar, Pramod P

    2013-11-01

    Cyanobacteria are a group of photosynthetic prokaryotes capable of utilizing solar energy to fix atmospheric carbon dioxide to biomass. Despite several "proof of principle" studies, low product yield is an impediment in commercialization of cyanobacteria-derived biofuels. Estimation of intracellular reaction rates by (13)C metabolic flux analysis ((13)C-MFA) would be a step toward enhancing biofuel yield via metabolic engineering. We report (13)C-MFA for Cyanothece sp. ATCC 51142, a unicellular nitrogen-fixing cyanobacterium, known for enhanced hydrogen yield under mixotrophic conditions. Rates of reactions in the central carbon metabolism under nitrogen-fixing and -non-fixing conditions were estimated by monitoring the competitive incorporation of (12)C and (13)C from unlabeled CO2 and uniformly labeled glycerol, respectively, into terminal metabolites such as amino acids. The observed labeling patterns suggest mixotrophic growth under both the conditions, with a larger fraction of unlabeled carbon in nitrate-sufficient cultures asserting a greater contribution of carbon fixation by photosynthesis and an anaplerotic pathway. Indeed, flux analysis complements the higher growth observed under nitrate-sufficient conditions. On the other hand, the flux through the oxidative pentose phosphate pathway and tricarboxylic acid cycle was greater in nitrate-deficient conditions, possibly to supply the precursors and reducing equivalents needed for nitrogen fixation. In addition, an enhanced flux through fructose-6-phosphate phosphoketolase possibly suggests the organism's preferred mode under nitrogen-fixing conditions. The (13)C-MFA results complement the reported predictions by flux balance analysis and provide quantitative insight into the organism's distinct metabolic features under nitrogen-fixing and -non-fixing conditions.

  17. Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

    Science.gov (United States)

    2014-01-01

    Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

  18. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research.

    Science.gov (United States)

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  19. Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.

    Science.gov (United States)

    Jia, Yuzhi; Viswakarma, Navin; Reddy, Janardan K

    2014-01-01

    Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic

  20. Visualization and Analysis of Complex Covert Networks

    DEFF Research Database (Denmark)

    Memon, Bisharat

    systems that are covert and hence inherently complex. My Ph.D. is positioned within the wider framework of CrimeFighter project. The framework envisions a number of key knowledge management processes that are involved in the workflow, and the toolbox provides supporting tools to assist human end......This report discusses and summarize the results of my work so far in relation to my Ph.D. project entitled "Visualization and Analysis of Complex Covert Networks". The focus of my research is primarily on development of methods and supporting tools for visualization and analysis of networked......-users (intelligence analysts) in harvesting, filtering, storing, managing, structuring, mining, analyzing, interpreting, and visualizing data about offensive networks. The methods and tools proposed and discussed in this work can also be applied to analysis of more generic complex networks....

  1. Network analysis of metabolic enzyme evolution in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Kraulis Per

    2004-02-01

    Full Text Available Abstract Background The two most common models for the evolution of metabolism are the patchwork evolution model, where enzymes are thought to diverge from broad to narrow substrate specificity, and the retrograde evolution model, according to which enzymes evolve in response to substrate depletion. Analysis of the distribution of homologous enzyme pairs in the metabolic network can shed light on the respective importance of the two models. We here investigate the evolution of the metabolism in E. coli viewed as a single network using EcoCyc. Results Sequence comparison between all enzyme pairs was performed and the minimal path length (MPL between all enzyme pairs was determined. We find a strong over-representation of homologous enzymes at MPL 1. We show that the functionally similar and functionally undetermined enzyme pairs are responsible for most of the over-representation of homologous enzyme pairs at MPL 1. Conclusions The retrograde evolution model predicts that homologous enzymes pairs are at short metabolic distances from each other. In general agreement with previous studies we find that homologous enzymes occur close to each other in the network more often than expected by chance, which lends some support to the retrograde evolution model. However, we show that the homologous enzyme pairs which may have evolved through retrograde evolution, namely the pairs that are functionally dissimilar, show a weaker over-representation at MPL 1 than the functionally similar enzyme pairs. Our study indicates that, while the retrograde evolution model may have played a small part, the patchwork evolution model is the predominant process of metabolic enzyme evolution.

  2. Synergizing metabolic flux analysis and nucleotide sugar metabolism to understand the control of glycosylation of recombinant protein in CHO cells

    LENUS (Irish Health Repository)

    Burleigh, Susan C

    2011-10-18

    Abstract Background The glycosylation of recombinant proteins can be altered by a range of parameters including cellular metabolism, metabolic flux and the efficiency of the glycosylation process. We present an experimental set-up that allows determination of these key processes associated with the control of N-linked glycosylation of recombinant proteins. Results Chinese hamster ovary cells (CHO) were cultivated in shake flasks at 0 mM glutamine and displayed a reduced growth rate, glucose metabolism and a slower decrease in pH, when compared to other glutamine-supplemented cultures. The N-linked glycosylation of recombinant human chorionic gonadotrophin (HCG) was also altered under these conditions; the sialylation, fucosylation and antennarity decreased, while the proportion of neutral structures increased. A continuous culture set-up was subsequently used to understand the control of HCG glycosylation in the presence of varied glutamine concentrations; when glycolytic flux was reduced in the absence of glutamine, the glycosylation changes that were observed in shake flask culture were similarly detected. The intracellular content of UDP-GlcNAc was also reduced, which correlated with a decrease in sialylation and antennarity of the N-linked glycans attached to HCG. Conclusions The use of metabolic flux analysis illustrated a case of steady state multiplicity, where use of the same operating conditions at each steady state resulted in altered flux through glycolysis and the TCA cycle. This study clearly demonstrated that the control of glycoprotein microheterogeneity may be examined by use of a continuous culture system, metabolic flux analysis and assay of intracellular nucleotides. This system advances our knowledge of the relationship between metabolic flux and the glycosylation of biotherapeutics in CHO cells and will be of benefit to the bioprocessing industry.

  3. Functional complexity of the axonal growth cone: a proteomic analysis.

    Directory of Open Access Journals (Sweden)

    Adriana Estrada-Bernal

    Full Text Available The growth cone, the tip of the emerging neurite, plays a crucial role in establishing the wiring of the developing nervous system. We performed an extensive proteomic analysis of axonal growth cones isolated from the brains of fetal Sprague-Dawley rats. Approximately 2000 proteins were identified at ≥ 99% confidence level. Using informatics, including functional annotation cluster and KEGG pathway analysis, we found great diversity of proteins involved in axonal pathfinding, cytoskeletal remodeling, vesicular traffic and carbohydrate metabolism, as expected. We also found a large and complex array of proteins involved in translation, protein folding, posttranslational processing, and proteasome/ubiquitination-dependent degradation. Immunofluorescence studies performed on hippocampal neurons in culture confirmed the presence in the axonal growth cone of proteins representative of these processes. These analyses also provide evidence for rough endoplasmic reticulum and reveal a reticular structure equipped with Golgi-like functions in the axonal growth cone. Furthermore, Western blot revealed the growth cone enrichment, relative to fetal brain homogenate, of some of the proteins involved in protein synthesis, folding and catabolism. Our study provides a resource for further research and amplifies the relatively recently developed concept that the axonal growth cone is equipped with proteins capable of performing a highly diverse range of functions.

  4. Phylogenomic analysis of secondary metabolism genes sheds light on their evolution in Aspergilli

    DEFF Research Database (Denmark)

    Theobald, Sebastian; Vesth, Tammi Camilla; Rasmussen, Jane Lind Nybo

    .Natural products are encoded by genes located in close proximity, called secondary metabolic gene clusters, which makes them interesting targets for genomic analysis. We use a modified version of the Secondary Metabolite Unique Regions Finder (SMURF) algorithm, combined with InterPro annotations to create...... approximate maximum likelihood trees of conserved domains from secondary metabolic genes across 56 species, giving insights into the secondary metabolism gene diversity and evolution.In this study we can describe the evolution of non ribosomal peptide synthetases (NRPS), polyketide synthases (PKS) and hybrids.......In the aspMine project, we are sequencing and analyzing over 300 species of Aspergilli, agroup of filamentous fungi rich in natural compounds. The vast amount of data obtained from these species challenges the way we were mining for products and requires new pipelines for secondary metabolite analysis...

  5. Metabolic syndrome in the rural population of Wardha, Central India: An exploratory factor analysis

    Directory of Open Access Journals (Sweden)

    Pradeep R Deshmukh

    2013-01-01

    Full Text Available Background and Objectives: Metabolic syndrome - a plausible precondition for type II diabetes and cardiovascular diseases is also on rise. To understand the mechanistic complexity of metabolic syndrome it is imperative to study the specific contribution of the determinants of metabolic syndrome. Such study can help to identify the most significant factor which may be of use in early detection as well as prevention efforts. Such information is scarcely available from India and especially from rural India. Hence, the present study was undertaken to explore for such factor which might be considered crucial for development of such pathogenesis particularly in rural population of Wardha. Methods: A cross-sectional study comprising of 300 subjects was carried out in rural area of Primary Health Center, attached to medical college with approximate 31,000 populations. The anthropometric parameters such as height, weight, waist circumference were measured. Overnight fasting samples were collected for lipid profile (total cholesterol, triglyceride, high density lipoproteins, low density lipoproteins, very low density lipoproteins and fasting blood glucose levels. The National Cholesterol Education Programme Adult Treatment Panel, ATP-III guidelines were used to categorize the study subjects. As many of the variables are highly intercorrelated, exploratory factor analysis was carried out to reduce the data to a smaller number of independent factors that accounts for the most of the variances in the data. Principal component analysis was used as a method of extraction. Results: For both sexes, three factors were extracted accounting for about 71% variance in the measured variables. An adiposity factor which accounted for highest explained variance (28%, was the initial factor extracted. It was loaded positively by waist circumference, triglyceride, and very low density lipoprotein and negatively loaded by high density lipoprotein. Second factor extracted

  6. Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yen Ling Low

    2010-07-01

    Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global = 0.0003. Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite

  7. Inflammasomes: sensors of metabolic stresses for vascular inflammation

    OpenAIRE

    Yin, Ying; Pastrana, Jahaira Lopez; Li, Xinyuan; Huang, Xiao; Mallilankaraman, karthik; Choi, Eric T.; Madesh, Muniswamy; Wang, Hong; Yang, Xiao-Feng

    2013-01-01

    Metabolic syndrome is a major health issue in the western world. An elevated pro-inflammatory state is often found in patients with metabolic diseases such as type 2 diabetes and obesity. Atherosclerosis is one such clinical manifestation of pro-inflammatory state associated with the vasculature. The exact mechanism by which metabolic stress induces this pro-inflammatory status and promotes atherogenesis remained elusive until the discovery of the inflammasome protein complex. This complex is...

  8. Impact of a Complex Food Microbiota on Energy Metabolism in the Model Organism Caenorhabditis elegans

    Directory of Open Access Journals (Sweden)

    Elena Zanni

    2015-01-01

    Full Text Available The nematode Caenorhabditis elegans is widely used as a model system for research on aging, development, and host-pathogen interactions. Little is currently known about the mechanisms underlying the effects exerted by foodborne microbes. We took advantage of C. elegans to evaluate the impact of foodborne microbiota on well characterized physiological features of the worms. Foodborne lactic acid bacteria (LAB consortium was used to feed nematodes and its composition was evaluated by 16S rDNA analysis and strain typing before and after colonization of the nematode gut. Lactobacillus delbrueckii, L. fermentum, and Leuconostoc lactis were identified as the main species and shown to display different worm gut colonization capacities. LAB supplementation appeared to decrease nematode lifespan compared to the animals fed with the conventional Escherichia coli nutrient source or a probiotic bacterial strain. Reduced brood size was also observed in microbiota-fed nematodes. Moreover, massive accumulation of lipid droplets was revealed by BODIPY staining. Altered expression of nhr-49, pept-1, and tub-1 genes, associated with obesity phenotypes, was demonstrated by RT-qPCR. Since several pathways are evolutionarily conserved in C. elegans, our results highlight the nematode as a valuable model system to investigate the effects of a complex microbial consortium on host energy metabolism.

  9. Assessing complexity of skin blood flow oscillations in response to locally applied heating and pressure in rats: Implications for pressure ulcer risk

    Science.gov (United States)

    Liao, Fuyuan; O'Brien, William D.; Jan, Yih-Kuen

    2013-10-01

    The objective of this study was to investigate the effects of local heating on the complexity of skin blood flow oscillations (BFO) under prolonged surface pressure in rats. Eleven Sprague-Dawley rats were studied: 7 rats underwent surface pressure with local heating (△t=10 °C) and 4 rats underwent pressure without heating. A pressure of 700 mmHg was applied to the right trochanter area of rats for 3 h. Skin blood flow was measured using laser Doppler flowmetry. The loading period was divided into nonoverlapping 30 min epochs. For each epoch, multifractal detrended fluctuation analysis (MDFA) was utilized to compute DFA coefficients and complexity of endothelial related metabolic, neurogenic, and myogenic frequencies of BFO. The results showed that under surface pressure, local heating led to a significant decrease in DFA coefficients of myogenic frequency during the initial epoch of loading period, a sustained decrease in complexity of myogenic frequency, and a significantly higher degree of complexity of metabolic frequency during the later phase of loading period. Surrogate tests showed that the reduction in complexity of myogenic frequency was associated with a loss of nonlinearity whereas increased complexity of metabolic frequency was associated with enhanced nonlinearity. Our results indicate that increased metabolic activity and decreased myogenic response due to local heating manifest themselves not only in magnitudes of metabolic and myogenic frequencies but also in their structural complexity. This study demonstrates the feasibility of using complexity analysis of BFO to monitor the ischemic status of weight-bearing skin and risk of pressure ulcers.

  10. Fast 2D NMR Spectroscopy for In vivo Monitoring of Bacterial Metabolism in Complex Mixtures

    Directory of Open Access Journals (Sweden)

    Rupashree Dass

    2017-07-01

    Full Text Available The biological toolbox is full of techniques developed originally for analytical chemistry. Among them, spectroscopic experiments are very important source of atomic-level structural information. Nuclear magnetic resonance (NMR spectroscopy, although very advanced in chemical and biophysical applications, has been used in microbiology only in a limited manner. So far, mostly one-dimensional 1H experiments have been reported in studies of bacterial metabolism monitored in situ. However, low spectral resolution and limited information on molecular topology limits the usability of these methods. These problems are particularly evident in the case of complex mixtures, where spectral peaks originating from many compounds overlap and make the interpretation of changes in a spectrum difficult or even impossible. Often a suite of two-dimensional (2D NMR experiments is used to improve resolution and extract structural information from internuclear correlations. However, for dynamically changing sample, like bacterial culture, the time-consuming sampling of so-called indirect time dimensions in 2D experiments is inefficient. Here, we propose the technique known from analytical chemistry and structural biology of proteins, i.e., time-resolved non-uniform sampling. The method allows application of 2D (and multi-D experiments in the case of quickly varying samples. The indirect dimension here is sparsely sampled resulting in significant reduction of experimental time. Compared to conventional approach based on a series of 1D measurements, this method provides extraordinary resolution and is a real-time approach to process monitoring. In this study, we demonstrate the usability of the method on a sample of Escherichia coli culture affected by ampicillin and on a sample of Propionibacterium acnes, an acne causing bacterium, mixed with a dose of face tonic, which is a complicated, multi-component mixture providing complex NMR spectrum. Through our experiments

  11. Isotope coded protein labeling coupled immunoprecipitation (ICPL-IP): a novel approach for quantitative protein complex analysis from native tissue.

    Science.gov (United States)

    Vogt, Andreas; Fuerholzner, Bettina; Kinkl, Norbert; Boldt, Karsten; Ueffing, Marius

    2013-05-01

    High confidence definition of protein interactions is an important objective toward the understanding of biological systems. Isotope labeling in combination with affinity-based isolation of protein complexes has increased in accuracy and reproducibility, yet, larger organisms--including humans--are hardly accessible to metabolic labeling and thus, a major limitation has been its restriction to small animals, cell lines, and yeast. As composition as well as the stoichiometry of protein complexes can significantly differ in primary tissues, there is a great demand for methods capable to combine the selectivity of affinity-based isolation as well as the accuracy and reproducibility of isotope-based labeling with its application toward analysis of protein interactions from intact tissue. Toward this goal, we combined isotope coded protein labeling (ICPL)(1) with immunoprecipitation (IP) and quantitative mass spectrometry (MS). ICPL-IP allows sensitive and accurate analysis of protein interactions from primary tissue. We applied ICPL-IP to immuno-isolate protein complexes from bovine retinal tissue. Protein complexes of immunoprecipitated β-tubulin, a highly abundant protein with known interactors as well as the lowly expressed small GTPase RhoA were analyzed. The results of both analyses demonstrate sensitive and selective identification of known as well as new protein interactions by our method.

  12. Isotope Coded Protein Labeling Coupled Immunoprecipitation (ICPL-IP): A Novel Approach for Quantitative Protein Complex Analysis From Native Tissue*

    Science.gov (United States)

    Vogt, Andreas; Fuerholzner, Bettina; Kinkl, Norbert; Boldt, Karsten; Ueffing, Marius

    2013-01-01

    High confidence definition of protein interactions is an important objective toward the understanding of biological systems. Isotope labeling in combination with affinity-based isolation of protein complexes has increased in accuracy and reproducibility, yet, larger organisms—including humans—are hardly accessible to metabolic labeling and thus, a major limitation has been its restriction to small animals, cell lines, and yeast. As composition as well as the stoichiometry of protein complexes can significantly differ in primary tissues, there is a great demand for methods capable to combine the selectivity of affinity-based isolation as well as the accuracy and reproducibility of isotope-based labeling with its application toward analysis of protein interactions from intact tissue. Toward this goal, we combined isotope coded protein labeling (ICPL)1 with immunoprecipitation (IP) and quantitative mass spectrometry (MS). ICPL-IP allows sensitive and accurate analysis of protein interactions from primary tissue. We applied ICPL-IP to immuno-isolate protein complexes from bovine retinal tissue. Protein complexes of immunoprecipitated β-tubulin, a highly abundant protein with known interactors as well as the lowly expressed small GTPase RhoA were analyzed. The results of both analyses demonstrate sensitive and selective identification of known as well as new protein interactions by our method. PMID:23268931

  13. Alteration in metabolic signature and lipid metabolism in patients with angina pectoris and myocardial infarction.

    Science.gov (United States)

    Park, Ju Yeon; Lee, Sang-Hak; Shin, Min-Jeong; Hwang, Geum-Sook

    2015-01-01

    Lipid metabolites are indispensable regulators of physiological and pathological processes, including atherosclerosis and coronary artery disease (CAD). However, the complex changes in lipid metabolites and metabolism that occur in patients with these conditions are incompletely understood. We performed lipid profiling to identify alterations in lipid metabolism in patients with angina and myocardial infarction (MI). Global lipid profiling was applied to serum samples from patients with CAD (angina and MI) and age-, sex-, and body mass index-matched healthy subjects using ultra-performance liquid chromatography/quadruple time-of-flight mass spectrometry and multivariate statistical analysis. A multivariate analysis showed a clear separation between the patients with CAD and normal controls. Lysophosphatidylcholine (lysoPC) and lysophosphatidylethanolamine (lysoPE) species containing unsaturated fatty acids and free fatty acids were associated with an increased risk of CAD, whereas species of lysoPC and lyso-alkyl PC containing saturated fatty acids were associated with a decreased risk. Additionally, PC species containing palmitic acid, diacylglycerol, sphingomyelin, and ceramide were associated with an increased risk of MI, whereas PE-plasmalogen and phosphatidylinositol species were associated with a decreased risk. In MI patients, we found strong positive correlation between lipid metabolites related to the sphingolipid pathway, sphingomyelin, and ceramide and acute inflammatory markers (high-sensitivity C-reactive protein). The results of this study demonstrate altered signatures in lipid metabolism in patients with angina or MI. Lipidomic profiling could provide the information to identity the specific lipid metabolites under the presence of disturbed metabolic pathways in patients with CAD.

  14. Gout and Metabolic Syndrome: a Tangled Web.

    Science.gov (United States)

    Thottam, Gabrielle E; Krasnokutsky, Svetlana; Pillinger, Michael H

    2017-08-26

    The complexity of gout continues to unravel with each new investigation. Gout sits at the intersection of multiple intrinsically complex processes, and its prevalence, impact on healthcare costs, and association with important co-morbidities make it increasingly relevant. The association between gout and type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, renal disease, and obesity suggest that either gout, or its necessary precursor hyperuricemia, may play an important role in the manifestations of the metabolic syndrome. In this review, we analyze the complex interconnections between gout and metabolic syndrome, by reviewing gout's physiologic and epidemiologic relationships with its major co-morbidities. Increasing evidence supports gout's association with metabolic syndrome. More specifically, both human studies and animal models suggest that hyperuricemia may play a role in promoting inflammation, hypertension and cardiovascular disease, adipogenesis and lipogenesis, insulin and glucose dysregulation, and liver disease. Fructose ingestion is associated with increased rates of hypertension, weight gain, impaired glucose tolerance, and dyslipidemia and is a key driver of urate biosynthesis. AMP kinase (AMPK) is a central regulator of processes that tend to mitigate against the metabolic syndrome. Within hepatocytes, leukocytes, and other cells, a fructose/urate metabolic loop drives key inhibitors of AMPK, including AMP deaminase and fructokinase, that may tilt the balance toward metabolic syndrome progression. Preliminary evidence suggests that agents that block the intracellular synthesis of urate may restore AMPK activity and help maintain metabolic homeostasis. Gout is both an inflammatory and a metabolic disease. With further investigation of urate's role, the possibility of proper gout management additionally mitigating metabolic syndrome is an evolving and important question.

  15. Maneuvering in the Complex Path from Genotype to Phenotype

    Science.gov (United States)

    Strohman, Richard

    2002-04-01

    Human disease phenotypes are controlled not only by genes but by lawful self-organizing networks that display system-wide dynamics. These networks range from metabolic pathways to signaling pathways that regulate hormone action. When perturbed, networks alter their output of matter and energy which, depending on the environmental context, can produce either a pathological or a normal phenotype. Study of the dynamics of these networks by approaches such as metabolic control analysis may provide new insights into the pathogenesis and treatment of complex diseases.

  16. Complex analysis a modern first course in function theory

    CERN Document Server

    Muir, Jerry R

    2015-01-01

    A thorough introduction to the theory of complex functions emphasizing the beauty, power, and counterintuitive nature of the subject Written with a reader-friendly approach, Complex Analysis: A Modern First Course in Function Theory features a self-contained, concise development of the fundamental principles of complex analysis. After laying groundwork on complex numbers and the calculus and geometric mapping properties of functions of a complex variable, the author uses power series as a unifying theme to define and study the many rich and occasionally surprising properties of analytic fun

  17. Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks

    Science.gov (United States)

    Chiappino-Pepe, Anush; Ataman, Meriç

    2017-01-01

    Novel antimalarial therapies are urgently needed for the fight against drug-resistant parasites. The metabolism of malaria parasites in infected cells is an attractive source of drug targets but is rather complex. Computational methods can handle this complexity and allow integrative analyses of cell metabolism. In this study, we present a genome-scale metabolic model (iPfa) of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA). Using previous absolute concentration data of the intraerythrocytic parasite, we applied TFA to iPfa and predicted up to 63 essential genes and 26 essential pairs of genes. Of the 63 genes, 35 have been experimentally validated and reported in the literature, and 28 have not been experimentally tested and include previously hypothesized or novel predictions of essential metabolic capabilities. Without metabolomics data, four of the genes would have been incorrectly predicted to be non-essential. TFA also indicated that substrate channeling should exist in two metabolic pathways to ensure the thermodynamic feasibility of the flux. Finally, analysis of the metabolic capabilities of P. falciparum led to the identification of both the minimal nutritional requirements and the genes that can become indispensable upon substrate inaccessibility. This model provides novel insight into the metabolic needs and capabilities of the malaria parasite and highlights metabolites and pathways that should be measured and characterized to identify potential thermodynamic bottlenecks and substrate channeling. The hypotheses presented seek to guide experimental studies to facilitate a better understanding of the parasite metabolism and the identification of targets for more efficient intervention. PMID:28333921

  18. Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks.

    Directory of Open Access Journals (Sweden)

    Anush Chiappino-Pepe

    2017-03-01

    Full Text Available Novel antimalarial therapies are urgently needed for the fight against drug-resistant parasites. The metabolism of malaria parasites in infected cells is an attractive source of drug targets but is rather complex. Computational methods can handle this complexity and allow integrative analyses of cell metabolism. In this study, we present a genome-scale metabolic model (iPfa of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA. Using previous absolute concentration data of the intraerythrocytic parasite, we applied TFA to iPfa and predicted up to 63 essential genes and 26 essential pairs of genes. Of the 63 genes, 35 have been experimentally validated and reported in the literature, and 28 have not been experimentally tested and include previously hypothesized or novel predictions of essential metabolic capabilities. Without metabolomics data, four of the genes would have been incorrectly predicted to be non-essential. TFA also indicated that substrate channeling should exist in two metabolic pathways to ensure the thermodynamic feasibility of the flux. Finally, analysis of the metabolic capabilities of P. falciparum led to the identification of both the minimal nutritional requirements and the genes that can become indispensable upon substrate inaccessibility. This model provides novel insight into the metabolic needs and capabilities of the malaria parasite and highlights metabolites and pathways that should be measured and characterized to identify potential thermodynamic bottlenecks and substrate channeling. The hypotheses presented seek to guide experimental studies to facilitate a better understanding of the parasite metabolism and the identification of targets for more efficient intervention.

  19. Plasma metabolic profiling of dairy cows affected with clinical ketosis using LC/MS technology.

    Science.gov (United States)

    Li, Y; Xu, C; Xia, C; Zhang, Hy; Sun, Lw; Gao, Y

    2014-01-01

    Ketosis in dairy cattle is an important metabolic disorder. Currently, the plasma metabolic profile of ketosis as determined using liquid chromatography-mass spectrometry (LC/MS) has not been reported. To investigate plasma metabolic profiles from cows with clinical ketosis in comparison to control cows. Twenty Holstein dairy cows were divided into two groups based on clinical signs and plasma β-hydroxybutyric acid and glucose concentrations 7-21 days postpartum: clinical ketosis and control cows. Plasma metabolic profiles were analyzed using LC/MS. Data were processed using principal component analysis and orthogonal partial least-squares discriminant analysis. Compared to control cows, the levels of valine, glycine, glycocholic, tetradecenoic acid, and palmitoleic acid increased significantly in clinical ketosis. On the other hand, the levels of arginine, aminobutyric acid, leucine/isoleucine, tryptophan, creatinine, lysine, norcotinine, and undecanoic acid decreased markedly. Our results showed that the metabolic changes in cows with clinical ketosis involve complex metabolic networks and signal transduction. These results are important for future studies elucidating the pathogenesis, diagnosis, and prevention of clinical ketosis in dairy cows.

  20. [Metabolic acidosis].

    Science.gov (United States)

    Regolisti, Giuseppe; Fani, Filippo; Antoniotti, Riccardo; Castellano, Giuseppe; Cremaschi, Elena; Greco, Paolo; Parenti, Elisabetta; Morabito, Santo; Sabatino, Alice; Fiaccadori, Enrico

    2016-01-01

    Metabolic acidosis is frequently observed in clinical practice, especially among critically ill patients and/or in the course of renal failure. Complex mechanisms are involved, in most cases identifiable by medical history, pathophysiology-based diagnostic reasoning and measure of some key acid-base parameters that are easily available or calculable. On this basis the bedside differential diagnosis of metabolic acidosis should be started from the identification of the two main subtypes of metabolic acidosis: the high anion gap metabolic acidosis and the normal anion gap (or hyperchloremic) metabolic acidosis. Metabolic acidosis, especially in its acute forms with elevated anion gap such as is the case of lactic acidosis, diabetic and acute intoxications, may significantly affect metabolic body homeostasis and patients hemodynamic status, setting the stage for true medical emergencies. The therapeutic approach should be first aimed at early correction of concurrent clinical problems (e.g. fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, hemodialysis for acute intoxications etc.), in parallel to the formulation of a diagnosis. In case of severe acidosis, the administration of alkalizing agents should be carefully evaluated, taking into account the risk of side effects, as well as the potential need of renal replacement therapy.

  1. Kinetic compartmental analysis of carnitine metabolism in the dog

    International Nuclear Information System (INIS)

    Rebouche, C.J.; Engel, A.G.

    1983-01-01

    This study was undertaken to quantitate the dynamic parameters of carnitine metabolism in the dog. Six mongrel dogs were given intravenous injections of L-[methyl-3H]carnitine and the specific radioactivity of carnitine was followed in plasma and urine for 19-28 days. The data were analyzed by kinetic compartmental analysis. A three-compartment, open-system model [(a) extracellular fluid, (b) cardiac and skeletal muscle, (c) other tissues, particularly liver and kidney] was adopted and kinetic parameters (carnitine flux, pool sizes, kinetic constants) were derived. In four of six dogs the size of the muscle carnitine pool obtained by kinetic compartmental analysis agreed (+/- 5%) with estimates based on measurement of carnitine concentrations in different muscles. In three of six dogs carnitine excretion rates derived from kinetic compartmental analysis agreed (+/- 9%) with experimentally measured values, but in three dogs the rates by kinetic compartmental analysis were significantly higher than the corresponding rates measured directly. Appropriate chromatographic analyses revealed no radioactive metabolites in muscle or urine of any of the dogs. Turnover times for carnitine were (mean +/- SEM): 0.44 +/- 0.05 h for extracellular fluid, 232 +/- 22 h for muscle, and 7.9 +/- 1.1 h for other tissues. The estimated flux of carnitine in muscle was 210 pmol/min/g of tissue. Whole-body turnover time for carnitine was 62.9 +/- 5.6 days (mean +/- SEM). Estimated carnitine biosynthesis ranged from 2.9 to 28 mumol/kg body wt/day. Results of this study indicate that kinetic compartmental analysis may be applicable to study of human carnitine metabolism

  2. Substrate metabolism in isolated rat jejunal epithelium. Analysis using 14C-radioisotopes

    International Nuclear Information System (INIS)

    Mallet, R.T.

    1986-01-01

    The jejunal epithelium absorbs nutrients from the intestinal lumen and is therefore the initial site for metabolism of these compounds. The purpose of this investigation is to analyze substrate metabolism in a preparation of jejunal epithelium relatively free of other tissues. Novel radioisotopic labelling techniques allow quantitation of substrate metabolism in the TCA cycle, Embden-Meyerhof (glycolytic) pathway, and hexose monophosphate shunt. For example, ratios of 14 CO 2 production from pairs of 14 C-pyruvate, and 14 C-succinate radioisotopes (CO 2 ratios) indicate the probability of TCA cycle intermediate efflux to generate compounds other than CO 2 . With (2,3- 14 C)succinate as tracer, the ratio of 14 C in carbon 4 + 5 versus carbon 2 + 3 of citrate, the citrate labelling ratio, equals the probability of TCA intermediate flux to the acetyl CoA-derived portion of citrate versus flux to the oxaloacetate-derived portion. The principal metabolic substrates for the jejunal epithelium are glucose and glutamine. CO 2 ratios indicate that glutamine uptake and metabolism is partially Na + -independent, and is saturable, with a half-maximal rate at physiological plasma glutamine concentrations. Glucose metabolism in the jejunal epithelium proceeds almost entirely via the Embden-Meyerhof pathway. Conversion of substrates to multi-carbon products in this tissue allows partial conservation of reduced carbon for further utilization in other tissues. In summary, metabolic modeling based on 14 C labelling ratios is a potentially valuable technique for analysis of metabolic flux patterns in cell preparations

  3. Complex harmonic modal analysis of rotor systems

    International Nuclear Information System (INIS)

    Han, Dong Ju

    2015-01-01

    Complex harmonic analysis for rotor systems has been proposed from the strict complex modal analysis based upon Floquet theory. In this process the harmonic balance method is adopted, effectively associated with conventional eigenvalue analysis. Also, the harmonic coefficients equivalent to dFRFs in harmonic mode has been derived in practice. The modes are classified from identifying the modal characteristics, and the adaptation of harmonic balance method has been proven by comparing the results of the stability analyses from Floque theory and the eigen analysis. The modal features of each critical speed are depicted in quantitatively and qualitatively by showing that the strengths of each component of the harmonic coefficients are estimated from the order of magnitude analysis according to their harmonic patterns. This effectiveness has been verified by comparing with the numerical solutions

  4. Complex surveys analysis of categorical data

    CERN Document Server

    Mukhopadhyay, Parimal

    2016-01-01

    The primary objective of this book is to study some of the research topics in the area of analysis of complex surveys which have not been covered in any book yet. It discusses the analysis of categorical data using three models: a full model, a log-linear model and a logistic regression model. It is a valuable resource for survey statisticians and practitioners in the field of sociology, biology, economics, psychology and other areas who have to use these procedures in their day-to-day work. It is also useful for courses on sampling and complex surveys at the upper-undergraduate and graduate levels. The importance of sample surveys today cannot be overstated. From voters’ behaviour to fields such as industry, agriculture, economics, sociology, psychology, investigators generally resort to survey sampling to obtain an assessment of the behaviour of the population they are interested in. Many large-scale sample surveys collect data using complex survey designs like multistage stratified cluster designs. The o...

  5. A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19

    Energy Technology Data Exchange (ETDEWEB)

    Hayakawa, Toru [National Institute for Environmental Studies, Environmental Health Sciences Division, Ibaraki (Japan); Chiba University, Faculty of Pharmaceutical Sciences, Chiba (Japan); Kobayashi, Yayoi; Cui, Xing; Hirano, Seishiro [National Institute for Environmental Studies, Environmental Health Sciences Division, Ibaraki (Japan)

    2005-04-01

    The metabolism of arsenic is generally accepted to proceed by repetitive reduction and oxidative methylation; the latter is mediated by arsenic methyltransferase (Cyt19). In human urine, the major metabolites of inorganic arsenicals such as arsenite (iAs{sup III}) and arsenate (iAs{sup V}) are monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}). On the other hand, in rat bile, the major metabolites of iAs{sup III} have been reported to be arsenic-glutathione (As-GSH) complexes. In the present study we investigate whether these As-GSH complexes are substrates for arsenic methyltransferase by using human recombinant Cyt19. Analyses by high-performance liquid chromatography-inductively coupled plasma mass spectrometry suggested that arsenic triglutathione (ATG) was generated nonenzymatically from iAs{sup III} when GSH was present at concentrations 2 mM or higher. Human recombinant Cyt19 catalyzed transfer of a methyl group from S-adenosyl-l-methionine to arsenic and produced monomethyl and dimethyl arsenicals. The methylation of arsenic was catalyzed by Cyt19 only when ATG was present in the reaction mixture. Moreover, monomethylarsonic diglutathione (MADG) was a substrate of Cyt19 for further methylation to dimethylarsinic glutathione (DMAG). On the other hand, monomethylarsonous acid (MMA{sup III}), a hydrolysis product of MADG, was not methylated to dimethyl arsenical by Cyt19. These results suggest that As-GSH complexes such as ATG and MADG were converted by Cyt19 to MADG and DMAG, respectively. Both MADG and DMAG were unstable in solution when the GSH concentration was lower than 1 mM, and were hydrolyzed and oxidized to MMA{sup V} and DMA{sup V}, respectively. Metabolism of iAs{sup III} to methylated arsenicals by Cyt19 was via ATG and MADG rather than by oxidative methylation of iAs{sup III} and MMA{sup III}. (orig.)

  6. Metabolic flux ratio analysis and cell staining suggest the existence of C4 photosynthesis in Phaeodactylum tricornutum.

    Science.gov (United States)

    Huang, A; Liu, L; Zhao, P; Yang, C; Wang, G C

    2016-03-01

    Mechanisms for carbon fixation via photosynthesis in the diatom Phaeodactylum tricornutum Bohlin were studied recently but there remains a long-standing debate concerning the occurrence of C4 photosynthesis in this species. A thorough investigation of carbon metabolism and the evidence for C4 photosynthesis based on organelle partitioning was needed. In this study, we identified the flux ratios between C3 and C4 compounds in P. tricornutum using (13)C-labelling metabolic flux ratio analysis, and stained cells with various cell-permeant fluorescent probes to investigate the likely organelle partitioning required for single-cell C4 photosynthesis. Metabolic flux ratio analysis indicated the C3/C4 exchange ratios were high. Cell staining indicated organelle partitioning required for single-cell C4 photosynthesis might exist in P. tricornutum. The results of (13)C-labelling metabolic flux ratio analysis and cell staining suggest single-cell C4 photosynthesis exists in P. tricornutum. This study provides insights into photosynthesis patterns of P. tricornutum and the evidence for C4 photosynthesis based on (13)C-labelling metabolic flux ratio analysis and organelle partitioning. © 2015 The Society for Applied Microbiology.

  7. Biotransformation of plutonium complexed with citric acid

    International Nuclear Information System (INIS)

    Francis, A.J.; Dodge, C.J.; Gillow, J.B.

    2006-01-01

    The presence of organic ligands in radioactive wastes is a major concern because of their potential for increasing the transport of radionuclides from disposal sites. Biotransformation of radionuclides complexed with organic ligands should precipitate the radionuclides and retard their migration. We investigated the biotransformation of Pu(IV) (10 -8 to 10 -5 M), by Pseudomonas fluorescens in the presence of excess citric acid. Analysis of 242 Pu-citrate by electrospray ionization-mass spectrometry (ESI-MS) indicated the presence of biligand Pu-cit 2 as the predominant complex. XANES and EXAFS analyses showed that Pu was in the +4 oxidation state and associated with citric acid as a mononuclear complex. Citric acid was metabolized by P. fluorescens at a rate of 4.9 μM/h, but in the presence of 10 -8 and 10 -6 M Pu, this rate decreased to 4.0 and 3.8 μM/h, respectively. An increase in the ionic strength of the medium from 0.18 M to 0.9 M lowered citrate metabolism by ∝ 65%. Pu added to the growth medium in the absence of bacteria remained as Pu(IV) in solution as a complex with citric acid. However, solvent extraction by thenoyltrifluoroacetone (TTA) and microfiltration (0.03 μm) of the medium containing bacteria after citrate biodegradation revealed the presence of polymeric Pu. The extent of formation of the Pu polymer depended on the Pu: citrate ratio, the extent of citrate metabolism, and the ionic strength of the medium. (orig.)

  8. Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes

    DEFF Research Database (Denmark)

    Min, Josine L; Nicholson, George; Halgrimsdottir, Ingileif

    2012-01-01

    Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue...... and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P100,000 individuals; rs10282458, affecting expression of RARRES2...... and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations....

  9. Metabolic mapping of the brain's response to visual stimulation: studies in humans

    International Nuclear Information System (INIS)

    Phelps, M.E.; Kuhl, D.E.; Mazziotta, J.C.

    1981-01-01

    These studies demonstrated increasing glucose metabolic rates in the human primary (PVC) and associative (AVC) visual cortex as the complexity of visual scenes increased. The metabolic response of the AVC increased more rapidly with scene complexity than that of the PVC, indicating the greater involvement of the higher order AVC for complex visual interpretations. Increases in local metabolic activity by as much as a factor of 2 above that of control subjects with eyes closed indicate the wide range and metabolic reserve of the visual cortex

  10. Fluvoxamine alters the activity of energy metabolism enzymes in the brain

    Directory of Open Access Journals (Sweden)

    Gabriela K. Ferreira

    2014-09-01

    Full Text Available Objective: Several studies support the hypothesis that metabolism impairment is involved in the pathophysiology of depression and that some antidepressants act by modulating brain energy metabolism. Thus, we evaluated the activity of Krebs cycle enzymes, the mitochondrial respiratory chain, and creatine kinase in the brain of rats subjected to prolonged administration of fluvoxamine. Methods: Wistar rats received daily administration of fluvoxamine in saline (10, 30, and 60 mg/kg for 14 days. Twelve hours after the last administration, rats were killed by decapitation and the prefrontal cortex, cerebral cortex, hippocampus, striatum, and cerebellum were rapidly isolated. Results: The activities of citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV were decreased after prolonged administration of fluvoxamine in rats. However, the activities of complex II, succinate dehydrogenase, and creatine kinase were increased. Conclusions: Alterations in activity of energy metabolism enzymes were observed in most brain areas analyzed. Thus, we suggest that the decrease in citrate synthase, malate dehydrogenase, and complexes I, II-III, and IV can be related to adverse effects of pharmacotherapy, but long-term molecular adaptations cannot be ruled out. In addition, we demonstrated that these changes varied according to brain structure or biochemical analysis and were not dose-dependent.

  11. Mathematical Analysis of Evolution, Information, and Complexity

    CERN Document Server

    Arendt, Wolfgang

    2009-01-01

    Mathematical Analysis of Evolution, Information, and Complexity deals with the analysis of evolution, information and complexity. The time evolution of systems or processes is a central question in science, this text covers a broad range of problems including diffusion processes, neuronal networks, quantum theory and cosmology. Bringing together a wide collection of research in mathematics, information theory, physics and other scientific and technical areas, this new title offers elementary and thus easily accessible introductions to the various fields of research addressed in the book.

  12. Comprehensive metabolic panel

    Science.gov (United States)

    Metabolic panel - comprehensive; Chem-20; SMA20; Sequential multi-channel analysis with computer-20; SMAC20; Metabolic panel 20 ... Chernecky CC, Berger BJ. Comprehensive metabolic panel (CMP) - blood. In: ... Tests and Diagnostic Procedures . 6th ed. St Louis, MO: ...

  13. Study of Stationary Phase Metabolism Via Isotopomer Analysis of Amino Acids from an Isolated Protein

    Energy Technology Data Exchange (ETDEWEB)

    Shaikh, AfshanS.; Tang, YinjieJ.; Mukhopadhyay, Aindrila; Martin, Hector Garcia; Gin, Jennifer; Benke, Peter; Keasling, Jay D.

    2009-09-14

    Microbial production of many commercially important secondary metabolites occurs during stationary phase, and methods to measure metabolic flux during this growth phase would be valuable. Metabolic flux analysis is often based on isotopomer information from proteinogenic amino acids. As such, flux analysis primarily reflects the metabolism pertinent to the growth phase during which most proteins are synthesized. To investigate central metabolism and amino acids synthesis activity during stationary phase, addition of fully 13C-labeled glucose followed by induction of green fluorescent protein (GFP) expression during stationary phase was used. Our results indicate that Escherichia coli was able to produce new proteins (i.e., GFP) in the stationary phase, and the amino acids in GFP were mostly from degraded proteins synthesized during the exponential growth phase. Among amino acid biosynthetic pathways, only those for serine, alanine, glutamate/glutamine, and aspartate/asparagine had significant activity during the stationary phase.

  14. Genome-scale metabolic analysis of Clostridium thermocellum for bioethanol production

    Directory of Open Access Journals (Sweden)

    Brooks J Paul

    2010-03-01

    Full Text Available Abstract Background Microorganisms possess diverse metabolic capabilities that can potentially be leveraged for efficient production of biofuels. Clostridium thermocellum (ATCC 27405 is a thermophilic anaerobe that is both cellulolytic and ethanologenic, meaning that it can directly use the plant sugar, cellulose, and biochemically convert it to ethanol. A major challenge in using microorganisms for chemical production is the need to modify the organism to increase production efficiency. The process of properly engineering an organism is typically arduous. Results Here we present a genome-scale model of C. thermocellum metabolism, iSR432, for the purpose of establishing a computational tool to study the metabolic network of C. thermocellum and facilitate efforts to engineer C. thermocellum for biofuel production. The model consists of 577 reactions involving 525 intracellular metabolites, 432 genes, and a proteomic-based representation of a cellulosome. The process of constructing this metabolic model led to suggested annotation refinements for 27 genes and identification of areas of metabolism requiring further study. The accuracy of the iSR432 model was tested using experimental growth and by-product secretion data for growth on cellobiose and fructose. Analysis using this model captures the relationship between the reduction-oxidation state of the cell and ethanol secretion and allowed for prediction of gene deletions and environmental conditions that would increase ethanol production. Conclusions By incorporating genomic sequence data, network topology, and experimental measurements of enzyme activities and metabolite fluxes, we have generated a model that is reasonably accurate at predicting the cellular phenotype of C. thermocellum and establish a strong foundation for rational strain design. In addition, we are able to draw some important conclusions regarding the underlying metabolic mechanisms for observed behaviors of C. thermocellum

  15. Analysis of complex networks using aggressive abstraction.

    Energy Technology Data Exchange (ETDEWEB)

    Colbaugh, Richard; Glass, Kristin.; Willard, Gerald

    2008-10-01

    This paper presents a new methodology for analyzing complex networks in which the network of interest is first abstracted to a much simpler (but equivalent) representation, the required analysis is performed using the abstraction, and analytic conclusions are then mapped back to the original network and interpreted there. We begin by identifying a broad and important class of complex networks which admit abstractions that are simultaneously dramatically simplifying and property preserving we call these aggressive abstractions -- and which can therefore be analyzed using the proposed approach. We then introduce and develop two forms of aggressive abstraction: 1.) finite state abstraction, in which dynamical networks with uncountable state spaces are modeled using finite state systems, and 2.) onedimensional abstraction, whereby high dimensional network dynamics are captured in a meaningful way using a single scalar variable. In each case, the property preserving nature of the abstraction process is rigorously established and efficient algorithms are presented for computing the abstraction. The considerable potential of the proposed approach to complex networks analysis is illustrated through case studies involving vulnerability analysis of technological networks and predictive analysis for social processes.

  16. Development and analysis of an in vivo-compatible metabolic network of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Reifman Jaques

    2010-11-01

    Full Text Available Abstract Background During infection, Mycobacterium tuberculosis confronts a generally hostile and nutrient-poor in vivo host environment. Existing models and analyses of M. tuberculosis metabolic networks are able to reproduce experimentally measured cellular growth rates and identify genes required for growth in a range of different in vitro media. However, these models, under in vitro conditions, do not provide an adequate description of the metabolic processes required by the pathogen to infect and persist in a host. Results To better account for the metabolic activity of M. tuberculosis in the host environment, we developed a set of procedures to systematically modify an existing in vitro metabolic network by enhancing the agreement between calculated and in vivo-measured gene essentiality data. After our modifications, the new in vivo network contained 663 genes, 838 metabolites, and 1,049 reactions and had a significantly increased sensitivity (0.81 in predicted gene essentiality than the in vitro network (0.31. We verified the modifications generated from the purely computational analysis through a review of the literature and found, for example, that, as the analysis suggested, lipids are used as the main source for carbon metabolism and oxygen must be available for the pathogen under in vivo conditions. Moreover, we used the developed in vivo network to predict the effects of double-gene deletions on M. tuberculosis growth in the host environment, explore metabolic adaptations to life in an acidic environment, highlight the importance of different enzymes in the tricarboxylic acid-cycle under different limiting nutrient conditions, investigate the effects of inhibiting multiple reactions, and look at the importance of both aerobic and anaerobic cellular respiration during infection. Conclusions The network modifications we implemented suggest a distinctive set of metabolic conditions and requirements faced by M. tuberculosis during

  17. Uranium complexes with macrosyclic polyethers. Synthesis and structural chemical analysis

    International Nuclear Information System (INIS)

    Elbasyouny, A.

    1983-01-01

    This dissertation reports about studies on the chemical coordination behaviour of uranium of oxidation stages IV and VI with regard to twelve different macrocyclic ligands. For the preparation of the complexes, for every system a different method has been developed. The elementary analysis of the various complexes including the uranium had been done by X-ray fluorescence analysis, and the structural characterization proceeded via vibrational, uv-vis and emission spectroscopy as well as 1 H-NMR and 13 C-spin-lattice relaxation time studies. Conformational analysis of the polyethers used allowed the structural changes in the complexes to be observed. The structural analysis of the hydrous uranium VI crown ether complexes yielded information of characteristic features of these types of complexes. The first coordination sphere of the uranyl ion with covalently bonded anion remains unchanged. As to the water content, there is a certain range. Depending upon the solvent used, the complexes have two or four H 2 O molecules per formula unit. (orig./EF) [de

  18. Multifractal analysis of complex networks

    International Nuclear Information System (INIS)

    Wang Dan-Ling; Yu Zu-Guo; Anh V

    2012-01-01

    Complex networks have recently attracted much attention in diverse areas of science and technology. Many networks such as the WWW and biological networks are known to display spatial heterogeneity which can be characterized by their fractal dimensions. Multifractal analysis is a useful way to systematically describe the spatial heterogeneity of both theoretical and experimental fractal patterns. In this paper, we introduce a new box-covering algorithm for multifractal analysis of complex networks. This algorithm is used to calculate the generalized fractal dimensions D q of some theoretical networks, namely scale-free networks, small world networks, and random networks, and one kind of real network, namely protein—protein interaction networks of different species. Our numerical results indicate the existence of multifractality in scale-free networks and protein—protein interaction networks, while the multifractal behavior is not clear-cut for small world networks and random networks. The possible variation of D q due to changes in the parameters of the theoretical network models is also discussed. (general)

  19. Mapping cancer cell metabolism with 13 C flux analysis: Recent progress and future challenges

    Directory of Open Access Journals (Sweden)

    Casey Scott Duckwall

    2013-01-01

    Full Text Available The reprogramming of energy metabolism is emerging as an important molecular hallmark of cancer cells. Recent discoveries linking specific metabolic alterations to cancer development have strengthened the idea that altered metabolism is more than a side effect of malignant transformation, but may in fact be a functional driver of tumor growth and progression in some cancers. As a result, dysregulated metabolic pathways have become attractive targets for cancer therapeutics. This review highlights the application of 13 C metabolic flux analysis (MFA to map the flow of carbon through intracellular biochemical pathways of cancer cells. We summarize several recent applications of MFA that have identified novel biosynthetic pathways involved in cancer cell proliferation and shed light on the role of specific oncogenes in regulating these pathways. Through such studies, it has become apparent that the metabolic phenotypes of cancer cells are not as homogeneous as once thought, but instead depend strongly on the molecular alterations and environmental factors at play in each case.

  20. Hierarchical analysis of dependency in metabolic networks.

    Science.gov (United States)

    Gagneur, Julien; Jackson, David B; Casari, Georg

    2003-05-22

    Elucidation of metabolic networks for an increasing number of organisms reveals that even small networks can contain thousands of reactions and chemical species. The intimate connectivity between components complicates their decomposition into biologically meaningful sub-networks. Moreover, traditional higher-order representations of metabolic networks as metabolic pathways, suffers from the lack of rigorous definition, yielding pathways of disparate content and size. We introduce a hierarchical representation that emphasizes the gross organization of metabolic networks in largely independent pathways and sub-systems at several levels of independence. The approach highlights the coupling of different pathways and the shared compounds responsible for those couplings. By assessing our results on Escherichia coli (E.coli metabolic reactions, Genetic Circuits Research Group, University of California, San Diego, http://gcrg.ucsd.edu/organisms/ecoli.html, 'model v 1.01. reactions') against accepted biochemical annotations, we provide the first systematic synopsis of an organism's metabolism. Comparison with operons of E.coli shows that low-level clusters are reflected in genome organization and gene regulation. Source code, data sets and supplementary information are available at http://www.mas.ecp.fr/labo/equipe/gagneur/hierarchy/hierarchy.html

  1. Animal metabolism

    International Nuclear Information System (INIS)

    Walburg, H.E.

    1977-01-01

    Studies on placental transport included the following: clearance of tritiated water as a baseline measurement for transport of materials across perfused placentas; transport of organic and inorganic mercury across the perfused placenta of the guinea pig in late gestation; and transport of cadmium across the perfused placenta of the guinea pig in late gestation. Studies on cadmium absorption and metabolism included the following: intestinal absorption and retention of cadmium in neonatal rats; uptake and distribution of an oral dose of cadmium in postweanling male and female, iron-deficient and normal rats; postnatal viability and growth in rat pups after oral cadmium administration during gestation; and the effect of calcium and phosphorus on the absorption and toxicity of cadmium. Studies on gastrointestinal absorption and mineral metabolism included: uptake and distribution of orally administered plutonium complex compounds in male mice; gastrointestinal absorption of 144 Ce in the newborn mouse, rat, and pig; and gastrointestinal absorption of 95 Nb by rats of different ages. Studies on iodine metabolism included the following: influence of thyroid status and thiocyanate on iodine metabolism in the bovine; effects of simulated fallout radiation on iodine metabolism in dairy cattle; and effects of feeding iodine binding agents on iodine metabolism in the calf

  2. Proteomic analysis reveals the diversity and complexity of membrane proteins in chickpea (Cicer arietinum L.

    Directory of Open Access Journals (Sweden)

    Jaiswal Dinesh Kumar

    2012-10-01

    Full Text Available Abstract Background Compartmentalization is a unique feature of eukaryotes that helps in maintaining cellular homeostasis not only in intra- and inter-organellar context, but also between the cells and the external environment. Plant cells are highly compartmentalized with a complex metabolic network governing various cellular events. The membranes are the most important constituents in such compartmentalization, and membrane-associated proteins play diverse roles in many cellular processes besides being part of integral component of many signaling cascades. Results To obtain valuable insight into the dynamic repertoire of membrane proteins, we have developed a proteome reference map of a grain legume, chickpea, using two-dimensional gel electrophoresis. MALDI-TOF/TOF and LC-ESI-MS/MS analysis led to the identification of 91 proteins involved in a variety of cellular functions viz., bioenergy, stress-responsive and signal transduction, metabolism, protein synthesis and degradation, among others. Significantly, 70% of the identified proteins are putative integral membrane proteins, possessing transmembrane domains. Conclusions The proteomic analysis revealed many resident integral membrane proteins as well as membrane-associated proteins including those not reported earlier. To our knowledge, this is the first report of membrane proteome from aerial tissues of a crop plant. The findings may provide a better understanding of the biochemical machinery of the plant membranes at the molecular level that might help in functional genomics studies of different developmental pathways and stress-responses.

  3. Significance and challenges of stereoselectivity assessing methods in drug metabolism

    Directory of Open Access Journals (Sweden)

    Zhuowei Shen

    2016-02-01

    Full Text Available Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs is expensive. As a detector of chromatographic methods, mass spectrometry (MS is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

  4. Quantitative Metabolomics and Instationary 13C-Metabolic Flux Analysis Reveals Impact of Recombinant Protein Production on Trehalose and Energy Metabolism in Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Joel Jordà

    2014-05-01

    Full Text Available Pichia pastoris has been recognized as an effective host for recombinant protein production. In this work, we combine metabolomics and instationary 13C metabolic flux analysis (INST 13C-MFA using GC-MS and LC-MS/MS to evaluate the potential impact of the production of a Rhizopus oryzae lipase (Rol on P. pastoris central carbon metabolism. Higher oxygen uptake and CO2 production rates and slightly reduced biomass yield suggest an increased energy demand for the producing strain. This observation is further confirmed by 13C-based metabolic flux analysis. In particular, the flux through the methanol oxidation pathway and the TCA cycle was increased in the Rol-producing strain compared to the reference strain. Next to changes in the flux distribution, significant variations in intracellular metabolite concentrations were observed. Most notably, the pools of trehalose, which is related to cellular stress response, and xylose, which is linked to methanol assimilation, were significantly increased in the recombinant strain.

  5. Coping with Complexity Model Reduction and Data Analysis

    CERN Document Server

    Gorban, Alexander N

    2011-01-01

    This volume contains the extended version of selected talks given at the international research workshop 'Coping with Complexity: Model Reduction and Data Analysis', Ambleside, UK, August 31 - September 4, 2009. This book is deliberately broad in scope and aims at promoting new ideas and methodological perspectives. The topics of the chapters range from theoretical analysis of complex and multiscale mathematical models to applications in e.g., fluid dynamics and chemical kinetics.

  6. Complex Evaluation Oxygen Status and Lipid Metabolism Indexes in Newborns with Perinatal Hypoxia and Hypovolemic Shock

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    Svetlana A. Perepelitsa

    2017-01-01

    Full Text Available Aim. To asses of metabolism, lipid metabolism and oxygen status parameters in newborns with perinatal hypoxia.Materials and Methods. 53 newborn babies born with signs of severe hypoxia and low Apgar scoring equal to 2 at the 1st minute of life were enrolled in the study. Newborns were divided into 2 groups depending on the presence of the clinical presentation of shock: Group 1 «Shock» and Group 2 «Acute intranatal hypoxia» (AIH. All newborns underwent testing for blood gas and acid-base balance, lactate level. Cholesterol and triglyceride levels in the central venous blood were also tested immediately after the birth and on the 5th day of life. Mechanical ventilation mode and parameters were registered. The mean airway pressure (MAP and the oxygen saturation index (OSI were calculated.Results. Severe decompensated metabolic lactic acidosis was diagnosed in a «Shock» group newborns at birth, thus indicating severe perinatal hypoxia which had triggered the development of shock. As for the «AIH» group newborns, they had hyperlactatemia alone. The most severe hypoxemia at birth was diagnosed in newborns of the «Shock» group; the OSI value in these infants was significantly higher than that in «AIH» infants (P<0.01. Despite the treatment and mechanical ventilation, during the posthypoxic period, newborns from the «Shock» group were characterized by increased OSI values over 12 hours after birth. Significantly high levels of OSI persisted for 48 hours after the delivery. Severe hypotriglyceridemia and hypocholesterolemia were found in both group newborns.Conclusion. The study demonstrated that there was intranatal complex metabolism impairment in the case of perinatal hypoxia; at birth, it manifested by metabolic acidosis of various degrees of severity and imbalance of triglycerides and cholesterol levels. The longer and more severe hypoxia is, the more severe acid-base balance and blood lactate level impairment at birth become

  7. Multi-objective experimental design for (13)C-based metabolic flux analysis.

    Science.gov (United States)

    Bouvin, Jeroen; Cajot, Simon; D'Huys, Pieter-Jan; Ampofo-Asiama, Jerry; Anné, Jozef; Van Impe, Jan; Geeraerd, Annemie; Bernaerts, Kristel

    2015-10-01

    (13)C-based metabolic flux analysis is an excellent technique to resolve fluxes in the central carbon metabolism but costs can be significant when using specialized tracers. This work presents a framework for cost-effective design of (13)C-tracer experiments, illustrated on two different networks. Linear and non-linear optimal input mixtures are computed for networks for Streptomyces lividans and a carcinoma cell line. If only glucose tracers are considered as labeled substrate for a carcinoma cell line or S. lividans, the best parameter estimation accuracy is obtained by mixtures containing high amounts of 1,2-(13)C2 glucose combined with uniformly labeled glucose. Experimental designs are evaluated based on a linear (D-criterion) and non-linear approach (S-criterion). Both approaches generate almost the same input mixture, however, the linear approach is favored due to its low computational effort. The high amount of 1,2-(13)C2 glucose in the optimal designs coincides with a high experimental cost, which is further enhanced when labeling is introduced in glutamine and aspartate tracers. Multi-objective optimization gives the possibility to assess experimental quality and cost at the same time and can reveal excellent compromise experiments. For example, the combination of 100% 1,2-(13)C2 glucose with 100% position one labeled glutamine and the combination of 100% 1,2-(13)C2 glucose with 100% uniformly labeled glutamine perform equally well for the carcinoma cell line, but the first mixture offers a decrease in cost of $ 120 per ml-scale cell culture experiment. We demonstrated the validity of a multi-objective linear approach to perform optimal experimental designs for the non-linear problem of (13)C-metabolic flux analysis. Tools and a workflow are provided to perform multi-objective design. The effortless calculation of the D-criterion can be exploited to perform high-throughput screening of possible (13)C-tracers, while the illustrated benefit of multi

  8. Analysis of growth of Lactobacillus plantarum WCFS1 on a complex medium using a genome-scale metabolic model

    NARCIS (Netherlands)

    Teusink, B.; Wiersma, A.; Molenaar, D.; Francke, C.; Vos, de W.M.; Siezen, R.J.; Smid, E.J.

    2006-01-01

    A genome-scale metabolic model of the lactic acid bacterium Lactobacillus plantarum WCFS1 was constructed based on genomic content and experimental data. The complete model includes 721 genes, 643 reactions, and 531 metabolites. Different stoichiometric modeling techniques were used for

  9. Mathematical modeling of cancer metabolism.

    Science.gov (United States)

    Medina, Miguel Ángel

    2018-04-01

    Systemic approaches are needed and useful for the study of the very complex issue of cancer. Modeling has a central position in these systemic approaches. Metabolic reprogramming is nowadays acknowledged as an essential hallmark of cancer. Mathematical modeling could contribute to a better understanding of cancer metabolic reprogramming and to identify new potential ways of therapeutic intervention. Herein, I review several alternative approaches to metabolic modeling and their current and future impact in oncology. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Metabolic Analysis of Medicinal Dendrobium officinale and Dendrobium huoshanense during Different Growth Years.

    Directory of Open Access Journals (Sweden)

    Qing Jin

    Full Text Available Metabolomics technology has enabled an important method for the identification and quality control of Traditional Chinese Medical materials. In this study, we isolated metabolites from cultivated Dendrobium officinale and Dendrobium huoshanense stems of different growth years in the methanol/water phase and identified them using gas chromatography coupled with mass spectrometry (GC-MS. First, a metabolomics technology platform for Dendrobium was constructed. The metabolites in the Dendrobium methanol/water phase were mainly sugars and glycosides, amino acids, organic acids, alcohols. D. officinale and D. huoshanense and their growth years were distinguished by cluster analysis in combination with multivariate statistical analysis, including principal component analysis (PCA and orthogonal partial least squares discriminant analysis (OPLS-DA. Eleven metabolites that contributed significantly to this differentiation were subjected to t-tests (P<0.05 to identify biomarkers that discriminate between D. officinale and D. huoshanense, including sucrose, glucose, galactose, succinate, fructose, hexadecanoate, oleanitrile, myo-inositol, and glycerol. Metabolic profiling of the chemical compositions of Dendrobium species revealed that the polysaccharide content of D. huoshanense was higher than that of D. officinale, indicating that the D. huoshanense was of higher quality. Based on the accumulation of Dendrobium metabolites, the optimal harvest time for Dendrobium was in the third year. This initial metabolic profiling platform for Dendrobium provides an important foundation for the further study of secondary metabolites (pharmaceutical active ingredients and metabolic pathways.

  11. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    OpenAIRE

    Huthmacher, Carola; Hoppe, Andreas; Bulik, Sascha; Holzh?tter, Hermann-Georg

    2010-01-01

    Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicte...

  12. Biotransformation of uranium and transition metal citrate complexes by clostridia

    International Nuclear Information System (INIS)

    Francis, A.J.; Joshi-Tope, G.A.; Dodge, C.J.; Gillow, J.B.

    2002-01-01

    Clostridium sphenoides, which uses citric acid as its sole carbon source, metabolized equimolar Fe(III)-citrate with the degradation of citric acid and the reduction of Fe(III) to Fe(II), but not the U(VI)-citrate complex. However, in the presence of excess citric acid or added glucose it was reduced to U(IV)-citrate. In contrast, Clostridium sp., which ferments glucose but not citrate, reduced Fe(III)-citrate to Fe(II)-citrate and U(VI)-citrate to U(IV)-citrate only when supplied with glucose. These results show that complexed uranium is readily accessible as an electron acceptor despite the bacterium's inability to metabolize the organic ligand complexed to the actinide. These results also show that the metabolism of the metal-citrate complex depends upon the type of complex formed between the metal and citric acid. Fe(III) forms a bidentate complex with citric acid and was metabolized, whereas U forms a binuclear complex with citric acid and was recalcitrant. (author)

  13. Complex of the equipment for instrumental element analysis

    International Nuclear Information System (INIS)

    Borisov, G.I.; Komkov, M.M.; Kuz'michev, V.A.

    1986-01-01

    Complex of the equipment for instrumental element analysis at the IR-8 reactor is designed, fabricated and taken into operation. The complex is provided with a multichannel system of vacuum pneumatic transport with radiation positions in the reactor horizontal tangential channel for neutron-activation analysis by short-lived isotopes; specialized dry vertical channels in a beryllium reflector of the reactor and remote system of radioactive sample replacement for neutron-activation analysis by long-lived isotopes; a specialized horizontal tangential channel for neutron beam extraction by means of a beryllium converter and remote device for studied sample replacement under radiation and measurement of prompt γ-radiation for neutron-radiation analysis; a measuring center using minicomputers for experimental data accumulation and processing and analysis control

  14. Construction and analysis of a genome-scale metabolic network for Bacillus licheniformis WX-02.

    Science.gov (United States)

    Guo, Jing; Zhang, Hong; Wang, Cheng; Chang, Ji-Wei; Chen, Ling-Ling

    2016-05-01

    We constructed the genome-scale metabolic network of Bacillus licheniformis (B. licheniformis) WX-02 by combining genomic annotation, high-throughput phenotype microarray (PM) experiments and literature-based metabolic information. The accuracy of the metabolic network was assessed by an OmniLog PM experiment. The final metabolic model iWX1009 contains 1009 genes, 1141 metabolites and 1762 reactions, and the predicted metabolic phenotypes showed an agreement rate of 76.8% with experimental PM data. In addition, key metabolic features such as growth yield, utilization of different substrates and essential genes were identified by flux balance analysis. A total of 195 essential genes were predicted from LB medium, among which 149 were verified with the experimental essential gene set of B. subtilis 168. With the removal of 5 reactions from the network, pathways for poly-γ-glutamic acid (γ-PGA) synthesis were optimized and the γ-PGA yield reached 83.8 mmol/h. Furthermore, the important metabolites and pathways related to γ-PGA synthesis and bacterium growth were comprehensively analyzed. The present study provides valuable clues for exploring the metabolisms and metabolic regulation of γ-PGA synthesis in B. licheniformis WX-02. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  15. Modeling of Zymomonas mobilis central metabolism for novel metabolic engineering strategies.

    Science.gov (United States)

    Kalnenieks, Uldis; Pentjuss, Agris; Rutkis, Reinis; Stalidzans, Egils; Fell, David A

    2014-01-01

    Mathematical modeling of metabolism is essential for rational metabolic engineering. The present work focuses on several types of modeling approach to quantitative understanding of central metabolic network and energetics in the bioethanol-producing bacterium Zymomonas mobilis. Combined use of Flux Balance, Elementary Flux Mode, and thermodynamic analysis of its central metabolism, together with dynamic modeling of the core catabolic pathways, can help to design novel substrate and product pathways by systematically analyzing the solution space for metabolic engineering, and yields insights into the function of metabolic network, hardly achievable without applying modeling tools.

  16. Differential RNA-seq, Multi-Network Analysis and Metabolic Regulation Analysis of Kluyveromyces marxianus Reveals a Compartmentalised Response to Xylose.

    Directory of Open Access Journals (Sweden)

    Du Toit W P Schabort

    Full Text Available We investigated the transcriptomic response of a new strain of the yeast Kluyveromyces marxianus, in glucose and xylose media using RNA-seq. The data were explored in a number of innovative ways using a variety of networks types, pathway maps, enrichment statistics, reporter metabolites and a flux simulation model, revealing different aspects of the genome-scale response in an integrative systems biology manner. The importance of the subcellular localisation in the transcriptomic response is emphasised here, revealing new insights. As was previously reported by others using a rich medium, we show that peroxisomal fatty acid catabolism was dramatically up-regulated in a defined xylose mineral medium without fatty acids, along with mechanisms to activate fatty acids and transfer products of β-oxidation to the mitochondria. Notably, we observed a strong up-regulation of the 2-methylcitrate pathway, supporting capacity for odd-chain fatty acid catabolism. Next we asked which pathways would respond to the additional requirement for NADPH for xylose utilisation, and rationalised the unexpected results using simulations with Flux Balance Analysis. On a fundamental level, we investigated the contribution of the hierarchical and metabolic regulation levels to the regulation of metabolic fluxes. Metabolic regulation analysis suggested that genetic level regulation plays a major role in regulating metabolic fluxes in adaptation to xylose, even for the high capacity reactions, which is unexpected. In addition, isozyme switching may play an important role in re-routing of metabolic fluxes in subcellular compartments in K. marxianus.

  17. Community health orientation of Indian Journal of Endocrinology and Metabolism: A bibliometric analysis of Indian Journal of Endocrinology and Metabolism

    Science.gov (United States)

    Kaushal, Kanica; Kalra, Sanjay

    2015-01-01

    Background: Endocrine and metabolic diseases especially diabetes have become focus areas for public health professionals. Indian Journal of Endocrinology and Metabolism (IJEM), a publication of Endocrine Society of India, is a peer-reviewed online journal, which covers technical and clinical studies related to health, ethical and social issues in field of diabetes, endocrinology and metabolism. This bibliometric analysis assesses the journal from a community health perspective. Materials and Methods: Every article published in IJEM over a period of 4 years (2011–2014) was accessed to review coverage of community health in the field of endocrinology. Results: Seven editorials, 30 review articles, 41 original articles, 12 brief communications, 20 letter to editors, 4 articles on guidelines and 2 in the section “endocrinology and gender” directly or indirectly dealt with community health aspects of endocrinology. Together these amounted to 17% of all articles published through these 4 years. There were 14 articles on general, 60 pertaining to pancreas and diabetes, 10 on thyroid, 7 on pituitary/adrenal/gonads, 21 on obesity and metabolism and 4 on parathyroid and bone; all community medicine related. Conclusion: Community health is an integral part of the modern endocrinology diabetology and metabolism practice and it received adequate journal space during the last 4 years. The coverage is broad based involving all the major endocrine disorders. PMID:25932398

  18. Community health orientation of Indian Journal of Endocrinology and Metabolism: A bibliometric analysis of Indian Journal of Endocrinology and Metabolism

    Directory of Open Access Journals (Sweden)

    Kanica Kaushal

    2015-01-01

    Full Text Available Background: Endocrine and metabolic diseases especially diabetes have become focus areas for public health professionals. Indian Journal of Endocrinology and Metabolism (IJEM, a publication of Endocrine Society of India, is a peer-reviewed online journal, which covers technical and clinical studies related to health, ethical and social issues in field of diabetes, endocrinology and metabolism. This bibliometric analysis assesses the journal from a community health perspective. Materials and Methods: Every article published in IJEM over a period of 4 years (2011-2014 was accessed to review coverage of community health in the field of endocrinology. Results: Seven editorials, 30 review articles, 41 original articles, 12 brief communications, 20 letter to editors, 4 articles on guidelines and 2 in the section "endocrinology and gender" directly or indirectly dealt with community health aspects of endocrinology. Together these amounted to 17% of all articles published through these 4 years. There were 14 articles on general, 60 pertaining to pancreas and diabetes, 10 on thyroid, 7 on pituitary/adrenal/gonads, 21 on obesity and metabolism and 4 on parathyroid and bone; all community medicine related. Conclusion: Community health is an integral part of the modern endocrinology diabetology and metabolism practice and it received adequate journal space during the last 4 years. The coverage is broad based involving all the major endocrine disorders.

  19. Mitofusin 2 as a driver that controls energy metabolism and insulin signaling.

    Science.gov (United States)

    Zorzano, Antonio; Hernández-Alvarez, María Isabel; Sebastián, David; Muñoz, Juan Pablo

    2015-04-20

    Mitochondrial dynamics is a complex process that impacts on mitochondrial biology. Recent evidence indicates that proteins participating in mitochondrial dynamics have additional cellular roles. Mitofusin 2 (Mfn2) is a potent modulator of mitochondrial metabolism with an impact on energy metabolism in muscle, liver, and hypothalamic neurons. In addition, Mfn2 is subjected to tight regulation. Hence, factors such as proinflammatory cytokines, lipid availability, or glucocorticoids block its expression, whereas exercise and increased energy expenditure promote its upregulation. Importantly, Mfn2 controls cell metabolism and insulin signaling by limiting reactive oxygen species production and by modulation of endoplasmic reticulum stress. In this connection, it is critical to understand precisely the molecular mechanisms involved in the global actions of Mfn2. Future directions should concentrate into the analysis of those mechanisms, and to fully demonstrate that Mfn2 represents a cellular hub that senses the metabolic and hormonal milieu and drives the control of metabolic homeostasis.

  20. Computational Modeling of Lipid Metabolism in Yeast

    Directory of Open Access Journals (Sweden)

    Vera Schützhold

    2016-09-01

    Full Text Available Lipid metabolism is essential for all major cell functions and has recently gained increasing attention in research and health studies. However, mathematical modeling by means of classical approaches such as stoichiometric networks and ordinary differential equation systems has not yet provided satisfactory insights, due to the complexity of lipid metabolism characterized by many different species with only slight differences and by promiscuous multifunctional enzymes.Here, we present a object-oriented stochastic model approach as a way to cope with the complex lipid metabolic network. While all lipid species are treated objects in the model, they can be modified by the respective converting reactions based on reaction rules, a hybrid method that integrates benefits of agent-based and classical stochastic simulation. This approach allows to follow the dynamics of all lipid species with different fatty acids, different degrees of saturation and different headgroups over time and to analyze the effect of parameter changes, potential mutations in the catalyzing enzymes or provision of different precursors. Applied to yeast metabolism during one cell cycle period, we could analyze the distribution of all lipids to the various membranes in time-dependent manner.The presented approach allows to efficiently treat the complexity of cellular lipid metabolism and to derive conclusions on the time- and location-dependent distributions of lipid species and their properties such as saturation. It is widely applicable, easily extendable and will provide further insights in healthy and diseased states of cell metabolism.

  1. Metabolic flux analysis of the halophilic archaeon Haladaptatus paucihalophilus.

    Science.gov (United States)

    Liu, Guangxiu; Zhang, Manxiao; Mo, Tianlu; He, Lian; Zhang, Wei; Yu, Yi; Zhang, Qi; Ding, Wei

    2015-11-27

    This work reports the (13)C-assisted metabolic flux analysis of Haladaptatus paucihalophilus, a halophilic archaeon possessing an intriguing osmoadaption mechanism. We showed that the carbon flow is through the oxidative tricarboxylic acid (TCA) cycle whereas the reductive TCA cycle is not operative in H. paucihalophilus. In addition, both threonine and the citramalate pathways contribute to isoleucine biosynthesis, whereas lysine is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway. Unexpected, the labeling patterns of glycine from the cells grown on [1-(13)C]pyruvate and [2-(13)C]pyruvate suggest that, unlike all the organisms investigated so far, in which glycine is produced exclusively from the serine hydroxymethyltransferase (SHMT) pathway, glycine biosynthesis in H. paucihalophilus involves different pathways including SHMT, threonine aldolase (TA) and the reverse reaction of glycine cleavage system (GCS), demonstrating for the first time that other pathways instead of SHMT can also make a significant contribution to the cellular glycine pool. Transcriptional analysis confirmed that both TA and GCS genes were transcribed in H. paucihalophilus, and the transcriptional level is independent of salt concentrations in the culture media. This study expands our understanding of amino acid biosynthesis and provides valuable insights into the metabolism of halophilic archaea. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. From Network Analysis to Functional Metabolic Modeling of the Human Gut Microbiota.

    Science.gov (United States)

    Bauer, Eugen; Thiele, Ines

    2018-01-01

    An important hallmark of the human gut microbiota is its species diversity and complexity. Various diseases have been associated with a decreased diversity leading to reduced metabolic functionalities. Common approaches to investigate the human microbiota include high-throughput sequencing with subsequent correlative analyses. However, to understand the ecology of the human gut microbiota and consequently design novel treatments for diseases, it is important to represent the different interactions between microbes with their associated metabolites. Computational systems biology approaches can give further mechanistic insights by constructing data- or knowledge-driven networks that represent microbe interactions. In this minireview, we will discuss current approaches in systems biology to analyze the human gut microbiota, with a particular focus on constraint-based modeling. We will discuss various community modeling techniques with their advantages and differences, as well as their application to predict the metabolic mechanisms of intestinal microbial communities. Finally, we will discuss future perspectives and current challenges of simulating realistic and comprehensive models of the human gut microbiota.

  3. Quantifying interictal metabolic activity in human temporal lobe epilepsy

    International Nuclear Information System (INIS)

    Henry, T.R.; Mazziotta, J.C.; Engel, J. Jr.; Christenson, P.D.; Zhang, J.X.; Phelps, M.E.; Kuhl, D.E.

    1990-01-01

    The majority of patients with complex partial seizures of unilateral temporal lobe origin have interictal temporal hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG PET) studies. Often, this hypometabolism extends to ipsilateral extratemporal sites. The use of accurately quantified metabolic data has been limited by the absence of an equally reliable method of anatomical analysis of PET images. We developed a standardized method for visual placement of anatomically configured regions of interest on FDG PET studies, which is particularly adapted to the widespread, asymmetric, and often severe interictal metabolic alterations of temporal lobe epilepsy. This method was applied by a single investigator, who was blind to the identity of subjects, to 10 normal control and 25 interictal temporal lobe epilepsy studies. All subjects had normal brain anatomical volumes on structural neuroimaging studies. The results demonstrate ipsilateral thalamic and temporal lobe involvement in the interictal hypometabolism of unilateral temporal lobe epilepsy. Ipsilateral frontal, parietal, and basal ganglial metabolism is also reduced, although not as markedly as is temporal and thalamic metabolism

  4. Dietary Interventions and Changes in Cardio-Metabolic Parameters in Metabolically Healthy Obese Subjects: A Systematic Review with Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Marta Stelmach-Mardas

    2016-07-01

    Full Text Available The aim of this systematic review was to assess the effect of diet on changes in parameters describing the body size phenotype of metabolically healthy obese subjects. The databases Medline, Scopus, Web of Knowledge and Embase were searched for clinical studies carried out between 1958 and June 2016 that reported the effect of dietary intervention on BMI, blood pressure, concentration of fasting triglyceride (TG, high density lipoprotein cholesterol (HDL-C, fasting glucose level, the homoeostatic model assessment of insulin resistance (HOMA-IR and high sensitivity C-Reactive Protein (hsCRP in metabolically healthy, obese subjects. Twelve clinical studies met inclusion criteria. The combined analyzed population consists of 1827 subjects aged 34.4 to 61.1 with a BMI > 30 kg/m2. Time of intervention ranged from eight to 104 weeks. The baseline characteristics related to lipid profile were more favorable for metabolically healthy obese than for metabolically unhealthy obese. The meta-analyses revealed a significant associations between restricted energy diet and BMI (95% confidence interval (CI: −0.88, −0.19, blood pressure (systolic blood pressure (SBP: −4.73 mmHg; 95% CI: −7.12, −2.33; and diastolic blood pressure (DBP: −2.75 mmHg; 95% CI: −4.30, −1.21 and TG (−0.11 mmol/l; 95% CI: −0.16, −0.06. Changes in fasting glucose, HOMA-IR and hsCRP did not show significant changes. Sufficient evidence was not found to support the use of specific diets in metabolically healthy obese subjects. This analysis suggests that the effect of caloric restriction exerts its effects through a reduction in BMI, blood pressure and triglycerides in metabolically healthy obese (MHO patients.

  5. In vitro formation of metabolic-intermediate cytochrome P450 complexes in rabbit liver microsomes by tiamulin and various macrolides.

    Science.gov (United States)

    Carletti, Monica; Gusson, Federica; Zaghini, Anna; Dacasto, Mauro; Marvasi, Luigi; Nebbia, Carlo

    2003-01-01

    Tiamulin and a number of macrolides were evaluated as to their ability in forming metabolic-intermediate (MI) complexes with cytochrome P450 in liver microsomes from rabbits bred for meat production. Complex formation, which occurred only in preparations where the expression of P450 3A was increased as the result of rifampicin pre-treatment and with different kinetics, was in the order tiamulin > erythromycin > TAO approximately roxithromycin approximately tylosin and did not take place with tilmicosin and spiramycin. Most of the tested compounds underwent an oxidative N-dealkylation and a good relationship could be found between the rate of N-dealkylase activity in induced preparations and the aptitude in generating MI complexes. Although the results from in vitro studies should be interpreted with caution, it is suggested that the potential for in vivo drug interactions also exists in the rabbit for tiamulin and for four out of the six tested macrolides.

  6. Metabolic Flux Analysis of Shewanella spp. Reveals Evolutionary Robustness in Central Carbon Metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Yinjie J.; Martin, Hector Garcia; Dehal, Paramvir S.; Deutschbauer, Adam; Llora, Xavier; Meadows, Adam; Arkin, Adam; Keasling, Jay D.

    2009-08-19

    Shewanella spp. are a group of facultative anaerobic bacteria widely distributed in marine and fresh-water environments. In this study, we profiled the central metabolic fluxes of eight recently sequenced Shewanella species grown under the same condition in minimal med-ium with [3-13C] lactate. Although the tested Shewanella species had slightly different growth rates (0.23-0.29 h31) and produced different amounts of acetate and pyruvate during early exponential growth (pseudo-steady state), the relative intracellular metabolic flux distributions were remarkably similar. This result indicates that Shewanella species share similar regulation in regard to central carbon metabolic fluxes under steady growth conditions: the maintenance of metabolic robustness is not only evident in a single species under genetic perturbations (Fischer and Sauer, 2005; Nat Genet 37(6):636-640), but also observed through evolutionary related microbial species. This remarkable conservation of relative flux profiles through phylogenetic differences prompts us to introduce the concept of metabotype as an alternative scheme to classify microbial fluxomics. On the other hand, Shewanella spp. display flexibility in the relative flux profiles when switching their metabolism from consuming lactate to consuming pyruvate and acetate.

  7. Integrative Genomic Analysis of Complex traits

    DEFF Research Database (Denmark)

    Ehsani, Ali Reza

    In the last decade rapid development in biotechnologies has made it possible to extract extensive information about practically all levels of biological organization. An ever-increasing number of studies are reporting miltilayered datasets on the entire DNA sequence, transceroption, protein...... expression, and metabolite abundance of more and more populations in a multitude of invironments. However, a solid model for including all of this complex information in one analysis, to disentangle genetic variation and the underlying genetic architecture of complex traits and diseases, has not yet been...

  8. An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids

    International Nuclear Information System (INIS)

    Feng Jianghua; Liu Huili; Zhang Limin; Bhakoo, Kishore; Lu Lehui

    2010-01-01

    Ultra-small superparamagnetic particles of iron oxides (USPIO) have been developed as intravenous organ/tissue-targeted contrast agents to improve magnetic resonance imaging (MRI) in vivo. However, their potential toxicity and effects on metabolism have attracted particular attention. In the present study, uncoated and dextran-coated USPIO were investigated by analyzing both rat urine and plasma metabonomes using high-resolution NMR-based metabonomic analysis in combination with multivariate statistical analysis. The wealth of information gathered on the metabolic profiles from rat urine and plasma has revealed subtle metabolic changes in response to USPIO administration. The metabolic changes include the elevation of urinary α-hydroxy-n-valerate, o- and p-HPA, PAG, nicotinate and hippurate accompanied by decreases in the levels of urinary α-ketoglutarate, succinate, citrate, N-methylnicotinamide, NAG, DMA, allantoin and acetate following USPIO administration. The changes associated with USPIO administration included a gradual increase in plasma glucose, N-acetyl glycoprotein, saturated fatty acid, citrate, succinate, acetate, GPC, ketone bodies (β-hydroxybutyrate, acetone and acetoacetate) and individual amino acids, such as phenylalanine, lysine, isoleucine, glycine, glutamine and glutamate and a gradual decrease of myo-inositol, unsaturated fatty acid and triacylglycerol. Hence USPIO administration effects are reflected in changes in a number of metabolic pathways including energy, lipid, glucose and amino acid metabolism. The size- and surface chemistry-dependent metabolic responses and possible toxicity were observed using NMR analysis of biofluids. These changes may be attributed to the disturbances of hepatic, renal and cardiac functions following USPIO administrations. The potential biotoxicity can be derived from metabonomic analysis and serum biochemistry analysis. Metabonomic strategy offers a promising approach for the detection of subtle

  9. An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids

    Science.gov (United States)

    Feng, Jianghua; Liu, Huili; Zhang, Limin; Bhakoo, Kishore; Lu, Lehui

    2010-10-01

    Ultra-small superparamagnetic particles of iron oxides (USPIO) have been developed as intravenous organ/tissue-targeted contrast agents to improve magnetic resonance imaging (MRI) in vivo. However, their potential toxicity and effects on metabolism have attracted particular attention. In the present study, uncoated and dextran-coated USPIO were investigated by analyzing both rat urine and plasma metabonomes using high-resolution NMR-based metabonomic analysis in combination with multivariate statistical analysis. The wealth of information gathered on the metabolic profiles from rat urine and plasma has revealed subtle metabolic changes in response to USPIO administration. The metabolic changes include the elevation of urinary α-hydroxy-n-valerate, o- and p-HPA, PAG, nicotinate and hippurate accompanied by decreases in the levels of urinary α-ketoglutarate, succinate, citrate, N-methylnicotinamide, NAG, DMA, allantoin and acetate following USPIO administration. The changes associated with USPIO administration included a gradual increase in plasma glucose, N-acetyl glycoprotein, saturated fatty acid, citrate, succinate, acetate, GPC, ketone bodies (β-hydroxybutyrate, acetone and acetoacetate) and individual amino acids, such as phenylalanine, lysine, isoleucine, glycine, glutamine and glutamate and a gradual decrease of myo-inositol, unsaturated fatty acid and triacylglycerol. Hence USPIO administration effects are reflected in changes in a number of metabolic pathways including energy, lipid, glucose and amino acid metabolism. The size- and surface chemistry-dependent metabolic responses and possible toxicity were observed using NMR analysis of biofluids. These changes may be attributed to the disturbances of hepatic, renal and cardiac functions following USPIO administrations. The potential biotoxicity can be derived from metabonomic analysis and serum biochemistry analysis. Metabonomic strategy offers a promising approach for the detection of subtle

  10. An insight into the metabolic responses of ultra-small superparamagnetic particles of iron oxide using metabonomic analysis of biofluids

    Energy Technology Data Exchange (ETDEWEB)

    Feng Jianghua [Department of Physics, Fujian Key Laboratory of Plasma and Magnetic Resonance, State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen, 361005 (China); Liu Huili; Zhang Limin [State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071 (China); Bhakoo, Kishore [Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A-STAR) 138667 (Singapore); Lu Lehui, E-mail: jianghua.feng@hotmail.com, E-mail: jianghua.feng@wipm.ac.cn [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022 (China)

    2010-10-01

    Ultra-small superparamagnetic particles of iron oxides (USPIO) have been developed as intravenous organ/tissue-targeted contrast agents to improve magnetic resonance imaging (MRI) in vivo. However, their potential toxicity and effects on metabolism have attracted particular attention. In the present study, uncoated and dextran-coated USPIO were investigated by analyzing both rat urine and plasma metabonomes using high-resolution NMR-based metabonomic analysis in combination with multivariate statistical analysis. The wealth of information gathered on the metabolic profiles from rat urine and plasma has revealed subtle metabolic changes in response to USPIO administration. The metabolic changes include the elevation of urinary {alpha}-hydroxy-n-valerate, o- and p-HPA, PAG, nicotinate and hippurate accompanied by decreases in the levels of urinary {alpha}-ketoglutarate, succinate, citrate, N-methylnicotinamide, NAG, DMA, allantoin and acetate following USPIO administration. The changes associated with USPIO administration included a gradual increase in plasma glucose, N-acetyl glycoprotein, saturated fatty acid, citrate, succinate, acetate, GPC, ketone bodies ({beta}-hydroxybutyrate, acetone and acetoacetate) and individual amino acids, such as phenylalanine, lysine, isoleucine, glycine, glutamine and glutamate and a gradual decrease of myo-inositol, unsaturated fatty acid and triacylglycerol. Hence USPIO administration effects are reflected in changes in a number of metabolic pathways including energy, lipid, glucose and amino acid metabolism. The size- and surface chemistry-dependent metabolic responses and possible toxicity were observed using NMR analysis of biofluids. These changes may be attributed to the disturbances of hepatic, renal and cardiac functions following USPIO administrations. The potential biotoxicity can be derived from metabonomic analysis and serum biochemistry analysis. Metabonomic strategy offers a promising approach for the detection of

  11. System-Level and Granger Network Analysis of Integrated Proteomic and Metabolomic Dynamics Identifies Key Points of Grape Berry Development at the Interface of Primary and Secondary Metabolism

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2017-06-01

    Full Text Available Grapevine is a fruit crop with worldwide economic importance. The grape berry undergoes complex biochemical changes from fruit set until ripening. This ripening process and production processes define the wine quality. Thus, a thorough understanding of berry ripening is crucial for the prediction of wine quality. For a systemic analysis of grape berry development we applied mass spectrometry based platforms to analyse the metabolome and proteome of Early Campbell at 12 stages covering major developmental phases. Primary metabolites involved in central carbon metabolism, such as sugars, organic acids and amino acids together with various bioactive secondary metabolites like flavonols, flavan-3-ols and anthocyanins were annotated and quantified. At the same time, the proteomic analysis revealed the protein dynamics of the developing grape berries. Multivariate statistical analysis of the integrated metabolomic and proteomic dataset revealed the growth trajectory and corresponding metabolites and proteins contributing most to the specific developmental process. K-means clustering analysis revealed 12 highly specific clusters of co-regulated metabolites and proteins. Granger causality network analysis allowed for the identification of time-shift correlations between metabolite-metabolite, protein- protein and protein-metabolite pairs which is especially interesting for the understanding of developmental processes. The integration of metabolite and protein dynamics with their corresponding biochemical pathways revealed an energy-linked metabolism before veraison with high abundances of amino acids and accumulation of organic acids, followed by protein and secondary metabolite synthesis. Anthocyanins were strongly accumulated after veraison whereas other flavonoids were in higher abundance at early developmental stages and decreased during the grape berry developmental processes. A comparison of the anthocyanin profile of Early Campbell to other

  12. System-Level and Granger Network Analysis of Integrated Proteomic and Metabolomic Dynamics Identifies Key Points of Grape Berry Development at the Interface of Primary and Secondary Metabolism.

    Science.gov (United States)

    Wang, Lei; Sun, Xiaoliang; Weiszmann, Jakob; Weckwerth, Wolfram

    2017-01-01

    Grapevine is a fruit crop with worldwide economic importance. The grape berry undergoes complex biochemical changes from fruit set until ripening. This ripening process and production processes define the wine quality. Thus, a thorough understanding of berry ripening is crucial for the prediction of wine quality. For a systemic analysis of grape berry development we applied mass spectrometry based platforms to analyse the metabolome and proteome of Early Campbell at 12 stages covering major developmental phases. Primary metabolites involved in central carbon metabolism, such as sugars, organic acids and amino acids together with various bioactive secondary metabolites like flavonols, flavan-3-ols and anthocyanins were annotated and quantified. At the same time, the proteomic analysis revealed the protein dynamics of the developing grape berries. Multivariate statistical analysis of the integrated metabolomic and proteomic dataset revealed the growth trajectory and corresponding metabolites and proteins contributing most to the specific developmental process. K-means clustering analysis revealed 12 highly specific clusters of co-regulated metabolites and proteins. Granger causality network analysis allowed for the identification of time-shift correlations between metabolite-metabolite, protein- protein and protein-metabolite pairs which is especially interesting for the understanding of developmental processes. The integration of metabolite and protein dynamics with their corresponding biochemical pathways revealed an energy-linked metabolism before veraison with high abundances of amino acids and accumulation of organic acids, followed by protein and secondary metabolite synthesis. Anthocyanins were strongly accumulated after veraison whereas other flavonoids were in higher abundance at early developmental stages and decreased during the grape berry developmental processes. A comparison of the anthocyanin profile of Early Campbell to other cultivars revealed

  13. Differential proteomic analysis reveals novel links between primary metabolism and antibiotic production in Amycolatopsis balhimycina

    DEFF Research Database (Denmark)

    Gallo, G.; Renzone, G.; Alduina, R.

    2010-01-01

    A differential proteomic analysis, based on 2-DE and MS procedures, was performed on Amycolatopsis balhimycina DSM5908, the actinomycete producing the vancomycin-like antibiotic balhimycin. A comparison of proteomic profiles before and during balhimycin production characterized differentially...... available over the World Wide Web as interactive web pages (http://www.unipa.it/ampuglia/Abal-proteome-maps). Functional clustering analysis revealed that differentially expressed proteins belong to functional groups involved in central carbon metabolism, amino acid metabolism and protein biosynthesis...... intermediates, were upregulated during antibiotic production. qRT-PCR analysis revealed that 8 out of 14 upregulated genes showed a positive correlation between changes at translational and transcriptional expression level. Furthermore, proteomic analysis of two nonproducing mutants, restricted to a sub...

  14. Prevalence of metabolic syndrome in Middle-East countries: Meta-analysis of cross-sectional studies.

    Science.gov (United States)

    Ansarimoghaddam, Alireza; Adineh, Hosein Ali; Zareban, Iraj; Iranpour, Sohrab; HosseinZadeh, Ali; Kh, Framanfarma

    Metabolic syndrome is an important metabolic disorder which impose noticeable burden on health system. We aimed to review and imply the prevalence of it in Middle-East countries. present study was a systematic review to present overview about metabolic disorder in Middle East. Electronic literature search of Medline database and Google scholar were done for English-language articles without time filtering, as well as for population-based or national studies of the prevalence of metabolic syndrome. The fallowing search terms were used simultaneously: prevalence of " metabolic syndrome" and "national study", "prevalence of metabolic syndrome in Middle East", "prevalence of metabolic syndrome" and "name of country", "metabolic syndrome &name of country". Additionally, relevant articles in bibliography were searched. Analysis of data was carried out in STATA version 11.0. out of 456 studies in first-step searching (selecting by title) 59 studies were recruited and reviewed. Prevalence of metabolic syndrome fluctuated by country and time of study. This amount was 2.2-44% in Turkish, 16-41% in Saudi-Arabia, 14-63 in Pakistan, 26-33 in Qatar, 9-36 in Kuwait, 22-50 in Emirate, 6-42 in Iran, and up to 23 in Yemen. Pooled estimate was 25%. Attributable risk for cardiovascular disease, coronary heart disease, and stroke was 15.87, 11.7, and 16.23, respectively. The prevalence rate of metabolic syndrome is high and it is noticeable cause for stroke, coronary heart disease, and cardiovascular disease. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  15. Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis.

    Science.gov (United States)

    Chen, Rui; Han, Su; Liu, Xuefeng; Wang, Kunpeng; Zhou, Yong; Yang, Chundong; Zhang, Xi

    2018-05-15

    Osteoarthritis (OA) is a degenerative synovial joint disease affecting people worldwide. However, the exact pathogenesis of OA remains unclear. Metabolomics analysis was performed to obtain insight into possible pathogenic mechanisms and diagnostic biomarkers of OA. Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQ-MS), followed by multivariate statistical analysis, was used to determine the serum amino acid profiles of 32 OA patients and 35 healthy controls. Variable importance for project values and Student's t-test were used to determine the metabolic abnormalities in OA. Another 30 OA patients were used as independent samples to validate the alterations in amino acids. MetaboAnalyst was used to identify the key amino acid pathways and construct metabolic networks describing their relationships. A total of 25 amino acids and four biogenic amines were detected by UPLC-TQ-MS. Differences in amino acid profiles were found between the healthy controls and OA patients. Alanine, γ-aminobutyric acid and 4-hydroxy-l-proline were important biomarkers distinguishing OA patients from healthy controls. The metabolic pathways with the most significant effects were involved in metabolism of alanine, aspartate, glutamate, arginine and proline. The results of this study improve understanding of the amino acid metabolic abnormalities and pathogenic mechanisms of OA at the molecular level. The metabolic perturbations may be important for the diagnosis and prevention of OA. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Cluster analysis of cardiovascular and metabolic risk factors in women of reproductive age.

    Science.gov (United States)

    Tzeng, Chii-Ruey; Chang, Yuan-chin Ivan; Chang, Yu-chia; Wang, Chia-Woei; Chen, Chi-Huang; Hsu, Ming-I

    2014-05-01

    To study the association between endocrine disturbances and metabolic complications in women seeking gynecologic care. Retrospective study, cluster analysis. Outpatient clinic, university medical center. 573 women, including 384 at low risk and 189 at high risk of cardiometabolic disease. None. Cardiovascular and metabolic parameters and clinical and biochemical characteristics. Risk factors for metabolic disease are associated with a low age of menarche, high levels of high-sensitivity C-reactive protein and liver enzymes, and low levels of sex hormone-binding globulin. Overweight/obese status, polycystic ovary syndrome, oligo/amenorrhea, and hyperandrogenism were found to increase the risk of cardiometabolic disease. However, hyperprolactinemia and premature ovarian failure were not associated with the risk of cardiometabolic disease. In terms of androgens, the serum total testosterone level and free androgen index but not androstenedione or dehydroepiandrosterone sulfate (DHEAS) were associated with cardiometabolic risk. Although polycystic ovary syndrome is associated with metabolic risk, obesity was the major determinant of cardiometabolic disturbances in reproductive-aged women. Hyperprolactinemia and premature ovarian failure were not associated with the risk of cardiovascular and metabolic diseases. NCT01826357. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  17. Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study.

    Science.gov (United States)

    Silvestri, Elena; Glinni, Daniela; Cioffi, Federica; Moreno, Maria; Lombardi, Assunta; de Lange, Pieter; Senese, Rosalba; Ceccarelli, Michele; Salzano, Anna Maria; Scaloni, Andrea; Lanni, Antonia; Goglia, Fernando

    2012-07-06

    A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (α1/β1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens.

  18. Special Year on Complex Analysis held at the University of Maryland

    CERN Document Server

    1987-01-01

    The past several years have witnessed a striking number of important developments in Complex Analysis. One of the characteristics of these developments has been to bridge the gap existing between the theory of functions of one and of several complex variables. The Special Year in Complex Analysis at the University of Maryland, and these proceedings, were conceived as a forum where these new developments could be presented and where specialists in different areas of complex analysis could exchange ideas. These proceedings contain both surveys of different subjects covered during the year as well as many new results and insights. The manuscripts are accessible not only to specialists but to a broader audience. Among the subjects touched upon are Nevanlinna theory in one and several variables, interpolation problems in Cn, estimations and integral representations of the solutions of the Cauchy-Riemann equations, the complex Monge-Ampère equation, geometric problems in complex analysis in Cn, applications of com...

  19. Complex Wavelet Based Modulation Analysis

    DEFF Research Database (Denmark)

    Luneau, Jean-Marc; Lebrun, Jérôme; Jensen, Søren Holdt

    2008-01-01

    Low-frequency modulation of sound carry important information for speech and music. The modulation spectrum i commonly obtained by spectral analysis of the sole temporal envelopes of the sub-bands out of a time-frequency analysis. Processing in this domain usually creates undesirable distortions...... polynomial trends. Moreover an analytic Hilbert-like transform is possible with complex wavelets implemented as an orthogonal filter bank. By working in an alternative transform domain coined as “Modulation Subbands”, this transform shows very promising denoising capabilities and suggests new approaches for joint...

  20. The Relationship between the Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Metabolic Syndrome.

    Science.gov (United States)

    Shin, Hyun-Gyu; Kim, Young-Kwang; Kim, Yong-Hwan; Jung, Yo-Han; Kang, Hee-Cheol

    2017-11-01

    Metabolic syndrome is associated with cardiovascular diseases and is characterized by insulin resistance. Recent studies suggest that the triglyceride/high-density lipoprotein cholesterol (TG/HDLC) ratio predicts insulin resistance better than individual lipid levels, including TG, total cholesterol, low-density lipoprotein cholesterol (LDLC), or HDLC. We aimed to elucidate the relationship between the TG/HDLC ratio and metabolic syndrome in the general Korean population. We evaluated the data of adults ≥20 years old who were enrolled in the Korean National Health and Nutrition Examination Survey in 2013 and 2014. Subjects with angina pectoris, myocardial infarction, stroke, or cancer were excluded. Metabolic syndrome was defined by the harmonized definition. We examined the odds ratios (ORs) of metabolic syndrome according to TG/HDLC ratio quartiles using logistic regression analysis (SAS ver. 9.4; SAS Institute Inc., Cary, NC, USA). Weighted complex sample analysis was also conducted. We found a significant association between the TG/HDLC ratio and metabolic syndrome. The cutoff value of the TG/HDLC ratio for the fourth quartile was ≥3.52. After adjustment, the OR for metabolic syndrome in the fourth quartile compared with that of the first quartile was 29.65 in men and 20.60 in women (Pmetabolic syndrome.

  1. LKB1 promotes metabolic flexibility in response to energy stress.

    Science.gov (United States)

    Parker, Seth J; Svensson, Robert U; Divakaruni, Ajit S; Lefebvre, Austin E; Murphy, Anne N; Shaw, Reuben J; Metallo, Christian M

    2017-09-01

    The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using 13 C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1. Re-expression of LKB1 also increased the capacity of cells to oxidize major mitochondrial substrates, including pyruvate, fatty acids, and glutamine. Furthermore, LKB1 expression promoted an adaptive response to energy stress induced by anchorage-independent growth. Finally, this diminished adaptability sensitized LKB1-deficient cells to combinatorial inhibition of mitochondrial complex I and glutaminase. Together, our data implicate LKB1 as a major regulator of adaptive metabolic reprogramming and suggest synergistic pharmacological strategies for mitigating LKB1-deficient NSCLC tumor growth. Copyright © 2016. Published by Elsevier Inc.

  2. 2005 Plant Metabolic Engineering Gordon Conference - July 10-15, 2005

    Energy Technology Data Exchange (ETDEWEB)

    Eleanore T. Wurtzel

    2006-06-30

    The post-genomic era presents new opportunities for manipulating plant chemistry for improvement of plant traits such as disease and stress resistance and nutritional qualities. This conference will provide a setting for developing multidisciplinary collaborations needed to unravel the dynamic complexity of plant metabolic networks and advance basic and applied research in plant metabolic engineering. The conference will integrate recent advances in genomics, with metabolite and gene expression analyses. Research discussions will explore how biosynthetic pathways interact with regard to substrate competition and channeling, plasticity of biosynthetic enzymes, and investigate the localization, structure, and assembly of biosynthetic metabolons in native and nonnative environments. The meeting will develop new perspectives for plant transgenic research with regard to how transgene expression may influence cellular metabolism. Incorporation of spectroscopic approaches for metabolic profiling and flux analysis combined with mathematical modeling will contribute to the development of rational metabolic engineering strategies and lead to the development of new tools to assess temporal and subcellular changes in metabolite pools. The conference will also highlight new technologies for pathway engineering, including use of heterologous systems, directed enzyme evolution, engineering of transcription factors and application of molecular/genetic techniques for controlling biosynthetic pathways.

  3. MicrobesFlux: a web platform for drafting metabolic models from the KEGG database

    Directory of Open Access Journals (Sweden)

    Feng Xueyang

    2012-08-01

    database. Our system facilitates users to reconstruct metabolic networks of organisms based on experimental information. Through human-computer interaction, MicrobesFlux provides users with reasonable predictions of microbial metabolism via flux balance analysis. This prototype platform can be a springboard for advanced and broad-scope modeling of complex biological systems by integrating other “omics” data or 13 C- metabolic flux analysis results. MicrobesFlux is available at http://tanglab.engineering.wustl.edu/static/MicrobesFlux.html and will be continuously improved based on feedback from users.

  4. Three-dimensional quantification of structures in trabecular bone using measures of complexity

    DEFF Research Database (Denmark)

    Marwan, Norbert; Kurths, Jürgen; Thomsen, Jesper Skovhus

    2009-01-01

    The study of pathological changes of bone is an important task in diagnostic procedures of patients with metabolic bone diseases such as osteoporosis as well as in monitoring the health state of astronauts during long-term space flights. The recent availability of high-resolution three-dimensiona......The study of pathological changes of bone is an important task in diagnostic procedures of patients with metabolic bone diseases such as osteoporosis as well as in monitoring the health state of astronauts during long-term space flights. The recent availability of high-resolution three......-dimensional (3D) imaging of bone challenges the development of data analysis techniques able to assess changes of the 3D microarchitecture of trabecular bone. We introduce an approach based on spatial geometrical properties and define structural measures of complexity for 3D image analysis. These measures...... evaluate different aspects of organization and complexity of 3D structures, such as complexity of its surface or shape variability. We apply these measures to 3D data acquired by high-resolution microcomputed tomography (µCT) from human proximal tibiae and lumbar vertebrae at different stages...

  5. Complexity Analysis of Industrial Organizations Based on a Perspective of Systems Engineering Analysts

    Directory of Open Access Journals (Sweden)

    I. H. Garbie

    2011-12-01

    Full Text Available Complexity in industrial organizations became more difficult and complex to be solved and it needs more attention from academicians and technicians. For these reasons, complexity in industrial organizations represents a new challenge in the next decades. Until now, analysis of industrial organizations complexity is still remaining a research topic of immense international interest and they require reduction in their complexity. In this paper, analysis of complexity in industrial organizations is shown based on the perspective of systems engineering analyst. In this perspective, analysis of complexity was divided into different levels and these levels were defined as complexity levels. A framework of analyzing these levels was proposed and suggested based on the complexity in industrial organizations. This analysis was divided into four main issues: industrial system vision, industrial system structure, industrial system operating, and industrial system evaluating. This analysis shows that the complexity of industrial organizations is still an ill-structured and a multi-dimensional problem.

  6. Uncovering transcriptional regulation of metabolism by using metabolic network topology

    DEFF Research Database (Denmark)

    Patil, Kiran Raosaheb; Nielsen, Jens

    2005-01-01

    in the metabolic network that follow a common transcriptional response. Thus, the algorithm enables identification of so-called reporter metabolites (metabolites around which the most significant transcriptional changes occur) and a set of connected genes with significant and coordinated response to genetic......Cellular response to genetic and environmental perturbations is often reflected and/or mediated through changes in the metabolism, because the latter plays a key role in providing Gibbs free energy and precursors for biosynthesis. Such metabolic changes are often exerted through transcriptional...... therefore developed an algorithm that is based on hypothesis-driven data analysis to uncover the transcriptional regulatory architecture of metabolic networks. By using information on the metabolic network topology from genome-scale metabolic reconstruction, we show that it is possible to reveal patterns...

  7. An Alternative Front End Analysis Strategy for Complex Systems

    Science.gov (United States)

    2014-12-01

    missile ( ABM ) system . Patriot is employed in the field through a battalion echelon organizational structure. The line battery is the basic building...Research Report 1981 An Alternative Front End Analysis Strategy for Complex Systems M. Glenn Cobb U.S. Army Research Institute...NUMBER W5J9CQ11D0003 An Alternative Front End Analysis Strategy for Complex Systems 5b. PROGRAM ELEMENT NUMBER 633007 6

  8. Assessment of chitosan-affected metabolic response by peroxisome proliferator-activated receptor bioluminescent imaging-guided transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Chia-Hung Kao

    Full Text Available Chitosan has been widely used in food industry as a weight-loss aid and a cholesterol-lowering agent. Previous studies have shown that chitosan affects metabolic responses and contributes to anti-diabetic, hypocholesteremic, and blood glucose-lowering effects; however, the in vivo targeting sites and mechanisms of chitosan remain to be clarified. In this study, we constructed transgenic mice, which carried the luciferase genes driven by peroxisome proliferator-activated receptor (PPAR, a key regulator of fatty acid and glucose metabolism. Bioluminescent imaging of PPAR transgenic mice was applied to report the organs that chitosan acted on, and gene expression profiles of chitosan-targeted organs were further analyzed to elucidate the mechanisms of chitosan. Bioluminescent imaging showed that constitutive PPAR activities were detected in brain and gastrointestinal tract. Administration of chitosan significantly activated the PPAR activities in brain and stomach. Microarray analysis of brain and stomach showed that several pathways involved in lipid and glucose metabolism were regulated by chitosan. Moreover, the expression levels of metabolism-associated genes like apolipoprotein B (apoB and ghrelin genes were down-regulated by chitosan. In conclusion, these findings suggested the feasibility of PPAR bioluminescent imaging-guided transcriptomic analysis on the evaluation of chitosan-affected metabolic responses in vivo. Moreover, we newly identified that downregulated expression of apoB and ghrelin genes were novel mechanisms for chitosan-affected metabolic responses in vivo.

  9. Norepinephrine metabolism in humans. Kinetic analysis and model

    International Nuclear Information System (INIS)

    Linares, O.A.; Jacquez, J.A.; Zech, L.A.; Smith, M.J.; Sanfield, J.A.; Morrow, L.A.; Rosen, S.G.; Halter, J.B.

    1987-01-01

    The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [ 3 H]NE infusion and postinfusion plasma disappearance of [ 3 H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [ 3 H]NE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P less than 0.01) and upright (r = 0.90-0.98, all P less than 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87 +/- 0.08 vs. 3.25 +/- 0.2 micrograms/min per m2, P less than 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5 +/- 0.6 vs. 4.7 +/- 0.3 liters, P less than 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80 +/- 0.11 vs. 1.21 +/- 0.08 liters/min per m2, P less than 0.001). We conclude that a two-compartment model is the minimal model that can accurately describe the kinetics of distribution and metabolism of NE in humans

  10. Genomic Analysis of Complex Microbial Communities in Wounds

    Science.gov (United States)

    2012-01-01

    Permutation Multivariate Analysis of Variance ( PerMANOVA ). We used PerMANOVA to test the null-hypothesis of no... permutation -based version of the multivariate analysis of variance (MANOVA). PerMANOVA uses the distances between samples to partition variance and...coli. Antibiotics, bacteria, community analysis , diabetes, pyrosequencing, wound, wound therapy, 16S rRNA gene Genomic Analysis of Complex

  11. Zea mays iRS1563: A Comprehensive Genome-Scale Metabolic Reconstruction of Maize Metabolism

    Science.gov (United States)

    Saha, Rajib; Suthers, Patrick F.; Maranas, Costas D.

    2011-01-01

    The scope and breadth of genome-scale metabolic reconstructions have continued to expand over the last decade. Herein, we introduce a genome-scale model for a plant with direct applications to food and bioenergy production (i.e., maize). Maize annotation is still underway, which introduces significant challenges in the association of metabolic functions to genes. The developed model is designed to meet rigorous standards on gene-protein-reaction (GPR) associations, elementally and charged balanced reactions and a biomass reaction abstracting the relative contribution of all biomass constituents. The metabolic network contains 1,563 genes and 1,825 metabolites involved in 1,985 reactions from primary and secondary maize metabolism. For approximately 42% of the reactions direct literature evidence for the participation of the reaction in maize was found. As many as 445 reactions and 369 metabolites are unique to the maize model compared to the AraGEM model for A. thaliana. 674 metabolites and 893 reactions are present in Zea mays iRS1563 that are not accounted for in maize C4GEM. All reactions are elementally and charged balanced and localized into six different compartments (i.e., cytoplasm, mitochondrion, plastid, peroxisome, vacuole and extracellular). GPR associations are also established based on the functional annotation information and homology prediction accounting for monofunctional, multifunctional and multimeric proteins, isozymes and protein complexes. We describe results from performing flux balance analysis under different physiological conditions, (i.e., photosynthesis, photorespiration and respiration) of a C4 plant and also explore model predictions against experimental observations for two naturally occurring mutants (i.e., bm1 and bm3). The developed model corresponds to the largest and more complete to-date effort at cataloguing metabolism for a plant species. PMID:21755001

  12. Phosphoketolase pathway contributes to carbon metabolism in cyanobacteria.

    Science.gov (United States)

    Xiong, Wei; Lee, Tai-Chi; Rommelfanger, Sarah; Gjersing, Erica; Cano, Melissa; Maness, Pin-Ching; Ghirardi, Maria; Yu, Jianping

    2015-12-07

    Central carbon metabolism in cyanobacteria comprises the Calvin-Benson-Bassham (CBB) cycle, glycolysis, the pentose phosphate (PP) pathway and the tricarboxylic acid (TCA) cycle. Redundancy in this complex metabolic network renders the rational engineering of cyanobacterial metabolism for the generation of biomass, biofuels and chemicals a challenge. Here we report the presence of a functional phosphoketolase pathway, which splits xylulose-5-phosphate (or fructose-6-phosphate) to acetate precursor acetyl phosphate, in an engineered strain of the model cyanobacterium Synechocystis (ΔglgC/xylAB), in which glycogen synthesis is blocked, and xylose catabolism enabled through the introduction of xylose isomerase and xylulokinase. We show that this mutant strain is able to metabolise xylose to acetate on nitrogen starvation. To see whether acetate production in the mutant is linked to the activity of phosphoketolase, we disrupted a putative phosphoketolase gene (slr0453) in the ΔglgC/xylAB strain, and monitored metabolic flux using (13)C labelling; acetate and 2-oxoglutarate production was reduced in the light. A metabolic flux analysis, based on isotopic data, suggests that the phosphoketolase pathway metabolises over 30% of the carbon consumed by ΔglgC/xylAB during photomixotrophic growth on xylose and CO2. Disruption of the putative phosphoketolase gene in wild-type Synechocystis also led to a deficiency in acetate production in the dark, indicative of a contribution of the phosphoketolase pathway to heterotrophic metabolism. We suggest that the phosphoketolase pathway, previously uncharacterized in photosynthetic organisms, confers flexibility in energy and carbon metabolism in cyanobacteria, and could be exploited to increase the efficiency of cyanobacterial carbon metabolism and photosynthetic productivity.

  13. Metabolic routes along digestive system of licorice: multicomponent sequential metabolism method in rat.

    Science.gov (United States)

    Zhang, Lei; Zhao, Haiyu; Liu, Yang; Dong, Honghuan; Lv, Beiran; Fang, Min; Zhao, Huihui

    2016-06-01

    This study was conducted to establish the multicomponent sequential metabolism (MSM) method based on comparative analysis along the digestive system following oral administration of licorice (Glycyrrhiza uralensis Fisch., leguminosae), a traditional Chinese medicine widely used for harmonizing other ingredients in a formulae. The licorice water extract (LWE) dissolved in Krebs-Ringer buffer solution (1 g/mL) was used to carry out the experiments and the comparative analysis was performed using HPLC and LC-MS/MS methods. In vitro incubation, in situ closed-loop and in vivo blood sampling were used to measure the LWE metabolic profile along the digestive system. The incubation experiment showed that the LWE was basically stable in digestive juice. A comparative analysis presented the metabolic profile of each prototype and its corresponding metabolites then. Liver was the major metabolic organ for LWE, and the metabolism by the intestinal flora and gut wall was also an important part of the process. The MSM method was practical and could be a potential method to describe the metabolic routes of multiple components before absorption into the systemic blood stream. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  14. Metabolic Compartmentation – A System Level Property of Muscle Cells

    Directory of Open Access Journals (Sweden)

    Theo Wallimann

    2008-05-01

    Full Text Available Problems of quantitative investigation of intracellular diffusion and compartmentation of metabolites are analyzed. Principal controversies in recently published analyses of these problems for the living cells are discussed. It is shown that the formal theoretical analysis of diffusion of metabolites based on Fick’s equation and using fixed diffusion coefficients for diluted homogenous aqueous solutions, but applied for biological systems in vivo without any comparison with experimental results, may lead to misleading conclusions, which are contradictory to most biological observations. However, if the same theoretical methods are used for analysis of actual experimental data, the apparent diffusion constants obtained are orders of magnitude lower than those in diluted aqueous solutions. Thus, it can be concluded that local restrictions of diffusion of metabolites in a cell are a system-level properties caused by complex structural organization of the cells, macromolecular crowding, cytoskeletal networks and organization of metabolic pathways into multienzyme complexes and metabolons. This results in microcompartmentation of metabolites, their channeling between enzymes and in modular organization of cellular metabolic networks. The perspectives of further studies of these complex intracellular interactions in the framework of Systems Biology are discussed.

  15. A tissue-specific approach to the analysis of metabolic changes in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Jürgen Hench

    Full Text Available The majority of metabolic principles are evolutionarily conserved from nematodes to humans. Caenorhabditis elegans has widely accelerated the discovery of new genes important to maintain organismic metabolic homeostasis. Various methods exist to assess the metabolic state in worms, yet they often require large animal numbers and tend to be performed as bulk analyses of whole worm homogenates, thereby largely precluding a detailed studies of metabolic changes in specific worm tissues. Here, we have adapted well-established histochemical methods for the use on C. elegans fresh frozen sections and demonstrate their validity for analyses of morphological and metabolic changes on tissue level in wild type and various mutant strains. We show how the worm presents on hematoxylin and eosin (H&E stained sections and demonstrate their usefulness in monitoring and the identification of morphological abnormalities. In addition, we demonstrate how Oil-Red-O staining on frozen worm cross-sections permits quantification of lipid storage, avoiding the artifact-prone fixation and permeabilization procedures of traditional whole-mount protocols. We also adjusted standard enzymatic stains for respiratory chain subunits (NADH, SDH, and COX to monitor metabolic states of various C. elegans tissues. In summary, the protocols presented here provide technical guidance to obtain robust, reproducible and quantifiable tissue-specific data on worm morphology as well as carbohydrate, lipid and mitochondrial energy metabolism that cannot be obtained through traditional biochemical bulk analyses of worm homogenates. Furthermore, analysis of worm cross-sections overcomes the common problem with quantification in three-dimensional whole-mount specimens.

  16. Genome-wide association mapping of leaf metabolic profiles for dissecting complex traits in maize.

    Science.gov (United States)

    Riedelsheimer, Christian; Lisec, Jan; Czedik-Eysenberg, Angelika; Sulpice, Ronan; Flis, Anna; Grieder, Christoph; Altmann, Thomas; Stitt, Mark; Willmitzer, Lothar; Melchinger, Albrecht E

    2012-06-05

    The diversity of metabolites found in plants is by far greater than in most other organisms. Metabolic profiling techniques, which measure many of these compounds simultaneously, enabled investigating the regulation of metabolic networks and proved to be useful for predicting important agronomic traits. However, little is known about the genetic basis of metabolites in crops such as maize. Here, a set of 289 diverse maize inbred lines was genotyped with 56,110 SNPs and assayed for 118 biochemical compounds in the leaves of young plants, as well as for agronomic traits of mature plants in field trials. Metabolite concentrations had on average a repeatability of 0.73 and showed a correlation pattern that largely reflected their functional grouping. Genome-wide association mapping with correction for population structure and cryptic relatedness identified for 26 distinct metabolites strong associations with SNPs, explaining up to 32.0% of the observed genetic variance. On nine chromosomes, we detected 15 distinct SNP-metabolite associations, each of which explained more then 15% of the genetic variance. For lignin precursors, including p-coumaric acid and caffeic acid, we found strong associations (P values to ) with a region on chromosome 9 harboring cinnamoyl-CoA reductase, a key enzyme in monolignol synthesis and a target for improving the quality of lignocellulosic biomass by genetic engineering approaches. Moreover, lignin precursors correlated significantly with lignin content, plant height, and dry matter yield, suggesting that metabolites represent promising connecting links for narrowing the genotype-phenotype gap of complex agronomic traits.

  17. Proteome- and transcriptome-driven reconstruction of the human myocyte metabolic network and its use for identification of markers for diabetes

    DEFF Research Database (Denmark)

    Väremo, Leif; Scheele, Camilla; Broholm, Christa

    2015-01-01

    -analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism......Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome...

  18. 13C Metabolic Flux Analysis for systematic metabolic engineering of S. cerevisiae for overproduction of fatty acids.

    Directory of Open Access Journals (Sweden)

    Amit Ghosh

    2016-10-01

    Full Text Available Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here we used flux-based modeling approaches to improve yields of fatty acids in S. cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Y. lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for down-regulation in terms of acetyl-CoA consumption. These genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg L of free fatty acids. With the addition of ATP citrate lyase and down-regulation of malate synthase the engineered strain produced 26 per cent more free fatty acids. Further increases in free fatty acid production of 33 per cent were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by 70 per cent.

  19. BCAA Metabolism and NH3 Homeostasis.

    Science.gov (United States)

    Conway, M E; Hutson, S M

    2016-01-01

    The branched chain amino acids (BCAA) are essential amino acids required not only for growth and development, but also as nutrient signals and as nitrogen donors to neurotransmitter synthesis and glutamate/glutamine cycling. Transamination and oxidative decarboxylation of the BCAAs are catalysed by the branched-chain aminotransferase proteins (BCATm, mitochondrial and BCATc, cytosolic) and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively. These proteins show tissue, cell compartmentation, and protein-protein interactions, which call for substrate shuttling or channelling and nitrogen transfer for oxidation to occur. Efficient regulation of these pathways is mediated through the redox environment and phosphorylation in response to dietary and hormonal stimuli. The wide distribution of these proteins allows for effective BCAA utilisation. We discuss how BCAT, BCKDC, and glutamate dehydrogenase operate in supramolecular complexes, allowing for efficient channelling of substrates. The role of BCAAs in brain metabolism is highlighted in rodent and human brain, where differential expression of BCATm indicates differences in nitrogen metabolism between species. Finally, we introduce a new role for BCAT, where a change in function is triggered by oxidation of its redox-active switch. Our understanding of how BCAA metabolism and nitrogen transfer is regulated is important as many studies now point to BCAA metabolic dysregulation in metabolic and neurodegenerative conditions.

  20. Identification of the receptor scavenging hemopexin-heme complexes

    DEFF Research Database (Denmark)

    Hvidberg, Vibeke; Maniecki, Maciej B; Jacobsen, Christian

    2005-01-01

    and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons......, and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin......-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation....

  1. Metabolic Effects of Hypoxia in Colorectal Cancer by 13C NMR Isotopomer Analysis

    Directory of Open Access Journals (Sweden)

    Ana M. Abrantes

    2014-01-01

    Full Text Available 13C NMR isotopomer analysis was used to characterize intermediary metabolism in three colorectal cancer cell lines (WiDr, LS1034, and C2BBe1 and determine the “metabolic remodeling” that occurs under hypoxia. Under normoxia, the three colorectal cancer cell lines present high rates of lactate production and can be seen as “Warburg” like cancer cells independently of substrate availability, since such profile was dominant at both high and low glucose media contents. The LS1034 was the less glycolytic of the three cell lines and was the most affected by the event of hypoxia, raising abruptly glucose consumption and lactate production. The other two colorectal cell lines, WiDr and C2BBe1, adapted better to hypoxia and were able to maintain their oxidative fluxes even at the very low levels of oxygen. These differential metabolic behaviors of the three colorectal cell lines show how important an adequate knowledge of the “metabolic remodeling” that follows a given cancer treatment is towards the correct (redesign of therapeutic strategies against cancer.

  2. Sirtuins as regulators of the yeast metabolic network

    Directory of Open Access Journals (Sweden)

    Markus eRalser

    2012-03-01

    Full Text Available There is growing evidence that the metabolic network is an integral regulator of cellularphysiology. Dynamic changes in metabolite concentrations, metabolic flux, or networktopology act as reporters of biological or environmental signals, and are required for the cellto trigger an appropriate biological reaction. Changes in the metabolic network are recognizedby specific sensory macromolecules and translated into a transcriptional or translationalresponse. The protein family of sirtuins, discovered more than 30 years ago as regulators ofsilent chromatin, seems to fulfill the role of a metabolic sensor during aging and conditions ofcaloric restriction. NAD+/NADH interconverting metabolic enzymes glyceraldehyde-3-phosphate dehydrogenase and alcohol dehydrogenase, as well as enzymes involved inNAD(H, synthesis provide or deprive NAD+ in close proximity to Sir2. This influence sirtuinactivity, and facilitates a dynamic response of the metabolic network to changes inmetabolism with effects on physiology and aging. The molecular network downstream Sir2,however, is complex. In just two orders, Sir2’s metabolism-related interactions span half ofthe yeast proteome, and are connected with virtually every physiological process. Thus,although it is fundamental to analyze single molecular mechanisms, it is at the same timecrucial to consider this genome-scale complexity when correlating single molecular eventswith phenotypes such as aging, cell growth, or stress resistance.

  3. Elucidating the role of the phenylacetic acid metabolic complex in the pathogenic activity of Rhizoctonia solani anastomosis group 3.

    Science.gov (United States)

    Bartz, Faith E; Glassbrook, Norman J; Danehower, David A; Cubeta, Marc A

    2012-01-01

    The soil fungus Rhizoctonia solani produces phytotoxic phenylacetic acid (PAA) and hydroxy (OH-) and methoxy (MeO-) derivatives of PAA. However, limited information is available on the specific role that these compounds play in the development of Rhizoctonia disease symptoms and concentration(s) required to induce a host response. Reports that PAA inhibits the growth of R. solani conflict with the established ability of the fungus to produce and metabolize PAA. Experiments were conducted to clarify the role of the PAA metabolic complex in Rhizoctonia disease. In this study the concentration of PAA and derivatives required to induce tomato root necrosis and stem canker, in the absence of the fungus, and the concentration that inhibits mycelial growth of R. solani were determined. The effect of exogenous PAA and derivatives of PAA on tomato seedling growth also was investigated. Growth of tomato seedlings in medium containing 0.1-7.5 mM PAA and derivatives induced necrosis of up to 85% of root system. Canker development resulted from injection of tomato seedling stems with 7.5 mM PAA, 3-OH-PAA, or 3-MeO-PAA. PAA in the growth medium reduced R. solani biomass, with 50% reduction observed at 7.5 mM. PAA, and derivatives were quantified from the culture medium of 14 isolates of R. solani belonging to three distinct anastomosis groups by GC-MS. The quantities ranged from below the limit of detection to 678 nM, below the concentrations experimentally determined to be phytotoxic. Correlation analyses revealed that isolates of R. solani that produced high PAA and derivatives in vitro also caused high mortality on tomato seedlings. The results of this investigation add to the body of evidence that the PAA metabolic complex is involved in Rhizoctonia disease development but do not indicate that production of these compounds is the primary or the only determinant of pathogenicity.

  4. Metabolomic Analysis in Brain Research: Opportunities & Challenges

    Directory of Open Access Journals (Sweden)

    Catherine G Vasilopoulou

    2016-05-01

    Full Text Available Metabolism being a fundamental part of molecular physiology, elucidating the structure and regulation of metabolic pathways is crucial for obtaining a comprehensive perspective of cellular function and understanding the underlying mechanisms of its dysfunction(s. Therefore, quantifying an accurate metabolic network activity map under various physiological conditions is among the major objectives of systems biology in the context of many biological applications. Especially for CNS, metabolic network activity analysis can substantially enhance our knowledge about the complex structure of the mammalian brain and the mechanisms of neurological disorders, leading to the design of effective therapeutic treatments. Metabolomics has emerged as the high-throughput quantitative analysis of the concentration profile of small molecular weight metabolites, which act as reactants and products in metabolic reactions and as regulatory molecules of proteins participating in many biological processes. Thus, the metabolic profile provides a metabolic activity fingerprint, through the simultaneous analysis of tens to hundreds of molecules of pathophysiological and pharmacological interest. The application of metabolomics is at its standardization phase in general, and the challenges for paving a standardized procedure are even more pronounced in brain studies. In this review, we support the value of metabolomics in brain research. Moreover, we demonstrate the challenges of designing and setting up a reliable brain metabolomic study, which, among other parameters, has to take into consideration the sex differentiation and the complexity of brain physiology manifested in its regional variation. We finally propose ways to overcome these challenges and design a study that produces reproducible and consistent results.

  5. From elementary flux modes to elementary flux vectors: Metabolic pathway analysis with arbitrary linear flux constraints

    Science.gov (United States)

    Klamt, Steffen; Gerstl, Matthias P.; Jungreuthmayer, Christian; Mahadevan, Radhakrishnan; Müller, Stefan

    2017-01-01

    Elementary flux modes (EFMs) emerged as a formal concept to describe metabolic pathways and have become an established tool for constraint-based modeling and metabolic network analysis. EFMs are characteristic (support-minimal) vectors of the flux cone that contains all feasible steady-state flux vectors of a given metabolic network. EFMs account for (homogeneous) linear constraints arising from reaction irreversibilities and the assumption of steady state; however, other (inhomogeneous) linear constraints, such as minimal and maximal reaction rates frequently used by other constraint-based techniques (such as flux balance analysis [FBA]), cannot be directly integrated. These additional constraints further restrict the space of feasible flux vectors and turn the flux cone into a general flux polyhedron in which the concept of EFMs is not directly applicable anymore. For this reason, there has been a conceptual gap between EFM-based (pathway) analysis methods and linear optimization (FBA) techniques, as they operate on different geometric objects. One approach to overcome these limitations was proposed ten years ago and is based on the concept of elementary flux vectors (EFVs). Only recently has the community started to recognize the potential of EFVs for metabolic network analysis. In fact, EFVs exactly represent the conceptual development required to generalize the idea of EFMs from flux cones to flux polyhedra. This work aims to present a concise theoretical and practical introduction to EFVs that is accessible to a broad audience. We highlight the close relationship between EFMs and EFVs and demonstrate that almost all applications of EFMs (in flux cones) are possible for EFVs (in flux polyhedra) as well. In fact, certain properties can only be studied with EFVs. Thus, we conclude that EFVs provide a powerful and unifying framework for constraint-based modeling of metabolic networks. PMID:28406903

  6. Hepatic Steatosis as a Marker of Metabolic Dysfunction

    Science.gov (United States)

    Fabbrini, Elisa; Magkos, Faidon

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID:26102213

  7. Development of a screening approach for exploring cell factory potential through metabolic flux analysis and physiology

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Nielsen, Kristian Fog; Thykær, Jette

    2012-01-01

    The recent developments within the field of metabolic engineering have significantly increased the speed by which fungal recombinant strains are being constructed, pushing focus towards physiological characterisation and analysis. This raises demand for a tool for diligent analysis of the recombi......The recent developments within the field of metabolic engineering have significantly increased the speed by which fungal recombinant strains are being constructed, pushing focus towards physiological characterisation and analysis. This raises demand for a tool for diligent analysis...... of the validation, already well described fungal strains were selected and tested using the described method and the developed method was subsequently used to test recombinant fungal strains producing the model polyketide 6-methylsalicylic acid. Diligent application of this strategy significantly reduces the cost...

  8. Thermodynamic principles governing metabolic operation : inference, analysis, and prediction

    NARCIS (Netherlands)

    Niebel, Bastian

    2015-01-01

    The principles governing metabolic flux are poorly understood. Because diverse organisms show similar metabolic flux patterns, we hypothesized that fundamental thermodynamic constraints might shape cellular metabolism. We developed a constraint-based model for Saccharomyces cerevisiae that included

  9. Current topics in pure and computational complex analysis

    CERN Document Server

    Dorff, Michael; Lahiri, Indrajit

    2014-01-01

    The book contains 13 articles, some of which are survey articles and others research papers. Written by eminent mathematicians, these articles were presented at the International Workshop on Complex Analysis and Its Applications held at Walchand College of Engineering, Sangli. All the contributing authors are actively engaged in research fields related to the topic of the book. The workshop offered a comprehensive exposition of the recent developments in geometric functions theory, planar harmonic mappings, entire and meromorphic functions and their applications, both theoretical and computational. The recent developments in complex analysis and its applications play a crucial role in research in many disciplines.

  10. Dysregulated metabolism contributes to oncogenesis

    Science.gov (United States)

    Hirschey, Matthew D.; DeBerardinis, Ralph J.; Diehl, Anna Mae E.; Drew, Janice E.; Frezza, Christian; Green, Michelle F.; Jones, Lee W.; Ko, Young H.; Le, Anne; Lea, Michael A.; Locasale, Jason W.; Longo, Valter D.; Lyssiotis, Costas A.; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P.; Pedersen, Peter L.; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Sivanand, Sharanya; Vander Heiden, Matthew G.; Wellen, Kathryn E.

    2015-01-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069

  11. Semi-automated curation of metabolic models via flux balance analysis: a case study with Mycoplasma gallisepticum.

    Directory of Open Access Journals (Sweden)

    Eddy J Bautista

    Full Text Available Primarily used for metabolic engineering and synthetic biology, genome-scale metabolic modeling shows tremendous potential as a tool for fundamental research and curation of metabolism. Through a novel integration of flux balance analysis and genetic algorithms, a strategy to curate metabolic networks and facilitate identification of metabolic pathways that may not be directly inferable solely from genome annotation was developed. Specifically, metabolites involved in unknown reactions can be determined, and potentially erroneous pathways can be identified. The procedure developed allows for new fundamental insight into metabolism, as well as acting as a semi-automated curation methodology for genome-scale metabolic modeling. To validate the methodology, a genome-scale metabolic model for the bacterium Mycoplasma gallisepticum was created. Several reactions not predicted by the genome annotation were postulated and validated via the literature. The model predicted an average growth rate of 0.358±0.12[Formula: see text], closely matching the experimentally determined growth rate of M. gallisepticum of 0.244±0.03[Formula: see text]. This work presents a powerful algorithm for facilitating the identification and curation of previously known and new metabolic pathways, as well as presenting the first genome-scale reconstruction of M. gallisepticum.

  12. Insights into Brain Glycogen Metabolism

    Science.gov (United States)

    Mathieu, Cécile; de la Sierra-Gallay, Ines Li; Duval, Romain; Xu, Ximing; Cocaign, Angélique; Léger, Thibaut; Woffendin, Gary; Camadro, Jean-Michel; Etchebest, Catherine; Haouz, Ahmed; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2016-01-01

    Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å) and in complex with its allosteric activator AMP (3.4 Å). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen. PMID:27402852

  13. Doing more with less (data): complexities of resource flow analysis in the Gauteng City-Region

    Science.gov (United States)

    Culwick, Christina; Götz, Graeme; Butcher, Siân; Harber, Jesse; Maree, Gillian; Mushongera, Darlington

    2017-12-01

    Urban metabolism is a growing field of study into resource flows through cities, and how these could be managed more sustainably. There are two main schools of thought on urban metabolism—metabolic flow analysis (MFA) and urban political ecology (UPE). The two schools remain siloed despite common foundations. This paper reflects on recent research by the Gauteng City-Region Observatory (GCRO) into urban sustainability transitions in South Africa’s Gauteng City-Region, a large and sprawling urban formation that faces a host of sustainability challenges including water deficits, erratic electricity supply, stretched infrastructure networks and increasingly carbon-intensive settlement patterns. Three GCRO research projects are reviewed. Each project began with the assumption that data collection on the region’s metabolism could enable an MFA or MFA-like analysis to highlight where possible resource efficiency and sustainability gains might be achieved. However, in each case we confronted severe data-limitations, and ended up asking UPE-style questions on the reasons for and implications of the chronic paucity of urban metabolism data. We have been led to conclude that urban metabolism research will require much more than just assembling and modelling flows data, although these efforts should not be abandoned. A synthesis of MFA and UPE is needed, which simultaneously builds a deeper understanding of resource flows and the systems that govern these flows. We support the emerging approach in political-industrial ecology literature which values both material data on and socio-political insight into urban metabolism, and emphasises the importance of multi-disciplinary and multi-dimensional analysis to inform decision-making in urban sustainability transitions.

  14. Analysis of Aspergillus nidulans metabolism at the genome-scale

    DEFF Research Database (Denmark)

    David, Helga; Ozcelik, İlknur Ş; Hofmann, Gerald

    2008-01-01

    of relevant secondary metabolites, was reconstructed based on detailed metabolic reconstructions available for A. niger and Saccharomyces cerevisiae, and information on the genetics, biochemistry and physiology of A. nidulans. Thereby, it was possible to identify metabolic functions without a gene associated...... a function. Results: In this work, we have manually assigned functions to 472 orphan genes in the metabolism of A. nidulans, by using a pathway-driven approach and by employing comparative genomics tools based on sequence similarity. The central metabolism of A. nidulans, as well as biosynthetic pathways......, in an objective and systematic manner. The functional assignments served as a basis to develop a mathematical model, linking 666 genes (both previously and newly annotated) to metabolic roles. The model was used to simulate metabolic behavior and additionally to integrate, analyze and interpret large-scale gene...

  15. Application of «Sensor signal analysis network» complex for distributed, time synchronized analysis of electromagnetic radiation

    Science.gov (United States)

    Mochalov, Vladimir; Mochalova, Anastasia

    2017-10-01

    The paper considers a developing software-hardware complex «Sensor signal analysis network» for distributed and time synchronized analysis of electromagnetic radiations. The areas of application and the main features of the complex are described. An example of application of the complex to monitor natural electromagnetic radiation sources is considered based on the data recorded in VLF range. A generalized functional scheme of stream analysis of signals by a complex functional node is suggested and its application for stream detection of atmospherics, whistlers and tweaks is considered.

  16. Metabolic patterns in prion diseases: an FDG PET voxel-based analysis

    Energy Technology Data Exchange (ETDEWEB)

    Prieto, Elena; Dominguez-Prado, Ines; Jesus Ribelles, Maria; Arbizu, Javier [Clinica Universidad de Navarra, Nuclear Medicine Department, Pamplona (Spain); Riverol, Mario; Ortega-Cubero, Sara; Rosario Luquin, Maria; Castro, Purificacion de [Clinica Universidad de Navarra, Neurology Department, Pamplona (Spain)

    2015-09-15

    Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. (orig.)

  17. Metabolic patterns in prion diseases: an FDG PET voxel-based analysis

    International Nuclear Information System (INIS)

    Prieto, Elena; Dominguez-Prado, Ines; Jesus Ribelles, Maria; Arbizu, Javier; Riverol, Mario; Ortega-Cubero, Sara; Rosario Luquin, Maria; Castro, Purificacion de

    2015-01-01

    Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. (orig.)

  18. Phylogenetic analysis of glycerol 3-phosphate acyltransferases in opisthokonts reveals unexpected ancestral complexity and novel modern biosynthetic components.

    Directory of Open Access Journals (Sweden)

    Heather C Smart

    Full Text Available Glycerolipid synthesis represents a central metabolic process of all forms of life. In the last decade multiple genes coding for enzymes responsible for the first step of the pathway, catalyzed by glycerol 3-phosphate acyltransferase (GPAT, have been described, and characterized primarily in model organisms like Saccharomyces cerevisiae and mice. Notoriously, the fungal enzymes share low sequence identity with their known animal counterparts, and the nature of their homology is unclear. Furthermore, two mitochondrial GPAT isoforms have been described in animal cells, while no such enzymes have been identified in Fungi. In order to determine if the yeast and mammalian GPATs are representative of the set of enzymes present in their respective groups, and to test the hypothesis that metazoan orthologues are indeed absent from the fungal clade, a comparative genomic and phylogenetic analysis was performed including organisms spanning the breadth of the Opisthokonta supergroup. Surprisingly, our study unveiled the presence of 'fungal' orthologs in the basal taxa of the holozoa and 'animal' orthologues in the basal holomycetes. This includes a novel clade of fungal homologues, with putative peroxisomal targeting signals, of the mitochondrial/peroxisomal acyltransferases in Metazoa, thus potentially representing an undescribed metabolic capacity in the Fungi. The overall distribution of GPAT homologues is suggestive of high relative complexity in the ancestors of the opisthokont clade, followed by loss and sculpting of the complement in the descendent lineages. Divergence from a general versatile metabolic model, present in ancestrally deduced GPAT complements, points to distinctive contributions of each GPAT isoform to lipid metabolism and homeostasis in contemporary organisms like humans and their fungal pathogens.

  19. Analysis of Cancer Metabolism by Imaging Hyperpolarized Nuclei: Prospects for Translation to Clinical Research

    Directory of Open Access Journals (Sweden)

    John Kurhanewicz

    2011-02-01

    Full Text Available A major challenge in cancer biology is to monitor and understand cancer metabolism in vivo with the goal of improved diagnosis and perhaps therapy. Because of the complexity of biochemical pathways, tracer methods are required for detecting specific enzyme-catalyzed reactions. Stable isotopes such as 13C or 15N with detection by nuclear magnetic resonance provide the necessary information about tissue biochemistry, but the crucial metabolites are present in low concentration and therefore are beyond the detection threshold of traditional magnetic resonance methods. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Although this effect is short-lived, hyperpolarized molecules can be generated in an aqueous solution and infused in vivo where metabolism generates products that can be imaged. This discovery lifts the primary constraint on magnetic resonance imaging for monitoring metabolism—poor sensitivity—while preserving the advantage of biochemical information. The purpose of this report was to briefly summarize the known abnormalities in cancer metabolism, the value and limitations of current imaging methods for metabolism, and the principles of hyperpolarization. Recent preclinical applications are described. Hyperpolarization technology is still in its infancy, and current polarizer equipment and methods are suboptimal. Nevertheless, there are no fundamental barriers to rapid translation of this exciting technology to clinical research and perhaps clinical care.

  20. Reconstruction and flux analysis of coupling between metabolic pathways of astrocytes and neurons: application to cerebral hypoxia

    Directory of Open Access Journals (Sweden)

    Akιn Ata

    2007-12-01

    Full Text Available Abstract Background It is a daunting task to identify all the metabolic pathways of brain energy metabolism and develop a dynamic simulation environment that will cover a time scale ranging from seconds to hours. To simplify this task and make it more practicable, we undertook stoichiometric modeling of brain energy metabolism with the major aim of including the main interacting pathways in and between astrocytes and neurons. Model The constructed model includes central metabolism (glycolysis, pentose phosphate pathway, TCA cycle, lipid metabolism, reactive oxygen species (ROS detoxification, amino acid metabolism (synthesis and catabolism, the well-known glutamate-glutamine cycle, other coupling reactions between astrocytes and neurons, and neurotransmitter metabolism. This is, to our knowledge, the most comprehensive attempt at stoichiometric modeling of brain metabolism to date in terms of its coverage of a wide range of metabolic pathways. We then attempted to model the basal physiological behaviour and hypoxic behaviour of the brain cells where astrocytes and neurons are tightly coupled. Results The reconstructed stoichiometric reaction model included 217 reactions (184 internal, 33 exchange and 216 metabolites (183 internal, 33 external distributed in and between astrocytes and neurons. Flux balance analysis (FBA techniques were applied to the reconstructed model to elucidate the underlying cellular principles of neuron-astrocyte coupling. Simulation of resting conditions under the constraints of maximization of glutamate/glutamine/GABA cycle fluxes between the two cell types with subsequent minimization of Euclidean norm of fluxes resulted in a flux distribution in accordance with literature-based findings. As a further validation of our model, the effect of oxygen deprivation (hypoxia on fluxes was simulated using an FBA-derivative approach, known as minimization of metabolic adjustment (MOMA. The results show the power of the

  1. Understanding the metabolic fate and assessing the biosafety of MnO nanoparticles by metabonomic analysis

    International Nuclear Information System (INIS)

    Li, Jinquan; Feng, Jianghua; Chen, Zhong; Zhao, Zhenghuan; Gao, Jinhao

    2013-01-01

    Recently, some types of MnO nanoparticle (Mn-NP) with favorable imaging capacity have been developed to improve the biocompatible profile of the existing Mn-based MRI contrast agent Mn-DPDP; however, the overall bio-effects and potential toxicity remain largely unknown. In this study, 1 H NMR-based metabolic profiling, integrated with traditional biochemical analysis and histopathological examinations, was used to investigate the absorption, distribution, metabolism, excretion and toxicity of Mn-NPs as candidates for MRI contrast agent. The metabolic responses in biofluids (plasma and urine) and tissues (liver, spleen, kidney, lung and brain) from rats could be divided into four classes following Mn-NP administration: Mn biodistribution-dependent, time-dependent, dose-dependent and complicated metabolic variations. The variations of these metabolites involved in lipid, energy, amino acid and other nutrient metabolism, which disclosed the metabolic fate and biological effects of Mn-NPs in rats. The changes of metabolic profile implied that the disturbance and impairment of biological functions induced by Mn-NP exposure were correlated with the particle size and the surface chemistry of nanoparticles. Integration of metabonomic technology with traditional methods provides a promising tool to understand the toxicological behavior of biomedical nanomaterials and will result in informed decision-making during drug development. (paper)

  2. Reconstruction and in silico analysis of metabolic network for an oleaginous yeast, Yarrowia lipolytica.

    Directory of Open Access Journals (Sweden)

    Pengcheng Pan

    Full Text Available With the emergence of energy scarcity, the use of renewable energy sources such as biodiesel is becoming increasingly necessary. Recently, many researchers have focused their minds on Yarrowia lipolytica, a model oleaginous yeast, which can be employed to accumulate large amounts of lipids that could be further converted to biodiesel. In order to understand the metabolic characteristics of Y. lipolytica at a systems level and to examine the potential for enhanced lipid production, a genome-scale compartmentalized metabolic network was reconstructed based on a combination of genome annotation and the detailed biochemical knowledge from multiple databases such as KEGG, ENZYME and BIGG. The information about protein and reaction associations of all the organisms in KEGG and Expasy-ENZYME database was arranged into an EXCEL file that can then be regarded as a new useful database to generate other reconstructions. The generated model iYL619_PCP accounts for 619 genes, 843 metabolites and 1,142 reactions including 236 transport reactions, 125 exchange reactions and 13 spontaneous reactions. The in silico model successfully predicted the minimal media and the growing abilities on different substrates. With flux balance analysis, single gene knockouts were also simulated to predict the essential genes and partially essential genes. In addition, flux variability analysis was applied to design new mutant strains that will redirect fluxes through the network and may enhance the production of lipid. This genome-scale metabolic model of Y. lipolytica can facilitate system-level metabolic analysis as well as strain development for improving the production of biodiesels and other valuable products by Y. lipolytica and other closely related oleaginous yeasts.

  3. Metabolic Adaptation to Muscle Ischemia

    Science.gov (United States)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  4. Music analysis and Kolmogorov complexity

    DEFF Research Database (Denmark)

    Meredith, David

    The goal of music analysis is to find the most satisfying explanations for musical works. It is proposed that this can best be achieved by attempting to write computer programs that are as short as possible and that generate representations that are as detailed as possible of the music...... that the program represents. If such an effective measure of analysis quality can be found, it could be used in a system that automatically finds the optimal analysis for any passage of music. Measuring program length in terms of number of source-code characters is shown to be problematic and an expression...... is proposed that overcomes some but not all of these problems. It is suggested that the solutions to the remaining problems may lie either in the field of concrete Kolmogorov complexity or in the design of languages specialized for expressing musical structure....

  5. Genome-Based Construction of the Metabolic Pathways of Orientia tsutsugamushi and Comparative Analysis within the Rickettsiales Order

    Directory of Open Access Journals (Sweden)

    Chan-Ki Min

    2008-01-01

    Full Text Available Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium that belongs to the order of Rickettsiales. Recently, we have reported that O. tsutsugamushi has a unique genomic structure, consisting of highly repetitive sequences, and suggested that it may provide valuable insight into the evolution of intracellular bacteria. Here, we have used genomic information to construct the major metabolic pathways of O. tsutsugamushi and performed a comparative analysis of the metabolic genes and pathways of O. tsutsugamushi with other members of the Rickettsiales order. While O. tsutsugamushi has the largest genome among the members of this order, mainly due to the presence of repeated sequences, its metabolic pathways have been highly streamlined. Overall, the metabolic pathways of O. tsutsugamushi were similar to Rickettsia but there were notable differences in several pathways including carbohydrate metabolism, the TCA cycle, and the synthesis of cell wall components as well as in the transport systems. Our results will provide a useful guide to the postgenomic analysis of O. tsutsugamushi and lead to a better understanding of the virulence and physiology of this intracellular pathogen.

  6. Understanding alternative fluxes/effluxes through comparative metabolic pathway analysis of phylum actinobacteria using a simplified approach.

    Science.gov (United States)

    Verma, Mansi; Lal, Devi; Saxena, Anjali; Anand, Shailly; Kaur, Jasvinder; Kaur, Jaspreet; Lal, Rup

    2013-12-01

    Actinobacteria are known for their diverse metabolism and physiology. Some are dreadful human pathogens whereas some constitute the natural flora for human gut. Therefore, the understanding of metabolic pathways is a key feature for targeting the pathogenic bacteria without disturbing the symbiotic ones. A big challenge faced today is multiple drug resistance by Mycobacterium and other pathogens that utilize alternative fluxes/effluxes. With the availability of genome sequence, it is now feasible to conduct the comparative in silico analysis. Here we present a simplified approach to compare metabolic pathways so that the species specific enzyme may be traced and engineered for future therapeutics. The analyses of four key carbohydrate metabolic pathways, i.e., glycolysis, pyruvate metabolism, tri carboxylic acid cycle and pentose phosphate pathway suggest the presence of alternative fluxes. It was found that the upper pathway of glycolysis was highly variable in the actinobacterial genomes whereas lower glycolytic pathway was highly conserved. Likewise, pentose phosphate pathway was well conserved in contradiction to TCA cycle, which was found to be incomplete in majority of actinobacteria. The clustering based on presence and absence of genes of these metabolic pathways clearly revealed that members of different genera shared identical pathways and, therefore, provided an easy method to identify the metabolic similarities/differences between pathogenic and symbiotic organisms. The analyses could identify isoenzymes and some key enzymes that were found to be missing in some pathogenic actinobacteria. The present work defines a simple approach to explore the effluxes in four metabolic pathways within the phylum actinobacteria. The analysis clearly reflects that actinobacteria exhibit diverse routes for metabolizing substrates. The pathway comparison can help in finding the enzymes that can be used as drug targets for pathogens without effecting symbiotic organisms

  7. 13C metabolic flux analysis: optimal design of isotopic labeling experiments.

    Science.gov (United States)

    Antoniewicz, Maciek R

    2013-12-01

    Measuring fluxes by 13C metabolic flux analysis (13C-MFA) has become a key activity in chemical and pharmaceutical biotechnology. Optimal design of isotopic labeling experiments is of central importance to 13C-MFA as it determines the precision with which fluxes can be estimated. Traditional methods for selecting isotopic tracers and labeling measurements did not fully utilize the power of 13C-MFA. Recently, new approaches were developed for optimal design of isotopic labeling experiments based on parallel labeling experiments and algorithms for rational selection of tracers. In addition, advanced isotopic labeling measurements were developed based on tandem mass spectrometry. Combined, these approaches can dramatically improve the quality of 13C-MFA results with important applications in metabolic engineering and biotechnology. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Correlation analysis of the Taurus molecular cloud complex

    International Nuclear Information System (INIS)

    Kleiner, S.C.

    1985-01-01

    Autocorrelation and power spectrum methods were applied to the analysis of the density and velocity structure of the Taurus Complex and Heiles Cloud 2 as traced out by 13 CO J = 1 → 0 molecular line observations obtained with the 14m antenna of the Five College Radio Astronomy Observatory. Statistically significant correlations in the spacing of density fluctuations within the Taurus Complex and Heiles 2 were uncovered. The length scales of the observed correlations correspond in magnitude to the Jeans wavelengths characterizing gravitational instabilities with (i) interstellar atomic hydrogen gas for the case of the Taurus complex, and (ii) molecular hydrogen for Heiles 2. The observed correlations may be the signatures of past and current gravitational instabilities frozen into the structure of the molecular gas. The appendices provide a comprehensive description of the analytical and numerical methods developed for the correlation analysis of molecular clouds

  9. Big and complex data analysis methodologies and applications

    CERN Document Server

    2017-01-01

    This volume conveys some of the surprises, puzzles and success stories in high-dimensional and complex data analysis and related fields. Its peer-reviewed contributions showcase recent advances in variable selection, estimation and prediction strategies for a host of useful models, as well as essential new developments in the field. The continued and rapid advancement of modern technology now allows scientists to collect data of increasingly unprecedented size and complexity. Examples include epigenomic data, genomic data, proteomic data, high-resolution image data, high-frequency financial data, functional and longitudinal data, and network data. Simultaneous variable selection and estimation is one of the key statistical problems involved in analyzing such big and complex data. The purpose of this book is to stimulate research and foster interaction between researchers in the area of high-dimensional data analysis. More concretely, its goals are to: 1) highlight and expand the breadth of existing methods in...

  10. Metabolic Analysis of Medicinal Dendrobium officinale and Dendrobium huoshanense during Different Growth Years.

    Science.gov (United States)

    Jin, Qing; Jiao, Chunyan; Sun, Shiwei; Song, Cheng; Cai, Yongping; Lin, Yi; Fan, Honghong; Zhu, Yanfang

    2016-01-01

    Metabolomics technology has enabled an important method for the identification and quality control of Traditional Chinese Medical materials. In this study, we isolated metabolites from cultivated Dendrobium officinale and Dendrobium huoshanense stems of different growth years in the methanol/water phase and identified them using gas chromatography coupled with mass spectrometry (GC-MS). First, a metabolomics technology platform for Dendrobium was constructed. The metabolites in the Dendrobium methanol/water phase were mainly sugars and glycosides, amino acids, organic acids, alcohols. D. officinale and D. huoshanense and their growth years were distinguished by cluster analysis in combination with multivariate statistical analysis, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Eleven metabolites that contributed significantly to this differentiation were subjected to t-tests (PDendrobium species revealed that the polysaccharide content of D. huoshanense was higher than that of D. officinale, indicating that the D. huoshanense was of higher quality. Based on the accumulation of Dendrobium metabolites, the optimal harvest time for Dendrobium was in the third year. This initial metabolic profiling platform for Dendrobium provides an important foundation for the further study of secondary metabolites (pharmaceutical active ingredients) and metabolic pathways.

  11. Computational Modeling of Human Metabolism and Its Application to Systems Biomedicine.

    Science.gov (United States)

    Aurich, Maike K; Thiele, Ines

    2016-01-01

    Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in interpretation, and new avenues are needed to address the complexity of both diseases and data. Constraint-based modeling is one formalism applied in systems biology. It relies on a genome-scale reconstruction that captures extensive biochemical knowledge regarding an organism. The human genome-scale metabolic reconstruction is increasingly used to understand normal cellular and disease states because metabolism is an important factor in many human diseases. The application of human genome-scale reconstruction ranges from mere querying of the model as a knowledge base to studies that take advantage of the model's topology and, most notably, to functional predictions based on cell- and condition-specific metabolic models built based on omics data.An increasing number and diversity of biomedical questions are being addressed using constraint-based modeling and metabolic models. One of the most successful biomedical applications to date is cancer metabolism, but constraint-based modeling also holds great potential for inborn errors of metabolism or obesity. In addition, it offers great prospects for individualized approaches to diagnostics and the design of disease prevention and intervention strategies. Metabolic models support this endeavor by providing easy access to complex high-throughput datasets. Personalized metabolic models have been introduced. Finally, constraint-based modeling can be used to model whole-body metabolism, which will enable the elucidation of metabolic interactions between organs and disturbances of these interactions as either causes or consequence of metabolic diseases. This chapter introduces constraint-based modeling and describes some of its contributions to systems biomedicine.

  12. Complex analysis with applications to flows and fields

    CERN Document Server

    Braga da Costa Campos, Luis Manuel

    2012-01-01

    Complex Analysis with Applications to Flows and Fields presents the theory of functions of a complex variable, from the complex plane to the calculus of residues to power series to conformal mapping. The book explores numerous physical and engineering applications concerning potential flows, the gravity field, electro- and magnetostatics, steady heat conduction, and other problems. It provides the mathematical results to sufficiently justify the solution of these problems, eliminating the need to consult external references.The book is conveniently divided into four parts. In each part, the ma

  13. Shifts in metabolic hydrogen sinks in the methanogenesis-inhibited ruminal fermentation: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Emilio M. Ungerfeld

    2015-02-01

    Full Text Available Maximizing the flow of metabolic hydrogen ([H] in the rumen away from CH4 and towards volatile fatty acids (VFA would increase the efficiency of ruminant production and decrease its environmental impact. The objectives of this meta-analysis were: i To quantify shifts in metabolic hydrogen sinks when inhibiting ruminal methanogenesis in vitro; and ii To understand the variation in shifts of metabolic hydrogen sinks among experiments and between batch and continuous cultures systems when methanogenesis is inhibited. Batch (28 experiments, N=193 and continuous (16 experiments, N=79 culture databases of experiments with at least 50% inhibition in CH4 production were compiled. Inhibiting methanogenesis generally resulted in less fermentation and digestion in most batch culture, but not in most continuous culture, experiments. Inhibiting CH4 production in batch cultures resulted in redirection of metabolic hydrogen towards propionate and H2 but not butyrate. In continuous cultures, there was no overall metabolic hydrogen redirection towards propionate or butyrate, and H2 as a proportion of metabolic hydrogen spared from CH4 production was numerically smaller compared to batch cultures. Dihydrogen accumulation was affected by type of substrate and methanogenesis inhibitor, with highly fermentable substrates resulting in greater redirection of metabolic hydrogen towards H2 when inhibiting methanogenesis, and some oils causing small or no H2 accumulation. In both batch and continuous culture, there was a decrease in metabolic hydrogen recovered as the sum of propionate, butyrate, CH4 and H2 when inhibiting methanogenesis, and it is speculated that as CH4 production decreases metabolic hydrogen could be increasingly incorporated into formate, microbial biomass, and, perhaps, reductive acetogenesis in continuous cultures. Energetic benefits of inhibiting methanogenesis depended on the inhibitor and its concentration and on the in vitro system.

  14. The compositional and evolutionary logic of metabolism

    International Nuclear Information System (INIS)

    Braakman, Rogier; Smith, Eric

    2013-01-01

    Metabolism is built on a foundation of organic chemistry, and employs structures and interactions at many scales. Despite these sources of complexity, metabolism also displays striking and robust regularities in the forms of modularity and hierarchy, which may be described compactly in terms of relatively few principles of composition. These regularities render metabolic architecture comprehensible as a system, and also suggests the order in which layers of that system came into existence. In addition metabolism also serves as a foundational layer in other hierarchies, up to at least the levels of cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, motivates us to interpret metabolism as a source of causation or constraint on many forms of organization in the biosphere. Many of the forms of modularity and hierarchy exhibited by metabolism are readily interpreted as stages in the emergence of catalytic control by living systems over organic chemistry, sometimes recapitulating or incorporating geochemical mechanisms. We identify as modules, either subsets of chemicals and reactions, or subsets of functions, that are re-used in many contexts with a conserved internal structure. At the small molecule substrate level, module boundaries are often associated with the most complex reaction mechanisms, catalyzed by highly conserved enzymes. Cofactors form a biosynthetically and functionally distinctive control layer over the small-molecule substrate. The most complex members among the cofactors are often associated with the reactions at module boundaries in the substrate networks, while simpler cofactors participate in widely generalized reactions. The highly tuned chemical structures of cofactors (sometimes exploiting distinctive properties of the elements of the periodic table) thereby act as ‘keys’ that incorporate classes of organic reactions

  15. Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.

    Science.gov (United States)

    La Rosa, Ruggero; Johansen, Helle Krogh; Molin, Søren

    2018-04-10

    surprising that conclusions from our investigations of bacterial evolution in the CF model system are different from what has been concluded from laboratory experiments. The analysis presented here of the metabolic and regulatory driving forces leading to successful adaptation to a new environment provides an important insight into the role of metabolism and its regulatory mechanisms for successful adaptation of microorganisms in dynamic and complex environments. Understanding the trajectories of adaptation, as well as the mechanisms behind slow growth and rewiring of regulatory and metabolic networks, is a key element to understand the adaptive robustness and evolvability of bacteria in the process of increasing their in vivo fitness when conquering new territories. Copyright © 2018 La Rosa et al.

  16. Muscle as a “Mediator“ of Systemic Metabolism

    Science.gov (United States)

    Baskin, Kedryn K.; Winders, Benjamin R.; Olson, Eric N.

    2015-01-01

    Skeletal and cardiac muscles play key roles in the regulation of systemic energy homeostasis and display remarkable plasticity in their metabolic responses to caloric availability and physical activity. In this Perspective we discuss recent studies highlighting transcriptional mechanisms that govern systemic metabolism by striated muscles. We focus on the participation of the Mediator complex in this process, and suggest that tissue-specific regulation of Mediator subunits impacts metabolic homeostasis. PMID:25651178

  17. A Swellable Microneedle Patch to Rapidly Extract Skin Interstitial Fluid for Timely Metabolic Analysis.

    Science.gov (United States)

    Chang, Hao; Zheng, Mengjia; Yu, Xiaojun; Than, Aung; Seeni, Razina Z; Kang, Rongjie; Tian, Jingqi; Khanh, Duong Phan; Liu, Linbo; Chen, Peng; Xu, Chenjie

    2017-10-01

    Skin interstitial fluid (ISF) is an emerging source of biomarkers for disease diagnosis and prognosis. Microneedle (MN) patch has been identified as an ideal platform to extract ISF from the skin due to its pain-free and easy-to-administrated properties. However, long sampling time is still a serious problem which impedes timely metabolic analysis. In this study, a swellable MN patch that can rapidly extract ISF is developed. The MN patch is made of methacrylated hyaluronic acid (MeHA) and further crosslinked through UV irradiation. Owing to the supreme water affinity of MeHA, this MN patch can extract sufficient ISF in a short time without the assistance of extra devices, which remarkably facilitates timely metabolic analysis. Due to covalent crosslinked network, the MN patch maintains the structure integrity in the swelling hydrated state without leaving residues in skin after usage. More importantly, the extracted ISF metabolites can be efficiently recovered from MN patch by centrifugation for the subsequent offline analysis of metabolites such as glucose and cholesterol. Given the recent trend of easy-to-use point-of-care devices for personal healthcare monitoring, this study opens a new avenue for the development of MN-based microdevices for sampling ISF and minimally invasive metabolic detection. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Ultra high resolution SFC-MS as a high throughput platform for metabolic phenotyping: application to metabolic profiling of rat and dog bile.

    Science.gov (United States)

    Jones, Michael D; Rainville, Paul D; Isaac, Giorgis; Wilson, Ian D; Smith, Norman W; Plumb, Robert S

    2014-09-01

    Ultra high resolution SFC-MS (on sub-2μm particles) coupled to mass spectrometry has been evaluated for the metabolic profiling of rat and dog bile. The selectivity of the SFC separation differed from that seen in previous reversed-phase UPLC-MS studies on bile, with the order of elution for analytes such as e.g., the bile acids showing many differences. The chromatography system showed excellent stability, reproducibility and robustness with relative standard deviation of less than 1% for retention time obtained over the course of the analysis. SFC showed excellent chromatographic performance with chromatographic peak widths in the order of 3s at the base of the peak. The use of supercritical fluid carbon dioxide as a mobile phase solvent also reduced the overall consumption of organic solvent by a factor of 3 and also reduced the overall analysis time by a factor of 30% compared to reversed-phase gradient LC. SFC-MS appear complementary to RPLC for the metabolic profiling of complex samples such as bile. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Transcriptomic analysis reveals metabolic switches and surface remodeling as key processes for stage transition in Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Luisa Berná

    2017-03-01

    Full Text Available American trypanosomiasis is a chronic and endemic disease which affects millions of people. Trypanosoma cruzi, its causative agent, has a life cycle that involves complex morphological and functional transitions, as well as a variety of environmental conditions. This requires a tight regulation of gene expression, which is achieved mainly by post-transcriptional regulation. In this work we conducted an RNAseq analysis of the three major life cycle stages of T. cruzi: amastigotes, epimastigotes and trypomastigotes. This analysis allowed us to delineate specific transcriptomic profiling for each stage, and also to identify those biological processes of major relevance in each state. Stage specific expression profiling evidenced the plasticity of T. cruzi to adapt quickly to different conditions, with particular focus on membrane remodeling and metabolic shifts along the life cycle. Epimastigotes, which replicate in the gut of insect vectors, showed higher expression of genes related to energy metabolism, mainly Krebs cycle, respiratory chain and oxidative phosphorylation related genes, and anabolism related genes associated to nucleotide and steroid biosynthesis; also, a general down-regulation of surface glycoprotein coding genes was seen at this stage. Trypomastigotes, living extracellularly in the bloodstream of mammals, express a plethora of surface proteins and signaling genes involved in invasion and evasion of immune response. Amastigotes mostly express membrane transporters and genes involved in regulation of cell cycle, and also express a specific subset of surface glycoprotein coding genes. In addition, these results allowed us to improve the annotation of the Dm28c genome, identifying new ORFs and set the stage for construction of networks of co-expression, which can give clues about coded proteins of unknown functions.

  20. Genome-scale modeling for metabolic engineering.

    Science.gov (United States)

    Simeonidis, Evangelos; Price, Nathan D

    2015-03-01

    We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information-an area which we expect will become increasingly important for metabolic engineering-and present recent developments in the field of metabolic and regulatory integration.

  1. Basic complex analysis a comprehensive course in analysis, part 2a

    CERN Document Server

    Simon, Barry

    2015-01-01

    A Comprehensive Course in Analysis by Poincaré Prize winner Barry Simon is a five-volume set that can serve as a graduate-level analysis textbook with a lot of additional bonus information, including hundreds of problems and numerous notes that extend the text and provide important historical background. Depth and breadth of exposition make this set a valuable reference source for almost all areas of classical analysis. Part 2A is devoted to basic complex analysis. It interweaves three analytic threads associated with Cauchy, Riemann, and Weierstrass, respectively. Cauchy's view focuses on th

  2. Metrical and dynamical aspects in complex analysis

    CERN Document Server

    2017-01-01

    The central theme of this reference book is the metric geometry of complex analysis in several variables. Bridging a gap in the current literature, the text focuses on the fine behavior of the Kobayashi metric of complex manifolds and its relationships to dynamical systems, hyperbolicity in the sense of Gromov and operator theory, all very active areas of research. The modern points of view expressed in these notes, collected here for the first time, will be of interest to academics working in the fields of several complex variables and metric geometry. The different topics are treated coherently and include expository presentations of the relevant tools, techniques and objects, which will be particularly useful for graduate and PhD students specializing in the area.

  3. Invitation to complex analysis

    CERN Document Server

    Boas, Ralph P

    2010-01-01

    Ideal for a first course in complex analysis, this book can be used either as a classroom text or for independent study. Written at a level accessible to advanced undergraduates and beginning graduate students, the book is suitable for readers acquainted with advanced calculus or introductory real analysis. The treatment goes beyond the standard material of power series, Cauchy's theorem, residues, conformal mapping, and harmonic functions by including accessible discussions of intriguing topics that are uncommon in a book at this level. The flexibility afforded by the supplementary topics and applications makes the book adaptable either to a short, one-term course or to a comprehensive, full-year course. Detailed solutions of the exercises both serve as models for students and facilitate independent study. Supplementary exercises, not solved in the book, provide an additional teaching tool. This second edition has been painstakingly revised by the author's son, himself an award-winning mathematical expositor...

  4. Vitamin A Metabolism: An Update

    Directory of Open Access Journals (Sweden)

    William S. Blaner

    2011-01-01

    Full Text Available Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years.

  5. Gut microbiota and metabolic syndrome.

    Science.gov (United States)

    Festi, Davide; Schiumerini, Ramona; Eusebi, Leonardo Henry; Marasco, Giovanni; Taddia, Martina; Colecchia, Antonio

    2014-11-21

    Gut microbiota exerts a significant role in the pathogenesis of the metabolic syndrome, as confirmed by studies conducted both on humans and animal models. Gut microbial composition and functions are strongly influenced by diet. This complex intestinal "superorganism" seems to affect host metabolic balance modulating energy absorption, gut motility, appetite, glucose and lipid metabolism, as well as hepatic fatty storage. An impairment of the fine balance between gut microbes and host's immune system could culminate in the intestinal translocation of bacterial fragments and the development of "metabolic endotoxemia", leading to systemic inflammation and insulin resistance. Diet induced weight-loss and bariatric surgery promote significant changes of gut microbial composition, that seem to affect the success, or the inefficacy, of treatment strategies. Manipulation of gut microbiota through the administration of prebiotics or probiotics could reduce intestinal low grade inflammation and improve gut barrier integrity, thus, ameliorating metabolic balance and promoting weight loss. However, further evidence is needed to better understand their clinical impact and therapeutic use.

  6. Metabolic pattern analysis of early detection in Alzheimer's disease from other types of dementias and correlated with cognitive function

    International Nuclear Information System (INIS)

    Ju, R. H.; Lee, C. W.; Jung, Y. A.; Sohn, H. S.; Kim, S. H.; Seo, T. S

    2004-01-01

    PET/CT studies have demonstrated temporoparietal hypometabolism in probable and definite Alzheimer's disease (AD), a pattern that may help differentiate AD from other types of dementias. Seeking to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Identification of individual differences in patterns of regional cerebral glucose metabolism (rCMRglc) interactions may be important for early detection of AD. We elucidate the relationship between reduced cognitive function and cerebral metabolism. Ten patients with the diagnosis of AD, 3 DLB patients underwent 18F-FDG PET CT. We applied statistical mapping procedure to evaluate the diagnostic power of rCMRglc patterns for differentiation and also correlated with Korean-mini mental status exam (K-MMSE) score include orientation time, place, registration, attention, calculation, recaIl, language and visuospatial function. Glucose metabolic pattern analysis confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortex. DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex. Covariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. AnaIysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled clinical criteria for DLB. occipital hypometabolism is a potential discriminate marker to distinguish DLB versus AD

  7. Analysis and design of complex impedance transforming marchand baluns

    DEFF Research Database (Denmark)

    Michaelsen, Rasmus Schandorph; Johansen, Tom Keinicke; Tamborg, Kjeld M.

    2014-01-01

    A new type of Marchand balun is presented in this paper, which has the property of complex impedance transformation. To allow the Marchand balun to transform between arbitrary complex impedances, three reactances should be added to the circuit. A detailed analysis of the circuit gives the governing...

  8. BioMet Toolbox: genome-wide analysis of metabolism

    DEFF Research Database (Denmark)

    Cvijovic, M.; Olivares Hernandez, Roberto; Agren, R.

    2010-01-01

    The rapid progress of molecular biology tools for directed genetic modifications, accurate quantitative experimental approaches, high-throughput measurements, together with development of genome sequencing has made the foundation for a new area of metabolic engineering that is driven by metabolic...

  9. Metabolic Coevolution in the Bacterial Symbiosis of Whiteflies and Related Plant Sap-Feeding Insects.

    Science.gov (United States)

    Luan, Jun-Bo; Chen, Wenbo; Hasegawa, Daniel K; Simmons, Alvin M; Wintermantel, William M; Ling, Kai-Shu; Fei, Zhangjun; Liu, Shu-Sheng; Douglas, Angela E

    2015-09-15

    Genomic decay is a common feature of intracellular bacteria that have entered into symbiosis with plant sap-feeding insects. This study of the whitefly Bemisia tabaci and two bacteria (Portiera aleyrodidarum and Hamiltonella defensa) cohoused in each host cell investigated whether the decay of Portiera metabolism genes is complemented by host and Hamiltonella genes, and compared the metabolic traits of the whitefly symbiosis with other sap-feeding insects (aphids, psyllids, and mealybugs). Parallel genomic and transcriptomic analysis revealed that the host genome contributes multiple metabolic reactions that complement or duplicate Portiera function, and that Hamiltonella may contribute multiple cofactors and one essential amino acid, lysine. Homologs of the Bemisia metabolism genes of insect origin have also been implicated in essential amino acid synthesis in other sap-feeding insect hosts, indicative of parallel coevolution of shared metabolic pathways across multiple symbioses. Further metabolism genes coded in the Bemisia genome are of bacterial origin, but phylogenetically distinct from Portiera, Hamiltonella and horizontally transferred genes identified in other sap-feeding insects. Overall, 75% of the metabolism genes of bacterial origin are functionally unique to one symbiosis, indicating that the evolutionary history of metabolic integration in these symbioses is strongly contingent on the pattern of horizontally acquired genes. Our analysis, further, shows that bacteria with genomic decay enable host acquisition of complex metabolic pathways by multiple independent horizontal gene transfers from exogenous bacteria. Specifically, each horizontally acquired gene can function with other genes in the pathway coded by the symbiont, while facilitating the decay of the symbiont gene coding the same reaction. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  10. Analysis of carbon and nitrogen co-metabolism in yeast by ultrahigh-resolution mass spectrometry applying 13C- and 15N-labeled substrates simultaneously

    International Nuclear Information System (INIS)

    Blank, Lars M.; Desphande, Rahul R.; Schmid, Andreas; Hayen, Heiko

    2012-01-01

    Alternative metabolic pathways inside a cell can be deduced using stable isotopically labeled substrates. One prerequisite is accurate measurement of the labeling pattern of targeted metabolites. Experiments are generally limited to the use of single-element isotopes, mainly 13 C. Here, we demonstrate the application of direct infusion nanospray, ultrahigh-resolution Fourier transform ion cyclotron resonance-mass spectrometry (FTICR-MS) for metabolic studies using differently labeled elemental isotopes simultaneously - i.e., 13 C and 15 N - in amino acids of a total protein hydrolysate. The optimized strategy for the analysis of metabolism by a hybrid linear ion trap-FTICR-MS comprises the collection of multiple adjacent selected ion monitoring scans. By limiting both the width of the mass range and the number of ions entering the ICR cell with automated gain control, sensitive measurements of isotopologue distribution were possible without compromising mass accuracy and isotope intensity mapping. The required mass-resolving power of more than 60,000 is only achievable on a routine basis by FTICR and Orbitrap mass spectrometers. Evaluation of the method was carried out by comparison of the experimental data to the natural isotope abundances of selected amino acids and by comparison to GC/MS results obtained from a labeling experiment with 13 C-labeled glucose. The developed method was used to shed light on the complexity of the yeast Saccharomyces cerevisiae carbon-nitrogen co-metabolism by administering both 13 C-labeled glucose and 15 N-labeled alanine. The results indicate that not only glutamate but also alanine acts as an amino donor during alanine and valine synthesis. Metabolic studies using FTICR-MS can exploit new possibilities by the use of multiple-labeled elemental isotopes. (orig.)

  11. Metabolomics analysis of metabolic effects of nicotinamide phosphoribosyltransferase (NAMPT inhibition on human cancer cells.

    Directory of Open Access Journals (Sweden)

    Vladimir Tolstikov

    Full Text Available Nicotinamide phosphoribosyltransferase (NAMPT plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide-consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry-based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer and HCT-116 (colorectal cancer cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA, and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.

  12. Salmonella Modulates Metabolism During Growth under Conditions that Induce Expression of Virulence Genes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young-Mo; Schmidt, Brian; Kidwai, Afshan S.; Jones, Marcus B.; Deatherage, Brooke L.; Brewer, Heather M.; Mitchell, Hugh D.; Palsson, Bernhard O.; McDermott, Jason E.; Heffron, Fred; Smith, Richard D.; Peterson, Scott N.; Ansong, Charles; Hyduke, Daniel R.; Metz, Thomas O.; Adkins, Joshua N.

    2013-04-05

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Excitingly, we observed possible sequestration of metabolites recently suggested to have immune modulating roles. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Model-guided analysis suggested that alterations in metabolism prioritized other activities necessary for pathogenesis instead, such as lipopolysaccharide biosynthesis.

  13. Quantitative Analysis of Complex Tropical Forest Stands: A Review ...

    African Journals Online (AJOL)

    The importance of data analysis in quantitative assessment of natural resources remains significant in the sustainable management of complex tropical forest resources. Analyses of data from complex tropical forest stands have not been easy or clear due to improper data management. It is pivotal to practical researches ...

  14. Melatonin for Atypical Antipsychotic-Induced Metabolic Adverse Effects: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    Ashwin Kamath

    2018-01-01

    Full Text Available The objective of our study was to determine the effect of melatonin administration on atypical antipsychotic-induced metabolic adverse effects in patients with psychiatric disorders. A systematic search was performed in PUBMED, Cochrane Library, Scopus, Web of Science, and EBSCOhost electronic databases. Randomized controlled trials studying the effect of melatonin on antipsychotic-induced metabolic adverse effects were identified and subjected to meta-analysis. Four studies were included in the meta-analysis, including 57 patients on melatonin and 61 patients on placebo. Melatonin produced a significant decrease in the diastolic blood pressure compared with placebo (mean difference = −4.44 [95% CI, −7.00 to −1.88]; p=0.0007; I2 = 13%, but not the systolic blood pressure (mean difference = −4.23 [95% CI, −8.11 to −0.36]; p=0.03; I2 = 0%. Although a decrease in the body mass index was seen in the melatonin group, the difference was not significant in the random-effects analysis model. To conclude, in patients on atypical antipsychotics, melatonin at a dose of up to 5 mg/day for a treatment duration of up to 12 weeks attenuated the rise in diastolic blood pressure compared with placebo but had no significant effects on other metabolic parameters.

  15. Melatonin for Atypical Antipsychotic-Induced Metabolic Adverse Effects: A Meta-Analysis of Randomized Controlled Trials.

    Science.gov (United States)

    Kamath, Ashwin; Rather, Zahoor Ahmad

    2018-01-01

    The objective of our study was to determine the effect of melatonin administration on atypical antipsychotic-induced metabolic adverse effects in patients with psychiatric disorders. A systematic search was performed in PUBMED, Cochrane Library, Scopus, Web of Science, and EBSCOhost electronic databases. Randomized controlled trials studying the effect of melatonin on antipsychotic-induced metabolic adverse effects were identified and subjected to meta-analysis. Four studies were included in the meta-analysis, including 57 patients on melatonin and 61 patients on placebo. Melatonin produced a significant decrease in the diastolic blood pressure compared with placebo (mean difference = -4.44 [95% CI, -7.00 to -1.88]; p = 0.0007; I 2 = 13%), but not the systolic blood pressure (mean difference = -4.23 [95% CI, -8.11 to -0.36]; p = 0.03; I 2 = 0%). Although a decrease in the body mass index was seen in the melatonin group, the difference was not significant in the random-effects analysis model. To conclude, in patients on atypical antipsychotics, melatonin at a dose of up to 5 mg/day for a treatment duration of up to 12 weeks attenuated the rise in diastolic blood pressure compared with placebo but had no significant effects on other metabolic parameters.

  16. The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex.

    Science.gov (United States)

    Griffeth, Valerie E M; Simon, Aaron B; Buxton, Richard B

    2015-01-01

    Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow-metabolism coupling (n=%ΔCBF/%ΔCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow-metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Structural Analysis of Complex Networks

    CERN Document Server

    Dehmer, Matthias

    2011-01-01

    Filling a gap in literature, this self-contained book presents theoretical and application-oriented results that allow for a structural exploration of complex networks. The work focuses not only on classical graph-theoretic methods, but also demonstrates the usefulness of structural graph theory as a tool for solving interdisciplinary problems. Applications to biology, chemistry, linguistics, and data analysis are emphasized. The book is suitable for a broad, interdisciplinary readership of researchers, practitioners, and graduate students in discrete mathematics, statistics, computer science,

  18. Positron computed tomography studies of cerebral metabolic responses to complex motor tasks

    International Nuclear Information System (INIS)

    Phelps, M.E.; Mazziotta, J.C.

    1984-01-01

    Human motor system organization was explored in 8 right-handed male subjects using /sup 18/F-fluorodeoxyglucose and positron computed tomography to measure cerebral glucose metabolism. Five subjects had triple studies (eyes closed) including: control (hold pen in right hand without moving), normal size writing (subject repeatedly writes name) and large (10-15 X normal) name writing. In these studies normal and large size writing had a similar distribution of metabolic responses when compared to control studies. Activations (percent change from control) were in the range of 12-20% and occurred in the striatum bilaterally > contralateral Rolandic cortex > contralateral thalamus. No significant activations were observed in the ipsilateral thalamus, Rolandic cortex or cerebellum (supplementary motor cortex was not examined). The magnitude of the metabolic response in the striatum was greater with the large versus normal sized writing. This differential response may be due to an increased number and topographic distribution of neurons responding with the same average activity between tasks or an increase in the functional activity of the same neuronal population between the two tasks (present spatial resolution inadequate to differentiate). When subjects (N=3) performed novel sequential finger movements, the maximal metabolic response was in the contralateral Rolandic cortex > striatum. Such studies provide a means of exploring human motor system organization, motor learning and provide a basis for examining patients with motor system disorders

  19. Pyruvate dehydrogenase complexes from the equine nematode, Parascaris equorum, and the canine cestode, Dipylidium caninum, helminths exhibiting anaerobic mitochondrial metabolism.

    Science.gov (United States)

    Diaz, F; Komuniecki, R W

    1994-10-01

    The pyruvate dehydrogenase complex (PDC) has been purified to apparent homogeneity from 2 parasitic helminths exhibiting anaerobic mitochondrial metabolism, the equine nematode, Parascaris equorum, and the canine cestode, Dipylidium caninum. The P. equorum PDC yielded 7 major bands when separated by SDS-PAGE. The bands of 72, 55-53.5, 41 and 36 kDa corresponded to E2, E3, E1 alpha and E1 beta, respectively. The complex also contained additional unidentified proteins of 43 and 45 kDa. Incubation of the complex with [2-14C]pyruvate resulted in the acetylation of only E2. These results suggest that the P. equorum PDC lacks protein X and exhibits an altered subunit composition, as has been described previously for the PDC of the related nematode, Ascaris suum. In contrast, the D. caninum PDC yielded only four major bands after SDS-PAGE of 59, 58, 39 and 34 kDa, which corresponded to E3, E2, E1 alpha and E1 beta, respectively. Incubation of the D. caninum complex with [2-14C]pyruvate resulted in the acetylation of E2 and a second protein which comigrated with E3, suggesting that the D. caninum complex contained protein X and had a subunit composition similar to PDCs from other eukaryotic organisms. Both helminth complexes appeared less sensitive to inhibition by elevated NADH/NAD+ ratios than complexes isolated from aerobic organisms, as would be predicted for PDCs from organisms exploiting microaerobic habitats. These results suggest that although these helminths have similar anaerobic mitochondrial pathways, they contain significantly different PDCs.

  20. Thermodynamics of complexity

    DEFF Research Database (Denmark)

    Westerhoff, Hans V.; Jensen, Peter Ruhdal; Snoep, Jacky L.

    1998-01-01

    -called emergent properties. Tendency towards increased entropy is an essential determinant for the behaviour of ideal gas mixtures, showing that even in the simplest physical/chemical systems, (dys)organisation of components is crucial for the behaviour of systems. This presentation aims at illustrating...... that the behaviour of two functionally interacting biological components (molecules, protein domains, pathways, organelles) differs from the behaviour these components would exhibit in isolation from one another, where the difference should be essential for the maintenance and growth of the living state, For a true...... understanding of this BioComplexity, modem thermodynamic concepts and methods (nonequilibrium thermodynamics, metabolic and hierarchical control analysis) will be needed. We shall propose to redefine nonequilibrium thermodynamics as: The science that aims at understanding the behaviour of nonequilibrium systems...

  1. Nutrients in Energy and One-Carbon Metabolism: Learning from Metformin Users

    Directory of Open Access Journals (Sweden)

    Fedra Luciano-Mateo

    2017-02-01

    Full Text Available Metabolic vulnerability is associated with age-related diseases and concomitant co-morbidities, which include obesity, diabetes, atherosclerosis and cancer. Most of the health problems we face today come from excessive intake of nutrients and drugs mimicking dietary effects and dietary restriction are the most successful manipulations targeting age-related pathways. Phenotypic heterogeneity and individual response to metabolic stressors are closely related food intake. Understanding the complexity of the relationship between dietary provision and metabolic consequences in the long term might provide clinical strategies to improve healthspan. New aspects of metformin activity provide a link to many of the overlapping factors, especially the way in which organismal bioenergetics remodel one-carbon metabolism. Metformin not only inhibits mitochondrial complex 1, modulating the metabolic response to nutrient intake, but also alters one-carbon metabolic pathways. Here, we discuss findings on the mechanism(s of action of metformin with the potential for therapeutic interpretations.

  2. Outlier-resilient complexity analysis of heartbeat dynamics

    Science.gov (United States)

    Lo, Men-Tzung; Chang, Yi-Chung; Lin, Chen; Young, Hsu-Wen Vincent; Lin, Yen-Hung; Ho, Yi-Lwun; Peng, Chung-Kang; Hu, Kun

    2015-03-01

    Complexity in physiological outputs is believed to be a hallmark of healthy physiological control. How to accurately quantify the degree of complexity in physiological signals with outliers remains a major barrier for translating this novel concept of nonlinear dynamic theory to clinical practice. Here we propose a new approach to estimate the complexity in a signal by analyzing the irregularity of the sign time series of its coarse-grained time series at different time scales. Using surrogate data, we show that the method can reliably assess the complexity in noisy data while being highly resilient to outliers. We further apply this method to the analysis of human heartbeat recordings. Without removing any outliers due to ectopic beats, the method is able to detect a degradation of cardiac control in patients with congestive heart failure and a more degradation in critically ill patients whose life continuation relies on extracorporeal membrane oxygenator (ECMO). Moreover, the derived complexity measures can predict the mortality of ECMO patients. These results indicate that the proposed method may serve as a promising tool for monitoring cardiac function of patients in clinical settings.

  3. Symmetry analysis in parametrisation of complex systems

    International Nuclear Information System (INIS)

    Sikora, W; Malinowski, J

    2010-01-01

    The symmetry analysis method based on the theory of group representations is used for description of complex systems and their behavior in this work. The first trial of using the symmetry analysis in modeling of behavior of complex social system is presented. The evacuation of large building scenarios are discussed as transition from chaotic to ordered states, described as movements of individuals according to fields of displacements, calculated correspondingly to given scenario. The symmetry of the evacuation space is taken into account in calculation of displacements field - the displacements related to every point of this space are presented in the coordinate frame in the best way adapted to given symmetry space group, which is the set of basic vectors of irreducible representation of given symmetry group. The results got with using the symmetry consideration are compared with corresponding results calculated under assumption of shortest way to exits (Voronoi assumption).

  4. Symmetry analysis in parametrisation of complex systems

    Energy Technology Data Exchange (ETDEWEB)

    Sikora, W; Malinowski, J, E-mail: sikora@novell.ftj.agh.edu.p [Faculty of Physics and Applied Computer Science, AGH - University of Science and Technology, Al. Mickiewicza 30, 30-059 Krakow (Poland)

    2010-03-01

    The symmetry analysis method based on the theory of group representations is used for description of complex systems and their behavior in this work. The first trial of using the symmetry analysis in modeling of behavior of complex social system is presented. The evacuation of large building scenarios are discussed as transition from chaotic to ordered states, described as movements of individuals according to fields of displacements, calculated correspondingly to given scenario. The symmetry of the evacuation space is taken into account in calculation of displacements field - the displacements related to every point of this space are presented in the coordinate frame in the best way adapted to given symmetry space group, which is the set of basic vectors of irreducible representation of given symmetry group. The results got with using the symmetry consideration are compared with corresponding results calculated under assumption of shortest way to exits (Voronoi assumption).

  5. Detecting variants with Metabolic Design, a new software tool to design probes for explorative functional DNA microarray development

    Directory of Open Access Journals (Sweden)

    Gravelat Fabrice

    2010-09-01

    Full Text Available Abstract Background Microorganisms display vast diversity, and each one has its own set of genes, cell components and metabolic reactions. To assess their huge unexploited metabolic potential in different ecosystems, we need high throughput tools, such as functional microarrays, that allow the simultaneous analysis of thousands of genes. However, most classical functional microarrays use specific probes that monitor only known sequences, and so fail to cover the full microbial gene diversity present in complex environments. We have thus developed an algorithm, implemented in the user-friendly program Metabolic Design, to design efficient explorative probes. Results First we have validated our approach by studying eight enzymes involved in the degradation of polycyclic aromatic hydrocarbons from the model strain Sphingomonas paucimobilis sp. EPA505 using a designed microarray of 8,048 probes. As expected, microarray assays identified the targeted set of genes induced during biodegradation kinetics experiments with various pollutants. We have then confirmed the identity of these new genes by sequencing, and corroborated the quantitative discrimination of our microarray by quantitative real-time PCR. Finally, we have assessed metabolic capacities of microbial communities in soil contaminated with aromatic hydrocarbons. Results show that our probe design (sensitivity and explorative quality can be used to study a complex environment efficiently. Conclusions We successfully use our microarray to detect gene expression encoding enzymes involved in polycyclic aromatic hydrocarbon degradation for the model strain. In addition, DNA microarray experiments performed on soil polluted by organic pollutants without prior sequence assumptions demonstrate high specificity and sensitivity for gene detection. Metabolic Design is thus a powerful, efficient tool that can be used to design explorative probes and monitor metabolic pathways in complex environments

  6. Advanced complex analysis a comprehensive course in analysis, part 2b

    CERN Document Server

    Simon, Barry

    2015-01-01

    A Comprehensive Course in Analysis by Poincaré Prize winner Barry Simon is a five-volume set that can serve as a graduate-level analysis textbook with a lot of additional bonus information, including hundreds of problems and numerous notes that extend the text and provide important historical background. Depth and breadth of exposition make this set a valuable reference source for almost all areas of classical analysis. Part 2B provides a comprehensive look at a number of subjects of complex analysis not included in Part 2A. Presented in this volume are the theory of conformal metrics (includ

  7. Correlation exploration of metabolic and genomic diversity in rice

    Directory of Open Access Journals (Sweden)

    Shinozaki Kazuo

    2009-12-01

    Full Text Available Abstract Background It is essential to elucidate the relationship between metabolic and genomic diversity to understand the genetic regulatory networks associated with the changing metabolo-phenotype among natural variation and/or populations. Recent innovations in metabolomics technologies allow us to grasp the comprehensive features of the metabolome. Metabolite quantitative trait analysis is a key approach for the identification of genetic loci involved in metabolite variation using segregated populations. Although several attempts have been made to find correlative relationships between genetic and metabolic diversity among natural populations in various organisms, it is still unclear whether it is possible to discover such correlations between each metabolite and the polymorphisms found at each chromosomal location. To assess the correlative relationship between the metabolic and genomic diversity found in rice accessions, we compared the distance matrices for these two "omics" patterns in the rice accessions. Results We selected 18 accessions from the world rice collection based on their population structure. To determine the genomic diversity of the rice genome, we genotyped 128 restriction fragment length polymorphism (RFLP markers to calculate the genetic distance among the accessions. To identify the variations in the metabolic fingerprint, a soluble extract from the seed grain of each accession was analyzed with one dimensional 1H-nuclear magnetic resonance (NMR. We found no correlation between global metabolic diversity and the phylogenetic relationships among the rice accessions (rs = 0.14 by analyzing the distance matrices (calculated from the pattern of the metabolic fingerprint in the 4.29- to 0.71-ppm 1H chemical shift and the genetic distance on the basis of the RFLP markers. However, local correlation analysis between the distance matrices (derived from each 0.04-ppm integral region of the 1H chemical shift against genetic

  8. INO80 Chromatin Remodeling Coordinates Metabolic Homeostasis with Cell Division

    Directory of Open Access Journals (Sweden)

    Graeme J. Gowans

    2018-01-01

    Full Text Available Adaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the yeast metabolic cycle (YMC. Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here, we demonstrate that the INO80 chromatin-remodeling complex is required to coordinate respiration and cell division with periodic gene expression. Specifically, INO80 mutants have severe defects in oxygen consumption and promiscuous cell division that is no longer coupled with metabolic status. In mutant cells, chromatin accessibility of periodic genes, including TORC1-responsive genes, is relatively static, concomitant with severely attenuated gene expression. Collectively, these results reveal that the INO80 complex mediates metabolic signaling to chromatin to restrict proliferation to metabolically optimal states.

  9. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    Directory of Open Access Journals (Sweden)

    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  10. The Mediator Complex and Lipid Metabolism

    OpenAIRE

    Zhang, Yi; Xiaoli,; Zhao, Xiaoping; Yang, Fajun

    2013-01-01

    The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understan...

  11. International Conference on Finite or Infinite Dimensional Complex Analysis and Applications

    CERN Document Server

    Tutschke, W; Yang, C

    2004-01-01

    There is almost no field in Mathematics which does not use Mathe­ matical Analysis. Computer methods in Applied Mathematics, too, are often based on statements and procedures of Mathematical Analysis. An important part of Mathematical Analysis is Complex Analysis because it has many applications in various branches of Mathematics. Since the field of Complex Analysis and its applications is a focal point in the Vietnamese research programme, the Hanoi University of Technology organized an International Conference on Finite or Infinite Dimensional Complex Analysis and Applications which took place in Hanoi from August 8 - 12, 2001. This conference th was the 9 one in a series of conferences which take place alternately in China, Japan, Korea and Vietnam each year. The first one took place th at Pusan University in Korea in 1993. The preceding 8 conference was th held in Shandong in China in August 2000. The 9 conference of the was the first one which took place above mentioned series of conferences in Vietnam....

  12. Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults

    International Nuclear Information System (INIS)

    Lee, Dong Soo; Oh, Jungsu S.; Lee, Jae Sung; Lee, Myung Chul; Kang, Hyejin; Kim, Heejung; Park, Hyojin

    2008-01-01

    Regionally connected areas of the resting brain can be detected by fluorodeoxyglucose-positron emission tomography (FDG-PET). Voxel-wise metabolic connectivity was examined, and normative data were established by performing interregional correlation analysis on statistical parametric mapping of FDG-PET data. Characteristics of seed volumes of interest (VOIs) as functional brain units were represented by their locations, sizes, and the independent methods of their determination. Seed brain areas were identified as population-based gyral VOIs (n=70) or as population-based cytoarchitectonic Brodmann areas (BA; n=28). FDG uptakes in these areas were used as independent variables in a general linear model to search for voxels correlated with average seed VOI counts. Positive correlations were searched in entire brain areas. In normal adults, one third of gyral VOIs yielded correlations that were confined to themselves, but in the others, correlated voxels extended to adjacent areas and/or contralateral homologous regions. In tens of these latter areas with extensive connectivity, correlated voxels were found across midline, and asymmetry was observed in the patterns of connectivity of left and right homologous seed VOIs. Most of the available BAs yielded correlations reaching contralateral homologous regions and/or neighboring areas. Extents of metabolic connectivity were not found to be related to seed VOI size or to the methods used to define seed VOIs. These findings indicate that patterns of metabolic connectivity of functional brain units depend on their regional locations. We propose that interregional correlation analysis of FDG-PET data offers a means of examining voxel-wise regional metabolic connectivity of the resting human brain. (orig.)

  13. Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dong Soo; Oh, Jungsu S.; Lee, Jae Sung; Lee, Myung Chul [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Kang, Hyejin [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Programs in Brain and Neuroscience, Seoul (Korea); Kim, Heejung; Park, Hyojin [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Interdisciplinary Program in Cognitive Science, Seoul (Korea)

    2008-09-15

    Regionally connected areas of the resting brain can be detected by fluorodeoxyglucose-positron emission tomography (FDG-PET). Voxel-wise metabolic connectivity was examined, and normative data were established by performing interregional correlation analysis on statistical parametric mapping of FDG-PET data. Characteristics of seed volumes of interest (VOIs) as functional brain units were represented by their locations, sizes, and the independent methods of their determination. Seed brain areas were identified as population-based gyral VOIs (n=70) or as population-based cytoarchitectonic Brodmann areas (BA; n=28). FDG uptakes in these areas were used as independent variables in a general linear model to search for voxels correlated with average seed VOI counts. Positive correlations were searched in entire brain areas. In normal adults, one third of gyral VOIs yielded correlations that were confined to themselves, but in the others, correlated voxels extended to adjacent areas and/or contralateral homologous regions. In tens of these latter areas with extensive connectivity, correlated voxels were found across midline, and asymmetry was observed in the patterns of connectivity of left and right homologous seed VOIs. Most of the available BAs yielded correlations reaching contralateral homologous regions and/or neighboring areas. Extents of metabolic connectivity were not found to be related to seed VOI size or to the methods used to define seed VOIs. These findings indicate that patterns of metabolic connectivity of functional brain units depend on their regional locations. We propose that interregional correlation analysis of FDG-PET data offers a means of examining voxel-wise regional metabolic connectivity of the resting human brain. (orig.)

  14. Unique attributes of cyanobacterial metabolism revealed by improved genome-scale metabolic modeling and essential gene analysis

    Science.gov (United States)

    Broddrick, Jared T.; Rubin, Benjamin E.; Welkie, David G.; Du, Niu; Mih, Nathan; Diamond, Spencer; Lee, Jenny J.; Golden, Susan S.; Palsson, Bernhard O.

    2016-01-01

    The model cyanobacterium, Synechococcus elongatus PCC 7942, is a genetically tractable obligate phototroph that is being developed for the bioproduction of high-value chemicals. Genome-scale models (GEMs) have been successfully used to assess and engineer cellular metabolism; however, GEMs of phototrophic metabolism have been limited by the lack of experimental datasets for model validation and the challenges of incorporating photon uptake. Here, we develop a GEM of metabolism in S. elongatus using random barcode transposon site sequencing (RB-TnSeq) essential gene and physiological data specific to photoautotrophic metabolism. The model explicitly describes photon absorption and accounts for shading, resulting in the characteristic linear growth curve of photoautotrophs. GEM predictions of gene essentiality were compared with data obtained from recent dense-transposon mutagenesis experiments. This dataset allowed major improvements to the accuracy of the model. Furthermore, discrepancies between GEM predictions and the in vivo dataset revealed biological characteristics, such as the importance of a truncated, linear TCA pathway, low flux toward amino acid synthesis from photorespiration, and knowledge gaps within nucleotide metabolism. Coupling of strong experimental support and photoautotrophic modeling methods thus resulted in a highly accurate model of S. elongatus metabolism that highlights previously unknown areas of S. elongatus biology. PMID:27911809

  15. Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.

    Science.gov (United States)

    Zieliński, Łukasz P; Smith, Anthony C; Smith, Alexander G; Robinson, Alan J

    2016-11-01

    Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Metabolic complications in oncology

    International Nuclear Information System (INIS)

    Sycova-Mila, Z.

    2012-01-01

    Currently, a lot of space and time is devoted to the therapy of oncologic diseases itself. To reach the good therapy results, complex care of the oncologic patient is needed. Management of complications linked with the disease itself and management of complications emerged after administration of chemotherapy, radiotherapy or targeted therapy, plays a significant role. In addition to infectious, hematological, neurological, cardiac or other complications, metabolic complications are relatively extensive and serious. One of the most frequent metabolic complications in oncology is tumor lysis syndrome, hyperuricemia, hypercalcaemia and syndrome of inappropriate secretion of antidiuretic hormone. (author)

  17. Linking neuronal brain activity to the glucose metabolism

    OpenAIRE

    Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regul...

  18. Simulation and Analysis of Complex Biological Processes: an Organisation Modelling Perspective

    NARCIS (Netherlands)

    Bosse, T.; Jonker, C.M.; Treur, J.

    2005-01-01

    This paper explores how the dynamics of complex biological processes can be modelled and simulated as an organisation of multiple agents. This modelling perspective identifies organisational structure occurring in complex decentralised processes and handles complexity of the analysis of the dynamics

  19. [Clinical analysis of metabolic syndrome in vertiginous diseases].

    Science.gov (United States)

    Yamanaka, Toshiaki; Fukuda, Takehiko; Sawai, Yachiyo; Shirota, Shiho; Shimizu, Naoki; Murai, Takayuki; Okamoto, Hideyuki; Fujita, Nobuya; Hosoi, Hiroshi

    2011-01-01

    To explore the relationship between metabolic syndrome and vertigo, we measured waist circumference, plasma glucose, triglycerides and blood pressure in 333 subjects aged 20-79 years with vertigo. We found overall metabolic syndrome prevalence defined by Japanese diagnostic criteria to be 13.2%, similar to that in other national surveys by the Japanese Ministry of Health, Labour and Welfare. The 6-fold higher prevalence in men over women exceeded that of other reports, however. The highest frequency was in vertebrobasilar insufficiency (VBI) disorders, suggesting that conditions such as VBI in men with vertigo could involve metabolic syndrome as a risk factor for vertigo incidence.

  20. Metabolic pathway analysis and kinetic studies for production of nattokinase in Bacillus subtilis.

    Science.gov (United States)

    Unrean, Pornkamol; Nguyen, Nhung H A

    2013-01-01

    We have constructed a reaction network model of Bacillus subtilis. The model was analyzed using a pathway analysis tool called elementary mode analysis (EMA). The analysis tool was used to study the network capabilities and the possible effects of altered culturing conditions on the production of a fibrinolytic enzyme, nattokinase (NK) by B. subtilis. Based on all existing metabolic pathways, the maximum theoretical yield for NK synthesis in B. subtilis under different substrates and oxygen availability was predicted and the optimal culturing condition for NK production was identified. To confirm model predictions, experiments were conducted by testing these culture conditions for their influence on NK activity. The optimal culturing conditions were then applied to batch fermentation, resulting in high NK activity. The EMA approach was also applied for engineering B. subtilis metabolism towards the most efficient pathway for NK synthesis by identifying target genes for deletion and overexpression that enable the cell to produce NK at the maximum theoretical yield. The consistency between experiments and model predictions proves the feasibility of EMA being used to rationally design culture conditions and genetic manipulations for the efficient production of desired products.

  1. An equipment complex for instrumental elementary analysis

    International Nuclear Information System (INIS)

    Borisov, G.I.; Komkov, M.M.; Kuz'michev, V.A.; Leonov, V.F.; Tarasov, Y.F.

    1986-01-01

    The competitiveness of elementary analysis on a research reactor depends, in many respects, on the provision of equipment which would permit the realization of the advantages of the analytical method. This paper describes the IR-8 reactor at the I.V. Kurchatov Institute of Atomic energy. In the design of the complex considerable attention was focused on automation and the radiation safety of the operations, which is of particular importance in the light of the large volumes of analysis

  2. Unravelling the shape and structural assembly of the photosynthetic GAPDH-CP12-PRK complex from Arabidopsis thaliana by small-angle X-ray scattering analysis.

    Science.gov (United States)

    Del Giudice, Alessandra; Pavel, Nicolae Viorel; Galantini, Luciano; Falini, Giuseppe; Trost, Paolo; Fermani, Simona; Sparla, Francesca

    2015-12-01

    Oxygenic photosynthetic organisms produce sugars through the Calvin-Benson cycle, a metabolism that is tightly linked to the light reactions of photosynthesis and is regulated by different mechanisms, including the formation of protein complexes. Two enzymes of the cycle, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK), form a supramolecular complex with the regulatory protein CP12 with the formula (GAPDH-CP122-PRK)2, in which both enzyme activities are transiently inhibited during the night. Small-angle X-ray scattering analysis performed on both the GAPDH-CP12-PRK complex and its components, GAPDH-CP12 and PRK, from Arabidopsis thaliana showed that (i) PRK has an elongated, bent and screwed shape, (ii) the oxidized N-terminal region of CP12 that is not embedded in the GAPDH-CP12 complex prefers a compact conformation and (iii) the interaction of PRK with the N-terminal region of CP12 favours the approach of two GAPDH tetramers. The interaction between the GAPDH tetramers may contribute to the overall stabilization of the GAPDH-CP12-PRK complex, the structure of which is presented here for the first time.

  3. Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine.

    Science.gov (United States)

    Selen Alpergin, Ebru S; Bolandnazar, Zeinab; Sabatini, Martina; Rogowski, Michael; Chiellini, Grazia; Zucchi, Riccardo; Assadi-Porter, Fariba M

    2017-01-01

    Complex diseases such as polycystic ovary syndrome (PCOS) are associated with intricate pathophysiological, hormonal, and metabolic feedbacks that make their early diagnosis challenging, thus increasing the prevalence risks for obesity, cardiovascular, and fatty liver diseases. To explore the crosstalk between endocrine and lipid metabolic pathways, we administered 3-iodothyronamine (T1AM), a natural analog of thyroid hormone, in a mouse model of PCOS and analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. T1AM administration induces a profound tissue-specific antilipogenic effect in liver and muscle by lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2, significantly increasing metabolites (glucogenic, amino acids, carnitine, and citrate) levels, while enhancing protection against oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1, and CYP17A1. Biochemical measurements provide further evidence of significant reduction in liver cholesterol and triglycerides in post-T1AM treatment. Our results shed light onto tissue-specific metabolic vs. hormonal pathway interactions, thus illuminating the intricacies within the pathophysiology of PCOS This study opens up new avenues to design drugs for targeted therapeutics to improve quality of life in complex metabolic diseases. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  4. MID Max: LC–MS/MS Method for Measuring the Precursor and Product Mass Isotopomer Distributions of Metabolic Intermediates and Cofactors for Metabolic Flux Analysis Applications

    DEFF Research Database (Denmark)

    McCloskey, Douglas; Young, Jamey D.; Xu, Sibei

    2016-01-01

    The analytical challenges to acquire accurate isotopic data of intracellular metabolic intermediates for stationary, nonstationary, and dynamic metabolic flux analysis (MFA) are numerous. This work presents MID Max, a novel LC–MS/MS workflow, acquisition, and isotopomer deconvolution method for MFA...... that takes advantage of additional scan types that maximizes the number of mass isotopomer distributions (MIDs) that can be acquired in a given experiment. The analytical method was found to measure the MIDs of 97 metabolites, corresponding to 74 unique metabolite-fragment pairs (32 precursor spectra and 42...

  5. Metabolic network modeling of microbial interactions in natural and engineered environmental systems

    Directory of Open Access Journals (Sweden)

    Octavio ePerez-Garcia

    2016-05-01

    Full Text Available We review approaches to characterize metabolic interactions within microbial communities using Stoichiometric Metabolic Network (SMN models for applications in environmental and industrial biotechnology. SMN models are computational tools used to evaluate the metabolic engineering potential of various organisms. They have successfully been applied to design and optimize the microbial production of antibiotics, alcohols and amino acids by single strains. To date however, such models have been rarely applied to analyze and control the metabolism of more complex microbial communities. This is largely attributed to the diversity of microbial community functions, metabolisms and interactions. Here, we firstly review different types of microbial interaction and describe their relevance for natural and engineered environmental processes. Next, we provide a general description of the essential methods of the SMN modeling workflow including the steps of network reconstruction, simulation through Flux Balance Analysis (FBA, experimental data gathering, and model calibration. Then we broadly describe and compare four approaches to model microbial interactions using metabolic networks, i.e. i lumped networks, ii compartment per guild networks, iii bi-level optimization simulations and iv dynamic-SMN methods. These approaches can be used to integrate and analyze diverse microbial physiology, ecology and molecular community data. All of them (except the lumped approach are suitable for incorporating species abundance data but so far they have been used only to model simple communities of two to eight different species. Interactions based on substrate exchange and competition can be directly modeled using the above approaches. However, interactions based on metabolic feedbacks, such as product inhibition and synthropy require extensions to current models, incorporating gene regulation and compounding accumulation mechanisms. SMN models of microbial

  6. Intellectual disabilities, neuronal posttranscriptional RNA metabolism, and RNA-binding proteins: three actors for a complex scenario.

    Science.gov (United States)

    Bardoni, Barbara; Abekhoukh, Sabiha; Zongaro, Samantha; Melko, Mireille

    2012-01-01

    Intellectual disability (ID) is the most frequent cause of serious handicap in children and young adults and interests 2-3% of worldwide population, representing a serious problem from the medical, social, and economic points of view. The causes are very heterogeneous. Genes involved in ID have various functions altering different pathways important in neuronal function. Regulation of mRNA metabolism is particularly important in neurons for synaptic structure and function. Here, we review ID due to alteration of mRNA metabolism. Functional absence of some RNA-binding proteins--namely, FMRP, FMR2P, PQBP1, UFP3B, VCX-A--causes different forms of ID. These proteins are involved in different steps of RNA metabolism and, even if a detailed analysis of their RNA targets has been performed so far only for FMRP, it appears clear that they modulate some aspects (translation, stability, transport, and sublocalization) of a subset of RNAs coding for proteins, whose function must be relevant for neurons. Two other proteins, DYRK1A and CDKL5, involved in Down syndrome and Rett syndrome, respectively, have been shown to have an impact on splicing efficiency of specific mRNAs. Both proteins are kinases and their effect is indirect. Interestingly, both are localized in nuclear speckles, the nuclear domains where splicing factors are assembled, stocked, and recycled and influence their biogenesis and/or their organization. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Differential effects of simple vs. complex carbohydrates on VLDL secretion rates and HDL metabolism in the guinea pig.

    Science.gov (United States)

    Fernandez, M L; Abdel-Fattah, G; McNamara, D J

    1995-04-28

    Guinea pigs were fed isocaloric diets containing 52% (w/w) carbohydrate, either sucrose or starch, to investigate effects of simple vs. complex carbohydrates on plasma VLDL and HDL metabolism. Plasma cholesterol concentrations were not different between dietary groups while plasma triacylglycerol (TAG) and VLDL cholesterol levels were significantly increased in animals fed the sucrose diet (P < 0.05). Hepatic VLDL TAG secretion rates measured following intravenous injection of Triton WR-1339 were not affected by carbohydrate type whereas the rate of apo B secretion was 1.9-fold higher in sucrose fed animals (P < 0.02). Nascent VLDL from the sucrose group contained less TAG per apo B suggesting that the higher plasma TAG in animals fed simple carbohydrates results from increased secretion of VLDL particles with lower TAG content. Sucrose fed animals exhibited higher concentrations of hepatic free cholesterol (P < 0.01) while hepatic TAG levels and acyl CoA:cholesterol acyltransferase (ACAT) activity were not different between groups. Plasma HDL cholesterol concentrations and composition, and plasma lecithin cholesterol acyltransferase (LCAT) activity were not affected by diet yet there was a positive correlation between HDL cholesteryl ester content and LCAT activities (r = 0.70, P < 0.05). Hepatic membranes from the sucrose group had a higher hepatic HDL binding protein number (Bmax) with no changes in the dissociation constant (Kd). These results suggest that at the same carbohydrate energy intake, simple sugars induce modest changes in HDL metabolism while VLDL metabolism is affected at multiple sites, as indicated by the higher concentrations of hepatic cholesterol, dissociation in the synthesis rates of VLDL components, and compositional changes in nascent and mature VLDL.

  8. Improving production of ?-lactam antibiotics by Penicillium chrysogenum : Metabolic engineering based on transcriptome analysis

    NARCIS (Netherlands)

    Veiga, T.

    2012-01-01

    In Chapters 2-5 of this thesis, the applicability of transcriptome analysis to guide metabolic engineering strategies in P. chrysogenum is explored by investigating four cellular processes that are of potential relevance for industrial production of ?-lactam antibiotics: - Regulation of secondary

  9. Complex metabolic interactions between benzo(a)pyrene and tributyltin in presence of dichlorodiphenyltrichloroethane in South American catfish Rhamdia quelen.

    Science.gov (United States)

    Oliveira, Heloísa H P; Babin, Mathieu; Garcia, Juan Ramon Esquivel; Filipak Neto, Francisco; Randi, Marco A F; Oliveira Ribeiro, Ciro A; Pelletier, Émilien

    2013-10-01

    In an attempt to explore complex metabolic interactions between toxicants present in polluted freshwater, hepatic metabolism of benzo(a)pyrene (BaP) and tributyltin (TBT) in fish was investigated when these compounds were administrated alone, mixed together and along with dichlorodiphenyltrichloroethane (DDT). Ten Rhamdia quelen per group were treated with a single intra-peritoneal (IP) dose (5-day experiment) or three successive doses (15-day experiment) either containing BaP (0.3; 3 or 30mgkg(-1)) or TBT (0.03; 0.3 or 3mgkg(-1)) or a combination of BaP+TBT, BaP+DDT, TBT+DDT and BaP+TBT+DDT under their respective lower doses, with DDT dose kept at 0.03mgkg(-1). Tetrahydroxy-benzo(a)pyrene (BaP-tetrol-I), and dibutyltin (DBT) and monobutyltin (MBT) were analyzed to assess BaP and TBT hepatic metabolism, respectively. A significant difference in BaP-tetrol-I concentration was observed in liver and bile between the lowest and the highest doses of BaP in both 5 and 15-day experiments. In the 15-day experiment, the presence of TBT with BaP reduced the amount of BaP-tetrol-I in bile compared to the BaP alone. The time of exposure and the number of doses affected BaP-tetrol-I concentration in the bile of fish exposed to BaP 0.3mgkg(-1) and BaP+DDT. TBT and its metabolites concentrations showed a dose-dependent increase in the liver in both experiments and in the bile in the 5-day experiment. TBT at its lowest dose was completely metabolized into DBT and MBT in the liver in the 15-day experiment. No TBT metabolites were detected in the bile of fish exposed to the mixtures in the 5-day experiment, except for a small MBT amount found in BaP+TBT+DDT. This study strengthens the hypothesis of a metabolic interaction between BaP and TBT in fish and suggests DDT as an important third player when present in the mixture. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Transcriptome analysis reveals candidate genes involved in luciferin metabolism in Luciola aquatilis (Coleoptera: Lampyridae

    Directory of Open Access Journals (Sweden)

    Wanwipa Vongsangnak

    2016-10-01

    Full Text Available Bioluminescence, which living organisms such as fireflies emit light, has been studied extensively for over half a century. This intriguing reaction, having its origins in nature where glowing insects can signal things such as attraction or defense, is now widely used in biotechnology with applications of bioluminescence and chemiluminescence. Luciferase, a key enzyme in this reaction, has been well characterized; however, the enzymes involved in the biosynthetic pathway of its substrate, luciferin, remains unsolved at present. To elucidate the luciferin metabolism, we performed a de novo transcriptome analysis using larvae of the firefly species, Luciola aquatilis. Here, a comparative analysis is performed with the model coleopteran insect Tribolium casteneum to elucidate the metabolic pathways in L. aquatilis. Based on a template luciferin biosynthetic pathway, combined with a range of protein and pathway databases, and various prediction tools for functional annotation, the candidate genes, enzymes, and biochemical reactions involved in luciferin metabolism are proposed for L. aquatilis. The candidate gene expression is validated in the adult L. aquatilis using reverse transcription PCR (RT-PCR. This study provides useful information on the bio-production of luciferin in the firefly and will benefit to future applications of the valuable firefly bioluminescence system.

  11. Elementary real and complex analysis

    CERN Document Server

    Shilov, Georgi E

    1996-01-01

    In this book the renowned Russian mathematician Georgi E. Shilov brings his unique perspective to real and complex analysis, an area of perennial interest in mathematics. Although there are many books available on the topic, the present work is specially designed for undergraduates in mathematics, science and engineering. A high level of mathematical sophistication is not required.The book begins with a systematic study of real numbers, understood to be a set of objects satisfying certain definite axioms. The concepts of a mathematical structure and an isomorphism are introduced in Chapter 2,

  12. Analysis of Land-Use Emergy Indicators Based on Urban Metabolism: A Case Study for Beijing

    Directory of Open Access Journals (Sweden)

    Qing Huang

    2015-06-01

    Full Text Available The correlation of urban metabolism and changes in land use is an important issue in urban ecology, but recent research lacks consideration of the mechanisms and interactions between them. In this research, we did an emergy analysis of the flows of materials, energy, and capital within the socioeconomic system of Beijing. We calculated emergy-based evaluation indices of urban metabolism and land use change, to analyze the relationship between urban metabolism and land use by correlation analysis and regression analysis. Results indicate that the socio-economic activities on built-up land depend on local, non-renewable resource exploitation and external resource inputs. The emergy utilization efficiency of farmland has consistently decreased, but there remains significant utilization potential there. Urban development in Beijing relies on production activities on built-up land, which is subjected to great environmental pressure during extraction of material resources. To keep the economy developing effectively, we suggest that Beijing should commit to development of a circular economy, and change the land-use concept to “Smart Growth”. In this paper, we efficaciously solve the problem of conflicting measurement units, and avoid the disadvantages of subjective assignment. Consequently, this work provides not only a more scientific way to study land problems, but also provides a reliable reference for ecological construction and economic development in Beijing.

  13. Prevalence of metabolic syndrome in Bangladesh: a systematic review and meta-analysis of the studies.

    Science.gov (United States)

    Chowdhury, Mohammad Ziaul Islam; Anik, Ataul Mustufa; Farhana, Zaki; Bristi, Piali Dey; Abu Al Mamun, B M; Uddin, Mohammad Jasim; Fatema, Jain; Akter, Tanjila; Tani, Tania Akhter; Rahman, Meshbahur; Turin, Tanvir C

    2018-03-02

    Metabolic syndrome (MS) is a cluster of health problems that set the stage for serious health conditions and places individuals at higher risk of cardiovascular disease, diabetes and stroke. The worldwide prevalence of MS in the adult population is on the rise and Bangladesh is no exception. According to some epidemiological study, MS is highly prevalent in Bangladesh and has increased dramatically in last few decades. To provide a clear picture of the current situation, we conducted a systematic review and meta-analysis with an objective to assess the prevalence of metabolic syndrome among the Bangladeshi population using data already published in the scientific literature. We searched MEDLINE, EMBASE and PubMed and manually checked references of all identified relevant publications that described the prevalence of MS in Bangladesh. Random effects meta-analysis was used to pool the prevalence. Heterogeneity was explored using formal tests and subgroup analyses. Study quality and publication bias was also explored. Electronic and grey literature search retrieved 491 potentially relevant papers. After removing duplicates, reviewing titles and abstracts and screening full texts, 10 studies were finally selected. Most of the studies were conducted in rural populations and study participants were mostly females. The weighted pooled prevalence of metabolic syndrome regardless of gender and criteria used to define metabolic syndrome, was 30.0% with high heterogeneity observed. Weighted pooled prevalence of metabolic syndrome is higher in females (32%) compared to males (25%) though not statistically significant (p = 0.434). Prevalence was highest (37%) when Modified NCEP ATP III criteria was used to define MS, while it was lowest (20%) when WHO criteria was used. In most cases, geographical area (urban/rural) was identified as a source of heterogeneity between the studies. Most of the studies met study quality assessment criteria's except adequate sample size

  14. Kinetic modeling of cell metabolism for microbial production.

    Science.gov (United States)

    Costa, Rafael S; Hartmann, Andras; Vinga, Susana

    2016-02-10

    Kinetic models of cellular metabolism are important tools for the rational design of metabolic engineering strategies and to explain properties of complex biological systems. The recent developments in high-throughput experimental data are leading to new computational approaches for building kinetic models of metabolism. Herein, we briefly survey the available databases, standards and software tools that can be applied for kinetic models of metabolism. In addition, we give an overview about recently developed ordinary differential equations (ODE)-based kinetic models of metabolism and some of the main applications of such models are illustrated in guiding metabolic engineering design. Finally, we review the kinetic modeling approaches of large-scale networks that are emerging, discussing their main advantages, challenges and limitations. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Metabolic flux analysis of the halophilic archaeon Haladaptatus paucihalophilus

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Guangxiu; Zhang, Manxiao [Key Laboratory of Desert and Desertification, Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou, 730000 (China); Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 (China); Mo, Tianlu [Department of Chemistry, Fudan University, Shanghai, 200433 (China); He, Lian [Key Laboratory of Combinatory Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071 (China); Zhang, Wei [Key Laboratory of Desert and Desertification, Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou, 730000 (China); Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 (China); Yu, Yi, E-mail: yu_yi@whu.edu.cn [Key Laboratory of Combinatory Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071 (China); Zhang, Qi, E-mail: qizhang@sioc.ac.cn [Department of Chemistry, Fudan University, Shanghai, 200433 (China); Ding, Wei, E-mail: dingw@lzu.edu.cn [Key Laboratory of Desert and Desertification, Cold and Arid Regions Environmental and Engineering Research Institute, Chinese Academy of Sciences, Lanzhou, 730000 (China); Key Laboratory of Extreme Environmental Microbial Resources and Engineering, Gansu Province, Lanzhou, 730000 (China); Department of Chemistry, Fudan University, Shanghai, 200433 (China)

    2015-11-27

    This work reports the {sup 13}C-assisted metabolic flux analysis of Haladaptatus paucihalophilus, a halophilic archaeon possessing an intriguing osmoadaption mechanism. We showed that the carbon flow is through the oxidative tricarboxylic acid (TCA) cycle whereas the reductive TCA cycle is not operative in H. paucihalophilus. In addition, both threonine and the citramalate pathways contribute to isoleucine biosynthesis, whereas lysine is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway. Unexpected, the labeling patterns of glycine from the cells grown on [1-{sup 13}C]pyruvate and [2-{sup 13}C]pyruvate suggest that, unlike all the organisms investigated so far, in which glycine is produced exclusively from the serine hydroxymethyltransferase (SHMT) pathway, glycine biosynthesis in H. paucihalophilus involves different pathways including SHMT, threonine aldolase (TA) and the reverse reaction of glycine cleavage system (GCS), demonstrating for the first time that other pathways instead of SHMT can also make a significant contribution to the cellular glycine pool. Transcriptional analysis confirmed that both TA and GCS genes were transcribed in H. paucihalophilus, and the transcriptional level is independent of salt concentrations in the culture media. This study expands our understanding of amino acid biosynthesis and provides valuable insights into the metabolism of halophilic archaea. - Highlights: • Serine hydroxymethyltransferase, threonine aldolase, and glycine cleavage system all contribute to the glycine pool of H. paucihalophilus. • Threonine and the citramalate pathways contribute equally to the isoleucine biosynthesis in H. paucihalophilus. • Lysine in H. paucihalophilus is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway. • Glycine biosynthesis is likely unrelated to the cell osmoadaption mechanism.

  16. Metabolic flux analysis of the halophilic archaeon Haladaptatus paucihalophilus

    International Nuclear Information System (INIS)

    Liu, Guangxiu; Zhang, Manxiao; Mo, Tianlu; He, Lian; Zhang, Wei; Yu, Yi; Zhang, Qi; Ding, Wei

    2015-01-01

    This work reports the "1"3C-assisted metabolic flux analysis of Haladaptatus paucihalophilus, a halophilic archaeon possessing an intriguing osmoadaption mechanism. We showed that the carbon flow is through the oxidative tricarboxylic acid (TCA) cycle whereas the reductive TCA cycle is not operative in H. paucihalophilus. In addition, both threonine and the citramalate pathways contribute to isoleucine biosynthesis, whereas lysine is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway. Unexpected, the labeling patterns of glycine from the cells grown on [1-"1"3C]pyruvate and [2-"1"3C]pyruvate suggest that, unlike all the organisms investigated so far, in which glycine is produced exclusively from the serine hydroxymethyltransferase (SHMT) pathway, glycine biosynthesis in H. paucihalophilus involves different pathways including SHMT, threonine aldolase (TA) and the reverse reaction of glycine cleavage system (GCS), demonstrating for the first time that other pathways instead of SHMT can also make a significant contribution to the cellular glycine pool. Transcriptional analysis confirmed that both TA and GCS genes were transcribed in H. paucihalophilus, and the transcriptional level is independent of salt concentrations in the culture media. This study expands our understanding of amino acid biosynthesis and provides valuable insights into the metabolism of halophilic archaea. - Highlights: • Serine hydroxymethyltransferase, threonine aldolase, and glycine cleavage system all contribute to the glycine pool of H. paucihalophilus. • Threonine and the citramalate pathways contribute equally to the isoleucine biosynthesis in H. paucihalophilus. • Lysine in H. paucihalophilus is synthesized through the diaminopimelate pathway and not through the α-aminoadipate pathway. • Glycine biosynthesis is likely unrelated to the cell osmoadaption mechanism.

  17. Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis.

    Science.gov (United States)

    Li, Li; Feng, Qiong; Ye, Ming; He, Yaojuan; Yao, Aling; Shi, Kun

    2017-11-01

    This meta-analysis provides an updated and comprehensive estimate of the effects of obesity on metabolic disorders in adolescent polycystic ovary syndrome (PCOS). Relevant articles consistent with the search terms published up to 31 January 2014 were retrieved from PubMed, EMBASE, PsycINFO and CENTRAL. Thirteen articles (16 independent studies) conformed to the inclusion criteria. The evaluated outcomes were the metabolic parameters of obese adolescents with PCOS (case group) relative to normal-weight adolescents with PCOS, or obese adolescents without PCOS. Compared with normal-weight adolescents with PCOS, the case group had significantly lower sex hormone-binding globulin and high-density lipoprotein cholesterol, and significantly higher triglycerides, leptin, fasting insulin, low-density lipoprotein cholesterol and free testosterone levels. Relative to obese adolescents without PCOS, the case group had significantly higher fasting insulin, low-density lipoprotein cholesterol, free testosterone levels and 2-h glucose during the oral glucose tolerance test. These results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant obesity. This study highlights the importance of preventing obesity during the management of adolescent PCOS. Impact statement What is already known about this subject: Obesity and PCOS share many of the same metabolic disorders, for example, hyperandrogenism and hyperinsulinemia with subsequent insulin resistance. Knowledge regarding metabolic features in obese adolescents with PCOS is limited, and there is concern whether obesity and PCOS are related. What do the results of this study add: Relative to PCOS adolescents of normal weight, obese adolescents with PCOS (the case group) had significantly lower SHBG and HDL-C, and significantly higher triglycerides, leptin, fasting insulin, LDL-C and free testosterone levels. The results indicate that metabolic disorders in adolescent PCOS are worsened by concomitant

  18. Flux-Enabled Exploration of the Role of Sip1 in Galactose Yeast Metabolism

    Directory of Open Access Journals (Sweden)

    Christopher M. Shymansky

    2017-05-01

    Full Text Available 13C metabolic flux analysis (13C MFA is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon known as glucose repression or carbon catabolite repression. The SIP1 gene, encoding a part of this complex, has received little attention, presumably, because its knockout lacks a growth phenotype. We present a fluxomic investigation of the relative effects of the presence of galactose in classically glucose-repressing media and/or knockout of SIP1 using a multi-scale variant of 13C MFA known as 2-Scale 13C metabolic flux analysis (2S-13C MFA. In this study, all strains have the galactose metabolism deactivated (gal1Δ background so as to be able to separate the metabolic effects purely related to glucose repression from those arising from galactose metabolism. The resulting flux profiles reveal that the presence of galactose in classically glucose-repressing conditions, for a CEN.PK113-7D gal1Δ background, results in a substantial decrease in pentose phosphate pathway (PPP flux and increased flow from cytosolic pyruvate and malate through the mitochondria toward cytosolic branched-chain amino acid biosynthesis. These fluxomic redistributions are accompanied by a higher maximum specific growth rate, both seemingly in violation of glucose repression. Deletion of SIP1 in the CEN.PK113-7D gal1Δ cells grown in mixed glucose/galactose medium results in a further increase. Knockout of this gene in cells grown in glucose-only medium results in no change in growth rate and a corresponding decrease in glucose and ethanol exchange fluxes and flux through pathways involved in aspartate/threonine biosynthesis. Glucose repression appears to be violated at a 1/10 ratio of galactose-to-glucose. Based on the scientific literature, we may have conducted our experiments

  19. Phylogenetic analysis of vitamin B12-related metabolism in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Douglas B. Young

    2015-03-01

    Full Text Available Comparison of genome sequences from clinical isolates of Mycobacterium tuberculosis with phylogenetically-related pathogens Mycobacterium marinum, Mycobacterium kansasii and Mycobacterium leprae reveals diversity amongst genes associated with vitamin B12-related metabolism. Diversity is generated by gene deletion events, differential acquisition of genes by horizontal transfer, and single nucleotide polymorphisms with predicted impact on protein function and transcriptional regulation. Differences in the B12 synthesis pathway, methionine biosynthesis, fatty acid catabolism, and DNA repair and replication are consistent with adaptations to different environmental niches and pathogenic lifestyles. While there is no evidence of further gene acquisition during expansion of the M. tuberculosis complex, the emergence of other forms of genetic diversity provides insights into continuing host-pathogen co-evolution and has the potential to identify novel targets for disease intervention.

  20. Perceived stress correlates with visceral obesity and lipid parameters of the metabolic syndrome: A systematic review and meta-analysis.

    Science.gov (United States)

    Tenk, Judit; Mátrai, Péter; Hegyi, Péter; Rostás, Ildikó; Garami, András; Szabó, Imre; Hartmann, Petra; Pétervári, Erika; Czopf, László; Hussain, Alizadeh; Simon, Mária; Szujó, Szabina; Balaskó, Márta

    2018-05-12

    Perceived stress has been proposed as a risk factor of metabolic syndrome. However, correlations between perceived stress and parameters of the metabolic syndrome have not been properly analyzed despite extensive research data on the topic. Our current meta-analysis aimed to examine the mutual association between perceived stress of patients and parameters of metabolic syndrome. This systematic review has been registered on the PROSPERO database (registration number CRD42017055293). Eligible studies divided participants based on their stress level or on the presence of metabolic syndrome. They reported at least one parameter of the metabolic syndrome or the stress level of the participants measured with some stress scale. Data from 17 articles met the eligibility criteria and were included. Random effects model with the DerSimonian and Laird weighting methods was applied. I-squared indicator and Q test were performed to assess heterogeneity. Although the majority of individual studies failed to demonstrate correlations between stress and their analyzed parameters of metabolic syndrome, our meta-analysis showed a significant association between stress and BMI [average effect size (ES) with 95% confidence interval (95%CI), ES = 0.65, 95%CI 0.16, 1.14), waist circumference (ES = 1.84 cm, 95%CI 0.79, 2.89) and serum triglyceride level (ES = 7.52 mg/dl, 95%CI 0.07, 14.96). Additional analysis confirmed effects of stress on serum HDL (ES = - 1.699 mg/dl, 95%CI -2.966, -0.432) and diastolic blood pressure (ES = 1.04 mmHg, 95%CI 0.18, 1.89). No correlations were found for fasting glucose or systolic blood pressure. No association between metabolic syndrome and stress level of patients was detected either. The potentially key role of visceral obesity in the association between perceived stress and dyslipidemia or diastolic blood pressure are discussed together with potential moderators (e.g. gender-differences, variations in stress assessment and

  1. From genomes to in silico cells via metabolic networks

    DEFF Research Database (Denmark)

    Borodina, Irina; Nielsen, Jens

    2005-01-01

    Genome-scale metabolic models are the focal point of systems biology as they allow the collection of various data types in a form suitable for mathematical analysis. High-quality metabolic networks and metabolic networks with incorporated regulation have been successfully used for the analysis...... of phenotypes from phenotypic arrays and in gene-deletion studies. They have also been used for gene expression analysis guided by metabolic network structure, leading to the identification of commonly regulated genes. Thus, genome-scale metabolic modeling currently stands out as one of the most promising...

  2. [Characterization of the Structure of the Prokaryotic Complex of Antarctic Permafrost by Molecular Genetic Techniques].

    Science.gov (United States)

    Manucharova, N A; Trosheva, E V; Kol'tsova, E M; Demkina, E V; Karaevskaya, E V; Rivkina, E M; Mardanov, A V; El'-Registan, G I

    2016-01-01

    A prokaryotic mesophilic organotrophic community responsible for 10% of the total microbial number determined by epifluorescence microscopy was reactivated in the samples ofAntarctic permafrost retrieved from the environment favoring long-term preservation of microbial communities (7500 years). No culturable forms were obtained without resuscitation procedures (CFU = 0). Proteobacteria, Actinobacteria, and Firmicutes were the dominant microbial groups in the complex. Initiation of the reactivated microbial complex by addition of chitin (0.1% wt/vol) resulted in an increased share of metabolically active biomass (up to 50%) due to the functional domination of chitinolytics caused by the target resource. Thus, sequential application of resuscitation procedures and initiation of a specific physiological group (in this case, chitinolytics) to a permafrost-preserved microbial community made it possible to reveal a prokaryotic complex capable of reversion of metabolic activity (FISH data), to determine its phylogenetic structure by metagenomic anal-ysis, and to isolate a pure culture of the dominant microorganism with high chitinolytic activity.

  3. iAB-RBC-283: A proteomically derived knowledge-base of erythrocyte metabolism that can be used to simulate its physiological and patho-physiological states.

    Science.gov (United States)

    Bordbar, Aarash; Jamshidi, Neema; Palsson, Bernhard O

    2011-07-12

    The development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology. Integrated analysis of the resulting omic data sets has proved to be hard to achieve. Metabolic network reconstructions enable complex relationships amongst molecular components to be represented formally in a biologically relevant manner while respecting physical constraints. In silico models derived from such reconstructions can then be queried or interrogated through mathematical simulations. Proteomic profiling studies of the mature human erythrocyte have shown more proteins present related to metabolic function than previously thought; however the significance and the causal consequences of these findings have not been explored. Erythrocyte proteomic data was used to reconstruct the most expansive description of erythrocyte metabolism to date, following extensive manual curation, assessment of the literature, and functional testing. The reconstruction contains 281 enzymes representing functions from glycolysis to cofactor and amino acid metabolism. Such a comprehensive view of erythrocyte metabolism implicates the erythrocyte as a potential biomarker for different diseases as well as a 'cell-based' drug-screening tool. The analysis shows that 94 erythrocyte enzymes are implicated in morbid single nucleotide polymorphisms, representing 142 pathologies. In addition, over 230 FDA-approved and experimental pharmaceuticals have enzymatic targets in the erythrocyte. The advancement of proteomic technologies and increased generation of high-throughput proteomic data have created the need for a means to analyze these data in a coherent manner. Network reconstructions provide a systematic means to integrate and analyze proteomic data in a biologically meaning manner. Analysis of the red cell proteome has revealed an unexpected level of complexity in the functional capabilities of human erythrocyte metabolism.

  4. /sup 15/N analysis in nutritional and metabolic research of infancy

    Energy Technology Data Exchange (ETDEWEB)

    Heine, W; Richter, I; Plath, C; Wutzke, K; Drescher, U [Rostock Univ. (German Democratic Republic). Bereich Medizin

    1982-01-01

    Investigation of protein metabolism in nutritional pediatric research by means of /sup 15/N tracer techniques has been relatively seldom used up to now. /sup 15/N-labelled compounds for these purposes are not injurious to health. The technique is based on oral or intravenous application of the tracer substances and on /sup 15/N analysis of the urine fractions. The subsequent calculation of protein synthesis and breakdown rate, turnover, and the reutilisation of amino acids from protein breakdown as well as the size of the metabolic pool offers detailed information of protein metabolism. Determination of these parameters were performed in infants on breast milk, formula feeding and on chemically defined diet. As an example of utilisation of D-amino acids for protein synthesis the /sup 15/N-D-phenylalanine retention of parenteral nutrition was found to be 33% of the applied doses at an average. An oral /sup 15/N-glycine loading test proved to be of value for the prediction of the therapeutic effect of human growth hormone. /sup 15/N tracer technique was also tested in utilizing /sup 15/N-urea for bacterial protein synthesis of the intestinal flora and by incorporation of /sup 15/N from /sup 15/N-glycine and /sup 15/N-lysine into the jejunal mucosa for measuring the enterocyte regeneration.

  5. Transcriptome Analysis of Sucrose Metabolism during Bulb Swelling and Development in Onion (Allium cepa L.

    Directory of Open Access Journals (Sweden)

    Yi Liang

    2016-09-01

    Full Text Available Allium cepa L. is a widely cultivated and economically significant vegetable crop worldwide, with beneficial dietary and health-related properties, but its sucrose metabolism is still poorly understood. To analyze sucrose metabolism during bulb swelling, and the development of sweet taste in onion, a global transcriptome profile of onion bulbs was undertaken at three different developmental stages, using RNA-seq. A total of 79,376 unigenes, with a mean length of 678 bp, was obtained. In total, 7% of annotated Clusters of Orthologous Groups (COG were involved in carbohydrate transport and metabolism. In the Kyoto Encyclopedia of Genes and Genomes (KEGG database, starch and sucrose metabolism (147, 2.40% constituted the primary metabolism pathway in the integrated library. The expression of sucrose transporter genes was greatest during the early-swelling stage, suggesting that sucrose transporters participated in sucrose metabolism mainly at an early stage of bulb development. A gene-expression analysis of the key enzymes of sucrose metabolism suggested that sucrose synthase, cell wall invertase and invertase were all likely to participate in the hydrolysis of sucrose, generating glucose and fructose. In addition, trehalose was hydrolyzed to two molecules of glucose by trehalase. From 15 to 40 days after swelling (DAS, both the glucose and fructose contents of bulbs increased, whereas the sucrose content decreased. The growth rate between 15 and 30 DAS was slower than that between 30 and 40 DAS, suggesting that the latter was a period of rapid expansion. The dataset generated by our transcriptome profiling will provide valuable information for further research.

  6. Primary metabolism in Lactobacillus sakei food isolates by proteomic analysis

    Directory of Open Access Journals (Sweden)

    Champomier-Vergès Marie-Christine

    2010-04-01

    Full Text Available Abstract Background Lactobacillus sakei is an important food-associated lactic acid bacterium commonly used as starter culture for industrial meat fermentation, and with great potential as a biopreservative in meat and fish products. Understanding the metabolic mechanisms underlying the growth performance of a strain to be used for food fermentations is important for obtaining high-quality and safe products. Proteomic analysis was used to study the primary metabolism in ten food isolates after growth on glucose and ribose, the main sugars available for L. sakei in meat and fish. Results Proteins, the expression of which varied depending on the carbon source were identified, such as a ribokinase and a D-ribose pyranase directly involved in ribose catabolism, and enzymes involved in the phosphoketolase and glycolytic pathways. Expression of enzymes involved in pyruvate and glycerol/glycerolipid metabolism were also affected by the change of carbon source. Interestingly, a commercial starter culture and a protective culture strain down-regulated the glycolytic pathway more efficiently than the rest of the strains when grown on ribose. The overall two-dimensional gel electrophoresis (2-DE protein expression pattern was similar for the different strains, though distinct differences were seen between the two subspecies (sakei and carnosus, and a variation of about 20% in the number of spots in the 2-DE gels was observed between strains. A strain isolated from fermented fish showed a higher expression of stress related proteins growing on both carbon sources. Conclusions It is obvious from the data obtained in this study that the proteomic approach efficiently identifies differentially expressed proteins caused by the change of carbon source. Despite the basic similarity in the strains metabolic routes when they ferment glucose and ribose, there were also interesting differences. From the application point of view, an understanding of regulatory

  7. Clinical relevance of the bile acid receptor TGR5 in metabolism

    DEFF Research Database (Denmark)

    van Nierop, F Samuel; Scheltema, Matthijs J; Eggink, Hannah M

    2017-01-01

    The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohep......The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...

  8. Systematic review and meta-analysis of the association between psoriasis and metabolic syndrome.

    Science.gov (United States)

    Rodríguez-Zúñiga, Milton José Max; García-Perdomo, Herney Andrés

    2017-10-01

    Several studies have shown a relationship between psoriasis and metabolic syndrome (MS), but no meta-analysis has been restricted to studies that adjusted for confounders. To determine the association between psoriasis and MS. A systematic review and meta-analysis of observational studies on psoriasis and MS in adults was performed from MEDLINE, Scopus, SciELO, Google Scholar, Science Direct, and LILACS from inception to January 2016. We performed a random effects model meta-analysis for those studies reporting adjusted odds ratios (ORs) with 95% confidence intervals (CIs). The subgroup analysis was related to geographic location, diagnosis criteria and risk of bias. In all, 14 papers including a total of 25,042 patients with psoriasis were analyzed. We found that MS was present in 31.4% of patients with psoriasis (OR, 1.42; 95% CI, 1.28-1.65). Middle Eastern studies (in Israel, Turkey, and Lebanon) (OR, 1.76, 95% CI, 0.86-2.67) reported a greater risk for MS than European studies (in Germany, Italy, the United Kingdom, Norway, and Denmark) (OR, 1.40; 95% CI, 1.25-1.55). Few adjusted studies existed, and there was inconsistency between publications. Because of the increased risk for MS, clinicians should consider screening patients with psoriasis for metabolic risk factors. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  9. Cancer Metabolism: A Modeling Perspective

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells...

  10. Putative drug and vaccine target protein identification using comparative genomic analysis of KEGG annotated metabolic pathways of Mycoplasma hyopneumoniae.

    Science.gov (United States)

    Damte, Dereje; Suh, Joo-Won; Lee, Seung-Jin; Yohannes, Sileshi Belew; Hossain, Md Akil; Park, Seung-Chun

    2013-07-01

    In the present study, a computational comparative and subtractive genomic/proteomic analysis aimed at the identification of putative therapeutic target and vaccine candidate proteins from Kyoto Encyclopedia of Genes and Genomes (KEGG) annotated metabolic pathways of Mycoplasma hyopneumoniae was performed for drug design and vaccine production pipelines against M.hyopneumoniae. The employed comparative genomic and metabolic pathway analysis with a predefined computational systemic workflow extracted a total of 41 annotated metabolic pathways from KEGG among which five were unique to M. hyopneumoniae. A total of 234 proteins were identified to be involved in these metabolic pathways. Although 125 non homologous and predicted essential proteins were found from the total that could serve as potential drug targets and vaccine candidates, additional prioritizing parameters characterize 21 proteins as vaccine candidate while druggability of each of the identified proteins evaluated by the DrugBank database prioritized 42 proteins suitable for drug targets. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model

    Science.gov (United States)

    Martin, François-Pierre J; Dumas, Marc-Emmanuel; Wang, Yulan; Legido-Quigley, Cristina; Yap, Ivan K S; Tang, Huiru; Zirah, Séverine; Murphy, Gerard M; Cloarec, Olivier; Lindon, John C; Sprenger, Norbert; Fay, Laurent B; Kochhar, Sunil; van Bladeren, Peter; Holmes, Elaine; Nicholson, Jeremy K

    2007-01-01

    Symbiotic gut microorganisms (microbiome) interact closely with the mammalian host's metabolism and are important determinants of human health. Here, we decipher the complex metabolic effects of microbial manipulation, by comparing germfree mice colonized by a human baby flora (HBF) or a normal flora to conventional mice. We perform parallel microbiological profiling, metabolic profiling by 1H nuclear magnetic resonance of liver, plasma, urine and ileal flushes, and targeted profiling of bile acids by ultra performance liquid chromatography–mass spectrometry and short-chain fatty acids in cecum by GC-FID. Top-down multivariate analysis of metabolic profiles reveals a significant association of specific metabotypes with the resident microbiome. We derive a transgenomic graph model showing that HBF flora has a remarkably simple microbiome/metabolome correlation network, impacting directly on the host's ability to metabolize lipids: HBF mice present higher ileal concentrations of tauro-conjugated bile acids, reduced plasma levels of lipoproteins but higher hepatic triglyceride content associated with depletion of glutathione. These data indicate that the microbiome modulates absorption, storage and the energy harvest from the diet at the systems level. PMID:17515922

  12. Complexity analysis based on generalized deviation for financial markets

    Science.gov (United States)

    Li, Chao; Shang, Pengjian

    2018-03-01

    In this paper, a new modified method is proposed as a measure to investigate the correlation between past price and future volatility for financial time series, known as the complexity analysis based on generalized deviation. In comparison with the former retarded volatility model, the new approach is both simple and computationally efficient. The method based on the generalized deviation function presents us an exhaustive way showing the quantization of the financial market rules. Robustness of this method is verified by numerical experiments with both artificial and financial time series. Results show that the generalized deviation complexity analysis method not only identifies the volatility of financial time series, but provides a comprehensive way distinguishing the different characteristics between stock indices and individual stocks. Exponential functions can be used to successfully fit the volatility curves and quantify the changes of complexity for stock market data. Then we study the influence for negative domain of deviation coefficient and differences during the volatile periods and calm periods. after the data analysis of the experimental model, we found that the generalized deviation model has definite advantages in exploring the relationship between the historical returns and future volatility.

  13. Metagenomic analysis revealed highly diverse microbial arsenic metabolism genes in paddy soils with low-arsenic contents

    International Nuclear Information System (INIS)

    Xiao, Ke-Qing; Li, Li-Guan; Ma, Li-Ping; Zhang, Si-Yu; Bao, Peng; Zhang, Tong; Zhu, Yong-Guan

    2016-01-01

    Microbe-mediated arsenic (As) metabolism plays a critical role in global As cycle, and As metabolism involves different types of genes encoding proteins facilitating its biotransformation and transportation processes. Here, we used metagenomic analysis based on high-throughput sequencing and constructed As metabolism protein databases to analyze As metabolism genes in five paddy soils with low-As contents. The results showed that highly diverse As metabolism genes were present in these paddy soils, with varied abundances and distribution for different types and subtypes of these genes. Arsenate reduction genes (ars) dominated in all soil samples, and significant correlation existed between the abundance of arr (arsenate respiration), aio (arsenite oxidation), and arsM (arsenite methylation) genes, indicating the co-existence and close-relation of different As resistance systems of microbes in wetland environments similar to these paddy soils after long-term evolution. Among all soil parameters, pH was an important factor controlling the distribution of As metabolism gene in five paddy soils (p = 0.018). To the best of our knowledge, this is the first study using high-throughput sequencing and metagenomics approach in characterizing As metabolism genes in the five paddy soil, showing their great potential in As biotransformation, and therefore in mitigating arsenic risk to humans. - Highlights: • Use metagenomics to analyze As metabolism genes in paddy soils with low-As content. • These genes were ubiquitous, abundant, and associated with diverse microbes. • pH as an important factor controlling their distribution in paddy soil. • Imply combinational effect of evolution and selection on As metabolism genes. - Metagenomics was used to analyze As metabolism genes in paddy soils with low-As contents. These genes were ubiquitous, abundant, and associated with diverse microbes.

  14. Relative Quantitative Proteomic Analysis of Brucella abortus Reveals Metabolic Adaptation to Multiple Environmental Stresses.

    Science.gov (United States)

    Zai, Xiaodong; Yang, Qiaoling; Yin, Ying; Li, Ruihua; Qian, Mengying; Zhao, Taoran; Li, Yaohui; Zhang, Jun; Fu, Ling; Xu, Junjie; Chen, Wei

    2017-01-01

    Brucella spp. are facultative intracellular pathogens that cause chronic brucellosis in humans and animals. The virulence of Brucella primarily depends on its successful survival and replication in host cells. During invasion of the host tissue, Brucella is simultaneously subjected to a variety of harsh conditions, including nutrient limitation, low pH, antimicrobial defenses, and extreme levels of reactive oxygen species (ROS) via the host immune response. This suggests that Brucella may be able to regulate its metabolic adaptation in response to the distinct stresses encountered during its intracellular infection of the host. An investigation into the differential proteome expression patterns of Brucella grown under the relevant stress conditions may contribute toward a better understanding of its pathogenesis and adaptive response. Here, we utilized a mass spectrometry-based label-free relative quantitative proteomics approach to investigate and compare global proteomic changes in B. abortus in response to eight different stress treatments. The 3 h short-term in vitro single-stress and multi-stress conditions mimicked the in vivo conditions of B. abortus under intracellular infection, with survival rates ranging from 3.17 to 73.17%. The proteomic analysis identified and quantified a total of 2,272 proteins and 74% of the theoretical proteome, thereby providing wide coverage of the B. abortus proteome. By including eight distinct growth conditions and comparing these with a control condition, we identified a total of 1,221 differentially expressed proteins (DEPs) that were significantly changed under the stress treatments. Pathway analysis revealed that most of the proteins were involved in oxidative phosphorylation, ABC transporters, two-component systems, biosynthesis of secondary metabolites, the citrate cycle, thiamine metabolism, and nitrogen metabolism; constituting major response mechanisms toward the reconstruction of cellular homeostasis and metabolic

  15. Emerging opportunities for the treatment of metabolic diseases

    DEFF Research Database (Denmark)

    Finan, Brian; Clemmensen, Christoffer; Müller, Timo D

    2015-01-01

    with integrated activities derived from multiple hormones involved in the physiological control of metabolism have emerged as one of the more promising candidates for reversing obesity. The inclusion of glucagon-like peptide-1 (GLP-1) as one of the constituents is a unifying factor amongst the majority......Obesity is a pathogenic gateway to the metabolic syndrome and the complications thereof, thus interventions aimed at preventing or reversing the metabolic derangements underlying obesity hold great therapeutic promise. However, the complexity of energy balance regulation, combined...

  16. Culinary plants and their potential impact on metabolic overload.

    Science.gov (United States)

    Kim, Ji Yeon; Kwon, Oran

    2011-07-01

    Contemporary human behavior has led a large proportion of the population to metabolic overload and obesity. Postprandial hyperlipidemia and hyperglycemia evoke redox imbalance in the short term and lead to complex chronic disease in the long term with repeated occurrence. Complex diseases are best prevented with complex components of plants; thus, current nutrition research has begun to focus on the development of plant-based functional foods and dietary supplements for health and well-being. Furthermore, given the wide range of species, parts, and secondary metabolites, culinary plants can contribute significant variety and complexity to the human diet. Although understanding the health benefits of culinary plants has been one of the great challenges in nutritional science due to their inherent complexity, it is an advantageous pursuit. This review will address the challenges and opportunities relating to studies of the health benefits of culinary plants, with an emphasis on obesity attributed to metabolic overload. © 2011 New York Academy of Sciences.

  17. Forensic relevance of glucuronidation in phase-II-metabolism of alcohols and drugs.

    Science.gov (United States)

    Kaeferstein, Herbert

    2009-04-01

    Forensic toxicology means detecting toxic or pharmacologically active substances in body fluids and organs and the evaluation and judgement of the respective results. In the legal judgement, not only the taken in active drugs, but also their metabolites are to be included. Regarding metabolism one distinguishes phase-I- and phase-II-metabolism. In the phase-I-metabolism, active substances are converted by oxidation, reduction or hydrolysis, but influencing the polarity of more lipophilic substances often not decisively. The pharmacological activity is often preserved or even increased. In phase-II-metabolism a highly hydrophilic substance--mostly glucuronic acid--is coupled to the active substances or the respective phase-I-metabolites. This reaction step decisively increases hydrophilicity of lipophilic substances, thus enhancing renal elimination and often also abolishing pharmacologically and/or toxicologically effects. Nevertheless the interaction of different drugs and alcohols in glucuronidation and the glucuronides of phase-II-metabolism still do not play a substantial role in the forensic-toxicological analysis and interpretation of results so far. However, in vitro investigations since 1999 in our lab show that such interactions are not unlikely. For valid interpretation of complex cases in the future it may become necessary not only to quantify drugs and the phase-I-metabolites but also the phase-II-metabolites and discuss possible interactions in the metabolism.

  18. Heritability and genetics of lipid metabolism

    DEFF Research Database (Denmark)

    Fenger, Mogens

    2007-01-01

    In this article, the concept of heritability and genetic effect will be reviewed and our current knowledge of the genetics of lipid metabolism summarized. The concepts of polygenic conditions and epistasis are discussed at length, and an effort is made to put the biological processes in context...... in the search for genetic factors influencing the metabolic pathways. Particular physiological heterogeneity is addressed and procedures to handle this complex issue are suggested....

  19. Myocardial ischemia analysis based on electrocardiogram QRS complex

    International Nuclear Information System (INIS)

    Song, J.; Yan, H.; Xu, Z.; Yu, X.; Zhu, R.

    2011-01-01

    Full text: Electrocardiogram (ECG) is an economic, convenient, and non-invasive detecting tool in myocardial ischemia (MI), and its clinical appearance is mainly exhibited by the changes in ST-T complex. Recently, QRS complex characters were proposed to analyze MI by more and more researchers. In this paper, various QRS complex characters were extracted in ECG signals, and their relationship was analyzed systematically. As a result, these characters were divided into two groups, and there existed good relationship among them for each group, while the poor relationship between the groups. Then these QRS complex characters were applied for statistical analysis on MI, and five characters had significant differences after ECG recording verification, which were: QRS upward and downward slopes, transient heart rate, angle R and angle Q. On the other hand, these QRS complex characters were analyzed in frequency domain. Experimental results showed that the frequency features of RR interval series (Heart Rate Variability, HRV), and QRS barycenter sequence had signjficant differences between MI states and normal states. Moreover, QRS barycenter sequence performed better. (author)

  20. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  1. Complex analysis and geometry

    CERN Document Server

    Silva, Alessandro

    1993-01-01

    The papers in this wide-ranging collection report on the results of investigations from a number of linked disciplines, including complex algebraic geometry, complex analytic geometry of manifolds and spaces, and complex differential geometry.

  2. Fire hazard analysis for Plutonium Finishing Plant complex

    International Nuclear Information System (INIS)

    MCKINNIS, D.L.

    1999-01-01

    A fire hazards analysis (FHA) was performed for the Plutonium Finishing Plant (PFP) Complex at the Department of Energy (DOE) Hanford site. The scope of the FHA focuses on the nuclear facilities/structures in the Complex. The analysis was conducted in accordance with RLID 5480.7, [DOE Directive RLID 5480.7, 1/17/94] and DOE Order 5480.7A, ''Fire Protection'' [DOE Order 5480.7A, 2/17/93] and addresses each of the sixteen principle elements outlined in paragraph 9.a(3) of the Order. The elements are addressed in terms of the fire protection objectives stated in paragraph 4 of DOE 5480.7A. In addition, the FHA also complies with WHC-CM-4-41, Fire Protection Program Manual, Section 3.4 [1994] and WHC-SD-GN-FHA-30001, Rev. 0 [WHC, 1994]. Objectives of the FHA are to determine: (1) the fire hazards that expose the PFP facilities, or that are inherent in the building operations, (2) the adequacy of the fire safety features currently located in the PFP Complex, and (3) the degree of compliance of the facility with specific fire safety provisions in DOE orders, related engineering codes, and standards

  3. Metabolic Ride” - One Concept Evaluation Tool For Metabolic Biochemistry Teaching For Graduate Students In Biological Sciences And Related Areas.

    Directory of Open Access Journals (Sweden)

    H. H. Gaeta et al.

    2017-07-01

    Full Text Available Biochemistry subject in general has a high degree of difficulty and complexity. Therefore, application of playful and creative games as teaching methodology has spread in various disciplines of life sciences. "METABOLIC RIDE" board game is a conceptual and perceptual evaluation tool for metabolic biochemistry teaching, aiming to review concepts transmitted in classroom, promoting a competitive challenge to students without denying tools that are at their disposal, stimulating their skills. OBJECTIVES. Correlate metabolic routes importance and their interconnections to establish that metabolic pathways are interconnected, such as a railway map. MATERIAL AND METHODS. This game was developed based on a board game Ticket to Ride. Players purchase enzyme cards, which must be used to claim metabolic routes. The goal is to complete the route previously drawn to earn points and the player who builds the longest continuous route will also earn bonus points. In each turn, players can: buy more card, claim a route or pick up additional destination tickets. The game should be played in groups of 5 to 6 students in 6 to 8 groups. Previously there will be theoretical classes. The activity was designed to last 4 hours. Use of didatic books and internet by players are encouraged. RESULTS. This game proved to be an excellent tool for student’s complementary evaluation, which stimulated teamwork and competitiveness within classroom, which allowed to analyze student’s perception regarding metabolic subjects. On the other hand, for teacher and students participating in compulsory traineeship program this game demonstrated to students new ways to approach complex subjects in biochemistry using creativity. CONCLUSION: Overall, students had a good impression of “Metabolic Ride” game since it helped to secure and administer metabolism subject in a competitive and team work way.

  4. Energy Metabolism in the Liver

    Science.gov (United States)

    Rui, Liangyou

    2014-01-01

    The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD). PMID:24692138

  5. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics

    Directory of Open Access Journals (Sweden)

    Francesco Gatto

    2016-07-01

    Full Text Available Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network.

  6. Signatures of arithmetic simplicity in metabolic network architecture.

    Directory of Open Access Journals (Sweden)

    William J Riehl

    2010-04-01

    Full Text Available Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that properties similar to those predicted for the artificial chemistry hold also for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity.

  7. Intentional risk management through complex networks analysis

    CERN Document Server

    Chapela, Victor; Moral, Santiago; Romance, Miguel

    2015-01-01

    This book combines game theory and complex networks to examine intentional technological risk through modeling. As information security risks are in constant evolution,  the methodologies and tools to manage them must evolve to an ever-changing environment. A formal global methodology is explained  in this book, which is able to analyze risks in cyber security based on complex network models and ideas extracted from the Nash equilibrium. A risk management methodology for IT critical infrastructures is introduced which provides guidance and analysis on decision making models and real situations. This model manages the risk of succumbing to a digital attack and assesses an attack from the following three variables: income obtained, expense needed to carry out an attack, and the potential consequences for an attack. Graduate students and researchers interested in cyber security, complex network applications and intentional risk will find this book useful as it is filled with a number of models, methodologies a...

  8. Complex eigenvalue analysis of railway wheel/rail squeal

    African Journals Online (AJOL)

    DR OKE

    Squeal noise from wheel/rail and brake disc/pad frictional contact is typical in railways. ... squeal noise by multibody simulation of a rail car running on rigid rails. ... system, traditional complex eigenvalue analysis by finite element was used.

  9. Complex finite element sensitivity method for creep analysis

    International Nuclear Information System (INIS)

    Gomez-Farias, Armando; Montoya, Arturo; Millwater, Harry

    2015-01-01

    The complex finite element method (ZFEM) has been extended to perform sensitivity analysis for mechanical and structural systems undergoing creep deformation. ZFEM uses a complex finite element formulation to provide shape, material, and loading derivatives of the system response, providing an insight into the essential factors which control the behavior of the system as a function of time. A complex variable-based quadrilateral user element (UEL) subroutine implementing the power law creep constitutive formulation was incorporated within the Abaqus commercial finite element software. The results of the complex finite element computations were verified by comparing them to the reference solution for the steady-state creep problem of a thick-walled cylinder in the power law creep range. A practical application of the ZFEM implementation to creep deformation analysis is the calculation of the skeletal point of a notched bar test from a single ZFEM run. In contrast, the standard finite element procedure requires multiple runs. The value of the skeletal point is that it identifies the location where the stress state is accurate, regardless of the certainty of the creep material properties. - Highlights: • A novel finite element sensitivity method (ZFEM) for creep was introduced. • ZFEM has the capability to calculate accurate partial derivatives. • ZFEM can be used for identification of the skeletal point of creep structures. • ZFEM can be easily implemented in a commercial software, e.g. Abaqus. • ZFEM results were shown to be in excellent agreement with analytical solutions

  10. High-resolution metagenomics targets major functional types in complex microbial communities

    Energy Technology Data Exchange (ETDEWEB)

    Kalyuzhnaya, Marina G.; Lapidus, Alla; Ivanova, Natalia; Copeland, Alex C.; McHardy, Alice C.; Szeto, Ernest; Salamov, Asaf; Grigoriev, Igor V.; Suciu, Dominic; Levine, Samuel R.; Markowitz, Victor M.; Rigoutsos, Isidore; Tringe, Susannah G.; Bruce, David C.; Richardson, Paul M.; Lidstrom, Mary E.; Chistoserdova, Ludmila

    2009-08-01

    Most microbes in the biosphere remain uncultured and unknown. Whole genome shotgun (WGS) sequencing of environmental DNA (metagenomics) allows glimpses into genetic and metabolic potentials of natural microbial communities. However, in communities of high complexity metagenomics fail to link specific microbes to specific ecological functions. To overcome this limitation, we selectively targeted populations involved in oxidizing single-carbon (C{sub 1}) compounds in Lake Washington (Seattle, USA) by labeling their DNA via stable isotope probing (SIP), followed by WGS sequencing. Metagenome analysis demonstrated specific sequence enrichments in response to different C{sub 1} substrates, highlighting ecological roles of individual phylotypes. We further demonstrated the utility of our approach by extracting a nearly complete genome of a novel methylotroph Methylotenera mobilis, reconstructing its metabolism and conducting genome-wide analyses. This approach allowing high-resolution genomic analysis of ecologically relevant species has the potential to be applied to a wide variety of ecosystems.

  11. Synthesis and physicochemical analysis of Sm (II, III) acetylacetone chelate complexes

    International Nuclear Information System (INIS)

    Kostyuk, N.N.; Dik, T.A.; Trebnikov, A.G.

    2004-01-01

    Sm (II, III) acetylacetone chelate complexes were synthesized by electrochemical method. It was shown that anode dissolution of the metal samarium over acetylacetone leads to formation of the Sm (II, III) chelate complexes: xSm(acac)2 · ySm(acac)3 · zH(acac). Factors x, y and z depend on quantity of the electricity, which flew through the electrolysis cell. The compositions of the obtained substances were confirmed by the physicochemical analysis (ultimate analysis, IR-, mass spectroscopy and thermal analysis (thermogravimetric, isothermal warming-up and differential scanning colorimetry). (Authors)

  12. Famine versus feast: understanding the metabolism of tumors in vivo.

    Science.gov (United States)

    Mayers, Jared R; Vander Heiden, Matthew G

    2015-03-01

    To fuel unregulated proliferation, cancer cells alter metabolism to support macromolecule biosynthesis. Cell culture studies have revealed how different oncogenic mutations and nutrients impact metabolism. Glucose and glutamine are the primary fuels used in vitro; however, recent studies have suggested that utilization of other amino acids as well as lipids and protein can also be important to cancer cells. Early investigations of tumor metabolism are translating these findings to the biology of whole tumors and suggest that additional complexity exists beyond nutrient availability alone in vivo. Whole-body metabolism and tumor heterogeneity also influence the metabolism of tumor cells, and successful targeting of metabolism for cancer therapy will require an understanding of tumor metabolism in vivo. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Fisetin as a promising antifungal agent against Cryptocococcus neoformans species complex.

    Science.gov (United States)

    Reis, M P C; Carvalho, C R C; Andrade, F A; Fernandes, O F L; Arruda, W; Silva, M R R

    2016-08-01

    The aim of this study was to investigate the mechanisms of action of fisetin, a flavonol with antifungal activity previously evaluated against the Cryptococcus neoformans species complex. Ergosterol content and flow cytometry analysis were determined for the C. neoformans species complex in the presence of fisetin and ultrastructural analysis of morphology was performed on Cryptococcus gattii and C. neoformans. Decrease in the total cellular ergosterol content after exposure to fisetin ranged from 25·4% after exposure to 128 μg ml(-1) to 21·6% after exposure to 64 μg ml(-1) of fisetin compared with the control (without fisetin). The fisetin effects obtained with flow cytometry showed metabolic impairment, and alterations in its normal morphology caused by fisetin in C. neoformans cells were verified using scanning electron microscopy. Fisetin is a compound that acts in the biosynthesis of ergosterol. Flow cytometry showed that fisetin reduced viability of the metabolically active cells of C. gattii, while morphological changes explain the action of fisetin in inhibiting growth of these fungi. This study supports the idea that fisetin may represent a good starting point for the development of future therapeutic substances for cryptococcosis. © 2016 The Society for Applied Microbiology.

  14. Metabolomic analysis based on 1H-nuclear magnetic resonance spectroscopy metabolic profiles in tuberculous, malignant and transudative pleural effusion

    Science.gov (United States)

    Wang, Cheng; Peng, Jingjin; Kuang, Yanling; Zhang, Jiaqiang; Dai, Luming

    2017-01-01

    Pleural effusion is a common clinical manifestation with various causes. Current diagnostic and therapeutic methods have exhibited numerous limitations. By involving the analysis of dynamic changes in low molecular weight catabolites, metabolomics has been widely applied in various types of disease and have provided platforms to distinguish many novel biomarkers. However, to the best of our knowledge, there are few studies regarding the metabolic profiling for pleural effusion. In the current study, 58 pleural effusion samples were collected, among which 20 were malignant pleural effusions, 20 were tuberculous pleural effusions and 18 were transudative pleural effusions. The small molecule metabolite spectrums were obtained by adopting 1H nuclear magnetic resonance technology, and pattern-recognition multi-variable statistical analysis was used to screen out different metabolites. One-way analysis of variance, and Student-Newman-Keuls and the Kruskal-Wallis test were adopted for statistical analysis. Over 400 metabolites were identified in the untargeted metabolomic analysis and 26 metabolites were identified as significantly different among tuberculous, malignant and transudative pleural effusions. These metabolites were predominantly involved in the metabolic pathways of amino acids metabolism, glycometabolism and lipid metabolism. Statistical analysis revealed that eight metabolites contributed to the distinction between the three groups: Tuberculous, malignant and transudative pleural effusion. In the current study, the feasibility of identifying small molecule biochemical profiles in different types of pleural effusion were investigated reveal novel biological insights into the underlying mechanisms. The results provide specific insights into the biology of tubercular, malignant and transudative pleural effusion and may offer novel strategies for the diagnosis and therapy of associated diseases, including tuberculosis, advanced lung cancer and congestive heart

  15. Genome-scale modelling of microbial metabolism with temporal and spatial resolution.

    Science.gov (United States)

    Henson, Michael A

    2015-12-01

    Most natural microbial systems have evolved to function in environments with temporal and spatial variations. A major limitation to understanding such complex systems is the lack of mathematical modelling frameworks that connect the genomes of individual species and temporal and spatial variations in the environment to system behaviour. The goal of this review is to introduce the emerging field of spatiotemporal metabolic modelling based on genome-scale reconstructions of microbial metabolism. The extension of flux balance analysis (FBA) to account for both temporal and spatial variations in the environment is termed spatiotemporal FBA (SFBA). Following a brief overview of FBA and its established dynamic extension, the SFBA problem is introduced and recent progress is described. Three case studies are reviewed to illustrate the current state-of-the-art and possible future research directions are outlined. The author posits that SFBA is the next frontier for microbial metabolic modelling and a rapid increase in methods development and system applications is anticipated. © 2015 Authors; published by Portland Press Limited.

  16. Widening the scope of incident analysis in complex work environments

    NARCIS (Netherlands)

    Vuuren, van W.; Kanse, L.; Manser, T.

    2003-01-01

    Incident analysis is commonly used as a tooi to provide information on how to improve health and safety in complex work environments. The effectiveness of this tooi, however, depends on how the analysis is actually carried out. The traditional view on incident analysis highlights the role of human

  17. Insight into Energy Conservation via Alternative Carbon Monoxide Metabolism in Carboxydothermus pertinax Revealed by Comparative Genome Analysis.

    Science.gov (United States)

    Fukuyama, Yuto; Omae, Kimiho; Yoneda, Yasuko; Yoshida, Takashi; Sako, Yoshihiko

    2018-05-04

    Carboxydothermus species are some of the most studied thermophilic carboxydotrophs. Their varied carboxydotrophic growth properties suggest distinct strategies for energy conservation via CO metabolism. In this study, we used comparative genome analysis of the genus Carboxydothermus to show variations in the CO dehydrogenase/energy-converting hydrogenase gene cluster, which is responsible for CO metabolism with H 2 production (hydrogenogenic CO metabolism). Indeed, ability or inability to produce H 2 with CO oxidation is explained by the presence or absence of this gene cluster in C. hydrogenoformans , C. islandicus , and C. ferrireducens Interestingly, despite its hydrogenogenic CO metabolism, C. pertinax lacks the Ni-CO dehydrogenase catalytic subunit (CooS-I) and its transcriptional regulator encoding genes in this gene cluster probably due to inversion. Transcriptional analysis in C. pertinax showed that the Ni-CO dehydrogenase gene ( cooS-II ) and distantly encoded energy-converting hydrogenase related genes were remarkably upregulated under 100% CO. In addition, when thiosulfate was available as a terminal electron acceptor under 100% CO, C. pertinax maximum cell density and maximum specific growth rate were 3.1-fold and 1.5-fold higher, respectively, than when thiosulfate was absent. The amount of H 2 produced was only 63% of the consumed CO, less than expected according to hydrogenogenic CO oxidation: CO + H 2 O → CO 2 + H 2 Accordingly, C. pertinax would couple CO oxidation by Ni-CO dehydrogenase-II with simultaneous reduction of not only H 2 O but thiosulfate when grown under 100% CO. IMPORTANCE Anaerobic hydrogenogenic carboxydotrophs are thought to fill a vital niche with scavenging potentially toxic CO and producing H 2 as available energy source for thermophilic microbes. This hydrogenogenic carboxydotrophy relies on a Ni-CO dehydrogenase/energy-converting hydrogenase gene cluster. This feature is thought to be as common to these organisms. However

  18. Complex Network Analysis of Guangzhou Metro

    OpenAIRE

    Yasir Tariq Mohmand; Fahad Mehmood; Fahd Amjad; Nedim Makarevic

    2015-01-01

    The structure and properties of public transportation networks can provide suggestions for urban planning and public policies. This study contributes a complex network analysis of the Guangzhou metro. The metro network has 236 kilometers of track and is the 6th busiest metro system of the world. In this paper topological properties of the network are explored. We observed that the network displays small world properties and is assortative in nature. The network possesses a high average degree...

  19. A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.

    Directory of Open Access Journals (Sweden)

    Hui-Qi Low

    Full Text Available BACKGROUND: The effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk. METHODOLOGY/PRINCIPAL FINDINGS: The study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint P(trend = 1.2×10(-6. CONCLUSIONS: Our study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.

  20. Mechanistic modeling of aberrant energy metabolism in human disease

    Directory of Open Access Journals (Sweden)

    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  1. Risk Analysis for Road Tunnels – A Metamodel to Efficiently Integrate Complex Fire Scenarios

    DEFF Research Database (Denmark)

    Berchtold, Florian; Knaust, Christian; Arnold, Lukas

    2018-01-01

    Fires in road tunnels constitute complex scenarios with interactions between the fire, tunnel users and safety measures. More and more methodologies for risk analysis quantify the consequences of these scenarios with complex models. Examples for complex models are the computational fluid dynamics...... complex scenarios in risk analysis. To face this challenge, we improved the metamodel used in the methodology for risk analysis presented on ISTSS 2016. In general, a metamodel quickly interpolates the consequences of few scenarios simulated with the complex models to a large number of arbitrary scenarios...... used in risk analysis. Now, our metamodel consists of the projection array-based design, the moving least squares method, and the prediction interval to quantify the metamodel uncertainty. Additionally, we adapted the projection array-based design in two ways: the focus of the sequential refinement...

  2. Synthesis, Spectral Analysis and Preliminary in Vitro Evaluation of Some Tetrapyrrolic Complexes with 3d Metal Ions

    Directory of Open Access Journals (Sweden)

    Radu Socoteanu

    2015-08-01

    Full Text Available In this paper, two tetrapyrrolic complexes, Zn(II-5-(3-hydroxyphenyl-10,15,20-tris-(4-acetoxy-3-methoxyphenylporphyrin and Cu(II-5-(3-hydroxyphenyl-10,15,20-tris-(4-acetoxy-3-methoxyphenylporphyrin were synthesized, and characterized from a spectral and biological point of view. The study provided data concerning the behavior of identical external substituents vs. two different core insertions. Some of the properties of the proposed tetrapyrrolic structures were highlighted, having photodynamic therapy of cancer as a targeted biomedical application. Elemental analysis, NMR, FTIR and UV-Vis data in various solvents were provided. A preliminary in vitro study on normal and cancer cultured cells was carried out for biocompatibility assessment in dark conditions. The preliminary in vitro study performed on human peripheral mononuclear cells exposed to tetrapyrrolic compounds (2 µM showed that the proposed compounds had a convenient cytotoxic profile on human normal peripheral blood mononuclear cells under dark conditions. Meanwhile, the investigated compounds reduced the number of metabolically active breast tumor MCF-7 cells, with the exception of Zn(II complex-containing a symmetrical ligand. Accordingly, preliminary in vitro data suggest that the proposed tetrapyrrolic compounds are good candidates for PDT, as they limit tumor expansion even under dark conditions, whilst sparing normal cells.

  3. Crystallization and preliminary X-ray analysis of PaaAC, the main component of the hydroxylase of the Escherichia coli phenylacetyl-coenzyme A oxygenase complex

    International Nuclear Information System (INIS)

    Grishin, Andrey M.; Ajamian, Eunice; Zhang, Linhua; Cygler, Miroslaw

    2010-01-01

    The expression, purification, crystallization and preliminary crystallographic analysis of the PaaAC complex is reported. This is the main component of the E. coliphenylacetyl-coenzyme A oxygenase complex. The Escherichia coli paa operon encodes enzymes of the phenylacetic acid-utilization pathway that metabolizes phenylacetate in the form of a coenzyme A (CoA) derivative. The phenylacetyl-coenzyme A oxygenase complex, which has been postulated to contain five components designated PaaABCDE, catalyzes ring hydroxylation of phenylacetyl-CoA. The PaaAC subcomplex shows low sequence similarity to other bacterial multicomponent monooxygenases (BMMs) and forms a separate branch on the phylogenetic tree. PaaAC, which catalyzes the hydroxylation reaction, was purified and crystallized in the absence of a bound ligand as well as in complexes with CoA, 3-hydroxybutyryl-CoA, benzoyl-CoA and the true substrate phenylacetyl-CoA. Crystals of the ligand-free enzyme belonged to space group P2 1 2 1 2 1 and diffracted to 2.65 Å resolution, whereas complexes with CoA and its derivatives crystallized in space group P4 1 2 1 2 and diffracted to ∼2.0 Å resolution. PaaAC represents the first crystallized BMM hydroxylase that utilizes a CoA-linked substrate

  4. Controlling cell-free metabolism through physiochemical perturbations.

    Science.gov (United States)

    Karim, Ashty S; Heggestad, Jacob T; Crowe, Samantha A; Jewett, Michael C

    2018-01-01

    Building biosynthetic pathways and engineering metabolic reactions in cells can be time-consuming due to complexities in cellular metabolism. These complexities often convolute the combinatorial testing of biosynthetic pathway designs needed to define an optimal biosynthetic system. To simplify the optimization of biosynthetic systems, we recently reported a new cell-free framework for pathway construction and testing. In this framework, multiple crude-cell extracts are selectively enriched with individual pathway enzymes, which are then mixed to construct full biosynthetic pathways on the time scale of a day. This rapid approach to building pathways aids in the study of metabolic pathway performance by providing a unique freedom of design to modify and control biological systems for both fundamental and applied biotechnology. The goal of this work was to demonstrate the ability to probe biosynthetic pathway performance in our cell-free framework by perturbing physiochemical conditions, using n-butanol synthesis as a model. We carried out three unique case studies. First, we demonstrated the power of our cell-free approach to maximize biosynthesis yields by mapping physiochemical landscapes using a robotic liquid-handler. This allowed us to determine that NAD and CoA are the most important factors that govern cell-free n-butanol metabolism. Second, we compared metabolic profile differences between two different approaches for building pathways from enriched lysates, heterologous expression and cell-free protein synthesis. We discover that phosphate from PEP utilization, along with other physiochemical reagents, during cell-free protein synthesis-coupled, crude-lysate metabolic system operation inhibits optimal cell-free n-butanol metabolism. Third, we show that non-phosphorylated secondary energy substrates can be used to fuel cell-free protein synthesis and n-butanol biosynthesis. Taken together, our work highlights the ease of using cell-free systems to explore

  5. Metabolic reconstruction of Setaria italica: a systems biology approach for integrating tissue-specific omics and pathway analysis of bioenergy grasses

    Directory of Open Access Journals (Sweden)

    Cristiana Gomes De Oliveira Dal'molin

    2016-08-01

    Full Text Available The urgent need for major gains in industrial crops productivity and in biofuel production from bioenergy grasses have reinforced attention on understanding C4 photosynthesis. Systems biology studies of C4 model plants may reveal important features of C4 metabolism. Here we chose foxtail millet (Setaria italica, as a C4 model plant and developed protocols to perform systems biology studies. As part of the systems approach, we have developed and used a genome-scale metabolic reconstruction in combination with the use of multi-omics technologies to gain more insights into the metabolism of S.italica. mRNA, protein and metabolite abundances, were measured in mature and immature stem/leaf phytomers and the multi-omics data were integrated into the metabolic reconstruction framework to capture key metabolic features in different developmental stages of the plant. RNA-Seq reads were mapped to the S. italica resulting for 83% coverage of the protein coding genes of S. italica. Besides revealing similarities and differences in central metabolism of mature and immature tissues, transcriptome analysis indicates significant gene expression of two malic enzyme isoforms (NADP- ME and NAD-ME. Although much greater expression levels of NADP-ME genes are observed and confirmed by the correspondent protein abundances in the samples, the expression of multiple genes combined to the significant abundance of metabolites that participates in C4 metabolism of NAD-ME and NADP-ME subtypes suggest that S. italica may use mixed decarboxylation modes of C4 photosynthetic pathways under different plant developmental stages. The overall analysis also indicates different levels of regulation in mature and immature tissues in carbon fixation, glycolysis, TCA cycle, amino acids, fatty acids, lignin and cellulose syntheses. Altogether, the multi-omics analysis reveals different biological entities and their interrelation and regulation over plant development. With this study

  6. Metabolic Reconstruction of Setaria italica: A Systems Biology Approach for Integrating Tissue-Specific Omics and Pathway Analysis of Bioenergy Grasses.

    Science.gov (United States)

    de Oliveira Dal'Molin, Cristiana G; Orellana, Camila; Gebbie, Leigh; Steen, Jennifer; Hodson, Mark P; Chrysanthopoulos, Panagiotis; Plan, Manuel R; McQualter, Richard; Palfreyman, Robin W; Nielsen, Lars K

    2016-01-01

    The urgent need for major gains in industrial crops productivity and in biofuel production from bioenergy grasses have reinforced attention on understanding C4 photosynthesis. Systems biology studies of C4 model plants may reveal important features of C4 metabolism. Here we chose foxtail millet (Setaria italica), as a C4 model plant and developed protocols to perform systems biology studies. As part of the systems approach, we have developed and used a genome-scale metabolic reconstruction in combination with the use of multi-omics technologies to gain more insights into the metabolism of S. italica. mRNA, protein, and metabolite abundances, were measured in mature and immature stem/leaf phytomers, and the multi-omics data were integrated into the metabolic reconstruction framework to capture key metabolic features in different developmental stages of the plant. RNA-Seq reads were mapped to the S. italica resulting for 83% coverage of the protein coding genes of S. italica. Besides revealing similarities and differences in central metabolism of mature and immature tissues, transcriptome analysis indicates significant gene expression of two malic enzyme isoforms (NADP- ME and NAD-ME). Although much greater expression levels of NADP-ME genes are observed and confirmed by the correspondent protein abundances in the samples, the expression of multiple genes combined to the significant abundance of metabolites that participates in C4 metabolism of NAD-ME and NADP-ME subtypes suggest that S. italica may use mixed decarboxylation modes of C4 photosynthetic pathways under different plant developmental stages. The overall analysis also indicates different levels of regulation in mature and immature tissues in carbon fixation, glycolysis, TCA cycle, amino acids, fatty acids, lignin, and cellulose syntheses. Altogether, the multi-omics analysis reveals different biological entities and their interrelation and regulation over plant development. With this study, we demonstrated

  7. iAB-RBC-283: A proteomically derived knowledge-base of erythrocyte metabolism that can be used to simulate its physiological and patho-physiological states

    Directory of Open Access Journals (Sweden)

    Palsson Bernhard O

    2011-07-01

    Full Text Available Abstract Background The development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology. Integrated analysis of the resulting omic data sets has proved to be hard to achieve. Metabolic network reconstructions enable complex relationships amongst molecular components to be represented formally in a biologically relevant manner while respecting physical constraints. In silico models derived from such reconstructions can then be queried or interrogated through mathematical simulations. Proteomic profiling studies of the mature human erythrocyte have shown more proteins present related to metabolic function than previously thought; however the significance and the causal consequences of these findings have not been explored. Results Erythrocyte proteomic data was used to reconstruct the most expansive description of erythrocyte metabolism to date, following extensive manual curation, assessment of the literature, and functional testing. The reconstruction contains 281 enzymes representing functions from glycolysis to cofactor and amino acid metabolism. Such a comprehensive view of erythrocyte metabolism implicates the erythrocyte as a potential biomarker for different diseases as well as a 'cell-based' drug-screening tool. The analysis shows that 94 erythrocyte enzymes are implicated in morbid single nucleotide polymorphisms, representing 142 pathologies. In addition, over 230 FDA-approved and experimental pharmaceuticals have enzymatic targets in the erythrocyte. Conclusion The advancement of proteomic technologies and increased generation of high-throughput proteomic data have created the need for a means to analyze these data in a coherent manner. Network reconstructions provide a systematic means to integrate and analyze proteomic data in a biologically meaning manner. Analysis of the red cell proteome has revealed an unexpected level of complexity in

  8. Efficiency of treatment and prevention of complications of parodontitis in patients with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    T. A. Pyndus

    2017-10-01

    Full Text Available Introduction. Given the increasing prevalence of metabolic syndrome among the population, the search for ways to treat and prevent major dental diseases in this somatic pathology is of great importance. Purpose of the study. The purpose of this work was to evaluate the effectiveness of the developed treatment and prophylaxis complex in patients with generalized parodontitis in combination with metabolic syndrome. Materials and methods. In in-depth studies, 53 people aged 30-55 years with a diagnosis of "chronic generalized parodontitis" and "metabolic syndrome" took part. The main group of patients in addition to basic therapy received a developed, pathogenetically substantiated therapeutic and prophylactic complex, 2 times a year. Evaluation of the dental status of patients was performed in the initial state, after the first course of prevention at 6 months and in a year. Results. Conclusions. The high clinical effectiveness of the developed complex, including preparations of antibacterial and anti-inflammatory action, reducing cholesterol, reducing vascular permeability, normalizing metabolism, blood circulation and fat metabolism, enhancing immunity and resistance of the organism is shown.

  9. Complexity, Analysis and Control of Singular Biological Systems

    CERN Document Server

    Zhang, Qingling; Zhang, Xue

    2012-01-01

    Complexity, Analysis and Control of Singular Biological Systems follows the control of real-world biological systems at both ecological and phyisological levels concentrating on the application of now-extensively-investigated singular system theory. Much effort has recently been dedicated to the modelling and analysis of developing bioeconomic systems and the text establishes singular examples of these, showing how proper control can help to maintain sustainable economic development of biological resources. The book begins from the essentials of singular systems theory and bifurcations before tackling  the use of various forms of control in singular biological systems using examples including predator-prey relationships and viral vaccination and quarantine control. Researchers and graduate students studying the control of complex biological systems are shown how a variety of methods can be brought to bear and practitioners working with the economics of biological systems and their control will also find the ...

  10. Energy metabolism in the liver.

    Science.gov (United States)

    Rui, Liangyou

    2014-01-01

    The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases. © 2014 American Physiological Society.

  11. Exercise Intensity Modulation of Hepatic Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Fábio S. Lira

    2012-01-01

    Full Text Available Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL, ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge.

  12. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials.

    Science.gov (United States)

    Grossmann, Mathis; Hoermann, Rudolf; Wittert, Gary; Yeap, Bu B

    2015-09-01

    The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial. To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials (RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome. A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature. Eligible studies were published placebo-controlled double-blind RCTs published in English. Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data. Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta-analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1·58 [-2·25, -0·91], P treatment effect was nonsignificant for RCTs using a more stringent computer-based equation (HOMA2), MD -0·19 [-0·86, 0·49], P = 0·58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD -0·15 [-0·39, 0·10], P = 0·25, or constitutional symptoms, Aging Male Symptom score, MD -2·49 [-5·81, 0·83], P = 0·14). This meta-analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome. © 2014 John Wiley & Sons Ltd.

  13. Uses of Activation Analysis in Studies of Mineral Element Metabolism in Man. Papers Given at a Panel Meeting

    International Nuclear Information System (INIS)

    1970-01-01

    In June, 1968, the International Atomic Energy Agency held a panel meeting in Teheran, Iran, to discuss some of the uses of activation analysis in studies of mineral element metabolism in man. The aims of the meeting were to identify and draw attention to specific medical problems to which activation analysis could be fruitfully applied, to review the capabilities of the technique itself, and to recommend specific action which the Agency might take to support further work in this field. The scientific papers presented at the meeting have been gathered together in this report, and it is hoped that their publication will be of interest to all concerned with mineral element metabolism in man, whether studied by activation analysis or by other methods

  14. Metabolic pathway analysis of Scheffersomyces (Pichia) stipitis: effect of oxygen availability on ethanol synthesis and flux distributions.

    Science.gov (United States)

    Unrean, Pornkamol; Nguyen, Nhung H A

    2012-06-01

    Elementary mode analysis (EMA) identifies all possible metabolic states of the cell metabolic network. Investigation of these states can provide a detailed insight into the underlying metabolism in the cell. In this study, the flux states of Scheffersomyces (Pichia) stipitis metabolism were examined. It was shown that increasing oxygen levels led to a decrease of ethanol synthesis. This trend was confirmed by experimental evaluation of S. stipitis in glucose-xylose fermentation. The oxygen transfer rate for an optimal ethanol production was 1.8 mmol/l/h, which gave the ethanol yield of 0.40 g/g and the ethanol productivity of 0.25 g/l/h. For a better understanding of the cell's regulatory mechanism in response to oxygenation levels, EMA was used to examine metabolic flux patterns under different oxygen levels. Up- and downregulation of enzymes in the network during the change of culturing condition from oxygen limitation to oxygen sufficiency were identified. The results indicated the flexibility of S. stipitis metabolism to cope with oxygen availability. In addition, relevant genetic targets towards improved ethanol-producing strains under all oxygenation levels were identified. These targeted genes limited the metabolic functionality of the cell to function according to the most efficient ethanol synthesis pathways. The presented approach is promising and can contribute to the development of culture optimization and strain engineers for improved lignocellulosic ethanol production by S. stipitis.

  15. Fire hazard analysis for Plutonium Finishing Plant complex

    Energy Technology Data Exchange (ETDEWEB)

    MCKINNIS, D.L.

    1999-02-23

    A fire hazards analysis (FHA) was performed for the Plutonium Finishing Plant (PFP) Complex at the Department of Energy (DOE) Hanford site. The scope of the FHA focuses on the nuclear facilities/structures in the Complex. The analysis was conducted in accordance with RLID 5480.7, [DOE Directive RLID 5480.7, 1/17/94] and DOE Order 5480.7A, ''Fire Protection'' [DOE Order 5480.7A, 2/17/93] and addresses each of the sixteen principle elements outlined in paragraph 9.a(3) of the Order. The elements are addressed in terms of the fire protection objectives stated in paragraph 4 of DOE 5480.7A. In addition, the FHA also complies with WHC-CM-4-41, Fire Protection Program Manual, Section 3.4 [1994] and WHC-SD-GN-FHA-30001, Rev. 0 [WHC, 1994]. Objectives of the FHA are to determine: (1) the fire hazards that expose the PFP facilities, or that are inherent in the building operations, (2) the adequacy of the fire safety features currently located in the PFP Complex, and (3) the degree of compliance of the facility with specific fire safety provisions in DOE orders, related engineering codes, and standards.

  16. Purification, crystallization and preliminary X-ray crystallographic analysis of the ETS domain of human Ergp55 in complex with the cfos promoter DNA sequence

    International Nuclear Information System (INIS)

    Gangwar, Shanti P.; Meena, Sita R.; Saxena, Ajay K.

    2012-01-01

    The ETS domain of human Ergp55 was purified and crystallized in native, complexes with E74, and cfos promoter DNA sequences. The X-ray intensity data set was collected on ETS–cfos promoter DNA complex crystal at 3.1 Å resolution to analyze the structure by molecular replacement technique. The Ergp55 protein belongs to the Ets family of transciption factors. The Ets transcription factors are involved in various developmental processes and the regulation of cancer metabolism. They contain a highly similar DNA-binding domain known as the ETS domain and have diverse functions in oncogenesis and physiology. The Ets transcription factors differ in their DNA-binding preference at the ETS site and the mechanisms by which they target genes are not clearly understood. To understand its DNA-binding mechanism, the ETS domain of Ergp55 was expressed and purified. The ETS domain was crystallized in the native form and in complex forms with DNA sequences from the E74 and cfos promoters. An X-ray diffraction data set was collected from an ETS–cfos DNA complex crystal at a wavelength of 0.9725 Å on the BM14 synchrotron beamline at the ESRF, France. The ETS–cfos DNA complex crystal belonged to space group C222 1 , with four molecules in the asymmetric unit. For structure analysis, initial phases for the ETS–cfos DNA complex were obtained by the molecular-replacement technique with Phaser in the CCP4 suite using the coordinates of Fli-1 protein and cfos DNA as search models. Structure analysis of the ETS–cfos DNA complex may possibly explain the DNA-binding specificity and its mechanism of interaction with the ETS domain of Ergp55

  17. Quantitative elementary mode analysis of metabolic pathways: the example of yeast glycolysis

    Directory of Open Access Journals (Sweden)

    Kanehisa Minoru

    2006-04-01

    Full Text Available Abstract Background Elementary mode analysis of metabolic pathways has proven to be a valuable tool for assessing the properties and functions of biochemical systems. However, little comprehension of how individual elementary modes are used in real cellular states has been achieved so far. A quantitative measure of fluxes carried by individual elementary modes is of great help to identify dominant metabolic processes, and to understand how these processes are redistributed in biological cells in response to changes in environmental conditions, enzyme kinetics, or chemical concentrations. Results Selecting a valid decomposition of a flux distribution onto a set of elementary modes is not straightforward, since there is usually an infinite number of possible such decompositions. We first show that two recently introduced decompositions are very closely related and assign the same fluxes to reversible elementary modes. Then, we show how such decompositions can be used in combination with kinetic modelling to assess the effects of changes in enzyme kinetics on the usage of individual metabolic routes, and to analyse the range of attainable states in a metabolic system. This approach is illustrated by the example of yeast glycolysis. Our results indicate that only a small subset of the space of stoichiometrically feasible steady states is actually reached by the glycolysis system, even when large variation intervals are allowed for all kinetic parameters of the model. Among eight possible elementary modes, the standard glycolytic route remains dominant in all cases, and only one other elementary mode is able to gain significant flux values in steady state. Conclusion These results indicate that a combination of structural and kinetic modelling significantly constrains the range of possible behaviours of a metabolic system. All elementary modes are not equal contributors to physiological cellular states, and this approach may open a direction toward a

  18. Phylogenomic reconstruction of archaeal fatty acid metabolism

    Science.gov (United States)

    Dibrova, Daria V.; Galperin, Michael Y.; Mulkidjanian, Armen Y.

    2014-01-01

    While certain archaea appear to synthesize and/or metabolize fatty acids, the respective pathways still remain obscure. By analyzing the genomic distribution of the key lipid-related enzymes, we were able to identify the likely components of the archaeal pathway of fatty acid metabolism, namely, a combination of the enzymes of bacterial-type β-oxidation of fatty acids (acyl-CoA-dehydrogenase, enoyl-CoA hydratase, and 3-hydroxyacyl-CoA dehydrogenase) with paralogs of the archaeal acetyl-CoA C-acetyltransferase, an enzyme of the mevalonate biosynthesis pathway. These three β-oxidation enzymes working in the reverse direction could potentially catalyze biosynthesis of fatty acids, with paralogs of acetyl-CoA C-acetyltransferase performing addition of C2 fragments. The presence in archaea of the genes for energy-transducing membrane enzyme complexes, such as cytochrome bc complex, cytochrome c oxidase, and diverse rhodopsins, was found to correlate with the presence of the proposed system of fatty acid biosynthesis. We speculate that because these membrane complexes functionally depend on fatty acid chains, their genes could have been acquired via lateral gene transfer from bacteria only by those archaea that already possessed a system of fatty acid biosynthesis. The proposed pathway of archaeal fatty acid metabolism operates in extreme conditions and therefore might be of interest in the context of biofuel production and other industrial applications. PMID:24818264

  19. Human Body Exergy Metabolism

    OpenAIRE

    Mady, Carlos Eduardo Keutenedjian

    2013-01-01

    The exergy analysis of the human body is a tool that can provide indicators of health and life quality. To perform the exergy balance it is necessary to calculate the metabolism on an exergy basis, or metabolic exergy, although there is not yet consensus in its calculation procedure. Hence, the aim of this work is to provide a general method to evaluate this physical quantity for human body based on indirect calorimetry data. To calculate the metabolism on an exergy basis it is necessary to d...

  20. A Quantitative Study of Oxygen as a Metabolic Regulator

    Science.gov (United States)

    Radhakrishnan, Krishnan; LaManna, Joseph C.; Cabrera, Marco E.

    1999-01-01

    An acute reduction in oxygen (O2) delivery to a tissue is generally associated with a decrease in phosphocreatine, increases in ADP, NADH/NAD, and inorganic phosphate, increased rates of glycolysis and lactate production, and reduced rates of pyruvate and fatty acid oxidation. However, given the complexity of the human bioenergetic system and its components, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in tissue O2 availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study, we extend a previously developed mathematical model of human bioenergetics to provide a physicochemical framework that permits quantitative understanding of O2 as a metabolic regulator. Specifically, the enhancement permits studying the effects of variations in tissue oxygenation and in parameters controlling the rate of cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The whole body is described as a bioenergetic system consisting of metabolically distinct tissue/organ subsystems that exchange materials with the blood. In order to study the dynamic response of each subsystem to stimuli, we solve the ordinary differential equations describing the temporal evolution of metabolite levels, given the initial concentrations. The solver used in the present study is the packaged code LSODE, as implemented in the NASA Lewis kinetics and sensitivity analysis code, LSENS. A major advantage of LSENS is the efficient procedures supporting systematic sensitivity analysis, which provides the basic methods for studying parameter sensitivities (i.e., changes in model behavior due to parameter variation

  1. Structured analysis and modeling of complex systems

    Science.gov (United States)

    Strome, David R.; Dalrymple, Mathieu A.

    1992-01-01

    The Aircrew Evaluation Sustained Operations Performance (AESOP) facility at Brooks AFB, Texas, combines the realism of an operational environment with the control of a research laboratory. In recent studies we collected extensive data from the Airborne Warning and Control Systems (AWACS) Weapons Directors subjected to high and low workload Defensive Counter Air Scenarios. A critical and complex task in this environment involves committing a friendly fighter against a hostile fighter. Structured Analysis and Design techniques and computer modeling systems were applied to this task as tools for analyzing subject performance and workload. This technology is being transferred to the Man-Systems Division of NASA Johnson Space Center for application to complex mission related tasks, such as manipulating the Shuttle grappler arm.

  2. Metabolic networks of Cucurbita maxima phloem.

    Science.gov (United States)

    Fiehn, Oliver

    2003-03-01

    Metabolomic analysis aims at a comprehensive characterization of biological samples. Yet, biologically meaningful interpretations are often limited by the poor spatial and temporal resolution of the acquired data sets. One way to remedy this is to limit the complexity of the cell types being studied. Cucurbita maxima Duch. vascular exudates provide an excellent material for metabolomics in this regard. Using automated mass spectral deconvolution, over 400 components have been detected in these exudates, but only 90 of them were tentatively identified. Many amino compounds were found in vascular exudates from leaf petioles at concentrations several orders of magnitude higher than in tissue disks from the same leaves, whereas hexoses and sucrose were found in far lower amounts. In order to find the expected impact of assimilation rates on sugar levels, total phloem composition of eight leaves from four plants was followed over 4.5 days. Surprisingly, no diurnal rhythm was found for any of the phloem metabolites that was statistically valid for all eight leaves. Instead, each leaf had its own distinct vascular exudate profile similar to leaves from the same plant, but clearly different from leaves harvested from plants at the same developmental stage. Thirty to forty per cent of all metabolite levels of individual leaves were different from the average of all metabolite profiles. Using metabolic co-regulation analysis, similarities and differences between the exudate profiles were more accurately characterized through network computation, specifically with respect to nitrogen metabolism.

  3. ¹³C-based metabolic flux analysis of Saccharomyces cerevisiae with a reduced Crabtree effect.

    Science.gov (United States)

    Kajihata, Shuichi; Matsuda, Fumio; Yoshimi, Mika; Hayakawa, Kenshi; Furusawa, Chikara; Kanda, Akihisa; Shimizu, Hiroshi

    2015-08-01

    Saccharomyces cerevisiae shows a Crabtree effect that produces ethanol in a high glucose concentration even under fully aerobic condition. For efficient production of cake yeast or compressed yeast for baking, ethanol by-production is not desired since glucose limited chemostat or fed-batch cultivations are performed to suppress the Crabtree effect. In this study, the (13)C-based metabolic flux analysis ((13)C-MFA) was performed for the S288C derived S. cerevisiae strain to characterize a metabolic state under the reduced Crabtree effect. S. cerevisiae cells were cultured at a low dilution rate (0.1 h(-1)) under the glucose-limited chemostat condition. The estimated metabolic flux distribution showed that the acetyl-CoA in mitochondria was mainly produced from pyruvate by pyruvate dehydrogenase (PDH) reaction and that the level of the metabolic flux through the pentose phosphate pathway was much higher than that of the Embden-Meyerhof-Parnas pathway, which contributes to high biomass yield at low dilution rate by supplying NADPH required for cell growth. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  4. Integrated stoichiometric, thermodynamic and kinetic modelling of steady state metabolism.

    Science.gov (United States)

    Fleming, R M T; Thiele, I; Provan, G; Nasheuer, H P

    2010-06-07

    The quantitative analysis of biochemical reactions and metabolites is at frontier of biological sciences. The recent availability of high-throughput technology data sets in biology has paved the way for new modelling approaches at various levels of complexity including the metabolome of a cell or an organism. Understanding the metabolism of a single cell and multi-cell organism will provide the knowledge for the rational design of growth conditions to produce commercially valuable reagents in biotechnology. Here, we demonstrate how equations representing steady state mass conservation, energy conservation, the second law of thermodynamics, and reversible enzyme kinetics can be formulated as a single system of linear equalities and inequalities, in addition to linear equalities on exponential variables. Even though the feasible set is non-convex, the reformulation is exact and amenable to large-scale numerical analysis, a prerequisite for computationally feasible genome scale modelling. Integrating flux, concentration and kinetic variables in a unified constraint-based formulation is aimed at increasing the quantitative predictive capacity of flux balance analysis. Incorporation of experimental and theoretical bounds on thermodynamic and kinetic variables ensures that the predicted steady state fluxes are both thermodynamically and biochemically feasible. The resulting in silico predictions are tested against fluxomic data for central metabolism in Escherichia coli and compare favourably with in silico prediction by flux balance analysis. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  5. Sugar Lego: gene composition of bacterial carbohydrate metabolism genomic loci.

    Science.gov (United States)

    Kaznadzey, Anna; Shelyakin, Pavel; Gelfand, Mikhail S

    2017-11-25

    Bacterial carbohydrate metabolism is extremely diverse, since carbohydrates serve as a major energy source and are involved in a variety of cellular processes. Bacterial genes belonging to same metabolic pathway are often co-localized in the chromosome, but it is not a strict rule. Gene co-localization in linked to co-evolution and co-regulation. This study focuses on a large-scale analysis of bacterial genomic loci related to the carbohydrate metabolism. We demonstrate that only 53% of 148,000 studied genes from over six hundred bacterial genomes are co-localized in bacterial genomes with other carbohydrate metabolism genes, which points to a significant role of singleton genes. Co-localized genes form cassettes, ranging in size from two to fifteen genes. Two major factors influencing the cassette-forming tendency are gene function and bacterial phylogeny. We have obtained a comprehensive picture of co-localization preferences of genes for nineteen major carbohydrate metabolism functional classes, over two hundred gene orthologous clusters, and thirty bacterial classes, and characterized the cassette variety in size and content among different species, highlighting a significant role of short cassettes. The preference towards co-localization of carbohydrate metabolism genes varies between 40 and 76% for bacterial taxa. Analysis of frequently co-localized genes yielded forty-five significant pairwise links between genes belonging to different functional classes. The number of such links per class range from zero to eight, demonstrating varying preferences of respective genes towards a specific chromosomal neighborhood. Genes from eleven functional classes tend to co-localize with genes from the same class, indicating an important role of clustering of genes with similar functions. At that, in most cases such co-localization does not originate from local duplication events. Overall, we describe a complex web formed by evolutionary relationships of bacterial

  6. Mathematical analysis of complex cellular activity

    CERN Document Server

    Bertram, Richard; Teka, Wondimu; Vo, Theodore; Wechselberger, Martin; Kirk, Vivien; Sneyd, James

    2015-01-01

    This book contains two review articles on mathematical physiology that deal with closely related topics but were written and can be read independently. The first article reviews the basic theory of calcium oscillations (common to almost all cell types), including spatio-temporal behaviors such as waves. The second article uses, and expands on, much of this basic theory to show how the interaction of cytosolic calcium oscillators with membrane ion channels can result in highly complex patterns of electrical spiking. Through these examples one can see clearly how multiple oscillatory processes interact within a cell, and how mathematical methods can be used to understand such interactions better. The two reviews provide excellent examples of how mathematics and physiology can learn from each other, and work jointly towards a better understanding of complex cellular processes. Review 1: Richard Bertram, Joel Tabak, Wondimu Teka, Theodore Vo, Martin Wechselberger: Geometric Singular Perturbation Analysis of Burst...

  7. State analysis requirements database for engineering complex embedded systems

    Science.gov (United States)

    Bennett, Matthew B.; Rasmussen, Robert D.; Ingham, Michel D.

    2004-01-01

    It has become clear that spacecraft system complexity is reaching a threshold where customary methods of control are no longer affordable or sufficiently reliable. At the heart of this problem are the conventional approaches to systems and software engineering based on subsystem-level functional decomposition, which fail to scale in the tangled web of interactions typically encountered in complex spacecraft designs. Furthermore, there is a fundamental gap between the requirements on software specified by systems engineers and the implementation of these requirements by software engineers. Software engineers must perform the translation of requirements into software code, hoping to accurately capture the systems engineer's understanding of the system behavior, which is not always explicitly specified. This gap opens up the possibility for misinterpretation of the systems engineer's intent, potentially leading to software errors. This problem is addressed by a systems engineering tool called the State Analysis Database, which provides a tool for capturing system and software requirements in the form of explicit models. This paper describes how requirements for complex aerospace systems can be developed using the State Analysis Database.

  8. Artificial Promoters for Metabolic Optimization

    DEFF Research Database (Denmark)

    Jensen, Peter Ruhdal; Hammer, Karin

    1998-01-01

    In this article, we review some of the expression systems that are available for Metabolic Control Analysis and Metabolic Engineering, and examine their advantages and disadvantages in different contexts. In a recent approach, artificial promoters for modulating gene expression in micro-organisms...

  9. Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.

    Science.gov (United States)

    Hasan, Maroof; Gonugunta, Vijay K; Dobbs, Nicole; Ali, Aktar; Palchik, Guillermo; Calvaruso, Maria A; DeBerardinis, Ralph J; Yan, Nan

    2017-01-24

    Three-prime repair exonuclease 1 knockout (Trex1 -/- ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 -/- mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 -/- background, and many metabolic defects persist in Trex1 -/- Irf3 -/- cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 -/- mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 -/- cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.

  10. DESIGN AND PERFORMANCE OF A XENOBIOTIC METABOLISM DATABASE MANAGER FOR METABOLIC SIMULATOR ENHANCEMENT AND CHEMICAL RISK ANALYSIS

    Science.gov (United States)

    A major uncertainty that has long been recognized in evaluating chemical toxicity is accounting for metabolic activation of chemicals resulting in increased toxicity. In silico approaches to predict chemical metabolism and to subsequently screen and prioritize chemicals for risk ...

  11. Protein complex prediction via dense subgraphs and false positive analysis.

    Directory of Open Access Journals (Sweden)

    Cecilia Hernandez

    Full Text Available Many proteins work together with others in groups called complexes in order to achieve a specific function. Discovering protein complexes is important for understanding biological processes and predict protein functions in living organisms. Large-scale and throughput techniques have made possible to compile protein-protein interaction networks (PPI networks, which have been used in several computational approaches for detecting protein complexes. Those predictions might guide future biologic experimental research. Some approaches are topology-based, where highly connected proteins are predicted to be complexes; some propose different clustering algorithms using partitioning, overlaps among clusters for networks modeled with unweighted or weighted graphs; and others use density of clusters and information based on protein functionality. However, some schemes still require much processing time or the quality of their results can be improved. Furthermore, most of the results obtained with computational tools are not accompanied by an analysis of false positives. We propose an effective and efficient mining algorithm for discovering highly connected subgraphs, which is our base for defining protein complexes. Our representation is based on transforming the PPI network into a directed acyclic graph that reduces the number of represented edges and the search space for discovering subgraphs. Our approach considers weighted and unweighted PPI networks. We compare our best alternative using PPI networks from Saccharomyces cerevisiae (yeast and Homo sapiens (human with state-of-the-art approaches in terms of clustering, biological metrics and execution times, as well as three gold standards for yeast and two for human. Furthermore, we analyze false positive predicted complexes searching the PDBe (Protein Data Bank in Europe database in order to identify matching protein complexes that have been purified and structurally characterized. Our analysis shows

  12. Epilepsy and astrocyte energy metabolism.

    Science.gov (United States)

    Boison, Detlev; Steinhäuser, Christian

    2018-06-01

    Epilepsy is a complex neurological syndrome characterized by neuronal hyperexcitability and sudden, synchronized electrical discharges that can manifest as seizures. It is now increasingly recognized that impaired astrocyte function and energy homeostasis play key roles in the pathogenesis of epilepsy. Excessive neuronal discharges can only happen, if adequate energy sources are made available to neurons. Conversely, energy depletion during seizures is an endogenous mechanism of seizure termination. Astrocytes control neuronal energy homeostasis through neurometabolic coupling. In this review, we will discuss how astrocyte dysfunction in epilepsy leads to distortion of key metabolic and biochemical mechanisms. Dysfunctional glutamate metabolism in astrocytes can directly contribute to neuronal hyperexcitability. Closure of astrocyte intercellular gap junction coupling as observed early during epileptogenesis limits activity-dependent trafficking of energy metabolites, but also impairs clearance of the extracellular space from accumulation of K + and glutamate. Dysfunctional astrocytes also increase the metabolism of adenosine, a metabolic product of ATP degradation that broadly inhibits energy-consuming processes as an evolutionary adaptation to conserve energy. Due to the critical role of astroglial energy homeostasis in the control of neuronal excitability, metabolic therapeutic approaches that prevent the utilization of glucose might represent a potent antiepileptic strategy. In particular, high fat low carbohydrate "ketogenic diets" as well as inhibitors of glycolysis and lactate metabolism are of growing interest for the therapy of epilepsy. © 2017 Wiley Periodicals, Inc.

  13. Metabolic profiling of a mapping population exposes new insights in the regulation of seed metabolism and seed, fruit, and plant relations.

    Directory of Open Access Journals (Sweden)

    David Toubiana

    Full Text Available To investigate the regulation of seed metabolism and to estimate the degree of metabolic natural variability, metabolite profiling and network analysis were applied to a collection of 76 different homozygous tomato introgression lines (ILs grown in the field in two consecutive harvest seasons. Factorial ANOVA confirmed the presence of 30 metabolite quantitative trait loci (mQTL. Amino acid contents displayed a high degree of variability across the population, with similar patterns across the two seasons, while sugars exhibited significant seasonal fluctuations. Upon integration of data for tomato pericarp metabolite profiling, factorial ANOVA identified the main factor for metabolic polymorphism to be the genotypic background rather than the environment or the tissue. Analysis of the coefficient of variance indicated greater phenotypic plasticity in the ILs than in the M82 tomato cultivar. Broad-sense estimate of heritability suggested that the mode of inheritance of metabolite traits in the seed differed from that in the fruit. Correlation-based metabolic network analysis comparing metabolite data for the seed with that for the pericarp showed that the seed network displayed tighter interdependence of metabolic processes than the fruit. Amino acids in the seed metabolic network were shown to play a central hub-like role in the topology of the network, maintaining high interactions with other metabolite categories, i.e., sugars and organic acids. Network analysis identified six exceptionally highly co-regulated amino acids, Gly, Ser, Thr, Ile, Val, and Pro. The strong interdependence of this group was confirmed by the mQTL mapping. Taken together these results (i reflect the extensive redundancy of the regulation underlying seed metabolism, (ii demonstrate the tight co-ordination of seed metabolism with respect to fruit metabolism, and (iii emphasize the centrality of the amino acid module in the seed metabolic network. Finally, the study

  14. Association of sleep quality components and wake time with metabolic syndrome: The Qazvin Metabolic Diseases Study (QMDS), Iran.

    Science.gov (United States)

    Zohal, Mohammadali; Ghorbani, Azam; Esmailzadehha, Neda; Ziaee, Amir; Mohammadi, Zahrasadat

    2017-11-01

    The aim of this study was to determine the association of sleep quality and sleep quantity with metabolic syndrome in Qazvin, Iran. this cross sectional study was conducted in 1079 residents of Qazvin selected by multistage cluster random sampling method in 2011. Metabolic syndrome was defined according to the criteria proposed by the national cholesterol education program third Adult treatment panel. Sleep was assessed using the Pittsburgh sleep quality index (PSQI). A logistic regression analysis was used to examine the association of sleep status and metabolic syndrome. Mean age was 40.08±10.33years. Of 1079, 578 (52.2%) were female, and 30.6% had metabolic syndrome. The total global PSQI score in the subjects with metabolic syndrome was significantly higher than subjects without metabolic syndrome (6.30±3.20 vs. 5.83±2.76, P=0.013). In logistic regression analysis, sleep disturbances was associated with 1.388 fold increased risk of metabolic syndrome after adjustment for age, gender, and body mass index. Sleep disturbances component was a predictor of metabolic syndrome in the present study. More longitudinal studies are necessary to understand the association of sleep quality and its components with metabolic syndrome. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  15. Enhancing Carbon Fixation by Metabolic Engineering: A Model System of Complex Network Modulation

    Energy Technology Data Exchange (ETDEWEB)

    Dr. Gregory Stephanopoulos

    2008-04-10

    In the first two years of this research we focused on the development of a DNA microarray for transcriptional studies in the photosynthetic organism Synechocystis and the elucidation of the metabolic pathway for biopolymer synthesis in this organism. In addition we also advanced the molecular biological tools for metabolic engineering of biopolymer synthesis in Synechocystis and initiated a series of physiological studies for the elucidation of the carbon fixing pathways and basic central carbon metabolism of these organisms. During the last two-year period we focused our attention on the continuation and completion of the last task, namely, the development of tools for basic investigations of the physiology of these cells through, primarily, the determination of their metabolic fluxes. The reason for this decision lies in the importance of fluxes as key indicators of physiology and the high level of information content they carry in terms of identifying rate limiting steps in a metabolic pathway. While flux determination is a well-advanced subject for heterotrophic organisms, for the case of autotrophic bacteria, like Synechocystis, some special challenges had to be overcome. These challenges stem mostly from the fact that if one uses {sup 13}C labeled CO{sub 2} for flux determination, the {sup 13}C label will mark, at steady state, all carbon atoms of all cellular metabolites, thus eliminating the necessary differentiation required for flux determination. This peculiarity of autotrophic organisms makes it imperative to carry out flux determination under transient conditions, something that had not been accomplished before. We are pleased to report that we have solved this problem and we are now able to determine fluxes in photosynthetic organisms from stable isotope labeling experiments followed by measurements of label enrichment in cellular metabolites using Gas Chromatography-Mass Spectrometry. We have conducted extensive simulations to test the method and

  16. Catalytic function of the mycobacterial binuclear iron monooxygenase in acetone metabolism.

    Science.gov (United States)

    Furuya, Toshiki; Nakao, Tomomi; Kino, Kuniki

    2015-10-01

    Mycobacteria such as Mycobacterium smegmatis strain mc(2)155 and Mycobacterium goodii strain 12523 are able to grow on acetone and use it as a source of carbon and energy. We previously demonstrated by gene deletion analysis that the mimABCD gene cluster, which encodes a binuclear iron monooxygenase, plays an essential role in acetone metabolism in these mycobacteria. In the present study, we determined the catalytic function of MimABCD in acetone metabolism. Whole-cell assays were performed using Escherichia coli cells expressing the MimABCD complex. When the recombinant E. coli cells were incubated with acetone, a product was detected by gas chromatography (GC) analysis. Based on the retention time and the gas chromatography-mass spectrometry (GC-MS) spectrum, the reaction product was identified as acetol (hydroxyacetone). The recombinant E. coli cells produced 1.02 mM of acetol from acetone within 24 h. Furthermore, we demonstrated that MimABCD also was able to convert methylethylketone (2-butanone) to 1-hydroxy-2-butanone. Although it has long been known that microorganisms such as mycobacteria metabolize acetone via acetol, this study provides the first biochemical evidence for the existence of a microbial enzyme that catalyses the conversion of acetone to acetol. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Metabolic assessments during extra-vehicular activity

    Science.gov (United States)

    Osipov, Yu. Yu.; Spichkov, A. N.; Filipenkov, S. N.

    Extra-vehicular activity (EVA) has a significant role during extended space flights. It demonstrates that humans can survive and perform useful work outside the Orbital Space Stations (OSS) while wearing protective space suits (SS). When the International Space Station 'Alpha'(ISSA) is fully operational, EVA assembly, installation, maintenance and repair operations will become an everyday repetitive work activity in space. It needs new ergonomic evaluation of the work/rest schedule for an increasing of the labor amount per EVA hour. The metabolism assessment is a helpful method to control the productivity of the EVA astronaut and to optimize the work/rest regime. Three following methods were used in Russia to estimate real-time metabolic rates during EVA: 1. Oxygen consumption, computed from the pressure drop in a high pressure bottle per unit time (with actual thermodynamic oxygen properties under high pressure and oxygen leakage taken into account). 2. Carbon dioxide production, computed from CO 2 concentration at the contaminant control cartridge and gas flow rate in the life support subsystem closed loop (nominal mode) or gas leakage in the SS open loop (emergency mode). 3. Heat removal, computed from the difference between the temperatures of coolant water or gas and its flow rate in a unit of time (with assumed humidity and wet oxygen state taken into account). Comparison of heat removal values with metabolic rates enables us to determine the thermal balance during an operative medical control of EVA at "Salyut-6", "Salyut-7" and "Mir" OSS. Complex analysis of metabolism, body temperature and heat rate supports a differential diagnosis between emotional and thermal components of stress during EVA. It gives a prognosis of human homeostasis during EVA. Available information has been acquired into an EVA data base which is an effective tool for ergonomical optimization.

  18. Twenty-one lectures on complex analysis a first course

    CERN Document Server

    Isaev, Alexander

    2017-01-01

    At its core, this concise textbook presents standard material for a first course in complex analysis at the advanced undergraduate level. This distinctive text will prove most rewarding for students who have a genuine passion for mathematics as well as certain mathematical maturity. Primarily aimed at undergraduates with working knowledge of real analysis and metric spaces, this book can also be used to instruct a graduate course. The text uses a conversational style with topics purposefully apportioned into 21 lectures, providing a suitable format for either independent study or lecture-based teaching. Instructors are invited to rearrange the order of topics according to their own vision. A clear and rigorous exposition is supported by engaging examples and exercises unique to each lecture; a large number of exercises contain useful calculation problems. Hints are given for a selection of the more difficult exercises. This text furnishes the reader with a means of learning complex analysis as well as a subtl...

  19. Screening for Inborn Errors of Metabolism

    Directory of Open Access Journals (Sweden)

    F.A. Elshaari

    2013-09-01

    Full Text Available Inborn errors of metabolism (IEM are a heterogeneous group of monogenic diseases that affect the metabolic pathways. The detection of IEM relies on a high index of clinical suspicion and co-ordinated access to specialized laboratory services. Biochemical analysis forms the basis of the final confirmed diagnosis in several of these disorders. The investigations fall into four main categories1.General metabolic screening tests2.Specific metabolite assays3.Enzyme studies4.DNA analysis The first approach to the diagnosis is by a multi-component analysis of body fluids in clinically selected patients, referred to as metabolic screening tests. These include simple chemical tests in the urine, blood glucose, acid-base profile, lactate, ammonia and liver function tests. The results of these tests can help to suggest known groups of metabolic disorders so that specific metabolites such as amino acids, organic acids, etc. can be estimated. However, not all IEM needs the approach of general screening. Lysosomal, peroxisomal, thyroid and adrenal disorders are suspected mainly on clinical grounds and pertinent diagnostic tests can be performed. The final diagnosis relies on the demonstration of the specific enzyme defect, which can be further confirmed by DNA studies.

  20. LC-MS Proteomics Analysis of the Insulin/IGF-1 Deficient Caenorhabditis elegans daf-2(e1370) Mutant Reveals Extensive Restructuring of Intermediary Metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Depuydt, Geert G.; Xie, Fang; Petyuk, Vladislav A.; Smolders, Arne; Brewer, Heather M.; Camp, David G.; Smith, Richard D.; Braeckman, Bart P.

    2014-02-20

    The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity and metabolism in C. elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass-spectrometry (LC-MS) based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2); daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the up-regulation of many core intermediary metabolic pathways. These include, glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid β-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complex I, II, III and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative for spatio-temporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. This restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves, possibly also shunting metabolites through alternative energy-generating pathways, in order to sustain longevity.

  1. LC–MS Proteomics Analysis of the Insulin/IGF-1-Deficient Caenorhabditis elegans daf-2(e1370) Mutant Reveals Extensive Restructuring of Intermediary Metabolism

    Science.gov (United States)

    2015-01-01

    The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity, and metabolism in Caenorhabditis elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including the expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass spectrometry (LC–MS)-based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2);daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the upregulation of many core intermediary metabolic pathways. These include glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid β-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complexes I, II, III, and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative of spatiotemporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. This restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves and possibly also shunting metabolites through alternative energy-generating pathways to sustain longevity. PMID:24555535

  2. Relative Quantitative Proteomic Analysis of Brucella abortus Reveals Metabolic Adaptation to Multiple Environmental Stresses

    Directory of Open Access Journals (Sweden)

    Xiaodong Zai

    2017-11-01

    Full Text Available Brucella spp. are facultative intracellular pathogens that cause chronic brucellosis in humans and animals. The virulence of Brucella primarily depends on its successful survival and replication in host cells. During invasion of the host tissue, Brucella is simultaneously subjected to a variety of harsh conditions, including nutrient limitation, low pH, antimicrobial defenses, and extreme levels of reactive oxygen species (ROS via the host immune response. This suggests that Brucella may be able to regulate its metabolic adaptation in response to the distinct stresses encountered during its intracellular infection of the host. An investigation into the differential proteome expression patterns of Brucella grown under the relevant stress conditions may contribute toward a better understanding of its pathogenesis and adaptive response. Here, we utilized a mass spectrometry-based label-free relative quantitative proteomics approach to investigate and compare global proteomic changes in B. abortus in response to eight different stress treatments. The 3 h short-term in vitro single-stress and multi-stress conditions mimicked the in vivo conditions of B. abortus under intracellular infection, with survival rates ranging from 3.17 to 73.17%. The proteomic analysis identified and quantified a total of 2,272 proteins and 74% of the theoretical proteome, thereby providing wide coverage of the B. abortus proteome. By including eight distinct growth conditions and comparing these with a control condition, we identified a total of 1,221 differentially expressed proteins (DEPs that were significantly changed under the stress treatments. Pathway analysis revealed that most of the proteins were involved in oxidative phosphorylation, ABC transporters, two-component systems, biosynthesis of secondary metabolites, the citrate cycle, thiamine metabolism, and nitrogen metabolism; constituting major response mechanisms toward the reconstruction of cellular

  3. Computational Flux Balance Analysis Predicts that Stimulation of Energy Metabolism in Astrocytes and their Metabolic Interactions with Neurons Depend on Uptake of K+ Rather than Glutamate.

    Science.gov (United States)

    DiNuzzo, Mauro; Giove, Federico; Maraviglia, Bruno; Mangia, Silvia

    2017-01-01

    Brain activity involves essential functional and metabolic interactions between neurons and astrocytes. The importance of astrocytic functions to neuronal signaling is supported by many experiments reporting high rates of energy consumption and oxidative metabolism in these glial cells. In the brain, almost all energy is consumed by the Na + /K + ATPase, which hydrolyzes 1 ATP to move 3 Na + outside and 2 K + inside the cells. Astrocytes are commonly thought to be primarily involved in transmitter glutamate cycling, a mechanism that however only accounts for few % of brain energy utilization. In order to examine the participation of astrocytic energy metabolism in brain ion homeostasis, here we attempted to devise a simple stoichiometric relation linking glutamatergic neurotransmission to Na + and K + ionic currents. To this end, we took into account ion pumps and voltage/ligand-gated channels using the stoichiometry derived from available energy budget for neocortical signaling and incorporated this stoichiometric relation into a computational metabolic model of neuron-astrocyte interactions. We aimed at reproducing the experimental observations about rates of metabolic pathways obtained by 13 C-NMR spectroscopy in rodent brain. When simulated data matched experiments as well as biophysical calculations, the stoichiometry for voltage/ligand-gated Na + and K + fluxes generated by neuronal activity was close to a 1:1 relationship, and specifically 63/58 Na + /K + ions per glutamate released. We found that astrocytes are stimulated by the extracellular K + exiting neurons in excess of the 3/2 Na + /K + ratio underlying Na + /K + ATPase-catalyzed reaction. Analysis of correlations between neuronal and astrocytic processes indicated that astrocytic K + uptake, but not astrocytic Na + -coupled glutamate uptake, is instrumental for the establishment of neuron-astrocytic metabolic partnership. Our results emphasize the importance of K + in stimulating the activation of

  4. Bile Acid Signaling in Liver Metabolism and Diseases

    Directory of Open Access Journals (Sweden)

    Tiangang Li

    2012-01-01

    Full Text Available Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.

  5. Urea metabolism in plants.

    Science.gov (United States)

    Witte, Claus-Peter

    2011-03-01

    Urea is a plant metabolite derived either from root uptake or from catabolism of arginine by arginase. In agriculture, urea is intensively used as a nitrogen fertilizer. Urea nitrogen enters the plant either directly, or in the form of ammonium or nitrate after urea degradation by soil microbes. In recent years various molecular players of plant urea metabolism have been investigated: active and passive urea transporters, the nickel metalloenzyme urease catalyzing the hydrolysis of urea, and three urease accessory proteins involved in the complex activation of urease. The degradation of ureides derived from purine breakdown has long been discussed as a possible additional metabolic source for urea, but an enzymatic route for the complete hydrolysis of ureides without a urea intermediate has recently been described for Arabidopsis thaliana. This review focuses on the proteins involved in plant urea metabolism and the metabolic sources of urea but also addresses open questions regarding plant urea metabolism in a physiological and agricultural context. The contribution of plant urea uptake and metabolism to fertilizer urea usage in crop production is still not investigated although globally more than half of all nitrogen fertilizer is applied to crops in the form of urea. Nitrogen use efficiency in crop production is generally well below 50% resulting in economical losses and creating ecological problems like groundwater pollution and emission of nitric oxides that can damage the ozone layer and function as greenhouse gasses. Biotechnological approaches to improve fertilizer urea usage bear the potential to increase crop nitrogen use efficiency. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  6. Positron emission tomography for measuring metabolism in vivo

    International Nuclear Information System (INIS)

    Feinendegen, L.E.

    1985-01-01

    Nuclear medical imaging always relates to changes at the cellular or molecular level of organization of the body. For years, such changes, summarily called metabolism, permitted radionuclides as tracers to produce information on rather gross organ structure and function. Yet, more recently, increasing emphasis is placed on metabolic reactions themselves; this development is of considerable promise to the clinician, because disease begins and nearly always expresses itself by alterations of metabolism. PET greatly helps to investigate and describe in vivo individual steps within the complex network of enzyme catalized reactions that maintain life; in fact, PET allows studies of biochemistry in vivo. (Author)

  7. Transcriptome sequencing and metabolite analysis reveals the role of delphinidin metabolism in flower colour in grape hyacinth

    OpenAIRE

    Lou, Qian; Liu, Yali; Qi, Yinyan; Jiao, Shuzhen; Tian, Feifei; Jiang, Ling; Wang, Yuejin

    2014-01-01

    Grape hyacinth (Muscari) is an important ornamental bulbous plant with an extraordinary blue colour. Muscari armeniacum, whose flowers can be naturally white, provides an opportunity to unravel the complex metabolic networks underlying certain biochemical traits, especially colour. A blue flower cDNA library of M. armeniacum and a white flower library of M. armeniacum f. album were used for transcriptome sequencing. A total of 89 926 uni-transcripts were isolated, 143 of which could be identi...

  8. Prevalence of metabolic syndrome and metabolic syndrome components in young adults: A pooled analysis