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Sample records for metabolic response modeling

  1. Modeling metabolic response to changes of enzyme amount in ...

    African Journals Online (AJOL)

    Based on the work of Hynne et al. (2001), in an in silico model of glycolysis, Saccharomyces cerevisiae is established by introducing an enzyme amount multiple factor (.) into the kinetic equations. The model is aimed to predict the metabolic response to the change of enzyme amount. With the help of .α, the amounts of ...

  2. Modeling metabolic response to changes of enzyme amount in ...

    African Journals Online (AJOL)

    Jane

    2010-10-11

    Oct 11, 2010 ... In this work, we first introduced the enzyme parameter (ɑ) into the kinetic equations and consequently established an in silico glycolysis model of Saccharomyces cerevisiae in XML format (Figure 1), based on the work of Hynn et al. (2001). Equation 1 shows how the ɑis introduced into the kinetic equation.

  3. Metabolic cost of neuronal information in an empirical stimulus-response model

    Czech Academy of Sciences Publication Activity Database

    Košťál, Lubomír; Lánský, Petr; McDonnell, M.D.

    2013-01-01

    Roč. 107, č. 3 (2013), s. 355-365 ISSN 0340-1200 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GAP103/11/0282; GA ČR(CZ) GPP103/12/P558 Institutional support: RVO:67985823 Keywords : information capacity * metabolic cost * stimulus-response curve Subject RIV: FH - Neurology Impact factor: 1.933, year: 2013

  4. Mathematical modelling of metabolism

    DEFF Research Database (Denmark)

    Gombert, Andreas Karoly; Nielsen, Jens

    2000-01-01

    Mathematical models of the cellular metabolism have a special interest within biotechnology. Many different kinds of commercially important products are derived from the cell factory, and metabolic engineering can be applied to improve existing production processes, as well as to make new processes...... availability of genomic information and powerful analytical techniques, mathematical models also serve as a tool for understanding the cellular metabolism and physiology....... available. Both stoichiometric and kinetic models have been used to investigate the metabolism, which has resulted in defining the optimal fermentation conditions, as well as in directing the genetic changes to be introduced in order to obtain a good producer strain or cell line. With the increasing...

  5. Metabolic response to Klebsiella pneumoniae infection in an experimental rat model.

    Directory of Open Access Journals (Sweden)

    Fangcong Dong

    Full Text Available Bacteremia, the presence of viable bacteria in the blood stream, is often associated with several clinical conditions. Bacteremia can lead to multiple organ failure if managed incorrectly, which makes providing suitable nutritional support vital for reducing bacteremia-associated mortality. In order to provide such information, we investigated the metabolic consequences of a Klebsiella pneumoniae (K. pneumoniae infection in vivo by employing a combination of (1H nuclear magnetic resonance spectroscopy and multivariate data analysis. K. pneumoniae was intravenously infused in rats; urine and plasma samples were collected at different time intervals. We found that K. pneumoniae-induced bacteremia stimulated glycolysis and the tricarboxylic acid cycle and also promoted oxidation of fatty acids and creatine phosphate to facilitate the energy-demanding host response. In addition, K. pneumoniae bacteremia also induced anti-endotoxin, anti-inflammatory and anti-oxidization responses in the host. Furthermore, bacteremia could cause a disturbance in the gut microbiotal functions as suggested by alterations in a range of amines and bacteria-host co-metabolites. Our results suggest that supplementation with glucose and a high-fat and choline-rich diet could ameliorate the burdens associated with bacteremia. Our research provides underlying pathological processes of bacteremia and a better understanding of the clinical and biochemical manifestations of bacteremia.

  6. Capturing the response of Clostridium acetobutylicum to chemical stressors using a regulated genome-scale metabolic model

    International Nuclear Information System (INIS)

    Dash, Satyakam; Mueller, Thomas J.; Venkataramanan, Keerthi P.; Papoutsakis, Eleftherios T.; Maranas, Costas D.

    2014-01-01

    Clostridia are anaerobic Gram-positive Firmicutes containing broad and flexible systems for substrate utilization, which have been used successfully to produce a range of industrial compounds. Clostridium acetobutylicum has been used to produce butanol on an industrial scale through acetone-butanol-ethanol (ABE) fermentation. A genome-scale metabolic (GSM) model is a powerful tool for understanding the metabolic capacities of an organism and developing metabolic engineering strategies for strain development. The integration of stress related specific transcriptomics information with the GSM model provides opportunities for elucidating the focal points of regulation

  7. Selected Metabolic Responses to Skateboarding

    Science.gov (United States)

    Hetzler, Ronald K.; Hunt, Ian; Stickley, Christopher D.; Kimura, Iris F.

    2011-01-01

    Despite the popularity of skateboarding worldwide, the authors believe that no previous studies have investigated the metabolic demands associated with recreational participation in the sport. Although metabolic equivalents (METs) for skateboarding were published in textbooks, the source of these values is unclear. Therefore, the rise in…

  8. Effects of sensitizers on cell respiration. 3. The effects of hypoxic cell radiosensitizers on oxidative metabolism and the radiation response of an in vitro tumour model

    Energy Technology Data Exchange (ETDEWEB)

    Durand, R E [Wisconsin Clinical Cancer Center, Madison (USA). Dept. of Human Oncology; Biaglow, J E; Greenstock, C L

    1978-06-01

    Physiological factors are important when considering the effects of radiosensitizers on the radiation response of complex systems such as multi-cellular spheroids. In this system, under conditions of unlimited nutrient supply, cells are rendered hypoxic by metabolism. Thus, using the spheroid system as an in vitro model of the tumour-cell microenvironment, we have determined the relative contribution of radiosensitization and respiratory effects of a number of electron-affinic sensitizers having potential clinical use. These studies are indicative of physiological responses at the cellular level, and suggest optimal drug administration schemes for obtaining maximal radiation response in vivo with hypoxic cell sensitizers.

  9. Substrate metabolism in the metabolic response to injury

    NARCIS (Netherlands)

    Romijn, J. A.

    2000-01-01

    In healthy subjects the metabolic response to starvation invokes regulatory mechanisms aimed at conservation of protein mass. This response is characterized by a decrease in energy expenditure and a progressive decrease in urinary N excretion. Many non-endocrine diseases induce anorexia and a

  10. 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.

  11. Computational model of cellular metabolic dynamics

    DEFF Research Database (Denmark)

    Li, Yanjun; Solomon, Thomas; Haus, Jacob M

    2010-01-01

    of the cytosol and mitochondria. The model simulated skeletal muscle metabolic responses to insulin corresponding to human hyperinsulinemic-euglycemic clamp studies. Insulin-mediated rate of glucose disposal was the primary model input. For model validation, simulations were compared with experimental data......: intracellular metabolite concentrations and patterns of glucose disposal. Model variations were simulated to investigate three alternative mechanisms to explain insulin enhancements: Model 1 (M.1), simple mass action; M.2, insulin-mediated activation of key metabolic enzymes (i.e., hexokinase, glycogen synthase......, by application of mechanism M.3, the model predicts metabolite concentration changes and glucose partitioning patterns consistent with experimental data. The reaction rate fluxes quantified by this detailed model of insulin/glucose metabolism provide information that can be used to evaluate the development...

  12. Regulation-Structured Dynamic Metabolic Model Provides a Potential Mechanism for Delayed Enzyme Response in Denitrification Process

    Energy Technology Data Exchange (ETDEWEB)

    Song, Hyun-Seob; Thomas, Dennis G.; Stegen, James C.; Li, Minjing; Liu, Chongxuan; Song, Xuehang; Chen, Xingyuan; Fredrickson, Jim K.; Zachara, John M.; Scheibe, Timothy D.

    2017-09-29

    In a recent study of denitrification dynamics in hyporheic zone sediments, we observed a significant time lag (up to several days) in enzymatic response to the changes in substrate concentration. To explore an underlying mechanism and understand the interactive dynamics between enzymes and nutrients, we developed a trait-based model that associates a community’s traits with functional enzymes, instead of typically used species guilds (or functional guilds). This enzyme-based formulation allows to collectively describe biogeochemical functions of microbial communities without directly parameterizing the dynamics of species guilds, therefore being scalable to complex communities. As a key component of modeling, we accounted for microbial regulation occurring through transcriptional and translational processes, the dynamics of which was parameterized based on the temporal profiles of enzyme concentrations measured using a new signature peptide-based method. The simulation results using the resulting model showed several days of a time lag in enzymatic responses as observed in experiments. Further, the model showed that the delayed enzymatic reactions could be primarily controlled by transcriptional responses and that the dynamics of transcripts and enzymes are closely correlated. The developed model can serve as a useful tool for predicting biogeochemical processes in natural environments, either independently or through integration with hydrologic flow simulators.

  13. Response to ‘comment on recent modeling studies of astrocyte–neuron metabolic interactions': much ado about nothing

    OpenAIRE

    Mangia, Silvia; DiNuzzo, Mauro; Giove, Federico; Carruthers, Anthony; Simpson, Ian A; Vannucci, Susan J

    2011-01-01

    For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte–neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmissio...

  14. Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia

    Directory of Open Access Journals (Sweden)

    Selena Marini

    2017-08-01

    Full Text Available Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE, accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

  15. Metabolic Responses to Weight Lifting

    Directory of Open Access Journals (Sweden)

    Arnold Nelson

    2017-04-01

    Full Text Available Editor's Note, The ability to lift heavy loads while performing multiple repetitions is not only highly correlated with muscle mass or the total number actomyosin interactions, but also metabolic functions that includes substrate concentrations and by-product removal.  Muscles use adenosine triphosphate (ATP in at least three locations during exercise; to run the actomyosin interaction, operate sarcoplasmic reticulum calcium pumps, and operate sarcolemma sodium and potassium pumps.  Weight lifting sessions are considered to be an intermittent activity that includes only a few second bursts of high force and/or velocity movements followed by rest periods of up to several minutes. Therefore, the anaerobic pathways such as the phosphagen and glycolytic systems are the initial pathways to respond due in part to the ability to match the increased rates of ATP depletion by increasing ATP production. After the initial resting ATP stores are used up, the phosphagen system starts contributing to ATP replenishment.  This system consists of reactions from the creatine kinase (CK pathway and the adenylate kinase (AK pathway.  However, the CK pathway can only work at max capacity for a short period for resting phosphocreatine (PCr concentrations are only about 4-6 times the amount of resting ATP stores.  Once the PCr concentrations are depleted, the AK reaction will begin by using two adenosine diphosphate (ADP to form one ATP and one adenosine monophosphate (AMP. Although ATP is produced in this pathway, this production of ATP does coincide with an increased concentration of AMP. This is problematic because increased AMP levels will in turn stimulate the adenylate deaminase reaction, which will produce ammonia (NH3. This conversion of AMP into NH3 will result in the muscle cell having a net loss of total adenine nucleotides available to resynthesize ATP.  Glycolysis is the next reaction in line, which increases its role in ATP replenishment as PCr

  16. Genome scale metabolic modeling of cancer

    DEFF Research Database (Denmark)

    Nilsson, Avlant; Nielsen, Jens

    2017-01-01

    of metabolism which allows simulation and hypotheses testing of metabolic strategies. It has successfully been applied to many microorganisms and is now used to study cancer metabolism. Generic models of human metabolism have been reconstructed based on the existence of metabolic genes in the human genome......Cancer cells reprogram metabolism to support rapid proliferation and survival. Energy metabolism is particularly important for growth and genes encoding enzymes involved in energy metabolism are frequently altered in cancer cells. A genome scale metabolic model (GEM) is a mathematical formalization...

  17. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    Directory of Open Access Journals (Sweden)

    Yuanyuan Zhang

    2014-06-01

    Full Text Available Erythropoietin (EPO regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR, suggest the potential for EPO response in metabolism and disease.

  18. Metabolic features of the cell danger response.

    Science.gov (United States)

    Naviaux, Robert K

    2014-05-01

    The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental

  19. Modelling of the metabolism of Zymomonas mobilis

    Energy Technology Data Exchange (ETDEWEB)

    Posten, C; Thoma, M

    1986-01-01

    In order to optimize fermentations with respect to media, reactor configuration, and control a structured model of the metabolism of Zymononas mobilis has been developed. The model is based on structure of metabolism, rate limiting steps, energy balance and metabolic elemental balances. A three-fold effect of ethanol has been observed concerning substrate-turnover, ammonia uptake and energy consumption. In addition to the metabolic view a structured cell-membrane-model should be considered.

  20. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses

    Directory of Open Access Journals (Sweden)

    Shivendra D. Shukla

    2015-11-01

    Full Text Available Chronic alcoholics who also binge drink (i.e., acute on chronic are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4% for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart. Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9, dually modified phosphoacetylated histone H3 (H3AcK9/PS10, and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10 and H3 ser 28 (H3S28 increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

  1. A second-generation computational modeling of cardiac electrophysiology: response of action potential to ionic concentration changes and metabolic inhibition.

    Science.gov (United States)

    Alaa, Nour Eddine; Lefraich, Hamid; El Malki, Imane

    2014-10-21

    Cardiac arrhythmias are becoming one of the major health care problem in the world, causing numerous serious disease conditions including stroke and sudden cardiac death. Furthermore, cardiac arrhythmias are intimately related to the signaling ability of cardiac cells, and are caused by signaling defects. Consequently, modeling the electrical activity of the heart, and the complex signaling models that subtend dangerous arrhythmias such as tachycardia and fibrillation, necessitates a quantitative model of action potential (AP) propagation. Yet, many electrophysiological models, which accurately reproduce dynamical characteristic of the action potential in cells, have been introduced. However, these models are very complex and are very time consuming computationally. Consequently, a large amount of research is consecrated to design models with less computational complexity. This paper is presenting a new model for analyzing the propagation of ionic concentrations and electrical potential in space and time. In this model, the transport of ions is governed by Nernst-Planck flux equation (NP), and the electrical interaction of the species is described by a new cable equation. These set of equations form a system of coupled partial nonlinear differential equations that is solved numerically. In the first we describe the mathematical model. To realize the numerical simulation of our model, we proceed by a finite element discretization and then we choose an appropriate resolution algorithm. We give numerical simulations obtained for different input scenarios in the case of suicide substrate reaction which were compared to those obtained in literature. These input scenarios have been chosen so as to provide an intuitive understanding of dynamics of the model. By accessing time and space domains, it is shown that interpreting the electrical potential of cell membrane at steady state is incorrect. This model is general and applies to ions of any charge in space and time

  2. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring.

    Science.gov (United States)

    Salomäki, Henriikka; Heinäniemi, Merja; Vähätalo, Laura H; Ailanen, Liisa; Eerola, Kim; Ruohonen, Suvi T; Pesonen, Ullamari; Koulu, Markku

    2014-01-01

    Despite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice. Female mice were on a high fat diet (HFD) prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Body weight and several metabolic parameters (e.g. body composition and glucose tolerance) were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment. Prenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC) was prominently affected both in the neonatal liver and adipose tissue. This study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood.

  3. Reconstruction of Oryza sativa indica Genome Scale Metabolic Model and Its Responses to Varying RuBisCO Activity, Light Intensity, and Enzymatic Cost Conditions

    Directory of Open Access Journals (Sweden)

    Ankita Chatterjee

    2017-11-01

    Full Text Available To combat decrease in rice productivity under different stresses, an understanding of rice metabolism is needed. Though there are different genome scale metabolic models (GSMs of Oryza sativa japonica, no GSM with gene-protein-reaction association exist for Oryza sativa indica. Here, we report a GSM, OSI1136 of O.s. indica, which includes 3602 genes and 1136 metabolic reactions and transporters distributed across the cytosol, mitochondrion, peroxisome, and chloroplast compartments. Flux balance analysis of the model showed that for varying RuBisCO activity (Vc/Vo (i the activity of the chloroplastic malate valve increases to transport reducing equivalents out of the chloroplast under increased photorespiratory conditions and (ii glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase can act as source of cytosolic ATP under decreased photorespiration. Under increasing light conditions we observed metabolic flexibility, involving photorespiration, chloroplastic triose phosphate and the dicarboxylate transporters of the chloroplast and mitochondrion for redox and ATP exchanges across the intracellular compartments. Simulations under different enzymatic cost conditions revealed (i participation of peroxisomal glutathione-ascorbate cycle in photorespiratory H2O2 metabolism (ii different modes of the chloroplastic triose phosphate transporters and malate valve, and (iii two possible modes of chloroplastic Glu–Gln transporter which were related with the activity of chloroplastic and cytosolic isoforms of glutamine synthetase. Altogether, our results provide new insights into plant metabolism.

  4. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

    Science.gov (United States)

    Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  5. Microalgal Metabolic Network Model Refinement through High-Throughput Functional Metabolic Profiling

    International Nuclear Information System (INIS)

    Chaiboonchoe, Amphun; Dohai, Bushra Saeed; Cai, Hong; Nelson, David R.; Jijakli, Kenan; Salehi-Ashtiani, Kourosh

    2014-01-01

    Metabolic modeling provides the means to define metabolic processes at a systems level; however, genome-scale metabolic models often remain incomplete in their description of metabolic networks and may include reactions that are experimentally unverified. This shortcoming is exacerbated in reconstructed models of newly isolated algal species, as there may be little to no biochemical evidence available for the metabolism of such isolates. The phenotype microarray (PM) technology (Biolog, Hayward, CA, USA) provides an efficient, high-throughput method to functionally define cellular metabolic activities in response to a large array of entry metabolites. The platform can experimentally verify many of the unverified reactions in a network model as well as identify missing or new reactions in the reconstructed metabolic model. The PM technology has been used for metabolic phenotyping of non-photosynthetic bacteria and fungi, but it has not been reported for the phenotyping of microalgae. Here, we introduce the use of PM assays in a systematic way to the study of microalgae, applying it specifically to the green microalgal model species Chlamydomonas reinhardtii. The results obtained in this study validate a number of existing annotated metabolic reactions and identify a number of novel and unexpected metabolites. The obtained information was used to expand and refine the existing COBRA-based C. reinhardtii metabolic network model iRC1080. Over 254 reactions were added to the network, and the effects of these additions on flux distribution within the network are described. The novel reactions include the support of metabolism by a number of d-amino acids, l-dipeptides, and l-tripeptides as nitrogen sources, as well as support of cellular respiration by cysteamine-S-phosphate as a phosphorus source. The protocol developed here can be used as a foundation to functionally profile other microalgae such as known microalgae mutants and novel isolates.

  6. Microalgal Metabolic Network Model Refinement through High-Throughput Functional Metabolic Profiling

    Energy Technology Data Exchange (ETDEWEB)

    Chaiboonchoe, Amphun; Dohai, Bushra Saeed; Cai, Hong; Nelson, David R. [Division of Science and Math, New York University Abu Dhabi, Abu Dhabi (United Arab Emirates); Center for Genomics and Systems Biology (CGSB), New York University Abu Dhabi Institute, Abu Dhabi (United Arab Emirates); Jijakli, Kenan [Division of Science and Math, New York University Abu Dhabi, Abu Dhabi (United Arab Emirates); Center for Genomics and Systems Biology (CGSB), New York University Abu Dhabi Institute, Abu Dhabi (United Arab Emirates); Engineering Division, Biofinery, Manhattan, KS (United States); Salehi-Ashtiani, Kourosh, E-mail: ksa3@nyu.edu [Division of Science and Math, New York University Abu Dhabi, Abu Dhabi (United Arab Emirates); Center for Genomics and Systems Biology (CGSB), New York University Abu Dhabi Institute, Abu Dhabi (United Arab Emirates)

    2014-12-10

    Metabolic modeling provides the means to define metabolic processes at a systems level; however, genome-scale metabolic models often remain incomplete in their description of metabolic networks and may include reactions that are experimentally unverified. This shortcoming is exacerbated in reconstructed models of newly isolated algal species, as there may be little to no biochemical evidence available for the metabolism of such isolates. The phenotype microarray (PM) technology (Biolog, Hayward, CA, USA) provides an efficient, high-throughput method to functionally define cellular metabolic activities in response to a large array of entry metabolites. The platform can experimentally verify many of the unverified reactions in a network model as well as identify missing or new reactions in the reconstructed metabolic model. The PM technology has been used for metabolic phenotyping of non-photosynthetic bacteria and fungi, but it has not been reported for the phenotyping of microalgae. Here, we introduce the use of PM assays in a systematic way to the study of microalgae, applying it specifically to the green microalgal model species Chlamydomonas reinhardtii. The results obtained in this study validate a number of existing annotated metabolic reactions and identify a number of novel and unexpected metabolites. The obtained information was used to expand and refine the existing COBRA-based C. reinhardtii metabolic network model iRC1080. Over 254 reactions were added to the network, and the effects of these additions on flux distribution within the network are described. The novel reactions include the support of metabolism by a number of d-amino acids, l-dipeptides, and l-tripeptides as nitrogen sources, as well as support of cellular respiration by cysteamine-S-phosphate as a phosphorus source. The protocol developed here can be used as a foundation to functionally profile other microalgae such as known microalgae mutants and novel isolates.

  7. Thermal sensation and thermophysiological responses with metabolic step-changes

    DEFF Research Database (Denmark)

    Goto, Tomonobu; Toftum, Jørn; deDear, Richard

    2006-01-01

    at sedentary activity. In a second experimental series, subjects alternated between rest and exercise as well as between exercise at different intensities at two temperature levels. Measurements comprised skin and oesophageal temperatures, heart rate and subjective responses. Thermal sensation started to rise....... The sensitivity of thermal sensation to changes in core temperature was higher for activity down-steps than for up-steps. A model was proposed that estimates transient thermal sensation after metabolic step-changes. Based on predictions by the model, weighting factors were suggested to estimate a representative...... average metabolic rate with varying activity levels, e.g. for the prediction of thermal sensation by steady-state comfort models. The activity during the most recent 5 min should be weighted 65%, during the prior 10-5 min 25% and during the prior 20-10 min 10%....

  8. Metabolic changes in serum metabolome in response to a meal.

    Science.gov (United States)

    Shrestha, Aahana; Müllner, Elisabeth; Poutanen, Kaisa; Mykkänen, Hannu; Moazzami, Ali A

    2017-03-01

    The change in serum metabolic response from fasting state to postprandial state provides novel insights into the impact of a single meal on human metabolism. Therefore, this study explored changes in serum metabolite profile after a single meal. Nineteen healthy postmenopausal women with normal glucose tolerance participated in the study. They received a meal consisting of refined wheat bread (50 g carbohydrates, 9 g protein, 4.2 g fat and 2.7 g dietary fibre), 40 g cucumber and 300 mL noncaloric orange drink. Blood samples were collected at fasting and five postprandial time points. Metabolic profile was measured by nuclear magnetic resonance and targeted liquid chromatography-mass spectrometry. Changes over time were assessed with multivariate models and ANOVA, with baseline as control. The metabolomic analyses demonstrated alterations in phospholipids, amino acids and their breakdown products, glycolytic products, acylcarnitines and ketone bodies after a single meal. More specifically, phosphatidylcholines, lysophosphatidylcholines and citrate displayed an overall declining pattern, while leucine, isoleucine, methionine and succinate increased initially but declined thereafter. A sharp decline in acylcarnitines and ketone bodies and increase in glycolytic products postprandially suggest a switch in the body's energy source from β-oxidation to glycolysis. Moreover, individuals with relatively high postprandial insulin responses generated a higher postprandial leucine responses compared to participants with lower insulin responses. The study demonstrated complex changes from catabolic to anabolic metabolism after a meal and indicated that the extent of postprandial responses is different between individuals with high and low insulin response.

  9. A strong response to selection on mass-independent maximal metabolic rate without a correlated response in basal metabolic rate.

    Science.gov (United States)

    Wone, B W M; Madsen, P; Donovan, E R; Labocha, M K; Sears, M W; Downs, C J; Sorensen, D A; Hayes, J P

    2015-04-01

    Metabolic rates are correlated with many aspects of ecology, but how selection on different aspects of metabolic rates affects their mutual evolution is poorly understood. Using laboratory mice, we artificially selected for high maximal mass-independent metabolic rate (MMR) without direct selection on mass-independent basal metabolic rate (BMR). Then we tested for responses to selection in MMR and correlated responses to selection in BMR. In other lines, we antagonistically selected for mice with a combination of high mass-independent MMR and low mass-independent BMR. All selection protocols and data analyses included body mass as a covariate, so effects of selection on the metabolic rates are mass adjusted (that is, independent of effects of body mass). The selection lasted eight generations. Compared with controls, MMR was significantly higher (11.2%) in lines selected for increased MMR, and BMR was slightly, but not significantly, higher (2.5%). Compared with controls, MMR was significantly higher (5.3%) in antagonistically selected lines, and BMR was slightly, but not significantly, lower (4.2%). Analysis of breeding values revealed no positive genetic trend for elevated BMR in high-MMR lines. A weak positive genetic correlation was detected between MMR and BMR. That weak positive genetic correlation supports the aerobic capacity model for the evolution of endothermy in the sense that it fails to falsify a key model assumption. Overall, the results suggest that at least in these mice there is significant capacity for independent evolution of metabolic traits. Whether that is true in the ancestral animals that evolved endothermy remains an important but unanswered question.

  10. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring.

    Directory of Open Access Journals (Sweden)

    Henriikka Salomäki

    Full Text Available AIMS: Despite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice. MATERIALS AND METHODS: Female mice were on a high fat diet (HFD prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD and subjected to HFD at adulthood (10-11 weeks. Body weight and several metabolic parameters (e.g. body composition and glucose tolerance were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment. RESULTS: Prenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC was prominently affected both in the neonatal liver and adipose tissue. CONCLUSION: This study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood.

  11. Precision metabolic engineering: The design of responsive, selective, and controllable metabolic systems.

    Science.gov (United States)

    McNerney, Monica P; Watstein, Daniel M; Styczynski, Mark P

    2015-09-01

    Metabolic engineering is generally focused on static optimization of cells to maximize production of a desired product, though recently dynamic metabolic engineering has explored how metabolic programs can be varied over time to improve titer. However, these are not the only types of applications where metabolic engineering could make a significant impact. Here, we discuss a new conceptual framework, termed "precision metabolic engineering," involving the design and engineering of systems that make different products in response to different signals. Rather than focusing on maximizing titer, these types of applications typically have three hallmarks: sensing signals that determine the desired metabolic target, completely directing metabolic flux in response to those signals, and producing sharp responses at specific signal thresholds. In this review, we will first discuss and provide examples of precision metabolic engineering. We will then discuss each of these hallmarks and identify which existing metabolic engineering methods can be applied to accomplish those tasks, as well as some of their shortcomings. Ultimately, precise control of metabolic systems has the potential to enable a host of new metabolic engineering and synthetic biology applications for any problem where flexibility of response to an external signal could be useful. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  12. 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.

  13. Climate and vegetation in a semi-arid savanna: Development of a climate–vegetation response model linking plant metabolic performance to climate and the effects on forage availability for large herbivores

    Directory of Open Access Journals (Sweden)

    Armin H. Seydack

    2012-02-01

    Developing the climate–vegetation response model involved three main components, namely (1 defining indicators of forage availability to herbivores (nitrogen productivity, nitrogen quality, carbon-nutrient quality, (2 identifying herbivore species guilds of similar nutritional requirements with respect to these indicators [bulk feeders with tolerance to fibrous herbage (buffalo, waterbuck, bulk feeders with preference for high nitrogen quality forage (short grass preference grazers: blue wildebeest and zebra and selective feeders where dietary items of relatively high carbon-nutrient quality represented key forage resources (selective grazers: sable antelope, roan antelope, tsessebe, eland] and (3 developing a process model where the expected effects of plant metabolic responses to climate on key forage resources were made explicit. According to the climate–vegetation response model both shorter-term transient temperature acclimation pulses and longer-term shifts in plant metabolic functionality settings were predicted to have occurred in response to temperature trends over the past century. These temperature acclimation responses were expected to have resulted in transient pulses of increased forage availability (increased nitrogen- and carbon-nutrient quality, as well as the progressive long-term decline of the carbon-nutrient quality of forage. Conservation implications: The climate–vegetation response model represents a research framework for further studies contributing towards the enhanced understanding of landscape-scale functioning of savanna systems with reference to the interplay between climate, vegetation and herbivore population dynamics. Gains in such understanding can support sound conservation management.

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

    Science.gov (United States)

    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.

  15. An optimization model for metabolic pathways.

    Science.gov (United States)

    Planes, F J; Beasley, J E

    2009-10-15

    Different mathematical methods have emerged in the post-genomic era to determine metabolic pathways. These methods can be divided into stoichiometric methods and path finding methods. In this paper we detail a novel optimization model, based upon integer linear programming, to determine metabolic pathways. Our model links reaction stoichiometry with path finding in a single approach. We test the ability of our model to determine 40 annotated Escherichia coli metabolic pathways. We show that our model is able to determine 36 of these 40 pathways in a computationally effective manner.

  16. Metabolic and adaptive immune responses induced in mice infected ...

    African Journals Online (AJOL)

    This study investigated metabolic and immuno-inflammatory responses of mice infected with tissue-dwelling larvae of Trichinella zimbabwensis and explored the relationship between infection, metabolic parameters and Th1/Th17 immune responses. Sixty (60) female BALB/c mice aged between 6 to 8 weeks old were ...

  17. Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: relation to dysregulated phosphatidylcholine metabolism.

    Science.gov (United States)

    Pan, Huei-Ju; Lin, Yiming; Chen, Yuqing E; Vance, Dennis E; Leiter, Edward H

    2006-07-01

    Given the heterogeneous nature of metabolic dysfunctions associated with insulin resistance and type 2 diabetes (T2D), a single pharmaceutical cannot be expected to provide complication-free therapy in all patients. Thiazolidinediones (TZD) increase insulin sensitivity, reduce blood glucose and improve cardiovascular parameters. However, in addition to increasing fat mass, TZD have the potential in certain individuals to exacerbate underlying hepatosteatosis and diabetic cardiomyopathy. Pharmacogenetics should allow patient selection to maximize therapy and minimize risk. To this end, we have combined two genetically diverse inbred strains, NON/Lt and NZO/Lt, to produce a "negative heterosis" increasing the frequency of T2D in F1 males. As in humans with T2D, treatment of diabetic and hyperlipemic F1 males with rosiglitazone (Rosi), an agonist of peroxisome proliferator-activated gamma receptor (PPARgamma), reverses these disease phenotypes. However, the hybrid genome perturbed both major pathways for phosphatidylcholine (PC) biosynthesis in the liver, and effected remarkable alterations in the composition of cardiolipin in heart mitochondria. These metabolic defects severely exacerbated an underlying hepatosteatosis and increased levels of the adipokine, plasminogen activator inhibitor-1 (PAI-1), a risk factor for cardiovascular events. This model system demonstrates how the power of mouse genetics can be used to identify the metabolic signatures of individuals who may be prone to drug side effects.

  18. 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...

  19. Ensemble Kinetic Modeling of Metabolic Networks from Dynamic Metabolic Profiles

    Directory of Open Access Journals (Sweden)

    Gengjie Jia

    2012-11-01

    Full Text Available Kinetic modeling of metabolic pathways has important applications in metabolic engineering, but significant challenges still remain. The difficulties faced vary from finding best-fit parameters in a highly multidimensional search space to incomplete parameter identifiability. To meet some of these challenges, an ensemble modeling method is developed for characterizing a subset of kinetic parameters that give statistically equivalent goodness-of-fit to time series concentration data. The method is based on the incremental identification approach, where the parameter estimation is done in a step-wise manner. Numerical efficacy is achieved by reducing the dimensionality of parameter space and using efficient random parameter exploration algorithms. The shift toward using model ensembles, instead of the traditional “best-fit” models, is necessary to directly account for model uncertainty during the application of such models. The performance of the ensemble modeling approach has been demonstrated in the modeling of a generic branched pathway and the trehalose pathway in Saccharomyces cerevisiae using generalized mass action (GMA kinetics.

  20. New paradigms for metabolic modeling of human cells

    DEFF Research Database (Denmark)

    Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally......, challenges in integration of cell/tissue models for simulation of whole body functions as well as integration of GEMs with other biological networks for generating complete cell/tissue models are presented.......Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we...

  1. Manipulation of the metabolic response in clinical practice

    DEFF Research Database (Denmark)

    Kehlet, H

    2000-01-01

    morbidity. Effective afferent neural blockade with continuous epidural local anesthetic techniques inhibits a major part of the endocrine metabolic response, leading to improved protein economy but without important effects on inflammatory or immunologic responses. In contrast, pain treatment with other...... modalities such as nonsteroidal antiinflammatory drugs (NSAIDs) and opioids has only a small inhibitory effect on endocrine metabolic responses. Preoperative high-dose glucocorticoid therapy provides additional pain relief and improves pulmonary function, but it reduces the inflammatory response (acute......-phase proteins, cytokines, hyperthermia) and immune function. Minimally invasive surgery leaves the endocrine metabolic responses largely unaltered but reduces the inflammatory response and immune suppression. Thus several techniques are available to modify the stress responses in elective surgery patients...

  2. Metabolic response to exogenous ethanol in yeast

    Indian Academy of Sciences (India)

    In this study, we applied this approach to evaluate the effects of increasing concentration of exogenous ethanol on the Saccharomyces cerevisiae fermentative metabolism. We show that the STOCSY analysis correctly identifies the different types of correlations among the enriched metabolites involved in the fermentation, ...

  3. The metabolic responses to aerial diffusion of essential oils.

    Directory of Open Access Journals (Sweden)

    Yani Wu

    Full Text Available Anxiety disorders are the most prevalent psychiatric disorders and affect a great number of people worldwide. Essential oils, take effects through inhalation or topical application, are believed to enhance physical, emotional, and spiritual well-being. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of essential oils in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive gas chromatography time-of-flight mass spectrometry (GC-TOFMS based metabonomics study that reveals the aromas-induced metabolic changes and the anxiolytic effect of aromas in elevated plus maze (EPM induced anxiety model rats. The significant alteration of metabolites in the EPM group was attenuated by aromas treatment, concurrent with the behavioral improvement with significantly increased open arms time and open arms entries. Brain tissue and urinary metabonomic analysis identified a number of altered metabolites in response to aromas intervention. These metabolic changes included the increased carbohydrates and lowered levels of neurotransmitters (tryptophan, serine, glycine, aspartate, tyrosine, cysteine, phenylalanine, hypotaurine, histidine, and asparagine, amino acids, and fatty acids in the brain. Elevated aspartate, carbohydrates (sucrose, maltose, fructose, and glucose, nucleosides and organic acids such as lactate and pyruvate were also observed in the urine. The EPM induced metabolic differences observed in urine or brain tissue was significantly reduced after 10 days of aroma inhalation, as noted with the loss of statistical significance on many of the metabolites in the aroma-EPM group. This study demonstrates, for the first time, that the metabonomics approach can capture the subtle metabolic changes resulting from exposure to essential oils

  4. 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.

  5. Rodent Models for Metabolic Syndrome Research

    Directory of Open Access Journals (Sweden)

    Sunil K. Panchal

    2011-01-01

    Full Text Available Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent.

  6. Possible stimuli for strength and power adaptation : acute metabolic responses.

    Science.gov (United States)

    Crewther, Blair; Cronin, John; Keogh, Justin

    2006-01-01

    The metabolic response to resistance exercise, in particular lactic acid or lactate, has a marked influence upon the muscular environment, which may enhance the training stimulus (e.g. motor unit activation, hormones or muscle damage) and thereby contribute to strength and power adaptation. Hypertrophy schemes have resulted in greater lactate responses (%) than neuronal and dynamic power schemes, suggesting possible metabolic-mediated changes in muscle growth. Factors such as age, sex, training experience and nutrition may also influence the lactate responses to resistance exercise and thereafter, muscular adaptation. Although the importance of the mechanical and hormonal stimulus to strength and power adaptation is well recognised, the contribution of the metabolic stimulus is largely unknown. Relatively few studies for example, have examined metabolic change across neuronal and dynamic power schemes, and not withstanding the fact that those mechanisms underpinning muscular adaptation, in relation to the metabolic stimulus, remain highly speculative. Inconsistent findings and methodological limitations within research (e.g. programme design, sampling period, number of samples) make interpretation further difficult. We contend that strength and power research needs to investigate those metabolic mechanisms likely to contribute to weight-training adaptation. Further research is also needed to examine the metabolic responses to different loading schemes, as well as interactions across age, sex and training status, so our understanding of how to optimise strength and power development is improved.

  7. A strong response to selection on mass-independent maximal metabolic rate without a correlated response in basal metabolic rate

    DEFF Research Database (Denmark)

    Wone, B W M; Madsen, Per; Donovan, E R

    2015-01-01

    Metabolic rates are correlated with many aspects of ecology, but how selection on different aspects of metabolic rates affects their mutual evolution is poorly understood. Using laboratory mice, we artificially selected for high maximal mass-independent metabolic rate (MMR) without direct selection...... on mass-independent basal metabolic rate (BMR). Then we tested for responses to selection in MMR and correlated responses to selection in BMR. In other lines, we antagonistically selected for mice with a combination of high mass-independent MMR and low mass-independent BMR. All selection protocols...... and data analyses included body mass as a covariate, so effects of selection on the metabolic rates are mass adjusted (that is, independent of effects of body mass). The selection lasted eight generations. Compared with controls, MMR was significantly higher (11.2%) in lines selected for increased MMR...

  8. Metabolic responses of Haliotis diversicolor to Vibrio parahaemolyticus infection.

    Science.gov (United States)

    Lu, Jie; Shi, Yanyan; Cai, Shuhui; Feng, Jianghua

    2017-01-01

    Vibrio parahemolyticus is a devastating bacterial pathogen that often causes outbreak of vibriosis in abalone Haliotis diversicolor. Elucidation of metabolic mechanisms of abalones in responding to V. parahemolyticus infection is essential for controlling the epidemic. In this work, 1 H NMR-based metabolomic techniques along with correlation and network analyses are used to investigate characteristic metabolites, as well as corresponding disturbed pathways in hepatopancreas and gill of H. diversicolor after V. parahemolyticus infection for 48 h. Results indicate that obvious gender- and tissue-specific metabolic responses are induced. Metabolic responses in female abalones are more clearly observed than those in males, which are primarily manifested in the accumulation of branched-chain amino acids and the depletion of organic osmolytes (homarine, betaine and taurine) in the infected gills of female abalones, as well as in the depletion of glutamate, branched-chain and aromatic amino acids in the infected hepatopancreases of female abalones. Moreover, based on major metabolic functions of the characteristic metabolites, we have found that V. parahemolyticus infection not only cause the disturbance in energy metabolism, nucleotide metabolism and osmotic balance, but also induce oxidative stress, immune stress and neurotoxic effect in different tissues with various mechanisms. Our study provides details of metabolic responses of abalones to V. parahemolyticus infection and will shed light on biochemical defence mechanisms of male and female hosts against pathogen infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Discriminating response groups in metabolic and regulatory pathway networks.

    Science.gov (United States)

    Van Hemert, John L; Dickerson, Julie A

    2012-04-01

    Analysis of omics experiments generates lists of entities (genes, metabolites, etc.) selected based on specific behavior, such as changes in response to stress or other signals. Functional interpretation of these lists often uses category enrichment tests using functional annotations like Gene Ontology terms and pathway membership. This approach does not consider the connected structure of biochemical pathways or the causal directionality of events. The Omics Response Group (ORG) method, described in this work, interprets omics lists in the context of metabolic pathway and regulatory networks using a statistical model for flow within the networks. Statistical results for all response groups are visualized in a novel Pathway Flow plot. The statistical tests are based on the Erlang distribution model under the assumption of independent and identically Exponential-distributed random walk flows through pathways. As a proof of concept, we applied our method to an Escherichia coli transcriptomics dataset where we confirmed common knowledge of the E.coli transcriptional response to Lipid A deprivation. The main response is related to osmotic stress, and we were also able to detect novel responses that are supported by the literature. We also applied our method to an Arabidopsis thaliana expression dataset from an abscisic acid study. In both cases, conventional pathway enrichment tests detected nothing, while our approach discovered biological processes beyond the original studies. We created a prototype for an interactive ORG web tool at http://ecoserver.vrac.iastate.edu/pathwayflow (source code is available from https://subversion.vrac.iastate.edu/Subversion/jlv/public/jlv/pathwayflow). The prototype is described along with additional figures and tables in Supplementary Material. julied@iastate.edu Supplementary data are available at Bioinformatics online.

  10. Metabolic engineering tools in model cyanobacteria.

    Science.gov (United States)

    Carroll, Austin L; Case, Anna E; Zhang, Angela; Atsumi, Shota

    2018-03-26

    Developing sustainable routes for producing chemicals and fuels is one of the most important challenges in metabolic engineering. Photoautotrophic hosts are particularly attractive because of their potential to utilize light as an energy source and CO 2 as a carbon substrate through photosynthesis. Cyanobacteria are unicellular organisms capable of photosynthesis and CO 2 fixation. While engineering in heterotrophs, such as Escherichia coli, has result in a plethora of tools for strain development and hosts capable of producing valuable chemicals efficiently, these techniques are not always directly transferable to cyanobacteria. However, recent efforts have led to an increase in the scope and scale of chemicals that cyanobacteria can produce. Adaptations of important metabolic engineering tools have also been optimized to function in photoautotrophic hosts, which include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9, 13 C Metabolic Flux Analysis (MFA), and Genome-Scale Modeling (GSM). This review explores innovations in cyanobacterial metabolic engineering, and highlights how photoautotrophic metabolism has shaped their development. Copyright © 2018 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

  11. Metabolic response to surgery in the cancer patient

    International Nuclear Information System (INIS)

    Brennan, M.F.

    1979-01-01

    The metabolic response to uncomplicated surgery in the patient undergoing primary therapy for malignancy is no different than the response to surgery of similar magnitude for benign disease. Hemodynamic, nutritional-endocrine, and convalescent changes are similar. However, with current aggressive approaches to the management of cancer, the patient often comes to surgery with evidence of major debilitating side effects from his progressive malignancy or from aggressive multimodality therapy. The surgeon must be aware of the consequences of the use of combination therapies on the expected metabolic response to surgery. Awareness of such problems such as the nutritional deficit will allow preventive methods to supercede mtabolic salvage procedures

  12. Neuro-fuzzy model of homocysteine metabolism

    Indian Academy of Sciences (India)

    In view of well-documented association of hyperhomocysteinaemia with a wide spectrum of diseases and higher incidence of vitamin deficiencies in Indians, we proposed a mathematical model to forecast the role of demographic and geneticvariables in influencing homocysteine metabolism and investigated the influence ...

  13. 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.

  14. Metabolic Response to Four Weeks of Muscular Endurance Resistance Training

    Directory of Open Access Journals (Sweden)

    John W. Farrell III

    2017-10-01

    Full Text Available Background: Previous investigations have shown that muscular endurance resistance training (MERT is conducive in improving the onset of blood lactate accumulation (OBLA. However, the metabolic response and time course for adaption is still unclear. Objective: The aims of the current study were to evaluate and track the metabolic response to an individual session of MERT as well as to assess performance adaptations of supplementing an aerobic exercise training program with four weeks of MERT. Methods: Seventeen aerobically active men were randomly assigned to either the experimental (EX or control group (CON, 9 EX and 8 CON. Baseline measures included a graded exercise test (GXT and 1-repetition maximum (1RM testing for leg press (LP, leg curl (LC, and leg extension (LE. CON continued their regular aerobic activity while the EX supplemented their regular aerobic exercise with 4 weeks of MERT. Results: No significant group differences were observed for all pre-training variables. Following four weeks of training no significant differences in cardiorespiratory or metabolic variables were observed for either group. However, significant improvements in LC and LE 1-RM were observed in EX compared to CON. Substantial accumulations in blood lactate were observed following each MERT session. Conclusion: Four weeks of MERT did not improve cardiorespiratory or metabolic variables, but did significantly improve LC and LE. MERT was also observed to induce a blood lactate response similar to that of HIIT. These findings suggest greater than four weeks is need to see metabolic adaptations conducive for improved aerobic performance using MERT.

  15. Metabolic development of the porcine placenta in response to alterations in maternal or fetal homeostasis

    International Nuclear Information System (INIS)

    Namsey, T.G.; kasser, T.R.; Hausman, G.J.; Martin, R.J.

    1986-01-01

    Porcine placenta has been utilized as a model for elucidating contributions of both fetal and maternal tissues to metabolic activity of the placenta in response to a variety of stresses. Alloxan diabetes, food restriction and genetic obesity all produced alterations in placental metablolism with differences in responses of fetal and maternal placentas. Further analysis of nutrient untilization by the placenta produced dramatic differences in the partitioning of substrates by fetal and maternal tissues during placental development. Metabolic activity of maternal tissue contributed to overall placental metabolic activity to a greater degree than fetal tissue. However, experiments with in utero fetal decapitation indicated that some of differences between fetal and maternal placental metabolic activity may be due to the influence of fetal regulatory mechanisms. Maternal endometrium plays a critical role in metabolic response of uteroplacenta and thus availability of nutrients to the fetus and fetal placenta. Differences in metabolic development of fetal and maternal tissues suggested that regulation of placental metabolism may originate from fetal as well as maternal sources

  16. Structural and metabolic responses of Ceratophyllum demersum to ...

    African Journals Online (AJOL)

    Eutrophication in water bodies affects the growth of aquatic plants. In this study, we conducted static experiments to better understand the structural and metabolic responses of Ceratophyllum demersum under eutrophication conditions. The anatomical structure, nitrogen (N) and phosphorous (P) levels in tissue, ...

  17. Long-term salt stress responsive growth, carbohydrate metabolism ...

    African Journals Online (AJOL)

    We investigated the long-term responses of tobacco tissues to salt stress, with a particular interest for growth parameters, proline (Pro) accumulation, and carbohydrate metabolism. Exposure of 17-day-old tobacco plants to 0.2 M NaCl was followed by a higher decrease in dry matter in roots than shoots with a decrease of ...

  18. [Dissociation of antihypertensive and metabolic response to losartan and spironolactone in experimental rats with metabolic sindrome].

    Science.gov (United States)

    Machado, Hussen; Pinheiro, Helady Sanders; Terra, Marcella Martins; Guerra, Martha de Oliveira; de Paula, Rogerio Baumgratz; Peters, Vera Maria

    2012-01-01

    The treatment of arterial hypertension (AH) in patients with metabolic syndrome (MS) is a challenge, since non drug therapies are difficult to implement and optimal pharmacological treatment is not fully established. To assess the blockade of the rennin angiotensin aldosterone system (RAAS) in blood pressure (BP) in renal function and morphology in an experimental model of MS induced by high fat diet. Wistar rats were fed on high fat diet from the fourth week of life, for 20 weeks. The groups received Losartan or Spironolactone from the eighth week of life. We weekly evaluated the body weight and BP by tail plethysmography. At the end of the experiment oral glucose tolerance, lipid profile, creatinine clearance tests, and the direct measurement of BP were performed. A morphometric kidney analysis was performed. The administration of high-fat diet was associated with the development of MS, characterized by central fat accumulation, hypertension, hyperglycemia and hypertriglyceridemia. In this model there were no changes in renal histomorphometry. The blockade of angiotensin II (Ang II) receptor AT1 prevented the development of hypertension. The mineralocorticoid blockage did not have antihypertensive efficacy but was associated with reduction of abdominal fat. The dissociation of the antihypertensive response to the blockades of Ang II receptors and mineralocorticoid indicates the involvement of Ang II in the pathogenesis of hypertension associated with obesity. Reduction of central obesity with Spironolactone suggests the presence of mineralocorticoid adipogenic effect.

  19. Dynamic Metabolic Model Building Based on the Ensemble Modeling Approach

    Energy Technology Data Exchange (ETDEWEB)

    Liao, James C. [Univ. of California, Los Angeles, CA (United States)

    2016-10-01

    Ensemble modeling of kinetic systems addresses the challenges of kinetic model construction, with respect to parameter value selection, and still allows for the rich insights possible from kinetic models. This project aimed to show that constructing, implementing, and analyzing such models is a useful tool for the metabolic engineering toolkit, and that they can result in actionable insights from models. Key concepts are developed and deliverable publications and results are presented.

  20. The human hepatocyte cell lines IHH and HepaRG : models to study glucose, lipid and lipoprotein metabolism

    NARCIS (Netherlands)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Helene; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Veronique; Staels, Bart

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological

  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. Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism

    DEFF Research Database (Denmark)

    Olsen, Rikke K J; Cornelius, Nanna; Gregersen, Niels

    2015-01-01

    Mitochondria play a key role in overall cell physiology and health by integrating cellular metabolism with cellular defense and repair mechanisms in response to physiological or environmental changes or stresses. In fact, dysregulation of mitochondrial stress responses and its consequences...... in the form of oxidative stress, has been linked to a wide variety of diseases including inborn errors of metabolism. In this review we will summarize how the functional state of mitochondria -- and especially the concentration of reactive oxygen species (ROS), produced in connection with the respiratory...... chain -- regulates cellular stress responses by redox regulation of nuclear gene networks involved in repair systems to maintain cellular homeostasis and health. Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism...

  3. Diabetogenic action of streptozotocin: relationship of dose to metabolic response

    Science.gov (United States)

    Junod, Alain; Lambert, André E.; Stauffacher, Werner; Renold, Albert E.

    1969-01-01

    The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections. PMID:4241908

  4. Applications of computational modeling in metabolic engineering of yeast

    DEFF Research Database (Denmark)

    Kerkhoven, Eduard J.; Lahtvee, Petri-Jaan; Nielsen, Jens

    2015-01-01

    a preferred flux distribution. These methods point to strategies for altering gene expression; however, fluxes are often controlled by post-transcriptional events. Moreover, GEMs are usually not taking into account metabolic regulation, thermodynamics and enzyme kinetics. To facilitate metabolic engineering......, it is necessary to expand the modeling of metabolism to consider kinetics of individual processes. This review will give an overview about models available for metabolic engineering of yeast and discusses their applications....

  5. Metabolic Response of Maize Roots to Hyperosmotic Shock 1

    Science.gov (United States)

    Spickett, Corinne M.; Smirnoff, Nicholas; Ratcliffe, R. George

    1992-01-01

    31P nuclear magnetic resonance spectroscopy was used to study the response of maize (Zea mays L.) root tips to hyperosmotic shock. The aim was to identify changes in metabolism that might be relevant to the perception of low soil water potential and the subsequent adaptation of the tissue to these conditions. Osmotic shock was found to result in two different types of response: changes in metabolite levels and changes in intracellular pH. The most notable metabolic changes, which were produced by all the osmotica tested, were increases in phosphocholine and vacuolar phosphate, with a transient increase in cytoplasmic phosphate. It was observed that treatment with ionic and nonionic osmotica produced different effects on the concentrations of bioenergetically important metabolites. It is postulated that these changes are the result of hydrolysis of phosphatidylcholine and other membrane phospholipids, due to differential activation of specific membrane-associated phospholipases by changes in the surface tension of the plasmalemma. These events may be important in the detection of osmotic shock and subsequent acclimatization. A cytoplasmic alkalinization was also observed during hyperosmotic treatment, and this response, which is consistent with the activation of the plasmalemma H+-ATPase, together with the other metabolic changes, may suggest the existence of a complex and integrated mechanism of osmoregulation. PMID:16669012

  6. AMPK regulates metabolism and survival in response to ionizing radiation

    International Nuclear Information System (INIS)

    Zannella, Vanessa E.; Cojocari, Dan; Hilgendorf, Susan; Vellanki, Ravi N.; Chung, Stephen; Wouters, Bradly G.; Koritzinsky, Marianne

    2011-01-01

    Background and purpose: AMPK is a metabolic sensor and an upstream inhibitor of mTOR activity. AMPK is phosphorylated by ionizing radiation (IR) in an ATM dependent manner, but the cellular consequences of this phosphorylation event have remained unclear. The objective of this study was to assess whether AMPK plays a functional role in regulating cellular responses to IR. Methods: The importance of AMPK expression for radiation responses was investigated using both MEFs (mouse embryo fibroblasts) double knockout for AMPK α1/α2 subunits and human colorectal carcinoma cells (HCT 116) with AMPK α1/α2 shRNA mediated knockdown. Results: We demonstrate here that IR results in phosphorylation of both AMPK and its substrate, ACC. IR moderately stimulated mTOR activity, and this was substantially exacerbated in the absence of AMPK. AMPK was required for IR induced expression of the mTOR inhibitor REDD1, indicating that AMPK restrains mTOR activity through multiple mechanisms. Likewise, cellular metabolism was deregulated following irradiation in the absence of AMPK, as evidenced by a substantial increase in oxygen consumption rates and lactate production. AMPK deficient cells showed impairment of the G1/S cell cycle checkpoint, and were unable to support long-term proliferation during starvation following radiation. Lastly, we show that AMPK proficiency is important for clonogenic survival after radiation during starvation. Conclusions: These data reveal novel functional roles for AMPK in regulating mTOR signaling, cell cycle, survival and metabolic responses to IR.

  7. Do diabetes and obesity affect the metabolic response to exercise?

    Science.gov (United States)

    Plomgaard, Peter; Weigert, Cora

    2017-07-01

    Exercise is recommended as therapeutic intervention for people at risk to develop type 2 diabetes to prevent or treat the disease. Recent studies on the influence of obesity and type 2 diabetes on the outcome of exercise programs are discussed. Poor glycemic control before an intervention can be a risk factor of reduced therapeutic benefit from exercise. But the acute metabolic response to exercise and the transcriptional profile of the working muscle is similar in healthy controls and type 2 diabetic patients, including but not limited to intact activation of skeletal muscle AMP-activated kinase signaling, glucose uptake and expression of peroxisome proliferator-activated receptor gamma coactivator 1α. The increase in plasma acylcarnitines during exercise is not influenced by type 2 diabetes or obesity. The hepatic response to exercise is dependent on the glucagon/insulin ratio and the exercise-induced increase in hepatokines such as fibroblast growth factor 21 and follistatin is impaired in type 2 diabetes and obesity, but consequences for the benefit from exercise are unknown yet. Severe metabolic dysregulation can reduce the benefit from exercise, but the intact response of key metabolic regulators in exercising skeletal muscle of diabetic patients demonstrates the effectiveness of exercise programs to treat the disease.

  8. Quantal Response: Nonparametric Modeling

    Science.gov (United States)

    2017-01-01

    capture the behavior of observed phenomena. Higher-order polynomial and finite-dimensional spline basis models allow for more complicated responses as the...flexibility as these are nonparametric (not constrained to any particular functional form). These should be useful in identifying nonstandard behavior via... deviance ∆ = −2 log(Lreduced/Lfull) is defined in terms of the likelihood function L. For normal error, Lfull = 1, and based on Eq. A-2, we have log

  9. Deciphering hepatocellular responses to metabolic and oncogenic stress

    Directory of Open Access Journals (Sweden)

    Kathrina L. Marcelo

    2015-08-01

    Full Text Available Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MΦ, and sinusoidal endothelial cells (SEC play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD or diethylnitrosamine (DEN, a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MΦ and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MΦ and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular “fingerprints” for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer.

  10. Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

    Directory of Open Access Journals (Sweden)

    Shashi Kant

    2013-08-01

    Full Text Available Saturated free fatty acid (FFA is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK pathway that activates cJun NH2-terminal kinase (JNK. Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to the metabolic effects of MLK deficiency. These data confirm that the MLK pathway plays a critical role in the metabolic response to obesity.

  11. Energetics of glucose metabolism: a phenomenological approach to metabolic network modeling.

    Science.gov (United States)

    Diederichs, Frank

    2010-08-12

    A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases of these new equations. For metabolic network modeling, variable conductances and driving forces are required to enable pathway control and to allow a rapid response to perturbations. When applied to oxidative phosphorylation, results of simulations show that whole oxidative phosphorylation cannot be described as a two-flux-system according to nonequilibrium thermodynamics, although all coupled reactions per se fulfill the equations of this theory. Simulations show that activation of ATP-coupled load reactions plus glucose oxidation is brought about by an increase of only two different conductances: a [Ca(2+)] dependent increase of cytosolic load conductances, and an increase of phosphofructokinase conductance by [AMP], which in turn becomes increased through [ADP] generation by those load reactions. In ventricular myocytes, this feedback mechanism is sufficient to increase cellular power output and O(2) consumption several fold, without any appreciable impairment of energetic parameters. Glucose oxidation proceeds near maximal power output, since transformed input and output conductances are nearly equal, yielding an efficiency of about 0.5. This conductance matching is fulfilled also by glucose oxidation of β-cells. But, as a price for the metabolic mechanism of glucose recognition, β-cells have only a limited capability to increase their power output.

  12. Genetic dissection in a mouse model reveals interactions between carotenoids and lipid metabolism[S

    Science.gov (United States)

    Palczewski, Grzegorz; Widjaja-Adhi, M. Airanthi K.; Amengual, Jaume; Golczak, Marcin; von Lintig, Johannes

    2016-01-01

    Carotenoids affect a rich variety of physiological functions in nature and are beneficial for human health. However, knowledge about their biological action and the consequences of their dietary accumulation in mammals is limited. Progress in this research field is limited by the expeditious metabolism of carotenoids in rodents and the confounding production of apocarotenoid signaling molecules. Herein, we established a mouse model lacking the enzymes responsible for carotenoid catabolism and apocarotenoid production, fed on either a β-carotene- or a zeaxanthin-enriched diet. Applying a genome wide microarray analysis, we assessed the effects of the parent carotenoids on the liver transcriptome. Our analysis documented changes in pathways for liver lipid metabolism and mitochondrial respiration. We biochemically defined these effects, and observed that β-carotene accumulation resulted in an elevation of liver triglycerides and liver cholesterol, while zeaxanthin accumulation increased serum cholesterol levels. We further show that carotenoids were predominantly transported within HDL particles in the serum of mice. Finally, we provide evidence that carotenoid accumulation influenced whole-body respiration and energy expenditure. Thus, we observed that accumulation of parent carotenoids interacts with lipid metabolism and that structurally related carotenoids display distinct biological functions in mammals. PMID:27389691

  13. 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.

  14. Metabolic imaging of tumor for diagnosis and response for therapy

    Science.gov (United States)

    Zagaynova, Elena; Shirmanova, Marina; Lukina, Maria; Dudenkova, Varvara; Ignatova, Nadezgda; Elagin, Vadim; Shlivko, Irena; Scheslavsky, Vladislav; Orlinskay, Natalia

    2018-02-01

    Nonlinear optical microscopy combined with fluorescence lifetime imaging is a non-invasive imaging technique, based on the study of fluorescence decay times of naturally occurring fluorescent molecules, enabling a noninvasive investigation of the biological tissue with subcellular resolution. Cancer exhibits altered cellular metabolism, which affects the autofluorescence of metabolic cofactors NAD(P)H and FAD. In this study features of tumor metabolism in different systems of organization (from cell culture to patient lesion) was showed. The observed differences in the relative contributions of free NAD(P)H and FAD testify to an increased a glycolytic metabolism in cancer cells compare to fibroblasts. In 3D spheroids, the cells of the proliferating zone had greater a1 and lower tm values than the cells of the quiescent zone, which likely is a consequence of their higher glycolytic rate. During the growth of colorectal cancer in the experimental mouse model, the contribution of the free component of NAD(P)H was increased. Dysplastic nevus and melanoma is characterized by raised contribution of free NADH compare to healthy skin. Therefore, melanoma cells had very short value of τ1.

  15. Genetic response to metabolic fluctuations: correlation between central carbon metabolism and DNA replication in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Szalewska-Pałasz Agnieszka

    2011-03-01

    Full Text Available Abstract Background Until now, the direct link between central carbon metabolism and DNA replication has been demonstrated only in Bacillus. subtilis. Therefore, we asked if this is a specific phenomenon, characteristic for this bacterium and perhaps for its close relatives, or a more general biological rule. Results We found that temperature-sensitivity of mutants in particular genes coding for replication proteins could be suppressed by deletions of certain genes coding for enzymes of the central carbon metabolism. Namely, the effects of dnaA46(ts mutation could be suppressed by dysfunction of pta or ackA, effects of dnaB(ts by dysfunction of pgi or pta, effects of dnaE486(ts by dysfunction of tktB, effects of dnaG(ts by dysfunction of gpmA, pta or ackA, and effects of dnaN159(ts by dysfunction of pta or ackA. The observed suppression effects were not caused by a decrease in bacterial growth rate. Conclusions The genetic correlation exists between central carbon metabolism and DNA replication in the model Gram-negative bacterium, E. coli. This link exists at the steps of initiation and elongation of DNA replication, indicating the important global correlation between metabolic status of the cell and the events leading to cell reproduction.

  16. Effect of radiographic contrast agents on leukocyte metabolic response

    Energy Technology Data Exchange (ETDEWEB)

    Hernanz-Schulman, M. [Dept. of Pediatric Radiology, Vanderbilt Children' s Hospital, Nashville, TN (United States); Vanholder, R.; Waterloos, M.A. [Dept. of Internal Medicine, Nephrology Section, University Hospital, Gent (Belgium); Hakim, R.; Schulman, G. [Department of Nephrology, Vanderbilt University Medical Center, Nashville, TN (United States)

    2000-06-01

    Barium, at clinical dilutions, causes a significant increase of baseline ''resting state'' phagocytic activity, which in turn leads to significant blunting of subsequent response to phagocytic challenge and adversely affects the response to all bacteria tested. There is no baseline activation of leukocytes by the water-soluble media, although there was some inhibition (rather than activation) of leukocyte metabolic activity. The effect of the water-soluble media in bacteria was more complex (although inhibition is minor compared to barium). Our data demonstrate that barium is a significat activator of phagocytic cells, which results in deactivation of phagocytic response when challenged; these dsata serve to explain the enhanced adverse effect of barium in cased of fecal peritonitis. (orig.)

  17. Effect of radiographic contrast agents on leukocyte metabolic response

    International Nuclear Information System (INIS)

    Hernanz-Schulman, M.; Vanholder, R.; Waterloos, M.A.; Hakim, R.; Schulman, G.

    2000-01-01

    Barium, at clinical dilutions, causes a significant increase of baseline ''resting state'' phagocytic activity, which in turn leads to significant blunting of subsequent response to phagocytic challenge and adversely affects the response to all bacteria tested. There is no baseline activation of leukocytes by the water-soluble media, although there was some inhibition (rather than activation) of leukocyte metabolic activity. The effect of the water-soluble media in bacteria was more complex (although inhibition is minor compared to barium). Our data demonstrate that barium is a significant activator of phagocytic cells, which results in deactivation of phagocytic response when challenged; these data serve to explain the enhanced adverse effect of barium in cased of fecal peritonitis. (orig.)

  18. Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

    Science.gov (United States)

    Martin-Lorenzo, Marta; Martinez, Paula J; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Prado, Jose Carlos; Segura, Julian; de la Cuesta, Fernando; Barderas, Maria G; Vivanco, Fernando; Ruilope, Luis Miguel; Alvarez-Llamas, Gloria

    2017-11-01

    Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered ( P citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. © 2017 American Heart Association, Inc.

  19. The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism

    DEFF Research Database (Denmark)

    Birkel, Garrett W.; Ghosh, Amit; Kumar, Vinay S.

    2017-01-01

    analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed.Results: The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes......, it introduces the capability to use C-13 labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale C-13 Metabolic Flux Analysis (2S-C-13 MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable...... insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs.Conclusions: jQMM will facilitate the design...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. Improving Bioenergy Crops through Dynamic Metabolic Modeling

    Directory of Open Access Journals (Sweden)

    Mojdeh Faraji

    2017-10-01

    Full Text Available Enormous advances in genetics and metabolic engineering have made it possible, in principle, to create new plants and crops with improved yield through targeted molecular alterations. However, while the potential is beyond doubt, the actual implementation of envisioned new strains is often difficult, due to the diverse and complex nature of plants. Indeed, the intrinsic complexity of plants makes intuitive predictions difficult and often unreliable. The hope for overcoming this challenge is that methods of data mining and computational systems biology may become powerful enough that they could serve as beneficial tools for guiding future experimentation. In the first part of this article, we review the complexities of plants, as well as some of the mathematical and computational methods that have been used in the recent past to deepen our understanding of crops and their potential yield improvements. In the second part, we present a specific case study that indicates how robust models may be employed for crop improvements. This case study focuses on the biosynthesis of lignin in switchgrass (Panicum virgatum. Switchgrass is considered one of the most promising candidates for the second generation of bioenergy production, which does not use edible plant parts. Lignin is important in this context, because it impedes the use of cellulose in such inedible plant materials. The dynamic model offers a platform for investigating the pathway behavior in transgenic lines. In particular, it allows predictions of lignin content and composition in numerous genetic perturbation scenarios.

  2. Liposoluble vitamins in Crustacean feed: Metabolic and Histological responses.

    Science.gov (United States)

    Fernández-Gimenez, Analía Verónica

    2016-05-01

    Vitamins are vital for normal growth and survival of living organisms and they are distributed in feedstuffs in small quantities. This review is focused on the liposoluble vitamins (A, D, E and K) in the diets and metabolic responses of the Argentine penaeoid shrimps Pleoticus muelleri and Artemesia longinaris, distributed along the South American coast line. Growth, survival and histological analyses serve as indicators of the nutritional value derived from vitamin deficiency. Liposoluble vitamins are also related to stress, antioxidant defense and immune response of shrimps. Effective diet for shrimp culture that provide not only macronutrients including protein and lipid but also micronutrients such as vitamins for optimal growth is an ever improving subject. This review may help formulating suitable feeds for shrimps.

  3. Do diabetes and obesity affect the metabolic response to exercise?

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Weigert, Cora

    2017-01-01

    control before an intervention can be a risk factor of reduced therapeutic benefit from exercise. But the acute metabolic response to exercise and the transcriptional profile of the working muscle is similar in healthy controls and type 2 diabetic patients, including but not limited to intact activation...... of skeletal muscle AMP-activated kinase signaling, glucose uptake and expression of peroxisome proliferator-activated receptor gamma coactivator 1α. The increase in plasma acylcarnitines during exercise is not influenced by type 2 diabetes or obesity. The hepatic response to exercise is dependent......PURPOSE OF REVIEW: Exercise is recommended as therapeutic intervention for people at risk to develop type 2 diabetes to prevent or treat the disease. Recent studies on the influence of obesity and type 2 diabetes on the outcome of exercise programs are discussed. RECENT FINDINGS: Poor glycemic...

  4. Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J; Richter, E; Madsbad, S

    1987-01-01

    with autonomic neuropathy (P less than 0.01) but was unchanged in the other groups. Since cardiac output increased to a similar extent in the three groups, the decrease in blood pressure was due to a significantly larger decrease (P less than 0.01) in total peripheral vascular resistance in the patients......Norepinephrine-induced vasoconstriction, which is mediated by alpha-adrenergic receptors, is accentuated in patients with autonomic neuropathy. In contrast, responses mediated by beta-adrenergic receptors, including vasodilatation and metabolic changes, have not been evaluated in these patients....... To study these responses, we administered epinephrine in a graded intravenous infusion (0.5 to 5 micrograms per minute) to seven diabetic patients without neuropathy, seven diabetic patients with autonomic neuropathy, and seven normal subjects. Mean arterial pressure decreased significantly in the patients...

  5. Metabolic response to glatiramer acetate therapy in multiple sclerosis patients

    Directory of Open Access Journals (Sweden)

    Lidia De Riccardis

    2016-12-01

    Full Text Available Glatiramer acetate (GA; Copaxone is a random copolymer of glutamic acid, lysine, alanine, and tyrosine used for the treatment of patients with multiple sclerosis (MS. Its mechanism of action has not been already fully elucidated, but it seems that GA has an immune-modulatory effect and neuro-protective properties. Lymphocyte mitochondrial dysfunction underlines the onset of several autoimmune disorders. In MS first diagnosis patients, CD4+, the main T cell subset involved in the pathogenesis of MS, undergo a metabolic reprogramming that consist in the up-regulation of glycolysis and in the down-regulation of oxidative phosphorylation. Currently, no works exist about CD4+ T cell metabolism in response to GA treatment. In order to provide novel insight into the potential use of GA in MS treatment, blood samples were collected from 20 healthy controls (HCs and from 20 RR MS patients prior and every 6 months during the 12 months of GA administration. GA treated patients' CD4+ T cells were compared with those from HCs analysing their mitochondrial activity through polarographic and enzymatic methods in association with their antioxidant status, through the analysis of SOD, GPx and CAT activities. Altogether, our findings suggest that GA is able to reduce CD4+ T lymphocytes' dysfunctions by increasing mitochondrial activity and their response to oxidative stress.

  6. Metabolic response to glatiramer acetate therapy in multiple sclerosis patients.

    Science.gov (United States)

    De Riccardis, Lidia; Ferramosca, Alessandra; Danieli, Antonio; Trianni, Giorgio; Zara, Vincenzo; De Robertis, Francesca; Maffia, Michele

    2016-12-01

    Glatiramer acetate (GA; Copaxone) is a random copolymer of glutamic acid, lysine, alanine, and tyrosine used for the treatment of patients with multiple sclerosis (MS). Its mechanism of action has not been already fully elucidated, but it seems that GA has an immune-modulatory effect and neuro-protective properties. Lymphocyte mitochondrial dysfunction underlines the onset of several autoimmune disorders. In MS first diagnosis patients, CD4 + , the main T cell subset involved in the pathogenesis of MS, undergo a metabolic reprogramming that consist in the up-regulation of glycolysis and in the down-regulation of oxidative phosphorylation. Currently, no works exist about CD4 + T cell metabolism in response to GA treatment. In order to provide novel insight into the potential use of GA in MS treatment, blood samples were collected from 20 healthy controls (HCs) and from 20 RR MS patients prior and every 6 months during the 12 months of GA administration. GA treated patients' CD4 + T cells were compared with those from HCs analysing their mitochondrial activity through polarographic and enzymatic methods in association with their antioxidant status, through the analysis of SOD, GPx and CAT activities. Altogether, our findings suggest that GA is able to reduce CD4 + T lymphocytes' dysfunctions by increasing mitochondrial activity and their response to oxidative stress.

  7. Cerebral Metabolic Changes Related to Oxidative Metabolism in a Model of Bacterial Meningitis Induced by Lipopolysaccharide

    DEFF Research Database (Denmark)

    Munk, Michael; Rom Poulsen, Frantz; Larsen, Lykke

    2018-01-01

    BACKGROUND: Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible...... with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis. METHODS: Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral...... dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO2, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed...

  8. Response of melanoma tumor phospholipid metabolism to chloroethyle nitrosourea: a high resolution proton NMR spectroscopy study.

    Science.gov (United States)

    Morvan, Daniel; Demidem, Aïcha; Madelmont, Jean-Claude

    2003-07-01

    Phospholipid metabolism is tightly involved in tumor growth regulation and tumor cell survival. The response of phospholipid metabolism to chloroethyle nitrosourea treatment is investigated in a murine B16 melanoma model. Measurements of phospholipid derivatives are performed on intact tumor tissue samples using one- and two-dimensional proton NMR spectroscopy. During the tumor growth inhibition phase under treatment, tumors overexpress phosphocholine, phosphoethanolamine, glycerophosphocholine and glycerophosphoethanolamine, whereas phosphatidylcholine and phosphatidylethanolamine levels are maintained to control levels. During re-growth, which remained quantitatively much below control growth, chloroethyle nitrosourea-treated melanoma tumors overexpress phosphocholine and phosphoethanolamine only. In treated melanoma, phosphatidylcholine levels show an inverse relationship with tumor growth rates. In conclusion, chloroethyle nitrosourea-treated melanoma tumors maintain their phosphatidylcholine levels and exhibit transformed phospholipid metabolism phenotype, by mechanisms that could participate in tumor cell survival.

  9. Modelling sequentially scored item responses

    NARCIS (Netherlands)

    Akkermans, W.

    2000-01-01

    The sequential model can be used to describe the variable resulting from a sequential scoring process. In this paper two more item response models are investigated with respect to their suitability for sequential scoring: the partial credit model and the graded response model. The investigation is

  10. Next-generation genome-scale models for metabolic engineering

    DEFF Research Database (Denmark)

    King, Zachary A.; Lloyd, Colton J.; Feist, Adam M.

    2015-01-01

    Constraint-based reconstruction and analysis (COBRA) methods have become widely used tools for metabolic engineering in both academic and industrial laboratories. By employing a genome-scale in silico representation of the metabolic network of a host organism, COBRA methods can be used to predict...... examples of applying COBRA methods to strain optimization are presented and discussed. Then, an outlook is provided on the next generation of COBRA models and the new types of predictions they will enable for systems metabolic engineering....

  11. Cell Wall Metabolism in Response to Abiotic Stress

    Science.gov (United States)

    Gall, Hyacinthe Le; Philippe, Florian; Domon, Jean-Marc; Gillet, Françoise; Pelloux, Jérôme; Rayon, Catherine

    2015-01-01

    This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic), transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i) an increased level in xyloglucan endotransglucosylase/hydrolase (XTH) and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii) an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions. PMID:27135320

  12. Sleep fragmentation alters brain energy metabolism without modifying hippocampal electrophysiological response to novelty exposure.

    Science.gov (United States)

    Baud, Maxime O; Parafita, Julia; Nguyen, Audrey; Magistretti, Pierre J; Petit, Jean-Marie

    2016-10-01

    Sleep is viewed as a fundamental restorative function of the brain, but its specific role in neural energy budget remains poorly understood. Sleep deprivation dampens brain energy metabolism and impairs cognitive functions. Intriguingly, sleep fragmentation, despite normal total sleep duration, has a similar cognitive impact, and in this paper we ask the question of whether it may also impair brain energy metabolism. To this end, we used a recently developed mouse model of 2 weeks of sleep fragmentation and measured 2-deoxy-glucose uptake and glycogen, glucose and lactate concentration in different brain regions. In order to homogenize mice behaviour during metabolic measurements, we exposed them to a novel environment for 1 h. Using an intra-hippocampal electrode, we first showed that hippocampal electroencephalograph (EEG) response to exploration was unaltered by 1 or 14 days of sleep fragmentation. However, after 14 days, sleep fragmented mice exhibited a lower uptake of 2-deoxy-glucose in cortex and hippocampus and lower cortical lactate levels than control mice. Our results suggest that long-term sleep fragmentation impaired brain metabolism to a similar extent as total sleep deprivation without affecting the neuronal responsiveness of hippocampus to a novel environment. © 2016 European Sleep Research Society.

  13. Sex differences in metabolic and adipose tissue responses to juvenile-onset obesity in sheep.

    Science.gov (United States)

    Bloor, Ian D; Sébert, Sylvain P; Saroha, Vivek; Gardner, David S; Keisler, Duane H; Budge, Helen; Symonds, Michael E; Mahajan, Ravi P

    2013-10-01

    Sex is a major factor determining adipose tissue distribution and the subsequent adverse effects of obesity-related disease including type 2 diabetes. The role of gender on juvenile obesity and the accompanying metabolic and inflammatory responses is not well established. Using an ovine model of juvenile onset obesity induced by reduced physical activity, we examined the effect of gender on metabolic, circulatory, and related inflammatory and energy-sensing profiles of the major adipose tissue depots. Despite a similar increase in fat mass with obesity between genders, males demonstrated a higher storage capacity of lipids within perirenal-abdominal adipocytes and exhibited raised insulin. In contrast, obese females became hypercortisolemic, a response that was positively correlated with central fat mass. Analysis of gene expression in perirenal-abdominal adipose tissue demonstrated the stimulation of inflammatory markers in males, but not females, with obesity. Obese females displayed increased expression of genes involved in the glucocorticoid axis and energy sensing in perirenal-abdominal, but not omental, adipose tissue, indicating a depot-specific mechanism that may be protective from the adverse effects of metabolic dysfunction and inflammation. In conclusion, young males are at a greater risk than females to the onset of comorbidities associated with juvenile-onset obesity. These sex-specific differences in cortisol and adipose tissue could explain the earlier onset of the metabolic-related diseases in males compared with females after obesity.

  14. Sleep fragmentation alters brain energy metabolism without modifying hippocampal electrophysiological response to novelty exposure

    KAUST Repository

    Baud, Maxime O.

    2016-05-03

    © 2016 European Sleep Research Society. Sleep is viewed as a fundamental restorative function of the brain, but its specific role in neural energy budget remains poorly understood. Sleep deprivation dampens brain energy metabolism and impairs cognitive functions. Intriguingly, sleep fragmentation, despite normal total sleep duration, has a similar cognitive impact, and in this paper we ask the question of whether it may also impair brain energy metabolism. To this end, we used a recently developed mouse model of 2 weeks of sleep fragmentation and measured 2-deoxy-glucose uptake and glycogen, glucose and lactate concentration in different brain regions. In order to homogenize mice behaviour during metabolic measurements, we exposed them to a novel environment for 1 h. Using an intra-hippocampal electrode, we first showed that hippocampal electroencephalograph (EEG) response to exploration was unaltered by 1 or 14 days of sleep fragmentation. However, after 14 days, sleep fragmented mice exhibited a lower uptake of 2-deoxy-glucose in cortex and hippocampus and lower cortical lactate levels than control mice. Our results suggest that long-term sleep fragmentation impaired brain metabolism to a similar extent as total sleep deprivation without affecting the neuronal responsiveness of hippocampus to a novel environment.

  15. In silico method for modelling metabolism and gene product expression at genome scale

    Energy Technology Data Exchange (ETDEWEB)

    Lerman, Joshua A.; Hyduke, Daniel R.; Latif, Haythem; Portnoy, Vasiliy A.; Lewis, Nathan E.; Orth, Jeffrey D.; Rutledge, Alexandra C.; Smith, Richard D.; Adkins, Joshua N.; Zengler, Karsten; Palsson, Bernard O.

    2012-07-03

    Transcription and translation use raw materials and energy generated metabolically to create the macromolecular machinery responsible for all cellular functions, including metabolism. A biochemically accurate model of molecular biology and metabolism will facilitate comprehensive and quantitative computations of an organism's molecular constitution as a function of genetic and environmental parameters. Here we formulate a model of metabolism and macromolecular expression. Prototyping it using the simple microorganism Thermotoga maritima, we show our model accurately simulates variations in cellular composition and gene expression. Moreover, through in silico comparative transcriptomics, the model allows the discovery of new regulons and improving the genome and transcription unit annotations. Our method presents a framework for investigating molecular biology and cellular physiology in silico and may allow quantitative interpretation of multi-omics data sets in the context of an integrated biochemical description of an organism.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  18. Metabolic and Transcriptional Response to Cofactor Perturbations in Escherichia coli

    DEFF Research Database (Denmark)

    Holm, Anders Koefoed; Blank, L.M.; Oldiges, M.

    2010-01-01

    Metabolic cofactors such as NADH and ATP play important roles in a large number of cellular reactions, and it is of great interest to dissect the role of these cofactors in different aspects of metabolism. Toward this goal, we overexpressed NADH oxidase and the soluble F1-ATPase in Escherichia coli...... of redox and energy metabolism and should help in developing metabolic engineering strategies in E. coli....

  19. A systems biology framework for modeling metabolic enzyme inhibition of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Reifman Jaques

    2009-09-01

    Full Text Available Abstract Background Because metabolism is fundamental in sustaining microbial life, drugs that target pathogen-specific metabolic enzymes and pathways can be very effective. In particular, the metabolic challenges faced by intracellular pathogens, such as Mycobacterium tuberculosis, residing in the infected host provide novel opportunities for therapeutic intervention. Results We developed a mathematical framework to simulate the effects on the growth of a pathogen when enzymes in its metabolic pathways are inhibited. Combining detailed models of enzyme kinetics, a complete metabolic network description as modeled by flux balance analysis, and a dynamic cell population growth model, we quantitatively modeled and predicted the dose-response of the 3-nitropropionate inhibitor on the growth of M. tuberculosis in a medium whose carbon source was restricted to fatty acids, and that of the 5'-O-(N-salicylsulfamoyl adenosine inhibitor in a medium with low-iron concentration. Conclusion The predicted results quantitatively reproduced the experimentally measured dose-response curves, ranging over three orders of magnitude in inhibitor concentration. Thus, by allowing for detailed specifications of the underlying enzymatic kinetics, metabolic reactions/constraints, and growth media, our model captured the essential chemical and biological factors that determine the effects of drug inhibition on in vitro growth of M. tuberculosis cells.

  20. Uptake, accumulation and metabolic response of ferricyanide in weeping willows.

    Science.gov (United States)

    Yu, Xiao-Zhang; Gu, Ji-Dong

    2009-01-01

    The remediation potential and metabolic responses of plants to ferricyanide were investigated using pre-rooted weeping willows (Salix babylonica L.) grown hydroponically in growth chambers and treated with potassium ferricyanide. Positive responses were observed for the plants exposed to cyanide recovered in plant biomass was constant in all treatments, indicating that transport is a major limiting step for the uptake of ferricyanide by plants. The majority of the ferricyanide taken up from the growth media was possibly assimilated during transport through plants. The velocity of the removal processes can be described by Michaelis-Menten kinetics, and the half-saturation constant (K(M)) and the maximum removal capacity (v(max)) were estimated to be 228.1 mg CN L(-1) and 36.43 mg CN kg(-1) d(-1), respectively, using non-linear regression methods. These results suggest that weeping willows can take up, transport and assimilate ferricyanide; and phytoremediation is an option for cleaning up the environmental sites contaminated with cyanide complexes.

  1. Neuro-fuzzy model of homocysteine metabolism

    Indian Academy of Sciences (India)

    SHAIK Mohammad Naushad

    2017-12-08

    Dec 8, 2017 ... Homocysteine is a nondietary amino acid, which is the byproduct of ... wide spectrum of diseases such as recurrent pregnancy loss (Govindaiah et al. ... A2756G, MTRR A66G were reported in the folate metabolic pathway ...

  2. Renal responses of trout to chronic respiratory and metabolic acidoses and metabolic alkalosis.

    Science.gov (United States)

    Wood, C M; Milligan, C L; Walsh, P J

    1999-08-01

    Exposure to hyperoxia (500-600 torr) or low pH (4.5) for 72 h or NaHCO(3) infusion for 48 h were used to create chronic respiratory (RA) or metabolic acidosis (MA) or metabolic alkalosis in freshwater rainbow trout. During alkalosis, urine pH increased, and [titratable acidity (TA) - HCO(-)(3)] and net H(+) excretion became negative (net base excretion) with unchanged NH(+)(4) efflux. During RA, urine pH did not change, but net H(+) excretion increased as a result of a modest rise in NH(+)(4) and substantial elevation in [TA - HCO(-)(3)] efflux accompanied by a large increase in inorganic phosphate excretion. However, during MA, urine pH fell, and net H(+) excretion was 3.3-fold greater than during RA, reflecting a similar increase in [TA - HCO(-)(3)] and a smaller elevation in phosphate but a sevenfold greater increase in NH(+)(4) efflux. In urine samples of the same pH, [TA - HCO(-)(3)] was greater during RA (reflecting phosphate secretion), and [NH(+)(4)] was greater during MA (reflecting renal ammoniagenesis). Renal activities of potential ammoniagenic enzymes (phosphate-dependent glutaminase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, alanine aminotransferase, phosphoenolpyruvate carboxykinase) and plasma levels of cortisol, phosphate, ammonia, and most amino acids (including glutamine and alanine) increased during MA but not during RA, when only alanine aminotransferase increased. The differential responses to RA vs. MA parallel those in mammals; in fish they may be keyed to activation of phosphate secretion by RA and cortisol mobilization by MA.

  3. A workflow for mathematical modeling of subcellular metabolic pathways in leaf metabolism of Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Thomas eNägele

    2013-12-01

    Full Text Available During the last decade genome sequencing has experienced a rapid technological development resulting in numerous sequencing projects and applications in life science. In plant molecular biology, the availability of sequence data on whole genomes has enabled the reconstruction of metabolic networks. Enzymatic reactions are predicted by the sequence information. Pathways arise due to the participation of chemical compounds as substrates and products in these reactions. Although several of these comprehensive networks have been reconstructed for the genetic model plant Arabidopsis thaliana, the integration of experimental data is still challenging. Particularly the analysis of subcellular organization of plant cells limits the understanding of regulatory instances in these metabolic networks in vivo. In this study, we develop an approach for the functional integration of experimental high-throughput data into such large-scale networks. We present a subcellular metabolic network model comprising 524 metabolic intermediates and 548 metabolic interactions derived from a total of 2769 reactions. We demonstrate how to link the metabolite covariance matrix of different Arabidopsis thaliana accessions with the subcellular metabolic network model for the inverse calculation of the biochemical Jacobian, finally resulting in the calculation of a matrix which satisfies a Lyaponov equation involving a covariance matrix. In this way, differential strategies of metabolite compartmentation and involved reactions were identified in the accessions when exposed to low temperature.

  4. Acute metabolic decompensation due to influenza in a mouse model of ornithine transcarbamylase deficiency

    Directory of Open Access Journals (Sweden)

    Peter J. McGuire

    2014-02-01

    Full Text Available The urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA. A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza using spf-ash mice, a model of OTC deficiency. Both wild-type (WT and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other

  5. Applications of computational modeling in metabolic engineering of yeast.

    Science.gov (United States)

    Kerkhoven, Eduard J; Lahtvee, Petri-Jaan; Nielsen, Jens

    2015-02-01

    Generally, a microorganism's phenotype can be described by its pattern of metabolic fluxes. Although fluxes cannot be measured directly, inference of fluxes is well established. In biotechnology the aim is often to increase the capacity of specific fluxes. For this, metabolic engineering methods have been developed and applied extensively. Many of these rely on balancing of intracellular metabolites, redox, and energy fluxes, using genome-scale models (GEMs) that in combination with appropriate objective functions and constraints can be used to predict potential gene targets for obtaining a preferred flux distribution. These methods point to strategies for altering gene expression; however, fluxes are often controlled by post-transcriptional events. Moreover, GEMs are usually not taking into account metabolic regulation, thermodynamics and enzyme kinetics. To facilitate metabolic engineering, tools from synthetic biology have emerged, enabling integration and assembly of naturally nonexistent, but well-characterized components into a living organism. To describe these systems kinetic models are often used and to integrate these systems with the standard metabolic engineering approach, it is necessary to expand the modeling of metabolism to consider kinetics of individual processes. This review will give an overview about models available for metabolic engineering of yeast and discusses their applications. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

  6. Constraint based modeling of metabolism allows finding metabolic cancer hallmarks and identifying personalized therapeutic windows.

    Science.gov (United States)

    Bordel, Sergio

    2018-04-13

    In order to choose optimal personalized anticancer treatments, transcriptomic data should be analyzed within the frame of biological networks. The best known human biological network (in terms of the interactions between its different components) is metabolism. Cancer cells have been known to have specific metabolic features for a long time and currently there is a growing interest in characterizing new cancer specific metabolic hallmarks. In this article it is presented a method to find personalized therapeutic windows using RNA-seq data and Genome Scale Metabolic Models. This method is implemented in the python library, pyTARG. Our predictions showed that the most anticancer selective (affecting 27 out of 34 considered cancer cell lines and only 1 out of 6 healthy mesenchymal stem cell lines) single metabolic reactions are those involved in cholesterol biosynthesis. Excluding cholesterol biosynthesis, all the considered cell lines can be selectively affected by targeting different combinations (from 1 to 5 reactions) of only 18 metabolic reactions, which suggests that a small subset of drugs or siRNAs combined in patient specific manners could be at the core of metabolism based personalized treatments.

  7. Concepts, challenges, and successes in modeling thermodynamics of metabolism.

    Science.gov (United States)

    Cannon, William R

    2014-01-01

    The modeling of the chemical reactions involved in metabolism is a daunting task. Ideally, the modeling of metabolism would use kinetic simulations, but these simulations require knowledge of the thousands of rate constants involved in the reactions. The measurement of rate constants is very labor intensive, and hence rate constants for most enzymatic reactions are not available. Consequently, constraint-based flux modeling has been the method of choice because it does not require the use of the rate constants of the law of mass action. However, this convenience also limits the predictive power of constraint-based approaches in that the law of mass action is used only as a constraint, making it difficult to predict metabolite levels or energy requirements of pathways. An alternative to both of these approaches is to model metabolism using simulations of states rather than simulations of reactions, in which the state is defined as the set of all metabolite counts or concentrations. While kinetic simulations model reactions based on the likelihood of the reaction derived from the law of mass action, states are modeled based on likelihood ratios of mass action. Both approaches provide information on the energy requirements of metabolic reactions and pathways. However, modeling states rather than reactions has the advantage that the parameters needed to model states (chemical potentials) are much easier to determine than the parameters needed to model reactions (rate constants). Herein, we discuss recent results, assumptions, and issues in using simulations of state to model metabolism.

  8. Computational fluid dynamics simulation of an industrial P. chrysogenum fermentation with a coupled 9-pool metabolic model : Towards rational scale-down and design optimization

    NARCIS (Netherlands)

    Haringa, C.; Tang, W.; Wang, G.; Deshmukh, A.T.; van Winden, Wouter A.; Chu, Ju; van Gulik, W.M.; Heijnen, J.J.; Mudde, R.F.; Noorman, H.J.

    2018-01-01

    We assess the effect of substrate heterogeneity on the metabolic response of P. chrysogenum in industrial bioreactors via the coupling of a 9-pool metabolic model with Euler-Lagrange CFD simulations. In this work, we outline how this coupled hydrodynamic-metabolic modeling can be utilized in 5

  9. Acute metabolic and physiologic response of goats to narcosis

    Science.gov (United States)

    Schatte, C. L.; Bennett, P. B.

    1973-01-01

    Assessment of the metabolic consequences of exposure to elevated partial pressures of nitrogen and helium under normobaric and hyperbaric conditions in goats. The results include the finding that hyperbaric nitrogen causes and increase in metabolic rate and a general decrease in blood constituent levels which is interpreted as reflecting a shift toward fatty acid metabolism at the expense of carbohydrates. A similar but more pronounced pattern was observed with hyperbaric helium.

  10. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism

    International Nuclear Information System (INIS)

    Ucciferri, Nadia; Sbrana, Tommaso; Ahluwalia, Arti

    2014-01-01

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell–cell or cell–tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  11. Allometric scaling and cell ratios in multi-organ in vitro models of human metabolism

    Directory of Open Access Journals (Sweden)

    Nadia eUcciferri

    2014-12-01

    Full Text Available Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step towards building an integrated picture of systemic metabolism and signalling in physiological or pathological conditions. However the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here we analyse the physiologic relationship between cells, cell metabolism and exchange in the human body using allometric rules, downscaling them to an organ-on-a plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (Cell Number Scaling Model, CNSM, and Metabolic and Surface Scaling model, MSSM are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions which can be extrapolated to the in vivo

  12. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism.

    Science.gov (United States)

    Ucciferri, Nadia; Sbrana, Tommaso; Ahluwalia, Arti

    2014-01-01

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  13. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Ucciferri, Nadia [CNR Institute of Clinical Physiology, Pisa (Italy); Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy); Sbrana, Tommaso [Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy); Ahluwalia, Arti, E-mail: arti.ahluwalia@unipi.it [CNR Institute of Clinical Physiology, Pisa (Italy); Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy)

    2014-12-17

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell–cell or cell–tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  14. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses.

    Science.gov (United States)

    Ou, Yang; Wang, Shang-Jui; Li, Dawei; Chu, Bo; Gu, Wei

    2016-11-01

    Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N 1 -acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.

  15. Metabolic Communication between Astrocytes and Neurons via Bicarbonate-Responsive Soluble Adenylyl Cyclase

    OpenAIRE

    Choi, Hyun B.; Gordon, Grant R.J.; Zhou, Ning; Tai, Chao; Rungta, Ravi L.; Martinez, Jennifer; Milner, Teresa A.; Ryu, Jae K.; McLarnon, James G.; Tresguerres, Martin; Levin, Lonny R.; Buck, Jochen; MacVicar, Brian A.

    2012-01-01

    Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO3−) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response t...

  16. Systematic analysis of rice (Oryza sativa) metabolic responses to herbivory.

    Science.gov (United States)

    Alamgir, Kabir Md; Hojo, Yuko; Christeller, John T; Fukumoto, Kaori; Isshiki, Ryutaro; Shinya, Tomonori; Baldwin, Ian T; Galis, Ivan

    2016-02-01

    Plants defend against attack from herbivores by direct and indirect defence mechanisms mediated by the accumulation of phytoalexins and release of volatile signals, respectively. While the defensive arsenals of some plants, such as tobacco and Arabidopsis are well known, most of rice's (Oryza sativa) defence metabolites and their effectiveness against herbivores remain uncharacterized. Here, we used a non-biassed metabolomics approach to identify many novel herbivory-regulated metabolic signatures in rice. Most were up-regulated by herbivore attack while only a few were suppressed. Two of the most prominent up-regulated signatures were characterized as phenolamides (PAs), p-coumaroylputrescine and feruloylputrescine. PAs accumulated in response to attack by both chewing insects, i.e. feeding of the lawn armyworm (Spodoptera mauritia) and the rice skipper (Parnara guttata) larvae, and the attack of the sucking insect, the brown planthopper (Nilaparvata lugens, BPH). In bioassays, BPH insects feeding on 15% sugar solution containing p-coumaroylputrescine or feruloylputrescine, at concentrations similar to those elicited by heavy BPH attack in rice, had a higher mortality compared to those feeding on sugar diet alone. Our results highlight PAs as a rapidly expanding new group of plant defence metabolites that are elicited by herbivore attack, and deter herbivores in rice and other plants. © 2015 John Wiley & Sons Ltd.

  17. Magnetic resonance metabolic profiling of breast cancer tissue obtained with core needle biopsy for predicting pathologic response to neoadjuvant chemotherapy.

    Directory of Open Access Journals (Sweden)

    Ji Soo Choi

    Full Text Available The purpose of this study was to determine whether metabolic profiling of core needle biopsy (CNB samples using high-resolution magic angle spinning (HR-MAS magnetic resonance spectroscopy (MRS could be used for predicting pathologic response to neoadjuvant chemotherapy (NAC in patients with locally advanced breast cancer. After institutional review board approval and informed consent were obtained, CNB tissue samples were collected from 37 malignant lesions in 37 patients before NAC treatment. The metabolic profiling of CNB samples were performed by HR-MAS MRS. Metabolic profiles were compared according to pathologic response to NAC using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA. Various metabolites including choline-containing compounds were identified and quantified by HR-MAS MRS in all 37 breast cancer tissue samples obtained by CNB. In univariate analysis, the metabolite concentrations and metabolic ratios of CNB samples obtained with HR-MAS MRS were not significantly different between different pathologic response groups. However, there was a trend of lower levels of phosphocholine/creatine ratio and choline-containing metabolite concentrations in the pathologic complete response group compared to the non-pathologic complete response group. In multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles showed visible discrimination between the pathologic response groups. This study showed OPLS-DA multivariate analysis using metabolic profiles of pretreatment CNB samples assessed by HR- MAS MRS may be used to predict pathologic response before NAC, although we did not identify the metabolite showing statistical significance in univariate analysis. Therefore, our preliminary results raise the necessity of further study on HR-MAS MR metabolic profiling of CNB samples for a large number of cancers.

  18. Supplementation of Saccharomyces cerevisiae modulates the metabolic response to lipopolysaccharide challenge in feedlot steers

    Science.gov (United States)

    Live yeast has the potential to serve as an alternative to the use of low-dose supplementation of antibiotics in cattle due to the ability to alter ruminant metabolism; which in turn may influence the immune response. Therefore, the objective of this study was to determine the metabolic response to ...

  19. Acute metabolic response to fasted and postprandial exercise

    Directory of Open Access Journals (Sweden)

    Lima FD

    2015-08-01

    Full Text Available Filipe Dinato de Lima,1,2 Ana Luiza Matias Correia,1 Denilson da Silva Teixeira,2 Domingos Vasco da Silva Neto,2 Ítalo Sávio Gonçalves Fernandes,2 Mário Boratto Xavier Viana,2 Mateus Petitto,2 Rodney Antônio da Silva Sampaio,2 Sandro Nobre Chaves,2 Simone Teixeira Alves,2 Renata Aparecida Elias Dantas,2 Márcio Rabelo Mota2 1University of Brasília, Brasília, DF, Brazil; 2Universitary Center of Brasília (UniCEUB, Brasília, DF, BrazilAbstract: The aim of this study was to analyze the acute metabolic response to exercise in fasting and postprandial. For this, ten individuals were submitted to an incremental treadmill test, with an initial speed of 5 and 1 km/h increments every minute, with no inclination, and a body composition assessment. After this 1st day, all volunteers were submitted to two experimental procedures (fasting and postprandial, with an aerobic exercise performed for 36 minutes at 65% of maximal oxygen consumption. At postprandial procedure, all subjects ingested a breakfast containing 59.3 g of carbohydrate (76.73%, 9.97 g of protein (12.90%, 8.01 g of lipids (10.37%, with a total energy intake of 349.17 kcal. An analysis of plasma concentration of triglycerides, lactate, and glucose was performed in two stages: before and after exercise. The Shapiro–Wilk test was used to verify the normality of the data. For analysis of glucose concentration, plasma lactate, and triglycerides, we used a repeated measures analysis of variance factorial 2×2, with Bonferroni multiple comparison test. The significance level of P<0.05 was adopted. The results indicated a maintenance level of glucose at fasting and a decrease in glucose concentration at postprandial exercise. Both conditions increase plasma lactate. Triglycerides also increased in the two experimental conditions; however, after exercise fasting, the increase was significantly higher than in the postprandial exercise. These data suggest that both exercises could increase

  20. Basal metabolic regulatory responses and rhythmic activity of ...

    African Journals Online (AJOL)

    ... Rattus sp. Low concentrations of kola nut extract stimulated the heart by increasing rate and force of contraction as well as metabolic rate. Higher concentrations reduced rate and amplitude of beat resulting, at still higher concentrations in heart failure. Keywords: Kolanut, extract, basal metabolic rate, mammalian heart ...

  1. Analysis of Neural-BOLD Coupling through Four Models of the Neural Metabolic Demand

    Directory of Open Access Journals (Sweden)

    Christopher W Tyler

    2015-12-01

    Full Text Available The coupling of the neuronal energetics to the blood-oxygen-level-dependent (BOLD response is still incompletely understood. To address this issue, we compared the fits of four plausible models of neurometabolic coupling dynamics to available data for simultaneous recordings of the local field potential (LFP and the local BOLD response recorded from monkey primary visual cortex over a wide range of stimulus durations. The four models of the metabolic demand driving the BOLD response were: direct coupling with the overall LFP; rectified coupling to the LFP; coupling with a slow adaptive component of the implied neural population response; and coupling with the non-adaptive intracellular input signal defined by the stimulus time course. Taking all stimulus durations into account, the results imply that the BOLD response is most closely coupled with metabolic demand derived from the intracellular input waveform, without significant influence from the adaptive transients and nonlinearities exhibited by the LFP waveform.

  2. Global patterns in lake ecosystem responses to warming based on the temperature dependence of metabolism.

    Science.gov (United States)

    Kraemer, Benjamin M; Chandra, Sudeep; Dell, Anthony I; Dix, Margaret; Kuusisto, Esko; Livingstone, David M; Schladow, S Geoffrey; Silow, Eugene; Sitoki, Lewis M; Tamatamah, Rashid; McIntyre, Peter B

    2017-05-01

    Climate warming is expected to have large effects on ecosystems in part due to the temperature dependence of metabolism. The responses of metabolic rates to climate warming may be greatest in the tropics and at low elevations because mean temperatures are warmer there and metabolic rates respond exponentially to temperature (with exponents >1). However, if warming rates are sufficiently fast in higher latitude/elevation lakes, metabolic rate responses to warming may still be greater there even though metabolic rates respond exponentially to temperature. Thus, a wide range of global patterns in the magnitude of metabolic rate responses to warming could emerge depending on global patterns of temperature and warming rates. Here we use the Boltzmann-Arrhenius equation, published estimates of activation energy, and time series of temperature from 271 lakes to estimate long-term (1970-2010) changes in 64 metabolic processes in lakes. The estimated responses of metabolic processes to warming were usually greatest in tropical/low-elevation lakes even though surface temperatures in higher latitude/elevation lakes are warming faster. However, when the thermal sensitivity of a metabolic process is especially weak, higher latitude/elevation lakes had larger responses to warming in parallel with warming rates. Our results show that the sensitivity of a given response to temperature (as described by its activation energy) provides a simple heuristic for predicting whether tropical/low-elevation lakes will have larger or smaller metabolic responses to warming than higher latitude/elevation lakes. Overall, we conclude that the direct metabolic consequences of lake warming are likely to be felt most strongly at low latitudes and low elevations where metabolism-linked ecosystem services may be most affected. © 2016 John Wiley & Sons Ltd.

  3. Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism.

    Directory of Open Access Journals (Sweden)

    Eleanor C Saunders

    2014-01-01

    Full Text Available Leishmania parasites alternate between extracellular promastigote stages in the insect vector and an obligate intracellular amastigote stage that proliferates within the phagolysosomal compartment of macrophages in the mammalian host. Most enzymes involved in Leishmania central carbon metabolism are constitutively expressed and stage-specific changes in energy metabolism remain poorly defined. Using (13C-stable isotope resolved metabolomics and (2H2O labelling, we show that amastigote differentiation is associated with reduction in growth rate and induction of a distinct stringent metabolic state. This state is characterized by a global decrease in the uptake and utilization of glucose and amino acids, a reduced secretion of organic acids and increased fatty acid β-oxidation. Isotopomer analysis showed that catabolism of hexose and fatty acids provide C4 dicarboxylic acids (succinate/malate and acetyl-CoA for the synthesis of glutamate via a compartmentalized mitochondrial tricarboxylic acid (TCA cycle. In vitro cultivated and intracellular amastigotes are acutely sensitive to inhibitors of mitochondrial aconitase and glutamine synthetase, indicating that these anabolic pathways are essential for intracellular growth and virulence. Lesion-derived amastigotes exhibit a similar metabolism to in vitro differentiated amastigotes, indicating that this stringent response is coupled to differentiation signals rather than exogenous nutrient levels. Induction of a stringent metabolic response may facilitate amastigote survival in a nutrient-poor intracellular niche and underlie the increased dependence of this stage on hexose and mitochondrial metabolism.

  4. Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity

    OpenAIRE

    Kant, Shashi; Barrett, Tamera; Vertii, Anastassiia; Noh, Yun Hee; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

    2013-01-01

    Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that l...

  5. Randomized Item Response Theory Models

    NARCIS (Netherlands)

    Fox, Gerardus J.A.

    2005-01-01

    The randomized response (RR) technique is often used to obtain answers on sensitive questions. A new method is developed to measure latent variables using the RR technique because direct questioning leads to biased results. Within the RR technique is the probability of the true response modeled by

  6. Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response

    Directory of Open Access Journals (Sweden)

    Hong Zhong

    2018-01-01

    Full Text Available In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

  7. Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response.

    Science.gov (United States)

    Zhong, Hong; Ma, Minjuan; Liang, Tingming; Guo, Li

    2018-01-01

    In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs) have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

  8. Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response.

    Science.gov (United States)

    Watson, Emma; MacNeil, Lesley T; Arda, H Efsun; Zhu, Lihua Julie; Walhout, Albertha J M

    2013-03-28

    Expression profiles are tailored according to dietary input. However, the networks that control dietary responses remain largely uncharacterized. Here, we combine forward and reverse genetic screens to delineate a network of 184 genes that affect the C. elegans dietary response to Comamonas DA1877 bacteria. We find that perturbation of a mitochondrial network composed of enzymes involved in amino acid metabolism and the TCA cycle affects the dietary response. In humans, mutations in the corresponding genes cause inborn diseases of amino acid metabolism, most of which are treated by dietary intervention. We identify several transcription factors (TFs) that mediate the changes in gene expression upon metabolic network perturbations. Altogether, our findings unveil a transcriptional response system that is poised to sense dietary cues and metabolic imbalances, illustrating extensive communication between metabolic networks in the mitochondria and gene regulatory networks in the nucleus. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Bone metabolism and hand grip strength response to aerobic versus ...

    African Journals Online (AJOL)

    porosis is incomplete and has prompted our interest to identify the type of effective osteogenic exercise. ... between aerobic and resistance exercise training in non-insulin dependent ... paired glucose metabolism on bone health as well as to.

  10. Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

    Science.gov (United States)

    Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

    2010-10-01

    Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

  11. Osteoarthritis and metabolic dysregulation: insights from a preclinical model

    NARCIS (Netherlands)

    Visser, H.M. de

    2018-01-01

    This thesis aims to identify the effect of metabolic factors, inflammatory processes and obesity in the pathophysiology of osteoarthritis (OA), using a high-fat diet and/or traumatic injury in a small animal model. The first part of this thesis describes, the rat Groove model of OA, using a one-time

  12. Dynamic optimal metabolic control theory: a cybernetic approach for modelling of the central nitrogen metabolism of S. cerevisiae

    NARCIS (Netherlands)

    Riel, van N.A.W.; Giuseppin, M.L.F.; Verrips, C.T.

    2000-01-01

    The theory of dynamic optimal metabolic control (DOMC), as developed by Giuseppin and Van Riel (Metab. Eng., 2000), is applied to model the central nitrogen metabolism (CNM) in Saccharomyces cerevisiae. The CNM represents a typical system encountered in advanced metabolic engineering. The CNM is the

  13. Metabolism

    Science.gov (United States)

    ... Are More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood Test: Basic Metabolic Panel (BMP) Activity: Endocrine System Growth Disorders Diabetes Center Thyroid Disorders Your Endocrine System Movie: Endocrine ...

  14. Metabolic and inflammatory responses to the common sweetener stevioside and a glycemic challenge in horses with equine metabolic syndrome.

    Science.gov (United States)

    Elzinga, S E; Rohleder, B; Schanbacher, B; McQuerry, K; Barker, V D; Adams, A A

    2017-07-01

    Extracts derived from the leaves of the stevia plant (stevioside) are commonly used as sweeteners for humans and horses. Stevioside appears to be safe for human consumption, including for individuals with insulin dysregulation. In the horse, the safety or metabolic effects of stevioside on normal animals or on those with metabolic dysfunction are unknown. Furthermore, the inflammatory response to a glycemic challenge or to stevioside in horses is not well defined. Therefore, the objective of this study was to measure the effects of stevioside and a glycemic challenge on insulin, glucose, and inflammatory responses in horses with a common metabolic dysfunction (equine metabolic syndrome or EMS) compared with non-EMS controls. To accomplish this, 15 horses were selected; 8 EMS and 7 age-matched controls. An oral sugar test was performed using Karo corn syrup (karo) or stevioside in a random crossover design. Horses were given 0.15 mL/kg body weight of karo or its equivalent grams of sugar in stevia dissolved in water. Blood samples were collected by jugular venipuncture before administration of either stevia or karo and at 60 and 240 min after administration. Serum was used for glucose and insulin determination and plasma for isolation of peripheral blood mononuclear cells (PBMCs) for inflammatory cytokine analysis via flow cytometry and reverse transcription PCR (RT-PCR). Stevia appeared to stimulate lower glycemic and insulinemic responses when compared to karo, in particular in EMS horses. EMS and control horses had inverse inflammatory responses to administration of either stevia or karo with EMS horses having a proinflammatory response (P ≤ 0.05). These data provide evidence as to why horses with EMS may be predisposed to developing laminitis, potentially as a result of an exaggerated inflammatory response to glycemic and insulinemic responses. Furthermore, the data provide new avenues for exploring mechanisms behind the syndrome, in particular when using a

  15. Climate Coping: Investigating Metabolic Responses in Crocosphaera watsonii

    Science.gov (United States)

    Harris, K.

    2016-02-01

    Climate change causes chemical alterations in the open oceans, such as warming which leads to stratification, affecting nutrient ratios. Changes in nutrient ratios result in species shifts and a change in phytoplankton physiology, affecting all marine life. Unicellular diazotrophic microorganisms play a vital role in our open ocean ecosystems. These organisms do so by implementing metabolic processes that contribute to various availability of nutrients including; nitrogen and carbon. The open ocean diazotrophs are represented by multiple strains of Crocosphaera watsonii. The specific aim of this study was to determine whether the phenotype in small and large strain C. watsonii differs, in response to exposure to altered temperature gradients, measured as changes in cell density, photosynthetic efficiency, and EPS production. Triplicate cultures of C. watsonii WH8501 and C. watsonii WH0003 were inoculated into 60 ml of sterile Vineyard Sound SO media at a 1:10 ratio. Each culture was grown under; warm light levels (˜63 µ E m-2 s-1) on a 14:10 day/night cycle at temperatures of 27oC or 29oC. C. watsonii WH8501 cultures were harvested on Day 11, and C. watsonii WH0003 cultures were harvested on Day 9. To evaluate cell growth, fluorescence measurements were taken daily. Aliquots of experimental cultures were evaluated for cell density using flow-cytrometry, photosynthetic efficiency using FIRe fluorescence, and EPS production using a TEP determination assay. Proteins were extracted and analyzed by LC-MS-MS mass spectrometry. There was a correlation between temperature and EPS production for the two strains, C. watsonii WH8501 had a significantly higher growth rate when grown at 29oC, and a lower growth rate at 27oC compared to C. watsonii WH0003. Cultures grown at 27oC produced more EPS than those grown at 29oC. However, overall C. watsonii WH0003 produced more EPS than C. watsonii WH8501. We an increase in the yield of photosystem II (Fv/Fm) in C. watsonii WH0003 vs

  16. The metabolic response of Candida albicans to farnesol under hyphae-inducing conditions.

    Science.gov (United States)

    Han, Ting-Li; Cannon, Richard D; Villas-Bôas, Silas G

    2012-12-01

    Farnesol is a quorum-sensing molecule (QSM) produced, and sensed, by the polymorphic fungus, Candida albicans. This cell-to-cell communication molecule is known to suppress the hyphal formation of C. albicans at high cell density. Despite many studies investigating the signalling mechanisms by which QSMs influence the morphogenesis of C. albicans, the downstream metabolic effect of these signalling pathways in response to farnesol-mediated morphogenesis remains obscure. Here, we have used metabolomics to investigate the metabolic response of C. albicans upon exposure to farnesol under hyphae-inducing conditions. We have found a general up-regulation of central carbon metabolic pathways when hyphal formation was suppressed by farnesol evidenced by a considerably larger number of central carbon metabolic intermediates detected under this condition at an overall lower intracellular level. By combining the metabolic profiles from farnesol-exposed cells with previous metabolomics data for C. albicans undergoing morphogenesis, we have identified several metabolic pathways that are likely to be associated with the morphogenetic process of C. albicans, as well as metabolic pathways such as those involved in lipid metabolism that appeared to be specifically affected by farnesol. Therefore, our results provide important new insights into the metabolic role of farnesol in C. albicans metabolism. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  17. Use of genome-scale microbial models for metabolic engineering

    DEFF Research Database (Denmark)

    Patil, Kiran Raosaheb; Åkesson, M.; Nielsen, Jens

    2004-01-01

    Metabolic engineering serves as an integrated approach to design new cell factories by providing rational design procedures and valuable mathematical and experimental tools. Mathematical models have an important role for phenotypic analysis, but can also be used for the design of optimal metaboli...... network structures. The major challenge for metabolic engineering in the post-genomic era is to broaden its design methodologies to incorporate genome-scale biological data. Genome-scale stoichiometric models of microorganisms represent a first step in this direction....

  18. Metabolic alterations in experimental models of depression

    Directory of Open Access Journals (Sweden)

    Maria G. Puiu

    2016-10-01

    Full Text Available Introduction: Major depressive disorder is one of the most prevalent psychiatric disorders and is associated with a severe impact on the personal functioning, thus with incurring significant direct and indirect costs. The presence of depression in patients with medical comorbidities increases the risks of myocardial infarction and decreases diabetes control, and adherence to treatment. The mechanism through which these effects are produced is still uncertain. Objectives of this study were to evaluate the metabolic alterations in female Wistar rats with induced depression, with and without administration of Agomelatine. The methods included two experiments. All data were analyzed by comparison with group I (control, and with each other. In the first experiment we induced depression by: exposure to chronic mild stress-group II; olfactory bulbectomy-group III; and exposure to chronic mild stress and hyperlipidic/ hyper caloric dietgroup IV. The second experiment was similar with the first but the rats received Agomelatine (0.16mg/ animal: group V (depression induced through exposure to chronic mild stress, VI (depression induced through olfactory bulbectomy and VII (depression induced through exposure to chronic mild stressing hyperlipidic/ hypercaloric diet. Weight, cholesterol, triglycerides and glycaemia were measured at day 0 and 28, and leptin value was measured at day 28. The results in the 1st experiment revealed significant differences (p<0.01 for weight and cholesterol in Group IV, for triglycerides in groups III and IV (p<0.001, and for glycaemia in group II. The 2nd experiment revealed significant differences (p<0.001 in group VII for weight and triglycerides, and in groups V and VI for triglycerides (p<0.01. In conclusion, significant correlations were found between high level of triglycerides and depression induced by chronic stress and olfactory bulbectomy. Agomelatine groups had a lower increase of triglycerides levels.

  19. Developmental Programming in Response to Intrauterine Growth Restriction Impairs Myoblast Function and Skeletal Muscle Metabolism

    Science.gov (United States)

    Yates, D. T.; Macko, A. R.; Nearing, M.; Chen, X.; Rhoads, R. P.; Limesand, S. W.

    2012-01-01

    Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR), skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization. PMID:22900186

  20. Developmental Programming in Response to Intrauterine Growth Restriction Impairs Myoblast Function and Skeletal Muscle Metabolism

    Directory of Open Access Journals (Sweden)

    D. T. Yates

    2012-01-01

    Full Text Available Fetal adaptations to placental insufficiency alter postnatal metabolic homeostasis in skeletal muscle by reducing glucose oxidation rates, impairing insulin action, and lowering the proportion of oxidative fibers. In animal models of intrauterine growth restriction (IUGR, skeletal muscle fibers have less myonuclei at birth. This means that myoblasts, the sole source for myonuclei accumulation in fibers, are compromised. Fetal hypoglycemia and hypoxemia are complications that result from placental insufficiency. Hypoxemia elevates circulating catecholamines, and chronic hypercatecholaminemia has been shown to reduce fetal muscle development and growth. We have found evidence for adaptations in adrenergic receptor expression profiles in myoblasts and skeletal muscle of IUGR sheep fetuses with placental insufficiency. The relationship of β-adrenergic receptors shifts in IUGR fetuses because Adrβ2 expression levels decline and Adrβ1 expression levels are unaffected in myofibers and increased in myoblasts. This adaptive response would suppress insulin signaling, myoblast incorporation, fiber hypertrophy, and glucose oxidation. Furthermore, this β-adrenergic receptor expression profile persists for at least the first month in IUGR lambs and lowers their fatty acid mobilization. Developmental programming of skeletal muscle adrenergic receptors partially explains metabolic and endocrine differences in IUGR offspring, and the impact on metabolism may result in differential nutrient utilization.

  1. Global host metabolic response to Plasmodium vivax infection: a 1H NMR based urinary metabonomic study

    Directory of Open Access Journals (Sweden)

    Sengupta Arjun

    2011-12-01

    Full Text Available Abstract Background Plasmodium vivax is responsible for the majority of malarial infection in the Indian subcontinent. This species of the parasite is generally believed to cause a relatively benign form of the disease. However, recent reports from different parts of the world indicate that vivax malaria can also have severe manifestation. Host response to the parasite invasion is thought to be an important factor in determining the severity of manifestation. In this paper, attempt was made to determine the host metabolic response associated with P. vivax infection by means of NMR spectroscopy-based metabonomic techniques in an attempt to better understand the disease pathology. Methods NMR spectroscopy of urine samples from P. vivax-infected patients, healthy individuals and non-malarial fever patients were carried out followed by multivariate statistical analysis. Two data analysis techniques were employed, namely, Principal Component Analysis [PCA] and Orthogonal Projection to Latent Structure Discriminant Analysis [OPLS-DA]. Several NMR signals from the urinary metabolites were further selected for univariate comparison among the classes. Results The urine metabolic profiles of P. vivax-infected patients were distinct from those of healthy individuals as well as of non-malarial fever patients. A highly predictive model was constructed from urine profile of malarial and non-malarial fever patients. Several metabolites were found to be varying significantly across these cohorts. Urinary ornithine seems to have the potential to be used as biomarkers of vivax malaria. An increasing trend in pipecolic acid was also observed. The results suggest impairment in the functioning of liver as well as impairment in urea cycle. Conclusions The results open up a possibility of non-invasive analysis and diagnosis of P. vivax using urine metabolic profile. Distinct variations in certain metabolites were recorded, and amongst these, ornithine may have the

  2. Whole-body CO2 production as an index of the metabolic response to sepsis

    Science.gov (United States)

    Whole-body carbon dioxide (CO2) production (RaCO2) is an index of substrate oxidation and energy expenditure; therefore, it may provide information about the metabolic response to sepsis. Using stable isotope techniques, we determined RaCO2 and its relationship to protein and glucose metabolism in m...

  3. Similar metabolic responses in pigs and humans to breads with different contents and compositions of dietary fibers: a metabolomics study

    DEFF Research Database (Denmark)

    Nielsen, Kirstine Lykke; Hartvigsen, Merete; Hedemann, Mette Skou

    2014-01-01

    Background: In nutritional studies, pigs are often used as models for humans because of nutritional and physiologic similarities. However, evidence supporting similar metabolic responses to nutritional interventions is lacking. Objective: The objective was to establish whether pigs and humans...... respond similarly to a nutritional intervention. Using metabolomics, we compared the acute metabolic response to 4 test breads between conventional pigs (growing) and adult human subjects (with the metabolic syndrome). Design: Six catheterized pigs and 15 human subjects were tested in a randomized...... different basal metabolome concentrations in the plasma of pigs and humans. Humans had higher contents of phosphatidylcholines, oleic acid, and carnitine in plasma, possibly reflecting a higher intake of meats and fats. In pigs, betaine, choline, creatinine, tryptophan, and phenylalanine were higher...

  4. Cardiovascular Changes in Animal Models of Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Alexandre M. Lehnen

    2013-01-01

    Full Text Available Metabolic syndrome has been defined as a group of risk factors that directly contribute to the development of cardiovascular disease and/or type 2 diabetes. Insulin resistance seems to have a fundamental role in the genesis of this syndrome. Over the past years to the present day, basic and translational research has used small animal models to explore the pathophysiology of metabolic syndrome and to develop novel therapies that might slow the progression of this prevalent condition. In this paper we discuss the animal models used for the study of metabolic syndrome, with particular focus on cardiovascular changes, since they are the main cause of death associated with the condition in humans.

  5. Opposite metabolic responses of shoots and roots to drought

    Czech Academy of Sciences Publication Activity Database

    Gargallo-Garriga, A.; Sardans, J.; Pérez-Trujillo, M.; Rivas-Ubach, A.; Oravec, Michal; Večeřová, Kristýna; Urban, Otmar; Jentsch, A.; Kreyling, J.; Beierkuhnlein, C.; Parella, T.; Penuelas, J.

    2014-01-01

    Roč. 4, č. 6829 (2014), s. 1-7 ISSN 2045-2322 Grant - others:AV ČR(CZ) M200871201 Institutional support: RVO:67179843 Keywords : shoot and roots * autotrophic and heterotrophic organs * environmental change * growth metabolism * water and nutirens Subject RIV: EH - Ecology, Behaviour Impact factor: 5.578, year: 2014

  6. Model-driven discovery of underground metabolic functions in Escherichia coli

    DEFF Research Database (Denmark)

    Guzmán, Gabriela I.; Utrilla, José; Nurk, Sergey

    2015-01-01

    -scale models, which have been widely used for predicting growth phenotypes in various environments or following a genetic perturbation; however, these predictions occasionally fail. Failed predictions of gene essentiality offer an opportunity for targeting biological discovery, suggesting the presence......E, and gltA and prpC. This study demonstrates how a targeted model-driven approach to discovery can systematically fill knowledge gaps, characterize underground metabolism, and elucidate regulatory mechanisms of adaptation in response to gene KO perturbations....

  7. 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

  8. In Vitro Disease Model of Microgravity Conditioning on Human Energy Metabolism

    Science.gov (United States)

    Snyder, Jessica; Culbertson, C.; Zhang, Ye; Emami, K.; Wu, H.; Sun, Wei

    2010-01-01

    NASA and its partners are committed to introducing appropriate new technology to enable learning and living safely beyond the Earth for extended periods of time in a sustainable and possibly indefinite manner. In the responsible acquisition of that goal, life sciences is tasked to tune and advance current medical technology to prepare for human health and wellness in the space environment. The space environment affects the condition and function of biological systems from organ level function to shape of individual organelles. The objective of this paper is to study the effect of microgravity on kinetics of drug metabolism. This fundamental characterization is meaningful to (1) scientific understanding of the response of biology to microgravity and (2) clinical dosing requirements and pharmacological thresholds during long term manned space exploration. Metabolism kinetics of the anti-nausea drug promethazine (PMZ) were determined by an in vitro ground model of 3-dimensional aggregates of human hepatocytes conditioned to weightlessness using a rotating wall bioreactor. The authors observed up-regulated PMZ conversion in model microgravity conditions and attribute this to effect to model microgravity conditioning acting on metabolic mechanisms of the cells. Further work is necessary to determine which particular cellular mechanisms are governing the experimental observations, but the authors conclude kinetics of drug metabolism are responsive to gravitational fields and further study of this sensitivity would improve dosing of pharmaceuticals to persons exposed to a microgravity environment.

  9. Metabolic profiling of the response to an oral glucose tolerance test detects subtle metabolic changes.

    NARCIS (Netherlands)

    Wopereis, S.; Rubingh, C.M. de; Erk, M.J. van; Verheij, E.R.; Vliet, T. van; Cnubben, N.H.; Smilde, A.K.; Greef, J. van der; Ommen, B. van; Hendriks, H.F.

    2009-01-01

    BACKGROUND: The prevalence of overweight is increasing globally and has become a serious health problem. Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. Novel tools to understand these processes are needed. Metabolic profiling is one

  10. Dynamic modeling of lactic acid fermentation metabolism with Lactococcus lactis.

    Science.gov (United States)

    Oh, Euhlim; Lu, Mingshou; Park, Changhun; Park, Changhun; Oh, Han Bin; Lee, Sang Yup; Lee, Jinwon

    2011-02-01

    A dynamic model of lactic acid fermentation using Lactococcus lactis was constructed, and a metabolic flux analysis (MFA) and metabolic control analysis (MCA) were performed to reveal an intensive metabolic understanding of lactic acid bacteria (LAB). The parameter estimation was conducted with COPASI software to construct a more accurate metabolic model. The experimental data used in the parameter estimation were obtained from an LC-MS/ MS analysis and time-course simulation study. The MFA results were a reasonable explanation of the experimental data. Through the parameter estimation, the metabolic system of lactic acid bacteria can be thoroughly understood through comparisons with the original parameters. The coefficients derived from the MCA indicated that the reaction rate of L-lactate dehydrogenase was activated by fructose 1,6-bisphosphate and pyruvate, and pyruvate appeared to be a stronger activator of L-lactate dehydrogenase than fructose 1,6-bisphosphate. Additionally, pyruvate acted as an inhibitor to pyruvate kinase and the phosphotransferase system. Glucose 6-phosphate and phosphoenolpyruvate showed activation effects on pyruvate kinase. Hexose transporter was the strongest effector on the flux through L-lactate dehydrogenase. The concentration control coefficient (CCC) showed similar results to the flux control coefficient (FCC).

  11. Metabolic Response to Food Restriction in Military-Eligible Women, with a Gender Comparison

    National Research Council Canada - National Science Library

    Young, Vernon

    1998-01-01

    Two major series of investigations are being undertaken to explore the metabolic responses of women who meet military standards for body-weight and percent body-fat to the nutritional stressors of food restriction...

  12. Metabolic Response to Food Restriction in Military-Eligible Women, With a Gender Comparison

    National Research Council Canada - National Science Library

    Young, Vernon

    1996-01-01

    Two major series of investigations will be undertaken to explore the metabolic responses of women, who meet military standards of body-weight and percent body-fat to the nutritional stressors of food restriction...

  13. Metabolic Response to Food Restriction in Military-Eligible Women, with a Gender Comparison

    National Research Council Canada - National Science Library

    Young, Vernon

    1997-01-01

    Two major series of investigations are being undertaken to explore the metabolic responses of women who meet military standards for body-weight and percent body-fat to the nutritional stressors of food restriction...

  14. Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk.

    Directory of Open Access Journals (Sweden)

    Cathy Slack

    2010-03-01

    Full Text Available Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF-1 signaling (IIS pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the

  15. LakeMetabolizer: An R package for estimating lake metabolism from free-water oxygen using diverse statistical models

    Science.gov (United States)

    Winslow, Luke; Zwart, Jacob A.; Batt, Ryan D.; Dugan, Hilary; Woolway, R. Iestyn; Corman, Jessica; Hanson, Paul C.; Read, Jordan S.

    2016-01-01

    Metabolism is a fundamental process in ecosystems that crosses multiple scales of organization from individual organisms to whole ecosystems. To improve sharing and reuse of published metabolism models, we developed LakeMetabolizer, an R package for estimating lake metabolism from in situ time series of dissolved oxygen, water temperature, and, optionally, additional environmental variables. LakeMetabolizer implements 5 different metabolism models with diverse statistical underpinnings: bookkeeping, ordinary least squares, maximum likelihood, Kalman filter, and Bayesian. Each of these 5 metabolism models can be combined with 1 of 7 models for computing the coefficient of gas exchange across the air–water interface (k). LakeMetabolizer also features a variety of supporting functions that compute conversions and implement calculations commonly applied to raw data prior to estimating metabolism (e.g., oxygen saturation and optical conversion models). These tools have been organized into an R package that contains example data, example use-cases, and function documentation. The release package version is available on the Comprehensive R Archive Network (CRAN), and the full open-source GPL-licensed code is freely available for examination and extension online. With this unified, open-source, and freely available package, we hope to improve access and facilitate the application of metabolism in studies and management of lentic ecosystems.

  16. Systematic construction of kinetic models from genome-scale metabolic networks.

    Directory of Open Access Journals (Sweden)

    Natalie J Stanford

    Full Text Available The quantitative effects of environmental and genetic perturbations on metabolism can be studied in silico using kinetic models. We present a strategy for large-scale model construction based on a logical layering of data such as reaction fluxes, metabolite concentrations, and kinetic constants. The resulting models contain realistic standard rate laws and plausible parameters, adhere to the laws of thermodynamics, and reproduce a predefined steady state. These features have not been simultaneously achieved by previous workflows. We demonstrate the advantages and limitations of the workflow by translating the yeast consensus metabolic network into a kinetic model. Despite crudely selected data, the model shows realistic control behaviour, a stable dynamic, and realistic response to perturbations in extracellular glucose concentrations. The paper concludes by outlining how new data can continuously be fed into the workflow and how iterative model building can assist in directing experiments.

  17. Systematic Construction of Kinetic Models from Genome-Scale Metabolic Networks

    Science.gov (United States)

    Smallbone, Kieran; Klipp, Edda; Mendes, Pedro; Liebermeister, Wolfram

    2013-01-01

    The quantitative effects of environmental and genetic perturbations on metabolism can be studied in silico using kinetic models. We present a strategy for large-scale model construction based on a logical layering of data such as reaction fluxes, metabolite concentrations, and kinetic constants. The resulting models contain realistic standard rate laws and plausible parameters, adhere to the laws of thermodynamics, and reproduce a predefined steady state. These features have not been simultaneously achieved by previous workflows. We demonstrate the advantages and limitations of the workflow by translating the yeast consensus metabolic network into a kinetic model. Despite crudely selected data, the model shows realistic control behaviour, a stable dynamic, and realistic response to perturbations in extracellular glucose concentrations. The paper concludes by outlining how new data can continuously be fed into the workflow and how iterative model building can assist in directing experiments. PMID:24324546

  18. Metabolic response of Candida albicans to phenylethyl alcohol under hyphae-inducing conditions.

    Science.gov (United States)

    Han, Ting-Li; Tumanov, Sergey; Cannon, Richard D; Villas-Boas, Silas G

    2013-01-01

    Phenylethyl alcohol was one of the first quorum sensing molecules (QSMs) identified in C. albicans. This extracellular signalling molecule inhibits the hyphal formation of C. albicans at high cell density. Little is known, however, about the underlying mechanisms by which this QSM regulates the morphological switches of C. albicans. Therefore, we have applied metabolomics and isotope labelling experiments to investigate the metabolic changes that occur in C. albicans in response to phenylethyl alcohol under defined hyphae-inducing conditions. Our results showed a global upregulation of central carbon metabolism when hyphal development was suppressed by phenylethyl alcohol. By comparing the metabolic changes in response to phenylethyl alcohol to our previous metabolomic studies, we were able to short-list 7 metabolic pathways from central carbon metabolism that appear to be associated with C. albicans morphogenesis. Furthermore, isotope-labelling data showed that phenylethyl alcohol is indeed taken up and catabolised by yeast cells. Isotope-labelled carbon atoms were found in the majority of amino acids as well as in lactate and glyoxylate. However, isotope-labelled carbon atoms from phenylethyl alcohol accumulated mainly in the pyridine ring of NAD(+)/NADH and NADP(-/)NADPH molecules, showing that these nucleotides were the main products of phenylethyl alcohol catabolism. Interestingly, two metabolic pathways where these nucleotides play an important role, nitrogen metabolism and nicotinate/nicotinamide metabolism, were also short-listed through our previous metabolomics works as metabolic pathways likely to be closely associated with C. albicans morphogenesis.

  19. Cardiovascular, hormonal and metabolic responses to graded exercise in juvenile diabetics with and without autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J; Galbo, H; Christensen, N J

    1980-01-01

    Thirteen juvenile diabetics were studied in order to determine if decreased beat-to-beat variation during deep respiration, indicating abnormal autonomic nerve function, imply that cardiovascular, hormonal and metabolic responses are impaired. Patients with decreased beat-to-beat variation had to...... to be more heavily stressed during exercise to reach a certain heart rate or catecholamine level. The relation between other metabolic and hormonal response is discussed....

  20. Metabolic response to feeding in Tupinambis merianae: circadian rhythm and a possible respiratory constraint.

    Science.gov (United States)

    Klein, Wilfried; Perry, Steven F; Abe, Augusto S; Andrade, Denis V

    2006-01-01

    The diurnal tegu lizard Tupinambis merianae exhibits a marked circadian variation in metabolism that is characterized by the significant increase in metabolism during part of the day. These increases in metabolic rate, found in the fasting animal, are absent during the first 2 d after meal ingestion but reappear subsequently, and the daily increase in metabolic rate is added to the increase in metabolic rate caused by digestion. During the first 2 d after feeding, priority is given to digestion, while on the third and following days, the metabolic demands are clearly added to each other. This response seems to be a regulated response of the animal, which becomes less active after food ingestion, rather than an inability of the respiratory system to support simultaneous demands at the beginning of digestion. The body cavity of Tupinambis is divided into two compartments by a posthepatic septum (PHS). Animals that had their PHS surgically removed showed no significant alteration in the postprandial metabolic response compared to tegus with intact PHS. The maximal metabolic increment during digestion, the relative cost of meal digestion, and the duration of the process were virtually unaffected by the removal of the PHS.

  1. 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.

  2. Metabolic Models of Protein Allocation Call for the Kinetome

    DEFF Research Database (Denmark)

    Nilsson, Avlant; Nielsen, Jens; Palsson, Bernhard

    2017-01-01

    The flux of metabolites in the living cell depend on enzyme activities. Recently, many metabolic phenotypes have been explained by computer models that incorporate enzyme activity data. To move further, the scientific community needs to measure the kinetics of all enzymes in a systematic way....

  3. Metabolism related toxicity of diclofenac in yeast as model system

    NARCIS (Netherlands)

    van Leeuwen, J.S.; Vredenburg, G.; Dragovic, S.; Tjong, T.F.; Vos, J.C.; Vermeulen, N.P.E.

    2010-01-01

    Diclofenac is a widely used drug that can cause serious hepatotoxicity, which has been linked to metabolism by cytochrome P450s (P450). To investigate the role of oxidative metabolites in diclofenac toxicity, a model for P450-related toxicity was set up in Saccharomyces cerevisiae. We expressed a

  4. Integrating cellular metabolism into a multiscale whole-body model.

    Directory of Open Access Journals (Sweden)

    Markus Krauss

    Full Text Available Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.

  5. Integrating Cellular Metabolism into a Multiscale Whole-Body Model

    Science.gov (United States)

    Krauss, Markus; Schaller, Stephan; Borchers, Steffen; Findeisen, Rolf; Lippert, Jörg; Kuepfer, Lars

    2012-01-01

    Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development. PMID:23133351

  6. Predicting effects of structural stress in a genome-reduced model bacterial metabolism

    Science.gov (United States)

    Güell, Oriol; Sagués, Francesc; Serrano, M. Ángeles

    2012-08-01

    Mycoplasma pneumoniae is a human pathogen recently proposed as a genome-reduced model for bacterial systems biology. Here, we study the response of its metabolic network to different forms of structural stress, including removal of individual and pairs of reactions and knockout of genes and clusters of co-expressed genes. Our results reveal a network architecture as robust as that of other model bacteria regarding multiple failures, although less robust against individual reaction inactivation. Interestingly, metabolite motifs associated to reactions can predict the propagation of inactivation cascades and damage amplification effects arising in double knockouts. We also detect a significant correlation between gene essentiality and damages produced by single gene knockouts, and find that genes controlling high-damage reactions tend to be expressed independently of each other, a functional switch mechanism that, simultaneously, acts as a genetic firewall to protect metabolism. Prediction of failure propagation is crucial for metabolic engineering or disease treatment.

  7. Metabolomics reveals differences in postprandial responses to breads and fasting metabolic characteristics associated with postprandial insulin demand in postmenopausal women.

    Science.gov (United States)

    Moazzami, Ali A; Shrestha, Aahana; Morrison, David A; Poutanen, Kaisa; Mykkänen, Hannu

    2014-06-01

    Changes in serum metabolic profile after the intake of different food products (e.g., bread) can provide insight into their interaction with human metabolism. Postprandial metabolic responses were compared after the intake of refined wheat (RWB), whole-meal rye (WRB), and refined rye (RRB) breads. In addition, associations between the metabolic profile in fasting serum and the postprandial concentration of insulin in response to different breads were investigated. Nineteen postmenopausal women with normal fasting glucose and normal glucose tolerance participated in a randomized, controlled, crossover meal study. The test breads, RWB (control), RRB, and WRB, providing 50 g of available carbohydrate, were each served as a single meal. The postprandial metabolic profile was measured using nuclear magnetic resonance and targeted LC-mass spectrometry and was compared between different breads using ANOVA and multivariate models. Eight amino acids had a significant treatment effect (P insulin. Women with higher fasting concentrations of leucine and isoleucine and lower fasting concentrations of sphingomyelins and phosphatidylcholines had higher insulin responses despite similar glucose concentration after all kinds of bread (cross-validated ANOVA, P = 0.048). High blood concentration of branched-chain amino acids, i.e., leucine and isoleucine, has been associated with the increased risk of diabetes, which suggests that additional consideration should be given to bread proteins in understanding the beneficial health effects of different kinds of breads. The present study suggests that the fasting metabolic profile can be used to characterize the postprandial insulin demand in individuals with normal glucose metabolism that can be used for establishing strategies for the stratification of individuals in personalized nutrition. © 2014 American Society for Nutrition.

  8. A Mathematical Model of Metabolism and Regulation Provides a Systems-Level View of How Escherichia coli Responds to Oxygen

    Directory of Open Access Journals (Sweden)

    Michael eEderer

    2014-03-01

    Full Text Available The efficient redesign of bacteria for biotechnological purposes, such as biofuel production, waste disposal or specific biocatalytic functions, requires a quantitative systems-level understanding of energy supply, carbon and redox metabolism. The measurement of transcript levels, metabolite concentrations and metabolic fluxes per se gives an incomplete picture. An appreciation of the interdependencies between the different measurement values is essential for systems-level understanding. Mathematical modeling has the potential to provide a coherent and quantitative description of the interplay between gene expression, metabolite concentrations and metabolic fluxes. Escherichia coli undergoes major adaptations in central metabolism when the availability of oxygen changes. Thus, an integrated description of the oxygen response provides a benchmark of our understanding of carbon, energy and redox metabolism. We present the first comprehensive model of the central metabolism of E. coli that describes steady-state metabolism at different levels of oxygen availability. Variables of the model are metabolite concentrations, gene expression levels, transcription factor activities, metabolic fluxes and biomass concentration. We analyze the model with respect to the production capabilities of central metabolism of E. coli. In particular, we predict how precursor and biomass concentration are affected by product formation.

  9. Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

    Science.gov (United States)

    Cordes, Henrik; Thiel, Christoph; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

    2018-01-01

    Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis , which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

  10. MR imaging of metabolic white matter diseases: Therapeutic response

    International Nuclear Information System (INIS)

    Gebarski, S.S.; Allen, R.

    1987-01-01

    In metabolic diseases affecting the brain, MR imaging abnormalities include white-matter signal aberrations suggesting myelination delay, dysmyelination and demyelination, pathologic iron storage, and finally, loss of substance usually in a nonspecific pattern. The authors suggest that MR imaging may have therapeutic implications: (1) classic galactosemia - white-matter signal aberration became normal after dietary therapy; (2) phenylketonuria - age- and sex-matched treated and nontreated adolescents showed marked differences in brain volume, with the treated patient's volume nearly normal; (3) maple syrup urine disease - gross white-matter signal aberration became nearly normal after dietary therapy; and (4) hyperglycinemia - relentless progression of white-matter signal aberration and loss of brain substance despite therapy. These data suggest that brain MR imaging may provide a therapeutic index in certain metabolic diseases

  11. Modeling metabolism and stage-specific growth of Plasmodium falciparum HB3 during the intraerythrocytic developmental cycle.

    Science.gov (United States)

    Fang, Xin; Reifman, Jaques; Wallqvist, Anders

    2014-10-01

    The human malaria parasite Plasmodium falciparum goes through a complex life cycle, including a roughly 48-hour-long intraerythrocytic developmental cycle (IDC) in human red blood cells. A better understanding of the metabolic processes required during the asexual blood-stage reproduction will enhance our basic knowledge of P. falciparum and help identify critical metabolic reactions and pathways associated with blood-stage malaria. We developed a metabolic network model that mechanistically links time-dependent gene expression, metabolism, and stage-specific growth, allowing us to predict the metabolic fluxes, the biomass production rates, and the timing of production of the different biomass components during the IDC. We predicted time- and stage-specific production of precursors and macromolecules for P. falciparum (strain HB3), allowing us to link specific metabolites to specific physiological functions. For example, we hypothesized that coenzyme A might be involved in late-IDC DNA replication and cell division. Moreover, the predicted ATP metabolism indicated that energy was mainly produced from glycolysis and utilized for non-metabolic processes. Finally, we used the model to classify the entire tricarboxylic acid cycle into segments, each with a distinct function, such as superoxide detoxification, glutamate/glutamine processing, and metabolism of fumarate as a byproduct of purine biosynthesis. By capturing the normal metabolic and growth progression in P. falciparum during the IDC, our model provides a starting point for further elucidation of strain-specific metabolic activity, host-parasite interactions, stress-induced metabolic responses, and metabolic responses to antimalarial drugs and drug candidates.

  12. Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses.

    Science.gov (United States)

    Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

    2017-08-01

    Fibroblast growth factor 21 (FGF21) is a hormone-like member of FGF family which controls metabolic multiorgan crosstalk enhancing energy expenditure through glucose and lipid metabolism. In addition, FGF21 acts as a stress hormone induced by endoplasmic reticulum stress and dysfunctions of mitochondria and autophagy in several tissues. FGF21 also controls stress responses and metabolism by modulating the functions of somatotropic axis and hypothalamic-pituitary-adrenal (HPA) pathway. FGF21 is a potent longevity factor coordinating interactions between energy metabolism and stress responses. Recent studies have revealed that FGF21 treatment can alleviate many age-related metabolic disorders, e.g. atherosclerosis, obesity, type 2 diabetes, and some cardiovascular diseases. In addition, transgenic mice overexpressing FGF21 have an extended lifespan. However, chronic metabolic and stress-related disorders involving inflammatory responses can provoke FGF21 resistance and thus disturb healthy aging process. First, we will describe the role of FGF21 in interorgan energy metabolism and explain how its functions as a stress hormone can improve healthspan. Next, we will examine both the induction of FGF21 expression via the integrated stress response and the molecular mechanism through which FGF21 enhances healthy aging. Finally, we postulate that FGF21 resistance, similarly to insulin resistance, jeopardizes human healthspan and accelerates the aging process. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Generalized framework for context-specific metabolic model extraction methods

    Directory of Open Access Journals (Sweden)

    Semidán eRobaina Estévez

    2014-09-01

    Full Text Available Genome-scale metabolic models are increasingly applied to investigate the physiology not only of simple prokaryotes, but also eukaryotes, such as plants, characterized with compartmentalized cells of multiple types. While genome-scale models aim at including the entirety of known metabolic reactions, mounting evidence has indicated that only a subset of these reactions is active in a given context, including: developmental stage, cell type, or environment. As a result, several methods have been proposed to reconstruct context-specific models from existing genome-scale models by integrating various types of high-throughput data. Here we present a mathematical framework that puts all existing methods under one umbrella and provides the means to better understand their functioning, highlight similarities and differences, and to help users in selecting a most suitable method for an application.

  14. Radiogenomics and radiotherapy response modeling

    Science.gov (United States)

    El Naqa, Issam; Kerns, Sarah L.; Coates, James; Luo, Yi; Speers, Corey; West, Catharine M. L.; Rosenstein, Barry S.; Ten Haken, Randall K.

    2017-08-01

    Advances in patient-specific information and biotechnology have contributed to a new era of computational medicine. Radiogenomics has emerged as a new field that investigates the role of genetics in treatment response to radiation therapy. Radiation oncology is currently attempting to embrace these recent advances and add to its rich history by maintaining its prominent role as a quantitative leader in oncologic response modeling. Here, we provide an overview of radiogenomics starting with genotyping, data aggregation, and application of different modeling approaches based on modifying traditional radiobiological methods or application of advanced machine learning techniques. We highlight the current status and potential for this new field to reshape the landscape of outcome modeling in radiotherapy and drive future advances in computational oncology.

  15. The human hepatocyte cell lines IHH and HepaRG: models to study glucose, lipid and lipoprotein metabolism.

    Science.gov (United States)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Hélène; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Véronique; Staels, Bart

    2012-07-01

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological stimuli is often lost. Here, we characterize two human hepatocyte cell lines, IHH and HepaRG, by analysing the expression and regulation of genes involved in glucose and lipid metabolism. Our results show that the glycolysis pathway is activated by glucose and insulin in both lines. Gluconeogenesis gene expression is induced by forskolin in IHH cells and inhibited by insulin in both cell lines. The lipogenic pathway is regulated by insulin in IHH cells. Finally, both cell lines secrete apolipoprotein B-containing lipoproteins, an effect promoted by increasing glucose concentrations. These two human cell lines are thus interesting models to study the regulation of glucose and lipid metabolism.

  16. HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology.

    Science.gov (United States)

    Berndt, Nikolaus; Bulik, Sascha; Wallach, Iwona; Wünsch, Tilo; König, Matthias; Stockmann, Martin; Meierhofer, David; Holzhütter, Hermann-Georg

    2018-06-19

    The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

  17. Pavement Aging Model by Response Surface Modeling

    Directory of Open Access Journals (Sweden)

    Manzano-Ramírez A.

    2011-10-01

    Full Text Available In this work, surface course aging was modeled by Response Surface Methodology (RSM. The Marshall specimens were placed in a conventional oven for time and temperature conditions established on the basis of the environment factors of the region where the surface course is constructed by AC-20 from the Ing. Antonio M. Amor refinery. Volatilized material (VM, load resistance increment (ΔL and flow resistance increment (ΔF models were developed by the RSM. Cylindrical specimens with real aging were extracted from the surface course pilot to evaluate the error of the models. The VM model was adequate, in contrast (ΔL and (ΔF models were almost adequate with an error of 20 %, that was associated with the other environmental factors, which were not considered at the beginning of the research.

  18. Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders.

    Science.gov (United States)

    MacLeod, Erin L; Hall, Kevin D; McGuire, Peter J

    2016-01-01

    Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection.

  19. Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

    Directory of Open Access Journals (Sweden)

    Jiye A

    Full Text Available The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML. However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML and patients resistant to imatinib (RCML had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA. In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention.

  20. Metabolism

    Science.gov (United States)

    ... lin), which signals cells to increase their anabolic activities. Metabolism is a complicated chemical process, so it's not ... how those enzymes or hormones work. When the metabolism of body chemicals is ... Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism ...

  1. Metabolic modeling of synthesis gas fermentation in bubble column reactors.

    Science.gov (United States)

    Chen, Jin; Gomez, Jose A; Höffner, Kai; Barton, Paul I; Henson, Michael A

    2015-01-01

    A promising route to renewable liquid fuels and chemicals is the fermentation of synthesis gas (syngas) streams to synthesize desired products such as ethanol and 2,3-butanediol. While commercial development of syngas fermentation technology is underway, an unmet need is the development of integrated metabolic and transport models for industrially relevant syngas bubble column reactors. We developed and evaluated a spatiotemporal metabolic model for bubble column reactors with the syngas fermenting bacterium Clostridium ljungdahlii as the microbial catalyst. Our modeling approach involved combining a genome-scale reconstruction of C. ljungdahlii metabolism with multiphase transport equations that govern convective and dispersive processes within the spatially varying column. The reactor model was spatially discretized to yield a large set of ordinary differential equations (ODEs) in time with embedded linear programs (LPs) and solved using the MATLAB based code DFBAlab. Simulations were performed to analyze the effects of important process and cellular parameters on key measures of reactor performance including ethanol titer, ethanol-to-acetate ratio, and CO and H2 conversions. Our computational study demonstrated that mathematical modeling provides a complementary tool to experimentation for understanding, predicting, and optimizing syngas fermentation reactors. These model predictions could guide future cellular and process engineering efforts aimed at alleviating bottlenecks to biochemical production in syngas bubble column reactors.

  2. Dealing with hunger: Metabolic stress responses in tumors

    Directory of Open Access Journals (Sweden)

    Michael A Reid

    2013-01-01

    Full Text Available Increased nutrient uptake and usage is a hallmark of many human malignancies. During the course of tumorigenesis, cancer cells often outstrip their local nutrient supply leading to periods of nutrient deprivation. Interestingly, cancer cells often develop strategies to adapt and survive these challenging conditions. Accordingly, understanding these processes is critical for developing therapies that target cancer metabolism. Exciting new progress has been made in elucidating the mechanisms used by cancer cells under nutrient restricted conditions. In this review, we highlight recent studies that have brought insight into how cancer cells deal with low nutrient environments.

  3. Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia.

    Directory of Open Access Journals (Sweden)

    Xin Fang

    Full Text Available The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB, to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to

  4. 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.

  5. Corticosterone-responsive and -unresponsive metabolic characteristics of adrenalectomized rats.

    Science.gov (United States)

    Hamelink, C R; Currie, P J; Chambers, J W; Castonguay, T W; Coscina, D V

    1994-09-01

    Glucocorticoids are important in influencing substrate flux through the metabolic pathways. This study was designed to answer the question "Does adrenalectomy (ADX) cause a shift toward fat metabolism as measured by a decrease in respiratory quotient (RQ)?" Male Sprague-Dawley rats were divided into four groups, ADX, ADX + 20% corticosterone (Cort) (ADX-20%), ADX + 40% Cort (ADX-40%), or sham-operated controls (Sham). ADX-20% received 50 mg and ADX-40% 100 mg Cort dissolved in 250-mg cholesterol pellets and placed subcutaneously. Each rat was monitored for 90 min four times both during a preoperative period and again after a 1-wk postsurgical recovery period in an indirect calorimeter. Cort prevented ADX-induced suppression of weight gain and food intake. ADX decreased motoric activity in both the light and dark periods. Cort restored activity to Sham levels. ADX decreased RQ only in the dark (0.858 ADX vs. 0.891 Sham) and was reversed only in the ADX-40% group. Energy expenditure (EE) was depressed in both the light and dark by ADX; Cort partially restored EE to Sham values in the light period.

  6. An accurate description of Aspergillus niger organic acid batch fermentation through dynamic metabolic modelling.

    Science.gov (United States)

    Upton, Daniel J; McQueen-Mason, Simon J; Wood, A Jamie

    2017-01-01

    Aspergillus niger fermentation has provided the chief source of industrial citric acid for over 50 years. Traditional strain development of this organism was achieved through random mutagenesis, but advances in genomics have enabled the development of genome-scale metabolic modelling that can be used to make predictive improvements in fermentation performance. The parent citric acid-producing strain of A. niger , ATCC 1015, has been described previously by a genome-scale metabolic model that encapsulates its response to ambient pH. Here, we report the development of a novel double optimisation modelling approach that generates time-dependent citric acid fermentation using dynamic flux balance analysis. The output from this model shows a good match with empirical fermentation data. Our studies suggest that citric acid production commences upon a switch to phosphate-limited growth and this is validated by fitting to empirical data, which confirms the diauxic growth behaviour and the role of phosphate storage as polyphosphate. The calibrated time-course model reflects observed metabolic events and generates reliable in silico data for industrially relevant fermentative time series, and for the behaviour of engineered strains suggesting that our approach can be used as a powerful tool for predictive metabolic engineering.

  7. Mouse Models as Predictors of Human Responses: Evolutionary Medicine.

    Science.gov (United States)

    Uhl, Elizabeth W; Warner, Natalie J

    Mice offer a number of advantages and are extensively used to model human diseases and drug responses. Selective breeding and genetic manipulation of mice have made many different genotypes and phenotypes available for research. However, in many cases, mouse models have failed to be predictive. Important sources of the prediction problem have been the failure to consider the evolutionary basis for species differences, especially in drug metabolism, and disease definitions that do not reflect the complexity of gene expression underlying disease phenotypes. Incorporating evolutionary insights into mouse models allow for unique opportunities to characterize the effects of diet, different gene expression profiles, and microbiomics underlying human drug responses and disease phenotypes.

  8. Maternal high-fat diet intensifies the metabolic response to stress in male rat offspring

    OpenAIRE

    Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Dargahi, Leila; Salimi, Mina; Rashidi, FatemehSadat

    2017-01-01

    Background The mother?s consumption of high-fat food can affect glucose metabolism and the hypothalamic?pituitary?adrenal axis responsiveness in the offspring and potentially affect the metabolic responses to stress as well. This study examines the effect of maternal high-fat diet on the expression of pancreatic glucose transporter 2 and the secretion of insulin in response to stress in offspring. Methods Female rats were randomly divided into normal and high-fat diet groups and were fed in a...

  9. Biofilm Formation Mechanisms of Pseudomonas aeruginosa Predicted via Genome-Scale Kinetic Models of Bacterial Metabolism

    Science.gov (United States)

    2016-03-15

    RESEARCH ARTICLE Biofilm Formation Mechanisms of Pseudomonas aeruginosa Predicted via Genome-Scale Kinetic Models of Bacterial Metabolism Francisco G...jaques.reifman.civ@mail.mil Abstract A hallmark of Pseudomonas aeruginosa is its ability to establish biofilm -based infections that are difficult to...eradicate. Biofilms are less susceptible to host inflammatory and immune responses and have higher antibiotic tolerance than free-living planktonic

  10. Modeling and Classification of Kinetic Patterns of Dynamic Metabolic Biomarkers in Physical Activity.

    Directory of Open Access Journals (Sweden)

    Marc Breit

    2015-08-01

    Full Text Available The objectives of this work were the classification of dynamic metabolic biomarker candidates and the modeling and characterization of kinetic regulatory mechanisms in human metabolism with response to external perturbations by physical activity. Longitudinal metabolic concentration data of 47 individuals from 4 different groups were examined, obtained from a cycle ergometry cohort study. In total, 110 metabolites (within the classes of acylcarnitines, amino acids, and sugars were measured through a targeted metabolomics approach, combining tandem mass spectrometry (MS/MS with the concept of stable isotope dilution (SID for metabolite quantitation. Biomarker candidates were selected by combined analysis of maximum fold changes (MFCs in concentrations and P-values resulting from statistical hypothesis testing. Characteristic kinetic signatures were identified through a mathematical modeling approach utilizing polynomial fitting. Modeled kinetic signatures were analyzed for groups with similar behavior by applying hierarchical cluster analysis. Kinetic shape templates were characterized, defining different forms of basic kinetic response patterns, such as sustained, early, late, and other forms, that can be used for metabolite classification. Acetylcarnitine (C2, showing a late response pattern and having the highest values in MFC and statistical significance, was classified as late marker and ranked as strong predictor (MFC = 1.97, P < 0.001. In the class of amino acids, highest values were shown for alanine (MFC = 1.42, P < 0.001, classified as late marker and strong predictor. Glucose yields a delayed response pattern, similar to a hockey stick function, being classified as delayed marker and ranked as moderate predictor (MFC = 1.32, P < 0.001. These findings coincide with existing knowledge on central metabolic pathways affected in exercise physiology, such as β-oxidation of fatty acids, glycolysis, and glycogenolysis. The presented modeling

  11. Dietary fatty acids linking postprandial metabolic response and chronic diseases.

    Science.gov (United States)

    Ortega, Almudena; Varela, Lourdes M; Bermudez, Beatriz; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

    2012-01-01

    Chronic diseases are by far one of the main causes of mortality in the world. One of the current global recommendations to counteract disability and premature death resulting from chronic diseases is to decrease the consumption of energy-dense high-fat diets, particularly those rich in saturated fatty acids (SFA). The most effective replacement for SFA in terms of risk factor outcomes for chronic disease are polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). The biochemical basis for healthy benefits of such a dietary pattern has been widely evaluated under fasting conditions. However, the increasing amount of data available from multiple studies suggest that the postprandial state, i.e., "the period that comprises and follows a meal", plays an important, yet underappreciated, role in the genesis of numerous pathological conditions. In this review, the potential of MUFA, PUFA, and SFA to postprandially affect selected metabolic abnormalities related to chronic diseases is discussed.

  12. Response to Cardiac Resynchronization Therapy: The Muscular Metabolic Pathway

    Directory of Open Access Journals (Sweden)

    Jérémie Jaussaud

    2011-01-01

    245±140 seconds (=.01. Peak VO2, VE/VCO2, peak circulatory power and NYHA were improved after CRT (13±4 to16±5 ml/kg/min (<.05, 45±16 to 39±13 (<.01, 1805±844 to 2225±1171 mmHg.ml/kg/min (<.01 and 3±0.35 to 1.88±0.4 (=.01. In addition, left ventricular ejection fraction and end-systolic volumes were improved from 24±8 to 29±7% (<.01 and from 157±69 to 122±55 ml (<.01. Conclusion. We suggest that CRT leads to an increase in oxidative muscular metabolism and postponed anaerobic threshold reducing exaggerated hyperventilation during exercise.

  13. A biokinetic and dosimetric model for the metabolism of uranium

    International Nuclear Information System (INIS)

    Wrenn, M.E.; Bertelli, L.; Durbin, P.W.; Eckerman, K.F.; Lipsztein, J.L.; Singh, N.P.

    1995-10-01

    Experiments involving injection and inhalation of uranium compounds into several animal species as well as those associated with humans are described and analyzed. A revised biokinetic and dosimetric model for the metabolism of uranium suitable for bioassay procedures is proposed. The model consists of a systematic part coupled to a model of the respiratory tract. The model has been tested against human data which incorporates in vivo measurements over the chest and measurements of urine, feces, and autopsy and biopsy samples.In particular the lung model of the International Commission on Radiological Protection, Publication 30 ( ICRP-30 ), has been modified in order to provide a model which more nearly predicts urinary excretion in accord with the experiences in humans and animals. We have also tested the data against the new ICRP (LUDEP) lung model. (author). 55 refs., 14 tabs., 33 figs

  14. A dynamic, mechanistic model of metabolism in adipose tissue of lactating dairy cattle.

    Science.gov (United States)

    McNamara, J P; Huber, K; Kenéz, A

    2016-07-01

    Research in dairy cattle biology has resulted in a large body of knowledge on nutrition and metabolism in support of milk production and efficiency. This quantitative knowledge has been compiled in several model systems to balance and evaluate rations and predict requirements. There are also systems models for metabolism and reproduction in the cow that can be used to support research programs. Adipose tissue plays a significant role in the success and efficiency of lactation, and recent research has resulted in several data sets on genomic differences and changes in gene transcription of adipose tissue in dairy cattle. To fully use this knowledge, we need to build and expand mechanistic, dynamic models that integrate control of metabolism and production. Therefore, we constructed a second-generation dynamic, mechanistic model of adipose tissue metabolism of dairy cattle. The model describes the biochemical interconversions of glucose, acetate, β-hydroxybutyrate (BHB), glycerol, C16 fatty acids, and triacylglycerols. Data gathered from our own research and published references were used to set equation forms and parameter values. Acetate, glucose, BHB, and fatty acids are taken up from blood. The fatty acids are activated to the acyl coenzyme A moieties. Enzymatically catalyzed reactions are explicitly described with parameters including maximal velocity and substrate sensitivity. The control of enzyme activity is partially carried out by insulin and norepinephrine, portraying control in the cow. Model behavior was adequate, with sensitive responses to changing substrates and hormones. Increased nutrient uptake and increased insulin stimulate triacylglycerol synthesis, whereas a reduction in nutrient availability or increase in norepinephrine increases triacylglycerol hydrolysis and free fatty acid release to blood. This model can form a basis for more sophisticated integration of existing knowledge and future studies on metabolic efficiency of dairy cattle

  15. Metabolic responses to high protein diet in Korean elite bodybuilders with high-intensity resistance exercise

    OpenAIRE

    Kim, Hyerang; Lee, Saningun; Choue, Ryowon

    2011-01-01

    Abstract Background High protein diet has been known to cause metabolic acidosis, which is manifested by increased urinary excretion of nitrogen and calcium. Bodybuilders habitually consumed excessive dietary protein over the amounts recommended for them to promote muscle mass accretion. This study investigated the metabolic response to high protein consumption in the elite bodybuilders. Methods Eight elite Korean bodybuilders within the age from 18 to 25, mean age 21.5 ± 2.6. For data collec...

  16. Construction of a Genome-Scale Metabolic Model of Arthrospira platensis NIES-39 and Metabolic Design for Cyanobacterial Bioproduction.

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    Katsunori Yoshikawa

    Full Text Available Arthrospira (Spirulina platensis is a promising feedstock and host strain for bioproduction because of its high accumulation of glycogen and superior characteristics for industrial production. Metabolic simulation using a genome-scale metabolic model and flux balance analysis is a powerful method that can be used to design metabolic engineering strategies for the improvement of target molecule production. In this study, we constructed a genome-scale metabolic model of A. platensis NIES-39 including 746 metabolic reactions and 673 metabolites, and developed novel strategies to improve the production of valuable metabolites, such as glycogen and ethanol. The simulation results obtained using the metabolic model showed high consistency with experimental results for growth rates under several trophic conditions and growth capabilities on various organic substrates. The metabolic model was further applied to design a metabolic network to improve the autotrophic production of glycogen and ethanol. Decreased flux of reactions related to the TCA cycle and phosphoenolpyruvate reaction were found to improve glycogen production. Furthermore, in silico knockout simulation indicated that deletion of genes related to the respiratory chain, such as NAD(PH dehydrogenase and cytochrome-c oxidase, could enhance ethanol production by using ammonium as a nitrogen source.

  17. Endocrine, metabolic and cardiovascular responses to adrenaline after abdominal surgery

    DEFF Research Database (Denmark)

    Hilsted, J; Wilken-Jensen, Charlotte; Birch, K

    1990-01-01

    Adrenaline-induced changes in heart rate, blood pressure, plasma adrenaline and noradrenaline, cortisol, glucagon, insulin, cAMP, glucose lactate, glycerol and beta-hydroxybutyrate were studied preoperatively and 4 and 24 h after skin incision in 8 patients undergoing elective cholecystectomy. Late...... postoperative responses of blood glucose, plasma cAMP, lactate and glycerol to adrenaline infusion were reduced, whereas other responses were unaffected. Blood glucose appearance and disappearance rate as assessed by [3H]3-glucose infusion was unchanged pre- and postoperatively. The increase in glucose...... appearance rate following adrenaline was similar pre- and postoperatively. These findings suggest that several beta-receptor-mediated responses to adrenaline are reduced after abdominal surgery....

  18. Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis

    Directory of Open Access Journals (Sweden)

    Fumiaki Obata

    2014-05-01

    Full Text Available Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM levels due to glycine N-methyltransferase (Gnmt upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.

  19. Plasticity in habitat use determines metabolic response of fish to global warming in stratified lakes.

    Science.gov (United States)

    Busch, Susan; Kirillin, Georgiy; Mehner, Thomas

    2012-09-01

    We used a coupled lake physics and bioenergetics-based foraging model to evaluate how the plasticity in habitat use modifies the seasonal metabolic response of two sympatric cold-water fishes (vendace and Fontane cisco, Coregonus spp.) under a global warming scenario for the year 2100. In different simulations, the vertically migrating species performed either a plastic strategy (behavioral thermoregulation) by shifting their population depth at night to maintain the temperatures occupied at current in-situ observations, or a fixed strategy (no thermoregulation) by keeping their occupied depths at night but facing modified temperatures. The lake physics model predicted higher temperatures above 20 m and lower temperatures below 20 m in response to warming. Using temperature-zooplankton relationships, the density of zooplankton prey was predicted to increase at the surface, but to decrease in hypolimnetic waters. Simulating the fixed strategy, growth was enhanced only for the deeper-living cisco due to the shift in thermal regime at about 20 m. In contrast, simulating the plastic strategy, individual growth of cisco and young vendace was predicted to increase compared to growth currently observed in the lake. Only growth rates of older vendace are reduced under future global warming scenarios irrespective of the behavioral strategy. However, performing behavioral thermoregulation would drive both species into the same depth layers, and hence will erode vertical microhabitat segregation and intensify inter-specific competition between the coexisting coregonids.

  20. The cross-tissue metabolic response of abalone (Haliotis midae) to functional hypoxia.

    Science.gov (United States)

    Venter, Leonie; Loots, Du Toit; Mienie, Lodewyk J; Jansen van Rensburg, Peet J; Mason, Shayne; Vosloo, Andre; Lindeque, Jeremie Z

    2018-03-23

    Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone ( Haliotis midae) subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids) for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

  1. The cross-tissue metabolic response of abalone (Haliotis midae to functional hypoxia

    Directory of Open Access Journals (Sweden)

    Leonie Venter

    2018-03-01

    Full Text Available Functional hypoxia is a stress condition caused by the abalone itself as a result of increased muscle activity, which generally necessitates the employment of anaerobic metabolism if the activity is sustained for prolonged periods. With that being said, abalone are highly reliant on anaerobic metabolism to provide partial compensation for energy production during oxygen-deprived episodes. However, current knowledge on the holistic metabolic response for energy metabolism during functional hypoxia, and the contribution of different metabolic pathways and various abalone tissues towards the overall accumulation of anaerobic end-products in abalone are scarce. Metabolomics analysis of adductor muscle, foot muscle, left gill, right gill, haemolymph and epipodial tissue samples indicated that South African abalone (Haliotis midae subjected to functional hypoxia utilises predominantly anaerobic metabolism, and depends on all of the main metabolite classes (proteins, carbohydrates and lipids for energy supply. Functional hypoxia caused increased levels of anaerobic end-products: lactate, alanopine, tauropine, succinate and alanine. Also, elevation in arginine levels was detected, confirming that abalone use phosphoarginine to generate energy during functional hypoxia. Different tissues showed varied metabolic responses to hypoxia, with functional hypoxia showing excessive changes in the adductor muscle and gills. From this metabolomics investigation, it becomes evident that abalone are metabolically able to produce sufficient amounts of energy when functional hypoxia is experienced. Also, tissue interplay enables the adjustment of H. midae energy requirements as their metabolism shifts from aerobic to anaerobic respiration during functional hypoxia. This article has an associated First Person interview with the first author of the paper.

  2. Biokinetic models for the metabolism of uranium: an overview

    International Nuclear Information System (INIS)

    Bertelli, Luiz; Lipsztein, Joyce L.; Melo, Dunstana R.; Puerta, Anselmo; Wrenn, McDonald E.

    1997-01-01

    This work reviews the main experiments involving uranium injection and inhalation into several animal species and those associated with humans as well. The literature was carefully selected to involve the uranium intake, distribution and excretion in humans and mammals. The available biokinetic models for the uranium metabolism, proposed by ICRP in Publications 2, 30 and 69, were shortly described and tested against the data. Human data which incorporates measurements of urine, autopsy and biopsy samples were also used completing the review of models associated with the systemic part. (author). 21 refs., 4 figs

  3. Irisin in response to exercise in humans with and without metabolic syndrome.

    Science.gov (United States)

    Huh, Joo Young; Siopi, Aikaterina; Mougios, Vassilis; Park, Kyung Hee; Mantzoros, Christos S

    2015-03-01

    Irisin is a recently identified exercise-induced myokine. However, the circulating levels of irisin in response to different types of exercise in subjects with metabolic syndrome are unknown. This study aimed to study the levels of irisin in healthy males and subjects with metabolic syndrome at baseline and in response to exercise. Each individual completed high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE) sessions in a random, crossover design. Percentage change in circulating irisin levels was examined. Two different irisin assays were used to compare the results of the RE study. Circulating irisin increased immediately after HIIE, CME, and RE and declined 1 hour later. The increase was greater in response to resistance compared with either high-intensity intermittent exercise or CME. Change in irisin in response to exercise did not differ between individuals with and without metabolic syndrome. Exercise is able to increase circulating irisin levels in individuals with the metabolic syndrome as well as healthy individuals. Whether this increase may contribute to the beneficial effects of exercise on patients with the metabolic syndrome remains to be studied further.

  4. Common motifs in the response of cereal primary metabolism to fungal pathogens are not based on similar transcriptional reprogramming

    Directory of Open Access Journals (Sweden)

    Lars Matthias Voll

    2011-08-01

    Full Text Available During compatible interactions with their host plants, biotrophic plant pathogens subvert host metabolism to ensure the sustained provision of nutrient assimilates by the colonized host cells. To investigate, whether common motifs can be revealed in the response of primary carbon and nitrogen metabolism towards colonization with biotrophic fungi in cereal leaves, we have conducted a combined metabolome and transcriptome study of three quite divergent pathosystems, the barley powdery mildew fungus (Blumeria graminis f.sp. hordei, the corn smut fungus Ustilago maydis and the maize anthracnose fungus Colletotrichum graminicola, the latter being a hemibiotroph that only exhibits an initial biotrophic phase during its establishment.Based on the analysis of 42 water-soluble metabolites, we were able to separate early biotrophic from late biotrophic interactions by hierarchical cluster analysis and principal component analysis, irrespective of the plant host. Interestingly, the corresponding transcriptome dataset could not discriminate between these stages of biotrophy, irrespective, of whether transcript data for genes of central metabolism or the entire transcriptome dataset was used. Strong differences in the transcriptional regulation of photosynthesis, glycolysis, the TCA cycle, lipid biosynthesis, and cell wall metabolism were observed between the pathosystems. Increased contents of Gln, Asn, and glucose as well as diminished contents of PEP and 3-PGA were common to early post-penetration stages of all interactions. On the transcriptional level, genes of the TCA cycle, nucleotide energy metabolism and amino acid biosynthesis exhibited consistent trends among the compared biotrophic interactions, identifying the requirement for metabolic energy and the rearrangement of amino acid pools as common transcriptional motifs during early biotrophy. Both metabolome and transcript data were employed to generate models of leaf primary metabolism during

  5. Organ-specific metabolic responses to drought in Pinus pinaster Ait.

    Science.gov (United States)

    de Miguel, Marina; Guevara, M Ángeles; Sánchez-Gómez, David; de María, Nuria; Díaz, Luis Manuel; Mancha, Jose A; Fernández de Simón, Brígida; Cadahía, Estrella; Desai, Nalini; Aranda, Ismael; Cervera, María-Teresa

    2016-05-01

    Drought is an important driver of plant survival, growth, and distribution. Water deficit affects different pathways of metabolism, depending on plant organ. While previous studies have mainly focused on the metabolic drought response of a single organ, analysis of metabolic differences between organs is essential to achieve an integrated understanding of the whole plant response. In this work, untargeted metabolic profiling was used to examine the response of roots, stems, adult and juvenile needles from Pinus pinaster Ait. full-sib individuals, subjected to a moderate and long lasting drought period. Cyclitols content showed a significant alteration, in response to drought in all organs examined, but other metabolites increased or decreased differentially depending on the analyzed organ. While a high number of flavonoids were only detected in aerial organs, an induction of the glutathione pathway was mainly detected in roots. This result may reflect different antioxidant mechanisms activated in aerial organs and roots. Metabolic changes were more remarkable in roots than in the other organs, highlighting its prominent role in the response to water stress. Significant changes in flavonoids and ascorbate metabolism were also observed between adult and juvenile needles, consistent with previously proven differential functional responses between the two developmental stages. Genetic polymorphisms in candidate genes coding for a Myb1 transcription factor and a malate dehydrogenase (EC 1.1.1.37) were associated with different concentration of phenylalanine, phenylpropanoids and malate, respectively. The results obtained will support further research on metabolites and genes potentially involved in functional mechanisms related to drought tolerance in trees. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  6. Reconstruction of genome-scale human metabolic models using omics data

    DEFF Research Database (Denmark)

    Ryu, Jae Yong; Kim, Hyun Uk; Lee, Sang Yup

    2015-01-01

    used to describe metabolic phenotypes of healthy and diseased human tissues and cells, and to predict therapeutic targets. Here we review recent trends in genome-scale human metabolic modeling, including various generic and tissue/cell type-specific human metabolic models developed to date, and methods......, databases and platforms used to construct them. For generic human metabolic models, we pay attention to Recon 2 and HMR 2.0 with emphasis on data sources used to construct them. Draft and high-quality tissue/cell type-specific human metabolic models have been generated using these generic human metabolic...... refined through gap filling, reaction directionality assignment and the subcellular localization of metabolic reactions. We review relevant tools for this model refinement procedure as well. Finally, we suggest the direction of further studies on reconstructing an improved human metabolic model....

  7. 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

  8. Jasmonate-responsive transcription factors regulating plant secondary metabolism.

    Science.gov (United States)

    Zhou, Meiliang; Memelink, Johan

    2016-01-01

    Plants produce a large variety of secondary metabolites including alkaloids, glucosinolates, terpenoids and phenylpropanoids. These compounds play key roles in plant-environment interactions and many of them have pharmacological activity in humans. Jasmonates (JAs) are plant hormones which induce biosynthesis of many secondary metabolites. JAs-responsive transcription factors (TFs) that regulate the JAs-induced accumulation of secondary metabolites belong to different families including AP2/ERF, bHLH, MYB and WRKY. Here, we give an overview of the types and functions of TFs that have been identified in JAs-induced secondary metabolite biosynthesis, and highlight their similarities and differences in regulating various biosynthetic pathways. We review major recent developments regarding JAs-responsive TFs mediating secondary metabolite biosynthesis, and provide suggestions for further studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Dynamical feedback between circadian clock and sucrose availability explains adaptive response of starch metabolism to various photoperiods

    Directory of Open Access Journals (Sweden)

    Francois Gabriel Feugier

    2013-01-01

    Full Text Available Plants deal with resource management during all their life. During the day they feed on photosynthetic carbon, sucrose, while storing a part into starch for night use. Careful control of carbon partitioning, starch degradation and sucrose export rates is crucial to avoid carbon starvation, insuring optimal growth whatever the photoperiod. Efficient regulation of these key metabolic rates can give an evolutionary advantage to plants. Here we propose a model of adaptive starch metabolism in response to various photoperiods. We assume the three key metabolic rates to be circadian regulated in leaves and that their phases of oscillations are shifted in response to sucrose starvation. We performed gradient descents for various photoperiod conditions to find the corresponding optimal sets of phase shifts that minimize starvation. Results at convergence were all consistent with experimental data: i diurnal starch profile showed linear increase during the day and linear decrease at night; ii shorter photoperiod tended to increase starch synthesis speed while decreasing its degradation speed during the longer night; iii sudden early dusk showed slower starch degradation during the longer night. Profiles that best explained observations corresponded to circadian regulation of all rates. This theoretical study would establish a framework for future research on feedback between starch metabolism and circadian clock as well as plant productivity.

  10. Topological and kinetic determinants of the modal matrices of dynamic models of metabolism.

    Directory of Open Access Journals (Sweden)

    Bin Du

    Full Text Available Large-scale kinetic models of metabolism are becoming increasingly comprehensive and accurate. A key challenge is to understand the biochemical basis of the dynamic properties of these models. Linear analysis methods are well-established as useful tools for characterizing the dynamic response of metabolic networks. Central to linear analysis methods are two key matrices: the Jacobian matrix (J and the modal matrix (M-1 arising from its eigendecomposition. The modal matrix M-1 contains dynamically independent motions of the kinetic model near a reference state, and it is sparse in practice for metabolic networks. However, connecting the structure of M-1 to the kinetic properties of the underlying reactions is non-trivial. In this study, we analyze the relationship between J, M-1, and the kinetic properties of the underlying network for kinetic models of metabolism. Specifically, we describe the origin of mode sparsity structure based on features of the network stoichiometric matrix S and the reaction kinetic gradient matrix G. First, we show that due to the scaling of kinetic parameters in real networks, diagonal dominance occurs in a substantial fraction of the rows of J, resulting in simple modal structures with clear biological interpretations. Then, we show that more complicated modes originate from topologically-connected reactions that have similar reaction elasticities in G. These elasticities represent dynamic equilibrium balances within reactions and are key determinants of modal structure. The work presented should prove useful towards obtaining an understanding of the dynamics of kinetic models of metabolism, which are rooted in the network structure and the kinetic properties of reactions.

  11. [Response of arbuscular mycorrhizal fungal lipid metabolism to symbiotic signals in mycorrhiza].

    Science.gov (United States)

    Tian, Lei; Li, Yuanjing; Tian, Chunjie

    2016-01-04

    Arbuscular mycorrhizal (AM) fungi play an important role in energy flow and nutrient cycling, besides their wide distribution in the cosystem. With a long co-evolution, AM fungi and host plant have formed a symbiotic relationship, and fungal lipid metabolism may be the key point to find the symbiotic mechanism in arbusculart mycorrhiza. Here, we reviewed the most recent progress on the interaction between AM fungal lipid metabolism and symbiotic signaling networks, especially the response of AM fungal lipid metabolism to symbiotic signals. Furthermore, we discussed the response of AM fungal lipid storage and release to symbiotic or non-symbiotic status, and the correlation between fungal lipid metabolism and nutrient transfer in mycorrhiza. In addition, we explored the feedback of the lipolysis process to molecular signals during the establishment of symbiosis, and the corresponding material conversion and energy metabolism besides the crosstalk of fungal lipid metabolism and signaling networks. This review will help understand symbiotic mechanism of arbuscular mycorrhiza fungi and further application in ecosystem.

  12. 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

  13. Cytolytic T lymphocyte responses to metabolically inactivated stimulator cells. I. Metabolic inactivation impairs both CD and LD antigen signals

    International Nuclear Information System (INIS)

    Kelso, A.; Boyle, W.

    1982-01-01

    The effects of metabolic inactivation of spleen cells on antigen presentation to precursors of alloreactive cytolytic T lymphocytes (T/sub c/) were examined. By serological methods, populations inactivated by ultraviolet irradiation, glutaraldehyde fixation or plasma membrane isolation were found to retain normal levels of H-2K/D and Ia antigens. However, comparison of the antigen doses required to stimulate secondary T/sub c/ responses in mixed leukocyte culture showed that the inactivated preparations were approximately 10-fold less immunogenic than X-irradiated spleen cells. Their total inability to stimulate primary cytolytic responses pointed to at least a 100-fold impairment of immunogenicity for unprimed T/sub c/ precursors in the case of uv-irradiated and glutaraldehyde-treated stimulator cells, and at least a 10-fold impairment for membrane fragments. Experiments showing that the capacity of cell monolayers to absorb precursor T/sub c/ from unprimed spleen populations was reduced following uv-irradiation or glutaraldehyde treatment provided direct evidence that this loss of immunogenicity was due in part to suboptimal antigen presentation to precursor T/sub c/. It is concluded that, in addition to the traditional view that these treatments damage the ''LD'' signal to helper T lymphocytes, metabolic inactivation also impairs recognition of ''CD'' determinants by precursor T/sub c/

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

    Science.gov (United States)

    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.

  15. An age dependent model for radium metabolism in man.

    Science.gov (United States)

    Johnson, J R

    1983-01-01

    The model developed by a Task Group of Committee 2 of ICRP to describe Alkaline Earth Metabolism in Adult Man (ICRP Publication 20) has been modified so that recycling is handled explicitly, and retention in mineral bone is represented by second compartments rather than by the product of a power function and an exponential. This model has been extended to include all ages from birth to adult man, and has been coupled with modified "ICRP" lung and G.I. tract models so that activity in organs can be calculated as functions of time during or after exposures. These activities, and age dependent "specific effective energy" factors, are then used to calculate age dependent dose rates, and dose commitments. This presentation describes this work, with emphasis on the model parameters and results obtained for radium.

  16. Age-dependent metabolic model of radionuclides in Human body

    International Nuclear Information System (INIS)

    Ye Changqing

    1986-01-01

    Age-dependent metabolic model of radionuclides in human body was introduced briefly. These data are necessary in setting up the secondary dose limit of internal exposure of the general public. For the gastro-intestinal tract model, it was shown that the dose of various sections of GI tract caused by unsoluble radioactive materials were influenced by the mass of section and mean residence time, both of which are age-dependent, but the absorption fraction f 1 through gastro-intestinal tract should be corrected only for the infant less than 1 year of age. For the lung model, it was indicated that the fraction of deposition or clearance of particles in the different compartments of lung were related to age. The doses of tracheobronchial and pulmonary compartment of adult for 222 Rn or 220 Rn with their decay products were one third of that of 6-years old child who received the maximum dose in comparison with other ages. The age-dependent metabolic models in organ and/or body of Tritium, Iodine-131, Caesium-137, radioactive Strontium, Radium and Plutonium were reported. A generalized approach for estimating the effect of age on deposition fractions and retention half-time were presented. Calculated results indicated that younger ages were characterized by increased deposition fraction and decreased half-time for retention. Representative examples were provided for 21 elements of current interest in health physics

  17. DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

    Science.gov (United States)

    Baroukh, Caroline; Muñoz-Tamayo, Rafael; Steyer, Jean-Philippe; Bernard, Olivier

    2014-01-01

    Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

  18. DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

    Directory of Open Access Journals (Sweden)

    Caroline Baroukh

    Full Text Available Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

  19. Metabolic phenotype in the mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Boraschi-Diaz, Iris; Tauer, Josephine T; El-Rifai, Omar; Guillemette, Delphine; Lefebvre, Geneviève; Rauch, Frank; Ferron, Mathieu; Komarova, Svetlana V

    2017-09-01

    Osteogenesis imperfecta (OI) is the most common heritable bone fragility disorder, usually caused by dominant mutations in genes coding for collagen type I alpha chains, COL1A1 or COL1A2 Osteocalcin (OCN) is now recognized as a bone-derived regulator of insulin secretion and sensitivity and glucose homeostasis. Since OI is associated with increased rates of bone formation and resorption, we hypothesized that the levels of undercarboxylated OCN are increased in OI. The objective of this study was to determine changes in OCN and to elucidate the metabolic phenotype in the Col1a1 Jrt/+ mouse, a model of dominant OI caused by a Col1a1 mutation. Circulating levels of undercarboxylated OCN were higher in 4-week-old OI mice and normal by 8 weeks of age. Young OI animals exhibited a sex-dependent metabolic phenotype, including increased insulin levels in males, improved glucose tolerance in females, lower levels of random glucose and low adiposity in both sexes. The rates of O 2 consumption and CO 2 production, as well as energy expenditure assessed using indirect calorimetry were significantly increased in OI animals of both sexes, whereas respiratory exchange ratio was significantly higher in OI males only. Although OI mice have significant physical impairment that may contribute to metabolic differences, we specifically accounted for movement and compared OI and WT animals during the periods of similar activity levels. Taken together, our data strongly suggest that OI animals have alterations in whole body energy metabolism that are consistent with the action of undercarboxylated osteocalcin. © 2017 Society for Endocrinology.

  20. SirT1 regulates energy metabolism and response to caloric restriction in mice.

    Directory of Open Access Journals (Sweden)

    Gino Boily

    Full Text Available The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.

  1. Antarctic fish in a changing world: metabolic, osmoregulatory and endocrine stress response

    Directory of Open Access Journals (Sweden)

    Pedro Miguel Guerreiro

    2015-10-01

    Full Text Available Fish around Antarctic Peninsula are exposed to the fastest climate change rate in the planet, up to ten times higher than the global average. The evolution in extreme stenothermal isolation was a strong selective pressure for the development of a highly endemic fish fauna, with likely structural and functional constraints. To which extent can coastal notothenioid fish adjust to the conditions forecasted by the models of climate change? Experiments were run in the Arctowski (PL station at Admiralty Bay, King George Island, in 2012/13. Fish, Notothenia rossii and N. coriiceps, were collected by boat at 5-25 meter deep using fishing poles and were transferred to experimental tanks in cold rooms acclimated to natural temperatures (0-2°C. Fish were exposed to rapid/ gradual changes in water temperature or/and salinity (to 6-8°C using thermostat-controlled heaters, to 20-10‰ by addition of freshwater to recirculating tanks, over a period of up to 10 days to evaluate the response of several physiological processes. The stress endocrine axis was tested by injecting known blockers/ agonists of cortisol release and receptors. Exposure to altered conditions had no effect in immediate mortality. Increased temperature reduced overall activity and behavioral response to stimuli, although it had no clear effect on mobilization of energetic substrate. Both cortisol and gene expression of metabolic-related proteins and glucocorticoid- and mineralocorticoid receptors were modified after heat shock, but that the cortisol response to handling was reduced. The rise in temperature induced a dependent decrease in plasma osmolality while increasing branchial Na+/K+-ATPase activity, thus decreasing osmoregulatory efficiency. In conclusion, Antarctic fish are reactive to environmental change, but that their ability to accommodate rapid or adaptive responses may be compromised.

  2. Formulation, construction and analysis of kinetic models of metabolism: A review of modelling frameworks

    DEFF Research Database (Denmark)

    Saa, Pedro A.; Nielsen, Lars K.

    2017-01-01

    Kinetic models are critical to predict the dynamic behaviour of metabolic networks. Mechanistic kinetic models for large networks remain uncommon due to the difficulty of fitting their parameters. Recent modelling frameworks promise new ways to overcome this obstacle while retaining predictive ca...

  3. Radiographic and metabolic response rates following image-guided stereotactic radiotherapy for lung tumors

    International Nuclear Information System (INIS)

    Mohammed, Nasiruddin; Grills, Inga S.; Wong, Ching-Yee Oliver; Galerani, Ana Paula; Chao, Kenneth; Welsh, Robert; Chmielewski, Gary; Yan Di; Kestin, Larry L.

    2011-01-01

    Purpose: To evaluate radiographic and metabolic response after stereotactic body radiotherapy (SBRT) for early lung tumors. Materials and methods: Thirty-nine tumors were treated prospectively with SBRT (dose = 48-60 Gy, 4-5 Fx). Thirty-six cases were primary NSCLC (T1N0 = 67%; T2N0 = 25%); three cases were solitary metastases. Patients were followed using CT and PET at 6, 16, and 52 weeks post-SBRT, with CT follow-up thereafter. RECIST and EORTC criteria were used to evaluate CT and PET responses. Results: At median follow-up of 9 months (0.4-26), RECIST complete response (CR), partial response (PR), and stable disease (SD) rates were 3%, 43%, 54% at 6 weeks; 15%, 38%, 46% at 16 weeks; 27%, 64%, 9% at 52 weeks. Mean baseline tumor volume was reduced by 46%, 70%, 87%, and 96%, respectively at 6, 16, 52, and 72 weeks. Mean baseline maximum standardized uptake value (SUV) was 8.3 (1.1-20.3) and reduced to 3.4, 3.0, and 3.7 at 6, 16, and 52 weeks after SBRT. EORTC metabolic CR/PR, SD, and progressive disease rates were 67%, 22%, 11% at 6 weeks; 86%, 10%, 3% at 16 weeks; 95%, 5%, 0% at 52 weeks. Conclusions: SBRT yields excellent RECIST and EORTC based response. Metabolic response is rapid however radiographic response occurs even after 1-year post treatment.

  4. Composite PET and MRI for accurate localization and metabolic modeling

    International Nuclear Information System (INIS)

    Bidaut, L.

    1991-01-01

    This paper reports that in order to help in analyzing PET data and really take advantage of their metabolic content, a system was designed and implemented to align and process data from various medical imaging modalities, particularly (but not only) for brain studies. Although this system is for now mostly used for anatomical localization, multi-modality ROIs and pharmaco-kinetic modeling, more multi-modality protocols will be implemented in the future, not only to help in PET reconstruction data correction and semi-automated ROI definition, but also for helping in improving diagnostic accuracy along with surgery and therapy planning

  5. Adipose tissue and metabolic and inflammatory responses to stroke are altered in obese mice

    Directory of Open Access Journals (Sweden)

    Michael J. Haley

    2017-10-01

    Full Text Available Obesity is an independent risk factor for stroke, although several clinical studies have reported that obesity improves stroke outcome. Obesity is hypothesised to aid recovery by protecting against post-stroke catabolism. We therefore assessed whether obese mice had an altered metabolic and inflammatory response to stroke. Obese ob/ob mice underwent a 20-min middle cerebral artery occlusion and 24-h reperfusion. Lipid metabolism and expression of inflammatory cytokines were assessed in the plasma, liver and adipose tissue. The obese-specific metabolic response to stroke was assessed in plasma using non-targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS metabolomics coupled with univariate and multivariate analysis. Obesity had no effect on the extent of weight loss 24 h after stroke but affected the metabolic and inflammatory responses to stroke, predominantly affecting lipid metabolism. Specifically, obese mice had increases in plasma free fatty acids and expression of adipose lipolytic enzymes. Metabolomics identified several classes of metabolites affected by stroke in obese mice, including fatty acids and membrane lipids (glycerophospholipids, lysophospholipids and sphingolipids. Obesity also featured increases in inflammatory cytokines in the plasma and adipose tissue. Overall, these results demonstrate that obesity affected the acute metabolic and inflammatory response to stroke and suggest a potential role for adipose tissue in this effect. These findings could have implications for longer-term recovery and also further highlight the importance of considering comorbidities in preclinical stroke research, especially when identifying biomarkers for stroke. However, further work is required to assess whether these changes translate into long-term effects on recovery.

  6. Metabolic Responses in Endothelial Cells Following Exposure to Ketone Bodies

    Directory of Open Access Journals (Sweden)

    Erika Meroni

    2018-02-01

    Full Text Available The ketogenic diet (KD is a high-fat, low-carbohydrate diet based on the induction of the synthesis of ketone bodies (KB. Despite its widespread use, the systemic impact of KD is not completely understood. The purpose of this study was to evaluate the effects of physiological levels of KB on HMEC-1 endothelial cells. To this aim, DNA oxidative damage and the activation of Nrf2, a known transcriptional factor involved in cell responses to oxidative stress, were assessed. The exposure of cells to KB exerted a moderate genotoxic effect, measured by a significant increase in DNA oxidative damage. However, cells pre-treated with KB for 48 h and subjected to a secondary oxidative insult (H2O2, significantly decreased DNA damage compared to control oxidized cells. This protection occurred by the activation of Nrf2 pathway. In KB-treated cells, we found increased levels of Nrf2 in nuclear extracts and higher gene expression of HO-1, a target gene of Nrf2, compared to control cells. These results suggest that KB, by inducing moderate oxidative stress, activate the transcription factor Nrf2, which induces the transcription of target genes involved in the cellular antioxidant defense system.

  7. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    )-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers......The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R...... indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site...

  8. RNA metabolism in Xylella fastidiosa during cold adaptation and survival responses

    Science.gov (United States)

    Fastidious plant pathogen Xylella fastidiosa has a reduced ability to adapt to cold temperatures, limiting persistence in perennial hosts, such as grapevine, growing in colder regions. RNA metabolism is an essential part of bacterial response to low temperature, including inducible expression of RNA...

  9. The effect of environmental temperature on immune response and metabolism of the young chicken

    NARCIS (Netherlands)

    Henken, A.M.

    1982-01-01

    The effect of environmental temperature on immune response and metabolism was studied in young chickens. Immunization was performed by injecting intramuscularly 0.5 ml packed SRBC (sheep red blood cells) in both thighs of 32 days old pullets ( WarrenSSL ). The

  10. Chromium supplementation enhances the metabolic response of steers to lipopolysaccharide (LPS) challenge

    Science.gov (United States)

    The effect of chromium (Cr; KemTRACE®brandChromiumProprionate 0.04%, Kemin Industries) supplementation on the metabolic response to LPS challenge was examined. Steers (n=20; 235±4 kg body weight (BW)) received a premix that added 0 (Con) or 0.2 mg/kg Cr to the total diet (DM (dry matter) basis) for ...

  11. The structure of wheat bread influences the postprandial metabolic response in healthy men

    NARCIS (Netherlands)

    Eelderink, Coby; Noort, Martijn W. J.; Sozer, Nesli; Koehorst, Martijn; Holst, Jens J.; Deacon, Carolyn F.; Rehfeld, Jens F.; Poutanen, Kaisa; Vonk, Roel J.; Oudhuis, Lizette; Priebe, Marion G.

    2015-01-01

    Postprandial high glucose and insulin responses after starchy food consumption, associated with an increased risk of developing several metabolic diseases, could possibly be improved by altering food structure. We investigated the influence of a compact food structure; different wheat products with

  12. Effects of energy restriction on acute adrenoceptor and metabolic responses to exercise in obese subjects

    NARCIS (Netherlands)

    Kempen, K.P.G.; Saris, W.H.M.; Senden, J.M.G.; Menheere, P.P.C.A.; Blaak, E.E.; van Baak, M.A.

    1994-01-01

    Effects of energy restriction on acute adrenoceptor and metabolic responses to exercise in obese subjects. Kempen KP, Saris WH, Senden JM, Menheere PP, Blaak EE, van Baak MA. Department of Human Biology, University of Limburg, Maastricht, The Netherlands. This study was intended to investigate the

  13. Liquid scintillation vial for radiometric assay of lymphocyte carbohydrate metabolism in response to mitogens

    International Nuclear Information System (INIS)

    Tran, N.; Wagner, H.N. Jr.

    1978-01-01

    We have demonstrated that mitogens--i.e., PHA and Con.A--stimulate lymphocyte carbohydrate metabolism using a liquid-scintillation vial with conventional liquid-scintillation detectors. The results showed that this enclosed system can be useful for development of rapid in vitro tests of lymphocytes immune responsiveness, as well as for radiometric detection of bacterial growth in various gaseous atmospheres

  14. Origin of endotoxemia influences the metabolic response to endotoxin in dogs

    NARCIS (Netherlands)

    Moeniralam, H. S.; Bemelman, W. A.; Romijn, J. A.; Endert, E.; Ackermans, M. T.; van Lanschot, J. J.; Hermsen, R. C.; Sauerwein, H. P.

    1997-01-01

    Different routes of endotoxin administration have been used to mimic inflammatory and metabolic responses observed during sepsis. Because the origin of endotoxemia may affect the reactions to endotoxin, we compared the induction of tumor necrosis factor (TNF), interleukin-6 (IL-6), hormones, and

  15. 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

  16. Metabolic Modeling of Common Escherichia coli Strains in Human Gut Microbiome

    Directory of Open Access Journals (Sweden)

    Yue-Dong Gao

    2014-01-01

    Full Text Available The recent high-throughput sequencing has enabled the composition of Escherichia coli strains in the human microbial community to be profiled en masse. However, there are two challenges to address: (1 exploring the genetic differences between E. coli strains in human gut and (2 dynamic responses of E. coli to diverse stress conditions. As a result, we investigated the E. coli strains in human gut microbiome using deep sequencing data and reconstructed genome-wide metabolic networks for the three most common E. coli strains, including E. coli HS, UTI89, and CFT073. The metabolic models show obvious strain-specific characteristics, both in network contents and in behaviors. We predicted optimal biomass production for three models on four different carbon sources (acetate, ethanol, glucose, and succinate and found that these stress-associated genes were involved in host-microbial interactions and increased in human obesity. Besides, it shows that the growth rates are similar among the models, but the flux distributions are different, even in E. coli core reactions. The correlations between human diabetes-associated metabolic reactions in the E. coli models were also predicted. The study provides a systems perspective on E. coli strains in human gut microbiome and will be helpful in integrating diverse data sources in the following study.

  17. Circadian clock genes Per1 and Per2 regulate the response of metabolism-associated transcripts to sleep disruption.

    Directory of Open Access Journals (Sweden)

    Jana Husse

    Full Text Available Human and animal studies demonstrate that short sleep or poor sleep quality, e.g. in night shift workers, promote the development of obesity and diabetes. Effects of sleep disruption on glucose homeostasis and liver physiology are well documented. However, changes in adipokine levels after sleep disruption suggest that adipocytes might be another important peripheral target of sleep. Circadian clocks regulate metabolic homeostasis and clock disruption can result in obesity and the metabolic syndrome. The finding that sleep and clock disruption have very similar metabolic effects prompted us to ask whether the circadian clock machinery may mediate the metabolic consequences of sleep disruption. To test this we analyzed energy homeostasis and adipocyte transcriptome regulation in a mouse model of shift work, in which we prevented mice from sleeping during the first six hours of their normal inactive phase for five consecutive days (timed sleep restriction--TSR. We compared the effects of TSR between wild-type and Per1/2 double mutant mice with the prediction that the absence of a circadian clock in Per1/2 mutants would result in a blunted metabolic response to TSR. In wild-types, TSR induces significant transcriptional reprogramming of white adipose tissue, suggestive of increased lipogenesis, together with increased secretion of the adipokine leptin and increased food intake, hallmarks of obesity and associated leptin resistance. Some of these changes persist for at least one week after the end of TSR, indicating that even short episodes of sleep disruption can induce prolonged physiological impairments. In contrast, Per1/2 deficient mice show blunted effects of TSR on food intake, leptin levels and adipose transcription. We conclude that the absence of a functional clock in Per1/2 double mutants protects these mice from TSR-induced metabolic reprogramming, suggesting a role of the circadian timing system in regulating the physiological effects

  18. Modelling central metabolic fluxes by constraint-based optimization reveals metabolic reprogramming of developing Solanum lycopersicum (tomato) fruit.

    Science.gov (United States)

    Colombié, Sophie; Nazaret, Christine; Bénard, Camille; Biais, Benoît; Mengin, Virginie; Solé, Marion; Fouillen, Laëtitia; Dieuaide-Noubhani, Martine; Mazat, Jean-Pierre; Beauvoit, Bertrand; Gibon, Yves

    2015-01-01

    Modelling of metabolic networks is a powerful tool to analyse the behaviour of developing plant organs, including fruits. Guided by our current understanding of heterotrophic metabolism of plant cells, a medium-scale stoichiometric model, including the balance of co-factors and energy, was constructed in order to describe metabolic shifts that occur through the nine sequential stages of Solanum lycopersicum (tomato) fruit development. The measured concentrations of the main biomass components and the accumulated metabolites in the pericarp, determined at each stage, were fitted in order to calculate, by derivation, the corresponding external fluxes. They were used as constraints to solve the model by minimizing the internal fluxes. The distribution of the calculated fluxes of central metabolism were then analysed and compared with known metabolic behaviours. For instance, the partition of the main metabolic pathways (glycolysis, pentose phosphate pathway, etc.) was relevant throughout fruit development. We also predicted a valid import of carbon and nitrogen by the fruit, as well as a consistent CO2 release. Interestingly, the energetic balance indicates that excess ATP is dissipated just before the onset of ripening, supporting the concept of the climacteric crisis. Finally, the apparent contradiction between calculated fluxes with low values compared with measured enzyme capacities suggest a complex reprogramming of the metabolic machinery during fruit development. With a powerful set of experimental data and an accurate definition of the metabolic system, this work provides important insight into the metabolic and physiological requirements of the developing tomato fruits. © 2014 The Authors The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.

  19. Larval starvation improves metabolic response to adult starvation in honey bees (Apis mellifera L.).

    Science.gov (United States)

    Wang, Ying; Campbell, Jacob B; Kaftanoglu, Osman; Page, Robert E; Amdam, Gro V; Harrison, Jon F

    2016-04-01

    Environmental changes during development have long-term effects on adult phenotypes in diverse organisms. Some of the effects play important roles in helping organisms adapt to different environments, such as insect polymorphism. Others, especially those resulting from an adverse developmental environment, have a negative effect on adult health and fitness. However, recent studies have shown that those phenotypes influenced by early environmental adversity have adaptive value under certain (anticipatory) conditions that are similar to the developmental environment, though evidence is mostly from morphological and behavioral observations and it is still rare at physiological and molecular levels. In the companion study, we applied a short-term starvation treatment to fifth instar honey bee larvae and measured changes in adult morphology, starvation resistance, hormonal and metabolic physiology and gene expression. Our results suggest that honey bees can adaptively respond to the predicted nutritional stress. In the present study, we further hypothesized that developmental starvation specifically improves the metabolic response of adult bees to starvation instead of globally affecting metabolism under well-fed conditions. Here, we produced adult honey bees that had experienced a short-term larval starvation, then we starved them for 12 h and monitored metabolic rate, blood sugar concentrations and metabolic reserves. We found that the bees that experienced larval starvation were able to shift to other fuels faster and better maintain stable blood sugar levels during starvation. However, developmental nutritional stress did not change metabolic rates or blood sugar levels in adult bees under normal conditions. Overall, our study provides further evidence that early larval starvation specifically improves the metabolic responses to adult starvation in honey bees. © 2016. Published by The Company of Biologists Ltd.

  20. In silico strain optimization by adding reactions to metabolic models.

    Science.gov (United States)

    Correia, Sara; Rocha, Miguel

    2012-07-24

    Nowadays, the concerns about the environment and the needs to increase the productivity at low costs, demand for the search of new ways to produce compounds with industrial interest. Based on the increasing knowledge of biological processes, through genome sequencing projects, and high-throughput experimental techniques as well as the available computational tools, the use of microorganisms has been considered as an approach to produce desirable compounds. However, this usually requires to manipulate these organisms by genetic engineering and/ or changing the enviromental conditions to make the production of these compounds possible. In many cases, it is necessary to enrich the genetic material of those microbes with hereologous pathways from other species and consequently adding the potential to produce novel compounds. This paper introduces a new plug-in for the OptFlux Metabolic Engineering platform, aimed at finding suitable sets of reactions to add to the genomes of selected microbes (wild type strain), as well as finding complementary sets of deletions, so that the mutant becomes able to overproduce compounds with industrial interest, while preserving their viability. The necessity of adding reactions to the metabolic model arises from existing gaps in the original model or motivated by the productions of new compounds by the organism. The optimization methods used are metaheuristics such as Evolutionary Algorithms and Simulated Annealing. The usefulness of this plug-in is demonstrated by a case study, regarding the production of vanillin by the bacterium E. coli.

  1. 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.

  2. Impact of prebiotics on metabolic and behavioral alterations in a mouse model of metabolic syndrome.

    Science.gov (United States)

    de Cossío, Lourdes Fernández; Fourrier, Célia; Sauvant, Julie; Everard, Amandine; Capuron, Lucile; Cani, Patrice D; Layé, Sophie; Castanon, Nathalie

    2017-08-01

    Mounting evidence shows that the gut microbiota, an important player within the gut-brain communication axis, can affect metabolism, inflammation, brain function and behavior. Interestingly, gut microbiota composition is known to be altered in patients with metabolic syndrome (MetS), who also often display neuropsychiatric symptoms. The use of prebiotics, which beneficially alters the microbiota, may therefore be a promising way to potentially improve physical and mental health in MetS patients. This hypothesis was tested in a mouse model of MetS, namely the obese and type-2 diabetic db/db mice, which display emotional and cognitive alterations associated with changes in gut microbiota composition and hippocampal inflammation compared to their lean db/+ littermates. We assessed the impact of chronic administration (8weeks) of prebiotics (oligofructose) on both metabolic (body weight, food intake, glucose homeostasis) and behavioral (increased anxiety-like behavior and impaired spatial memory) alterations characterizing db/db mice, as well as related neurobiological correlates, with particular attention to neuroinflammatory processes. Prebiotic administration improved excessive food intake and glycemic dysregulations (glucose tolerance and insulin resistance) in db/db mice. This was accompanied by an increase of plasma anti-inflammatory cytokine IL-10 levels and hypothalamic mRNA expression of the anorexigenic cytokine IL-1β, whereas unbalanced mRNA expression of hypothalamic orexigenic (NPY) and anorexigenic (CART, POMC) peptides was unchanged. We also detected signs of improved blood-brain-barrier integrity in the hypothalamus of oligofructose-treated db/db mice (normalized expression of tight junction proteins ZO-1 and occludin). On the contrary, prebiotic administration did not improve behavioral alterations and associated reduction of hippocampal neurogenesis displayed by db/db mice, despite normalization of increased hippocampal IL-6 mRNA expression. Of note

  3. The metabolic cost of mounting an immune response in male brown anoles (Anolis sagrei).

    Science.gov (United States)

    Cox, Christian L; Peaden, Robert T; Cox, Robert M

    2015-09-09

    The tradeoff between reproduction and survival is central to life-history theory and is thought to reflect underlying energetic tradeoffs between reproduction and self-maintenance. Immune responses to parasites and pathogens are important components of self-maintenance in many species, but whether these defenses impose significant energetic costs has only been tested in a handful of organisms. We tested for a metabolic cost of mounting an immune response in the male brown anole (Anolis sagrei), a lizard in which we have previously shown that reproduction causes a marked reduction in immune response to the novel antigen phytohaemagglutinin (PHA). We treated captive male anoles with a subcutaneous injection of either PHA, which induces an immune response that manifests as localized swelling, or saline vehicle as a control. Prior to injection and at 24, 48, and 72 hr post-injection, we measured swelling at the site of injection and whole-animal resting metabolic rate (RMR) using stop-flow respirometry. Although we detected a robust swelling response to PHA at 24, 48, and 72 hr post-injection, mean RMR did not differ between treatments at any of these time points. However, within the PHA treatment group, RMR increased with the extent of swelling, suggesting a variable metabolic cost that scales with the magnitude of the induced immune response. Although individual anoles varied considerably in the extent to which they responded to PHA challenge, our results suggest that an immune response can impose a substantial metabolic cost (potentially as much as 63% above baseline RMR) for individuals that do respond maximally. J. Exp. Zool. 9999A:XX-XX, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  4. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-01-01

    Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

  5. Seaweed supplements normalise metabolic, cardiovascular and liver responses in high-carbohydrate, high-fat fed rats.

    Science.gov (United States)

    Kumar, Senthil Arun; Magnusson, Marie; Ward, Leigh C; Paul, Nicholas A; Brown, Lindsay

    2015-02-02

    Increased seaweed consumption may be linked to the lower incidence of metabolic syndrome in eastern Asia. This study investigated the responses to two tropical green seaweeds, Ulva ohnoi (UO) and Derbesia tenuissima (DT), in a rat model of human metabolic syndrome. Male Wistar rats (330-340 g) were fed either a corn starch-rich diet or a high-carbohydrate, high-fat diet with 25% fructose in drinking water, for 16 weeks. High-carbohydrate, high-fat diet-fed rats showed the signs of metabolic syndrome leading to abdominal obesity, cardiovascular remodelling and non-alcoholic fatty liver disease. Food was supplemented with 5% dried UO or DT for the final 8 weeks only. UO lowered total final body fat mass by 24%, systolic blood pressure by 29 mmHg, and improved glucose utilisation and insulin sensitivity. In contrast, DT did not change total body fat mass but decreased plasma triglycerides by 38% and total cholesterol by 17%. UO contained 18.1% soluble fibre as part of 40.9% total fibre, and increased magnesium, while DT contained 23.4% total fibre, essentially as insoluble fibre. UO was more effective in reducing metabolic syndrome than DT, possibly due to the increased intake of soluble fibre and magnesium.

  6. Seaweed Supplements Normalise Metabolic, Cardiovascular and Liver Responses in High-Carbohydrate, High-Fat Fed Rats

    Directory of Open Access Journals (Sweden)

    Senthil Arun Kumar

    2015-02-01

    Full Text Available Increased seaweed consumption may be linked to the lower incidence of metabolic syndrome in eastern Asia. This study investigated the responses to two tropical green seaweeds, Ulva ohnoi (UO and Derbesia tenuissima (DT, in a rat model of human metabolic syndrome. Male Wistar rats (330–340 g were fed either a corn starch-rich diet or a high-carbohydrate, high-fat diet with 25% fructose in drinking water, for 16 weeks. High-carbohydrate, high-fat diet-fed rats showed the signs of metabolic syndrome leading to abdominal obesity, cardiovascular remodelling and non-alcoholic fatty liver disease. Food was supplemented with 5% dried UO or DT for the final 8 weeks only. UO lowered total final body fat mass by 24%, systolic blood pressure by 29 mmHg, and improved glucose utilisation and insulin sensitivity. In contrast, DT did not change total body fat mass but decreased plasma triglycerides by 38% and total cholesterol by 17%. UO contained 18.1% soluble fibre as part of 40.9% total fibre, and increased magnesium, while DT contained 23.4% total fibre, essentially as insoluble fibre. UO was more effective in reducing metabolic syndrome than DT, possibly due to the increased intake of soluble fibre and magnesium.

  7. Seaweed Supplements Normalise Metabolic, Cardiovascular and Liver Responses in High-Carbohydrate, High-Fat Fed Rats

    Science.gov (United States)

    Kumar, Senthil Arun; Magnusson, Marie; Ward, Leigh C.; Paul, Nicholas A.; Brown, Lindsay

    2015-01-01

    Increased seaweed consumption may be linked to the lower incidence of metabolic syndrome in eastern Asia. This study investigated the responses to two tropical green seaweeds, Ulva ohnoi (UO) and Derbesia tenuissima (DT), in a rat model of human metabolic syndrome. Male Wistar rats (330–340 g) were fed either a corn starch-rich diet or a high-carbohydrate, high-fat diet with 25% fructose in drinking water, for 16 weeks. High-carbohydrate, high-fat diet-fed rats showed the signs of metabolic syndrome leading to abdominal obesity, cardiovascular remodelling and non-alcoholic fatty liver disease. Food was supplemented with 5% dried UO or DT for the final 8 weeks only. UO lowered total final body fat mass by 24%, systolic blood pressure by 29 mmHg, and improved glucose utilisation and insulin sensitivity. In contrast, DT did not change total body fat mass but decreased plasma triglycerides by 38% and total cholesterol by 17%. UO contained 18.1% soluble fibre as part of 40.9% total fibre, and increased magnesium, while DT contained 23.4% total fibre, essentially as insoluble fibre. UO was more effective in reducing metabolic syndrome than DT, possibly due to the increased intake of soluble fibre and magnesium. PMID:25648511

  8. Metabolic modelling of polyhydroxyalkanoate copolymers production by mixed microbial cultures

    Directory of Open Access Journals (Sweden)

    Reis Maria AM

    2008-07-01

    Full Text Available Abstract Background This paper presents a metabolic model describing the production of polyhydroxyalkanoate (PHA copolymers in mixed microbial cultures, using mixtures of acetic and propionic acid as carbon source material. Material and energetic balances were established on the basis of previously elucidated metabolic pathways. Equations were derived for the theoretical yields for cell growth and PHA production on mixtures of acetic and propionic acid as functions of the oxidative phosphorylation efficiency, P/O ratio. The oxidative phosphorylation efficiency was estimated from rate measurements, which in turn allowed the estimation of the theoretical yield coefficients. Results The model was validated with experimental data collected in a sequencing batch reactor (SBR operated under varying feeding conditions: feeding of acetic and propionic acid separately (control experiments, and the feeding of acetic and propionic acid simultaneously. Two different feast and famine culture enrichment strategies were studied: (i either with acetate or (ii with propionate as carbon source material. Metabolic flux analysis (MFA was performed for the different feeding conditions and culture enrichment strategies. Flux balance analysis (FBA was used to calculate optimal feeding scenarios for high quality PHA polymers production, where it was found that a suitable polymer would be obtained when acetate is fed in excess and the feeding rate of propionate is limited to ~0.17 C-mol/(C-mol.h. The results were compared with published pure culture metabolic studies. Conclusion Acetate was more conducive toward the enrichment of a microbial culture with higher PHA storage fluxes and yields as compared to propionate. The P/O ratio was not only influenced by the selected microbial culture, but also by the carbon substrate fed to each culture, where higher P/O ratio values were consistently observed for acetate than propionate. MFA studies suggest that when mixtures of

  9. Genome-scale modeling using flux ratio constraints to enable metabolic engineering of clostridial metabolism in silico.

    Science.gov (United States)

    McAnulty, Michael J; Yen, Jiun Y; Freedman, Benjamin G; Senger, Ryan S

    2012-05-14

    Genome-scale metabolic networks and flux models are an effective platform for linking an organism genotype to its phenotype. However, few modeling approaches offer predictive capabilities to evaluate potential metabolic engineering strategies in silico. A new method called "flux balance analysis with flux ratios (FBrAtio)" was developed in this research and applied to a new genome-scale model of Clostridium acetobutylicum ATCC 824 (iCAC490) that contains 707 metabolites and 794 reactions. FBrAtio was used to model wild-type metabolism and metabolically engineered strains of C. acetobutylicum where only flux ratio constraints and thermodynamic reversibility of reactions were required. The FBrAtio approach allowed solutions to be found through standard linear programming. Five flux ratio constraints were required to achieve a qualitative picture of wild-type metabolism for C. acetobutylicum for the production of: (i) acetate, (ii) lactate, (iii) butyrate, (iv) acetone, (v) butanol, (vi) ethanol, (vii) CO2 and (viii) H2. Results of this simulation study coincide with published experimental results and show the knockdown of the acetoacetyl-CoA transferase increases butanol to acetone selectivity, while the simultaneous over-expression of the aldehyde/alcohol dehydrogenase greatly increases ethanol production. FBrAtio is a promising new method for constraining genome-scale models using internal flux ratios. The method was effective for modeling wild-type and engineered strains of C. acetobutylicum.

  10. Computer modelling of HT gas metabolism in humans

    International Nuclear Information System (INIS)

    Peterman, B.F.

    1982-01-01

    A mathematical model was developed to simulate the metabolism of HT gas in humans. The rate constants of the model were estimated by fitting the calculated curves to the experimental data by Pinson and Langham in 1957. The calculations suggest that the oxidation of HT gas (which probably occurs as a result of the enzymatic action of hydrogenase present in bacteria of human gut) occurs at a relatively low rate with a half-time of 10-12 hours. The inclusion of the dose due to the production of the HT oxidation product (HTO) in the soft tissues lowers the value of derived air concentration by about 50%. Furthermore the relationship between the concentration of HTO in urine and the dose to the lung from HT in the air in lungs is linear after short HT exposures, and hence HTO concentrations in urine can be used to estimate the upper limits on the lung dose from HT exposures. (author)

  11. Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase.

    Science.gov (United States)

    Choi, Hyun B; Gordon, Grant R J; Zhou, Ning; Tai, Chao; Rungta, Ravi L; Martinez, Jennifer; Milner, Teresa A; Ryu, Jae K; McLarnon, James G; Tresguerres, Martin; Levin, Lonny R; Buck, Jochen; MacVicar, Brian A

    2012-09-20

    Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO₃⁻) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO₃⁻ entry via the electrogenic NaHCO₃ cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K⁺](ext) and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Muscular and metabolic responses to different Nordic walking techniques, when style matters.

    Science.gov (United States)

    Pellegrini, Barbara; Boccia, Gennaro; Zoppirolli, Chiara; Rosa, Raffaela; Stella, Federico; Bortolan, Lorenzo; Rainoldi, Alberto; Schena, Federico

    2018-01-01

    Due to poling action and upper body engagement, Nordic walking (NW) has additional health benefits with respect to conventional walking. The aim of this study was to evaluate the differences in muscle activation and metabolic responses between NW, performed with the technique suggested by NW instructors, and with some modifications in the way to move upper limb and poles. Ten NW instructors volunteered to walk on a treadmill at 5.5 km•h-1 in five conditions: walking (W), Nordic walking (NW), NW with a weak poling action (NWweak), with straight-upper limbs moving the shoulders (NWshoulder) and with elbow flexion-extension pattern and shoulder freezed (NWelbow). Poling forces, body segments and poles movement, upper and lower body muscle activation, as well as metabolic parameters were measured.All modified NW techniques elicited lower muscular activation and metabolic responses with respect to the suggested NW technique (P walking instructors, sport technicians and practitioners should be aware that any deviation from the technique usually suggested might lead to lower benefits. However it is worth to note that any walking technique with poles elicits higher metabolic responses and muscular activation than walking.

  13. Comprehensive Mapping of Pluripotent Stem Cell Metabolism Using Dynamic Genome-Scale Network Modeling

    Directory of Open Access Journals (Sweden)

    Sriram Chandrasekaran

    2017-12-01

    Full Text Available Summary: Metabolism is an emerging stem cell hallmark tied to cell fate, pluripotency, and self-renewal, yet systems-level understanding of stem cell metabolism has been limited by the lack of genome-scale network models. Here, we develop a systems approach to integrate time-course metabolomics data with a computational model of metabolism to analyze the metabolic state of naive and primed murine pluripotent stem cells. Using this approach, we find that one-carbon metabolism involving phosphoglycerate dehydrogenase, folate synthesis, and nucleotide synthesis is a key pathway that differs between the two states, resulting in differential sensitivity to anti-folates. The model also predicts that the pluripotency factor Lin28 regulates this one-carbon metabolic pathway, which we validate using metabolomics data from Lin28-deficient cells. Moreover, we identify and validate metabolic reactions related to S-adenosyl-methionine production that can differentially impact histone methylation in naive and primed cells. Our network-based approach provides a framework for characterizing metabolic changes influencing pluripotency and cell fate. : Chandrasekaran et al. use computational modeling, metabolomics, and metabolic inhibitors to discover metabolic differences between various pluripotent stem cell states and infer their impact on stem cell fate decisions. Keywords: systems biology, stem cell biology, metabolism, genome-scale modeling, pluripotency, histone methylation, naive (ground state, primed state, cell fate, metabolic network

  14. Changes in energy metabolism in response to 48 h of overfeeding and fasting in Caucasians and Pima Indians

    DEFF Research Database (Denmark)

    Weyer, C; Vozarova, B; Ravussin, E

    2001-01-01

    Differences in the metabolic response to overfeeding and starvation may confer susceptibility or resistance to obesity in humans. To further examine this hypothesis, we assessed the changes in 24 h energy metabolism in response to short-term overfeeding and fasting in Caucasians (C) and Pima...... Indians (I), a population with a very high propensity for obesity....

  15. Investigating the Cellular and Metabolic Responses of World-Class Canoeists Training: A Sportomics Approach

    Directory of Open Access Journals (Sweden)

    Wagner Santos Coelho

    2016-11-01

    Full Text Available (1 Background: We have been using the Sportomics approach to evaluate biochemical and hematological changes in response to exercise. The aim of this study was to evaluate the metabolic and hematologic responses of world-class canoeists during a training session; (2 Methods: Blood samples were taken at different points and analyzed for their hematological properties, activities of selected enzymes, hormones, and metabolites; (3 Results: Muscle stress biomarkers were elevated in response to exercise which correlated with modifications in the profile of white blood cells, where a leukocyte rise was observed after the canoe session. These results were accompanied by an increase in other exercise intensity parameters such as lactatemia and ammonemia. Adrenocorticotropic hormone and cortisol increased during the exercise sessions. The acute rise in both erythrocytes and white blood profile were probably due to muscle cell damage, rather than hepatocyte integrity impairment; (4 Conclusion: The cellular and metabolic responses found here, together with effective nutrition support, are crucial to understanding the effects of exercise in order to assist in the creation of new training and recovery planning. Also we show that Sportomics is a primal tool for training management and performance improvement, as well as to the understanding of metabolic response to exercise.

  16. Metabolic response to optic centers to visual stimuli in the albino rat: anatomical and physiological considerations

    International Nuclear Information System (INIS)

    Toga, A.W.; Collins, R.C.

    1981-01-01

    The functional organization of the visual system was studied in the albino rat. Metabolic differences were measured using the 14 C-2-deoxyglucose (DG) autoradiographic technique during visual stimulation of one entire retina in unrestrained animals. All optic centers responded to changes in light intensity but to different degrees. The greatest change occurred in the superior colliculus, less in the lateral geniculate, and considerably less in second-order sites such as layer IV of visual cortex. These optic centers responded in particular to on/off stimuli, but showed no incremental change during pattern reversal or movement of orientation stimuli. Both the superior colliculus and lateral geniculate increased their metabolic rate as the frequency of stimulation increased, but the magnitude was twice as great in the colliculus. The histological pattern of metabolic change in the visual system was not homogenous. In the superior colliculus glucose utilization increased only in stratum griseum superficiale and was greatest in visuotopic regions representing the peripheral portions of the visual field. Similarly, in the lateral geniculate, only the dorsal nucleus showed an increased response to greater stimulus frequencies. Second-order regions of the visual system showed changes in metabolism in response to visual stimulation, but no incremental response specific for type or frequency of stimuli. To label proteins of axoplasmic transport to study the terminal fields of retinal projections 14 C-amino acids were used. This was done to study how the differences in the magnitude of the metabolic response among optic centers were related to the relative quantity of retinofugal projections to these centers

  17. Transcriptome Analysis Identifies Key Metabolic Changes in the Hooded Seal (Cystophora cristata Brain in Response to Hypoxia and Reoxygenation.

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    Mariana Leivas Müller Hoff

    Full Text Available The brain of diving mammals tolerates low oxygen conditions better than the brain of most terrestrial mammals. Previously, it has been demonstrated that the neurons in brain slices of the hooded seal (Cystophora cristata withstand hypoxia longer than those of mouse, and also tolerate reduced glucose supply and high lactate concentrations. This tolerance appears to be accompanied by a shift in the oxidative energy metabolism to the astrocytes in the seal while in terrestrial mammals the aerobic energy production mainly takes place in neurons. Here, we used RNA-Seq to compare the effect of hypoxia and reoxygenation in vitro on brain slices from the visual cortex of hooded seals. We saw no general reduction of gene expression, suggesting that the response to hypoxia and reoxygenation is an actively regulated process. The treatments caused the preferential upregulation of genes related to inflammation, as found before e.g. in stroke studies using mammalian models. Gene ontology and KEGG pathway analyses showed a downregulation of genes involved in ion transport and other neuronal processes, indicative for a neuronal shutdown in response to a shortage of O2 supply. These differences may be interpreted in terms of an energy saving strategy in the seal's brain. We specifically analyzed the regulation of genes involved in energy metabolism. Hypoxia and reoxygenation caused a similar response, with upregulation of genes involved in glucose metabolism and downregulation of the components of the pyruvate dehydrogenase complex. We also observed upregulation of the monocarboxylate transporter Mct4, suggesting increased lactate efflux. Together, these data indicate that the seal brain responds to the hypoxic challenge by a relative increase in the anaerobic energy metabolism.

  18. Modeling the role of negative cooperativity in metabolic regulation and homeostasis.

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    Eliot C Bush

    Full Text Available A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.

  19. Role of Glucocorticoids in the Response to Unloading of Muscle Protein and Amino Acid Metabolism

    Science.gov (United States)

    Tischler, M. E.; Jaspers, S. R.

    1985-01-01

    Intact control (weight bearing) and suspended rats gained weight at a similar rate during a 6 day period. Adrenaectomized (adx) weight bearing rats gained less weight during this period while adrenalectomized suspended rats showed no significant weight gain. Cortisol treatment of both of these groups of animals caused a loss of body weight. Results from these studies show several important findings: (1) Metabolic changes in the extensor digitorum longus muscle of suspended rats are due primarily to increased circulating gluccorticoids; (2) Metabolic changes in the soleus due to higher steroid levels are probably potentiated by greater numbers of receptors; and (3) Not all metabolic responses in the unloaded soleus muscle are due to direct action of elevated glucocorticoids or increased sensitivity to these hormones.

  20. Brain glucose metabolism in an animal model of depression.

    Science.gov (United States)

    Detka, J; Kurek, A; Kucharczyk, M; Głombik, K; Basta-Kaim, A; Kubera, M; Lasoń, W; Budziszewska, B

    2015-06-04

    An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to

  1. The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism

    Directory of Open Access Journals (Sweden)

    Katsumi Iizuka

    2017-02-01

    Full Text Available Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP is a glucose-activated transcription factor that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase, fructolysis (Glut5, ketohexokinase, and lipogenesis (acetyl CoA carboxylase, fatty acid synthase. ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp−/− mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as fibroblast growth factor-21 and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome.

  2. Dynamic Responses of Phosphorus Metabolism to Acute and Chronic Dietary Phosphorus-Limitation in Daphnia

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    Nicole D. Wagner

    2017-06-01

    Full Text Available Food quality is highly dynamic within lake ecosystems and varies spatially and temporally over the growing season. Consumers may need to continuously adjust their metabolism in response to this variation in dietary nutrient content. However, the rates of metabolic responses to changes in food nutrient content has received little direct study. Here, we examine responses in two metabolic phosphorus (P pools, ribonucleic acids (RNA and adenosine triphosphate (ATP, along with body mass and body P content in Daphnia magna exposed to chronic and acute dietary P-limitation. First, we examined food quality effects on animals consuming different food carbon (C:P quality over a 14 day period. Then, we raised daphnids on one food quality for 4 days, switched them to contrasting dietary treatments, and measured changes in their metabolic responses at shorter time-scales (over 48 h. Animal P, RNA, and ATP content all changed through ontogeny with adults containing relatively less of these pools with increasing body mass. Irrespective of age, Daphnia consuming high C:P diets had lower body %P, %RNA, %ATP, and mass compared to animals eating low C:P diets. Diet switching experiments revealed diet dependent changes in body %P, %RNA, %ATP, and animal mass within 48 h. We found that Daphnia switched from low to high C:P diets had some metabolic buffering capacity with decreases in body %P occurring after 24 h but mass remaining similar to initial diet conditions for 36 h after the diet switch. Switching Daphnia from low to high C:P diets caused a decrease in the RNA:P ratio after 48 h. Daphnia switched from high to low C:P diets increased their body P, RNA, and ATP content within 8–24 h. This switch from high to low C:P diets also led to increased RNA:P ratios in animal bodies. Overall, our study revealed that consumer P metabolism reflects both current and past diet due to more dynamic and rapid changes in P biochemistry than total body mass. This metabolic

  3. STRESS RESPONSE STUDIES USING ANIMAL MODELS

    Science.gov (United States)

    This presentation will provide the evidence that ozone exposure in animal models induce neuroendocrine stress response and this stress response modulates lung injury and inflammation through adrenergic and glucocorticoid receptors.

  4. Ruminant Nutrition Symposium: ruminant production and metabolic responses to heat stress.

    Science.gov (United States)

    Baumgard, L H; Rhoads, R P

    2012-06-01

    Heat stress compromises efficient animal production by marginalizing nutrition, management, and genetic selection efforts to maximize performance endpoints. Modifying farm infrastructure has yielded modest success in mitigating heat stress-related losses, yet poor production during the summer remains arguably the costliest issue facing livestock producers. Reduced output (e.g., milk yield and muscle growth) during heat stress was traditionally thought to result from decreased nutrient intake (i.e., a classic biological response shared by all animals during environmental-induced hyperthermia). Our recent observations have begun to challenge this belief and indicate heat-stressed animals employ novel homeorhetic strategies to direct metabolic and fuel selection priorities independently of nutrient intake or energy balance. Alterations in systemic physiology support a shift in carbohydrate metabolism, evident by increased basal and stimulated circulating insulin concentrations. Perhaps most intriguing given the energetic shortfall of the heat-stressed animal is the apparent lack of basal adipose tissue mobilization coupled with a reduced responsiveness to lipolytic stimuli. Thus, the heat stress response markedly alters postabsorptive carbohydrate, lipid, and protein metabolism independently of reduced feed intake through coordinated changes in fuel supply and utilization by multiple tissues. Interestingly, the systemic, cellular, and molecular changes appear conserved amongst different species and physiological states. Ultimately, these changes result in the reprioritization of fuel selection during heat stress, which appears to be primarily responsible for reduced ruminant animal productivity during the warm summer months.

  5. Maternal Diet, Metabolic State, and Inflammatory Response Exert Unique and Long-Lasting Influences on Offspring Behavior in Non-Human Primates

    Directory of Open Access Journals (Sweden)

    Jacqueline R. Thompson

    2018-04-01

    Full Text Available Nutritional status influences brain health and gestational exposure to metabolic disorders (e.g. obesity and diabetes increases the risk of neuropsychiatric disorders. The aim of the present study was to further investigate the role of maternal Western-style diet (WSD, metabolic state, and inflammatory factors in the programming of Japanese macaque offspring behavior. Utilizing structural equation modeling, we investigated the relationships between maternal diet, prepregnancy adiposity, third trimester insulin response, and plasma cytokine levels on 11-month-old offspring behavior. Maternal WSD was associated with greater reactive and ritualized anxiety in offspring. Maternal adiposity and third trimester macrophage-derived chemokine (MDC exerted opposing effects on offspring high-energy outbursts. Elevated levels of this behavior were associated with low maternal MDC and increased prepregnancy adiposity. This is the first study to show that maternal MDC levels influence offspring behavior. We found no evidence suggesting maternal peripheral inflammatory response mediated the effect of maternal diet and metabolic state on aberrant offspring behavior. Additionally, the extent of maternal metabolic impairment differentially influenced chemokine response. Elevated prepregnancy adiposity suppressed third trimester chemokines, while obesity-induced insulin resistance augmented peripheral chemokine levels. WSD also directly increased maternal interleukin-12. This is the first non-human primate study to delineate the effects of maternal diet and metabolic state on gestational inflammatory environment and subsequent offspring behavior. Our findings give insight to the complex mechanisms by which diet, metabolic state, and inflammation during pregnancy exert unique influences on offspring behavioral regulation.

  6. Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction.

    Science.gov (United States)

    Volek, Jeff S; Feinman, Richard D

    2005-11-16

    surprising but has not been explicitly stated before. The known effects of CHO-induced hypertriglyceridemia, the HDL-lowering effect of low fat, high CHO interventions and the obvious improvement in glucose and insulin from CHO restriction should have made this evident. In addition, recent studies suggest that a subset of MetS, the ratio of TAG/HDL, is a good marker for insulin resistance and risk of CVD, and this indicator is reliably reduced by CHO restriction and exacerbated by high CHO intake. Inability to make this connection in the past has probably been due to the fact that individual responses have been studied in isolation as well as to the emphasis of traditional therapeutic approaches on low fat rather than low CHO. We emphasize that MetS is not a disease but a collection of markers. Individual physicians must decide whether high LDL, or other risk factors are more important than the features of MetS in any individual case but if MetS is to be considered it should be recognized that reducing CHO will bring improvement. Response of symptoms to CHO restriction might thus provide a new experimental criterion for MetS in the face of on-going controversy about a useful definition. As a guide to future research, the idea that control of insulin metabolism by CHO intake is, to a first approximation, the underlying mechanism in MetS is a testable hypothesis.

  7. Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction

    Directory of Open Access Journals (Sweden)

    Feinman Richard D

    2005-11-01

    conclusion is probably not surprising but has not been explicitly stated before. The known effects of CHO-induced hypertriglyceridemia, the HDL-lowering effect of low fat, high CHO interventions and the obvious improvement in glucose and insulin from CHO restriction should have made this evident. In addition, recent studies suggest that a subset of MetS, the ratio of TAG/HDL, is a good marker for insulin resistance and risk of CVD, and this indicator is reliably reduced by CHO restriction and exacerbated by high CHO intake. Inability to make this connection in the past has probably been due to the fact that individual responses have been studied in isolation as well as to the emphasis of traditional therapeutic approaches on low fat rather than low CHO. We emphasize that MetS is not a disease but a collection of markers. Individual physicians must decide whether high LDL, or other risk factors are more important than the features of MetS in any individual case but if MetS is to be considered it should be recognized that reducing CHO will bring improvement. Response of symptoms to CHO restriction might thus provide a new experimental criterion for MetS in the face of on-going controversy about a useful definition. As a guide to future research, the idea that control of insulin metabolism by CHO intake is, to a first approximation, the underlying mechanism in MetS is a testable hypothesis.

  8. Parameterization of a ruminant model of phosphorus digestion and metabolism.

    Science.gov (United States)

    Feng, X; Knowlton, K F; Hanigan, M D

    2015-10-01

    The objective of the current work was to parameterize the digestive elements of the model of Hill et al. (2008) using data collected from animals that were ruminally, duodenally, and ileally cannulated, thereby providing a better understanding of the digestion and metabolism of P fractions in growing and lactating cattle. The model of Hill et al. (2008) was fitted and evaluated for adequacy using the data from 6 animal studies. We hypothesized that sufficient data would be available to estimate P digestion and metabolism parameters and that these parameters would be sufficient to derive P bioavailabilities of a range of feed ingredients. Inputs to the model were dry matter intake; total feed P concentration (fPtFd); phytate (Pp), organic (Po), and inorganic (Pi) P as fractions of total P (fPpPt, fPoPt, fPiPt); microbial growth; amount of Pi and Pp infused into the omasum or ileum; milk yield; and BW. The available data were sufficient to derive all model parameters of interest. The final model predicted that given 75 g/d of total P input, the total-tract digestibility of P was 40.8%, Pp digestibility in the rumen was 92.4%, and in the total-tract was 94.7%. Blood P recycling to the rumen was a major source of Pi flow into the small intestine, and the primary route of excretion. A large proportion of Pi flowing to the small intestine was absorbed; however, additional Pi was absorbed from the large intestine (3.15%). Absorption of Pi from the small intestine was regulated, and given the large flux of salivary P recycling, the effective fractional small intestine absorption of available P derived from the diet was 41.6% at requirements. Milk synthesis used 16% of total absorbed P, and less than 1% was excreted in urine. The resulting model could be used to derive P bioavailabilities of commonly used feedstuffs in cattle production. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  9. The effect of temperature and body weight on the routine metabolic rate and postprandial metabolic response in mulloway, Argyrosomus japonicus.

    Science.gov (United States)

    Pirozzi, Igor; Booth, Mark A

    2009-09-01

    Specific dynamic action (SDA) is the energy expended on the physiological processes associated with meal digestion and is strongly influenced by the characteristics of the meal and the body weight (BW) and temperature of the organism. This study assessed the effects of temperature and body weight on the routine metabolic rate (RMR) and postprandial metabolic response in mulloway, Argyrosomus japonicus. RMR and SDA were established at 3 temperatures (14, 20 and 26 degrees C). 5 size classes of mulloway ranging from 60 g to 1.14 kg were used to establish RMR with 3 of the 5 size classes (60, 120 and 240 g) used to establish SDA. The effect of body size on the mass-specific RMR (mg O(2) kg(-1) h(-1)) varied significantly depending on the temperature; there was a greater relative increase in the mass-specific RMR for smaller mulloway with increasing temperature. No statistical differences were found between the mass exponent (b) values at each temperature when tested against H(0): b=0.8. The gross RMR of mulloway (mg O(2) fish(-1) h(-1)) can be described as function of temperature (T; 14-26 degrees C) as: (0.0195T-0.0454)BW(g)(0.8) and the mass-specific RMR (mg O(2) kg(-1) h(-1)) can be described as: (21.042T-74.867)BW(g)(-0.2). Both SDA duration and time to peak SDA were influenced by temperature and body weight; SDA duration occurred within 41-89 h and peak time occurred within 17-38 h of feeding. The effect of body size on peak metabolic rate varied significantly depending on temperature, generally increasing with temperature and decreasing with increasing body size. Peak gross oxygen consumption (MO(2): mg O(2) fish(-1) h(-1)) scaled allometrically with BW. Temperature, but not body size, significantly affected SDA scope, although the difference was numerically small. There was a trend for MO(2) above RMR over the SDA period to increase with temperature; however, this was not statistically significant. The average proportion of energy expended over the SDA period

  10. Prediction of lithium-ion battery capacity with metabolic grey model

    International Nuclear Information System (INIS)

    Chen, Lin; Lin, Weilong; Li, Junzi; Tian, Binbin; Pan, Haihong

    2016-01-01

    Given the popularity of Lithium-ion batteries in EVs (electric vehicles), predicting the capacity quickly and accurately throughout a battery's full life-time is still a challenging issue for ensuring the reliability of EVs. This paper proposes an approach in predicting the varied capacity with discharge cycles based on metabolic grey theory and consider issues from two perspectives: 1) three metabolic grey models will be presented, including MGM (metabolic grey model), MREGM (metabolic Residual-error grey model), and MMREGM (metabolic Markov-residual-error grey model); 2) the universality of these models will be explored under different conditions (such as various discharge rates and temperatures). Furthermore, the research findings in this paper demonstrate the excellent performance of the prediction depending on the three models; however, the precision of the MREGM model is inferior compared to the others. Therefore, we have obtained the conclusion in which the MGM model and the MMREGM model have excellent performances in predicting the capacity under a variety of load conditions, even using few data points for modeling. Also, the universality of the metabolic grey prediction theory is verified by predicting the capacity of batteries under different discharge rates and different temperatures. - Highlights: • The metabolic mechanism is introduced in a grey system for capacity prediction. • Three metabolic grey models are presented and studied. • The universality of these models under different conditions is assessed. • A few data points are required for predicting the capacity with these models.

  11. Response Styles in the Partial Credit Model

    OpenAIRE

    Tutz, Gerhard; Schauberger, Gunther; Berger, Moritz

    2016-01-01

    In the modelling of ordinal responses in psychological measurement and survey- based research, response styles that represent specific answering patterns of respondents are typically ignored. One consequence is that estimates of item parameters can be poor and considerably biased. The focus here is on the modelling of a tendency to extreme or middle categories. An extension of the Partial Credit Model is proposed that explicitly accounts for this specific response style. In contrast to exi...

  12. Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models123

    Science.gov (United States)

    Rubin, Lewis P; Ross, A Catharine; Stephensen, Charles B; Bohn, Torsten; Tanumihardjo, Sherry A

    2017-01-01

    The association between inflammation and vitamin A (VA) metabolism and status assessment has been documented in multiple studies with animals and humans. The relation between inflammation and carotenoid status is less clear. Nonetheless, it is well known that carotenoids are associated with certain health benefits. Understanding these relations is key to improving health outcomes and mortality risk in infants and young children. Hyporetinolemia, i.e., low serum retinol concentrations, occurs during inflammation, and this can lead to the misdiagnosis of VA deficiency. On the other hand, inflammation causes impaired VA absorption and urinary losses that can precipitate VA deficiency in at-risk groups of children. Many epidemiologic studies have suggested that high dietary carotenoid intake and elevated plasma concentrations are correlated with a decreased risk of several chronic diseases; however, large-scale carotenoid supplementation trials have been unable to confirm the health benefits and in some cases resulted in controversial results. However, it has been documented that dietary carotenoids and retinoids play important roles in innate and acquired immunity and in the body’s response to inflammation. Although animal models have been useful in investigating retinoid effects on developmental immunity, it is more challenging to tease out the effects of carotenoids because of differences in the absorption, kinetics, and metabolism between humans and animal models. The current understanding of the relations between inflammation and retinoid and carotenoid metabolism and status are the topics of this review. PMID:28298266

  13. Metabolic Effects of Inflammation on Vitamin A and Carotenoids in Humans and Animal Models.

    Science.gov (United States)

    Rubin, Lewis P; Ross, A Catharine; Stephensen, Charles B; Bohn, Torsten; Tanumihardjo, Sherry A

    2017-03-01

    The association between inflammation and vitamin A (VA) metabolism and status assessment has been documented in multiple studies with animals and humans. The relation between inflammation and carotenoid status is less clear. Nonetheless, it is well known that carotenoids are associated with certain health benefits. Understanding these relations is key to improving health outcomes and mortality risk in infants and young children. Hyporetinolemia, i.e., low serum retinol concentrations, occurs during inflammation, and this can lead to the misdiagnosis of VA deficiency. On the other hand, inflammation causes impaired VA absorption and urinary losses that can precipitate VA deficiency in at-risk groups of children. Many epidemiologic studies have suggested that high dietary carotenoid intake and elevated plasma concentrations are correlated with a decreased risk of several chronic diseases; however, large-scale carotenoid supplementation trials have been unable to confirm the health benefits and in some cases resulted in controversial results. However, it has been documented that dietary carotenoids and retinoids play important roles in innate and acquired immunity and in the body's response to inflammation. Although animal models have been useful in investigating retinoid effects on developmental immunity, it is more challenging to tease out the effects of carotenoids because of differences in the absorption, kinetics, and metabolism between humans and animal models. The current understanding of the relations between inflammation and retinoid and carotenoid metabolism and status are the topics of this review. © 2017 American Society for Nutrition.

  14. Metabolic responses to pyruvate kinase deletion in lysine producing Corynebacterium glutamicum

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    Wittmann Christoph

    2008-03-01

    Full Text Available Abstract Background Pyruvate kinase is an important element in flux control of the intermediate metabolism. It catalyzes the irreversible conversion of phosphoenolpyruvate into pyruvate and is under allosteric control. In Corynebacterium glutamicum, this enzyme was regarded as promising target for improved production of lysine, one of the major amino acids in animal nutrition. In pyruvate kinase deficient strains the required equimolar ratio of the two lysine precursors oxaloacetate and pyruvate can be achieved through concerted action of the phosphotransferase system (PTS and phosphoenolpyruvate carboxylase (PEPC, whereby a reduced amount of carbon may be lost as CO2 due to reduced flux into the tricarboxylic acid (TCA cycle. In previous studies, deletion of pyruvate kinase in lysine-producing C. glutamicum, however, did not yield a clear picture and the exact metabolic consequences are not fully understood. Results In this work, deletion of the pyk gene, encoding pyruvate kinase, was carried out in the lysine-producing strain C. glutamicum lysCfbr, expressing a feedback resistant aspartokinase, to investigate the cellular response to deletion of this central glycolytic enzyme. Pyk deletion was achieved by allelic replacement, verified by PCR analysis and the lack of in vitro enzyme activity. The deletion mutant showed an overall growth behavior (specific growth rate, glucose uptake rate, biomass yield which was very similar to that of the parent strain, but differed in slightly reduced lysine formation, increased formation of the overflow metabolites dihydroxyacetone and glycerol and in metabolic fluxes around the pyruvate node. The latter involved a flux shift from pyruvate carboxylase (PC to PEPC, by which the cell maintained anaplerotic supply of the TCA cycle. This created a metabolic by-pass from PEP to pyruvate via malic enzyme demonstrating its contribution to metabolic flexibility of C. glutamicum on glucose. Conclusion The metabolic

  15. Metabolic responses to high protein diet in Korean elite bodybuilders with high-intensity resistance exercise

    Directory of Open Access Journals (Sweden)

    Choue Ryowon

    2011-07-01

    Full Text Available Abstract Background High protein diet has been known to cause metabolic acidosis, which is manifested by increased urinary excretion of nitrogen and calcium. Bodybuilders habitually consumed excessive dietary protein over the amounts recommended for them to promote muscle mass accretion. This study investigated the metabolic response to high protein consumption in the elite bodybuilders. Methods Eight elite Korean bodybuilders within the age from 18 to 25, mean age 21.5 ± 2.6. For data collection, anthropometry, blood and urinary analysis, and dietary assessment were conducted. Results They consumed large amounts of protein (4.3 ± 1.2 g/kg BW/day and calories (5,621.7 ± 1,354.7 kcal/day, as well as more than the recommended amounts of vitamins and minerals, including potassium and calcium. Serum creatinine (1.3 ± 0.1 mg/dl and potassium (5.9 ± 0.8 mmol/L, and urinary urea nitrogen (24.7 ± 9.5 mg/dl and creatinine (2.3 ± 0.7 mg/dl were observed to be higher than the normal reference ranges. Urinary calcium (0.3 ± 0.1 mg/dl, and phosphorus (1.3 ± 0.4 mg/dl were on the border of upper limit of the reference range and the urine pH was in normal range. Conclusions Increased urinary excretion of urea nitrogen and creatinine might be due to the high rates of protein metabolism that follow high protein intake and muscle turnover. The obvious evidence of metabolic acidosis in response to high protein diet in the subjects with high potassium intake and intensive resistance exercise were not shown in this study results. However, this study implied that resistance exercise with adequate mineral supplementation, such as potassium and calcium, could reduce or offset the negative effects of protein-generated metabolic changes. This study provides preliminary information of metabolic response to high protein intake in bodybuilders who engaged in high-intensity resistance exercise. Further studies will be needed to determine the effects of the intensity

  16. Incorporating Protein Biosynthesis into the Saccharomyces cerevisiae Genome-scale Metabolic Model

    DEFF Research Database (Denmark)

    Olivares Hernandez, Roberto

    Based on stoichiometric biochemical equations that occur into the cell, the genome-scale metabolic models can quantify the metabolic fluxes, which are regarded as the final representation of the physiological state of the cell. For Saccharomyces Cerevisiae the genome scale model has been construc......Based on stoichiometric biochemical equations that occur into the cell, the genome-scale metabolic models can quantify the metabolic fluxes, which are regarded as the final representation of the physiological state of the cell. For Saccharomyces Cerevisiae the genome scale model has been...

  17. Deciphering the mechanisms involved in Portulaca oleracea (C4) response to drought: metabolic changes including crassulacean acid-like metabolism induction and reversal upon re-watering.

    Science.gov (United States)

    D'Andrea, Rodrigo Matías; Andreo, Carlos Santiago; Lara, María Valeria

    2014-11-01

    Portulaca oleracea is a C(4) plant; however, under drought it can change its carbon fixation metabolism into a crassulacean acid metabolism (CAM)-like one. While the C(3) -CAM shift is well known, the C(4) -CAM transition has only been described in Portulaca. Here, a CAM-like metabolism was induced in P. oleracea by drought and then reversed by re-watering. Physiological and biochemical approaches were undertaken to evaluate the drought and recovery responses. In CAM-like plants, chlorophyll fluorescence parameters were transitory affected and non-radiative energy dissipation mechanisms were induced. Induction of flavonoids, betalains and antioxidant machinery may be involved in photosynthetic machinery protection. Metabolic analysis highlights a clear metabolic shift, when a CAM-like metabolism is induced and then reversed. Increases in nitrogenous compounds like free amino acids and urea, and of pinitol could contribute to withstand drought. Reciprocal variations in arginase and urease in drought-stressed and in re-watered plants suggest urea synthesis is strictly regulated. Recovery of C(4) metabolism was accounted by CO(2) assimilation pattern and malate levels. Increases in glycerol and in polyamines would be of importance of re-watered plants. Collectively, in P. oleracea multiple strategies, from induction of several metabolites to the transitory development of a CAM-like metabolism, participate to enhance its adaptation to drought. © 2014 Scandinavian Plant Physiology Society.

  18. Effect of dietary restriction on immune response of laboratory mice divergently selected for basal metabolic rate.

    Science.gov (United States)

    Książek, Aneta; Konarzewski, Marek

    2012-01-01

    To study whether dietary restriction (DR; 70% of ad lib. feeding)-elicited immunosuppression results from the trade-off between the costs of mounting an immune response and the metabolic costs of maintenance, we subjected mice from two divergent lines selected for high basal metabolic rate (H-BMR) and low BMR (L-BMR) to 4 wk of DR and then challenged them with keyhole limpet hemocyanin (KLH) antigen. Those line types differ genetically with respect to BMR and to the mass of metabolically expensive internal organs, which are larger in H-BMR mice. In mice of both line types, DR resulted in a significant reduction of body mass, an immune response, and the downsizing of spleen, lymph nodes, thymus, heart, and kidneys but not small intestines. DR resulted in a greater reduction of the spleen and lymph nodes in mice of the H-BMR line type, whereas the thymus was more affected in L-BMR line type. In contrast, immunization resulted in an increase of liver mass in DR mice of both line types. A comparison of the results of current and earlier studies on the same mouse line types suggests that metabolic trade-offs involving the costs of an immune response are more apparent when animals are forced to increase energy demands (e.g., by cold exposure) compared to when energy demands are decreased through DR. Our findings also suggest that divelrgent selection on BMR resulted in between-line-type differences in T-cell- and B-cell-mediated types of an immune response. More generally, our results indicate that production of a wide repertoire of antibodies is not correlated with high BMR.

  19. Metabolic Response to NAD Depletion across Cell Lines Is Highly Variable.

    Science.gov (United States)

    Xiao, Yang; Kwong, Mandy; Daemen, Anneleen; Belvin, Marcia; Liang, Xiaorong; Hatzivassiliou, Georgia; O'Brien, Thomas

    2016-01-01

    Nicotinamide adenine dinucleotide (NAD) is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner. To explore this we selected two non-small cell lung carcinoma cell lines that are sensitive to the NAMPT inhibitor GNE-617 (A549, NCI-H1334), one that shows intermediate sensitivity (NCI-H441), and one that is insensitive (LC-KJ). Even though NAD was reduced in all cell lines there was surprising heterogeneity in their metabolic response. Both sensitive cell lines reduced glycolysis and levels of di- and tri-nucleotides and modestly increased oxidative phosphorylation, but they differed in their ability to combat oxidative stress. H1334 cells activated the stress kinase AMPK, whereas A549 cells were unable to activate AMPK as they contain a mutation in LKB1, which prevents activation of AMPK. However, A549 cells increased utilization of the Pentose Phosphate pathway (PPP) and had lower reactive oxygen species (ROS) levels than H1334 cells, indicating that A549 cells are better able to modulate an increase in oxidative stress. Inherent resistance of LC-KJ cells is associated with higher baseline levels of NADPH and a delayed reduction of NAD upon NAMPT inhibition. Our data reveals that cell lines show heterogeneous response to NAD depletion and that the underlying molecular and genetic framework in cells can influence the metabolic response to NAMPT inhibition.

  20. Metabolic Response to NAD Depletion across Cell Lines Is Highly Variable.

    Directory of Open Access Journals (Sweden)

    Yang Xiao

    Full Text Available Nicotinamide adenine dinucleotide (NAD is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM to nicotinamide mononucleotide (NMN, the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner. To explore this we selected two non-small cell lung carcinoma cell lines that are sensitive to the NAMPT inhibitor GNE-617 (A549, NCI-H1334, one that shows intermediate sensitivity (NCI-H441, and one that is insensitive (LC-KJ. Even though NAD was reduced in all cell lines there was surprising heterogeneity in their metabolic response. Both sensitive cell lines reduced glycolysis and levels of di- and tri-nucleotides and modestly increased oxidative phosphorylation, but they differed in their ability to combat oxidative stress. H1334 cells activated the stress kinase AMPK, whereas A549 cells were unable to activate AMPK as they contain a mutation in LKB1, which prevents activation of AMPK. However, A549 cells increased utilization of the Pentose Phosphate pathway (PPP and had lower reactive oxygen species (ROS levels than H1334 cells, indicating that A549 cells are better able to modulate an increase in oxidative stress. Inherent resistance of LC-KJ cells is associated with higher baseline levels of NADPH and a delayed reduction of NAD upon NAMPT inhibition. Our data reveals that cell lines show heterogeneous response to NAD depletion and that the underlying molecular and genetic framework in cells can influence the metabolic response to NAMPT inhibition.

  1. Exercise electrocardiographic responses and serum cystatin C levels among metabolic syndrome patients without overt diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Tanindi A

    2011-02-01

    Full Text Available Asli Tanindi1 Hilal Olgun1 Ayse Tuncel2 Bulent Celik3 Hatice Pasaoglu2 Bulent Boyaci11Department of Cardiology, 2Department of Medical Biochemistry, Faculty of Medicine, 3Department of Statistics, Faculty of Health Sciences, Gazi University, Ankara, TurkeyObjectives: An impaired heart rate response during exercise (chronotropic incompetence and an impaired heart rate recovery (HRR after exercise are predictors of cardiovascular risk and mortality. Cystatin C is a novel marker for cardiovascular disease. We aimed to investigate exercise electrocardiographic responses in patients with metabolic syndrome who were without overt diabetes mellitus, in addition to the association of serum cystatin C levels with the exercise electrocardiographic test results.Method: Forty-three consecutive patients admitted to a cardiology outpatient clinic without angina pectoris were recruited if they met criteria for metabolic syndrome but did not have overt diabetes mellitus. Serum cystatin C levels were measured, and all participants underwent exercise electrocardiographic testing. Patients who were found to have ischemia had a coronary angiography procedure.Results: The mean cystatin C level of patients was higher in metabolic syndrome group than healthy controls (610.1 ± 334.02 vs 337.3 ± 111.01 µg/L; P < 0.001. The percentage of patients with ischemia confirmed by coronary angiography was 13.9% in the metabolic syndrome group. Cystatin C levels in the ischemic patients of the metabolic syndrome group were higher than that in nonischemic patients (957.00 ± 375.6 vs 553.8 ± 295.3 µg /L; P = 0.005. Chronotropic incompetence was observed in 30.2% of the patients with metabolic syndrome compared with 16.7% in the control group (P = 0.186. Chronotropic response indices were 0.8 ± 0.18 versus 0.9 ± 0.10 for the two groups, respectively (P = 0.259. HRR was significantly lower in the metabolic syndrome patients compared with the controls (20.1 ± 8.01 vs 25.2

  2. A new kinetic model for human iodine metabolism

    International Nuclear Information System (INIS)

    Ficken, V.J.; Allen, E.W.; Adams, G.D.

    1985-01-01

    A new kinetic model of iodine metabolism incorporating preferential organification of tyrosil (TYR) residues of thyroglobulin is developed and evaluated for euthyroid (n=5) and hyperthyroid (n=11) subjects. Iodine and peripheral T4 metabolims were measured with oral /sup 131/I-NaI and intravenous /sup 125/I-74 respectively. Data (obtained over 10 days) and kinetic model are analyzed using the SAAM27 program developed by Berman (1978). Compartment rate constants (mean rate per hour +- ISD) are tabulated in this paper. Thyroid and renal iodide clearance compare favorably with values reported in the literature. TYR rate constants were not unique; however, values obtained are within the range of rate constants determined from the invitro data reported by others. Intraluminal iodine as coupled TYR is predicted to be 21% for euthyroid and 59% for hyperthyroid subjects compared to analytical chemical methods of 30% and 51% respectively determined elsewhere. The authors plan to evaluate this model as a method of predicting the thyroid radiation dose from orally administered I/sup 131/

  3. Metabolomics Reveals Metabolically Healthy and Unhealthy Obese Individuals Differ in their Response to a Caloric Challenge.

    Directory of Open Access Journals (Sweden)

    Flavia Badoud

    Full Text Available To determine if metabolically healthy obese (MHO individuals have a different metabolic response to a standardized diet compared to lean healthy (LH and metabolically unhealthy obese (MUO individuals.Thirty adults (35-70 yrs were classified as LH, MHO, and MUO according to anthropometric and clinical measurements. Participants consumed a standardized high calorie meal (~1330 kcal. Blood glucose and insulin were measured at fasting, and 15, 30, 60, 90 and 120 min postprandially. Additional blood samples were collected for the targeted analysis of amino acids (AAs and derivatives, and fatty acids (FAs.The postprandial response (i.e., area under the curve, AUC for serum glucose and insulin were similar between MHO and LH individuals, and significantly lower than MUO individuals (p < 0.05. Minor differences were found in postprandial responses for AAs between MHO and MUO individuals, while three polyunsaturated FAs (linoleic acid, γ-linolenic acid, arachidonic acid showed smaller changes in serum after the meal in MHO individuals compared to MUO. Fasting levels for various AAs (notably branched-chain AA and FAs (e.g., saturated myristic and palmitic acids were found to correlate with glucose and insulin AUC.MHO individuals show preserved insulin sensitivity and a greater ability to adapt to a caloric challenge compared to MUO individuals.

  4. Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats.

    Science.gov (United States)

    Overton, J M; Williams, T D; Chambers, J B; Rashotte, M E

    2001-04-01

    The primary purpose of the study was to test the hypothesis that reduced leptin signaling is necessary to elicit the cardiovascular and metabolic responses to fasting. Lean (Fa/?; normal leptin receptor; n = 7) and obese (fa/fa; mutated leptin receptor; n = 8) Zucker rats were instrumented with telemetry transmitters and housed in metabolic chambers at 23 degrees C (12:12-h light-dark cycle) for continuous (24 h) measurement of metabolic and cardiovascular variables. Before fasting, mean arterial pressure (MAP) was higher (MAP: obese = 103 +/- 3; lean = 94 +/- 1 mmHg), whereas oxygen consumption (VO(2): obese = 16.5 +/- 0.3; lean = 18.6 +/- 0.2 ml. min(-1). kg(-0.75)) was lower in obese Zucker rats compared with their lean controls. Two days of fasting had no effect on MAP in either lean or obese Zucker rats, whereas VO(2) (obese = -3.1 +/- 0.3; lean = -2.9 +/- 0.1 ml. min(-1). kg(-0.75)) and heart rate (HR: obese = -56 +/- 4; lean = -42 +/- 4 beats/min) were decreased markedly in both groups. Fasting increased HR variability both in lean (+1.8 +/- 0.4 ms) and obese (+2.6 +/- 0.3 ms) Zucker rats. After a 6-day period of ad libitum refeeding, when all parameters had returned to near baseline levels, the cardiovascular and metabolic responses to 2 days of thermoneutrality (ambient temperature 29 degrees C) were determined. Thermoneutrality reduced VO(2) (obese = -2.4 +/- 0.2; lean = -3.3 +/- 0.2 ml. min(-1). kg(-0.75)), HR (obese = -46 +/- 5; lean = -55 +/- 4 beats/min), and MAP (obese = -13 +/- 6; lean = -10 +/- 1 mmHg) similarly in lean and obese Zucker rats. The results indicate that the cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in Zucker rats and suggest that intact leptin signaling may not be requisite for the metabolic and cardiovascular responses to reduced energy intake.

  5. The structure of wheat bread influences the postprandial metabolic response in healthy men.

    Science.gov (United States)

    Eelderink, Coby; Noort, Martijn W J; Sozer, Nesli; Koehorst, Martijn; Holst, Jens J; Deacon, Carolyn F; Rehfeld, Jens F; Poutanen, Kaisa; Vonk, Roel J; Oudhuis, Lizette; Priebe, Marion G

    2015-10-01

    Postprandial high glucose and insulin responses after starchy food consumption, associated with an increased risk of developing several metabolic diseases, could possibly be improved by altering food structure. We investigated the influence of a compact food structure; different wheat products with a similar composition were created using different processing conditions. The postprandial glucose kinetics and metabolic response to bread with a compact structure (flat bread, FB) was compared to bread with a porous structure (control bread, CB) in a randomized, crossover study with ten healthy male volunteers. Pasta (PA), with a very compact structure, was used as the control. The rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR) was calculated using stable isotopes. Furthermore, postprandial plasma concentrations of glucose, insulin, several intestinal hormones and bile acids were analyzed. The structure of FB was considerably more compact compared to CB, as confirmed by microscopy, XRT analysis (porosity) and density measurements. Consumption of FB resulted in lower peak glucose, insulin and glucose-dependent insulinotropic polypeptide (ns) responses and a slower initial RaE compared to CB. These variables were similar to the PA response, except for RaE which remained slower over a longer period after PA consumption. Interestingly, the GCR after FB was higher than expected based on the insulin response, indicating increased insulin sensitivity or insulin-independent glucose disposal. These results demonstrate that the structure of wheat bread can influence the postprandial metabolic response, with a more compact structure being more beneficial for health. Bread-making technology should be further explored to create healthier products.

  6. 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.

  7. L-carnitine: a partner between immune response and lipid metabolism ?

    Directory of Open Access Journals (Sweden)

    Giuseppe Famularo

    1993-01-01

    Full Text Available The authors demonstrated that in vivo administered L-carnitine strongly ameliorated the immune response in both healthy individuals receiving Intralipid and ageing subjects with cardiovascular diseases, as shown by the enhancement of mixed lymphocyte reaction. Notably, in the latter group L-carnitine treatment also resulted in a significant reduction of serum levels of both cholesterol and triglycerides. Therefore, the hypothesis is that L-carnitine supplementation could ameliorate both the dysregulated immune response and the abnormal lipid metabolism in several conditions.

  8. Humoral and cell-mediated immune responses to influenza vaccination in equine metabolic syndrome (EMS) horses.

    Science.gov (United States)

    Elzinga, Sarah; Reedy, Stephanie; Barker, Virginia D; Chambers, Thomas M; Adams, Amanda A

    2018-05-01

    Obesity is an increasing problem in the equine population with recent reports indicating that the percentage of overweight horses may range anywhere from 20.6-51%. Obesity in horses has been linked to more serious health concerns such as equine metabolic syndrome (EMS). EMS is a serious problem in the equine industry given its defining characteristics of insulin dysregualtion and obesity, as well as the involvement of laminitis. Little research however has been conducted to determine the effects of EMS on routine healthcare of these horses, in particular how they respond to vaccination. It has been shown that obese humans and mice have decreased immune responses to vaccination. EMS may have similar effects on vaccine responses in horses. If this is the case, these animals may be more susceptible to disease, acting as unknown disease reservoirs. Therefore, we investigated the effects of EMS on immune responses to routine influenza vaccination. Twenty-five adult horses of mixed-sex and mixed-breed (8-21 years old) horses; 13 EMS and 12 non-EMS were selected. Within each group, 4 horses served as non-vaccinate saline controls and the remaining horses were vaccinated with a commercially available equine influenza vaccine. Vaccination (influenza or saline) was administered on weeks 0 and 3, and peripheral blood samples taken on week 0 prior to vaccination and on weeks 1, 2, 3, 4, and 5 post vaccination. Blood samples were used to measure hemagglutination inhibition (HI) titers and equine influenza specific IgGa, IgGb, and IgGT levels. Blood samples were also used to isolate peripheral blood mononuclear cells (PBMCs) for analysis of cell mediated immune (CMI) responses via real-time polymerase chain reaction (RT-PCR). All horses receiving influenza vaccination responded with significant increases (P equine influenza specific antibodies following vaccination compared to saline controls. EMS did not significantly affect (P > 0.05) humoral immune responses as measured

  9. Type 2 responses at the interface between immunity and fat metabolism.

    Science.gov (United States)

    Odegaard, Justin I; Chawla, Ajay

    2015-10-01

    Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect 'healthy' physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize the literature regarding type 2 immunity's role in adipose tissue physiology and allude to its potential therapeutic implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Stochastic Still Water Response Model

    DEFF Research Database (Denmark)

    Friis-Hansen, Peter; Ditlevsen, Ove Dalager

    2002-01-01

    In this study a stochastic field model for the still water loading is formulated where the statistics (mean value, standard deviation, and correlation) of the sectional forces are obtained by integration of the load field over the relevant part of the ship structure. The objective of the model is...... out that an important parameter of the stochastic cargo field model is the mean number of containers delivered by each customer.......In this study a stochastic field model for the still water loading is formulated where the statistics (mean value, standard deviation, and correlation) of the sectional forces are obtained by integration of the load field over the relevant part of the ship structure. The objective of the model...... is to establish the stochastic load field conditional on a given draft and trim of the vessel. The model contributes to a realistic modelling of the stochastic load processes to be used in a reliability evaluation of the ship hull. Emphasis is given to container vessels. The formulation of the model for obtaining...

  11. Metabolic responses of primary and transformed cells to intracellular Listeria monocytogenes.

    Directory of Open Access Journals (Sweden)

    Nadine Gillmaier

    Full Text Available The metabolic response of host cells, in particular of primary mammalian cells, to bacterial infections is poorly understood. Here, we compare the carbon metabolism of primary mouse macrophages and of established J774A.1 cells upon Listeria monocytogenes infection using (13C-labelled glucose or glutamine as carbon tracers. The (13C-profiles of protein-derived amino acids from labelled host cells and intracellular L. monocytogenes identified active metabolic pathways in the different cell types. In the primary cells, infection with live L. monocytogenes increased glycolytic activity and enhanced flux of pyruvate into the TCA cycle via pyruvate dehydrogenase and pyruvate carboxylase, while in J774A.1 cells the already high glycolytic and glutaminolytic activities hardly changed upon infection. The carbon metabolism of intracellular L. monocytogenes was similar in both host cells. Taken together, the data suggest that efficient listerial replication in the cytosol of the host cells mainly depends on the glycolytic activity of the hosts.

  12. Photoacoustic microscopy of cerebral hemodynamic and oxygen-metabolic responses to anesthetics

    Science.gov (United States)

    Cao, Rui; Li, Jun; Ning, Bo; Sun, Naidi; Wang, Tianxiong; Zuo, Zhiyi; Hu, Song

    2017-02-01

    General anesthetics are known to have profound effects on cerebral hemodynamics and neuronal activities. However, it remains a challenge to directly assess anesthetics-induced hemodynamic and oxygen-metabolic changes from the true baseline under wakefulness at the microscopic level, due to the lack of an enabling technology for high-resolution functional imaging of the awake mouse brain. To address this challenge, we have developed head-restrained photoacoustic microscopy (PAM), which enables simultaneous imaging of the cerebrovascular anatomy, total concentration and oxygen saturation of hemoglobin (CHb and sO2), and blood flow in awake mice. From these hemodynamic measurements, two important metabolic parameters, oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2), can be derived. Side-by-side comparison of the mouse brain under wakefulness and anesthesia revealed multifaceted cerebral responses to isoflurane, a volatile anesthetic widely used in preclinical research and clinical practice. Key observations include elevated cerebral blood flow (CBF) and reduced oxygen extraction and metabolism.

  13. Metabolomics Analysis of Hormone-Responsive and Triple-Negative Breast Cancer Cell Responses to Paclitaxel Identify Key Metabolic Differences.

    Science.gov (United States)

    Stewart, Delisha A; Winnike, Jason H; McRitchie, Susan L; Clark, Robert F; Pathmasiri, Wimal W; Sumner, Susan J

    2016-09-02

    To date, no targeted therapies are available to treat triple negative breast cancer (TNBC), while other breast cancer subtypes are responsive to current therapeutic treatment. Metabolomics was conducted to reveal differences in two hormone receptor-negative TNBC cell lines and two hormone receptor-positive Luminal A cell lines. Studies were conducted in the presence and absence of paclitaxel (Taxol). TNBC cell lines had higher levels of amino acids, branched-chain amino acids, nucleotides, and nucleotide sugars and lower levels of proliferation-related metabolites like choline compared with Luminal A cell lines. In the presence of paclitaxel, each cell line showed unique metabolic responses, with some similarities by type. For example, in the Luminal A cell lines, levels of lactate and creatine decreased while certain choline metabolites and myo-inositol increased with paclitaxel. In the TNBC cell lines levels of glutamine, glutamate, and glutathione increased, whereas lysine, proline, and valine decreased in the presence of drug. Profiling secreted inflammatory cytokines in the conditioned media demonstrated a greater response to paclitaxel in the hormone-positive Luminal cells compared with a secretion profile that suggested greater drug resistance in the TNBC cells. The most significant differences distinguishing the cell types based on pathway enrichment analyses were related to amino acid, lipid and carbohydrate metabolism pathways, whereas several biological pathways were differentiated between the cell lines following treatment.

  14. Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation

    Energy Technology Data Exchange (ETDEWEB)

    Noecker, Cecilia; Eng, Alexander; Srinivasan, Sujatha; Theriot, Casey M.; Young, Vincent B.; Jansson, Janet K.; Fredricks, David N.; Borenstein, Elhanan; Sanchez, Laura M.

    2015-12-22

    ABSTRACT

    Multiple molecular assays now enable high-throughput profiling of the ecology, metabolic capacity, and activity of the human microbiome. However, to date, analyses of such multi-omic data typically focus on statistical associations, often ignoring extensive prior knowledge of the mechanisms linking these various facets of the microbiome. Here, we introduce a comprehensive framework to systematically link variation in metabolomic data with community composition by utilizing taxonomic, genomic, and metabolic information. Specifically, we integrate available and inferred genomic data, metabolic network modeling, and a method for predicting community-wide metabolite turnover to estimate the biosynthetic and degradation potential of a given community. Our framework then compares variation in predicted metabolic potential with variation in measured metabolites’ abundances to evaluate whether community composition can explain observed shifts in the community metabolome, and to identify key taxa and genes contributing to the shifts. Focusing on two independent vaginal microbiome data sets, each pairing 16S community profiling with large-scale metabolomics, we demonstrate that our framework successfully recapitulates observed variation in 37% of metabolites. Well-predicted metabolite variation tends to result from disease-associated metabolism. We further identify several disease-enriched species that contribute significantly to these predictions. Interestingly, our analysis also detects metabolites for which the predicted variation negatively correlates with the measured variation, suggesting environmental control points of community metabolism. Applying this framework to gut microbiome data sets reveals similar trends, including prediction of bile acid metabolite shifts. This framework is an important first step toward a system-level multi-omic integration and an improved mechanistic understanding of the microbiome activity and dynamics in

  15. The obese Göttingen minipig as a model of the metabolic syndrome

    DEFF Research Database (Denmark)

    Johansen, T.; Malmlöf, K.; Hansen, Harald S.

    2001-01-01

    The objective of the study reported here was to induce obesity in the female Göttingen minipig to establish a model of the human metabolic syndrome. Nine- to ten-month-old female Göttingen minipigs received a high-fat high-energy (HFE) diet or a low-fat, low-energy (LFE) diet. The energy contents...... of the metabolic impairments seen in obese humans, and may thus serve as a model of the metabolic syndrome....

  16. 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....

  17. Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: Form food intake to metabolic disease

    NARCIS (Netherlands)

    Koopmans, S.J.; Schuurman, T.

    2015-01-01

    (Mini)pigs have proven to be a valuable animal model in nutritional, metabolic and cardiovascular research and in some other biomedical research areas (toxicology, neurobiology). The large resemblance of (neuro)anatomy, the gastro-intestinal tract, body size, body composition, and the omnivorous

  18. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

    Energy Technology Data Exchange (ETDEWEB)

    Shannahan, Jonathan H. [Curriculum in Toxicology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 (United States); Alzate, Oscar [Systems Proteomics Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599 (United States); Winnik, Witold M.; Andrews, Debora [Proteomics Core, Research Core Unit, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Schladweiler, Mette C. [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Ghio, Andrew J. [Clinical Research Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Chapel Hill, NC 27599 (United States); Gavett, Stephen H. [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Kodavanti, Urmila P., E-mail: Kodavanti.Urmila@epa.gov [Cardiopulmonary and Immunotoxicology Branch, Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States)

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins involved

  19. Genetic dissection in a mouse model reveals interactions between carotenoids and lipid metabolism.

    Science.gov (United States)

    Palczewski, Grzegorz; Widjaja-Adhi, M Airanthi K; Amengual, Jaume; Golczak, Marcin; von Lintig, Johannes

    2016-09-01

    Carotenoids affect a rich variety of physiological functions in nature and are beneficial for human health. However, knowledge about their biological action and the consequences of their dietary accumulation in mammals is limited. Progress in this research field is limited by the expeditious metabolism of carotenoids in rodents and the confounding production of apocarotenoid signaling molecules. Herein, we established a mouse model lacking the enzymes responsible for carotenoid catabolism and apocarotenoid production, fed on either a β-carotene- or a zeaxanthin-enriched diet. Applying a genome wide microarray analysis, we assessed the effects of the parent carotenoids on the liver transcriptome. Our analysis documented changes in pathways for liver lipid metabolism and mitochondrial respiration. We biochemically defined these effects, and observed that β-carotene accumulation resulted in an elevation of liver triglycerides and liver cholesterol, while zeaxanthin accumulation increased serum cholesterol levels. We further show that carotenoids were predominantly transported within HDL particles in the serum of mice. Finally, we provide evidence that carotenoid accumulation influenced whole-body respiration and energy expenditure. Thus, we observed that accumulation of parent carotenoids interacts with lipid metabolism and that structurally related carotenoids display distinct biological functions in mammals. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  20. Metabolic Engineering and Modeling of Metabolic Pathways to Improve Hydrogen Production by Photosynthetic Bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Jiao, Y. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Navid, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2014-12-19

    traits act as the biocatalysts of the process designed to both enhance the system efficiency of CO2 fixation and the net hydrogen production rate. Additionally we applied metabolic engineering approaches guided by computational modeling for the chosen model microorganisms to enable efficient hydrogen production.

  1. Cardiovascular and Metabolic Responses to the Ingestion of Caffeinated Herbal Tea: Drink It Hot or Cold?

    Science.gov (United States)

    Maufrais, Claire; Sarafian, Delphine; Dulloo, Abdul; Montani, Jean-Pierre

    2018-01-01

    Aim: Tea is usually consumed at two temperatures (as hot tea or as iced tea). However, the importance of drink temperature on the cardiovascular system and on metabolism has not been thoroughly investigated. The purpose of this study was to compare the cardiovascular, metabolic and cutaneous responses to the ingestion of caffeinated herbal tea (Yerba Mate) at cold or hot temperature in healthy young subjects. We hypothesized that ingestion of cold tea induces a higher increase in energy expenditure than hot tea without eliciting any negative effects on the cardiovascular system. Methods: Cardiovascular, metabolic and cutaneous responses were analyzed in 23 healthy subjects (12 men and 11 women) sitting comfortably during a 30-min baseline and 90 min following the ingestion of 500 mL of an unsweetened Yerba Mate tea ingested over 5 min either at cold (~3°C) or hot (~55°C) temperature, according to a randomized cross-over design. Results: Averaged over the 90 min post-drink ingestion and compared to hot tea, cold tea induced (1) a decrease in heart rate (cold tea: -5 ± 1 beats.min -1 ; hot tea: -1 ± 1 beats.min -1 , p hot tea: +3.7%, p hot tea while decreasing cardiac load as suggested by the decrease in the double product. Further experiments are needed to evaluate the clinical impact of unsweetened caffeinated herbal tea at a cold temperature for weight control.

  2. Effects of Simulated Smog Atmospheres in Rodent Models of Metabolic and Immunologic Dysfunction.

    Science.gov (United States)

    McGee Hargrove, Marie; Snow, Samantha J; Luebke, Robert W; Wood, Charles E; Krug, Jonathan D; Krantz, Q Todd; King, Charly; Copeland, Carey B; McCullough, Shaun D; Gowdy, Kymberly M; Kodavanti, Urmila P; Gilmour, M Ian; Gavett, Stephen H

    2018-03-06

    Air pollution is a diverse and dynamic mixture of gaseous and particulate matter, limiting our understanding of associated adverse health outcomes. The biological effects of two simulated smog atmospheres (SA) with different compositions but similar air quality health indexes were compared in a nonobese diabetic rat model (Goto-Kakizaki, GK) and three mouse immune models (house dust mite (HDM) allergy, antibody response to heat-killed pneumococcus, and resistance to influenza A infection). In GK rats, both SA-PM (high particulate matter) and SA-O 3 (high ozone) decreased cholesterol levels immediately after a 4-h exposure, whereas only SA-O 3 increased airflow limitation. Airway responsiveness to methacholine was increased in HDM-allergic mice compared with nonallergic mice, but exposure to SA-PM or SA-O 3 did not significantly alter responsiveness. Exposure to SA-PM did not affect the IgM response to pneumococcus, and SA-O 3 did not affect virus titers, although inflammatory cytokine levels were decreased in mice infected at the end of a 7-day exposure. Collectively, acute SA exposures produced limited health effects in animal models of metabolic and immune diseases. Effects of SA-O 3 tended to be greater than those of SA-PM, suggesting that gas-phase components in photochemically derived multipollutant mixtures may be of greater concern than secondary organic aerosol PM.

  3. Diurnal changes in CN metabolism and response of rice seedlings to UV-B radiation.

    Science.gov (United States)

    Yun, Hyejin; Lim, Sunhyung; Kim, Yangmin X; Lee, Yejin; Lee, Seulbi; Lee, Deogbae; Park, Keewoong; Sung, Jwakyung

    2018-03-13

    Plants regulate a number of primary metabolites, including carbohydrates, organic acids, and amino acids, in response to UV-B radiation. Therefore, it is essential to understand the time-dependent response of rice plants to UV-B stress. This study focused on the response of plants to UV-B at different leaf developmental phases (emerging, growing, and maturing) in an attempt to fully comprehend the metabolic shift. We analyzed the expression levels of genes related to starch/sucrose metabolism in the leaf blades of rice seedlings (Oryza sativa L. "Saechuchenog") exposed to UV-B irradiation for short (1 day) and long terms (5 days) using quantitative real-time polymerase chain reaction. We also examined the diurnal variations in the contents of primary metabolites using an established GCTOF-MS (gas chromatography time of flight-mass spectrometry) method. The results showed that the levels of primary metabolites were largely dependent upon the diurnal rhythm and leaf developmental phase. The young leaves (sink) produced and accumulated starch rather than sucrose. The short-term (4 h, 1 day) UV-B exposure inhibited sucrose synthesis, which could be the first target of UV-B radiation. Following short- and long-term (5 days) exposure to UV-B radiation, the dynamic response of primary metabolites was evaluated. It was found that the content of carbohydrates decreased throughout the period of exposure to UV-B stress, especially in terms of sucrose concentration. However, the content of the majority of amino acids increased after an early decrease. Our data revealed that the metabolic response, as well as the gene expression, differed with the period (intensity) of exposure to UV-B radiation and with the phase of leaf development. These findings provide new insights for a better understanding of the metabolic response of a variety of plant species exposed to a wide range of UV-B radiation. Copyright © 2018. Published by Elsevier GmbH.

  4. Drosophila as a Model to Study the Link between Metabolism and Cancer

    DEFF Research Database (Denmark)

    Herranz, Hector; Cohen, Stephen M.

    2017-01-01

    new approaches to therapy. Drosophila melanogaster is emerging as a valuable model to study multiple aspects of tumor formation and malignant transformation. In this review, we discuss the use of Drosophila as model to study how changes in cellular metabolism, as well as metabolic disease, contribute...

  5. Responses of the metabolism of the larvae of Pocillopora damicornis to ocean acidification and warming.

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    Emily B Rivest

    Full Text Available Ocean acidification and warming are expected to threaten the persistence of tropical coral reef ecosystems. As coral reefs face multiple stressors, the distribution and abundance of corals will depend on the successful dispersal and settlement of coral larvae under changing environmental conditions. To explore this scenario, we used metabolic rate, at holobiont and molecular levels, as an index for assessing the physiological plasticity of Pocillopora damicornis larvae from this site to conditions of ocean acidity and warming. Larvae were incubated for 6 hours in seawater containing combinations of CO2 concentration (450 and 950 µatm and temperature (28 and 30°C. Rates of larval oxygen consumption were higher at elevated temperatures. In contrast, high CO2 levels elicited depressed metabolic rates, especially for larvae released later in the spawning period. Rates of citrate synthase, a rate-limiting enzyme in aerobic metabolism, suggested a biochemical limit for increasing oxidative capacity in coral larvae in a warming, acidifying ocean. Biological responses were also compared between larvae released from adult colonies on the same day (cohorts. The metabolic physiology of Pocillopora damicornis larvae varied significantly by day of release. Additionally, we used environmental data collected on a reef in Moorea, French Polynesia to provide information about what adult corals and larvae may currently experience in the field. An autonomous pH sensor provided a continuous time series of pH on the natal fringing reef. In February/March, 2011, pH values averaged 8.075 ± 0.023. Our results suggest that without adaptation or acclimatization, only a portion of naïve Pocillopora damicornis larvae may have suitable metabolic phenotypes for maintaining function and fitness in an end-of-the century ocean.

  6. Metabolic response of Geobacter sulfurreducens towards electron donor/acceptor variation

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    Lovley Derek R

    2010-11-01

    Full Text Available Abstract Background Geobacter sulfurreducens is capable of coupling the complete oxidation of organic compounds to iron reduction. The metabolic response of G. sulfurreducens towards variations in electron donors (acetate, hydrogen and acceptors (Fe(III, fumarate was investigated via 13C-based metabolic flux analysis. We examined the 13C-labeling patterns of proteinogenic amino acids obtained from G. sulfurreducens cultured with 13C-acetate. Results Using 13C-based metabolic flux analysis, we observed that donor and acceptor variations gave rise to differences in gluconeogenetic initiation, tricarboxylic acid cycle activity, and amino acid biosynthesis pathways. Culturing G. sulfurreducens cells with Fe(III as the electron acceptor and acetate as the electron donor resulted in pyruvate as the primary carbon source for gluconeogenesis. When fumarate was provided as the electron acceptor and acetate as the electron donor, the flux analysis suggested that fumarate served as both an electron acceptor and, in conjunction with acetate, a carbon source. Growth on fumarate and acetate resulted in the initiation of gluconeogenesis by phosphoenolpyruvate carboxykinase and a slightly elevated flux through the oxidative tricarboxylic acid cycle as compared to growth with Fe(III as the electron acceptor. In addition, the direction of net flux between acetyl-CoA and pyruvate was reversed during growth on fumarate relative to Fe(III, while growth in the presence of Fe(III and acetate which provided hydrogen as an electron donor, resulted in decreased flux through the tricarboxylic acid cycle. Conclusions We gained detailed insight into the metabolism of G. sulfurreducens cells under various electron donor/acceptor conditions using 13C-based metabolic flux analysis. Our results can be used for the development of G. sulfurreducens as a chassis for a variety of applications including bioremediation and renewable biofuel production.

  7. Metabolic Responses and Pacing Strategies during Successive Sprint Skiing Time Trials

    DEFF Research Database (Denmark)

    Andersson, Erik; Holmberg, Hans-Christer; Ørtenblad, Niels

    2016-01-01

    PURPOSE: To examine the metabolic responses and pacing strategies during the performance of successive sprint time trials (STTs) in cross-country skiing. METHODS: Ten well-trained male cross-country skiers performed four self-paced 1300-m STTs on a treadmill, each separated by 45 min of recovery...... to estimate the anaerobic energy supply. RESULTS: The individual trial-to-trial variability in STT performance time was 1.3%, where variations in O2 deficit and V˙O2 explained 69% (P 0.05) of the variation in performance. The first and last STTs were equally fast (228 ± 10 s), and ~ 1...... on the first than second course half. In addition, metabolic rates were substantially higher (~_30%) for uphill than for flat skiing, indicating that pacing was regulated to the terrain. CONCLUSIONS: The fastest STTs were characterized primarily by a greater anaerobic energy production, which also explained 69...

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

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    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.

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

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    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.

  10. A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation

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    Mc Auley Mark T

    2012-10-01

    Full Text Available Abstract Background Global demographic changes have stimulated marked interest in the process of aging. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age. Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion. Results The model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34 mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic

  11. Metabolic syndrome is associated with poor treatment response to antiviral therapy in chronic hepatitis C genotype 3 patients.

    Science.gov (United States)

    Aziz, Hafsa; Gill, Uzma; Raza, Abida; Gill, Muzaffar L

    2014-05-01

    Hepatitis C viral (HCV) infection is caused by an RNA virus. HCV infection is considered to induce systemic disease that causes steatosis, alters lipid metabolism, and results in metabolic syndrome. This study aimed to investigate the therapeutic outcome in HCV genotype 3 patients with metabolic syndrome. A total of 621 HCV-positive patients who visited the hospital for treatment were screened. Among these, 441 patients were enrolled for antiviral therapy. These enrolled patients were assessed for metabolic syndrome according to the International Diabetes Federation criteria. Group A included patients with metabolic syndrome and group B included patients without metabolic syndrome. All patients received peginterferon-α2a (180 μg/week) and ribavirin (10 mg/kg/day) for 6 months. The prevalence of metabolic syndrome in chronic HCV patients was 37.9%. We observed that metabolic syndrome was more common among female compared with male participants (43.9 vs. 28.8%, P=0.005). It was found that sustained virologic response (SVR) rates were significantly higher in the patients in group B (without metabolic syndrome) compared with the patients in group A who had metabolic syndrome (72.2 vs. 43.7%, Pmetabolic syndrome and a correlation of metabolic syndrome with nonresponse to antiviral therapy was observed. An interesting correlation among metabolic syndrome, age, and SVR was found: with age, SVR decreases, while metabolic syndrome increases. Metabolic syndrome has an influence on therapeutic outcomes in terms of SVR. Moreover, this information can identify patients who might have a low chance of attaining an SVR and a timely decision may protect the patients from the adverse effects of therapy.

  12. TIGER: Toolbox for integrating genome-scale metabolic models, expression data, and transcriptional regulatory networks

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    Jensen Paul A

    2011-09-01

    Full Text Available Abstract Background Several methods have been developed for analyzing genome-scale models of metabolism and transcriptional regulation. Many of these methods, such as Flux Balance Analysis, use constrained optimization to predict relationships between metabolic flux and the genes that encode and regulate enzyme activity. Recently, mixed integer programming has been used to encode these gene-protein-reaction (GPR relationships into a single optimization problem, but these techniques are often of limited generality and lack a tool for automating the conversion of rules to a coupled regulatory/metabolic model. Results We present TIGER, a Toolbox for Integrating Genome-scale Metabolism, Expression, and Regulation. TIGER converts a series of generalized, Boolean or multilevel rules into a set of mixed integer inequalities. The package also includes implementations of existing algorithms to integrate high-throughput expression data with genome-scale models of metabolism and transcriptional regulation. We demonstrate how TIGER automates the coupling of a genome-scale metabolic model with GPR logic and models of transcriptional regulation, thereby serving as a platform for algorithm development and large-scale metabolic analysis. Additionally, we demonstrate how TIGER's algorithms can be used to identify inconsistencies and improve existing models of transcriptional regulation with examples from the reconstructed transcriptional regulatory network of Saccharomyces cerevisiae. Conclusion The TIGER package provides a consistent platform for algorithm development and extending existing genome-scale metabolic models with regulatory networks and high-throughput data.

  13. The contribution of mathematical modeling to understanding the dynamic aspects of rumen metabolism

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    André Bannink

    2016-11-01

    Full Text Available All rumen models cover the main drivers of variation in rumen function, which are feed intake, the differences between feedstuffs and feeds in their intrinsic rumen degradation characteristics, and fractional outflow rate of fluid and particulate matter. Dynamic modeling approaches are best suited to the prediction of more nuanced responses in rumen metabolism, and represent the dynamics of the interaction between substrates and micro-organisms and inter-microbial interactions. The concepts of dynamics are discussed for the case of rumen starch digestion as influenced by starch intake rate and frequency of feed intake, and for the case of fermentation of fiber in the large intestine. Adding representations of new functional classes of micro-organisms (i.e. with new characteristics from the perspective of whole rumen function in rumen models only delivers new insights if complemented by the dynamics of their interactions with other functional classes. Rumen fermentation conditions have to be represented due to their profound impact on the dynamics of substrate degradation and microbial metabolism. Although the importance of rumen acidity is generally acknowledged, more emphasis is needed on predicting its variation as well as variation in the processes that underlie rumen fluid dynamics. The rumen wall has an important role in adapting to rapid changes in the rumen environment, clearing of volatile fatty acids (VFA, and maintaining rumen pH within limits. Dynamics of rumen wall epithelia and its role in VFA absorption needs to be better represented in models which aim to predict rumen responses across nutritional or physiological states. For a detailed prediction of rumen N balance there is merit in a dynamic modeling approach compared to the static approaches adopted in current protein evaluation systems. Improvement is needed on previous attempts to predict rumen VFA profiles, and this should be pursued by introducing factors that relate more

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

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    Feng Xueyang

    2012-08-01

    Full Text Available Abstract Background Concurrent with the efforts currently underway in mapping microbial genomes using high-throughput sequencing methods, systems biologists are building metabolic models to characterize and predict cell metabolisms. One of the key steps in building a metabolic model is using multiple databases to collect and assemble essential information about genome-annotations and the architecture of the metabolic network for a specific organism. To speed up metabolic model development for a large number of microorganisms, we need a user-friendly platform to construct metabolic networks and to perform constraint-based flux balance analysis based on genome databases and experimental results. Results We have developed a semi-automatic, web-based platform (MicrobesFlux for generating and reconstructing metabolic models for annotated microorganisms. MicrobesFlux is able to automatically download the metabolic network (including enzymatic reactions and metabolites of ~1,200 species from the KEGG database (Kyoto Encyclopedia of Genes and Genomes and then convert it to a metabolic model draft. The platform also provides diverse customized tools, such as gene knockouts and the introduction of heterologous pathways, for users to reconstruct the model network. The reconstructed metabolic network can be formulated to a constraint-based flux model to predict and analyze the carbon fluxes in microbial metabolisms. The simulation results can be exported in the SBML format (The Systems Biology Markup Language. Furthermore, we also demonstrated the platform functionalities by developing an FBA model (including 229 reactions for a recent annotated bioethanol producer, Thermoanaerobacter sp. strain X514, to predict its biomass growth and ethanol production. Conclusion MicrobesFlux is an installation-free and open-source platform that enables biologists without prior programming knowledge to develop metabolic models for annotated microorganisms in the KEGG

  15. Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models

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    Hammami Ines

    2012-07-01

    Full Text Available Abstract Background The tumor microenvironment contains a vast array of pro- and anti-inflammatory cytokines that alter myelopoiesis and lead to the maturation of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs. Incubating bone marrow (BM precursors with a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF and interleukin-6 (IL-6 generated a tumor-infiltrating MDSC-like population that impaired anti-tumor specific T-cell functions. This in vitro experimental approach was used to simulate MDSC maturation, and the cellular metabolic response was then monitored. A complementary experimental model that inhibited L-arginine (L-Arg metabolizing enzymes in MSC-1 cells, an immortalized cell line derived from primary MDSCs, was used to study the metabolic events related to immunosuppression. Results Exposure of BM cells to GM-CSF and IL-6 activated, within 24 h, L-Arg metabolizing enzymes which are responsible for the MDSCs immunosuppressive potential. This was accompanied by an increased uptake of L-glutamine (L-Gln and glucose, the latter being metabolized by anaerobic glycolysis. The up-regulation of nutrient uptake lead to the accumulation of TCA cycle intermediates and lactate as well as the endogenous synthesis of L-Arg and the production of energy-rich nucleotides. Moreover, inhibition of L-Arg metabolism in MSC-1 cells down-regulated central carbon metabolism activity, including glycolysis, glutaminolysis and TCA cycle activity, and led to a deterioration of cell bioenergetic status. The simultaneous increase of cell specific concentrations of ATP and a decrease in ATP-to-ADP ratio in BM-derived MDSCs suggested cells were metabolically active during maturation. Moreover, AMP-activated protein kinase (AMPK was activated during MDSC maturation in GM-CSF and IL-6–treated cultures, as revealed by the continuous increase of AMP-to-ATP ratios and the phosphorylation of AMPK. Likewise, AMPK activity was

  16. Integration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.).

    Science.gov (United States)

    Moschen, Sebastián; Di Rienzo, Julio A; Higgins, Janet; Tohge, Takayuki; Watanabe, Mutsumi; González, Sergio; Rivarola, Máximo; García-García, Francisco; Dopazo, Joaquin; Hopp, H Esteban; Hoefgen, Rainer; Fernie, Alisdair R; Paniego, Norma; Fernández, Paula; Heinz, Ruth A

    2017-07-01

    By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.

  17. Metabolic response of Pseudomonas putida during redox biocatalysis in the presence of a second octanol phase.

    Science.gov (United States)

    Blank, Lars M; Ionidis, Georgios; Ebert, Birgitta E; Bühler, Bruno; Schmid, Andreas

    2008-10-01

    A key limitation of whole-cell redox biocatalysis for the production of valuable, specifically functionalized products is substrate/product toxicity, which can potentially be overcome by using solvent-tolerant micro-organisms. To investigate the inter-relationship of solvent tolerance and energy-dependent biocatalysis, we established a model system for biocatalysis in the presence of toxic low logP(ow) solvents: recombinant solvent-tolerant Pseudomonas putida DOT-T1E catalyzing the stereospecific epoxidation of styrene in an aqueous/octanol two-liquid phase reaction medium. Using (13)C tracer based metabolic flux analysis, we investigated the central carbon and energy metabolism and quantified the NAD(P)H regeneration rate in the presence of toxic solvents and during redox biocatalysis, which both drastically increased the energy demands of solvent-tolerant P. putida. According to the driven by demand concept, the NAD(P)H regeneration rate was increased up to eightfold by two mechanisms: (a) an increase in glucose uptake rate without secretion of metabolic side products, and (b) reduced biomass formation. However, in the presence of octanol, only approximately 1% of the maximally observed NAD(P)H regeneration rate could be exploited for styrene epoxidation, of which the rate was more than threefold lower compared with operation with a non-toxic solvent. This points to a high energy and redox cofactor demand for cell maintenance, which limits redox biocatalysis in the presence of octanol. An estimated upper bound for the NAD(P)H regeneration rate available for biocatalysis suggests that cofactor availability does not limit redox biocatalysis under optimized conditions, for example, in the absence of toxic solvent, and illustrates the high metabolic capacity of solvent-tolerant P. putida. This study shows that solvent-tolerant P. putida have the remarkable ability to compensate for high energy demands by boosting their energy metabolism to levels up to an order of

  18. Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle

    Science.gov (United States)

    Henriksen, Erik J.; Tischler, Marc E.; Johnson, David G.

    1986-01-01

    Hind leg muscles of female rats were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D(U-C-14) glucose, release of lactate and pyruvate, incorporation of D-(U-C-14) glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-(1,2-H-3) glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased, by 50 percent the concentration of insuling receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.

  19. Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses.

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    Webb, Tonya J; Carey, Gregory B; East, James E; Sun, Wenji; Bollino, Dominique R; Kimball, Amy S; Brutkiewicz, Randy R

    2016-08-01

    Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5(')-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. The effect of metabolic alkalosis on the ventilatory response in healthy subjects.

    Science.gov (United States)

    Oppersma, E; Doorduin, J; van der Hoeven, J G; Veltink, P H; van Hees, H W H; Heunks, L M A

    2018-02-01

    Patients with acute respiratory failure may develop respiratory acidosis. Metabolic compensation by bicarbonate production or retention results in posthypercapnic alkalosis with an increased arterial bicarbonate concentration. The hypothesis of this study was that elevated plasma bicarbonate levels decrease respiratory drive and minute ventilation. In an intervention study in 10 healthy subjects the ventilatory response using a hypercapnic ventilatory response (HCVR) test was assessed, before and after administration of high dose sodium bicarbonate. Total dose of sodiumbicarbonate was 1000 ml 8.4% in 3 days. Plasma bicarbonate increased from 25.2 ± 2.2 to 29.2 ± 1.9 mmol/L. With increasing inspiratory CO 2 pressure during the HCVR test, RR, V t , Pdi, EAdi and V E increased. The clinical ratio ΔV E /ΔP et CO 2 remained unchanged, but Pdi, EAdi and V E were significantly lower after bicarbonate administration for similar levels of inspired CO 2 . This study demonstrates that in healthy subjects metabolic alkalosis decreases the neural respiratory drive and minute ventilation, as a response to inspiratory CO 2 . Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  1. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics.

    Science.gov (United States)

    Cortassa, Sonia; Aon, Miguel A; Marbán, Eduardo; Winslow, Raimond L; O'Rourke, Brian

    2003-04-01

    We present an integrated thermokinetic model describing control of cardiac mitochondrial bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca(2+) handling. The kinetic component of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH(2), which in turn are used by the electron transport chain to establish a proton motive force (Delta mu(H)), driving the F(1)F(0)-ATPase. In addition, mitochondrial matrix Ca(2+), determined by Ca(2+) uniporter and Na(+)/Ca(2+) exchanger activities, regulates activity of the TCA cycle enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. The model is described by twelve ordinary differential equations for the time rate of change of mitochondrial membrane potential (Delta Psi(m)), and matrix concentrations of Ca(2+), NADH, ADP, and TCA cycle intermediates. The model is used to predict the response of mitochondria to changes in substrate delivery, metabolic inhibition, the rate of adenine nucleotide exchange, and Ca(2+). The model is able to reproduce, qualitatively and semiquantitatively, experimental data concerning mitochondrial bioenergetics, Ca(2+) dynamics, and respiratory control. Significant increases in oxygen consumption (V(O(2))), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic Ca(2+), are obtained when the Ca(2+)-sensitive dehydrogenases are the main rate-controlling steps of respiratory flux. These responses diminished when control is shifted downstream (e.g., the respiratory chain or adenine nucleotide translocator). The time-dependent behavior of the model, under conditions simulating an increase in workload, closely reproduces experimentally observed mitochondrial NADH dynamics in heart trabeculae subjected to changes in pacing frequency. The steady-state and time-dependent behavior of the model support the hypothesis that mitochondrial matrix Ca(2+) plays an

  2. Model for Managing Corporate Social Responsibility

    Directory of Open Access Journals (Sweden)

    Tamara Vlastelica Bakić

    2015-05-01

    Full Text Available As a crossfuncional process in the organization, effective management of corporate social responsibility requires a definition of strategies, programs and an action plan that structures this process from its initiation to the measurement of end effects. Academic literature on the topic of corporate social responsibility is mainly focused on the exploration of the business case for the concept, i.e., the determination of effects of social responsibility on individual aspects of the business. Scientific research so far has shown not to have been committed to formalizing management concept in this domain to a satisfactory extent; it is for this reason that this paper attempts to present one model for managing corporate social responsibility. The model represents a contribution to the theory and business practice of corporate social responsibility, as it offers a strategic framework for systematic planning, implementation and evaluation of socially responsible activities and programs.

  3. Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in In Vivo Mammary Tumor Models

    Science.gov (United States)

    2015-02-01

    Bird , L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, N. Ramanujam, Metabolic mapping of MCF10A human breast cells...1   Award Number: W81XWH-12-1-0025 TITLE: Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in In Vivo Mammary... Metabolic Changes in In Vivo Mammary Tumor Models 5b. GRANT NUMBER BC112240 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Betty Diamond 5d. PROJECT NUMBER

  4. Energetic and metabolic transient response of Saccharomyces cerevisiae to benzoic acid.

    Science.gov (United States)

    Kresnowati, M T A P; van Winden, W A; van Gulik, W M; Heijnen, J J

    2008-11-01

    Saccharomyces cerevisiae is known to be able to adapt to the presence of the commonly used food preservative benzoic acid with a large energy expenditure. Some mechanisms for the adaptation process have been suggested, but its quantitative energetic and metabolic aspects have rarely been discussed. This study discusses use of the stimulus response approach to quantitatively study the energetic and metabolic aspects of the transient adaptation of S. cerevisiae to a shift in benzoic acid concentration, from 0 to 0.8 mM. The information obtained also serves as the basis for further utilization of benzoic acid as a tool for targeted perturbation of the energy system, which is important in studying the kinetics and regulation of central carbon metabolism in S. cerevisiae. Using this experimental set-up, we found significant fast-transient (< 3000 s) increases in O(2) consumption and CO(2) production rates, of approximately 50%, which reflect a high energy requirement for the adaptation process. We also found that with a longer exposure time to benzoic acid, S. cerevisiae decreases the cell membrane permeability for this weak acid by a factor of 10 and decreases the cell size to approximately 80% of the initial value. The intracellular metabolite profile in the new steady-state indicates increases in the glycolytic and tricarboxylic acid cycle fluxes, which are in agreement with the observed increases in specific glucose and O(2) uptake rates.

  5. Tributyltin toxicity in abalone (Haliotis diversicolor supertexta) assessed by antioxidant enzyme activity, metabolic response, and histopathology.

    Science.gov (United States)

    Zhou, Jin; Zhu, Xiao-shan; Cai, Zhong-hua

    2010-11-15

    A toxicity test was performed to investigate the possible harmful effects of tributyltin (TBT) on abalone (Haliotis diversicolor supertexta). Animals were exposed to TBT in a range of environmentally relevant concentrations (2, 10 and 50 ng/L) for 30 days under laboratory conditions. TBT-free conditions were used as control treatments. The activity of antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD), and malondialdehyde (MDA), along with levels of haemolymph metabolites, and hepatopancreas histopathology were analyzed. The results showed that TBT decreased SOD activity, and increased POD level and MDA production in a dose-dependent way, indicating that oxidative injury was induced by TBT. Haemolymph metabolite measurements showed that TBT increased alanine and glutamate levels, and decreased glucose content, which suggested perturbation of energy metabolism. Elevated levels of acetate and pyruvate in the haemolymph indicated partial alteration of lipid metabolism. A decrease in lactate and an increase in succinate, an intermediate of the tricarboxylic acid (TCA) cycle, indicated disturbance of amino acid metabolism. Hepatopancreas tissues also exhibited inflammatory responses characterized by histopathological changes such as cell swelling, granular degeneration, and inflammation. Taken together, these results demonstrated that TBT was a potential toxin with a variety of deleterious effects on abalone. Copyright © 2010 Elsevier B.V. All rights reserved.

  6. Responsive eLearning exercises to enhance student interaction with metabolic pathways.

    Science.gov (United States)

    Roesler, William J; Dreaver-Charles, Kristine

    2018-05-01

    Successful learning of biochemistry requires students to engage with the material. In the past this often involved students writing out pathways by hand, and more recently directing students to online resources such as videos, songs, and animated slide presentations. However, even these latter resources do not really provide students an opportunity to engage with the material in an active fashion. As part of an online introductory metabolism course that was developed at our university, we created a series of twelve online interactive activities using Adobe Captivate 9. These activities targeted glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, the citric acid cycle, and fatty acid oxidation. The interactive exercises consisted of two types. One involved dragging objects such as names of enzymes or allosteric modifiers to their correct drop locations such as a particular point in a metabolic pathway, a specific enzyme, and so forth. A second type involved clicking on objects, locations within a pathway, and so forth, in response to a particular question. In both types of exercises, students received feedback on their decisions in order to enhance learning. The student feedback received on these activities was very positive, and indicated that they found them to increase their confidence in the material and that they had learned the key principles of each pathway. © 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):223-229, 2018. © 2018 The International Union of Biochemistry and Molecular Biology.

  7. Metabolic Profiling of Dendrobium officinale in Response to Precursors and Methyl Jasmonate

    Directory of Open Access Journals (Sweden)

    Chunyan Jiao

    2018-03-01

    Full Text Available Alkaloids are the main active ingredients in the medicinal plant Dendrobium officinale. Based on the published genomic and transcriptomic data, a proposed terpenoid indole alkaloid (TIA biosynthesis pathway may be present in D. officinale. In this study, protocorm-like bodies (PLBs with a high-yielding production of alkaloids were obtained by the optimization of tryptophan, secologanin and methyl jasmonate (MeJA treatment. The results showed that the total alkaloid content was 2.05 times greater than that of the control group when the PLBs were fed with 9 µM tryptophan, 6 µM secologanin and 100 µM MeJA after 36 days. HPLC analysis showed that strictosidine synthase (STR activity also increased in the treated plants. A total of 78 metabolites were identified using gas chromatography-mass spectrometry (GC-MS in combination with liquid chromatography-mass spectrometry (LC-MS methods; 29 differential metabolites were identified according to the multivariate statistical analysis. Among them, carapanaubine, a kind of TIA, exhibited dramatically increased levels. In addition, a possible underlying process of the metabolic flux from related metabolism to the TIA biosynthetic pathway was enhanced. These results provide a comprehensive view of the metabolic changes related to alkaloid biosynthesis, especially TIA biosynthesis, in response to tryptophan, secologanin and MeJA treatment.

  8. Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

    KAUST Repository

    Jolivet, Renaud

    2015-02-26

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

  9. Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

    Science.gov (United States)

    Jolivet, Renaud; Coggan, Jay S.; Allaman, Igor; Magistretti, Pierre J.

    2015-01-01

    Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging. PMID:25719367

  10. Multi-timescale modeling of activity-dependent metabolic coupling in the neuron-glia-vasculature ensemble.

    Directory of Open Access Journals (Sweden)

    Renaud Jolivet

    2015-02-01

    Full Text Available Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS are still debated. To address this question, we developed a detailed biophysical model of the brain's metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

  11. GENOME-BASED MODELING AND DESIGN OF METABOLIC INTERACTIONS IN MICROBIAL COMMUNITIES

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Mahadevan

    2012-10-01

    With the advent of genome sequencing, omics technologies, bioinformatics and genome-scale modeling, researchers now have unprecedented capabilities to analyze and engineer the metabolism of microbial communities. The goal of this review is to summarize recent applications of genome-scale metabolic modeling to microbial communities. A brief introduction to lumped community models is used to motivate the need for genome-level descriptions of individual species and their metabolic interactions. The review of genome-scale models begins with static modeling approaches, which are appropriate for communities where the extracellular environment can be assumed to be time invariant or slowly varying. Dynamic extensions of the static modeling approach are described, and then applications of genome-scale models for design of synthetic microbial communities are reviewed. The review concludes with a summary of metagenomic tools for analyzing community metabolism and an outlook for future research.

  12. The conceptual model of organization social responsibility

    OpenAIRE

    LUO, Lan; WEI, Jingfu

    2014-01-01

    With the developing of the research of CSR, people more and more deeply noticethat the corporate should take responsibility. Whether other organizations besides corporatesshould not take responsibilities beyond their field? This paper puts forward theconcept of organization social responsibility on the basis of the concept of corporate socialresponsibility and other theories. And the conceptual models are built based on theconception, introducing the OSR from three angles: the types of organi...

  13. Hidden Markov Item Response Theory Models for Responses and Response Times.

    Science.gov (United States)

    Molenaar, Dylan; Oberski, Daniel; Vermunt, Jeroen; De Boeck, Paul

    2016-01-01

    Current approaches to model responses and response times to psychometric tests solely focus on between-subject differences in speed and ability. Within subjects, speed and ability are assumed to be constants. Violations of this assumption are generally absorbed in the residual of the model. As a result, within-subject departures from the between-subject speed and ability level remain undetected. These departures may be of interest to the researcher as they reflect differences in the response processes adopted on the items of a test. In this article, we propose a dynamic approach for responses and response times based on hidden Markov modeling to account for within-subject differences in responses and response times. A simulation study is conducted to demonstrate acceptable parameter recovery and acceptable performance of various fit indices in distinguishing between different models. In addition, both a confirmatory and an exploratory application are presented to demonstrate the practical value of the modeling approach.

  14. From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations.

    Science.gov (United States)

    Green, Charlotte J; Pramfalk, Camilla; Morten, Karl J; Hodson, Leanne

    2015-01-01

    The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD. Copyright © 2015 the American Physiological Society.

  15. Response moderation models for conditional dependence between response time and response accuracy.

    Science.gov (United States)

    Bolsinova, Maria; Tijmstra, Jesper; Molenaar, Dylan

    2017-05-01

    It is becoming more feasible and common to register response times in the application of psychometric tests. Researchers thus have the opportunity to jointly model response accuracy and response time, which provides users with more relevant information. The most common choice is to use the hierarchical model (van der Linden, 2007, Psychometrika, 72, 287), which assumes conditional independence between response time and accuracy, given a person's speed and ability. However, this assumption may be violated in practice if, for example, persons vary their speed or differ in their response strategies, leading to conditional dependence between response time and accuracy and confounding measurement. We propose six nested hierarchical models for response time and accuracy that allow for conditional dependence, and discuss their relationship to existing models. Unlike existing approaches, the proposed hierarchical models allow for various forms of conditional dependence in the model and allow the effect of continuous residual response time on response accuracy to be item-specific, person-specific, or both. Estimation procedures for the models are proposed, as well as two information criteria that can be used for model selection. Parameter recovery and usefulness of the information criteria are investigated using simulation, indicating that the procedure works well and is likely to select the appropriate model. Two empirical applications are discussed to illustrate the different types of conditional dependence that may occur in practice and how these can be captured using the proposed hierarchical models. © 2016 The British Psychological Society.

  16. Photons, photosynthesis, and high-performance computing: challenges, progress, and promise of modeling metabolism in green algae

    International Nuclear Information System (INIS)

    Chang, C H; Graf, P; Alber, D M; Kim, K; Murray, G; Posewitz, M; Seibert, M

    2008-01-01

    The complexity associated with biological metabolism considered at a kinetic level presents a challenge to quantitative modeling. In particular, the relatively sparse knowledge of parameters for enzymes with known kinetic responses is problematic. The possible space of these parameters is of high-dimension, and sampling of such a space typifies a combinatorial explosion of possible dynamic states. However, with sufficient quantitative transcriptomics, proteomics, and metabolomics data at hand, these challenges could be met by high-performance software with sampling, fitting, and optimization capabilities. With this in mind, we present the High-Performance Systems Biology Toolkit HiPer SBTK, an evolving software package to simulate, fit, and optimize metabolite concentrations and fluxes within the space of rate and binding parameters associated with detailed enzyme kinetic models. We present our chosen modeling paradigm for the formulation of metabolic pathway models, the means to address the challenge of representing such models in a precise and persistent fashion using the standardized Systems Biology Markup Language, and our second-generation model of H2-associated Chlamydomonas metabolism. Processing of such models for hierarchically parallelized simulation and optimization, job specification by the user through a GUI interface, software capabilities and initial scaling data, and the mapping of the computation to biological questions is also discussed. Moreover, we present near-term future software and model development goals

  17. Hypothalamic miR-219 regulates individual metabolic differences in response to diet-induced weight cycling

    Directory of Open Access Journals (Sweden)

    Mariana Schroeder

    2018-03-01

    Full Text Available Consumption of a low calorie diet is the most common approach to lose weight. While generally effective at first, it is frequently followed by a relapse where the pre-diet weight is regained, and often exceeded. This pattern of repeated weight loss/regain is referred to as weight cycling and the resulting metabolic response varies greatly between individuals. Objective: We attempted to address the issue of individual differences in the response to weight cycling in male mice. Methods: We first exposed adult wild type mice to repeated cycles of high/low fat food. Next, using a lentiviral approach, we knocked-down or over-expressed miR-219 in the ventromedial hypothalamus (VMH of an additional mouse cohort and performed a full metabolic assessment. Results: Exposure of wild type males to weight cycling resulted in the division of the cohort into subsets of resistant versus metabolic-syndrome-prone (MS animals, which differed in their metabolic profile and hypothalamic miR-219 levels. Lentiviral knock-down of miR-219 in the VMH led to exacerbation of metabolic syndrome. In contrast, over-expression of miR-219 resulted in moderation of the metabolic syndrome phenotype. Conclusions: Our results suggest a role for miR-219 in the mediation of the metabolic phenotype resulting from repeated weight cycling. Keywords: Weight cycling, Metabolic syndrome, miRNAs, Ventromedial hypothalamus, High fat diet, Diabetes

  18. Mechanical and Metabolic Responses to Traditional and Cluster Set Configurations in the Bench Press Exercise.

    Science.gov (United States)

    García-Ramos, Amador; González-Hernández, Jorge M; Baños-Pelegrín, Ezequiel; Castaño-Zambudio, Adrián; Capelo-Ramírez, Fernando; Boullosa, Daniel; Haff, Guy G; Jiménez-Reyes, Pedro

    2017-10-20

    García-Ramos, A, González-Hernández, JM, Baños-Pelegrín, E, Castaño-Zambudio, A, Capelo-Ramírez, F, Boullosa, D, Haff, GG, and Jiménez-Reyes, P. Mechanical and metabolic responses to traditional and cluster set configurations in the bench press exercise. J Strength Cond Res XX(X): 000-000, 2017-This study aimed to compare mechanical and metabolic responses between traditional (TR) and cluster (CL) set configurations in the bench press exercise. In a counterbalanced randomized order, 10 men were tested with the following protocols (sets × repetitions [inter-repetition rest]): TR1: 3 × 10 (0-second), TR2: 6 × 5 (0-second), CL5: 3 × 10 (5-second), CL10: 3 × 10 (10-second), and CL15: 3 × 10 (15-second). The number of repetitions (30), interset rest (5 minutes), and resistance applied (10 repetition maximum) were the same for all set configurations. Movement velocity and blood lactate concentration were used to assess the mechanical and metabolic responses, respectively. The comparison of the first and last set of the training session revealed a significant decrease in movement velocity for TR1 (Effect size [ES]: -0.92), CL10 (ES: -0.85), and CL15 (ES: -1.08) (but not for TR2 [ES: -0.38] and CL5 [ES: -0.37]); while blood lactate concentration was significantly increased for TR1 (ES: 1.11), TR2 (ES: 0.90), and CL5 (ES: 1.12) (but not for CL10 [ES: 0.03] and CL15 [ES: -0.43]). Based on velocity loss, set configurations were ranked as follows: TR1 (-39.3 ± 7.3%) > CL5 (-20.2 ± 14.7%) > CL10 (-12.9 ± 4.9%), TR2 (-10.3 ± 5.3%), and CL15 (-10.0 ± 2.3%). The set configurations were ranked as follows based on the lactate concentration: TR1 (7.9 ± 1.1 mmol·L) > CL5 (5.8 ± 0.9 mmol·L) > TR2 (4.2 ± 0.7 mmol·L) > CL10 (3.5 ± 0.4 mmol·L) and CL15 (3.4 ± 0.7 mmol·L). These results support the use of TR2, CL10, and CL15 for the maintenance of high mechanical outputs, while CL10 and CL15 produce less metabolic stress than TR2.

  19. A single night light exposure acutely alters hormonal and metabolic responses in healthy participants

    Directory of Open Access Journals (Sweden)

    Mohammed S Albreiki

    2017-01-01

    Full Text Available Many animal studies have reported an association between melatonin suppression and the disturbance of metabolic responses; yet, few human studies have investigated bright light effects on metabolic and hormonal responses at night. This study investigated the impact of light on plasma hormones and metabolites prior to, and after, an evening meal in healthy participants. Seventeen healthy participants, 8 females (22.2 ± 2.59 years, mean ± s.d. and 9 males (22.8 ± 3.5 years were randomised to a two-way cross-over design protocol; dim light (DL (500 lux sessions, separated by at least seven days. Saliva and plasma samples were collected prior to and after a standard evening meal at specific intervals. Plasma non-esterified fatty acid (NEFA levels were significantly higher pre-meal in DL compared to BL (P < 0.01. Plasma glucose and insulin levels were significantly greater post-meal in the BL compared to DL session (P = 0.02, P = 0.001, respectively. Salivary melatonin levels were significantly higher in the DL compared to those in BL session (P = 0.005. BL at night was associated with significant increases in plasma glucose and insulin suggestive of glucose intolerance and insulin insensitivity. Raised pre-prandial NEFA levels may be due to changes in insulin sensitivity or the presence of melatonin and/or light at night. Plasma triglyceride (TAG levels were the same in both sessions. These results may explain some of the health issues reported in shift workers; however, further studies are needed to elucidate the cause of these metabolic changes.

  20. Metabolic responses of the Antarctic fishes Notothenia rossii and Notothenia coriiceps to sewage pollution.

    Science.gov (United States)

    Rodrigues, Edson; Feijó-Oliveira, Mariana; Suda, Cecília Nohome Kawagoe; Vani, Gannabathula Sree; Donatti, Lucélia; Rodrigues, Edson; Lavrado, Helena Passeri

    2015-10-01

    The present study aimed to assess the sewage effects of the Brazilian Antarctic Station Comandante Ferraz, Admiralty Bay, King George Island, on the hepatic metabolism (energetic, antioxidant, and arginase levels) and levels of plasma constituents of two Antarctic fish species Notothenia rossii and N. coriiceps. The bioassays were conducted under controlled temperature (0 °C) and salinity (35 psu), exposing the fish for 96 h, to sewage effluent diluted in seawater to 0.5 % (v/v). Liver homogenates were tested for the specific activities of the enzymes glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GPase), hexokinase, citrate synthase, lactate dehydrogenase, malate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutathione reductase, catalase, and arginase. Plasma levels of glucose, triacylglycerides, cholesterol, total protein, albumin, chloride, magnesium, calcium, and inorganic phosphate were also determined. In N. rossii, the decrease in citrate synthase and the increase in G6Pase and GPase suggested that the sewage effluent activated glycogenolysis and hepatic gluconeogenesis, whereas is N. coriiceps, only G6Pase levels were increased. In N. rossii, sewage effluent induced hypertriglyceridemia without modulating glucose plasma levels, in contrast to N. coriiceps, which developed hypoglycemia without elevating plasma triglyceride levels. The decrease in glutathione reductase levels in N. coriiceps and in superoxide dismutase and catalase in N. rossii suggest that these two species are susceptible to oxidative stress stemming from the production of reactive oxygen species. An increase in magnesium in N. rossii and a decrease in N. coriiceps showed that sewage effluent compromised the control of plasma levels of this cation. Although phylogenetically close, both species of Antarctic fish exhibited different metabolic responses to the sewage effluent, with N. coriiceps showing greater susceptibility to the toxic effects of the

  1. Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome.

    Science.gov (United States)

    Yanes, Licy L; Romero, Damian G; Moulana, Mohaddetheh; Lima, Roberta; Davis, Deborah D; Zhang, Huimin; Lockhart, Rachel; Racusen, Lorraine C; Reckelhoff, Jane F

    2011-04-01

    Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated. This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined. Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

  2. Mathematical Modeling and Dynamic Simulation of Metabolic Reaction Systems Using Metabolome Time Series Data

    Directory of Open Access Journals (Sweden)

    Kansuporn eSriyudthsak

    2016-05-01

    Full Text Available The high-throughput acquisition of metabolome data is greatly anticipated for the complete understanding of cellular metabolism in living organisms. A variety of analytical technologies have been developed to acquire large-scale metabolic profiles under different biological or environmental conditions. Time series data are useful for predicting the most likely metabolic pathways because they provide important information regarding the accumulation of metabolites, which implies causal relationships in the metabolic reaction network. Considerable effort has been undertaken to utilize these data for constructing a mathematical model merging system properties and quantitatively characterizing a whole metabolic system in toto. However, there are technical difficulties between benchmarking the provision and utilization of data. Although hundreds of metabolites can be measured, which provide information on the metabolic reaction system, simultaneous measurement of thousands of metabolites is still challenging. In addition, it is nontrivial to logically predict the dynamic behaviors of unmeasurable metabolite concentrations without sufficient information on the metabolic reaction network. Yet, consolidating the advantages of advancements in both metabolomics and mathematical modeling remain to be accomplished. This review outlines the conceptual basis of and recent advances in technologies in both the research fields. It also highlights the potential for constructing a large-scale mathematical model by estimating model parameters from time series metabolome data in order to comprehensively understand metabolism at the systems level.

  3. A Physiologically-Based Pharmacokinetic (PBPK) Model With Metabolic Interactions of Chloroform (CHCL3) and Trichloroethylene

    Science.gov (United States)

    Exposure to mixtures is frequent, but biologic pathways such as metabolic inhibition, are poorly understood. CHCl3 and TCE are model volatiles frequently co-occurring; combined exposure results in less than additive hepatotoxicity. Here, we explore the underlying metabolic inte...

  4. Mathematical Modeling and Dynamic Simulation of Metabolic Reaction Systems Using Metabolome Time Series Data.

    Science.gov (United States)

    Sriyudthsak, Kansuporn; Shiraishi, Fumihide; Hirai, Masami Yokota

    2016-01-01

    The high-throughput acquisition of metabolome data is greatly anticipated for the complete understanding of cellular metabolism in living organisms. A variety of analytical technologies have been developed to acquire large-scale metabolic profiles under different biological or environmental conditions. Time series data are useful for predicting the most likely metabolic pathways because they provide important information regarding the accumulation of metabolites, which implies causal relationships in the metabolic reaction network. Considerable effort has been undertaken to utilize these data for constructing a mathematical model merging system properties and quantitatively characterizing a whole metabolic system in toto. However, there are technical difficulties between benchmarking the provision and utilization of data. Although, hundreds of metabolites can be measured, which provide information on the metabolic reaction system, simultaneous measurement of thousands of metabolites is still challenging. In addition, it is nontrivial to logically predict the dynamic behaviors of unmeasurable metabolite concentrations without sufficient information on the metabolic reaction network. Yet, consolidating the advantages of advancements in both metabolomics and mathematical modeling remain to be accomplished. This review outlines the conceptual basis of and recent advances in technologies in both the research fields. It also highlights the potential for constructing a large-scale mathematical model by estimating model parameters from time series metabolome data in order to comprehensively understand metabolism at the systems level.

  5. Transcriptional, proteomic, and metabolic responses to lithium in galactose-grown yeast cells

    DEFF Research Database (Denmark)

    Bro, Christoffer; Regenberg, Birgitte; Lagniel, G.

    2003-01-01

    Lithium is highly toxic to yeast when grown in galactose medium mainly because phosphoglucomutase, a key enzyme of galactose metabolism, is inhibited. We studied the global protein and gene expression profiles of Saccharomyces cerevisiae grown in galactose in different time intervals after addition...... of lithium. These results were related to physiological studies where both secreted and intracellular metabolites were determined. Microarray analysis showed that 664 open reading frames were down-regulated and 725 up-regulated in response to addition of lithium. Genes involved in transcription, translation......-regulated proteins were also identified as being changed on the mRNA level. Functional clusters obtained from proteome data were coincident with transcriptional clusters. Physiological studies showed that acetate, glycerol, and glycogen accumulate in response to lithium, as reflected in expression data, whereas...

  6. Proteomic Analysis of Metabolic Responses to Biofuels and Chemicals in Photosynthetic Cyanobacteria.

    Science.gov (United States)

    Sun, T; Chen, L; Zhang, W

    2017-01-01

    Recent progresses in various "omics" technologies have enabled quantitative measurements of biological molecules in a high-throughput manner. Among them, high-throughput proteomics is a rapidly advancing field that offers a new means to quantify metabolic changes at protein level, which has significantly facilitated our understanding of cellular process, such as protein synthesis, posttranslational modifications, and degradation in responding to environmental perturbations. Cyanobacteria are autotrophic prokaryotes that can perform oxygenic photosynthesis and have recently attracted significant attentions as one promising alternative to traditionally biomass-based "microbial cell factories" to produce green fuels and chemicals. However, early studies have shown that the low tolerance to toxic biofuels and chemicals represented one major hurdle for further improving productivity of the cyanobacterial production systems. To address the issue, metabolic responses and their regulation of cyanobacterial cells to toxic end-products need to be defined. In this chapter, we discuss recent progresses in interpreting cyanobacterial responses to biofuels and chemicals using high-throughput proteomics approach, aiming to provide insights and guidelines on how to enhance tolerance and productivity of biofuels or chemicals in the renewable cyanobacteria systems in the future. © 2017 Elsevier Inc. All rights reserved.

  7. Growth, metabolism and physiological response of the sea cucumber, Apostichopus japonicus Selenka during periods of inactivity

    Science.gov (United States)

    Du, Rongbin; Zang, Yuanqi; Tian, Xiangli; Dong, Shuanglin

    2013-03-01

    The growth, metabolism and physiological response of the sea cucumber, Apostichopus japonicus, were investigated during periods of inactivity. The body weight, oxygen consumption rate (OCR), activities of acidic phosphatase (ACP), alkaline phosphatase (AKP), catalase (CAT) and superoxide dismutase (SOD), and content of heat shock protein 70 (Hsp70) in the body wall and coelomic fluid of A. japonicus were measured during starvation, experimental aestivation and aestivation. The results showed that the body weight of sea cucumber in the three treatments decreased significantly during the experimental period ( P sea cucumber reduced in starvation and experimental aestivation treatments, but increased gradually in natural aestivation treatment. The activities of ACP and AKP of sea cucumber decreased gradually in all treatments, whereas those of SOD and CAT as well as Hsp70 content decreased in the starvation and experimental aestivation treatments and increased in natural aestivation treatment. The sea cucumber entered a state of aestivation at 24°C. To some extent, the animals in experimental aestivation were different from those in natural aestivation in metabolism and physiological response. These findings suggested that the aestivation mechanism of A. japonicus is complex and may not be attributed to the elevated temperature only.

  8. Correlations of Eisenia fetida metabolic responses to extractable phenanthrene concentrations through time

    Energy Technology Data Exchange (ETDEWEB)

    McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda; Simpson, Andre J. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4 (Canada); Simpson, Myrna J., E-mail: myrna.simpson@utoronto.c [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail, Toronto, Ontario, M1C 1A4 (Canada)

    2010-06-15

    Eisenia fetida earthworms were exposed to phenanthrene for thirty days to compare hydroxypropyl-beta-cyclodextrin (HPCD) extraction of soil and {sup 1}H NMR earthworm metabolomics as indicators of bioavailability. The phenanthrene 28-d LC{sub 50} value was 750 mg/kg (632-891, 95% confidence intervals) for the peat soil tested. The initial phenanthrene concentration was 319 mg/kg, which biodegraded to 16 mg/kg within 15 days, at which time HPCD extraction suggested that phenanthrene was no longer bioavailable. Multivariate statistical analysis of {sup 1}H NMR spectra for E. fetida tissue extracts indicated that phenanthrene exposed and control earthworms differed throughout the 30 day experiment despite the low phenanthrene concentrations present after 15 days. This metabolic response was better correlated to total phenanthrene concentrations (Q{sup 2} = 0.59) than HPCD-extractable phenanthrene concentrations (Q{sup 2} = 0.46) suggesting that {sup 1}H NMR metabolomics offers considerable promise as a novel, molecular-level method to directly monitor the bioavailability of contaminants to earthworms in the environment. - Metabolic responses of Eisenia fetida earthworms to phenanthrene exposure are better correlated to total phenanthrene concentrations than to cyclodextrin-extractable concentrations through time.

  9. Time course of the response of carbohydrate metabolism to unloading of the soleus

    Science.gov (United States)

    Henriksen, Erik J.; Tischler, Marc E.

    1988-01-01

    The time course of the response of carbohydrate metabolism to unloading was studied in the soleus muscle of rats subjected to tail-cast suspension. In the fresh soleus, 12 hours of unloading led to higher concentrations of glycogen and lower activity ratios of both glycogen synthase and glycogen phosphorylase. These changes were still evident on day three. Thereafter, the increased glycogen concentration apparently diminished the activity ratio of glycogen synthase, leading to a subsequent fall in the total glycogen content after day one. After 24 hours of unloading, when no significant atrophy was detectable, there was no differential response to insulin for in vitro glucose metabolism. On day three, the soleus atrophied significantly and displayed a greater sensitivity to insulin for most of these parameters compared to the weight-bearing control muscle. However, insulin sensitivity for glycogen synthesis was unchanged. These results showed that the increased sensitivity to insulin of the unloaded soleus is associated with the degree of muscle atrophy, likely due to an increased insulin binding capacity relative to muscle mass. This study also showed that insulin regulation of glucose uptake and of glycogen synthesis is affected differentially in the unloaded soleus muscle.

  10. Noninvasive presymptomatic detection of Cercospora beticola infection and identification of early metabolic responses in sugar beet

    Directory of Open Access Journals (Sweden)

    Hans-Peter Mock

    2016-09-01

    Full Text Available Cercospora beticola is an economically significant fungal pathogen of sugar beet, and is the causative pathogen of Cercospora leaf spot. Selected host genotypes with contrasting degree of susceptibility to the disease have been exploited to characterize the patterns of metabolite responses to fungal infection, and to devise a pre-symptomatic, non-invasive method of detecting the presence of the pathogen. Sugar beet genotypes were analyzed for metabolite profiles and hyperspectral signatures. Correlation of data matrices from both approaches facilitated identification of candidates for metabolic markers. Hyperspectral imaging was highly predictive with a classification accuracy of 98.5-99.9 % in detecting C. beticola. Metabolite analysis revealed metabolites altered by the host as part of a successful defence response: these were L-DOPA, 12-hydroxyjasmonic acid 12-O-β-D-glucoside, pantothenic acid and 5-O-feruloylquinic acid. The accumulation of glucosylvitexin in the resistant cultivar suggests it acts as a constitutively-produced protectant. The study establishes a proof-of-concept for an unbiased, presymptomatic and non-invasive detection system for the presence of C. beticola. The test needs to be validated with a larger set of genotypes, to be scalable to the level of a crop improvement program, aiming to speed up the selection for resistant cultivars of sugar beet. Untargeted metabolic profiling is a valuable tool to identify metabolites which correlate with hyperspectral data.

  11. Correlations of Eisenia fetida metabolic responses to extractable phenanthrene concentrations through time

    International Nuclear Information System (INIS)

    McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda; Simpson, Andre J.; Simpson, Myrna J.

    2010-01-01

    Eisenia fetida earthworms were exposed to phenanthrene for thirty days to compare hydroxypropyl-β-cyclodextrin (HPCD) extraction of soil and 1 H NMR earthworm metabolomics as indicators of bioavailability. The phenanthrene 28-d LC 50 value was 750 mg/kg (632-891, 95% confidence intervals) for the peat soil tested. The initial phenanthrene concentration was 319 mg/kg, which biodegraded to 16 mg/kg within 15 days, at which time HPCD extraction suggested that phenanthrene was no longer bioavailable. Multivariate statistical analysis of 1 H NMR spectra for E. fetida tissue extracts indicated that phenanthrene exposed and control earthworms differed throughout the 30 day experiment despite the low phenanthrene concentrations present after 15 days. This metabolic response was better correlated to total phenanthrene concentrations (Q 2 = 0.59) than HPCD-extractable phenanthrene concentrations (Q 2 = 0.46) suggesting that 1 H NMR metabolomics offers considerable promise as a novel, molecular-level method to directly monitor the bioavailability of contaminants to earthworms in the environment. - Metabolic responses of Eisenia fetida earthworms to phenanthrene exposure are better correlated to total phenanthrene concentrations than to cyclodextrin-extractable concentrations through time.

  12. Computational Modelling of the Metabolic States Regulated by the Kinase Akt

    Directory of Open Access Journals (Sweden)

    Ettore eMosca

    2012-11-01

    Full Text Available Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB, also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.

  13. Maternal high-fat diet intensifies the metabolic response to stress in male rat offspring.

    Science.gov (United States)

    Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Dargahi, Leila; Salimi, Mina; Rashidi, FatemehSadat

    2017-01-01

    The mother's consumption of high-fat food can affect glucose metabolism and the hypothalamic-pituitary-adrenal axis responsiveness in the offspring and potentially affect the metabolic responses to stress as well. This study examines the effect of maternal high-fat diet on the expression of pancreatic glucose transporter 2 and the secretion of insulin in response to stress in offspring. Female rats were randomly divided into normal and high-fat diet groups and were fed in accordance with their given diets from pre-pregnancy to the end of lactation. The offspring were divided into control (NC and HFC) and stress (NS and HFS) groups based on their mothers' diet and exposure to stress in adulthood. After the two-week stress induction period was over, an intraperitoneal glucose tolerance test (IPGTT) was performed and plasma glucose and insulin levels were assessed. The pancreas was then removed for measuring insulin secretion from the isolated islets as well as glucose transporter 2 mRNA expression and protein levels. According to the results obtained, plasma corticosterone concentrations increased significantly on days 1 and 14 of the stress induction period and were lower on the last day compared to on the first day. In both the NS and HFS groups, stress reduced plasma insulin concentration in the IPGTT without changing the plasma glucose concentration, suggesting an increased insulin sensitivity in the NS and HFS groups, although more markedly in the latter. Stress reduced insulin secretion (at high glucose concentrations) and increased glucose transporter 2 mRNA and protein expression, especially in the HFS group. Mothers' high-fat diet appears to intensify the stress response by changing the programming of the neuroendocrine system in the offspring.

  14. Gender comparison of psychophysical forces, cardiopulmonary, and muscle metabolic responses during a simulated cart pushing task.

    Science.gov (United States)

    Maikala, Rammohan V; Ciriello, Vincent M; Dempsey, Patrick G; O'Brien, Niall V

    2010-10-01

    The purpose was to compare psychophysiological responses between healthy male and female workers during dynamic pushing. Using a psychophysical approach, 27 participants chose an acceptable force that they could push over a 7.6m distance at a frequency of 1 push per min on a treadmill. On a separate day, cardiopulmonary (e.g., whole-body oxygen uptake, heart rate, ventilation volume) and muscle metabolic measurements (change in muscle blood volume [ΔtHb] and Tissue Oxygenation Index [TOI]) from the right and left gastrocnemius muscles were collected simultaneously while participants pushed the previously chosen acceptable force on the treadmill at a similar frequency and distance for 2h. Results showed no significant difference between men and women for integrated force exerted on the instrumented treadmill handle and cardiopulmonary responses. In contrast, women demonstrated 45.7% lower ΔtHb but 3.6% higher TOI in the gastrocnemius region as compared to men, suggesting a lower hemoglobin concentration in women and high venous oxygen saturation during pushing. When ΔtHb and TOI were corrected for both body mass and pushing force, the disparity in gender was retained, implying an increased muscle oxygen saturation per force development in women than men during pushing. In the left gastrocnemius region, ΔtHb was 60% lower and TOI was 5.7% higher in women than men, suggesting an uneven muscle loading during pushing. Overall, the gender similarity in cardiopulmonary responses versus disparity in muscle metabolic responses suggest the importance of evaluating human performance during physical work at both whole-body and localized muscle levels. Copyright © 2010 Elsevier B.V. All rights reserved.

  15. Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses

    International Nuclear Information System (INIS)

    Zhang Qiang; Pi Jingbo; Woods, Courtney G.; Andersen, Melvin E.

    2009-01-01

    Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

  16. Phase I to II cross-induction of xenobiotic metabolizing enzymes: a feedforward control mechanism for potential hormetic responses.

    Science.gov (United States)

    Zhang, Qiang; Pi, Jingbo; Woods, Courtney G; Andersen, Melvin E

    2009-06-15

    Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

  17. Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

    Directory of Open Access Journals (Sweden)

    Cassandra Collins

    2017-09-01

    Full Text Available Armillaria mellea is a major plant pathogen. Yet, the strategies the organism uses to infect susceptible species, degrade lignocellulose and other plant material and protect itself against plant defences and its own glycodegradative arsenal are largely unknown. Here, we use a combination of gel and MS-based proteomics to profile A. mellea under conditions of oxidative stress and changes in growth matrix. 2-DE and LC-MS/MS were used to investigate the response of A. mellea to H2O2 and menadione/FeCl3 exposure, respectively. Several proteins were detected with altered abundance in response to H2O2, but not menadione/FeCl3 (i.e., valosin-containing protein, indicating distinct responses to these different forms of oxidative stress. One protein, cobalamin-independent methionine synthase, demonstrated a common response in both conditions, which may be a marker for a more general stress response mechanism. Further changes to the A. mellea proteome were investigated using MS-based proteomics, which identified changes to putative secondary metabolism (SM enzymes upon growth in agar compared to liquid cultures. Metabolomic analyses revealed distinct profiles, highlighting the effect of growth matrix on SM production. This establishes robust methods by which to utilize comparative proteomics to characterize this important phytopathogen.

  18. Modeling the frequency response of photovoltaic inverters

    NARCIS (Netherlands)

    Ernauli Christine Aprilia, A.; Cuk, V.; Cobben, J.F.G.; Ribeiro, P.F.; Kling, W.L.

    2012-01-01

    The increased presence of photovoltaic (PV) systems inevitably affects the power quality in the grid. This new reality demands grid power quality studies involving PV inverters. This paper proposes several frequency response models in the form of equivalent circuits. Models are based on laboratory

  19. Corporate Social Responsibility Agreements Model for Community ...

    African Journals Online (AJOL)

    Corporate Social Responsibility Agreements Model for Community ... their host communities with concomitant adverse effect on mining operations. ... sustainable community development an integral part of the mining business. This paper presents the evolutionary strategic models, with differing principles and action plans, ...

  20. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted...... for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies....

  1. Transcriptome data modeling for targeted plant metabolic engineering.

    Science.gov (United States)

    Yonekura-Sakakibara, Keiko; Fukushima, Atsushi; Saito, Kazuki

    2013-04-01

    The massive data generated by omics technologies require the power of bioinformatics, especially network analysis, for data mining and doing data-driven biology. Gene coexpression analysis, a network approach based on comprehensive gene expression data using microarrays, is becoming a standard tool for predicting gene function and elucidating the relationship between metabolic pathways. Differential and comparative gene coexpression analyses suggest a change in coexpression relationships and regulators controlling common and/or specific biological processes. In conjunction with the newly emerging genome editing technology, network analysis integrated with other omics data should pave the way for robust and practical plant metabolic engineering. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Experimental data and dose-response models

    International Nuclear Information System (INIS)

    Ullrich, R.L.

    1985-01-01

    Dose-response relationships for radiation carcinogenesis have been of interest to biologists, modelers, and statisticians for many years. Despite his interest there are few instances in which there are sufficient experimental data to allow the fitting of various dose-response models. In those experimental systems for which data are available the dose-response curves for tumor induction for the various systems cannot be described by a single model. Dose-response models which have been observed following acute exposures to gamma rays include threshold, quadratic, and linear models. Data on sex, age, and environmental influences of dose suggest a strong role of host factors on the dose response. With decreasing dose rate the effectiveness of gamma ray irradiation tends to decrease in essentially every instance. In those cases in which the high dose rate dose response could be described by a quadratic model, the effect of dose rate is consistent with predictions based on radiation effects on the induction of initial events. Whether the underlying reasons for the observed dose-rate effect is a result of effects on the induction of initial events or is due to effects on the subsequent steps in the carcinogenic process is unknown. Information on the dose response for tumor induction for high LET (linear energy transfer) radiations such as neutrons is even more limited. The observed dose and dose rate data for tumor induction following neutron exposure are complex and do not appear to be consistent with predictions based on models for the induction of initial events

  3. Effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia in the frequently sampled intravenous glucose tolerance test.

    Science.gov (United States)

    Shin, Mi-Kyung; Han, Woobum; Joo, Hoon; Bevans-Fonti, Shannon; Shiota, Masakazu; Stefanovski, Darko; Polotsky, Vsevolod Y

    2017-04-01

    Obstructive sleep apnea is associated with type 2 diabetes. We have previously developed a mouse model of intermittent hypoxia (IH) mimicking oxyhemoglobin desaturations in patients with sleep apnea and have shown that IH increases fasting glucose, hepatic glucose output, and plasma catecholamines. We hypothesize that adrenal medulla modulates glucose responses to IH and that such responses can be prevented by adrenal medullectomy. We performed adrenal medullectomy or sham surgery in lean C57BL/6J mice, which were exposed to IH or intermittent air (control) for 4 wk followed by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in unanesthetized unrestrained animals. IH was administered during the 12-h light phase (9 AM to 9 PM) by decreasing inspired oxygen from 21 to 6.5% 60 cycles/h. Insulin sensitivity (S I ), insulin independent glucose disposal [glucose effectiveness (S G )], and the insulin response to glucose (AIR G ) were determined using the minimal model method. In contrast to our previous data obtained in restrained mice, IH did not affect fasting blood glucose and plasma insulin levels in sham-operated mice. IH significantly decreased S G but did not affect S I and AIR G Adrenal medullectomy decreased fasting blood glucose and plasma insulin levels and increased glycogen synthesis in the liver in hypoxic mice but did not have a significant effect on the FSIVGTT metrics. We conclude that, in the absence of restraints, IH has no effect on glucose metabolism in lean mice with exception of decreased S G , whereas adrenal medullectomy decreases fasting glucose and insulin levels in the IH environment. NEW & NOTEWORTHY To our knowledge, this is the first study examining the role of adrenal catecholamines in glucose metabolism during intermittent hypoxia (IH) in unanesthetized unrestrained C57BL/6J mice. We report that IH did not affect fasting glucose and insulin levels nor insulin sensitivity and insulin secretion during, whereas glucose

  4. Modeling of Pharmaceutical Biotransformation by Enriched Nitrifying Culture under Different Metabolic Conditions

    DEFF Research Database (Denmark)

    Xu, Yifeng; Chen, Xueming; Yuan, Zhiguo

    2018-01-01

    Pharmaceutical removal could be significantly enhanced through cometabolism during nitrification processes. To date, pharmaceutical biotransformation models have not considered the formation of transformation products associated with the metabolic type of microorganisms. Here we report a comprehe......Pharmaceutical removal could be significantly enhanced through cometabolism during nitrification processes. To date, pharmaceutical biotransformation models have not considered the formation of transformation products associated with the metabolic type of microorganisms. Here we report...... a comprehensive model to describe and evaluate the biodegradation of pharmaceuticals and the formation of their biotransformation products by enriched nitrifying cultures. The biotransformation of parent compounds was linked to the microbial processes via cometabolism induced by ammonium-oxidizing bacteria (AOB......) growth, metabolism by AOB, cometabolism by heterotrophs (HET) growth, and metabolism by HET in the model framework. The model was calibrated and validated using experimental data from pharmaceutical biodegradation experiments at realistic levels, taking two pharmaceuticals as examples, i.e., atenolol...

  5. Interpreting expression data with metabolic flux models: predicting Mycobacterium tuberculosis mycolic acid production.

    Directory of Open Access Journals (Sweden)

    Caroline Colijn

    2009-08-01

    Full Text Available Metabolism is central to cell physiology, and metabolic disturbances play a role in numerous disease states. Despite its importance, the ability to study metabolism at a global scale using genomic technologies is limited. In principle, complete genome sequences describe the range of metabolic reactions that are possible for an organism, but cannot quantitatively describe the behaviour of these reactions. We present a novel method for modeling metabolic states using whole cell measurements of gene expression. Our method, which we call E-Flux (as a combination of flux and expression, extends the technique of Flux Balance Analysis by modeling maximum flux constraints as a function of measured gene expression. In contrast to previous methods for metabolically interpreting gene expression data, E-Flux utilizes a model of the underlying metabolic network to directly predict changes in metabolic flux capacity. We applied E-Flux to Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB. Key components of mycobacterial cell walls are mycolic acids which are targets for several first-line TB drugs. We used E-Flux to predict the impact of 75 different drugs, drug combinations, and nutrient conditions on mycolic acid biosynthesis capacity in M. tuberculosis, using a public compendium of over 400 expression arrays. We tested our method using a model of mycolic acid biosynthesis as well as on a genome-scale model of M. tuberculosis metabolism. Our method correctly predicts seven of the eight known fatty acid inhibitors in this compendium and makes accurate predictions regarding the specificity of these compounds for fatty acid biosynthesis. Our method also predicts a number of additional potential modulators of TB mycolic acid biosynthesis. E-Flux thus provides a promising new approach for algorithmically predicting metabolic state from gene expression data.

  6. Waterborne cadmium and nickel impact oxidative stress responses and retinoid metabolism in yellow perch

    International Nuclear Information System (INIS)

    Defo, Michel A.; Bernatchez, Louis; Campbell, Peter G.C.; Couture, Patrice

    2014-01-01

    Highlights: • Cd and Ni affected indicators of retinoid metabolism and oxidative stress in fish. • Liver rdh-2 transcription levels increase in fish exposed to waterborne Cd. • Liver REH and LdRAT activities increase with increasing kidney Cd concentration. • Changes at molecular levels do not always mean changes at the functional levels. • Multi-level biological approaches are needed when assessing fish metal toxicology. - Abstract: In this experiment, we studied the transcriptional and functional (enzymatic) responses of yellow perch (Perca flavescens) to metal stress, with a focus on oxidative stress and vitamin A metabolism. Juvenile yellow perch were exposed to two environmentally relevant concentrations of waterborne cadmium (Cd) and nickel (Ni) for a period of 6 weeks. Kidney Cd and Ni bioaccumulation significantly increased with increasing metal exposure. The major retinoid metabolites analyzed in liver and muscle decreased with metal exposure except at high Cd exposure where no variation was reported in liver. A decrease in free plasma dehydroretinol was also observed with metal exposure. In the liver of Cd-exposed fish, both epidermal retinol dehydrogenase 2 transcription level and corresponding enzyme activities retinyl ester hydrolase and lecithin dehydroretinyl acyl transferase increased. In contrast, muscle epidermal retinol dehydrogenase 2 transcription level decreased with Cd exposure. Among antioxidant defences, liver transcription levels of catalase, microsomal glutathione-S-transferase-3 and glucose-6-phosphate dehydrogenase were generally enhanced in Cd-exposed fish and this up-regulation was accompanied by an increase in the activities of corresponding enzymes, except for microsomal glutathione-S-transferase. No consistent pattern in antioxidant defence responses was observed between molecular and biochemical response when fish were exposed to Ni, suggesting a non-synchronous response of antioxidant defence in fish exposed to

  7. Waterborne cadmium and nickel impact oxidative stress responses and retinoid metabolism in yellow perch

    Energy Technology Data Exchange (ETDEWEB)

    Defo, Michel A. [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada); Bernatchez, Louis [Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, Québec G1V 0A6 (Canada); Campbell, Peter G.C. [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada); Couture, Patrice, E-mail: patrice.couture@ete.inrs.ca [Institut national de la recherche scientifique (INRS), Centre Eau Terre Environnement, 490 de la Couronne, Québec, Québec G1K 9A9 (Canada)

    2014-09-15

    Highlights: • Cd and Ni affected indicators of retinoid metabolism and oxidative stress in fish. • Liver rdh-2 transcription levels increase in fish exposed to waterborne Cd. • Liver REH and LdRAT activities increase with increasing kidney Cd concentration. • Changes at molecular levels do not always mean changes at the functional levels. • Multi-level biological approaches are needed when assessing fish metal toxicology. - Abstract: In this experiment, we studied the transcriptional and functional (enzymatic) responses of yellow perch (Perca flavescens) to metal stress, with a focus on oxidative stress and vitamin A metabolism. Juvenile yellow perch were exposed to two environmentally relevant concentrations of waterborne cadmium (Cd) and nickel (Ni) for a period of 6 weeks. Kidney Cd and Ni bioaccumulation significantly increased with increasing metal exposure. The major retinoid metabolites analyzed in liver and muscle decreased with metal exposure except at high Cd exposure where no variation was reported in liver. A decrease in free plasma dehydroretinol was also observed with metal exposure. In the liver of Cd-exposed fish, both epidermal retinol dehydrogenase 2 transcription level and corresponding enzyme activities retinyl ester hydrolase and lecithin dehydroretinyl acyl transferase increased. In contrast, muscle epidermal retinol dehydrogenase 2 transcription level decreased with Cd exposure. Among antioxidant defences, liver transcription levels of catalase, microsomal glutathione-S-transferase-3 and glucose-6-phosphate dehydrogenase were generally enhanced in Cd-exposed fish and this up-regulation was accompanied by an increase in the activities of corresponding enzymes, except for microsomal glutathione-S-transferase. No consistent pattern in antioxidant defence responses was observed between molecular and biochemical response when fish were exposed to Ni, suggesting a non-synchronous response of antioxidant defence in fish exposed to

  8. Modeling the role of covalent enzyme modification in Escherichia coli nitrogen metabolism

    International Nuclear Information System (INIS)

    Kidd, Philip B; Wingreen, Ned S

    2010-01-01

    In the bacterium Escherichia coli, the enzyme glutamine synthetase (GS) converts ammonium into the amino acid glutamine. GS is principally active when the cell is experiencing nitrogen limitation, and its activity is regulated by a bicyclic covalent modification cascade. The advantages of this bicyclic-cascade architecture are poorly understood. We analyze a simple model of the GS cascade in comparison to other regulatory schemes and conclude that the bicyclic cascade is suboptimal for maintaining metabolic homeostasis of the free glutamine pool. Instead, we argue that the lag inherent in the covalent modification of GS slows the response to an ammonium shock and thereby allows GS to transiently detoxify the cell, while maintaining homeostasis over longer times

  9. Dynamic metabolic modeling of heterotrophic and mixotrophic microalgal growth on fermentative wastes.

    Directory of Open Access Journals (Sweden)

    Caroline Baroukh

    2017-06-01

    Full Text Available Microalgae are promising microorganisms for the production of numerous molecules of interest, such as pigments, proteins or triglycerides that can be turned into biofuels. Heterotrophic or mixotrophic growth on fermentative wastes represents an interesting approach to achieving higher biomass concentrations, while reducing cost and improving the environmental footprint. Fermentative wastes generally consist of a blend of diverse molecules and it is thus crucial to understand microalgal metabolism in such conditions, where switching between substrates might occur. Metabolic modeling has proven to be an efficient tool for understanding metabolism and guiding the optimization of biomass or target molecule production. Here, we focused on the metabolism of Chlorella sorokiniana growing heterotrophically and mixotrophically on acetate and butyrate. The metabolism was represented by 172 metabolic reactions. The DRUM modeling framework with a mildly relaxed quasi-steady-state assumption was used to account for the switching between substrates and the presence of light. Nine experiments were used to calibrate the model and nine experiments for the validation. The model efficiently predicted the experimental data, including the transient behavior during heterotrophic, autotrophic, mixotrophic and diauxic growth. It shows that an accurate model of metabolism can now be constructed, even in dynamic conditions, with the presence of several carbon substrates. It also opens new perspectives for the heterotrophic and mixotrophic use of microalgae, especially for biofuel production from wastes.

  10. Reproductive and metabolic phenotype of a mouse model of PCOS

    NARCIS (Netherlands)

    E. Leonie (E.); A.F. van Houten (A.); P. Kramer (Piet); A. McLuskey; B. Karels (Bas); A.P.N. Themmen (Axel); J.A. Visser (Jenny)

    2012-01-01

    textabstractPolycystic ovary syndrome (PCOS), the most common endocrine disorder in women in their reproductive age, is characterized by both reproductive and metabolic features. Recent studies in human, nonhuman primates, and sheep suggest that hyperandrogenism plays an important role in the

  11. Glucocorticoids, metabolic adaptations and recovery : studies in specific mouse models

    NARCIS (Netherlands)

    Auvinen, Hanna Elina

    2013-01-01

    Today’s Western society and work promotes a sedentary lifestyle. This, coupled with high caloric food availability has increased obesity followed by an increased prevalence of the metabolic syndrome (MetS), type 2 diabetes (T2D) and cardiovascular diseases (CVD). Epidemiological data show a clear

  12. Energetic Metabolism and Biochemical Adaptation: A Bird Flight Muscle Model

    Science.gov (United States)

    Rioux, Pierre; Blier, Pierre U.

    2006-01-01

    The main objective of this class experiment is to measure the activity of two metabolic enzymes in crude extract from bird pectoral muscle and to relate the differences to their mode of locomotion and ecology. The laboratory is adapted to stimulate the interest of wildlife management students to biochemistry. The enzymatic activities of cytochrome…

  13. Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients

    Directory of Open Access Journals (Sweden)

    Gabriela Jiménez-Valerio

    2016-05-01

    Full Text Available Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.

  14. SU-C-303-02: Correlating Metabolic Response to Radiation Therapy with HIF-1alpha Expression

    International Nuclear Information System (INIS)

    Campos, D; Peeters, W; Nickel, K; Eliceiri, K; Kimple, R; Van Der Kogel, A; Kissick, M

    2015-01-01

    Purpose: To understand radiation induced alterations in cellular metabolism which could be used to assess treatment or normal tissue response to aid in patient-specific adaptive radiotherapy. This work aims to compare the metabolic response of two head and neck cell lines, one malignant (UM-SCC-22B) and one benign (Normal Oral Keratinocyte), to ionizing radiation. Responses are compared to alterations in HIF-1alpha expression. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Measurements of metabolism and HIF-1alpha expression were taken before and X minutes after a 10 Gy dose of radiation delivered via an orthovoltage x-ray source. In vitro changes in metabolic activity were measured via fluorescence lifetime imaging (FLIM) to assess the mean lifetime of NADH autofluorescence following a dose of 10 Gy. HIF-1alpha expression was measured via immunohistochemical staining of in vitro treated cells and expression was quantified using the FIJI software package. Results: FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways for malignant cells; whereas this benign cell line showed little change in metabolic signature. Immunohistochemical analysis showed significant changes in HIF-1alpha expression in response to 10 Gy of radiation that correlate to metabolic profiles. Conclusion: Radiation induces significant changes in metabolic activity and HIF-1alpha expression. These alterations occur on time scales approximating the duration of common radiation treatments (approximately tens of minutes). Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response

  15. SU-C-303-02: Correlating Metabolic Response to Radiation Therapy with HIF-1alpha Expression

    Energy Technology Data Exchange (ETDEWEB)

    Campos, D [University of Wisconsin Madison, Madison, WI (United States); Peeters, W [Radboud University Medical Center, Nijmegen, GA (United States); Nickel, K [University of Wisconsin, Madison, WI (United States); Eliceiri, K; Kimple, R; Van Der Kogel, A; Kissick, M [University of Wisconsin, Madison, Wisconsin (United States)

    2015-06-15

    Purpose: To understand radiation induced alterations in cellular metabolism which could be used to assess treatment or normal tissue response to aid in patient-specific adaptive radiotherapy. This work aims to compare the metabolic response of two head and neck cell lines, one malignant (UM-SCC-22B) and one benign (Normal Oral Keratinocyte), to ionizing radiation. Responses are compared to alterations in HIF-1alpha expression. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Measurements of metabolism and HIF-1alpha expression were taken before and X minutes after a 10 Gy dose of radiation delivered via an orthovoltage x-ray source. In vitro changes in metabolic activity were measured via fluorescence lifetime imaging (FLIM) to assess the mean lifetime of NADH autofluorescence following a dose of 10 Gy. HIF-1alpha expression was measured via immunohistochemical staining of in vitro treated cells and expression was quantified using the FIJI software package. Results: FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways for malignant cells; whereas this benign cell line showed little change in metabolic signature. Immunohistochemical analysis showed significant changes in HIF-1alpha expression in response to 10 Gy of radiation that correlate to metabolic profiles. Conclusion: Radiation induces significant changes in metabolic activity and HIF-1alpha expression. These alterations occur on time scales approximating the duration of common radiation treatments (approximately tens of minutes). Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

  16. Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level.

    Directory of Open Access Journals (Sweden)

    Hongyu Li

    Full Text Available Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

  17. Responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes: a randomized trial.

    Directory of Open Access Journals (Sweden)

    Susan J van Dijk

    Full Text Available The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes.In a cross-over design 42 men (age 50-70 y consumed three high-fat shakes containing saturated fat (SFA, monounsaturated fat (MUFA or n-3 polyunsaturated (PUFA. Men were selected on BMI and health status (lean, obese or obese diabetic and phenotyped with MRI for adipose tissue distribution. Before and 2 and 4 h after shake consumption blood was drawn for measurement of expression of metabolic and inflammation-related genes in peripheral blood mononuclear cells (PBMCs, plasma triglycerides (TAG, glucose, insulin, cytokines and ex vivo PBMC immune response capacity. The MUFA and n-3 PUFA challenge, compared to the SFA challenge, induced higher changes in expression of inflammation genes MCP1 and IL1β in PBMCs. Obese and obese diabetic subjects had different PBMC gene expression and metabolic responses to high-fat challenges compared to lean subjects. The MUFA challenge induced the most pronounced TAG response, mainly in obese and obese diabetic subjects.The PBMC gene expression response and metabolic response to high-fat challenges were affected by fat type and metabolic risk phenotype. Based on our results we suggest using a MUFA challenge to reveal differences in response capacity of subjects.ClinicalTrials.gov NCT00977262.

  18. Proprietary tomato extract improves metabolic response to high-fat meal in healthy normal weight subjects

    Directory of Open Access Journals (Sweden)

    Xavier Deplanque

    2016-10-01

    Full Text Available Background: Low-density lipoprotein (LDL oxidation is a risk factor for atherosclerosis. Lycopene and tomato-based products have been described as potent inhibitors of LDL oxidation. Objectives: To evaluate the effect of a 2-week supplementation with a carotenoid-rich tomato extract (CRTE standardized for a 1:1 ratio of lycopene and phytosterols, on post-prandial LDL oxidation after a high-fat meal. Design: In a randomized, double-blind, parallel-groups, placebo-controlled study, 146 healthy normal weight individuals were randomly assigned to a daily dose of CRTE standardized for tomato phytonutrients or placebo during 2 weeks. Oxidized LDL (OxLDL, glucose, insulin, and triglyceride (TG responses were measured for 8 h after ingestion of a high-fat meal before and at the end of intervention. Results: Plasma lycopene, phytofluene, and phytoene were increased throughout the study period in the CRTE group compared to placebo. CRTE ingestion significantly improved changes in OxLDL response to high-fat meal compared to placebo after 2 weeks (p<0.0001. Changes observed in glucose, insulin, and TG responses were not statistically significant after 2 weeks of supplementation, although together they may suggest a trend of favorable effect on metabolic outcomes after a high-fat meal. Conclusions: Two-week supplementation with CRTE increased carotenoids levels in plasma and improved oxidized LDL response to a high-fat meal in healthy normal weight individuals.

  19. Steady-state global optimization of metabolic non-linear dynamic models through recasting into power-law canonical models.

    Science.gov (United States)

    Pozo, Carlos; Marín-Sanguino, Alberto; Alves, Rui; Guillén-Gosálbez, Gonzalo; Jiménez, Laureano; Sorribas, Albert

    2011-08-25

    Design of newly engineered microbial strains for biotechnological purposes would greatly benefit from the development of realistic mathematical models for the processes to be optimized. Such models can then be analyzed and, with the development and application of appropriate optimization techniques, one could identify the modifications that need to be made to the organism in order to achieve the desired biotechnological goal. As appropriate models to perform such an analysis are necessarily non-linear and typically non-convex, finding their global optimum is a challenging task. Canonical modeling techniques, such as Generalized Mass Action (GMA) models based on the power-law formalism, offer a possible solution to this problem because they have a mathematical structure that enables the development of specific algorithms for global optimization. Based on the GMA canonical representation, we have developed in previous works a highly efficient optimization algorithm and a set of related strategies for understanding the evolution of adaptive responses in cellular metabolism. Here, we explore the possibility of recasting kinetic non-linear models into an equivalent GMA model, so that global optimization on the recast GMA model can be performed. With this technique, optimization is greatly facilitated and the results are transposable to the original non-linear problem. This procedure is straightforward for a particular class of non-linear models known as Saturable and Cooperative (SC) models that extend the power-law formalism to deal with saturation and cooperativity. Our results show that recasting non-linear kinetic models into GMA models is indeed an appropriate strategy that helps overcoming some of the numerical difficulties that arise during the global optimization task.

  20. Steady-state global optimization of metabolic non-linear dynamic models through recasting into power-law canonical models

    Directory of Open Access Journals (Sweden)

    Sorribas Albert

    2011-08-01

    Full Text Available Abstract Background Design of newly engineered microbial strains for biotechnological purposes would greatly benefit from the development of realistic mathematical models for the processes to be optimized. Such models can then be analyzed and, with the development and application of appropriate optimization techniques, one could identify the modifications that need to be made to the organism in order to achieve the desired biotechnological goal. As appropriate models to perform such an analysis are necessarily non-linear and typically non-convex, finding their global optimum is a challenging task. Canonical modeling techniques, such as Generalized Mass Action (GMA models based on the power-law formalism, offer a possible solution to this problem because they have a mathematical structure that enables the development of specific algorithms for global optimization. Results Based on the GMA canonical representation, we have developed in previous works a highly efficient optimization algorithm and a set of related strategies for understanding the evolution of adaptive responses in cellular metabolism. Here, we explore the possibility of recasting kinetic non-linear models into an equivalent GMA model, so that global optimization on the recast GMA model can be performed. With this technique, optimization is greatly facilitated and the results are transposable to the original non-linear problem. This procedure is straightforward for a particular class of non-linear models known as Saturable and Cooperative (SC models that extend the power-law formalism to deal with saturation and cooperativity. Conclusions Our results show that recasting non-linear kinetic models into GMA models is indeed an appropriate strategy that helps overcoming some of the numerical difficulties that arise during the global optimization task.

  1. Proteomic Profiles of Adipose and Liver Tissues from an Animal Model of Metabolic Syndrome Fed Purple Vegetables

    Directory of Open Access Journals (Sweden)

    Hala M Ayoub

    2018-04-01

    Full Text Available Metabolic Syndrome (MetS is a complex disorder that predisposes an individual to Cardiovascular Diseases and type 2 Diabetes Mellitus. Proteomics and bioinformatics have proven to be an effective tool to study complex diseases and mechanisms of action of nutrients. We previously showed that substitution of the majority of carbohydrate in a high fat diet by purple potatoes (PP or purple carrots (PC improved insulin sensitivity and hypertension in an animal model of MetS (obese Zucker rats compared to a control sucrose-rich diet. In the current study, we used TMT 10plex mass tag combined with LC-MS/MS technique to study proteomic modulation in the liver (n = 3 samples/diet and adipose tissue (n = 3 samples/diet of high fat diet-fed rats with or without substituting sucrose for purple vegetables, followed by functional enrichment analysis, in an attempt to elucidate potential molecular mechanisms responsible for the phenotypic changes seen with purple vegetable feeding. Protein folding, lipid metabolism and cholesterol efflux were identified as the main modulated biological themes in adipose tissue, whereas lipid metabolism, carbohydrate metabolism and oxidative stress were the main modulated themes in liver. We propose that enhanced protein folding, increased cholesterol efflux and higher free fatty acid (FFA re-esterification are mechanisms by which PP and PC positively modulate MetS pathologies in adipose tissue, whereas, decreased de novo lipogenesis, oxidative stress and FFA uptake, are responsible for the beneficial effects in liver. In conclusion, we provide molecular evidence for the reported metabolic health benefits of purple carrots and potatoes and validate that these vegetables are good choices to replace other simple carbohydrate sources for better metabolic health.

  2. Modification of nucleotide metabolism in relationship with differentiation and in response to irradiation in human tumour cells

    International Nuclear Information System (INIS)

    Wei, Shuang

    1998-01-01

    This research thesis reports the study of the metabolism of nucleotides in human tumour cells. The first part addresses the modifications of nucleotide (more specifically purine) metabolism in relationship with human melanoma cell proliferation and differentiation. The second part addresses the modifications of this metabolism in response to an irradiation in human colon tumour cells. For each part, the author proposes a bibliographic synthesis, and a presentation of studied cells and of methods used to grow cells, and respectively to proliferate and differentiate them or to irradiate them, and then discusses the obtained results [fr

  3. Multiscale modeling of mucosal immune responses

    Science.gov (United States)

    2015-01-01

    Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T cell differentiation and tissue level cell-cell interactions was developed to illustrate the capabilities, power and scope of ENISI MSM. Background Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Implementation Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. Conclusion We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut

  4. Multiscale modeling of mucosal immune responses.

    Science.gov (United States)

    Mei, Yongguo; Abedi, Vida; Carbo, Adria; Zhang, Xiaoying; Lu, Pinyi; Philipson, Casandra; Hontecillas, Raquel; Hoops, Stefan; Liles, Nathan; Bassaganya-Riera, Josep

    2015-01-01

    Computational techniques are becoming increasingly powerful and modeling tools for biological systems are of greater needs. Biological systems are inherently multiscale, from molecules to tissues and from nano-seconds to a lifespan of several years or decades. ENISI MSM integrates multiple modeling technologies to understand immunological processes from signaling pathways within cells to lesion formation at the tissue level. This paper examines and summarizes the technical details of ENISI, from its initial version to its latest cutting-edge implementation. Object-oriented programming approach is adopted to develop a suite of tools based on ENISI. Multiple modeling technologies are integrated to visualize tissues, cells as well as proteins; furthermore, performance matching between the scales is addressed. We used ENISI MSM for developing predictive multiscale models of the mucosal immune system during gut inflammation. Our modeling predictions dissect the mechanisms by which effector CD4+ T cell responses contribute to tissue damage in the gut mucosa following immune dysregulation.Computational modeling techniques are playing increasingly important roles in advancing a systems-level mechanistic understanding of biological processes. Computer simulations guide and underpin experimental and clinical efforts. This study presents ENteric Immune Simulator (ENISI), a multiscale modeling tool for modeling the mucosal immune responses. ENISI's modeling environment can simulate in silico experiments from molecular signaling pathways to tissue level events such as tissue lesion formation. ENISI's architecture integrates multiple modeling technologies including ABM (agent-based modeling), ODE (ordinary differential equations), SDE (stochastic modeling equations), and PDE (partial differential equations). This paper focuses on the implementation and developmental challenges of ENISI. A multiscale model of mucosal immune responses during colonic inflammation, including CD4+ T

  5. An in vitro model for screening estrogen activity of environmental samples after metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Chahbane, N.; Schramm, K.W. [GSF - Forschungszentrum fuer Umwelt und Gesundheit Neuherberg GmbH, Oberschleissheim (Germany). Inst. fuer Oekologische Chemie; Kettrup, A. [Technische Univ. Muenchen, Freising (Germany). Lehrstuhl fuer Oekologische Chemie

    2004-09-15

    For a few years, yeast estrogen assay (YES) was accepted as a reliable and economic model for screening of environmental estrogens. Though the chemicals directly act with estrogen receptor (ER) can be filtered out by this model, there are still chemicals act with ER only after metabolism and some chemicals eliminate their estrogen activities after metabolism. That is to say, their metabolites exert or have stronger estrogen activities than themselves, which can be called bio-activation. In this case, for the lack of the metabolism enzyme system as human and other animals, only the assay with recombinant yeast cells is insufficient. So, it is necessary to combine the YES with metabolism procedure to evaluate the estrogen activities of these chemicals. The most common method used currently for in vitro metabolic activation in mutagenicity testing and also be applied to the estrogen screening field is S-9 mixture. Also, there is an attempt to develop a chemical model for cytochrome P450 as a bio-mimetic metabolic activation system. All these methods can be used as in vitro models for metabolism. Compare with these models, using whole H4II E cells for metabolism is an alternative and with superiorities. It has the excellence of short experiment period as all other in vitro models, but is much more close to the real surroundings as in vivo. Furthermore, the activity of 7-ethoxyresorufin-O-deethylase (EROD) can be easily measured during the whole incubation period for us to discuss the metabolic activities in a quantitative foundation, not only in qualitative. Methoxychlor is one of the chemicals with bio-activation ability. When directly used in the YES, it shows weak estrogen activity. But a main metabolite of methoxychlor, 2,2-bis (p-hydroxyphenyl) - 1,1,1-trichloroethane (HPTE) is a known estrogen mimic. For the long time using methoxychlor as a pesticide and its clear background, it is an ideal chemical to establish this in vitro system.

  6. Genetic Determinants of Cardio-Metabolic Risk: A Proposed Model for Phenotype Association and Interaction

    Science.gov (United States)

    Blackett, Piers R; Sanghera, Dharambir K

    2012-01-01

    This review provides a translational and unifying summary of metabolic syndrome genetics and highlights evidence that genetic studies are starting to unravel and untangle origins of the complex and challenging cluster of disease phenotypes. The associated genes effectively express in the brain, liver, kidney, arterial endothelium, adipocytes, myocytes and β cells. Progression of syndrome traits has been associated with ectopic lipid accumulation in the arterial wall, visceral adipocytes, myocytes, and liver. Thus it follows that the genetics of dyslipidemia, obesity, and non-alcoholic fatty liver (NAFLD) disease are central in triggering progression of the syndrome to overt expression of disease traits, and have become a key focus of interest for early detection and for designing prevention and treatments. To support the “birds’ eye view” approach we provide a road-map depicting commonality and interrelationships between the traits and their genetic and environmental determinants based on known risk factors, metabolic pathways, pharmacological targets, treatment responses, gene networks, pleiotropy, and association with circadian rhythm. Although only a small portion of the known heritability is accounted for and there is insufficient support for clinical application of gene-based prediction models, there is direction and encouraging progress in a rapidly moving field that is beginning to show clinical relevance. PMID:23351585

  7. Zebrafish as a Model System for Investigating the Compensatory Regulation of Ionic Balance during Metabolic Acidosis

    Directory of Open Access Journals (Sweden)

    Lletta Lewis

    2018-04-01

    Full Text Available Zebrafish (Danio rerio have become an important model for integrative physiological research. Zebrafish inhabit a hypo-osmotic environment; to maintain ionic and acid-base homeostasis, they must actively take up ions and secrete acid to the water. The gills in the adult and the skin at larval stage are the primary sites of ionic regulation in zebrafish. The uptake of ions in zebrafish is mediated by specific ion transporting cells termed ionocytes. Similarly, in mammals, ion reabsorption and acid excretion occur in specific cell types in the terminal region of the renal tubules (distal convoluted tubule and collecting duct. Previous studies have suggested that functional regulation of several ion transporters/channels in the zebrafish ionocytes resembles that in the mammalian renal cells. Additionally, several mechanisms involved in regulating the epithelial ion transport during metabolic acidosis are found to be similar between zebrafish and mammals. In this article, we systemically review the similarities and differences in ionic regulation between zebrafish and mammals during metabolic acidosis. We summarize the available information on the regulation of epithelial ion transporters during acidosis, with a focus on epithelial Na+, Cl− and Ca2+ transporters in zebrafish ionocytes and mammalian renal cells. We also discuss the neuroendocrine responses to acid exposure, and their potential role in ionic compensation. Finally, we identify several knowledge gaps that would benefit from further study.

  8. Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions

    Directory of Open Access Journals (Sweden)

    Fenja Klevenhusen

    2015-10-01

    Full Text Available Left displaced abomasum (LDA is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1 evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2 establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca, but greater concentrations of non-esterified fatty acids (NEFA and beta-hydroxy-butyrate (BHBA, in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA, regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA.

  9. Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions.

    Science.gov (United States)

    Klevenhusen, Fenja; Humer, Elke; Metzler-Zebeli, Barbara; Podstatzky-Lichtenstein, Leopold; Wittek, Thomas; Zebeli, Qendrim

    2015-10-13

    Left displaced abomasum (LDA) is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1) evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2) establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca), but greater concentrations of non-esterified fatty acids (NEFA) and beta-hydroxy-butyrate (BHBA), in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA), regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA.

  10. Investigating genotype-phenotype relationships in Saccharomyces cerevisiae metabolic network through stoichiometric modeling

    DEFF Research Database (Denmark)

    Brochado, Ana Rita

    processes. Metabolism is an extensively studied and characterised subcellular system, for which several modeling approaches have been proposed over the last 20 years. Nowadays, stoichiometric modeling of metabolism is done at the genome scale and it has diverse applications, many of them for helping....... This chapter aims at providing the reader with relevant state-of-the-art information concerning Systems Biology, Genome-Scale Metabolic Modeling and Metabolic Engineering. Particular attention is given to the yeast Saccharomyces cerevisiae, the eukaryotic model organism used thought the thesis.......A holistic view of the cell is fundamental for gaining insights into genotype to phenotype relationships. Systems Biology is a discipline within Biology, which uses such holistic approach by focusing on the development and application of tools for studying the structure and dynamics of cellular...

  11. 14C and tritium dynamics in wild mammals: a metabolic model

    International Nuclear Information System (INIS)

    Galeriu, D.; Beresford, N.A.; Melintescu, A.; Crout, N.M.J.; Takeda, H.

    2004-01-01

    The protection of biota from ionising radiations needs reliable predictions of radionuclide dynamics in wild animals. Data specific for many wild animals radionuclide combinations is lacking and a number of approaches including allometry have been proposed to address this. However, for 14 C and tritium, which are integral components of animals tissues and their diets, a different approach is needed in the absence of experimental data. Here we propose a metabolically based model which can be parameterized predominantly on the basis of published metabolic data. We begin with a metabolic definition of the 14 C and OBT loss rate (assumed to be the same) from the whole body and also specific organs, using available information on field metabolic rate and body composition. The mammalian body is conceptually partitioned into compartments (body water, viscera, adipose, muscle, blood and remainder) and a simple model defined using net maintenance and growth needs of mammals. Intake and excretion, and transfer to body water are modelled using basic metabolic knowledge and published relationships. The model is tested with data from studies using rats and sheep. It provides a reliable prediction for whole body and muscle activity concentrations without the requirement for any calibration specific to 3 H and 14 C. Predictions from the model for representative wild mammals (as selected to be reference organisms within international programmes) are presented. Potential developments of a metabolic model for birds and the application of our work to human food chain modelling are also discussed. (author)

  12. Predicting growth of the healthy infant using a genome scale metabolic model.

    Science.gov (United States)

    Nilsson, Avlant; Mardinoglu, Adil; Nielsen, Jens

    2017-01-01

    An estimated 165 million children globally have stunted growth, and extensive growth data are available. Genome scale metabolic models allow the simulation of molecular flux over each metabolic enzyme, and are well adapted to analyze biological systems. We used a human genome scale metabolic model to simulate the mechanisms of growth and integrate data about breast-milk intake and composition with the infant's biomass and energy expenditure of major organs. The model predicted daily metabolic fluxes from birth to age 6 months, and accurately reproduced standard growth curves and changes in body composition. The model corroborates the finding that essential amino and fatty acids do not limit growth, but that energy is the main growth limiting factor. Disruptions to the supply and demand of energy markedly affected the predicted growth, indicating that elevated energy expenditure may be detrimental. The model was used to simulate the metabolic effect of mineral deficiencies, and showed the greatest growth reduction for deficiencies in copper, iron, and magnesium ions which affect energy production through oxidative phosphorylation. The model and simulation method were integrated to a platform and shared with the research community. The growth model constitutes another step towards the complete representation of human metabolism, and may further help improve the understanding of the mechanisms underlying stunting.

  13. Energy metabolism and metabolomics response of Pacific white shrimp Litopenaeus vannamei to sulfide toxicity.

    Science.gov (United States)

    Li, Tongyu; Li, Erchao; Suo, Yantong; Xu, Zhixin; Jia, Yongyi; Qin, Jian G; Chen, Liqiao; Gu, Zhimin

    2017-02-01

    The toxicity and poisoning mechanisms of sulfide were studied in Litopenaeus vannamei from the perspective of energy metabolism and metabolomics. The lethal concentrations of sulfide in L. vannamei (LC50) at 24h, 48h, 72h, and 96h were determined. Sulfide at a concentration of 0, 1/10 (425.5μg/L), and 1/5 (851μg/L) of the LC 50 at 96h was used to test the metabolic responses of L. vannamei for 21days. The chronic exposure of shrimp to a higher sulfide concentration of 851μg/L decreased shrimp survival but did not affect weight gain or the hepatopancreas index. The glycogen content in the hepatopancreas and muscle and the activity of hepatopancreas cytochrome C oxidase of the shrimp exposed to all sulfide concentrations were significantly lower, and the serum glucose and lactic acid levels and lactic acid dehydrogenase activity were significantly lower than those in the control. Metabolomics assays showed that shrimp exposed to sulfide had lower amounts of serum pyruvic acid, succinic acid, glycine, alanine, and proline in the 425.5μg/L group and phosphate, succinic acid, beta-alanine, serine, and l-histidine in the 851μg/L group than in the control. Chronic sulfide exposure could disturb protein synthesis in shrimp but enhance gluconeogenesis and substrate absorption for ATP synthesis and tricarboxylic acid cycles to provide extra energy to cope with sulfide stress. Chronic sulfide exposure could adversely affect the health status of L. vannamei, as indicated by the high amounts of serum n-ethylmaleamic acid, pyroglutamic acid, aspartic acid and phenylalanine relative to the control. This study indicates that chronic exposure of shrimp to sulfide can decrease health and lower survival through functional changes in gluconeogenesis, protein synthesis and energy metabolism. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Single toxin dose-response models revisited

    Energy Technology Data Exchange (ETDEWEB)

    Demidenko, Eugene, E-mail: eugened@dartmouth.edu [Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH03756 (United States); Glaholt, SP, E-mail: sglaholt@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States); Kyker-Snowman, E, E-mail: ek2002@wildcats.unh.edu [Department of Natural Resources and the Environment, University of New Hampshire, Durham, NH03824 (United States); Shaw, JR, E-mail: joeshaw@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Chen, CY, E-mail: Celia.Y.Chen@dartmouth.edu [Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States)

    2017-01-01

    The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.

  15. Hypogonadotropic hypogonadism and metabolic syndrome: insights from the high-fat diet experimental rabbit animal model.

    Science.gov (United States)

    Morelli, Annamaria; Vignozzi, Linda; Maggi, Mario

    2016-06-01

    The etiology of metabolic syndrome (MetS) is complex and involves the interplay between environmental, lifestyle and genetic determinants. MetS in men can be associated with a biochemical pattern of partial hypogonadotropic hypogonadism (HH). A similar pattern has been noted in both men and women with a variety of acute illnesses and chronic diseases, and there is ongoing debate regarding whether this phenomenon might adaptive (e.g. diverting resources from reproduction into survival), or maladaptive (e.g. anemia, sarcopenia, osteopenia and fatigue of androgen-deficiency amplify and widen the adverse consequences of the original disease-trigger). In women with hypothalamic amenorrhea (HA-HH secondary to chronic bioenergetic deficit from dietary restriction and/or intensive exercise), a genetic link to congenital HH (CHH) was recently established; women carrying monoallelic CHH gene mutations will typically not develop CHH, but are significantly more susceptible to HA. However, the male reproductive axis seems to be more resistant to similar environmental insults. In contrast, MetS-associated HH (mHH) is specifically a male phenomenon; the reproductive phenotype of females with MetS tending instead towards hyperandrogenism, rather than hypogonadism. The underlying pathogenic mechanisms responsible for mHH have not been clearly identified and, as yet, there has been no investigation of a potential role for CHH mutation carriage in its etiology. Over the decades, the use of either genetic- or diet-induced obesity and/or MetS animal models has greatly helped to illuminate the complex etiology of metabolic dysregulation, but the strong relationship between obesity/MetS and mHH in males has been largely neglected, with little or no information about the regulation of reproductive function by metabolic factors under conditions of bioenergetic excess. However, the pathogenic link between MetS and HH in males has been recently investigated in an animal model of high fat

  16. Modeling of oxygen transport and cellular energetics explains observations on in vivo cardiac energy metabolism.

    Directory of Open Access Journals (Sweden)

    Daniel A Beard

    2006-09-01

    Full Text Available Observations on the relationship between cardiac work rate and the levels of energy metabolites adenosine triphosphate (ATP, adenosine diphosphate (ADP, and phosphocreatine (CrP have not been satisfactorily explained by theoretical models of cardiac energy metabolism. Specifically, the in vivo stability of ATP, ADP, and CrP levels in response to changes in work and respiratory rate has eluded explanation. Here a previously developed model of mitochondrial oxidative phosphorylation, which was developed based on data obtained from isolated cardiac mitochondria, is integrated with a spatially distributed model of oxygen transport in the myocardium to analyze data obtained from several laboratories over the past two decades. The model includes the components of the respiratory chain, the F0F1-ATPase, adenine nucleotide translocase, and the mitochondrial phosphate transporter at the mitochondrial level; adenylate kinase, creatine kinase, and ATP consumption in the cytoplasm; and oxygen transport between capillaries, interstitial fluid, and cardiomyocytes. The integrated model is able to reproduce experimental observations on ATP, ADP, CrP, and inorganic phosphate levels in canine hearts over a range of workload and during coronary hypoperfusion and predicts that cytoplasmic inorganic phosphate level is a key regulator of the rate of mitochondrial respiration at workloads for which the rate of cardiac oxygen consumption is less than or equal to approximately 12 mumol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 mumol min(-1 g(-1, model predictions deviate from the experimental data, indicating that at high work rates, additional regulatory mechanisms that are not currently incorporated into the model may be important. Nevertheless, the integrated model explains metabolite levels observed at low to moderate workloads and the changes in metabolite levels and tissue oxygenation observed during graded

  17. Autonomous journaling response using data model LUTS

    Science.gov (United States)

    Jaenisch, Holger; Handley, James; Albritton, Nathaniel; Whitener, David; Burnett, Randel; Caspers, Robert; Moren, Stephen; Alexander, Thomas; Maddox, William, III; Albritton, William, Jr.

    2009-04-01

    Matching journal entries to appropriate context responses can be a daunting problem, especially when there are no salient keyword matches between the entry and the proposed library of appropriate responses. We examine a real-world application for matching interactive journaling requests for guidance to an a priori established archive of sufficient multimedia responses. We show the analysis required to enable a Data Model based algorithm to group journaling entries according to intrinsic context information and type. We demonstrate a new lookup table (LUT) classifier that exploits all available data in LUT form.

  18. 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.

  19. Muscle Damage and Metabolic Responses to Repeated-Sprint Running With and Without Deceleration.

    Science.gov (United States)

    Minahan, Clare L; Poke, Daniel P; Morrison, Jaime; Bellinger, Phillip M

    2018-04-04

    Minahan, CL, Poke, DP, Morrison, J, and Bellinger, PM. Muscle damage and metabolic responses to repeated-sprint running with and without deceleration. J Strength Cond Res XX(X): 000-000, 2017-This study aimed to determine whether repeated-sprint running with deceleration aggravates markers of muscle damage or delays the recovery of performance compared with repeated-sprint running without deceleration. Fourteen male team-sport athletes performed 2 randomly ordered testing sessions on a nonmotorized treadmill with one session requiring participants to decelerate (TMd) within 4 seconds before stopping or immediately step to the side of the treadmill belt at the completion of each sprint (TMa). Peak and mean velocities, speed decrement, blood lactate concentrations, and oxygen uptake were monitored during the repeated-sprint running protocols. Countermovement vertical jump (CMJ) performance, perceived muscle soreness, sit-and-reach flexibility, plasma creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin (Mb) concentrations were quantified immediately before and after and 45 minutes, 24 and 48 hours after repeated-sprint running protocols. Although muscle damage was indicated by increases in CK, LDH, and Mb (p ≤ 0.05) in both groups, there was no significant effect of condition (TMa vs. TMd) on any of the measured performance or physiological variables (p > 0.05). The present study indicated that the removal of deceleration from repeated-sprint running on a nonmotorized treadmill has no effect on metabolism or performance during or after repeated-sprint running or markers of muscle damage.

  20. Transcriptomic Changes in Response to Putrescine Production in Metabolically Engineered Corynebacterium glutamicum

    Directory of Open Access Journals (Sweden)

    Zhen Li

    2017-10-01

    Full Text Available Putrescine is widely used in industrial production of bioplastics, pharmaceuticals, agrochemicals, and surfactants. Although engineered Corynebacterium glutamicum has been successfully used to produce high levels of putrescine, the overall cellular physiological and metabolic changes caused by overproduction of putrescine remains unclear. To reveal the transcriptional changes that occur in response to putrescine production in an engineered C. glutamicum strain, a comparative transcriptomic analysis was carried out. Overproduction of putrescine resulted in transcriptional downregulation of genes involved in glycolysis; the TCA cycle, pyruvate degradation, biosynthesis of some amino acids, oxidative phosphorylation; vitamin biosynthesis (thiamine and vitamin 6, metabolism of purine, pyrimidine and sulfur, and ATP-, NAD-, and NADPH-consuming enzymes. The transcriptional levels of genes involved in ornithine biosynthesis and NADPH-forming related enzymes were significantly upregulated in the putrescine producing C. glutamicum strain PUT-ALE. Comparative transcriptomic analysis provided some genetic modification strategies to further improve putrescine production. Repressing ATP- and NADPH-consuming enzyme coding gene expression via CRISPRi enhanced putrescine production.

  1. Interactions between negative energy balance, metabolic diseases, uterine health and immune response in transition dairy cows.

    Science.gov (United States)

    Esposito, Giulia; Irons, Pete C; Webb, Edward C; Chapwanya, Aspinas

    2014-01-30

    The biological cycles of milk production and reproduction determine dairying profitability thus making management decisions dynamic and time-dependent. Diseases also negatively impact on net earnings of a dairy enterprise. Transition cows in particular face the challenge of negative energy balance (NEB) and/or disproportional energy metabolism (fatty liver, ketosis, subacute, acute ruminal acidosis); disturbed mineral utilization (milk fever, sub-clinical hypocalcemia); and perturbed immune function (retained placenta, metritis, mastitis). Consequently NEB and reduced dry matter intake are aggravated. The combined effects of all these challenges are reduced fertility and milk production resulting in diminishing profits. Risk factors such as NEB, inflammation and impairment of the immune response are highly cause-and-effect related. Thus, managing cows during the transition period should be geared toward reducing NEB or feeding specially formulated diets to improve immunity. Given that all cows experience a reduced feed intake and body condition, infection and inflammation of the uterus after calving, there is a need for further research on the immunology of transition dairy cows. Integrative approaches at the molecular, cellular and animal level may unravel the complex interactions between disturbed metabolism and immune function that predispose cows to periparturient diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Transcriptomic Changes in Response to Putrescine Production in Metabolically Engineered Corynebacterium glutamicum

    Science.gov (United States)

    Li, Zhen; Liu, Jian-Zhong

    2017-01-01

    Putrescine is widely used in industrial production of bioplastics, pharmaceuticals, agrochemicals, and surfactants. Although engineered Corynebacterium glutamicum has been successfully used to produce high levels of putrescine, the overall cellular physiological and metabolic changes caused by overproduction of putrescine remains unclear. To reveal the transcriptional changes that occur in response to putrescine production in an engineered C. glutamicum strain, a comparative transcriptomic analysis was carried out. Overproduction of putrescine resulted in transcriptional downregulation of genes involved in glycolysis; the TCA cycle, pyruvate degradation, biosynthesis of some amino acids, oxidative phosphorylation; vitamin biosynthesis (thiamine and vitamin 6), metabolism of purine, pyrimidine and sulfur, and ATP-, NAD-, and NADPH-consuming enzymes. The transcriptional levels of genes involved in ornithine biosynthesis and NADPH-forming related enzymes were significantly upregulated in the putrescine producing C. glutamicum strain PUT-ALE. Comparative transcriptomic analysis provided some genetic modification strategies to further improve putrescine production. Repressing ATP- and NADPH-consuming enzyme coding gene expression via CRISPRi enhanced putrescine production. PMID:29089930

  3. Metabolic and cardiorespiratory response in swimmers during head-out immersion: a prospective study.

    Science.gov (United States)

    Mesfar, Mohamed A; Zendah, Ines; Gharsalli, Houda; Ben Hassen, Chokri; Ghedira, Habib

    2012-11-01

    Sport represents a stress for the body. Many metabolic and cardiorespiratory changes are known during physical activity.However, litte is known in swimmers particularly during head-out immersion. To determine the metabolic and cardiorespiratory response in swimmers during head-out immersion. The energetic, cardiovascular function and ventilatory requirements of a 10 min steady state arm exercise performed by 13 healthy subjects in air and during immersion up to the hip in 26°C water were compared. The same ergometric work load was achieved with an average maximum oxygen uptake of 3.9 ± 2.63 l/min in air versus 3.55 ± 2.48 l/min in water (p=0.953). During exercise, the average values of minute ventilation, ventilation equivalent for oxygen, ventilation equivalent for CO2, peak expiratory flow, respiratory exchange ratio and heart rate were not different in water and in air. However, first ventilatory threshold was significantly higher in water than in air. The mean value of the first ventilatory threshold was 0.89 ± 0.23 l/min in air, and 1.08 ± 0.23 l/min in water immersion; (p=0.016). These results suggest that training swimmers favoring immersion (weight belts) may improve their aerobic capacity.

  4. Metabolic Discrimination of Select List Agents by Monitoring Cellular Responses in a Multianalyte Microphysiometer

    Directory of Open Access Journals (Sweden)

    John Wikswo

    2009-03-01

    Full Text Available Harnessing the potential of cells as complex biosensors promises the potential to create sensitive and selective detectors for discrimination of biodefense agents. Here we present toxin detection and suggest discrimination using cells in a multianalyte microphysiometer (MMP that is capable of simultaneously measuring flux changes in four extracellular analytes (acidification rate, glucose uptake, oxygen uptake, and lactate production in real-time. Differential short-term cellular responses were observed between botulinum neurotoxin A and ricin toxin with neuroblastoma cells, alamethicin and anthrax protective antigen with RAW macrophages, and cholera toxin, muscarine, 2,4-dinitro-phenol, and NaF with CHO cells. These results and the post exposure dynamics and metabolic recovery observed in each case suggest the usefulness of cell-based detectors to discriminate between specific analytes and classes of compounds in a complex matrix, and furthermore to make metabolic inferences on the cellular effects of the agents. This may be particularly valuable for classifying unknown toxins.

  5. Metabolic responses to sulfur dioxide in grapevine (Vitis vinifera L.: photosynthetic tissues and berries

    Directory of Open Access Journals (Sweden)

    Michael James Considine

    2015-02-01

    Full Text Available Research on sulfite metabolism in plants has historically been undertaken within the context of industrial pollution. Resolution of the problem of sulfur pollution has led to sulfur deficiency in many soils and questions remain concerning how different plant organs deal with reactive and potentially toxic sulfur metabolites. In this review, we discuss sulfur dioxide/ sulfite assimilation in grape berries in relation to gene expression and quality traits, features that remain significant to the food industry. We consider the intrinsic metabolism of sulfite and its consequences for fruit biology and postharvest physiology, comparing the different responses in fruit and leaves. We also highlight inconsistencies in what is considered the ‘ambient’ environmental or industrial exposures to SO2. We discuss these findings in relation to the persistent threat to the table grape industry that intergovernmental agencies will revoke the industry’s exemption to the worldwide ban on the use of SO2 for preservation of fresh foods. Transcriptome profiling studies on fruit suggest that added value may accrue from effects of SO2 fumigation on the expression of genes encoding components involved in processes that underpin traits related to customer satisfaction, particularly in table grapes, where SO¬2 fumigation may extend for several months.

  6. Metabolic responses to sulfur dioxide in grapevine (Vitis vinifera L.): photosynthetic tissues and berries.

    Science.gov (United States)

    Considine, Michael J; Foyer, Christine H

    2015-01-01

    Research on sulfur metabolism in plants has historically been undertaken within the context of industrial pollution. Resolution of the problem of sulfur pollution has led to sulfur deficiency in many soils. Key questions remain concerning how different plant organs deal with reactive and potentially toxic sulfur metabolites. In this review, we discuss sulfur dioxide/sulfite assimilation in grape berries in relation to gene expression and quality traits, features that remain significant to the food industry. We consider the intrinsic metabolism of sulfite and its consequences for fruit biology and postharvest physiology, comparing the different responses in fruit and leaves. We also highlight inconsistencies in what is considered the "ambient" environmental or industrial exposures to SO2. We discuss these findings in relation to the persistent threat to the table grape industry that intergovernmental agencies will revoke the industry's exemption to the worldwide ban on the use of SO2 for preservation of fresh foods. Transcriptome profiling studies on fruit suggest that added value may accrue from effects of SO2 fumigation on the expression of genes encoding components involved in processes that underpin traits related to customer satisfaction, particularly in table grapes, where SO2 fumigation may extend for several months.

  7. Food odors trigger an endocrine response that affects food ingestion and metabolism.

    Science.gov (United States)

    Lushchak, Oleh V; Carlsson, Mikael A; Nässel, Dick R

    2015-08-01

    Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin-like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling.

  8. Macrophage Interaction with Paracoccidioides brasiliensis Yeast Cells Modulates Fungal Metabolism and Generates a Response to Oxidative Stress.

    Directory of Open Access Journals (Sweden)

    Juliana Alves Parente-Rocha

    Full Text Available Macrophages are key players during Paracoccidioides brasiliensis infection. However, the relative contribution of the fungal response to counteracting macrophage activity remains poorly understood. In this work, we evaluated the P. brasiliensis proteomic response to macrophage internalization. A total of 308 differentially expressed proteins were detected in P. brasiliensis during infection. The positively regulated proteins included those involved in alternative carbon metabolism, such as enzymes involved in gluconeogenesis, beta-oxidation of fatty acids and amino acids catabolism. The down-regulated proteins during P. brasiliensis internalization in macrophages included those related to glycolysis and protein synthesis. Proteins involved in the oxidative stress response in P. brasiliensis yeast cells were also up-regulated during macrophage infection, including superoxide dismutases (SOD, thioredoxins (THX and cytochrome c peroxidase (CCP. Antisense knockdown mutants evaluated the importance of CCP during macrophage infection. The results suggested that CCP is involved in a complex system of protection against oxidative stress and that gene silencing of this component of the antioxidant system diminished the survival of P. brasiliensis in macrophages and in a murine model of infection.

  9. 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.

  10. Transgenic Mouse Models for Alcohol Metabolism, Toxicity and Cancer

    OpenAIRE

    Heit, Claire; Dong, Hongbin; Chen, Ying; Shah, Yatrik M.; Thompson, David C.; Vasiliou, Vasilis

    2015-01-01

    Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in...

  11. Improved evidence-based genome-scale metabolic models for maize leaf, embryo, and endosperm

    Energy Technology Data Exchange (ETDEWEB)

    Seaver, Samuel M. D.; Bradbury, Louis M. T.; Frelin, Océane; Zarecki, Raphy; Ruppin, Eytan; Hanson, Andrew D.; Henry, Christopher S.

    2015-03-10

    There is a growing demand for genome-scale metabolic reconstructions for plants, fueled by the need to understand the metabolic basis of crop yield and by progress in genome and transcriptome sequencing. Methods are also required to enable the interpretation of plant transcriptome data to study how cellular metabolic activity varies under different growth conditions or even within different organs, tissues, and developmental stages. Such methods depend extensively on the accuracy with which genes have been mapped to the biochemical reactions in the plant metabolic pathways. Errors in these mappings lead to metabolic reconstructions with an inflated number of reactions and possible generation of unreliable metabolic phenotype predictions. Here we introduce a new evidence-based genome-scale metabolic reconstruction of maize, with significant improvements in the quality of the gene-reaction associations included within our model. We also present a new approach for applying our model to predict active metabolic genes based on transcriptome data. This method includes a minimal set of reactions associated with low expression genes to enable activity of a maximum number of reactions associated with high expression genes. We apply this method to construct an organ-specific model for the maize leaf, and tissue specific models for maize embryo and endosperm cells. We validate our models using fluxomics data for the endosperm and embryo, demonstrating an improved capacity of our models to fit the available fluxomics data. All models are publicly available via the DOE Systems Biology Knowledgebase and PlantSEED, and our new method is generally applicable for analysis transcript profiles from any plant, paving the way for further in silico studies with a wide variety of plant genomes.

  12. Metabolic response of Danaüs archippus and Saccharomyces cerevisiae to weak oscillatory magnetic fields

    Science.gov (United States)

    Russell, D. N.; Webb, S. J.

    1981-09-01

    Respiration of the insect larva, Danaüs archippus, and the yeast, Saccharomyces cerevisiae, in log phase has been monitored before and after an oscillatory magnetic insult of 0.005 Gauss rms amplitude and 40 50 min duration. Frequencies used were 10 16 Hz for the insect and 100 200 Hz for the yeast. Depression of as much as 30% in metabolic rate has been found to occur immediately after the field is both imposed and eliminated with a general recovery over the 30-min period thereafter both in and out of the imposed field, although complete recovery to original levels may take much longer. Evidence is given that the response may depend on the frequency pattern used. This data is used to formulate an hypothesis whereby changes in the geomagnetic field variability pattern may act as a biochronometric zeitgeber.

  13. Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.

    Science.gov (United States)

    Tamboli, Robyn A; Antoun, Joseph; Sidani, Reem M; Clements, Austin; Harmata, Emily E; Marks-Shulman, Pam; Gaylinn, Bruce D; Williams, Brandon; Clements, Ronald H; Albaugh, Vance L; Abumrad, Naji N

    2017-09-01

    Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg -1  min -1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion. These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB. © 2017 John Wiley & Sons Ltd.

  14. Dynamic optimal control of homeostasis: an integrative system approach for modeling of the central nitrogen metabolism in Saccharomyces cerevisiae.

    Science.gov (United States)

    van Riel, N A; Giuseppin, M L; Verrips, C T

    2000-01-01

    The theory of dynamic optimal metabolic control (DOMC), as developed by Giuseppin and Van Riel (Metab. Eng., 2000), is applied to model the central nitrogen metabolism (CNM) in Saccharomyces cerevisiae. The CNM represents a typical system encountered in advanced metabolic engineering. The CNM is the source of the cellular amino acids and proteins, including flavors and potentially valuable biomolecules; therefore, it is also of industrial interest. In the DOMC approach the cell is regarded as an optimally controlled system. Given the metabolic genotype, the cell faces a control problem to maintain an optimal flux distribution in a changing environment. The regulation is based on strategies and balances feedback control of homeostasis and feedforward regulation for adaptation. The DOMC approach is an integrative, holistic approach, not based on mechanistic descriptions and (therefore) not biased by the variation present in biochemical and molecular biological data. It is an effective tool to structure the rapidly increasing amount of data on the function of genes and pathways. The DOMC model is used successfully to predict the responses of pulses of ammonia and glutamine to nitrogen-limited continuous cultures of a wild-type strain and a glutamine synthetase-negative mutant. The simulation results are validated with experimental data.

  15. 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

  16. 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

  17. 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

  18. Diagnostics for Linear Models With Functional Responses

    OpenAIRE

    Xu, Hongquan; Shen, Qing

    2005-01-01

    Linear models where the response is a function and the predictors are vectors are useful in analyzing data from designed experiments and other situations with functional observations. Residual analysis and diagnostics are considered for such models. Studentized residuals are defined and their properties are studied. Chi-square quantile-quantile plots are proposed to check the assumption of Gaussian error process and outliers. Jackknife residuals and an associated test are proposed to det...

  19. Fagus sylvatica L. provenances maintain different leaf metabolic profiles and functional response

    Science.gov (United States)

    Aranda, Ismael; Sánchez-Gómez, David; de Miguel, Marina; Mancha, Jose Antonio; Guevara, María Angeles; Cadahía, Estrella; Fernández de Simón, María Brígida

    2017-07-01

    Most temperate forest tree species will suffer important environmental changes as result of the climate change. Adaptiveness to local conditions could change at different sites in the future. In this context, the study of intra-specific variability is important to clarify the singularity of different local populations. Phenotypic differentiation between three beech provenances covering a wide latitudinal range (Spain/ES, Germany/DE and Sweden/SE), was studied in a greenhouse experiment. Non-target leaf metabolite profiles and ecophysiological response was analyzed in well-watered and water stressed seedlings. There was a provenance-specific pattern in the relative concentrations of some leaf metabolites regardless watering treatment. The DE and SE from the center and north of the distribution area of the species showed a clear differentiation from the ES provenance in the relative concentration of some metabolites. Thus the ES provenance from the south maintained larger relative concentration of some organic and amino acids (e.g. fumaric and succinic acids or valine and isoleucine), and in some secondary metabolites (e.g. kaempferol, caffeic and ferulic acids). The ecophysiological response to mild water stress was similar among the three provenances as a consequence of the moderate water stress applied to seedlings, although leaf N isotope composition (δ15N) and leaf C:N ratio were higher and lower respectively in DE than in the other two provenances. This would suggest potential differences in the capacity to uptake and post-process nitrogen according to provenance. An important focus of the study was to address for the first time inter-provenance leaf metabolic diversity in beech from a non-targeted metabolic profiling approach that allowed differentiation of the three studied provenances.

  20. Model-based design of bistable cell factories for metabolic engineering.

    Science.gov (United States)

    Srinivasan, Shyam; Cluett, William R; Mahadevan, Radhakrishnan

    2018-04-15

    Metabolism can exhibit dynamic phenomena like bistability due to the presence of regulatory motifs like the positive feedback loop. As cell factories, microorganisms with bistable metabolism can have a high and a low product flux at the two stable steady states, respectively. The exclusion of metabolic regulation and network dynamics limits the ability of pseudo-steady state stoichiometric models to detect the presence of bistability, and reliably assess the outcomes of design perturbations to metabolic networks. Using kinetic models of metabolism, we assess the change in the bistable characteristics of the network, and suggest designs based on perturbations to the positive feedback loop to enable the network to produce at its theoretical maximum rate. We show that the most optimal production design in parameter space, for a small bistable metabolic network, may exist at the boundary of the bistable region separating it from the monostable region of low product fluxes. The results of our analysis can be broadly applied to other bistable metabolic networks with similar positive feedback network topologies. This can complement existing model-based design strategies by providing a smaller number of feasible designs that need to be tested in vivo. http://lmse.biozone.utoronto.ca/downloads/. krishna.mahadevan@utoronto.ca. Supplementary data are available at Bioinformatics online.

  1. Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia.

    Science.gov (United States)

    Jackson, Kim G; Walden, Charlotte M; Murray, Peter; Smith, Adrian M; Minihane, Anne M; Lovegrove, Julie A; Williams, Christine M

    2013-08-01

    Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia. Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t=0 min) and lunch (t=330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples. MetS subjects with 3 or 4 components were subdivided into those without (n=34) and with (n=23) fasting hyperglycaemia (≥5.6 mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (Pcurve (AUC) and incremental AUC (P ≤0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (Pglucose to be an important predictor of the postprandial TAG and glucose response. Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. The Metabolic Response to Stress and Infection in Critically Ill Children: The Opportunity of an Individualized Approach

    Directory of Open Access Journals (Sweden)

    Valentina De Cosmi

    2017-09-01

    Full Text Available The metabolic response to stress and infection is closely related to the corresponding requirements of energy and nutrients. On a general level, the response is driven by a complex endocrine network and related to the nature and severity of the insult. On an individual level, the effects of nutritional interventions are highly variable and a possible source of complications. This narrative review aims to discuss the metabolic changes in critically-ill children and the potential of developing personalized nutritional interventions. Through a literature search strategy, we have investigated the importance of blood glucose levels, the nutritional aspects of the different phases of acute stress response, and the reliability of the available tools to assess the energy expenditure. The dynamics of metabolism during stressful events reveals the difficult balance between risk of hypo- or hyperglycemia and under- or overfeeding. Within this context, individualized and accurate measurement of energy expenditure may help in defining the metabolic needs of patients. Given the variability of the metabolic response in critical conditions, randomized clinical studies in ill children are needed to evaluate the effect of individualized nutritional intervention on health outcomes.

  3. Maximal exercise electrocardiographic responses and coronary heart disease mortality among men with metabolic syndrome.

    Science.gov (United States)

    Lyerly, G William; Sui, Xuemei; Church, Timothy S; Lavie, Carl J; Hand, Gregory A; Blair, Steven N

    2010-03-01

    To examine the association between abnormal exercise electrocardiographic (E-ECG) test results and mortality (all-cause and that resulting from coronary heart disease [CHD] or cardiovascular disease [CVD]) in a large population of asymptomatic men with metabolic syndrome (MetS). A total of 9191 men (mean age, 46.9 years) met the criteria of having MetS. All completed a maximal E-ECG treadmill test (May 14, 1979, through April 9, 2001) and were without a previous CVD event or diabetes at baseline. Main outcomes were all-cause mortality, mortality due to CHD, and mortality due to CVD. Cox regression analysis was used to quantify the mortality risk according to E-ECG responses. During a follow-up of 14 years, 633 deaths (242 CVD and 150 CHD) were identified. Mortality rates and hazard ratios (HRs) across E-ECG responses were the following: for all-cause mortality: HR, 1.36; 95% confidence interval (CI), 1.09-1.70 for equivocal responses and HR, 1.41; 95% CI, 1.12-1.77 for abnormal responses (P(trend)<.001); for mortality due to CVD: HR, 1.29; 95% CI, 0.88-1.88 for equivocal responses and HR, 2.04; 95% CI, 1.46-2.84 for abnormal responses (P(trend)<.001); and for mortality due to CHD: HR, 1.62; 95% CI, 1.02-2.56 for equivocal responses and HR, 2.45; 95% CI, 1.62-3.69 for abnormal responses (P(trend)<.001). A positive gradient for CHD, CVD, and all-cause mortality rates across E-ECG categories within 3, 4, or 5 MetS components was observed (P<.001 for all). Among men with MetS, an abnormal E-ECG response was associated with higher risk of all-cause, CVD, and CHD mortality. These findings underscore the importance of E-ECG tests to identify men with MetS who are at risk of dying.

  4. Mitochondrial metabolism in early neural fate and its relevance for neuronal disease modeling.

    Science.gov (United States)

    Lorenz, Carmen; Prigione, Alessandro

    2017-12-01

    Modulation of energy metabolism is emerging as a key aspect associated with cell fate transition. The establishment of a correct metabolic program is particularly relevant for neural cells given their high bioenergetic requirements. Accordingly, diseases of the nervous system commonly involve mitochondrial impairment. Recent studies in animals and in neural derivatives of human pluripotent stem cells (PSCs) highlighted the importance of mitochondrial metabolism for neural fate decisions in health and disease. The mitochondria-based metabolic program of early neurogenesis suggests that PSC-derived neural stem cells (NSCs) may be used for modeling neurological disorders. Understanding how metabolic programming is orchestrated during neural commitment may provide important information for the development of therapies against conditions affecting neural functions, including aging and mitochondrial disorders. Copyright © 2017. Published by Elsevier Ltd.

  5. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations.

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia; Kefi, Rym

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  6. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations

    Science.gov (United States)

    Jmel, Haifa; Romdhane, Lilia; Ben Halima, Yosra; Hechmi, Meriem; Naouali, Chokri; Dallali, Hamza; Hamdi, Yosr; Shan, Jingxuan; Abid, Abdelmajid; Jamoussi, Henda; Trabelsi, Sameh; Chouchane, Lotfi; Luiselli, Donata; Abdelhak, Sonia

    2018-01-01

    Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with

  7. Type of diet modulates the metabolic response to sleep deprivation in rats

    Directory of Open Access Journals (Sweden)

    Martins Paulo JF

    2011-12-01

    Full Text Available Abstract Background Evidence suggests that sleep loss is associated with an increased risk of obesity and diabetes; however, animal models have failed to produce weight gain under sleep deprivation (SD. Previous studies have suggested that this discrepancy could be due to more extreme SD conditions in experimental animals, their higher resting metabolic rate than that of humans, and the decreased opportunity for animals to ingest high-calorie foods. Thus, our objective was to determine whether diets with different textures/compositions could modify feeding behavior and affect the metabolic repercussions in SD in rats. Methods Three groups of male rats were used: one was designated as control, one was sleep deprived for 96 h by the platform technique (SD-96h and one was SD-96h followed by a 24-h recovery (rebound. In the first experiment, the animals were fed chow pellets (CPs; in the second, they received high-fat diet and in the third, they were fed a liquid diet (LD. Results We observed that SD induces energy deficits that were related to changes in feeding behavior and affected by the type of diet consumed. Regardless of the diet consumed, SD consistently increased animals' glucagon levels and decreased their leptin and triacylglycerol levels and liver glycogen stores. However, such changes were mostly avoided in the rats on the liquid diet. SD induces a wide range of metabolic and hormonal changes that are strongly linked to the severity of weight loss. Conclusions The LD, but not the CP or high-fat diets, favored energy intake, consequently lessening the energy deficit induced by SD.

  8. Lipid metabolic dose response to dietary alpha-linolenic acid in monk parrot (Myiopsitta monachus).

    Science.gov (United States)

    Petzinger, Christina; Heatley, J J; Bailey, Christopher A; Bauer, John E

    2014-03-01

    Monk parrots (Myiopsitta monachus) are susceptible to atherosclerosis, a progressive disease characterized by the formation of plaques in the arteries accompanied by underlying chronic inflammation. The family of n-3 fatty acids, especially eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), have consistently been shown to reduce atherosclerotic risk factors in humans and other mammals. Some avian species have been observed to convert α-linolenic acid (18:3n-3, ALA) to EPA and DHA (Htin et al. in Arch Geflugelk 71:258-266, 2007; Petzinger et al. in J Anim Physiol Anim Nutr, 2013). Therefore, the metabolic effects of including flaxseed oil, as a source of ALA, in the diet at three different levels (low, medium, and high) on the lipid metabolism of Monk parrots was evaluated through measuring plasma total cholesterol (TC), free cholesterol (FC), triacylglycerols (TAG), and phospholipid fatty acids. Feed intake, body weight, and body condition score were also assessed. Thus the dose and possible saturation response of increasing dietary ALA at constant linoleic acid (18:2n-6, LNA) concentration on lipid metabolism in Monk parrots (M. monachus) was evaluated. Calculated esterified cholesterol in addition to plasma TC, FC, and TAG were unaltered by increasing dietary ALA. The high ALA group had elevated levels of plasma phospholipid ALA, EPA, and docosapentaenoic acid (DPAn-3, 22:5n-3). The medium and high ALA groups had suppressed plasma phospholipid 20:2n-6 and adrenic acid (22:4n-6, ADA) compared to the low ALA group. When the present data were combined with data from a previous study (Petzinger et al. in J Anim Physiol Anim Nutr, 2013) a dose response to dietary ALA was observed when LNA was constant. Plasma phospholipid ALA, EPA, DPAn-3, DHA, and total n-3 were positively correlated while 20:2n-6, di-homo-gamma-linoleic acid (20:3n-6Δ7), arachidonic acid (20:4n-6), ADA, and total n-6 were inversely correlated with dietary en% ALA.

  9. Mesoscale Modelling of the Response of Aluminas

    International Nuclear Information System (INIS)

    Bourne, N. K.

    2006-01-01

    The response of polycrystalline alumina to shock is not well addressed. There are several operating mechanisms that only hypothesized which results in models which are empirical. A similar state of affairs in reactive flow modelling led to the development of mesoscale representations of the flow to illuminate operating mechanisms. In this spirit, a similar effort is undergone for a polycrystalline alumina. Simulations are conducted to observe operating mechanisms at the micron scale. A method is then developed to extend the simulations to meet response at the continuum level where measurements are made. The approach is validated by comparison with continuum experiments. The method and results are presented, and some of the operating mechanisms are illuminated by the observed response

  10. 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

  11. Lawyer Proliferation and the Social Responsibility Model.

    Science.gov (United States)

    Wines, William A.

    1989-01-01

    Drawing on the model of social responsibility that colleges of business have been teaching, the boom in lawyer education is examined. It is argued that law schools are irresponsible in overselling the benefits of law school graduation, creating a surplus of lawyers whose abilities could be used as well elsewhere. (MSE)

  12. Modelling of demand response and market power

    International Nuclear Information System (INIS)

    Kristoffersen, B.B.; Donslund, B.; Boerre Eriksen, P.

    2004-01-01

    Demand-side flexibility and demand response to high prices are prerequisites for the proper functioning of the Nordic power market. If the consumers are unwilling to respond to high prices, the market may fail the clearing, and this may result in unwanted forced demand disconnections. Being the TSO of Western Denmark, Eltra is responsible of both security of supply and the design of the power market within its area. On this basis, Eltra has developed a new mathematical model tool for analysing the Nordic wholesale market. The model is named MARS (MARket Simulation). The model is able to handle hydropower and thermal production, nuclear power and wind power. Production, demand and exchanges modelled on an hourly basis are new important features of the model. The model uses the same principles as Nord Pool (The Nordic Power Exchange), including the division of the Nordic countries into price areas. On the demand side, price elasticity is taken into account and described by a Cobb-Douglas function. Apart from simulating perfect competition markets, particular attention has been given to modelling imperfect market conditions, i.e. exercise of market power on the supply side. Market power is simulated by using game theory, including the Nash equilibrium concept. The paper gives a short description of the MARS model. Besides, focus is on the application of the model in order to illustrate the importance of demand response in the Nordic market. Simulations with different values of demand elasticity are compared. Calculations are carried out for perfect competition and for the situation in which market power is exercised by the large power producers in the Nordic countries (oligopoly). (au)

  13. Stress hormone release is a key component of the metabolic response to lipopolysaccharide (LPS): studies in hypopituitary and healthy subjects

    DEFF Research Database (Denmark)

    Bach, Ermina; Møller, Andreas Buch; Jørgensen, Jens Otto Lunde

    2016-01-01

    OBJECTIVE: Lipopolysaccharide (LPS) generates acute and chronic inflammatory and metabolic responses during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but it is unclear whether these responses depend on intact pituitary release...... but not in HP. LPS increased whole body palmitate fluxes (3-fold) and decreased palmitate specific activity 40-50 % in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 - an inhibitor of lipolysis) adipose tissue mRNA was decreased in CTR. LPS increased phenylalanine fluxes significantly more in CTR, whereas...

  14. 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

  15. A motivational model for environmentally responsible behavior.

    Science.gov (United States)

    Tabernero, Carmen; Hernández, Bernardo

    2012-07-01

    This paper presents a study examining whether self-efficacy and intrinsic motivation are related to environmentally responsible behavior (ERB). The study analysed past environmental behavior, self-regulatory mechanisms (self-efficacy, satisfaction, goals), and intrinsic and extrinsic motivation in relation to ERBs in a sample of 156 university students. Results show that all the motivational variables studied are linked to ERB. The effects of self-efficacy on ERB are mediated by the intrinsic motivation responses of the participants. A theoretical model was created by means of path analysis, revealing the power of motivational variables to predict ERB. Structural equation modeling was used to test and fit the research model. The role of motivational variables is discussed with a view to creating adequate learning contexts and experiences to generate interest and new sensations in which self-efficacy and affective reactions play an important role.

  16. Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

    Science.gov (United States)

    Oesch, F; Fabian, E; Landsiedel, Robert

    2018-06-18

    Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which-taken with great caution because of the still very limited data-the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive

  17. Physiological and Metabolic Changes of Purslane (Portulaca oleracea L.) in Response to Drought, Heat, and Combined Stresses

    Science.gov (United States)

    Jin, Rui; Wang, Yanping; Liu, Ruijie; Gou, Junbo; Chan, Zhulong

    2016-01-01

    Purslane (Portulaca oleracea L.) is a fleshy herbaceous plant. So far, little information is available on the response of this plant to combined drought and heat stress. In this study, changes in physiological and metabolic levels were characterized after treatments with drought, heat and combined stresses. Both individual and combined stress treatments increased malondialdehyde (MDA), electrolyte leakage (EL), O2•− and activities of superoxide dismutase (SOD), peroxidase (POD), while declined chlorophyll content. No significant differences were found between control and treatments in leaf water content (LWC) and catalase (CAT) activity. Additionally, 37 metabolic compounds were detected in purslane. Through pathway analysis, 17 metabolites were directly involved in the glycolysis metabolic pathway. The present study indicated that combined drought and heat stress caused more serious damage in purslane than individual stress. To survive, purslane has a high capability to cope with environmental stress conditions through activation of physiological and metabolic pathways. PMID:26779204

  18. Physiological and metabolic changes of purslane (Portulaca oleracea L. in response to drought, heat and combined stresses

    Directory of Open Access Journals (Sweden)

    Rui eJin

    2016-01-01

    Full Text Available Purslane (Portulaca oleracea L. is a fleshy herbaceous plant. So far, little information is available on the response of this plant to combined drought and heat stress. In this study, changes in physiological and metabolic levels were characterized after treatments with drought, heat and combined stresses. Both individual and combined stress treatments increased malondialdehyde (MDA, electrolyte leakage (EL, O2•− and activities of superoxide dismutase (SOD, peroxidase (POD, while declined chlorophyll content. No significant differences were found between control and treatments in leaf water content (LWC and catalase (CAT activity. Additionally, 37 metabolic compounds were detected in purslane. Through pathway analysis, 17 metabolites were directly involved in the glycolysis metabolic pathway. The present study indicated that combined drought and heat stress caused more serious damage in purslane than individual stress. To survive, purslane has a high capability to cope with environmental stress conditions through activation of physiological and metabolic pathways.

  19. Caenorhabditis elegans: A Useful Model for Studying Metabolic Disorders in Which Oxidative Stress Is a Contributing Factor

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    Elizabeth Moreno-Arriola

    2014-01-01

    Full Text Available Caenorhabditis elegans is a powerful model organism that is invaluable for experimental research because it can be used to recapitulate most human diseases at either the metabolic or genomic level in vivo. This organism contains many key components related to metabolic and oxidative stress networks that could conceivably allow us to increase and integrate information to understand the causes and mechanisms of complex diseases. Oxidative stress is an etiological factor that influences numerous human diseases, including diabetes. C. elegans displays remarkably similar molecular bases and cellular pathways to those of mammals. Defects in the insulin/insulin-like growth factor-1 signaling pathway or increased ROS levels induce the conserved phase II detoxification response via the SKN-1 pathway to fight against oxidative stress. However, it is noteworthy that, aside from the detrimental effects of ROS, they have been proposed as second messengers that trigger the mitohormetic response to attenuate the adverse effects of oxidative stress. Herein, we briefly describe the importance of C. elegans as an experimental model system for studying metabolic disorders related to oxidative stress and the molecular mechanisms that underlie their pathophysiology.

  20. Improving the precision of lake ecosystem metabolism estimates by identifying predictors of model uncertainty

    Science.gov (United States)

    Rose, Kevin C.; Winslow, Luke A.; Read, Jordan S.; Read, Emily K.; Solomon, Christopher T.; Adrian, Rita; Hanson, Paul C.

    2014-01-01

    Diel changes in dissolved oxygen are often used to estimate gross primary production (GPP) and ecosystem respiration (ER) in aquatic ecosystems. Despite the widespread use of this approach to understand ecosystem metabolism, we are only beginning to understand the degree and underlying causes of uncertainty for metabolism model parameter estimates. Here, we present a novel approach to improve the precision and accuracy of ecosystem metabolism estimates by identifying physical metrics that indicate when metabolism estimates are highly uncertain. Using datasets from seventeen instrumented GLEON (Global Lake Ecological Observatory Network) lakes, we discovered that many physical characteristics correlated with uncertainty, including PAR (photosynthetically active radiation, 400-700 nm), daily variance in Schmidt stability, and wind speed. Low PAR was a consistent predictor of high variance in GPP model parameters, but also corresponded with low ER model parameter variance. We identified a threshold (30% of clear sky PAR) below which GPP parameter variance increased rapidly and was significantly greater in nearly all lakes compared with variance on days with PAR levels above this threshold. The relationship between daily variance in Schmidt stability and GPP model parameter variance depended on trophic status, whereas daily variance in Schmidt stability was consistently positively related to ER model parameter variance. Wind speeds in the range of ~0.8-3 m s–1 were consistent predictors of high variance for both GPP and ER model parameters, with greater uncertainty in eutrophic lakes. Our findings can be used to reduce ecosystem metabolism model parameter uncertainty and identify potential sources of that uncertainty.

  1. SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention – the TULIP Study

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    Stefan Norbert

    2008-11-01

    Full Text Available Abstract Background Sirtuin1 (SIRT1 regulates gene expression in distinct metabolic pathways and mediates beneficial effects of caloric restriction in animal models. In humans, SIRT1 genetic variants associate with fasting energy expenditure. To investigate the relevance of SIRT1 for human metabolism and caloric restriction, we analyzed SIRT1 genetic variants in respect to the outcome of a controlled lifestyle intervention in Caucasians at risk for type 2 diabetes. Methods A total of 1013 non-diabetic Caucasians from the Tuebingen Family Study (TUEF were genotyped for four tagging SIRT1 SNPs (rs730821, rs12413112, rs7069102, rs2273773 for cross-sectional association analyses with prediabetic traits. SNPs that associated with basal energy expenditure in the TUEF cohort were additionally analyzed in 196 individuals who underwent a controlled lifestyle intervention (Tuebingen Lifestyle Intervention Program; TULIP. Multivariate regressions analyses with adjustment for relevant covariates were performed to detect associations of SIRT1 variants with the changes in anthropometrics, weight, body fat or metabolic characteristics (blood glucose, insulin sensitivity, insulin secretion and liver fat, measured by magnetic resonance techniques after the 9-month follow-up test in the TULIP study. Results Minor allele (X/A carriers of rs12413112 (G/A had a significantly lower basal energy expenditure (p = 0.04 and an increased respiratory quotient (p = 0.02. This group (rs12413112: X/A was resistant against lifestyle-induced improvement of fasting plasma glucose (GG: -2.01%, X/A: 0.53%; p = 0.04, had less increase in insulin sensitivity (GG: 17.3%, X/A: 9.6%; p = 0.05 and an attenuated decline in liver fat (GG: -38.4%, X/A: -7.5%; p = 0.01. Conclusion SIRT1 plays a role for the individual lifestyle intervention response, possibly owing to decreased basal energy expenditure and a lower lipid-oxidation rate in rs12413112 X/A allele carriers. SIRT1 genetic

  2. Modeling the mechanical response of PBX 9501

    Energy Technology Data Exchange (ETDEWEB)

    Ragaswamy, Partha [Los Alamos National Laboratory; Lewis, Matthew W [Los Alamos National Laboratory; Liu, Cheng [Los Alamos National Laboratory; Thompson, Darla G [Los Alamos National Laboratory

    2010-01-01

    An engineering overview of the mechanical response of Plastic-Bonded eXplosives (PBXs), specifically PBX 9501, will be provided with emphasis on observed mechanisms associated with different types of mechanical testing. Mechanical tests in the form of uniaxial tension, compression, cyclic loading, creep (compression and tension), and Hopkinson bar show strain rate and temperature dependence. A range of mechanical behavior is observed which includes small strain recoverable response in the form of viscoelasticity; change in stiffness and softening beyond peak strength due to damage in the form microcracks, debonding, void formation and the growth of existing voids; inelastic response in the form of irrecoverable strain as shown in cyclic tests, and viscoelastic creep combined with plastic response as demonstrated in creep and recovery tests. The main focus of this paper is to elucidate the challenges and issues involved in modeling the mechanical behavior of PBXs for simulating thermo-mechanical responses in engineering components. Examples of validation of a constitutive material model based on a few of the observed mechanisms will be demonstrated against three point bending, split Hopkinson pressure bar and Brazilian disk geometry.

  3. Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI.

    Science.gov (United States)

    Nelson, Sarah J

    2011-07-01

    MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T(1) -weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T(2) lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti

  4. The establishment of animal model of radiation-skin-burn and its changes of tissue metabolism

    International Nuclear Information System (INIS)

    Lu Xingan; Wu Shiliang; Wang Xiuzhen; Zhou Yinghui; Feng Yizhong; Tian Ye; Peng Miao

    2001-01-01

    The biochemistry metabolic changes of the tissues induced by 60 Co γ radiation or by accelerator β radiation on the animal local tissues were observed. The experiment results were shown as follows: (1) 60 Co γ radiation can induce the metabolic changes of the local tissue and led to ulcer or death. (2) Accelerator β radiation at the same dose of γ radiation can only produce ulcer but no death. (3) The biochemistry metabolic changes of the tissues induced by 60 Co γ radiation are similar to that by β radiation, but as a radiation-burn animal model, the latter is better

  5. Insulin response of the glucose and fatty acid metabolism in dry dairy cows across a range of body condition scores.

    Science.gov (United States)

    De Koster, J; Hostens, M; Van Eetvelde, M; Hermans, K; Moerman, S; Bogaert, H; Depreester, E; Van den Broeck, W; Opsomer, G

    2015-07-01

    The objective of the present research was to determine the insulin response of the glucose and fatty acid metabolism in dry dairy cows with a variable body condition score (BCS). Ten pregnant Holstein Friesian dairy cows (upcoming parity 2 to 5) were selected based on BCS at the beginning of the study (2mo before expected parturition date). During the study, animals were monitored weekly for BCS and backfat thickness and in the last 2wk, blood samples were taken for determination of serum nonesterified fatty acid (NEFA) concentration. Animals underwent a hyperinsulinemic euglycemic clamp test in the third week before the expected parturition date. The hyperinsulinemic euglycemic clamp test consisted of 4 consecutive insulin infusions with increasing insulin doses: 0.1, 0.5, 2, and 5mIU/kg per minute. For each insulin infusion period, a steady state was defined as a period of 30min where no or minor changes of the glucose infusion were necessary to keep the blood glucose concentration constant and near basal levels. During the steady state, the glucose infusion rate [steady state glucose infusion rate (SSGIR) in µmol/kg per minute] and NEFA concentration [steady state NEFA concentration (SSNEFA) in mmol/L] were determined and reflect the insulin response of the glucose and fatty acid metabolism. Dose response curves were created based on the insulin concentrations during the steady state and the SSGIR or SSNEFA. The shape of the dose response curves is determined by the concentration of insulin needed to elicit the half maximal effect (EC50) and the maximal SSGIR or the minimal SSNEFA for the glucose or fatty acid metabolism, respectively. The maximal SSGIR was negatively associated with variables reflecting adiposity of the cows (BCS, backfat thickness, NEFA concentration during the dry period, and absolute weight of the different adipose depots determined after euthanasia and dissection of the different depots), whereas the EC50 of the glucose metabolism was

  6. A model to study intestinal and hepatic metabolism of propranolol in the dog.

    Science.gov (United States)

    Mills, P C; Siebert, G A; Roberts, M S

    2004-02-01

    A model to investigate hepatic drug uptake and metabolism in the dog was developed for this study. Catheters were placed in the portal and hepatic veins during exploratory laparotomy to collect pre- and posthepatic blood samples at defined intervals. Drug concentrations in the portal vein were taken to reflect intestinal uptake and metabolism of an p.o. administered drug (propranolol), while differences in drug and metabolite concentrations between portal and hepatic veins reflected hepatic uptake and metabolism. A significant difference in propranolol concentration between hepatic and portal veins confirmed a high hepatic extraction of this therapeutic agent in the dog. This technically uncomplicated model may be used experimentally or clinically to determine hepatic function and metabolism of drugs that may be administered during anaesthesia and surgery.

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

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    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

  8. Road transport and diet affect metabolic response to exercise in horses.

    Science.gov (United States)

    Connysson, M; Muhonen, S; Jansson, A

    2017-11-01

    This study investigated the effects of transport and diet on metabolic response during a subsequent race-like test in Standardbred horses in training fed a forage-only diet and a 50:50 forage:oats diet. Six trained and raced Standardbred trotter mares were used. Two diets, 1 forage-only diet (FONLY) and 1 diet with 50% of DM intake from forage and 50% from oats (FOATS), were fed for two 29-d periods in a crossover design. At Day 21, the horses were subjected to transport for 100 km before and after they performed an exercise test (transport test [TT]). At Day 26, the horses performed a control test (CT), in which they were kept in their stall before and after the exercise test. Blood samples were collected throughout the study, and heart rate and water intake were recorded. Heart rate and plasma cortisol, glucose, and NEFA concentrations were greater for the TT than for the CT ( = 0.008, = 0.020, = 0.010, and = 0.0002, respectively) but were not affected by diet. Plasma acetate concentration was lower during the TT than during the CT ( = 0.034) and greater for the FONLY than for the FOATS ( = 0.003). There were no overall effects of the TT compared with the CT on total plasma protein concentration (TPP), but TPP was lower with the FONLY than with the FOATS ( = 0.016). There was no overall effect of the TT compared with the CT on water intake, but water intake was greater with the FONLY than the FOATS ( = 0.011). There were no overall effects of transport or diet on BW, plasma lactate, or plasma urea concentration. It was concluded that both transport and diet affect metabolic response during exercise in horses. Aerobic energy supply was most likely elevated by transportation and by the FONLY. The FONLY also decreased exercise-induced effects on extracellular fluid regulation. These results highlight the importance of experimental design in nutrition studies. If the aim is to examine how a diet affects exercise response in competition horses, transport should

  9. Modulation of the growth and metabolic response of cyanobacteria by the multifaceted activity of naringenin.

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    Beata Żyszka

    Full Text Available The interactions between the plant-derived bioflavonoid, naringenin, and prokaryotic microalgae representatives (cyanobacteria, were investigated with respect to its influence on the growth and metabolic response of these microorganisms. To achieve reliable results, the growth of cyanobacteria was determined based on measurements of chlorophyll content, morphological changes were assessed through microscopic observations, and the chemical response of cells was determined using liquid and gas chromatography (HPLC; GC-FID. The results show that micromolar levels of naringenin stimulated the growth of cyanobacteria. Increased growth was observed for halophilic strains at naringenin concentrations below 40 mg L-1, and in freshwater strains at concentrations below 20 mg L-1. The most remarkable stimulation was observed for the freshwater species Nostoc muscorum, which had a growth rate that was up to 60% higher than in the control. When naringenin was examined at concentrations above 40 mg L-1, the growth of the tested microorganisms was inhibited. Simultaneously, an intensive excretion of exopolysaccharides was observed. Microscopic observations strongly suggest that these effects resulted from a structural disturbance of cyanobacterial cell walls that was exerted by naringenin. This phenomenon, in combination with the absorption of naringenin into cell wall structures, influenced cell permeability and thus the growth of bacteria. Fortunately, almost all the naringenin added to the culture was incorporated into to cell substructures and could be recovered through extraction, raising the possibility that this modulator could be recycled.

  10. Consistency of metabolic responses and appetite sensations under postabsorptive and postprandial conditions.

    Science.gov (United States)

    Gonzalez, Javier T; Veasey, Rachel C; Rumbold, Penny L S; Stevenson, Emma J

    2012-10-01

    The present study aimed to investigate the reliability of metabolic and subjective appetite responses under fasted conditions and following consumption of a cereal-based breakfast. Twelve healthy, physically active males completed two postabsorption (PA) and two postprandial (PP) trials in a randomised order. In PP trials a cereal based breakfast providing 1859 kJ of energy was consumed. Expired gas samples were used to estimate energy expenditure and fat oxidation and 100mm visual analogue scales were used to determine appetite sensations at baseline and every 30 min for 120 min. Reliability was assessed using limits of agreement, coefficient of variation (CV), intraclass coefficient of correlation and 95% confidence limits of typical error. The limits of agreement and typical error were 292.0 and 105.5 kJ for total energy expenditure, 9.3 and 3.4 g for total fat oxidation and 22.9 and 8.3mm for time-averaged AUC for hunger sensations, respectively over the 120 min period in the PP trial. The reliability of energy expenditure and appetite in the 2h response to a cereal-based breakfast would suggest that an intervention requires a 211 kJ and 16.6mm difference in total postprandial energy expenditure and time-averaged hunger AUC to be meaningful, fat oxidation would require a 6.7 g difference which may not be sensitive to most meal manipulations. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis

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    Anastasia V. Ponasenko

    2017-01-01

    Full Text Available Infective endocarditis (IE is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE.

  12. Inherited Variation in Cytokine, Acute Phase Response, and Calcium Metabolism Genes Affects Susceptibility to Infective Endocarditis

    Science.gov (United States)

    Rutkovskaya, Natalia V.; Kondyukova, Natalia V.; Odarenko, Yuri N.; Kazachek, Yana V.; Tsepokina, Anna V.; Barbarash, Leonid S.

    2017-01-01

    Infective endocarditis (IE) is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1β and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE. PMID:28659664

  13. NGC1300 dynamics - II. The response models

    Science.gov (United States)

    Kalapotharakos, C.; Patsis, P. A.; Grosbøl, P.

    2010-10-01

    We study the stellar response in a spectrum of potentials describing the barred spiral galaxy NGC1300. These potentials have been presented in a previous paper and correspond to three different assumptions as regards the geometry of the galaxy. For each potential we consider a wide range of Ωp pattern speed values. Our goal is to discover the geometries and the Ωp supporting specific morphological features of NGC1300. For this purpose we use the method of response models. In order to compare the images of NGC1300 with the density maps of our models, we define a new index which is a generalization of the Hausdorff distance. This index helps us to find out quantitatively which cases reproduce specific features of NGC1300 in an objective way. Furthermore, we construct alternative models following a Schwarzschild-type technique. By this method we vary the weights of the various energy levels, and thus the orbital contribution of each energy, in order to minimize the differences between the response density and that deduced from the surface density of the galaxy, under certain assumptions. We find that the models corresponding to Ωp ~ 16 and 22 kms-1kpc-1 are able to reproduce efficiently certain morphological features of NGC1300, with each one having its advantages and drawbacks. Based on observations collected at the European Southern Observatory, Chile: programme ESO 69.A-0021. E-mail: ckalapot@phys.uoa.gr (CK); patsis@academyofathens.gr (PAP); pgrosbol@eso.org (PG)

  14. PET studies of brain energy metabolism in a model of subcortical dementia: progressive supranuclear Palsy

    International Nuclear Information System (INIS)

    Blin, J.; Baron, J.C.; Cambon, H.

    1988-01-01

    In 41 patients with clinically determined Progressive Supranuclear Palsy, a model of degenerative subcortical dementia, alterations in regional brain energy metabolism with respect to control subjects have been investigated using positron computed tomography and correlated to clinical and neuropsychological scores. A generalized significant reduction in brain metabolism was found, which predominated in the prefrontal cortex in accordance with, and statistically correlated to, the frontal neuropsychological score

  15. Generation and Validation of the iKp1289 Metabolic Model for Klebsiella pneumoniae KPPR1

    Energy Technology Data Exchange (ETDEWEB)

    Henry, Christopher S.; Rotman, Ella; Lathem, Wyndham W.; Tyo, Keith E. J.; Hauser, Alan R.; Mandel, Mark J.

    2017-02-15

    Klebsiella pneumoniae has a reputation for causing a wide range of infectious conditions, with numerous highly virulent and antibiotic-resistant strains. Metabolic models have the potential to provide insights into the growth behavior, nutrient requirements, essential genes, and candidate drug targets in these strains. Here we develop a metabolic model for KPPR1, a highly virulent strain of K. pneumoniae. We apply a combination of Biolog phenotype data and fitness data to validate and refine our KPPR1 model. The final model displays a predictive accuracy of 75% in identifying potential carbon and nitrogen sources for K. pneumoniae and of 99% in predicting nonessential genes in rich media. We demonstrate how this model is useful in studying the differences in the metabolic capabilities of the low-virulence MGH 78578 strain and the highly virulent KPPR1 strain. For example, we demonstrate that these strains differ in carbohydrate metabolism, including the ability to metabolize dulcitol as a primary carbon source. Our model makes numerous other predictions for follow-up verification and analysis.

  16. The metabolic and temporal basis of muscle hypertrophy in response to resistance exercise.

    Science.gov (United States)

    Brook, Matthew S; Wilkinson, Daniel J; Smith, Kenneth; Atherton, Philip J

    2016-09-01

    Constituting ∼40% of body mass, skeletal muscle has essential locomotory and metabolic functions. As such, an insight into the control of muscle mass is of great importance for maintaining health and quality-of-life into older age, under conditions of cachectic disease and with rehabilitation. In healthy weight-bearing individuals, muscle mass is maintained by the equilibrium between muscle protein synthesis (MPS) and muscle protein breakdown; when this balance tips in favour of MPS hypertrophy occurs. Despite considerable research into pharmacological/nutraceutical interventions, resistance exercise training (RE-T) remains the most potent stimulator of MPS and hypertrophy (in the majority of individuals). However, the mechanism(s) and time course of hypertrophic responses to RE-T remain poorly understood. We would suggest that available data are very much in favour of the notion that the majority of hypertrophy occurs in the early phases of RE-T (though still controversial to some) and that, for the most part, continued gains are hard to come by. Whilst the mechanisms of muscle hypertrophy represent the culmination of mechanical, auto/paracrine and endocrine events, the measurement of MPS remains a cornerstone for understanding the control of hypertrophy - mainly because it is the underlying driving force behind skeletal muscle hypertrophy. Development of sophisticated isotopic techniques (i.e. deuterium oxide) that lend to longer term insight into the control of hypertrophy by sustai