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21 Publications visible to you, out of a total of 21
A systematic strategy for large-scale analysis of genotype phenotype correlations: identification of candidate genes involved in African trypanosomiasis

Abstract (Expand)

It is increasingly common to combine Microarray and Quantitative Trait Loci data to aid the search for candidate genes responsible for phenotypic variation. Workflows provide a means of systematically … processing these large datasets and also represent a framework for the re-use and the explicit declaration of experimental methods. In this article, we highlight the issues facing the manual analysis of microarray and QTL data for the discovery of candidate genes underlying complex phenotypes. We show how automated approaches provide a systematic means to investigate genotype-phenotype correlations. This methodology was applied to a use case of resistance to African trypanosomiasis in the mouse. Pathways represented in the results identified Daxx as one of the candidate genes within the Tir1 QTL region. Subsequent re-sequencing in Daxx identified a deletion of an amino acid, identified in susceptible mouse strains, in the Daxx-p53 protein-binding region. This supports recent experimental evidence that apoptosis could be playing a role in the trypanosomiasis resistance phenotype. Workflows developed in this investigation, including a guide to loading and executing them with example data, are available at http://workflows.mygrid.org.uk/repository/myGrid/PaulFisher/.

Authors: Paul Fisher, Cornelia Hedeler, Firstname Lastname, Helen Hulme, Harry Noyes, Stephen Kemp, Robert Stevens, Andrew Brass

Date Published: 20th Aug 2007

Publication Type: Not specified

Taverna: a tool for building and running workflows of services

Abstract (Expand)

Taverna is an application that eases the use and integration of the growing number of molecular biology tools and databases available on the web, especially web services. It allows bioinformaticians … to construct workflows or pipelines of services to perform a range of different analyses, such as sequence analysis and genome annotation. These high-level workflows can integrate many different resources into a single analysis. Taverna is available freely under the terms of the GNU Lesser General Public License (LGPL) from http://taverna.sourceforge.net/.

Authors: Duncan Hull, Firstname Lastname, Robert Stevens, Firstname Lastname, Mathew R Pocock, Peter Li, Tom Oinn

Date Published: 18th Jul 2006

Publication Type: Not specified

Metabolic control analysis of glycerol synthesis in Saccharomyces cerevisiae

Abstract (Expand)

Glycerol, a major by-product of ethanol fermentation by Saccharomyces cerevisiae, is of significant importance to the wine, beer, and ethanol production industries. To gain a clearer understanding of … and to quantify the extent to which parameters of the pathway affect glycerol flux in S. cerevisiae, a kinetic model of the glycerol synthesis pathway has been constructed. Kinetic parameters were collected from published values. Maximal enzyme activities and intracellular effector concentrations were determined experimentally. The model was validated by comparing experimental results on the rate of glycerol production to the rate calculated by the model. Values calculated by the model agreed well with those measured in independent experiments. The model also mimics the changes in the rate of glycerol synthesis at different phases of growth. Metabolic control analysis values calculated by the model indicate that the NAD(+)-dependent glycerol 3-phosphate dehydrogenase-catalyzed reaction has a flux control coefficient (C(J)v1) of approximately 0.85 and exercises the majority of the control of flux through the pathway. Response coefficients of parameter metabolites indicate that flux through the pathway is most responsive to dihydroxyacetone phosphate concentration (R(J)DHAP= 0.48 to 0.69), followed by ATP concentration (R(J)ATP = -0.21 to -0.50). Interestingly, the pathway responds weakly to NADH concentration (R(J)NADH = 0.03 to 0.08). The model indicates that the best strategy to increase flux through the pathway is not to increase enzyme activity, substrate concentration, or coenzyme concentration alone but to increase all of these parameters in conjunction with each other.

Authors: Garth R Cronwright, Johann M Rohwer, Bernard A Prior

Date Published: 30th Aug 2002

Publication Type: Not specified

Is the glycolytic flux in Lactococcus lactis primarily controlled by the redox charge? Kinetics of NAD(+) and NADH pools determined in vivo by 13C NMR

Abstract (Expand)

The involvement of nicotinamide adenine nucleotides (NAD(+), NADH) in the regulation of glycolysis in Lactococcus lactis was investigated by using (13)C and (31)P NMR to monitor in vivo the kinetics … of the pools of NAD(+), NADH, ATP, inorganic phosphate (P(i)), glycolytic intermediates, and end products derived from a pulse of glucose. Nicotinic acid specifically labeled on carbon 5 was synthesized and used in the growth medium as a precursor of pyridine nucleotides to allow for in vivo detection of (13)C-labeled NAD(+) and NADH. The capacity of L. lactis MG1363 to regenerate NAD(+) was manipulated either by turning on NADH oxidase activity or by knocking out the gene encoding lactate dehydrogenase (LDH). An LDH(-) deficient strain was constructed by double crossover. Upon supply of glucose, NAD(+) was constant and maximal (approximately 5 mm) in the parent strain (MG1363) but decreased abruptly in the LDH(-) strain both under aerobic and anaerobic conditions. NADH in MG1363 was always below the detection limit as long as glucose was available. The rate of glucose consumption under anaerobic conditions was 7-fold lower in the LDH(-) strain and NADH reached high levels (2.5 mm), reflecting severe limitation in regenerating NAD(+). However, under aerobic conditions the glycolytic flux was nearly as high as in MG1363 despite the accumulation of NADH up to 1.5 mm. Glyceraldehyde-3-phosphate dehydrogenase was able to support a high flux even in the presence of NADH concentrations much higher than those of the parent strain. We interpret the data as showing that the glycolytic flux in wild type L. lactis is not primarily controlled at the level of glyceraldehyde-3-phosphate dehydrogenase by NADH. The ATP/ADP/P(i) content could play an important role.

Authors: Ana Rute Neves, Rita Ventura, Nahla Mansour, Claire Shearman, Michael J Gasson, Christopher Maycock, Ana Ramos, Helena Santos

Date Published: 13th May 2002

Publication Type: Not specified

Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enzymes? Testing biochemistry

Abstract (Expand)

This paper examines whether the in vivo behavior of yeast glycolysis can be understood in terms of the in vitro kinetic properties of the constituent enzymes. In nongrowing, anaerobic, compressed … Saccharomyces cerevisiae the values of the kinetic parameters of most glycolytic enzymes were determined. For the other enzymes appropriate literature values were collected. By inserting these values into a kinetic model for glycolysis, fluxes and metabolites were calculated. Under the same conditions fluxes and metabolite levels were measured. In our first model, branch reactions were ignored. This model failed to reach the stable steady state that was observed in the experimental flux measurements. Introduction of branches towards trehalose, glycogen, glycerol and succinate did allow such a steady state. The predictions of this branched model were compared with the empirical behavior. Half of the enzymes matched their predicted flux in vivo within a factor of 2. For the other enzymes it was calculated what deviation between in vivo and in vitro kinetic characteristics could explain the discrepancy between in vitro rate and in vivo flux.

Authors: Firstname Lastname, J Passarge, C A Reijenga, E Esgalhado, C C van der Weijden, M Schepper, M C Walsh, B M Bakker, K van Dam, H V Westerhoff, Firstname Lastname

Date Published: 22nd Aug 2000

Publication Type: Not specified

Modeling the cell division cycle: cdc2 and cyclin interactions

Abstract (Expand)

The proteins cdc2 and cyclin form a heterodimer (maturation promoting factor) that controls the major events of the cell cycle. A mathematical model for the interactions of cdc2 and cyclin is constructed. … Simulation and analysis of the model show that the control system can operate in three modes: as a steady state with high maturation promoting factor activity, as a spontaneous oscillator, or as an excitable switch. We associate the steady state with metaphase arrest in unfertilized eggs, the spontaneous oscillations with rapid division cycles in early embryos, and the excitable switch with growth-controlled division cycles typical of nonembryonic cells.

Author: J. J. Tyson

Date Published: 15th Aug 1991

Publication Type: Not specified

Changes in erythrocyte 2,3 diphosphoglycerate in women following short term maximal exercise

Abstract (Expand)

15 untrained women were subjected to a walking treadmill test to determine the influence of maximal exercise upon synthesis of erythrocyte 2,3 DPG. Although there was a 9.8% increase in the 2,3 DPG … content following exercise, there was a concomitant 9.4% increase in the hemoglobin level; therefore, when 2,3 DPG is expressed as a ratio to hemoglobin (See Article), there was no significant change as a result of exercise stress. It was suggested that three additive factors produced during strenuous exercise; decreased pH; increased hemoglobin concentration; and increased CO2 production result in by-product inhibition of 2,3 DPG synthesis. It is concluded that 2,3 DPG does not provide a physiologic benefit in the adaptation of the oxygen transport system to exercise.

Authors: H W Bonner, C A Tate, C K Buffington

Date Published: 5th Dec 1975

Publication Type: Not specified

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