Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.Peer reviewedPublisher PD

Trat data of Daphnia pulex

Trait data for individual Daphnia pulex from either fish cue- or mideg cue treatment. Below follows a description of the column labels: CLONE - the maternal clone; POND - the pond from which the clone was collected; CUE TREATMENT - the predator cue added to the water; AGE MATURITY - age at maturity (days); SIZE MATURITY - the size at maturity (mm), ADULT GROWTH RATE - the increase in size as adults (day-1); R - the reproductive fitness calculated from the life tabl

The Effects of Exercise Intensity vs. Metabolic State on the Variability and Magnitude of Left Ventricular Twist Mechanics during Exercise.

Increased left ventricular (LV) twist and untwisting rate (LV twist mechanics) are essential responses of the heart to exercise. However, previously a large variability in LV twist mechanics during exercise has been observed, which complicates the interpretation of results. This study aimed to determine some of the physiological sources of variability in LV twist mechanics during exercise. Sixteen healthy males (age: 22 ± 4 years, [Formula: see text]O2peak: 45.5 ± 6.9 ml∙kg-1∙min-1, range of individual anaerobic threshold (IAT): 32-69% of [Formula: see text]O2peak) were assessed at rest and during exercise at: i) the same relative exercise intensity, 40%peak, ii) at 2% above IAT, and, iii) at 40%peak with hypoxia (40%peak+HYP). LV volumes were not significantly different between exercise conditions (P > 0.05). However, the mean margin of error of LV twist was significantly lower (F2,47 = 2.08, P 0.05). Overall, LV twist mechanics were linearly related to rate pressure product. During exercise, the intra-individual variability of LV twist mechanics is smaller at the same relative exercise intensity compared with IAT. However, the absolute magnitude (degrees) of LV twist mechanics appears to be associated with the prevailing rate pressure product. Exercise tests that evaluate LV twist mechanics should be standardised by relative exercise intensity and rate pressure product be taken into account when interpreting results

Iron-Dependent Hydrogenases of Entamoeba histolytica and Giardia lamblia: Activity of the Recombinant Entamoebic Enzyme and Evidence for Lateral Gene Transfer

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Variability of LV twist mechanics during three different exercise conditions.

<p>The graphs show the variability of LV twist and untwisting rate during three exercise conditions, performed by the same individuals. The variability of LV twist was significantly greater during exercise at 2% above individual anaerobic threshold (IAT + 2%), while the variability of LV untwisting rate was statistically not different between exercise conditions. Data are mean ± 99% CI.</p

Metabolic responses during three exercise conditions.

<p>The lower arterial oxygen saturation (SpO₂) during exercise at 40%_peak in hypoxia (40%peak+HYP) did not affect total whole-body oxygen consumption (O₂) due to a compensatory increase in ventilation (VE). However, as a consequence of altered metabolism, lactate and RER were significantly increased during 40%peak+HYP. IAT = individual anaerobic threshold; *: <i>P</i> < 0.05; **: <i>P</i> < 0.01; ***: <i>P</i> < 0.001.</p

General cardiovascular function and LV twist mechanics at rest and during three exercise conditions.

<p>General cardiovascular function and LV twist mechanics at rest and during three exercise conditions.</p

Effect of hypoxia on LV twist and untwisting rate during exercise.

<p>Despite the same whole-body oxygen consumption (O₂) and LV volumes, hypoxia significantly increased LV twist mechanics (<b>A</b>), indicating that relative exercise intensity cannot be the sole determinant of the absolute magnitude of LV twist mechanics. However, when LV twist mechanics were plotted against rate pressure product (RPP), a clear linear relationship was observed, suggesting that myocardial work may ultimately predict the magnitude of LV twist and untwisting rate (<b>B</b>).</p