1,535 research outputs found
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
The Reproducibility of a Kinematically-Derived Axis of the Knee versus Digitized Anatomical Landmarks using a Knee Navigation System
Component position is critical to longevity of knee arthroplasties. Femoral component rotation is typically referenced from the transepicondylar axis (TEA), the anterior-posterior (AP) axis or the posterior condylar axis. Other studies have shown high variability in locating the TEA while proposing digitization of other landmarks such as the AP axis as a less-variable reference. This study uses a navigation system to compare the reproducibility of computing a kinematically-derived, navigated knee axis (NKA) to digitizing the TEA and AP axis. Twelve knees from unembalmed cadavers were tested. Four arthroplasty surgeons digitized the femoral epicondyles and the AP axis direction as well as flexed and extended the knee repeatedly to allow for NKA determination. The variance of the NKA axis determined under neutral loading conditions was smaller than the variance of the TEA axis when the kinematics were measured in the closed surgical condition (P<0.001). However, varus, valgus, and internal loading of the leg increased the variability of the NKA. Distraction of the leg during knee flexion and extension preserved the low variability of the NKA. In conclusion, a kinematically-derived NKA under neutral or distraction loading is more reproducible than the TEA and AP axis determined by digitization
Quantization of Midisuperspace Models
We give a comprehensive review of the quantization of midisuperspace models.
Though the main focus of the paper is on quantum aspects, we also provide an
introduction to several classical points related to the definition of these
models. We cover some important issues, in particular, the use of the principle
of symmetric criticality as a very useful tool to obtain the required
Hamiltonian formulations. Two main types of reductions are discussed: those
involving metrics with two Killing vector fields and spherically symmetric
models. We also review the more general models obtained by coupling matter
fields to these systems. Throughout the paper we give separate discussions for
standard quantizations using geometrodynamical variables and those relying on
loop quantum gravity inspired methods.Comment: To appear in Living Review in Relativit
Heart rate monitoring on the stroke unit. What does heart beat tell about prognosis? An observational study
<p>Abstract</p> <p>Background</p> <p>Guidelines recommend maintaining the heart rate (HR) of acute stroke patients within physiological limits; data on the frequency and predictors of significant deviations from these limits are scarce.</p> <p>Methods</p> <p>Demographical data, stroke risk factors, NIH stroke scale score, lesion size and location, and ECG parameters were prospectively assessed in 256 patients with ischemic stroke. Patients were continuously monitored for at least 24 hours on a certified stroke unit. Tachycardia (HR ≥120 bpm) and bradycardia (HR <45 bpm) and cardiac rhythm (sinus rhythm or atrial fibrillation) were documented. We investigated the influence of risk factors on HR disturbances and their respective influence on dependence (modified Rankin Scale ≥ 3 after three months) and mortality.</p> <p>Results</p> <p>HR ≥120 bpm occurred in 39 patients (15%). Stroke severity (larger lesion size/higher NIHSS-score on admission), atrial fibrillation and HR on admission predicted its occurrence. HR <45 bpm occurred in 12 patients (5%) and was predicted by lower HR on admission. Neither HR ≥120 nor HR <45 bpm independently predicted poor outcome at three moths. Stroke location had no effect on the occurrence of HR violations. Clinical severity and age remained the only consistent predictors of poor outcome.</p> <p>Conclusions</p> <p>Significant tachycardia and bradycardia are frequent phenomena in acute stroke; however they do not independently predict clinical course or outcome. Continuous monitoring allows detecting rhythm disturbances in stroke patients and allows deciding whether urgent medical treatment is necessary.</p
Stochastic Gravity: Theory and Applications
Whereas semiclassical gravity is based on the semiclassical Einstein equation
with sources given by the expectation value of the stress-energy tensor of
quantum fields, stochastic semiclassical gravity is based on the
Einstein-Langevin equation, which has in addition sources due to the noise
kernel. In the first part, we describe the fundamentals of this new theory via
two approaches: the axiomatic and the functional. In the second part, we
describe three applications of stochastic gravity theory. First, we consider
metric perturbations in a Minkowski spacetime, compute the two-point
correlation functions of these perturbations and prove that Minkowski spacetime
is a stable solution of semiclassical gravity. Second, we discuss structure
formation from the stochastic gravity viewpoint. Third, we discuss the
backreaction of Hawking radiation in the gravitational background of a black
hole and describe the metric fluctuations near the event horizon of an
evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews
in Relativity gr-qc/0307032 ; it includes new sections on the Validity of
Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric
Fluctuations of an Evaporating Black Hol
Stochastic Gravity: Theory and Applications
Whereas semiclassical gravity is based on the semiclassical Einstein equation
with sources given by the expectation value of the stress-energy tensor of
quantum fields, stochastic semiclassical gravity is based on the
Einstein-Langevin equation, which has in addition sources due to the noise
kernel.In the first part, we describe the fundamentals of this new theory via
two approaches: the axiomatic and the functional. In the second part, we
describe three applications of stochastic gravity theory. First, we consider
metric perturbations in a Minkowski spacetime: we compute the two-point
correlation functions for the linearized Einstein tensor and for the metric
perturbations. Second, we discuss structure formation from the stochastic
gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in
the gravitational background of a quasi-static black hole.Comment: 75 pages, no figures, submitted to Living Reviews in Relativit
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