Local modulation of chemoattractant concentrations by single cells: dissection using a bulk-surface computational model

Chemoattractant gradients are usually considered in terms of sources and sinks that are independent of the chemotactic cell. However, recent interest has focused on ‘self-generated’ gradients, in which cell populations create their own local gradients as they move. Here, we consider the interplay between chemoattractants and single cells. To achieve this, we extend a recently developed computational model to incorporate breakdown of extracellular attractants by membrane-bound enzymes. Model equations are parametrized, using the published estimates from Dictyostelium cells chemotaxing towards cyclic AMP. We find that individual cells can substantially modulate their local attractant field under physiologically appropriate conditions of attractant and enzymes. This means the attractant concentration perceived by receptors can be a small fraction of the ambient concentration. This allows efficient chemotaxis in chemoattractant concentrations that would be saturating without local breakdown. Similar interactions in which cells locally mould a stimulus could function in many types of directed cell motility, including haptotaxis, durotaxis and even electrotaxis

Effects of Apamin and Charybdtoxin on Endothelium Independent Vasodilatation : Implications in the study of EDHF

Endothelial derived hyperpolarizing factor (EDHF), together with endothelial derived NO and prostacyclin represent the major endogenous vasodilator hormone pathways (Coleman et al, 2004). Since the chemical nature of EDHF is uncertain, many studies have relied on pharmacological tools. Often EDHF described as the endothelial dependent dilation which is resistant to a combination of drugs that inhibit NO synthase (usually L-NAME) and cyclo-oxygenase (usually indomethacin) but abolished by those that block large and small Ca2+-activated K+ channels (BKCa and SKCa; with charybdotoxin plus apamin respectively). This approach relies on each of these drugs being selective for endothelial dependent responses. In the current study we have taken a different approach to most and performed experiments where inhibitors were added to endothelium denuded vessels after dilators induced stable vasodilatation. Male Wistar rats (200 ± 15.4g) were killed by lethal exposure to CO2. Second order mesenteric arteries were mounted in isometric wire myographs and vasomotor responses recorded as described previously (Harrington and Mitchell, 2004). In some experiments vessels were contracted with EC80 concentration of U46619, dilation was then induced by the addition of 3x10-6M acetylcholine or 3x10-6M SNP. When either L-NAME (10-4M) or charybdotoxin (10-7M) plus apamin (5x10-7M) were added after acetylcholine the vasodilatation was immediately and completely reversed (Figure A and B respectively). In other experiments, endothelium independent vasodilation induced by SNP, were also reversed by charybdotoxin plus apamin, but not L-NAME. Figure A. Example trace of an artery re-contracting following the addition of L-NAME in pre-contracted arteries dilated with acetylcholine. Bar Graphs show re-contraction of arteries in response to L-NAME or charybdotoxin plus apamin (C+A) in arteries with endothelium, dilated with acetylcholine (Figure B) or without endothelium dilated with SNP (Figure C). This data demonstrates that charybdotoxin and apamin have pharmacological effects independent of the endothelium, at the level of smooth muscle cell function. These observations suggest results obtained with these drugs in relation to EDHF studies, should be treated with caution. Harrington L and Mitchell JA (2004) Br J Pharmacol 143: 611-617 Coleman et al (2004) Clin Ex Pharm Phys 31; 641-649Peer reviewedFinal Accepted Versio

A computational method for the coupled solution of reaction–diffusion equations on evolving domains and manifolds: application to a model of cell migration and chemotaxis

In this paper, we devise a moving mesh finite element method for the approximate solution of coupled bulk–surface reaction–diffusion equations on an evolving two dimensional domain. Fundamental to the success of the method is the robust generation of bulk and surface meshes. For this purpose, we use a novel moving mesh partial differential equation (MMPDE) approach. The developed method is applied to model problems with known analytical solutions; these experiments indicate second-order spatial and temporal accuracy. Coupled bulk–surface problems occur frequently in many areas; in particular, in the modelling of eukaryotic cell migration and chemotaxis. We apply the method to a model of the two-way interaction of a migrating cell in a chemotactic field, where the bulk region corresponds to the extracellular region and the surface to the cell membrane

Is voice therapy an effective treatment for dysphonia? A randomised controlled trial

OBJECTIVES: To assess the overall efficacy of voice therapy for dysphonia. DESIGN: Single blind randomised controlled trial. SETTING: Outpatient clinic in a teaching hospital. Participants: 204 outpatients aged 17-87 with a primary symptom of persistent hoarseness for at least two months. INTERVENTIONS: After baseline assessments, patients were randomised to six weeks of either voice therapy or no treatment. Assessments were repeated at six weeks on the 145 (71%) patients who continued to this stage and at 12-14 weeks on the 133 (65%) patients who completed the study. The assessments at the three time points for the 70 patients who completed treatment and the 63 patients in the group given no treatment were compared. MAIN OUTCOME MEASURES: Ratings of laryngeal features, Buffalo voice profile, amplitude and pitch perturbation, voice profile questionnaire, hospital anxiety and depression scale, clinical interview schedule, SF-36. RESULTS: Voice therapy improved voice quality as assessed by rating by patients (P=0.001) and rating by observer (P<0.001). The treatment effects for these two outcomes were 4.1 (95% confidence interval 1.7 to 6.6) points and 0.82 (0.50 to 1.13) points. Amplitude perturbation showed improvement at six weeks (P=0.005) but not on completion of the study. Patients with dysphonia had appreciable psychological distress and lower quality of life than controls, but voice therapy had no significant impact on either of these variables. CONCLUSION: Voice therapy is effective in improving voice quality as assessed by self rated and observer rated methods

Role of the endothelium and COX-1 in prostacyclin generation by whole vessels stimulated with different agonists

Prostacyclin is an important cardioprotective hormone produced by the vascular wall, whose synthesis is dependent on cyclo-oxygenase (COX) enzymes. In healthy vessels the endothelium is thought to be the main site of prostacyclin release (Moncada et al 1977). Two isoforms of COX exist, and we have recently published data demonstrating that it is COX-1 rather than COX-2 that drives the production of prostacyclin in mouse aorta (Kirkby et al 2012). In this study we aimed to extend these observations by investigating what proportion of the COX-1 driven aortic prostacyclin production that comes from the endothelium versus the rest of the vessel wall (smooth muscle layers and adventitia). To do this, we explored how removal of the endothelium would influence the ability of aortic tissue to release prostacyclin in response to a range of agonists that are known to activate the endothelium and the vessel wallNon peer reviewe

Optimal estimation of drift and diffusion coefficients in the presence of static localization error

No abstract available

A computational method for the coupled solution of reaction-diffusion equations on evolving domains and manifolds : application to a model of cell migration and chemotaxis

In this paper, we devise a moving mesh finite element method for the approximate solution of coupled bulk-surface reaction-diffusion equations on an evolving two dimensional domain. Fundamental to the success of the method is the robust generation of bulk and surface meshes. For this purpose, we use a novel moving mesh partial differential equation (MMPDE) approach. The developed method is applied to model problems with known analytical solutions; these experiments indicate second-order spatial and temporal accuracy. Coupled bulk-surface problems occur frequently in many areas; in particular, in the modelling of eukaryotic cell migration and chemotaxis. We apply the method to a model of the two-way interaction of a migrating cell in a chemotactic field, where the bulk region corresponds to the extracellular region and the surface to the cell membrane

Problems With Complex Actions

We consider Euclidean functional integrals involving actions which are not exclusively real. This situation arises, for example, when there are $t$-odd terms in the the Minkowski action. Writing the action in terms of only real fields (which is always possible), such terms appear as explicitly imaginary terms in the Euclidean action. The usual quanization procedure which involves finding the critical points of the action and then quantizing the spectrum of fluctuations about these critical points fails. In the case of complex actions, there do not exist, in general, any critical points of the action on the space of real fields, the critical points are in general complex. The proper definition of the function integral then requires the analytic continuation of the functional integration into the space of complex fields so as to pass through the complex critical points according to the method of steepest descent. We show a simple example where this procedure can be carried out explicitly. The procedure of finding the critical points of the real part of the action and quantizing the corresponding fluctuations, treating the (exponential of the) complex part of the action as a bounded integrable function is shown to fail in our explicit example, at least perturbatively.Comment: 6+epsilon pages, no figures, presented at Theory CANADA

An hr-adaptive method for the cubic nonlinear Schrödinger equation

The nonlinear Schrödinger equation (NLSE) is one of the most important equations in quantum mechanics, and appears in a wide range of applications including optical fibre communications, plasma physics and biomolecule dynamics. It is a notoriously difficult problem to solve numerically as solutions have very steep temporal and spatial gradients. Adaptive moving mesh methods (r-adaptive) attempt to optimise the accuracy obtained using a fixed number of nodes by moving them to regions of steep solution features. This approach on its own is however limited if the solution becomes more or less difficult to resolve over the period of interest. Adaptive mesh refinement (h-adaptive), where the mesh is locally coarsened or refined, is an alternative adaptive strategy which is popular for time-independent problems. In this paper, we consider the effectiveness of a combined method (hr-adaptive) to solve the NLSE in one space dimension. Simulations are presented indicating excellent solution accuracy compared to other moving mesh approaches. The method is also shown to control the spatial error based on the user's input error tolerance. Evidence is also presented indicating second-order spatial convergence using a novel monitor function to generate the adaptive moving mesh

Anisotropy in the Antiferromagnetic Spin Fluctuations of Sr2RuO4

It has been proposed that Sr_2RuO_4 exhibits spin triplet superconductivity mediated by ferromagnetic fluctuations. So far neutron scattering experiments have failed to detect any clear evidence of ferromagnetic spin fluctuations but, instead, this type of experiments has been successful in confirming the existence of incommensurate spin fluctuations near q=(1/3 1/3 0). For this reason there have been many efforts to associate the contributions of such incommensurate fluctuations to the mechanism of its superconductivity. Our unpolarized inelastic neutron scattering measurements revealed that these incommensurate spin fluctuations possess c-axis anisotropy with an anisotropic factor \chi''_{c}/\chi''_{a,b} of \sim 2.8. This result is consistent with some theoretical ideas that the incommensurate spin fluctuations with a c-axis anisotropy can be a origin of p-wave superconductivity of this material.Comment: 5 pages, 3 figures; accepted for publication in PR