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Search Results: 1 - 10 of 226078 matches for " Geoffrey R. Holmes "
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Drift-Diffusion Analysis of Neutrophil Migration during Inflammation Resolution in a Zebrafish Model
Geoffrey R. Holmes,Giles Dixon,Sean R. Anderson,Constantino Carlos Reyes-Aldasoro,Philip M. Elks,Stephen A. Billings,Moira K. B. Whyte,Visakan Kadirkamanathan,Stephen A. Renshaw
Advances in Hematology , 2012, DOI: 10.1155/2012/792163
Abstract: Neutrophils must be removed from inflammatory sites for inflammation to resolve. Recent work in zebrafish has shown neutrophils can migrate away from inflammatory sites, as well as die in situ. The signals regulating the process of reverse migration are of considerable interest, but remain unknown. We wished to study the behaviour of neutrophils during reverse migration, to see whether they moved away from inflamed sites in a directed fashion in the same way as they are recruited or whether the inherent random component of their migration was enough to account for this behaviour. Using neutrophil-driven photoconvertible Kaede protein in transgenic zebrafish larvae, we were able to specifically label neutrophils at an inflammatory site generated by tailfin transection. The locations of these neutrophils over time were observed and fitted using regression methods with two separate models: pure-diffusion and drift-diffusion equations. While a model hypothesis test (the F-test) suggested that the datapoints could be fitted by the drift-diffusion model, implying a fugetaxis process, dynamic simulation of the models suggested that migration of neutrophils away from a wound is better described by a zero-drift, “diffusion” process. This has implications for understanding the mechanisms of reverse migration and, by extension, neutrophil retention at inflammatory sites. 1. Introduction The fate of neutrophils following completion of the inflammatory programme is of critical importance for the outcome of episodes of acute inflammation and can determine whether there is prompt healing of a wound or the development of chronic inflammation and tissue injury. Neutrophils recruited to sites of inflammation may leave the site or die in situ [1]. The most widely accepted mechanism of neutrophil disposal is the programmed cell death or apoptosis, of the neutrophil followed by macrophage uptake and clearance (reviewed in [2]). Recently, other routes have been proposed; neutrophils may move away from the inflamed site into the bloodstream (“reverse transmigration” [3]), by migration through other tissues (“retrograde chemotaxis” or “reverse migration” [4–6]), or be lost into the inflammatory exudate [7, 8]. Current understanding of the process of reverse migration is reviewed elsewhere [9]. The uncertainty as to the in vivo fates of individual cells relates in part to the difficulty in following individual cells during inflammation resolution in vivo. The transgenic zebrafish model is emerging as a key model for the study of vertebrate immunity [10] and allows direct
The Neutrophil's Eye-View: Inference and Visualisation of the Chemoattractant Field Driving Cell Chemotaxis In Vivo
Visakan Kadirkamanathan, Sean R. Anderson, Stephen A. Billings, Xiliang Zhang, Geoffrey R. Holmes, Constantino C. Reyes-Aldasoro, Philip M. Elks, Stephen A. Renshaw
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035182
Abstract: As we begin to understand the signals that drive chemotaxis in vivo, it is becoming clear that there is a complex interplay of chemotactic factors, which changes over time as the inflammatory response evolves. New animal models such as transgenic lines of zebrafish, which are near transparent and where the neutrophils express a green fluorescent protein, have the potential to greatly increase our understanding of the chemotactic process under conditions of wounding and infection from video microscopy data. Measurement of the chemoattractants over space (and their evolution over time) is a key objective for understanding the signals driving neutrophil chemotaxis. However, it is not possible to measure and visualise the most important contributors to in vivo chemotaxis, and in fact the understanding of the main contributors at any particular time is incomplete. The key insight that we make in this investigation is that the neutrophils themselves are sensing the underlying field that is driving their action and we can use the observations of neutrophil movement to infer the hidden net chemoattractant field by use of a novel computational framework. We apply the methodology to multiple in vivo neutrophil recruitment data sets to demonstrate this new technique and find that the method provides consistent estimates of the chemoattractant field across the majority of experiments. The framework that we derive represents an important new methodology for cell biologists investigating the signalling processes driving cell chemotaxis, which we label the neutrophils eye-view of the chemoattractant field.
Groups Having Elements Conjugate to Their Squares and Connections with Dynamical Systems  [PDF]
Geoffrey R. Goodson
Applied Mathematics (AM) , 2010, DOI: 10.4236/am.2010.15055
Abstract: In recent years, dynamical systems which are conjugate to their squares have been studied in ergodic theory. In this paper we study the consequences of groups having elements which are conjugate to their squares and consider examples arising from topological dynamics and more general dynamical systems
Debate: PCI vs CABG: a moving target, but we are gaining
David R Holmes
Trials , 2001, DOI: 10.1186/cvm-2-6-263
Abstract: The treatment of patients with coronary artery disease continues to evolve. This evolution proceeds in fits and starts – rapid changes interspersed with plateaus. Upon reaching each plateau, there is the temptation to believe that it is now time to address the question, once and for all, of what is the best treatment strategy for patients. Such an approach has some disadvantages: the procedure is continually evolving; yardsticks (endpoints) in use also continue to change; and patients (and their expectations) continue to change. These caveats are not meant to denigrate randomized clinical trials because they remain the key to evidence-based medicine.The three components of current treatment strategy – medical therapy, surgical revascularization, and percutaneous coronary intervention (PCI) – are all changing. Medical therapy, however, should remain the mainstay. Intensive risk-factor modification with medical therapy is essential, irrespective of whether it is the sole therapy or whether the patient requires revascularization.Surgical revascularization has also changed [1-5]. This change has arguably (but probably) been the result of the competition from the "newer kid on the block" – PCI. Even surgeons have finally embraced the ideal of "less invasiveness" with new approaches such as the minimally invasive "beating heart surgery".However, the field that has changed the most is PCI, with the introduction of stents (previously only used in few patients up to the mid-1990s, but now in approximately 90% of cases) [6-9], threnopyndines [10-12], and glycoprotein (GP) IIb/IIIa inhibitors [13-17]. It has been documented to reduce enzyme elevation post-procedure, and may improve harder endpoints in other patient groups.The article by Bhatt and Topol, in this issue of Current Controlled Trials in Cardiovascular Medicine, reviews the latest trials comparing stenting with bypass surgery, for the treatment of multivessel coronary disease [18]. Both the Arterial Revascularisatio
Dynamical Systems, Stability, and Chaos
R. Ball,P. Holmes
Physics , 2007,
Abstract: In this expository and resources chapter we review selected aspects of the mathematics of dynamical systems, stability, and chaos, within a historical framework that draws together two threads of its early development: celestial mechanics and control theory, and focussing on qualitative theory. From this perspective we show how concepts of stability enable us to classify dynamical equations and their solutions and connect the key issues of nonlinearity, bifurcation, control, and uncertainty that are common to time-dependent problems in natural and engineered systems. We discuss stability and bifurcations in three simple model problems, and conclude with a survey of recent extensions of stability theory to complex networks.
An efficient, nonlinear stability analysis for detecting pattern formation in reaction diffusion systems
William R. Holmes
Physics , 2012,
Abstract: Reaction diffusion systems are often used to study pattern formation in biological systems. However, most methods for understanding their behavior are challenging and can rarely be applied to complex systems common in biological applications. I present a relatively simple and efficient, non-linear stability technique that greatly aids such analysis when rates of diffusion are substantially different. This technique reduces a system of reaction diffusion equations to a system of ordinary differential equations tracking the evolution of a large amplitude, spatially localized perturbation of a homogeneous steady state. Stability properties of this system, determined using standard bifurcation techniques and software, describe both linear and non-linear patterning regimes of the reaction diffusion system. I describe the class of systems this method can be applied to and demonstrate its application. Analysis of Schnakenberg and substrate inhibition models is performed to demonstrate the methods capabilities in simplified settings and show that even these simple models have non-linear patterning regimes not previously detected. Analysis of a protein regulatory network related to chemotaxis shows its application in a more complex setting where other non-linear methods become intractable. Predictions of this method are verified against results of numerical simulation, linear stability, and full PDE bifurcation analyses.
Social participation and healthy ageing: a neglected, significant protective factor for chronic non communicable conditions
Wendy R Holmes, Jennifer Joseph
Globalization and Health , 2011, DOI: 10.1186/1744-8603-7-43
Abstract: Current international policy initiatives to address the increasing prevalence of non-communicable chronic diseases are focused on cardiovascular disease, diabetes, respiratory disease and cancers, responsible for much premature mortality. Interventions to modify their shared risk factors of high salt and fat diets, inactivity, smoking and alcohol use are advocated. But older people also suffer chronic conditions that primarily affect quality of life, and have a wider range of risk factors. There is strong epidemiological and physiological evidence that social isolation, in particular, is as important a risk factor for chronic diseases as the 'lifestyle' risk factors, yet it is currently neglected. There are useful experiences of inexpensive and sustainable strategies to improve social participation among older people in low and lower middle income countries. Our experience with forming Elders' Clubs with retired tea estate workers in Sri Lanka suggests many benefits, including social support and participation, inter-generational contact, a collective voice, and facilitated access to health promotion activities, and to health care and social welfare services.Policies to address the increase in chronic non-communicable diseases should include consideration of healthy ageing, conditions that affect quality of life, and strategies to increase social participation. There are useful examples showing that it is feasible to catalyse the formation of Elders' Clubs or older people's associations which become self-sustaining, promote social participation, and improve health and well-being of elders and their families.Governments and the World Health Organization have recognised the huge burden of preventable disease, disability, death and distress caused by the non communicable diseases (NCDs). Advocacy by the World Health Organization has recently pushed NCDs up the international health agenda. In September 2011 world leaders discussed the Prevention and Control of NCDs at th
On a new symmetry of the solutions of the wave equation in the background of a Kerr black hole
Horst R. Beyer,Irina Holmes
Mathematics , 2006, DOI: 10.1088/0264-9381/25/13/135014
Abstract: This short paper derives the constant of motion of a scalar field in the gravitational field of a Kerr black hole which is associated to a Killing tensor of that space-time. In addition, there is found a related new symmetry operator S for the solutions of the wave equation in that background. That operator is a partial differential operator with a leading order time derivative of the first order that commutes with a normal form of the wave operator. That form is obtained by multiplication of the wave operator from the left with the reciprocal of the coefficient function of its second order time derivative. It is shown that S induces an operator that commutes with the generator of time evolution in a formulation of the initial value problem for the wave equation in the setting of strongly continuous semigroups.
Discrimination and reliability: Equal partners?
Geoffrey R Norman
Health and Quality of Life Outcomes , 2008, DOI: 10.1186/1477-7525-6-81
Abstract: There are several definitions of discrimination. Two, from the Webster dictionary, are: 1) the process by which two stimuli differing in some aspect are responded to differently, and 2) the quality or power of finely distinguishing. It seems to me that the manuscript by Hankins [1], in attempting to elaborate on 1), shows considerable absence of 2).To begin with, a small disclaimer: The “McMaster Framework” is hardly endorsed by all at McMaster. In fact, my co-author Dave Streiner and I, both of us originally from McMaster, in our textbook [2] specifically challenge the Kirshner and Guyatt [3] notion of different kinds of instruments for different purposes.And now to the matter at hand. Hankins [1] attempts to show that reliability is not a good measure of discrimination, and that instruments can be reliable but not discriminating, and vice versa. But, while he refers to formulas for both reliability and discrimination (more on this in a moment), he does not actually define either. This is not just pedantry; in my view, reliability is, by definition, an index of the ability of an instrument to discriminate among individuals. To quote an authority on the subject, me [1]:“..the reliability coefficients reflects the extent to which a measurement instrument can differentiate among individuals, since the magnitude of the coefficient is directly related to the variability between subjects”.An almost perfect paraphrase of the Webster definition above. Fundamentally all reliability coefficients are intraclass coefficients, and mathematically reflect the proportion of the variance in the observations that relate to real differences among subjects. The formula is:The numerator expresses variability due to different responses among individuals. The denominator expresses all variability. So reliability is a measure of the extent to which people differ, expressed as a number between 0 and 1. QED – reliability is discrimination. This is also precisely consistent with Hawkins' “te
Transformation from “Carbon Valley” to a “Post-Carbon Society” in a Climate Change Hot Spot: the Coalfields of the Hunter Valley, New South Wales, Australia
Geoffrey R. Evans
Ecology and Society , 2008,
Abstract: This paper examines the possibilities for transformation of a climate-change hot spot—the coal-producing Hunter Region of New South Wales, Australia—using complex adaptive systems (CAS) theory. It uses CAS theory to understand the role of coal in the region’s history and efforts to strengthen the ecological, economic, and social resilience of the region’s coal industry in the face of demands for a shift from fossil fuel dependency to clean, renewable energy and genuine resilience and sustainability. It uses CAS theory to understand ways in which the resilience of two alternative futures, labeled “Carbon Valley” and “Post-Carbon Society” (Heinberg 2004), might evolve. The paper discusses ways in which changes implemented through the efforts of local communities at local, smaller scales of the nested systems seek to influence the evolution of adaptive cycles of the system at the local, national, and global scales. It identifies the influences of “attractors,” defined as factors driving the evolution of the system, that are influential across the panarchy. These include climate change threats, markets, regulatory regimes, political alliances, and local concerns about the environmental and social impacts of the Hunter’s coal dependency. These factors are weakening the apparent resilience of the coal industry, which is being propped up by the coal industry corporations, labor unions, and governments to maintain coal dependency in the Carbon Valley. Moreover, they are creating an alternative basin of attraction in which a Post-Carbon Society might emerge from the system’s evolutionary processes.
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