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Search Results: 1 - 10 of 471184 matches for " Stephen A. Renshaw "
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Zebrafish models of the immune response: taking it on the ChIn
Stephen A Renshaw, Philip W Ingham
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-148
Abstract: The rise of multicellular animals, to what we might consider the pinnacle of human culture, relies on their ability to defend themselves against unicellular organisms competing for the same environmental resources. To aid in the constant battle waged with would-be pathogens, powerful and complex immune structures have developed, built on a series of molecular and cellular advances made by evolution hundreds of millions of years ago. Over the past century, an increasing understanding of the immune system, together with advances in public health and antimicrobial chemotherapy, have had a huge impact in preventing infectious disease and extending human lifespan. In recent decades, however, the emergence of multi-drug-resistant bacteria and the inexorable rise in inflammatory diseases threaten to undermine these improvements in health: the need for a detailed understanding of the immune system has never been more pressing. In BMC Biology, d'Alen?on and colleagues [1] report a novel method for high-throughput in vivo analysis of immune-cell function that offers new and exciting prospects for our understanding of the immune system, as well as for the discovery of new drugs with which to manipulate it.Our understanding of innate immunity began with the observations of Elie Metchnikoff, who in 1882 pricked a starfish larva with a thorn from his garden. The insult provided an immune stimulus comprising both infection and tissue injury, prompting the recruitment of cells that attempted to ingest the thorn. The transparency of the starfish larva allowed Metchnikoff to observe the remarkable behavior of these cells, which we now know as phagocytes, thus founding the science of cellular immunology.A hundred and fifty years later, the model organism has changed, but the principles remain the same. In a recent paper in Cell, Tobin and colleagues [2] followed Metchnikoff's lead and injected transparent zebrafish larvae with the bacterium Mycobacterium marinum to identify mutants wi
The molecular controls of resolution of inflammation: what can we learn from zebrafish?
Stephen. A. Renshaw,Catherine. A. Loynes,Daniel. M. Trushell,Philip. W. Ingham
European Respiratory Review , 2006,
Abstract: Although we are separated from zebrafish by 160 million years of evolution, we share many features of the innate and adaptive immune systems. In addition, we can manipulate the genome of zebrafish, and observe the effects on inflammation in vivo as they are transparent in their larval stages. This has exciting implications for the study of inflammatory diseases. We have established a model of inflammation in the zebrafish tail, in which caspase dependent cell death is required for resolution. For example, addition of the pan-caspase inhibitor zVD added at 4 hours after tailfin injury increases the number of neutrophils present from 6.0+/–1.0 to 28.9+/– 3.3 (mean +/– s.e.m. p<0.001 n = 3). The transparency of the larvae makes these an ideal model for the study of in vivo inflammation, and we have generated fluorescent systems for the easy visualisation of neutrophilic inflammation and resolution in vivo. We are also performing an unbiased forward genetic screen for mutants with defective resolution of inflammation, and to date have identified 38 putative mutants. These techniques allow new approaches to understanding the molecular controls of inflammation resolution.
Effective Caspase Inhibition Blocks Neutrophil Apoptosis and Reveals Mcl-1 as Both a Regulator and a Target of Neutrophil Caspase Activation
David J. Wardle,Joseph Burgon,Ian Sabroe,Colin D. Bingle,Moira K. B. Whyte,Stephen A. Renshaw
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015768
Abstract: Human tissue inflammation is terminated, at least in part, by the death of inflammatory neutrophils by apoptosis. The regulation of this process is therefore key to understanding and manipulating inflammation resolution. Previous data have suggested that the short-lived pro-survival Bcl-2 family protein, Mcl-1, is instrumental in determining neutrophil lifespan. However, Mcl-1 can be cleaved following caspase activity, and the possibility therefore remains that the observed fall in Mcl-1 levels is due to caspase activity downstream of caspase activation, rather than being a key event initiating apoptosis in human neutrophils.
Regulation of Neutrophil Senescence by MicroRNAs
Jon R. Ward,Paul R. Heath,James W. Catto,Moira K. B. Whyte,Marta Milo,Stephen A. Renshaw
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015810
Abstract: Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease.
Clonal Expansion during Staphylococcus aureus Infection Dynamics Reveals the Effect of Antibiotic Intervention
Gareth McVicker,Tomasz K. Prajsnar,Alexander Williams,Nelly L. Wagner,Michael Boots,Stephen A. Renshaw,Simon J. Foster
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1003959
Abstract: To slow the inexorable rise of antibiotic resistance we must understand how drugs impact on pathogenesis and influence the selection of resistant clones. Staphylococcus aureus is an important human pathogen with populations of antibiotic-resistant bacteria in hospitals and the community. Host phagocytes play a crucial role in controlling S. aureus infection, which can lead to a population “bottleneck” whereby clonal expansion of a small fraction of the initial inoculum founds a systemic infection. Such population dynamics may have important consequences on the effect of antibiotic intervention. Low doses of antibiotics have been shown to affect in vitro growth and the generation of resistant mutants over the long term, however whether this has any in vivo relevance is unknown. In this work, the population dynamics of S. aureus pathogenesis were studied in vivo using antibiotic-resistant strains constructed in an isogenic background, coupled with systemic models of infection in both the mouse and zebrafish embryo. Murine experiments revealed unexpected and complex bacterial population kinetics arising from clonal expansion during infection in particular organs. We subsequently elucidated the effect of antibiotic intervention within the host using mixed inocula of resistant and sensitive bacteria. Sub-curative tetracycline doses support the preferential expansion of resistant microorganisms, importantly unrelated to effects on growth rate or de novo resistance acquisition. This novel phenomenon is generic, occurring with methicillin-resistant S. aureus (MRSA) in the presence of β-lactams and with the unrelated human pathogen Pseudomonas aeruginosa. The selection of resistant clones at low antibiotic levels can result in a rapid increase in their prevalence under conditions that would previously not be thought to favor them. Our results have key implications for the design of effective treatment regimes to limit the spread of antimicrobial resistance, where inappropriate usage leading to resistance may reduce the efficacy of life-saving drugs.
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.
Hypoxia Inducible Factor Signaling Modulates Susceptibility to Mycobacterial Infection via a Nitric Oxide Dependent Mechanism
Philip M. Elks ,Sabrina Brizee,Michiel van der Vaart,Sarah R. Walmsley,Fredericus J. van Eeden,Stephen A. Renshaw equal contributor,Annemarie H. Meijer equal contributor
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003789
Abstract: Tuberculosis is a current major world-health problem, exacerbated by the causative pathogen, Mycobacterium tuberculosis (Mtb), becoming increasingly resistant to conventional antibiotic treatment. Mtb is able to counteract the bactericidal mechanisms of leukocytes to survive intracellularly and develop a niche permissive for proliferation and dissemination. Understanding of the pathogenesis of mycobacterial infections such as tuberculosis (TB) remains limited, especially for early infection and for reactivation of latent infection. Signaling via hypoxia inducible factor α (HIF-α) transcription factors has previously been implicated in leukocyte activation and host defence. We have previously shown that hypoxic signaling via stabilization of Hif-1α prolongs the functionality of leukocytes in the innate immune response to injury. We sought to manipulate Hif-α signaling in a well-established Mycobacterium marinum (Mm) zebrafish model of TB to investigate effects on the host's ability to combat mycobacterial infection. Stabilization of host Hif-1α, both pharmacologically and genetically, at early stages of Mm infection was able to reduce the bacterial burden of infected larvae. Increasing Hif-1α signaling enhanced levels of reactive nitrogen species (RNS) in neutrophils prior to infection and was able to reduce larval mycobacterial burden. Conversely, decreasing Hif-2α signaling enhanced RNS levels and reduced bacterial burden, demonstrating that Hif-1α and Hif-2α have opposing effects on host susceptibility to mycobacterial infection. The antimicrobial effect of Hif-1α stabilization, and Hif-2α reduction, were demonstrated to be dependent on inducible nitric oxide synthase (iNOS) signaling at early stages of infection. Our findings indicate that induction of leukocyte iNOS by stabilizing Hif-1α, or reducing Hif-2α, aids the host during early stages of Mm infection. Stabilization of Hif-1α therefore represents a potential target for therapeutic intervention against tuberculosis.
PhagoSight: An Open-Source MATLAB? Package for the Analysis of Fluorescent Neutrophil and Macrophage Migration in a Zebrafish Model
Katherine M. Henry, Luke Pase, Carlos Fernando Ramos-Lopez, Graham J. Lieschke, Stephen A. Renshaw, Constantino Carlos Reyes-Aldasoro
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072636
Abstract: Neutrophil migration in zebrafish larvae is increasingly used as a model to study the response of these leukocytes to different determinants of the cellular inflammatory response. However, it remains challenging to extract comprehensive information describing the behaviour of neutrophils from the multi-dimensional data sets acquired with widefield or confocal microscopes. Here, we describe PhagoSight, an open-source software package for the segmentation, tracking and visualisation of migrating phagocytes in three dimensions. The algorithms in PhagoSight extract a large number of measurements that summarise the behaviour of neutrophils, but that could potentially be applied to any moving fluorescent cells. To derive a useful panel of variables quantifying aspects of neutrophil migratory behaviour, and to demonstrate the utility of PhagoSight, we evaluated changes in the volume of migrating neutrophils. Cell volume increased as neutrophils migrated towards the wound region of injured zebrafish. PhagoSight is openly available as MATLAB? m-files under the GNU General Public License. Synthetic data sets and a comprehensive user manual are available from http://www.phagosight.org.
Interpersonal Angular Relations between Players Constrain Decision-Making on the Passing Velocity in Futsal  [PDF]
Umberto Cesar Corrêa, Luis Vilar, Keith Davids, Ian Renshaw
Advances in Physical Education (APE) , 2014, DOI: 10.4236/ape.2014.42013

The aim of this study was to investigate the influence of interpersonal interactions between players on the regulation of ball passing velocity in the team sport of futsal. For this purpose 28 sequences of play, in which passes were performed between outfield players, were selected from an elite futsal competition and analyzed using TACTO software. Relative angles between attackers and defenders were used to examine interpersonal coordination tendencies that emerged during performance. Results showed that ball passing velocity was constrained by the rate of change of the angle created by the following vectors: “ball carrier-ball receiver” and “ball carrier-ball receiver’s nearest defender”. Passing velocity remained the same when that angular value remained within a critical threshold range between ?18.16°/s to 11.26°/s. Beyond those critical threshold values, angular relations between participants seemed to enter into a new critical state requiring the emergence of a new passing velocity for performance success. The findings of this study allowed us to conclude that passing velocity during competitive performance in futsal was regulated by the rate of change of an angle established by the interaction between the ball carrier to ball receiver vector with the ball carrier to ball receiver’s nearest defender vector.

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