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Search Results: 1 - 10 of 406579 matches for " Philip M. Elks "
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A Method for the In Vivo Measurement of Zebrafish Tissue Neutrophil Lifespan
Giles Dixon,Philip M. Elks,Catherine A. Loynes,Moira K. B. Whyte
ISRN Hematology , 2012, DOI: 10.5402/2012/915868
Abstract:
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.
Mycobacteria Counteract a TLR-Mediated Nitrosative Defense Mechanism in a Zebrafish Infection Model
Philip M. Elks, Michiel van der Vaart, Vincent van Hensbergen, Esther Schutz, Michael J. Redd, Emi Murayama, Herman P. Spaink, Annemarie H. Meijer
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100928
Abstract: Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments.
Interaction of TNF with Angiotensin II Contributes to Mitochondrial Oxidative Stress and Cardiac Damage in Rats
Nithya Mariappan, Carrie M. Elks, Masudul Haque, Joseph Francis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046568
Abstract: Recent evidence suggests that tumor necrosis factor alpha (TNF) and angiotensin II (ANGII) induce oxidative stress contribute to cardiovascular disease progression. Here, we examined whether an interaction between TNF and ANGII contributes to altered cardiac mitochondrial biogenesis and ATP production to cause cardiac damage in rats. Rats received intraperitoneal injections of TNF (30 μg/kg), TNF + losartan (LOS, 1 mg/kg), or vehicle for 5 days. Left ventricular (LV) function was measured using echocardiography. Rats were sacrificed and LV tissues removed for gene expression, electron paramagnetic resonance and mitochondrial assays. TNF administration significantly increased expression of the NADPH oxidase subunit, gp91phox, and the angiotensin type 1 receptor (AT-1R) and decreased eNOS in the LV of rats. Rats that received TNF only had increased production rates of superoxide, peroxynitrite and total reactive oxygen species (ROS) in the cytosol and increased production rates of superoxide and hydrogen peroxide in mitochondria. Decreased activities of mitochondrial complexes I, II, and III and mitochondrial genes were observed in rats given TNF. In addition, TNF administration also resulted in a decrease in fractional shortening and an increase in Tei index, suggesting diastolic dysfunction. TNF administration with concomitant LOS treatment attenuated mitochondrial damage, restored cardiac function, and decreased expression of AT1-R and NADPH oxidase subunits. Mitochondrial biogenesis and function is severely impaired by TNF as evidenced by downregulation of mitochondrial genes and increased free radical production, and may contribute to cardiac damage. These defects are independent of the downregulation of mitochondrial gene expression, suggesting novel mechanisms for mitochondrial dysfunction in rats given TNF.
Honesty, power and bootstrapping in composite interval quantitative trait locus mapping  [PDF]
Philip M. Service
Open Journal of Genetics (OJGen) , 2013, DOI: 10.4236/ojgen.2013.32016
Abstract:

In a typical composite interval mapping experiment, the probability of obtaining false QTL is likely to be at least an order of magnitude greater than the nominal experiment-wise Type I error rate, as set by permutation test. F2 mapping crosses were simulated with three different genetic maps. Each map contained ten QTL on either three, six or twelve linkage groups. QTL effects were additive only, and heritability was 50%. Each linkage group had 11 evenly-spaced (10 cM) markers. Selective genotyping was used. Simulated data were analyzed by composite interval mapping with the Zmapqtl program of QTL Cartographer. False positives were minimized by using the largest feasible number of markers to control genetic background effects. Bootstrapping was then used to recover mapping power lost to the large number of conditioning markers. Bootstrapping is shown to be a useful tool for QTL discovery, although it can also produce false positives. Quantitative bootstrap support—the proportion of bootstrap replicates in which a significant likelihood maximum occurred in a given marker interval—was positively correlated with the probability that the likelihood maxima revealed a true QTL. X-linked QTL were detected with much lower power than autosomal QTL. It is suggested that QTL mapping experiments should be supported by accompanying simulations that replicate the marker map, crossing design, sample size, and method of analysis used for the actual experiment.

A Blueberry-Enriched Diet Attenuates Nephropathy in a Rat Model of Hypertension via Reduction in Oxidative Stress
Carrie M. Elks, Scott D. Reed, Nithya Mariappan, Barbara Shukitt-Hale, James A. Joseph, Donald K. Ingram, Joseph Francis
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024028
Abstract: Objective and Background To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB) have among the highest antioxidant capacities of fruits and vegetables. Methods and Results Male spontaneously hypertensive rats received a BB-enriched diet (2% w/w) or an isocaloric control diet for 6 or 12 weeks or 2 days. Compared to controls, rats fed BB-enriched diet for 6 or 12 weeks exhibited lower blood pressure, improved glomerular filtration rate, and decreased renovascular resistance. As measured by electron paramagnetic resonance spectroscopy, significant decreases in total reactive oxygen species (ROS), peroxynitrite, and superoxide production rates were observed in kidney tissues in rats on long-term dietary treatment, consistent with reduced pathology and improved function. Additionally, measures of antioxidant status improved; specifically, renal glutathione and catalase activities increased markedly. Contrasted to these observations indicating reduced OS in the BB group after long-term feeding, similar measurements made in rats fed the same diet for only 2 days yielded evidence of increased OS; specifically, significant increases in total ROS, peroxynitrite, and superoxide production rates in all tissues (kidney, brain, and liver) assayed in BB-fed rats. These results were evidence of “hormesis” during brief exposure, which dissipated with time as indicated by enhanced levels of catalase in heart and liver of BB group. Conclusion Long-term feeding of BB-enriched diet lowered blood pressure, preserved renal hemodynamics, and improved redox status in kidneys of hypertensive rats and concomitantly demonstrated the potential to delay or attenuate development of hypertension-induced renal injury, and these effects appear to be mediated by a short-term hormetic response.
Alpha-synuclein truncation and disease  [PDF]
Caroline M. Ritchie, Philip J. Thomas
Health (Health) , 2012, DOI: 10.4236/health.2012.431175
Abstract: Alpha-synuclein is the major component of Lewy bodies, insoluble protein aggregates, found in patients with Parkinson’s disease, diffuse Lewy body disease, and the Lewy body variant of Alzheimer’s disease. Alpha-synuclein has been found within Lewy bodies to contain many different modifications, including nitration, phosphorylation, ubiquitination, and truncation. C-terminally truncated forms of alpha-synuclein aggregate faster than the full-length protein in vitro, and are thus believed to play a role in Lewy body formation and disease progression. Pathological studies of post mortem brain tissue and the generation of transgenic mouse models further support a role of C-terminally truncated forms of alpha-synuclein in disease. Several enzymes, some of which function extracellularly, have been implicated in the production of these C-terminally truncated forms of alpha-synuclein. However, the enzymes responsible for alphasynuclein truncation in vivo have not yet been firmly established.
Desmatamento na Amaz?nia: dinamica, impactos e controle
Fearnside, Philip M.;
Acta Amazonica , 2006, DOI: 10.1590/S0044-59672006000300018
Abstract: deforestation in amazonia proceeds at a rapid rate for various reasons, many of which depend on government decisions. deforestation causes losses of environmental services that are more valuable than the short-lived uses that replace the forest. these services include maintenance of biodiversity, of water cycling and of the stocks of carbon that avoid further intensification of the greenhouse effect. feedbacks between climatic changes and the forest through such processes as forest fires, tree mortality from drought and heat and the release of carbon stocks in the soil represent dangers for the climate, the forest and the brazilian population. recent events indicate that deforestation can be controlled, given the political will, because the underlying processes depend on human decisions.
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