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Webster J.P.,Royal Veterinary College University of London | Borlase A.,Royal Veterinary College University of London | Rudge J.W.,London School of Hygiene and Tropical Medicine | Rudge J.W.,Mahidol University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2017

Multi-host infectious agents challenge our abilities to understand, predict and manage disease dynamics. Within this, many infectious agents are also able to use, simultaneously or sequentially, multiple modes of transmission. Furthermore, the relative importance of different host species and modes can itself be dynamic, with potential for switches and shifts in host range and/or transmission mode in response to changing selective pressures, such as those imposed by disease control interventions. The epidemiology of such multi-host, multi-mode infectious agents thereby can involve a multi-faceted community of definitive and intermediate/secondary hosts or vectors, often together with infectious stages in the environment, all of which may represent potential targets, as well as specific challenges, particularly where disease elimination is proposed. Here, we explore, focusing on examples from both human and animal pathogen systems, why and how we should aim to disentangle and quantify the relative importance of multi-host multi-mode infectious agent transmission dynamics under contrasting conditions, and ultimately, how this can be used to help achieve efficient and effective disease control. © 2017 The Authors.


Vara D.,University of Bath | Campanella M.,Royal Veterinary College University of London | Campanella M.,University College London | Pula G.,University of Bath
British Journal of Pharmacology | Year: 2013

Background and Purpose NADPH oxidases (NOXs) contribute to platelet activation by a largely unknown mechanism. Here, we studied the effect of the novel NOX inhibitor 2-acetylphenothiazine (2-APT) on human platelet functional responses and intracellular signaling pathways. Experimental Approach The generation of superoxide ions was assessed by single cell imaging on adhering platelets using dihydroethidium (DHE), while other reactive oxygen species (ROS) were detected with 5-(and-6)-carboxy-2,7-dichlorodihydrofluorescein diacetate (CM-H2-DCFDA). Whole blood thrombus formation, washed platelet aggregation, integrin αIIbβ3 inside-out signalling, Syk phosphorylation and PKC activation were analysed to understand the functional consequences of NOX inhibition by 2-APT in platelets. Key Results Superoxide ion generation stimulated by platelet adhesion on collagen and fibrinogen was significantly inhibited by 2-APT in concentration-dependent manner (IC 50 = 306 nM and 227 nM, respectively), whereas cumulative ROS accumulation was not affected by this pharmacological agent. 2-APT also abolished collagen-dependent whole blood thrombus formation and washed platelet aggregation in response to collagen but not thrombin. The activation of integrin αIIbβ3 and PKC in response to the GPVI-specific agonist collagen-related peptide (CRP) was significantly reduced, whereas the same responses to thrombin were not significantly affected by 2-APT. Finally, Syk activation in response to collagen but not thrombin was inhibited by 2-APT. Conclusions and Implications Taken together, our results suggest that 2-APT attenuates GPVI-specific signalling and is a novel inhibitor of collagen-induced platelet responses. Therefore, NOXs could represent a novel target for the discovery of anti-thrombotic drugs. © 2012 The British Pharmacological Society.


Bomphrey R.J.,Royal Veterinary College University of London | Nakata T.,Royal Veterinary College University of London | Nakata T.,Chiba University | Phillips N.,Royal Veterinary College University of London | Walker S.M.,University of Oxford
Nature | Year: 2017

Mosquitoes exhibit unusual wing kinematics; their long, slender wings flap at remarkably high frequencies for their size (>800 Hz)and with lower stroke amplitudes than any other insect group. This shifts weight support away from the translation-dominated, aerodynamic mechanisms used by most insects, as well as by helicopters and aeroplanes, towards poorly understood rotational mechanisms that occur when pitching at the end of each half-stroke. Here we report free-flight mosquito wing kinematics, solve the full Navier-Stokes equations using computational fluid dynamics with overset grids, and validate our results with in vivo flow measurements. We show that, although mosquitoes use familiar separated flow patterns, much of the aerodynamic force that supports their weight is generated in a manner unlike any previously described for a flying animal. There are three key features: leading-edge vortices (a well-known mechanism that appears to be almost ubiquitous in insect flight), trailing-edge vortices caused by a form of wake capture at stroke reversal, and rotational drag. The two new elements are largely independent of the wing velocity, instead relying on rapid changes in the pitch angle (wing rotation) at the end of each half-stroke, and they are therefore relatively immune to the shallow flapping amplitude. Moreover, these mechanisms are particularly well suited to high aspect ratio mosquito wings. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Pitsillides A.A.,Royal Veterinary College University of London | Beier F.,University of Western Ontario
Nature Reviews Rheumatology | Year: 2011

The cellular and molecular mechanisms responsible for the initiation and progression of osteoarthritis (OA), and in particular cartilage degeneration in OA, are not completely understood. Increasing evidence implicates developmental processes in OA etiology and pathogenesis. Herein, we review this evidence. We first examine subtle changes in cartilage development and the specification and formation of joints, which predispose to OA development, and second, we review the switch from an articular to a hypertrophic chondrocyte phenotype that is thought to be part of the OA pathological process ultimately resulting in cartilage degeneration. The latest studies are summarized and we discuss the concepts emerging from these findings in cartilage biology, in the light of our understanding of the developmental processes involved. © 2011 Macmillan Publishers Limited. All rights reserved.


Allenspach K.,Royal Veterinary College University of London
Veterinary Clinics of North America - Small Animal Practice | Year: 2011

The mucosal immune system is at the forefront of defense against invading pathogens, but at the same time, it must maintain tolerance toward commensals and food antigens in the intestinal lumen. The interplay between the innate immune response and commensal microorganisms is essential to maintaining this balance. Great progress has been made in identifying some of the genetic predispositions underlying inflammatory bowel disease in certain breeds, such as the German shepherd dog. Several immunologic markers are discussed with respect to their clinical usefulness in the diagnosis and management of inflammatory bowel disease. © 2011 Elsevier Inc.


Poulet B.,Royal Veterinary College University of London
Arthritis and rheumatism | Year: 2012

Chronological age is a powerful epidemiologic risk factor for osteoarthritis (OA), a multifactorial disease that is characterized by articular cartilage (AC) degradation. It is unclear from a molecular perspective how aging interacts with OA to produce this risk to AC integrity. To address this key question, we used in vivo time-course analysis of OA development and murine interstrain variability in natural susceptibility to OA to examine changes in non-OA-prone CBA mice versus OA-prone STR/Ort mice, which develop disease that bears significant histologic resemblance to human OA. Through global transcriptome profiling, we attempted to discover the molecular signature linked with both OA vulnerability and progression. Affymetrix Mouse Gene 1.0 ST Array profiles were generated from AC samples derived from CBA and STR/Ort mice at 3 different ages, corresponding to the stages prior to, at, and late after the natural onset of OA in the STR/Ort mice. We found that the OA in STR/Ort mice exhibited a molecular phenotype resembling human OA, and we pinpointed a central role of NF-κB signaling and the emergence of an immune-related signature in OA cartilage over time. We discovered that, strikingly, young healthy AC has a highly expressed skeletal muscle gene expression program, which is switched off during maturation, but is intriguingly retained in AC during OA development in STR/Ort mice. This study is the first to show that AC chondrocytes share a high-abundance gene-expression program with skeletal muscle. We show that failure to switch this program off, as well as the restoration of this program, is associated with inappropriate expression of NF-κB signaling pathways, skeletal muscle-related genes, and induction and/or progression of OA. Copyright © 2012 by the American College of Rheumatology.


Daley M.A.,Royal Veterinary College University of London | Biewener A.A.,Harvard University
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Here, we used an obstacle treadmill experiment to investigate the neuromuscular control of locomotion in uneven terrain. We measured in vivo function of two distal muscles of the guinea fowl, lateral gastrocnemius (LG) and digital flexor-IV (DF), during level running, and two uneven terrains, with 5 and 7 cm obstacles. Uneven terrain required one step onto an obstacle every four to five strides. We compared both perturbed and unperturbed strides in uneven terrain to level terrain. When the bird stepped onto an obstacle, the leg became crouched, both muscles acted at longer lengths and produced greater work, and body height increased. Muscle activation increased on obstacle strides in the LG, but not the DF, suggesting a greater reflex contribution to LG. In unperturbed strides in uneven terrain, swing preactivation of DF increased by 5 per cent compared with level terrain, suggesting feed-forward tuning of leg impedance. Across conditions, the neuromechanical factors in work output differed between the two muscles, probably due to differences in muscle-tendon architecture. LG work depended primarily on fascicle length, whereas DF work depended on both length and velocity during loading. These distal muscles appear to play a critical role in stability by rapidly sensing and responding to altered leg-ground interaction. This journal is © 2011 The Royal Society.


Haddadi H.,Royal Veterinary College University of London
Computer Communication Review | Year: 2010

Online advertising is currently the richest source of revenue for many Internet giants. The increased number of online businesses, specialized websites and modern profiling techniques have all contributed to an explosion of the income of ad brokers from online advertising. The single biggest threat to this growth, is however, click-fraud. Trained botnets and individuals are hired by click-fraud specialists in order to maximize the revenue of certain users from the ads they publish on their websites, or to launch an attack between competing businesses. In this note we wish to raise the awareness of the networking research community on potential research areas within the online advertising field. As an example strategy, we present Bluff ads; a class of ads that join forces in order to increase the effort level for click-fraud spammers. Bluff ads are either targeted ads, with irrelevant display text, or highly relevant display text, with irrelevant targeting information. They act as a litmus test for the legitimacy of the individual clicking on the ads. Together with standard threshold-based methods, fake ads help to decrease click-fraud levels.


Usherwood J.R.,Royal Veterinary College University of London
Biology Letters | Year: 2013

Larger terrestrial animals tend to support their weight with more upright limbs. This makes structural sense, reducing the loading on muscles and bones, which is disproportionately challenging in larger animals. However, it does not account for why smaller animals are more crouched; instead, they could enjoy relatively more slender supporting structures or higher safety factors. Here, an alternative account for the scaling of posture is proposed, with close parallels to the scaling of jump performance. If the costs of locomotion are related to the volume of active muscle, and the active muscle volume required depends on both the work and the power demanded during the push-off phase of each step (not just the net positive work), then the disproportional scaling of requirements for work and push-off power are revealing. Larger animals require relatively greater active muscle volumes for dynamically similar gaits (e.g. top walking speed)-which may present an ultimate constraint to the size of running animals. Further, just as for jumping, animals with shorter legs and briefer push-off periods are challenged to provide the power (not the work) required for push-off. This can be ameliorated by having relatively long push-off periods, potentially accounting for the crouched stance of small animals.


Su D.-M.,University of North Texas Health Science Center | Aw D.,Royal Veterinary College University of London | Palmer D.B.,Royal Veterinary College University of London
Current Opinion in Immunology | Year: 2013

The major function of the immune system is to provide protection against pathogens, in order to prevent infections and potential death. However, with increasing age the immune system undergoes alterations culminating in a progressive deterioration in the ability to respond to infection and vaccination. The precise mechanisms associated with immunosenescence have not been fully elucidated although extensive analyses have suggested that intrinsic defects within immune cells are potentially involved. Despite the stromal niche playing a critical role in the development and activation of immune cells, the role of extrinsic factors within the microenvironment in immunosenescence is less well understood. Moreover, emerging evidence suggests that the aged microenvironment contributes significantly to the age-associated decline of immune function and additionally may offer a potential target for rejuvenating the immune system. Indeed, rejuvenation strategies which have targeted the thymic stromal microenvironment have proved to be successful in recovering thymic function in the aged. © 2013 Elsevier Ltd.

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