Simultaneous determination of wave speed and arrival time of reflected waves using the pressure-velocity loop

This is the post print version of the article. The official published version can be found at the link below.In a previous paper we demonstrated that the linear portion of the pressure–velocity loop (PU-loop) corresponding to early systole could be used to calculate the local wave speed. In this paper we extend this work to show that determination of the time at which the PU-loop first deviates from linearity provides a convenient way to determine the arrival time of reflected waves (Tr). We also present a new technique using the PU-loop that allows for the determination of wave speed and Tr simultaneously. We measured pressure and flow in elastic tubes of different diameters, where a strong reflection site existed at known distances away form the measurement site. We also measured pressure and flow in the ascending aorta of 11 anaesthetised dogs where a strong reflection site was produced through total arterial occlusion at four different sites. Wave speed was determined from the initial slope of the PU-loop and Tr was determined using a new algorithm that detects the sampling point at which the initial linear part of the PU-loop deviates from linearity. The results of the new technique for detecting Tr were comparable to those determined using the foot-to-foot and wave intensity analysis methods. In elastic tubes Tr detected using the new algorithm was almost identical to that detected using wave intensity analysis and foot-to-foot methods with a maximum difference of 2%. Tr detected using the PU-loop in vivo highly correlated with that detected using wave intensity analysis (r 2 = 0.83, P < 0.001). We conclude that the new technique described in this paper offers a convenient and objective method for detecting Tr, and allows for the dynamic determination of wave speed and Tr, simultaneously

Effects of seagrasses and algae of the Caulerpa family on hydrodynamics and particle-trapping rates

The widespread decline of seagrass beds within the Mediterranean often results in the replacement of seagrasses by opportunistic green algae of the Caulerpa family. Because Caulerpa beds have a different height, stiffness and density compared to seagrasses, these changes in habitat type modify the interaction of the seafloor with hydrodynamics, influencing key processes such as sediment resuspension and particle trapping. Here, we compare the effects on hydrodynamics and particle trapping of Caulerpa taxifolia, C. racemosa, and C. prolifera with the Mediterranean seagrasses Cymodocea nodosa and Posidonia oceanica. All macrophyte canopies reduced near-bed volumetric flow rates compared to bare sediment, vertical profiles of turbulent kinetic energy revealed peak values around the top of the canopies, and maximum values of Reynolds stress increased by a factor of between 1.4 (C. nodosa) and 324.1 (P. oceanica) when vegetation was present. All canopies enhanced particle retention rates compared to bare sediment. The experimental C. prolifera canopy was the most effective at particle retention (m2 habitat); however, C. racemosa had the largest particle retention capacity per structure surface area. Hence, in terms of enhancing particle trapping and reducing hydrodynamic forces at the sediment surface, Caulerpa beds provided a similar or enhanced function compared to P.oceanica and C. nodosa. However, strong seasonality in the leaf area index of C. racemosa and C. taxifolia within the Mediterranean, combined with a weak rhizome structure, suggests that sediments maybe unprotected during winter storms, when most erosion occurs. Hence, replacement of seagrass beds with Caulerpa is likely to have a major influence on annual sediment dynamics at ecosystem scales.This research was funded by the European Network of Excellence ‘‘Marine Biodiversity and Ecosystem Function’’ (MarBEF); FP6, EC contract no. 505446 and a grant from the Fundacio ´n BBVA. EPM was supported by a European Union Marie Curie host fellowship for transfer of knowledge, MTKD-CT-2004-509254, the Spanish national project EVAMARIA (CTM2005-00395/MAR) and the regional government of Andalusia project FUNDIV(P07-RNM-2516)

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Owning an overweight or underweight body: distinguishing the physical, experienced and virtual body

Our bodies are the most intimately familiar objects we encounter in our perceptual environment. Virtual reality provides a unique method to allow us to experience having a very different body from our own, thereby providing a valuable method to explore the plasticity of body representation. In this paper, we show that women can experience ownership over a whole virtual body that is considerably smaller or larger than their physical body. In order to gain a better understanding of the mechanisms underlying body ownership, we use an embodiment questionnaire, and introduce two new behavioral response measures: an affordance estimation task (indirect measure of body size) and a body size estimation task (direct measure of body size). Interestingly, after viewing the virtual body from first person perspective, both the affordance and the body size estimation tasks indicate a change in the perception of the size of the participant’s experienced body. The change is biased by the size of the virtual body (overweight or underweight). Another novel aspect of our study is that we distinguish between the physical, experienced and virtual bodies, by asking participants to provide affordance and body size estimations for each of the three bodies separately. This methodological point is important for virtual reality experiments investigating body ownership of a virtual body, because it offers a better understanding of which cues (e.g. visual, proprioceptive, memory, or a combination thereof) influence body perception, and whether the impact of these cues can vary between different setups

Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection

Self-Association of an Activating Natural Killer Cell Receptor, KIR2DS1

As a major component of the innate immune system, natural killer cells are responsible for activating the cytolytic killing of certain pathogen-infected or tumor cells. The self-recognition of natural killer cells is achieved in part by the killer cell immunoglobulin-like receptors (KIRs) protein family. In the current study, using a suite of biophysical methods, we investigate the self-association of an activating KIR, KIR2DS1. This KIR is of particular interest because when in the presence of the HLA-Cw6 protein, KIR2DS1 becomes a major risk factor for psoriasis, an autoimmune chronic skin disease. Using circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, we reveal that KIR2DS1 self-associates in a well-defined fashion. Our novel results on an activating KIR allow us to suggest a working model for the KIR2DS1- HLA class I molecular mechanism

An Outer Membrane Receptor of Neisseria meningitidis Involved in Zinc Acquisition with Vaccine Potential

Since the concentration of free iron in the human host is low, efficient iron-acquisition mechanisms constitute important virulence factors for pathogenic bacteria. In Gram-negative bacteria, TonB-dependent outer membrane receptors are implicated in iron acquisition. It is far less clear how other metals that are also scarce in the human host are transported across the bacterial outer membrane. With the aim of identifying novel vaccine candidates, we characterized in this study a hitherto unknown receptor in Neisseria meningitidis. We demonstrate that this receptor, designated ZnuD, is produced under zinc limitation and that it is involved in the uptake of zinc. Upon immunization of mice, it was capable of inducing bactericidal antibodies and we could detect ZnuD-specific antibodies in human convalescent patient sera. ZnuD is highly conserved among N. meningitidis isolates and homologues of the protein are found in many other Gram-negative pathogens, particularly in those residing in the respiratory tract. We conclude that ZnuD constitutes a promising candidate for the development of a vaccine against meningococcal disease for which no effective universal vaccine is available. Furthermore, the results suggest that receptor-mediated zinc uptake represents a novel virulence mechanism that is particularly important for bacterial survival in the respiratory tract

Differences in avoidable mortality between migrants and the native Dutch in the Netherlands

BACKGROUND: The quality of the healthcare system and its role in influencing mortality of migrant groups can be explored by examining ethnic variations in 'avoidable' mortality. This study investigates the association between the level of mortality from 'avoidable' causes and ethnic origin in the Netherlands and identifies social factors that contribute to this association. METHODS: Data were obtained from cause of death and population registries in the period 1995–2000. We compared mortality rates for selected 'avoidable' conditions for Turkish, Moroccan, Surinamese and Antillean/Aruban groups to native Dutch. RESULTS: We found slightly elevated risk in total 'avoidable' mortality for migrant populations (RR = 1.13). Higher risks of death among migrants were observed from almost all infectious diseases (most RR > 3.00) and several chronic conditions including asthma, diabetes and cerebro-vascular disorders (most RR > 1.70). Migrant women experienced a higher risk of death from maternity-related conditions (RR = 3.37). Surinamese and Antillean/Aruban population had a higher mortality risk (RR = 1.65 and 1.31 respectively), while Turkish and Moroccans experienced a lower risk of death (RR = 0.93 and 0.77 respectively) from all 'avoidable' conditions compared to native Dutch. Control for demographic and socioeconomic factors explained a substantial part of ethnic differences in 'avoidable' mortality. CONCLUSION: Compared to the native Dutch population, total 'avoidable' mortality was slightly elevated for all migrants combined. Mortality risks varied greatly by cause of death and ethnic origin. The substantial differences in mortality for a few 'avoidable' conditions suggest opportunities for quality improvement within specific areas of the healthcare system targeted to disadvantaged groups