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Search Results: 1 - 10 of 225495 matches for " Nick R. Waterfield "
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Diversity of Xenorhabdus and Photorhabdus spp. and Their Symbiotic Entomopathogenic Nematodes from Thailand
Aunchalee Thanwisai,Sarunporn Tandhavanant,Natnaree Saiprom,Nick R. Waterfield,Phan Ke Long,Helge B. Bode,Sharon J. Peacock,Narisara Chantratita
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043835
Abstract: Xenorhabdus and Photorhabdus spp. are bacterial symbionts of entomopathogenic nematodes (EPNs). In this study, we isolated and characterized Xenorhabdus and Photorhabdus spp. from across Thailand together with their associated nematode symbionts, and characterized their phylogenetic diversity. EPNs were isolated from soil samples using a Galleria-baiting technique. Bacteria from EPNs were cultured and genotyped based on recA sequence. The nematodes were identified based on sequences of 28S rDNA and internal transcribed spacer regions. A total of 795 soil samples were collected from 159 sites in 13 provinces across Thailand. A total of 126 EPNs isolated from samples taken from 10 provinces were positive for Xenorhabdus (n = 69) or Photorhabdus spp. (n = 57). Phylogenetic analysis separated the 69 Xenorhabdus isolates into 4 groups. Groups 1, 2 and 3 consisting of 52, 13 and 1 isolates related to X. stockiae, and group 4 consisting of 3 isolates related to X. miraniensis. The EPN host for isolates related to X. stockiae was S. websteri, and for X. miraniensis was S. khoisanae. The Photorhabdus species were identified as P. luminescens (n = 56) and P. asymbiotica (n = 1). Phylogenenic analysis divided P. luminescens into five groups. Groups 1 and 2 consisted of 45 and 8 isolates defined as subspecies hainanensis and akhurstii, respectively. One isolate was related to hainanensis and akhurstii, two isolates were related to laumondii, and one isolate was the pathogenic species P. asymbiotica subsp. australis. H. indica was the major EPN host for Photorhabdus. This study reveals the genetic diversity of Xenorhabdus and Photorhabdus spp. and describes new associations between EPNs and their bacterial symbionts in Thailand.
The Role of TcdB and TccC Subunits in Secretion of the Photorhabdus Tcd Toxin Complex
Guowei Yang,Nicholas R. Waterfield
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003644
Abstract: The Toxin Complex (TC) is a large multi-subunit toxin encoded by a range of bacterial pathogens. The best-characterized examples are from the insect pathogens Photorhabdus, Xenorhabdus and Yersinia. They consist of three large protein subunits, designated A, B and C that assemble in a 5:1:1 stoichiometry. Oral toxicity to a range of insects means that some have the potential to be developed as pest control technology. The three subunit proteins do not encode any recognisable export sequences and as such little progress has been made in understanding their secretion. We have developed heterologous TC production and secretion models in E. coli and used them to ascribe functions to different domains of the crucial B+C sub-complex. We have determined that the B and C subunits use a secretion mechanism that is either encoded by the proteins themselves or employ an as yet undefined system common to laboratory strains of E. coli. We demonstrate that both the N-terminal domains of the B and C subunits are required for secretion of the whole complex. We propose a model whereby the N-terminus of the C-subunit toxin exports the B+C sub-complex across the inner membrane while that of the B-subunit allows passage across the outer membrane. We also demonstrate that even in the absence of the B-subunit, that the C-subunit can also facilitate secretion of the larger A-subunit. The recognition of this novel export system is likely to be of importance to future protein secretion studies. Finally, the identification of homologues of B and C subunits in diverse bacterial pathogens, including Burkholderia and Pseudomonas, suggests that these toxins are likely to be important in a range of different hosts, including man.
The KdpD/KdpE Two-Component System: Integrating K+ Homeostasis and Virulence
Zo? N. Freeman,Steve Dorus,Nicholas R. Waterfield
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003201
Abstract: The two-component system (TCS) KdpD/KdpE, extensively studied for its regulatory role in potassium (K+) transport, has more recently been identified as an adaptive regulator involved in the virulence and intracellular survival of pathogenic bacteria, including Staphylococcus aureus, entero-haemorrhagic Escherichia coli, Salmonella typhimurium, Yersinia pestis, Francisella species, Photorhabdus asymbiotica, and mycobacteria. Key homeostasis requirements monitored by KdpD/KdpE and other TCSs such as PhoP/PhoQ are critical to survival in the stressful conditions encountered by pathogens during host interactions. It follows these TCSs may therefore acquire adaptive roles in response to selective pressures associated with adopting a pathogenic lifestyle. Given the central role of K+ in virulence, we propose that KdpD/KdpE, as a regulator of a high-affinity K+ pump, has evolved virulence-related regulatory functions. In support of this hypothesis, we review the role of KdpD/KdpE in bacterial infection and summarize evidence that (i) KdpD/KdpE production is correlated with enhanced virulence and survival, (ii) KdpE regulates a range of virulence loci through direct promoter binding, and (iii) KdpD/KdpE regulation responds to virulence-related conditions including phagocytosis, exposure to microbicides, quorum sensing signals, and host hormones. Furthermore, antimicrobial stress, osmotic stress, and oxidative stress are associated with KdpD/KdpE activity, and the system's accessory components (which allow TCS fine-tuning or crosstalk) provide links to stress response pathways. KdpD/KdpE therefore appears to be an important adaptive TCS employed during host infection, promoting bacterial virulence and survival through mechanisms both related to and distinct from its conserved role in K+ regulation.
Inactivation of the Antibacterial and Cytotoxic Properties of Silver Ions by Biologically Relevant Compounds
Geraldine Mulley, A. Tobias A. Jenkins, Nicholas R. Waterfield
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094409
Abstract: There has been a recent surge in the use of silver as an antimicrobial agent in a wide range of domestic and clinical products, intended to prevent or treat bacterial infections and reduce bacterial colonization of surfaces. It has been reported that the antibacterial and cytotoxic properties of silver are affected by the assay conditions, particularly the type of growth media used in vitro. The toxicity of Ag+ to bacterial cells is comparable to that of human cells. We demonstrate that biologically relevant compounds such as glutathione, cysteine and human blood components significantly reduce the toxicity of silver ions to clinically relevant pathogenic bacteria and primary human dermal fibroblasts (skin cells). Bacteria are able to grow normally in the presence of silver nitrate at >20-fold the minimum inhibitory concentration (MIC) if Ag+ and thiols are added in a 1:1 ratio because the reaction of Ag+ with extracellular thiols prevents silver ions from interacting with cells. Extracellular thiols and human serum also significantly reduce the antimicrobial activity of silver wound dressings Aquacel-Ag (Convatec) and Acticoat (Smith & Nephew) to Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli in vitro. These results have important implications for the deployment of silver as an antimicrobial agent in environments exposed to biological tissue or secretions. Significant amounts of money and effort have been directed at the development of silver-coated medical devices (e.g. dressings, catheters, implants). We believe our findings are essential for the effective design and testing of antimicrobial silver coatings.
Drosophila Embryos as Model Systems for Monitoring Bacterial Infection in Real Time
Isabella Vlisidou equal contributor,Andrea J. Dowling equal contributor,Iwan R. Evans,Nicholas Waterfield,Richard H. ffrench-Constant,Will Wood
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000518
Abstract: Drosophila embryos are well studied developmental microcosms that have been used extensively as models for early development and more recently wound repair. Here we extend this work by looking at embryos as model systems for following bacterial infection in real time. We examine the behaviour of injected pathogenic (Photorhabdus asymbiotica) and non-pathogenic (Escherichia coli) bacteria and their interaction with embryonic hemocytes using time-lapse confocal microscopy. We find that embryonic hemocytes both recognise and phagocytose injected wild type, non-pathogenic E. coli in a Dscam independent manner, proving that embryonic hemocytes are phagocytically competent. In contrast, injection of bacterial cells of the insect pathogen Photorhabdus leads to a rapid ‘freezing’ phenotype of the hemocytes associated with significant rearrangement of the actin cytoskeleton. This freezing phenotype can be phenocopied by either injection of the purified insecticidal toxin Makes Caterpillars Floppy 1 (Mcf1) or by recombinant E. coli expressing the mcf1 gene. Mcf1 mediated hemocyte freezing is shibire dependent, suggesting that endocytosis is required for Mcf1 toxicity and can be modulated by dominant negative or constitutively active Rac expression, suggesting early and unexpected effects of Mcf1 on the actin cytoskeleton. Together these data show how Drosophila embryos can be used to track bacterial infection in real time and how mutant analysis can be used to genetically dissect the effects of specific bacterial virulence factors.
Clinopyroxene from basaltic rocks of the Erzgebirge - Kru né hory Mts. - implications for modelling the magmatic plumbing system
Rnick R,Renno A
Journal of Geosciences , 2010, DOI: 10.3190/jgeosci.077
Abstract: The Erzgebirge - Kru né hory area is part of the NW flank of the Eger - Oh e Rift. Within this rift-related area, basaltic rocks with low (< 3.5 wt. %) and high contents (> 3.5 wt. %) of TiO2 occur. The distribution of these basaltic rock types shows strong spatial dependency. Ti-rich basalts are concentrated in the western Erzgebirge - Kru né hory Mts. with a sharp change at longitude 13.3 °E. Clinopyroxene and olivine are the most abundant phenocrysts. The zoning and chemistry of the clinopyroxene act as a recorder of the different stages of the magmatic plumbing systems. Seven different types of clinopyroxene phenocrysts are defined with four distinct chemical types: Cr-rich clinopyroxene, green-core pyroxene, Mg-rich clinopyroxene and finely zoned Ti-rich clinopyroxene with sector zoning.
Chemical and petrographic analysis of individual zones within clinopyroxenes allow the qualitative description of distinct steps of the multistage, regionally diverse processes yielding to the formation of both Ti-rich basalts in the W as well as Ti-poor basalts in the E. Two different types of asthenospheric melts are suggested, with increased activities of H2O and potassium in the western Erzgebirge Mts. During ascent they incorporated xenoliths and xenocrysts both of the mantle (peridotite, olivine and Cr-rich clinopyroxene) and the crustal (granitic and gneissic rocks, quartz and feldspar) origin. Furthermore, green cores of clinopyroxene were introduced into the magmas. Fractionation processes took place within lithospheric magma chambers, having been accompanied by reaction of xenocrysts and xenoliths with the melt. The residence time in the magma chambers associated with the eastern and western part of the Erzgebirge appears to have been totally different: short in the eastern and long in the western parts. Within the latter, no mantle-derived xenoliths, xenocrysts, or magmatic olivines are found. It is inferred that these xenoliths and crystals settled to the bottom of the magma chambers forming cumulates and therefore did not come to the surface. In contrast, the basaltic rocks of the East still contain mantle-derived xenoliths and xenocrysts as well as magmatic olivine. The size and amount of clinopyroxene phenocrysts in the West significantly exceed that of the East. Moreover, the crystallization of giant clinopyroxenes was restricted to the West. Mixing of the magmas with Ti-rich melts, presumably derived from eclogitic source, took place in crustal magma chambers. In any case, the proportion of Ti-rich melts in the West signifi
Gene therapy for carcinoma of the breast: Genetic toxins
Georges Vassaux, Nick R Lemoine
Breast Cancer Research , 1999, DOI: 10.1186/bcr25
Abstract: The first demonstration of the use of controlled expression of an exogenous gene encoding a toxin as a mean of killing cancer cells was described in 1986 [1]. In those experiments, a direct suicide gene (the diphtheria toxin A chain) was used. Extrapolated to a clinical scenario, the use of such a potent genetic toxin (a single diphtheria toxin A chain molecule is capable of killing a cell) would require efficient and very reliable selective targeting of cancer cells. This targeting can be achieved by targeted delivery [2] or by transcriptional targeting [3]. For breast cancer gene therapy, a few promoters have already been used to drive the expression of genetic toxins (Table 1). With current tools, however, accurate targeting cannot be achieved. To accommodate these safety issues, a whole branch of cancer gene therapy has been dedicated to the design of more controllable and specific genetic toxins. These new 'suicide' genes can be classified into two groups: the metabolic suicide genes and the dominant-negative class of suicide genes. This review describes the rationale of these suicide systems and presents their potential applications in breast cancer therapies.This strategy relies upon intracellular conversion of a relatively nontoxic prodrug into a toxic drug by an enzyme of xenobiotic origin, and has been referred to as genetic prodrug activation therapy (GPAT). Plant, fungi, bacteria and viruses often utilize unique metabolic pathways that are adapted to their life cycles and environments. These metabolic routes are not used by mammalian cells. In the case of pathogen infections, the distinctive enzymes responsible for these functions have been the target of prodrugs that are developed to be selectively metabolized in infected cells, leading to their destruction. This process is selective, because the prodrug is not toxic to healthy, uninfected mammalian cells.The transfer of the genes encoding these enzymes to mammalian cells is sufficient to confer sensiti
Triviality and the Precision Bound on the Higgs Mass
R. Sekhar Chivukula,Nick Evans
Physics , 1999, DOI: 10.1016/S0370-2693(99)00972-7
Abstract: The triviality of the scalar sector of the standard one-doublet Higgs model implies that this model is only an effective low-energy theory valid below some cut-off scale Lambda. For a heavy higgs this scale must be relatively low (10 TeV or less). Additional interactions coming from the underlying theory, and suppressed by the scale Lambda, give rise to model-dependent corrections to precisely measured electroweak quantities. Dimension six operators arising from the underlying physics naturally contribute to the S and T parameters, and their effects should be included in a global fit to the precision data that determines any limit on the Higgs mass. Using dimensional analysis, we estimate the expected size of these corrections in a custodially-symmetric strongly-interacting underlying theory. Taking these operators' coefficients to be of natural size gives sufficiently large contributions to the T parameter to reconcile Higgs masses as large as 400-500 GeV with the precision data.
Perfect commuting graphs
John R. Britnell,Nick Gill
Mathematics , 2013,
Abstract: We classify the finite quasisimple groups whose commuting graph is perfect and we give a general structure theorem for finite groups whose commuting graph is perfect.
Pdl1 Is a Putative Lipase that Enhances Photorhabdus Toxin Complex Secretion
Guowei Yang,Carmen Sara Hernández-Rodríguez,Michael L. Beeton,Paul Wilkinson,Richard H. ffrench-Constant,Nicholas R. Waterfield
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002692
Abstract: The Toxin Complex (TC) is a large multi-subunit toxin first characterized in the insect pathogens Photorhabdus and Xenorhabdus, but now seen in a range of pathogens, including those of humans. These complexes comprise three protein subunits, A, B and C which in the Xenorhabdus toxin are found in a 4:1:1 stoichiometry. Some TCs have been demonstrated to exhibit oral toxicity to insects and have the potential to be developed as a pest control technology. The lack of recognisable signal sequences in the three large component proteins hinders an understanding of their mode of secretion. Nevertheless, we have shown the Photorhabdus luminescens (Pl) Tcd complex has been shown to associate with the bacteria's surface, although some strains can also release it into the surrounding milieu. The large number of tc gene homologues in Pl make study of the export process difficult and as such we have developed and validated a heterologous Escherichia coli expression model to study the release of these important toxins. In addition to this model, we have used comparative genomics between a strain that releases high levels of Tcd into the supernatant and one that retains the toxin on its surface, to identify a protein responsible for enhancing secretion and release of these toxins. This protein is a putative lipase (Pdl1) which is regulated by a small tightly linked antagonist protein (Orf53). The identification of homologues of these in other bacteria, linked to other virulence factor operons, such as type VI secretion systems, suggests that these genes represent a general and widespread mechanism for enhancing toxin release in Gram negative pathogens.
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