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Search Results: 1 - 10 of 466491 matches for " Susan A Joyce "
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Identification of genes involved in the mutualistic colonization of the nematode Heterorhabditis bacteriophora by the bacterium Photorhabdus luminescens
Catherine A Easom, Susan A Joyce, David J Clarke
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-45
Abstract: In this work we genetically tagged P. luminescens TT01 with gfp and constructed a library containing over 3200 mutants using the suicide vector, pUT-Km2. Using a combination of in vitro symbiosis assays and fluorescent microscopy we screened this library for mutants that were affected in their ability to colonize the IJ i.e. with decreased transmission frequencies. In total 8 mutants were identified with transmission frequencies of ≤ 30% compared to wild-type. These mutants were mapped to 6 different genetic loci; the pbgPE operon, galE, galU, proQ, asmA and hdfR. The pbgPE, galE and galU mutants were all predicted to be involved in LPS biosynthesis and, in support of this, we have shown that these mutants are avirulent and sensitive to the cationic antimicriobial peptide, polymyxin B. On the other hand the proQ, asmA and hdfR mutants were not affected in virulence and were either as resistant (proQ) or slightly more sensitive (asmA, hdfR) to polymyxin B than the wild-type (WT).This is the first report describing the outcome of a comprehensive screen looking for transmission mutants in Photorhabdus. In total 6 genetic loci were identified and we present evidence that all of these loci are involved in the assembly and/or maintenance of LPS and other factors associated with the cell surface. Interestingly several, but not all, of the transmission mutants identified were also avirulent suggesting that there is a significant, but not complete, genetic overlap between pathogenicity and mutualism. Therefore, this study highlights the importance of the cell surface in mediating the symbiotic and pathogenic interactions of Photorhabdus.Photorhabdus are a genus of bioluminescent, entomopathogenic bacteria that are members of the family Enterobacteriaceae and are thus closely related to Escherichia coli and other important mammalian pathogens. As part of their normal life-cycle Photorhabdus also have a mutualistic interaction with nematodes from the family Heterorhabditis (fo
Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-kappaB-dependent pathway
Susan ZY Lo, James H Steer, David A Joyce
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3248
Abstract: Caspase-3 activity, annexin-V binding/7-aminoactinomycin D (7-AAD) exclusion and cell-cycle analysis were used to measure steps in apoptosis of primary murine macrophages and cells of the RAW264.7 macrophage cell line that had been exposed to clinically-relevant concentrations of MTX and TNF-α.MTX induces apoptosis in primary murine macrophages at concentrations as low as 100 nM in vitro. TNF-α, which has a context-dependent ability to increase or to suppress apoptosis, efficiently suppresses MTX-induced macrophage apoptosis. This depends on NF-κB signaling, initiated through TNF Receptor Type 1 ligation. Macrophage colony stimulating factor, the primary macrophage survival and differentiation factor, does not activate NF-κB or protect macrophages from MTX-induced apoptosis. A weak NF-κB activator, Receptor Activator of NF-κB Ligand (RANKL) is likewise ineffective. Blocking NF-κB in TNF-α-exposed macrophages allowed pro-apoptotic actions of TNF-α to dominate, even in the absence of MTX. MTX itself does not promote apoptosis through interference with NF-κB signaling.These findings provide another mechanism by which TNF-α sustains macrophage numbers in inflamed tissue and identify a further point of clinical complementarity between MTX and anti-TNF-α treatments for rheumatoid arthritis.Synovial inflammatory macrophages have a central role in maintaining disease activity in rheumatoid arthritis (RA). Macrophage numbers in tissue are regulated by recruitment, local proliferation, local cell death and emigration to draining lymph nodes [1,2]. Synovial macrophage apoptosis has also been observed in synovium in RA [3,4]. A suppressed rate of apoptosis would contribute to maintaining inflammatory macrophage numbers, and thus clinical activity, in macrophage-dependent conditions. An enhanced rate of synovial macrophage apoptosis is reported in RA patients responding to anti-TNF-α treatments [4] as a delayed, rather than an early phenomenon [5]. Macrophage apoptosis has also
The role of iron uptake in pathogenicity and symbiosis in Photorhabdus luminescens TT01
Robert J Watson, Peter Millichap, Susan A Joyce, Stuart Reynolds, David J Clarke
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-177
Abstract: We constructed targeted deletion mutants of exbD, feoABC and yfeABCD in P. luminescens TT01. The exbD mutant was predicted to be crippled in its ability to obtain Fe3+ and we show that this mutant does not grow well in iron-limited media. We also show that this mutant was avirulent to the insect but was unaffected in its symbiotic interaction with Heterorhabditis. Furthermore we show that a mutation in feoABC (encoding a predicted Fe2+ permease) was unaffected in both virulence and symbiosis whilst the divalent cation transporter encoded by yfeABCD is required for virulence in the Tobacco Hornworm, Manduca sexta (Lepidoptera) but not in the Greater Wax Moth, Galleria mellonella (Lepidoptera). Moreover the Yfe transporter also appears to have a role during colonization of the IJ stage of the nematode.In this study we show that iron uptake (via the TonB complex and the Yfe transporter) is important for the virulence of P. luminescens to insect larvae. Moreover this study also reveals that the Yfe transporter appears to be involved in Mn2+-uptake during growth in the gut lumen of the IJ nematode. Therefore, the Yfe transporter in P. luminescens TT01 is important during colonization of both the insect and nematode and, moreover, the metal ion transported by this pathway is host-dependent.Photorhabdus is a genus of Gram negative bioluminescent bacteria that are members of the Enterobacteriaceae and are therefore close relatives of important mammalian pathogens such as Escherichia coli and Salmonella. Photorhabdus have a complex life-style that involves a pathogenic interaction with insect larvae and a mutualistic interaction with nematodes from the family Heterorhabditis (for recent reviews see [1,2]). The bacteria can be normally found colonizing the gut of the infective juvenile (IJ) stage of the nematode. The IJ is a free-living, soil-dwelling stage of the nematode whose role is to seek out and infect susceptible insect larvae. Once inside the insect the IJ regurgitat
Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for glial and neural-related molecules in central nervous system mixed glial cell cultures: neurotrophins, growth factors and structural proteins
Robert P Lisak, Joyce A Benjamins, Beverly Bealmear, Liljana Nedelkoska, Bin Yao, Susan Land, Diane Studzinski
Journal of Neuroinflammation , 2007, DOI: 10.1186/1742-2094-4-30
Abstract: To examine changes in gene expression that might occur in glial cells exposed to the secreted products of immune cells, we have used gene array analysis to assess the early effects of different cytokine mixtures on mixed CNS glia in culture. We compared the effects of cytokines typical of Th1 and Th2 lymphocytes and monocyte/macrophages (M/M) on CNS glia after 6 hours of treatment.In this paper we focus on changes with potential relevance for neuroprotection and axon/glial interactions. Each mixture of cytokines induced a unique pattern of changes in genes for neurotrophins, growth and maturation factors and related receptors; most notably an alternatively spliced form of trkC was markedly downregulated by Th1 and M/M cytokines, while Th2 cytokines upregulated BDNF. Genes for molecules of potential importance in axon/glial interactions, including cell adhesion molecules, connexins, and some molecules traditionally associated with neurons showed significant changes, while no genes for myelin-associated genes were regulated at this early time point. Unexpectedly, changes occurred in several genes for proteins initially associated with retina, cancer or bone development, and not previously reported in glial cells.Each of the three cytokine mixtures induced specific changes in gene expression that could be altered by pharmacologic strategies to promote protection of the central nervous system.The pathogenesis of lesions in the central nervous system (CNS) of patients with multiple sclerosis (MS) represents the end product of several immune processes. Secretion of cytokines by infiltrating inflammatory cells as well as by endogenous glia contributes directly and indirectly to the pathogenesis of the MS lesions [1,2]. Whether the initial lesions in CNS white matter affect oligodendrocytes [3] or activated microglia in normal appearing white matter (NAWM) [4] is still not clear, but inflammatory cells are part of active and chronic active lesions, the type I and II lesions
A Mariner Transposon-Based Signature-Tagged Mutagenesis System for the Analysis of Oral Infection by Listeria monocytogenes
Joanne Cummins, Pat G. Casey, Susan A. Joyce, Cormac G. M. Gahan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075437
Abstract: Listeria monocytogenes is a Gram-positive foodborne pathogen and the causative agent of listerosis a disease that manifests predominately as meningitis in the non-pregnant individual or infection of the fetus and spontaneous abortion in pregnant women. Common-source outbreaks of foodborne listeriosis are associated with significant morbidity and mortality. However, relatively little is known concerning the mechanisms that govern infection via the oral route. In order to aid functional genetic analysis of the gastrointestinal phase of infection we designed a novel signature-tagged mutagenesis (STM) system based upon the invasive L. monocytogenes 4b serotype H7858 strain. To overcome the limitations of gastrointestinal infection by L. monocytogenes in the mouse model we created a H7858 strain that is genetically optimised for oral infection in mice. Furthermore our STM system was based upon a mariner transposon to favour numerous and random transposition events throughout the L. monocytogenes genome. Use of the STM bank to investigate oral infection by L. monocytogenes identified 21 insertion mutants that demonstrated significantly reduced potential for infection in our model. The sites of transposon insertion included lmOh7858_0671 (encoding an internalin homologous to Lmo0610), lmOh7858_0898 (encoding a putative surface-expressed LPXTG protein homologous to Lmo0842), lmOh7858_2579 (encoding the HupDGC hemin transport system) and lmOh7858_0399 (encoding a putative fructose specific phosphotransferase system). We propose that this represents an optimised STM system for functional genetic analysis of foodborne/oral infection by L. monocytogenes.
Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome
Joyce Villanueva, Susan Lee, Edward H Giannini, Thomas B Graham, Murray H Passo, Alexandra Filipovich, Alexei A Grom
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1453
Abstract: The term 'macrophage activation syndrome' (MAS) in pediatric rheumatology refers to a set of symptoms caused by the excessive activation and proliferation of T cells and well-differentiated macrophages [1-4]. This activation leads to an overwhelming inflammatory reaction that can be fatal. The pathognomonic features of this syndrome are found in bone marrow aspirates: numerous, well-differentiated macrophages (or histiocytes) actively phagocytosing hematopoietic elements. Although MAS has been increasingly recognized in association with almost any rheumatic disease, it is by far most common in the systemic form of juvenile rheumatoid arthritis (JRA) [1,5-11].Clinically, MAS has strong similarities to familial hemophagocytic lymphohistiocytosis (FHLH) and virus-associated or reactive hemophagocytic lymphohistiocytosis (HLH) [2-4]. The immune abnormalities in the familial form of HLH have been studied extensively, and the most consistent finding has been global impairment of cytotoxic lymphocyte and natural killer (NK) cell function [12-14]. In about 50% of patients with FHLH in North America, these immunologic abnormalities are secondary to mutations in the gene encoding perforin, a protein that mediates the cytotoxic activity of NK and T cells [15]. Although it has been proposed that abnormal cytotoxic cells might fail to provide appropriate apoptotic signals for the removal of activated macrophages and T-cells after infection is cleared [16], the exact pathways that would link the decreased NK and cytotoxic T cell function with macrophage expansion have not been confirmed.We have previously reported that, as in HLH, NK function is profoundly depressed in the vast majority of patients with MAS [17] suggesting that this immunologic abnormality might be relevant to the pathogenesis of the syndrome. In the present study we sought to assess the extent of NK dysfunction in the most common rheumatic disease of childhood, JRA.JRA is a chronic, idiopathic, inflammatory diso
Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures
Robert P Lisak, Joyce A Benjamins, Beverly Bealmear, Liljana Nedelkoska, Diane Studzinski, Ernest Retland, Bin Yao, Susan Land
Journal of Neuroinflammation , 2009, DOI: 10.1186/1742-2094-6-4
Abstract: We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M).In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1) seen at 6 hours with microarray.Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter signaling in glia.Genomic analysis has been applied to investigate changes occurring in the central nervous system (CNS) in multiple sclerosis (MS). These include analyses of acute and chronic active lesions, lesions from patients at different stages of MS, an
Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study
Maureen S. Durkin,Matthew J. Maenner,F. John Meaney,Susan E. Levy,Carolyn DiGuiseppi,Joyce S. Nicholas,Russell S. Kirby,Jennifer A. Pinto-Martin,Laura A. Schieve
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011551
Abstract: This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES).
Molecular Mechanisms of Mouse Skin Tumor Promotion
Joyce E. Rundhaug,Susan M. Fischer
Cancers , 2010, DOI: 10.3390/cancers2020436
Abstract: Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-α and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion.
Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma
Cristiane A Dalla-Torre, Maisa Yoshimoto, Chung-Hae Lee, Anthony M Joshua, Silvia RC de Toledo, Ant?nio S Petrilli, Joyce AD Andrade, Susan Chilton-MacNeill, Maria Zielenska, Jeremy A Squire
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-237
Abstract: In this study, we used pathway-focused low density expression cDNA arrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on osteosarcoma patient tumor samples and correlated with clinical and pathological data.THBS3, SPARC and SPP1 were identified as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p = 0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51/55 (96.3%) osteosarcoma samples derived from 43 patients, and correlated with the worst event-free survival (p = 0.03) and relapse free survival (p = 0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis.In this study three genes were identified with pattern of differential gene expression associated with a phenotypic role in metastasis and invasion. Interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker.Osteosarcoma (OS) is a rare tumor of children and young adults. The peak of incidence occurs in the second decade of life [1]. In Brazil, it is estimated that a total of 350 new cases of OS are diagnosed per ye
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