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Search Results: 1 - 10 of 365258 matches for " Michael S. Gilmore "
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Structure, Function, and Biology of the Enterococcus faecalis Cytolysin
Daria Van Tyne,Melissa J. Martin,Michael S. Gilmore
Toxins , 2013, DOI: 10.3390/toxins5050895
Abstract: Enterococcus faecalis is a Gram-positive commensal member of the gut microbiota of a wide range of organisms. With the advent of antibiotic therapy, it has emerged as a multidrug resistant, hospital-acquired pathogen. Highly virulent strains of E. faecalis express a pore-forming exotoxin, called cytolysin, which lyses both bacterial and eukaryotic cells in response to quorum signals. Originally described in the 1930s, the cytolysin is a member of a large class of lanthionine-containing bacteriocins produced by Gram-positive bacteria. While the cytolysin shares some core features with other lantibiotics, it possesses unique characteristics as well. The current understanding of cytolysin biosynthesis, structure/function relationships, and contribution to the biology of E. faecalis are reviewed, and opportunities for using emerging technologies to advance this understanding are discussed.
Genetic Diversity among Enterococcus faecalis
Shonna M. McBride, Vincent A. Fischetti, Donald J. LeBlanc, Robert C. Moellering, Michael S. Gilmore
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000582
Abstract: Enterococcus faecalis, a ubiquitous member of mammalian gastrointestinal flora, is a leading cause of nosocomial infections and a growing public health concern. The enterococci responsible for these infections are often resistant to multiple antibiotics and have become notorious for their ability to acquire and disseminate antibiotic resistances. In the current study, we examined genetic relationships among 106 strains of E. faecalis isolated over the past 100 years, including strains identified for their diversity and used historically for serotyping, strains that have been adapted for laboratory use, and isolates from previously described E. faecalis infection outbreaks. This collection also includes isolates first characterized as having novel plasmids, virulence traits, antibiotic resistances, and pathogenicity island (PAI) components. We evaluated variation in factors contributing to pathogenicity, including toxin production, antibiotic resistance, polymorphism in the capsule (cps) operon, pathogenicity island (PAI) gene content, and other accessory factors. This information was correlated with multi-locus sequence typing (MLST) data, which was used to define genetic lineages. Our findings show that virulence and antibiotic resistance traits can be found within many diverse lineages of E. faecalis. However, lineages have emerged that have caused infection outbreaks globally, in which several new antibiotic resistances have entered the species, and in which virulence traits have converged. Comparing genomic hybridization profiles, using a microarray, of strains identified by MLST as spanning the diversity of the species, allowed us to identify the core E. faecalis genome as consisting of an estimated 2057 unique genes.
A Metalloproteinase Secreted by Streptococcus pneumoniae Removes Membrane Mucin MUC16 from the Epithelial Glycocalyx Barrier
Bharathi Govindarajan, Balaraj B. Menon, Sandra Spurr-Michaud, Komal Rastogi, Michael S. Gilmore, Pablo Argüeso, Ilene K. Gipson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032418
Abstract: The majority of bacterial infections occur across wet-surfaced mucosal epithelia, including those that cover the eye, respiratory tract, gastrointestinal tract and genitourinary tract. The apical surface of all these mucosal epithelia is covered by a heavily glycosylated glycocalyx, a major component of which are membrane-associated mucins (MAMs). MAMs form a barrier that serves as one of the first lines of defense against invading bacteria. While opportunistic bacteria rely on pre-existing defects or wounds to gain entry to epithelia, non opportunistic bacteria, especially the epidemic disease-causing ones, gain access to epithelial cells without evidence of predisposing injury. The molecular mechanisms employed by these non opportunistic pathogens to breach the MAM barrier remain unknown. To test the hypothesis that disease-causing non opportunistic bacteria gain access to the epithelium by removal of MAMs, corneal, conjunctival, and tracheobronchial epithelial cells, cultured to differentiate to express the MAMs, MUCs 1, 4, and 16, were exposed to a non encapsulated, non typeable strain of Streptococcus pneumoniae (SP168), which causes epidemic conjunctivitis. The ability of strain SP168 to induce MAM ectodomain release from epithelia was compared to that of other strains of S. pneumoniae, as well as the opportunistic pathogen Staphylococcus aureus. The experiments reported herein demonstrate that the epidemic disease-causing S. pneumoniae species secretes a metalloproteinase, ZmpC, which selectively induces ectodomain shedding of the MAM MUC16. Furthermore, ZmpC-induced removal of MUC16 from the epithelium leads to loss of the glycocalyx barrier function and enhanced internalization of the bacterium. These data suggest that removal of MAMs by bacterial enzymes may be an important virulence mechanism employed by disease-causing non opportunistic bacteria to gain access to epithelial cells to cause infection.
Staphylococcus aureus Activates the NLRP3 Inflammasome in Human and Rat Conjunctival Goblet Cells
Victoria E. McGilligan, Meredith S. Gregory-Ksander, Dayu Li, Jonathan E. Moore, Robin R. Hodges, Michael S. Gilmore, Tara C. B. Moore, Darlene A. Dartt
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074010
Abstract: The conjunctiva is a moist mucosal membrane that is constantly exposed to an array of potential pathogens and triggers of inflammation. The NACHT, leucine rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) is a Nod-like receptor that can sense pathogens or other triggers, and is highly expressed in wet mucosal membranes. NLRP3 is a member of the multi-protein complex termed the NLRP3 inflammasome that activates the caspase 1 pathway, inducing the secretion of biologically active IL-1β, a major initiator and promoter of inflammation. The purpose of this study was to: (1) determine whether NLRP3 is expressed in the conjunctiva and (2) determine whether goblet cells specifically contribute to innate mediated inflammation via secretion of IL-1β. We report that the receptors known to be involved in the priming and activation of the NLRP3 inflammasome, the purinergic receptors P2X4 and P2X7 and the bacterial Toll-like receptor 2 are present and functional in conjunctival goblet cells. Toxin-containing Staphylococcus aureus (S. aureus), which activates the NLRP3 inflammasome, increased the expression of the inflammasome proteins NLRP3, ASC and pro- and mature caspase 1 in conjunctival goblet cells. The biologically active form of IL-1β was detected in goblet cell culture supernatants in response to S. aureus, which was reduced when the cells were treated with the caspase 1 inhibitor Z-YVAD. We conclude that the NLRP3 inflammasome components are present in conjunctival goblet cells. The NRLP3 inflammasome appears to be activated in conjunctival goblet cells by toxin-containing S. aureus via the caspase 1 pathway to secrete mature IL1-β. Thus goblet cells contribute to the innate immune response in the conjunctiva by activation of the NLRP3 inflammasome.
GAIA: Origin and Evolution of the Milky Way
Gerry Gilmore,Michael Perryman,L Lindegren,F Favata,E Hoeg,M Lattanzi,X Luri,F Mignard,S Roeser,P. T. deZeeuw
Physics , 1998, DOI: 10.1117/12.317134
Abstract: GAIA is a short-listed candidate for the ESA Cornerstone mission C5, meeting the ESA Survey Committee requirement for an observatory mission, dedicated to astrometry, providing 10 micro-arcsecond accuracy at 15th magnitude. The GAIA mission concept follows the dramatic success of the ESA HIPPARCOS mission, utilising a continuously scanning spacecraft, accurately measuring 1-D coordinates along great circles, in (at least) two simultaneous fields of view, separated by a known angle. These 1-D relative coordinates are later converted to the five astrometric parameters of position and motions in a global analysis. GAIA will provide precise astrometry and multi-colour photometry for all the one billion stars, quasars, and compact galaxies to I=20 on the sky. GAIA will additionally provide the sixth phase-space parameter, radial velocity, from a slitless spectroscopic survey of most stars brighter than about magnitude 17. The technical challenges are considerable, but achievable. The scientific returns are spectacular, with greatest impact in the study of stellar populations and dynamical structure of the galaxies of our Local Group, and in providing the first complete census of the stars and massive planets in the Solar neighbourhood. GAIA will revolutionise our knowledge of the origin and evolution of our Milky Way Galaxy, and of the distribution of planetary systems around other stars.
Photodynamic and Antibiotic Therapy Impair the Pathogenesis of Enterococcus faecium in a Whole Animal Insect Model
José Chibebe Junior, Beth B. Fuchs, Caetano P. Sabino, Juliana C. Junqueira, Antonio O. C. Jorge, Martha S. Ribeiro, Michael S. Gilmore, Louis B. Rice, George P. Tegos, Michael R. Hamblin, Eleftherios Mylonakis
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055926
Abstract: Enterococcus faecium has emerged as one of the most important pathogens in healthcare-associated infections worldwide due to its intrinsic and acquired resistance to many antibiotics, including vancomycin. Antimicrobial photodynamic therapy (aPDT) is an alternative therapeutic platform that is currently under investigation for the control and treatment of infections. PDT is based on the use of photoactive dye molecules, widely known as photosensitizer (PS). PS, upon irradiation with visible light, produces reactive oxygen species that can destroy lipids and proteins causing cell death. We employed Galleria mellonella (the greater wax moth) caterpillar fatally infected with E. faecium to develop an invertebrate host model system that can be used to study the antimicrobial PDT (alone or combined with antibiotics). In the establishment of infection by E. faecium in G. mellonella, we found that the G. mellonella death rate was dependent on the number of bacterial cells injected into the insect hemocoel and all E. faecium strains tested were capable of infecting and killing G. mellonella. Antibiotic treatment with ampicillin, gentamicin or the combination of ampicillin and gentamicin prolonged caterpillar survival infected by E. faecium (P = 0.0003, P = 0.0001 and P = 0.0001, respectively). In the study of antimicrobial PDT, we verified that methylene blue (MB) injected into the insect followed by whole body illumination prolonged the caterpillar survival (P = 0.0192). Interestingly, combination therapy of larvae infected with vancomycin-resistant E. faecium, with antimicrobial PDT followed by vancomycin, significantly prolonged the survival of the caterpillars when compared to either antimicrobial PDT (P = 0.0095) or vancomycin treatment alone (P = 0.0025), suggesting that the aPDT made the vancomycin resistant E. faecium strain more susceptible to vancomycin action. In summary, G. mellonella provides an invertebrate model host to study the antimicrobial PDT and to explore combinatorial aPDT-based treatments.
Caged black hole thermodynamics: Charge, the extremal limit, and finite size effects
James B. Gilmore,Andreas Ross,Michael Smolkin
Physics , 2009, DOI: 10.1088/1126-6708/2009/09/104
Abstract: We extend the effective field theory treatment of the thermodynamics of small compactified black holes to the case of charged black holes. The relevant thermodynamic quantities are computed to second order in the parameter \lambda\sim(r_0/L)^(d-3). We discuss how the addition of charge to a caged black hole may delay the phase transition to a black string. In the extremal limit, we construct an exact black hole solution which serves as a check for our perturbative results. Finite size effects are also included through higher order operators in the worldline action. We calculate how the thermodynamic quantities are modified in the presence of these operators, and show they enter beyond order \lambda^2 as in the uncharged case. Finally, we use the exact solution to constrain the Wilson coefficients of the finite size operators in the extremal limit.
Persisting Viral Sequences Shape Microbial CRISPR-based Immunity
Ariel D. Weinberger ? ,Christine L. Sun ?,Mateusz M. Pluciński,Vincent J. Denef,Brian C. Thomas,Philippe Horvath,Rodolphe Barrangou,Michael S. Gilmore,Wayne M. Getz,Jillian F. Banfield
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002475
Abstract: Well-studied innate immune systems exist throughout bacteria and archaea, but a more recently discovered genomic locus may offer prokaryotes surprising immunological adaptability. Mediated by a cassette-like genomic locus termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), the microbial adaptive immune system differs from its eukaryotic immune analogues by incorporating new immunities unidirectionally. CRISPR thus stores genomically recoverable timelines of virus-host coevolution in natural organisms refractory to laboratory cultivation. Here we combined a population genetic mathematical model of CRISPR-virus coevolution with six years of metagenomic sequencing to link the recoverable genomic dynamics of CRISPR loci to the unknown population dynamics of virus and host in natural communities. Metagenomic reconstructions in an acid-mine drainage system document CRISPR loci conserving ancestral immune elements to the base-pair across thousands of microbial generations. This ‘trailer-end conservation’ occurs despite rapid viral mutation and despite rapid prokaryotic genomic deletion. The trailer-ends of many reconstructed CRISPR loci are also largely identical across a population. ‘Trailer-end clonality’ occurs despite predictions of host immunological diversity due to negative frequency dependent selection (kill the winner dynamics). Statistical clustering and model simulations explain this lack of diversity by capturing rapid selective sweeps by highly immune CRISPR lineages. Potentially explaining ‘trailer-end conservation,’ we record the first example of a viral bloom overwhelming a CRISPR system. The polyclonal viruses bloom even though they share sequences previously targeted by host CRISPR loci. Simulations show how increasing random genomic deletions in CRISPR loci purges immunological controls on long-lived viral sequences, allowing polyclonal viruses to bloom and depressing host fitness. Our results thus link documented patterns of genomic conservation in CRISPR loci to an evolutionary advantage against persistent viruses. By maintaining old immunities, selection may be tuning CRISPR-mediated immunity against viruses reemerging from lysogeny or migration.
Drosophila Host Model Reveals New Enterococcus faecalis Quorum-Sensing Associated Virulence Factors
Neuza Teixeira, Sriram Varahan, Matthew J. Gorman, Kelli L. Palmer, Anna Zaidman-Remy, Ryoji Yokohata, Jiro Nakayama, Lynn E. Hancock, António Jacinto, Michael S. Gilmore, Maria de Fátima Silva Lopes
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064740
Abstract: Enterococcus faecalis V583 is a vancomycin-resistant clinical isolate which belongs to the hospital-adapted clade, CC2. This strain harbours several factors that have been associated with virulence, including the fsr quorum-sensing regulatory system that is known to control the expression of GelE and SprE proteases. To discriminate between genes directly regulated by Fsr, and those indirectly regulated as the result of protease expression or activity, we compared gene expression in isogenic mutants of V583 variously defective in either Fsr quorum sensing or protease expression. Quorum sensing was artificially induced by addition of the quorum signal, GBAP, exogenously in a controlled manner. The Fsr regulon was found to be restricted to five genes, gelE, sprE, ef1097, ef1351 and ef1352. Twelve additional genes were found to be dependent on the presence of GBAP-induced proteases. Induction of GelE and SprE by GBAP via Fsr resulted in accumulation of mRNA encoding lrgAB, and this induction was found to be lytRS dependent. Drosophila infection was used to discern varying levels of toxicity stemming from mutations in the fsr quorum regulatory system and the genes that it regulates, highlighting the contribution of LrgAB and bacteriocin EF1097 to infection toxicity. A contribution of SprE to infection toxicity was also detected. This work brought to light new players in E. faecalis success as a pathogen and paves the way for future studies on host tolerance mechanisms to infections caused by this important nosocomial pathogen.
The Kinematics, Orbit, and Survival of the Sagittarius Dwarf Spheroidal Galaxy
Rodrigo Ibata,Rosemary Wyse,Gerard Gilmore,Michael Irwin,Nicholas Suntzeff
Physics , 1996, DOI: 10.1086/118283
Abstract: The Sagittarius galaxy (Sgr), the closest satellite galaxy of the Milky Way, has survived for many orbits about the Galaxy. Extant numerical calculations modeled this galaxy as a system with a centrally-concentrated mass profile, following the light, and found that it should lose more than one-half of its mass every 2--4 orbits and be completely disrupted long before now. Apparently Sgr, and by implication other dSph galaxies, do not have a centrally-concentrated profile for their dark matter. We develop a model in which the stars of the Sgr dwarf are embedded in a constant-density dark matter halo, representing the core of a tidally-limited system, and show that this is consistent with its survival. We present new photometric and kinematic observations of Sgr and show these data are consistent with this explanation for the continued existence of this galaxy. Sgr is being tidally distorted and is tidally limited, but is not disrupted as yet. The corresponding minimum total mass is $10^9 \msun$, while the central mass to visual light ratio $\sim 50$ in Solar units. Our new photographic photometry allows the detection of main-sequence stars of Sgr over an area of $22\deg \times 8\deg$. Sgr is prolate, with axis ratios $\sim$~3:1:1. For an adopted distance of $16 \pm 2 \kpc$ from the Galactic center on the opposite side of the Galaxy to the Sun, the major axis is $\gta 9 \kpc$ long and is aligned approximately normal to the plane of the Milky Way Galaxy, roughly following the coordinate line $\ell=5^\circ$. The central velocity dispersion of giant stars which are members of Sgr is $11.4 \pm 0.7 \kms$ and is consistent with being constant over the face of the galaxy. The gradient in mean line-of-sight velocity with position along the
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