Publications

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glyconanobiotics: novel carbohydrated nanoparticle antibiotics for mrsa and bacillus anthracis.this report describes the synthesis and evaluation of glycosylated polyacrylate nanoparticles that have covalently-bound antibiotics within their framework. the requisite glycosylated drug monomers were prepared from one of three known antibiotics, an n-sec-butylthio beta-lactam, ciprofloxacin, and a penicillin, by acylation with 3-o-acryloyl-1,2-o-isopropylidene-5,6 bis((chlorosuccinyl)oxy)-d-glucofuranose (7) or 6-o-acetyl-3-o-acryloyl-1,2-o-isopropylidene-5-(chlorosuccinyl)oxy-alpha-d-glucofu ...200818063370
persistence of category a select agents in the environment. 200818065629
potential dissemination of bacillus anthracis utilizing human lung epithelial cells.dissemination of bacillus anthracis spores from the lung is a critical early event in the establishment of inhalational anthrax. we recently reported that b. anthracis could adhere to and be internalized by cultured intestinal epithelial and fibroblast cells. here, using gentamicin protection assays and/or electron microscopy, we found that sterne strain 7702 spores were able to adhere to and subsequently be internalized by polarized a549 cells and primary human small airway epithelial cells. we ...200818067609
antigen delivered by anthrax lethal toxin induces the development of memory cd8+ t cells that can be rapidly boosted and display effector functions.memory cd8+ t cells are essential for protective immunity against many intracellular pathogens; therefore, stimulation of this population of cells is an important goal of vaccination. we have previously shown that a detoxified derivative of bacillus anthracis anthrax lethal toxin (lt) can deliver heterologous cd8+ t-cell epitopes to the major histocompatibility complex class i processing and presentation pathway of murine host cells and that immunization of mice with these lt-antigen fusion prot ...200818086810
expression of functional bacillus spoiisab toxin-antitoxin modules in escherichia coli.spoiisa and spoiisb proteins from bacillus subtilis belong to a recently described bacterial programmed-cell death system. the current work demonstrates that the toxin-antitoxin module is also functional in escherichia coli cells, where the expression of spoiisa toxin leads to transient growth arrest coupled with cell lysis, and spoiisa-induced death can be prevented by coexpression of its cognate antitoxin, spoiisb. escherichia coli cells appear to be able to escape the spoiisa killing by activ ...200818096016
behavior of bacillus anthracis strains sterne and ames k0610 in sterile raw ground beef.the behavior of bacillus anthracis sterne spores in sterile raw ground beef was measured at storage temperatures of 2 to 70 degrees c, encompassing both bacterial growth and death. b. anthracis sterne was weakly inactivated (-0.003 to -0.014 log10 cfu/h) at storage temperatures of 2 to 16 degrees c and at temperatures greater than and equal to 45 degrees c. growth was observed from 17 to 44 degrees c. at these intermediate temperatures, b. anthracis sterne displayed growth patterns with lag, gro ...200818083866
identification by quantitative carrier test of surrogate spore-forming bacteria to assess sporicidal chemicals for use against bacillus anthracis.the spores of six strains of bacillus anthracis (four virulent and two avirulent) were compared with those of four other types of spore-forming bacteria for their resistance to four liquid chemical sporicides (sodium hypochlorite at 5,000 ppm available chlorine, 70,000 ppm accelerated h2o2, 1,000 ppm chlorine dioxide, and 3,000 ppm peracetic acid). all test bacteria were grown in a 1:10 dilution of columbia broth (with manganese) incubated at 37 degrees c for 72 h. the spore suspensions, heat tr ...200818083869
clostridium botulinum c2 toxin. identification of the binding site for chloroquine and related compounds and influence of the binding site on properties of the c2ii channel.clostridium botulinum c2 toxin belongs to the family of binary ab type toxins that are structurally organized into distinct enzyme (a, c2i) and binding (b, c2ii) components. the proteolytically activated 60-kda c2ii binding component is essential for c2i transport into target cells. it oligomerizes into heptamers and forms channels in lipid bilayer membranes. the c2ii channel is cation-selective and can be blocked by chloroquine and related compounds. residues 303-330 of c2ii contain a conserved ...200818077455
synthesis of an anthrose derivative and production of polyclonal antibodies for the detection of anthrax spores.a straightforward synthesis of a derivative of anthrose, the non-reducing terminal fragment of the antigenic tetrasaccharide from bacillus anthracis, was achieved starting from d-galactose. this hapten is able to induce a highly specific and sensitive immune response in rabbit when attached to a carrier protein.200818155682
a mathematical simulation of the inflammatory response to anthrax infection.bacillus anthracis (anthrax) can trigger an acute inflammatory response that results in multisystem organ failure and death. previously, we developed a mathematical model of acute inflammation after gram-negative infection that had been matched qualitatively to literature data. we modified the properties of the invading bacteria in that model to those specific to b. anthracis and simulated the host response to anthrax infection. we simulated treatment strategies against anthrax in a genetically ...200818157069
low molecular weight inhibitors of the protease anthrax lethal factor.anthrax lethal factor (lf) is a zinc-dependent metalloprotease that together with the protective antigen constitute the anthrax lethal toxin, the most prominent virulence factor of the disease anthrax. this review summarizes the current knowledge on anthrax toxicity and defense in relation to lf. particular emphasis is placed on the structural aspects of lf, the properties of its substrates and the achievements in the design of low molecular weight inhibitors of the catalytic activity of the met ...200818336349
anthrax lethal toxin and salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms.caspase-1 cleaves the inactive il-1beta and il-18 precursors into active inflammatory cytokines. in salmonella-infected macrophages, caspase-1 also mediates a pathway of proinflammatory programmed cell death termed "pyroptosis." we demonstrate active caspase-1 diffusely distributed in the cytoplasm and localized in discrete foci within macrophages responding to either salmonella infection or intoxication by bacillus anthracis lethal toxin (lt). both stimuli triggered caspase-1-dependent lysis in ...200818337499
bacillus spore classification via surface-enhanced raman spectroscopy and principal component analysis.surface-enhanced raman spectroscopy (sers) can provide rapid fingerprinting of biomaterial in a nondestructive manner. the adsorption of colloidal silver to biological material suppresses native biofluorescence while providing electromagnetic surface enhancement of the normal raman signal. this work validates the applicability of qualitative ser spectroscopy for analysis of bacterial species by utilizing principal component analysis (pca) to show discrimination of biological threat simulants, ba ...200818339232
genome assembly forensics: finding the elusive mis-assembly.we present the first collection of tools aimed at automated genome assembly validation. this work formalizes several mechanisms for detecting mis-assemblies, and describes their implementation in our automated validation pipeline, called amosvalidate. we demonstrate the application of our pipeline in both bacterial and eukaryotic genome assemblies, and highlight several assembly errors in both draft and finished genomes. the software described is compatible with common assembly formats and is re ...200818341692
examination of intrinsic sulfonamide resistance in bacillus anthracis: a novel assay for dihydropteroate synthase.dihydropteroate synthase (dhps) catalyzes the formation of dihydropteroate and mg-pyrophosphate from 6-hydroxymethyl-7,8-dihydropterin diphosphate and para-aminobenzoic acid. the bacillus anthracis dhps is intrinsically resistant to sulfonamides. however, using a radioassay that monitors the dihydropteroate product, the enzyme was inhibited by the same sulfonamides. a continuous spectrophotometric assay for measuring the enzymatic activity of dhps was developed and used to examine the effects of ...200818342015
both cd4+ and cd8+ t cells respond to antigens fused to anthrax lethal toxin.the lethal toxin produced by bacillus anthracis is a bipartite toxin in which the first protein, protective antigen (pa), transports the second protein, lethal factor, across the host cell membrane. we have previously shown that cd8(+) t-cell epitopes fused to a nontoxic derivative of lethal factor (lfn) are delivered into the host cell cytosol in a pa-dependent manner. delivery of these antigens targets them to the intracellular major histocompatibility complex (mhc) class i processing and pres ...200818347032
modeling the logistics of response to anthrax bioterrorism.a bioterrorism attack with an agent such as anthrax will require rapid deployment of medical and pharmaceutical supplies to exposed individuals. how should such a logistical system be organized? how much capacity should be built into each element of the bioterrorism response supply chain?200818349432
evidence against a human cell-specific role for lrp6 in anthrax toxin entry.the role of the cellular protein lrp6 in anthrax toxin entry is controversial. previous studies showed that lrp6 was important for efficient intoxication of human m2182 prostate carcinoma cells but other studies performed with cells from gene-knockout mice demonstrated no role for either lrp6 or the related lrp5 protein in anthrax toxin entry. one possible explanation for this discrepancy is that lrp6 may be important for anthrax toxin entry into human, but not mouse, cells. to test this idea we ...200818350154
application of in vivo induced antigen technology (iviat) to bacillus anthracis.in vivo induced antigen technology (iviat) is an immuno-screening technique that identifies bacterial antigens expressed during infection and not during standard in vitro culturing conditions. we applied iviat to bacillus anthracis and identified paga, seven members of a n-acetylmuramoyl-l-alanine amidase autolysin family, three p60 family lipoproteins, two transporters, spore cortex lytic protein sleb, a penicillin binding protein, a putative prophage holin, respiratory nitrate reductase narg, ...200818350160
copi coatomer complex proteins facilitate the translocation of anthrax lethal factor across vesicular membranes in vitro.the delivery of the diphtheria toxin catalytic domain (dta) from acidified endosomes into the cytoplasm of eukaryotic cells requires protein-protein interactions between the toxin and a cytosolic translocation factor (ctf) complex. a conserved peptide motif, t1, within the dt transmembrane helix 1 mediates these interactions. because the t1 motif is also present in the n-terminal segments of lethal factor (lf) and edema factor (ef) in anthrax toxin, we asked whether lf entry into the cell might ...200818356299
the systemic administration of lethal toxin achieves a growth delay of human melanoma and neuroblastoma xenografts: assessment of receptor contribution.two of the three components of anthrax toxin, protective antigen (pa) and lethal factor (lf), together known as lethal toxin (letx), reportedly show anti-tumor activity in melanoma in vitro and in vivo. the growth inhibitory activity of letx in culture was determined in nine human cancer cell lines, including melanoma, neuroblastoma and adenocarcinoma cells, as well as in human umbilical vein endothelial cells (huvec). the contribution of the two known pa receptor proteins, antxr1/tem8 and antxr ...200818360701
[pathology of inoculation]. 200818361288
high resolution genotyping of bacillus anthracis outbreak strains using four highly mutable single nucleotide repeat markers.bacillus anthracis is a genetically monomorphic bacterium with little diversity to be expected during an outbreak. this study used more rapidly evolving genetic markers on outbreak samples to ascertain genetic diversity.200818363651
bsla, a pxo1-encoded adhesin of bacillus anthracis.the gram-positive pathogen bacillus anthracis causes anthrax, a fulminant and lethal infection of mammals. two large virulence plasmids, pxo1 and pxo2, harbour genes required for anthrax pathogenesis and encode secreted toxins or provide for the poly gamma-d-glutamic acid capsule. in addition to capsule, b. anthracis harbours additional cell wall envelope structures, including the surface layer (s-layer), which is composed of crystalline protein arrays. we sought to identify the b. anthracis env ...200818366441
rapid polymerase chain reaction-based screening assay for bacterial biothreat agents.to design and evaluate a rapid polymerase chain reaction (pcr)-based assay for detecting eubacteria and performing early screening for selected class a biothreat bacterial pathogens.200818370996
commingling regulatory systems following acquisition of virulence plasmids by bacillus anthracis.the conversion of a bacterium from a non-pathogenic to a pathogenic existence is usually associated with the acquisition of virulence factors, the genes of which gain entry through bacteriophage infection, transposable elements or plasmid transfer. pathogenesis research is mostly focused on how these factors enable the bacterium to infect the host or evade the repertoire of host defenses. less effort is expended on understanding how the invading genes are affected by the complex regulatory circu ...200818374574
bacillus anthracis: balancing innocent research with dual-use potential.anthrax euronet, a coordination action of the eu 6th framework programme, was designed to strengthen networking activities between anthrax research groups in europe and to harmonise protocols for testing anthrax vaccines and therapeutics. inevitably, the project also addressed aspects of the current political issues of biosecurity and dual-use research, i.e. research into agents of important diseases of man, livestock or agriculture that could be used as agents of bioterrorism. this review provi ...200818375178
in vivo efficacy of beta-cyclodextrin derivatives against anthrax lethal toxin.we evaluated the in vivo efficacy of three beta-cyclodextrin derivatives that block the anthrax protective antigen pore. these compounds were at least 15-fold more potent than previously described beta-cyclodextrins in protecting against anthrax lethal toxin in a rat model. one of the drugs was shown to protect mice from bacterial infection.200818378717
comparison of the essential cellular functions of the two mura genes of bacillus anthracis.targeted antisense and gene replacement mutagenesis experiments demonstrate that only the mura1 gene and not the mura2 gene is required for the normal cellular growth of bacillus anthracis. antisense-based modulation of mura1 gene expression hypersensitizes cells to the mura-specific antibiotic fosfomycin despite the normally high resistance of b. anthracis to this drug.200818378720
profile: interview with rajeev venkayya, md, director, global health delivery, bill & melinda gates foundation, and former special assistant to the president and senior director for biodefense, white house homeland security council. 200818386969
implementing the cities readiness initiative: lessons learned from boston.the federally funded cities readiness initiative (cri) requires seamless federal, state, and local public health coordination to provide antibiotics to an entire city population within 48 hours of an aerosolized release of anthrax. we document practical lessons learned from the development and implementation of the boston cri plan. key themes center on heightened emphasis on security, a new mass protection model of dispensing, neighborhood-centric clinic site selection, online training of medica ...200818388657
decontamination of fluid milk containing bacillus spores using commercial household products.although commercial sanitizers can inactivate bacterial spores in food processing environments, relatively little data exist as to the decontamination of products and surfaces by consumers using commercial household products. should a large scale bioterrorism incident occur in which consumer food products were contaminated with a pathogenic sporeformer such as bacillus anthracis, there may be a need to decontaminate these products before disposal as liquid or solid waste. studies were conducted ...200818389688
anthrax in saskatchewan 2006: an outbreak overview. 200818390096
bioterrorism: class a agents and their potential presentations in immunocompromised patients.a bioterrorism attack would be particularly challenging for medical professionals caring for patients with cancer who often have weakened immune systems. knowledge of the class a agents and the potential variable presentations in immunocompromised patients is key to early recognition of an outbreak and prompt reporting. the purpose of this article is to present the class a agents: bacillus anthracis (anthrax), botulinum toxin (botulism), variola virus (smallpox), yersinia pestis (pneumonic plagu ...200818390465
inactivation of bacillus anthracis spores by a combination of biocides and heating under high-temperature short-time pasteurization conditions.the milk supply is considered a primary route for a bioterrorism attack with bacillus anthracis spores because typical high-temperature short-time (htst) pasteurization conditions cannot inactivate spores. in the event of intentional contamination, an effective method to inactivate the spores in milk under htst processing conditions is needed. this study was undertaken to identify combinations and concentrations of biocides that can inactivate b. anthracis spores at temperatures in the htst rang ...200818390680
bayesian-integrated microbial forensics.in the aftermath of the 2001 anthrax letters, researchers have been exploring ways to predict the production environment of unknown-source microorganisms. culture medium, presence of agar, culturing temperature, and drying method are just some of the broad spectrum of characteristics an investigator might like to infer. the effects of many of these factors on microorganisms are not well understood, but the complex way in which microbes interact with their environments suggests that numerous anal ...200818390682
conference report on public health and clinical guidelines for anthrax.on march 13-14, 2006, a meeting on anthrax, sponsored by the centers for disease control and prevention (cdc) in collaboration with the southeastern center for emerging biologic threats, was held at emory university in atlanta, georgia, usa. the meeting's agenda included discussion of postexposure prophylaxis (pep), screening and evaluation, and treatment of the various manifestations of human anthrax. the goal was to convene subject matter experts for a review of research developments and clini ...200818394267
single nucleotide polymorphism typing of bacillus anthracis from sverdlovsk tissue.a small number of conserved canonical single nucleotide polymorphisms (cansnp) that define major phylogenetic branches for bacillus anthracis were used to place a sverdlovsk patient's b. anthracis genotype into 1 of 12 subgroups. reconstruction of the paga gene also showed a unique snp that defines a new lineage for b. anthracis.200818394287
real time detection of anthrax spores using highly specific anti-ea1 recombinant antibodies produced by competitive panning.we describe a targeted approach for the production of biological recognition elements capable of fast, specific detection of anthrax spores on biosensor surfaces. the aim was to produce single chain antibodies (scfvs) to ea1, a bacillus anthracis s-layer protein that is also present, although not identical, in related to bacillus species. the aim of the work was to produce antibodies that would detect b. anthracis ea1 protein and intact spores with a high degree of specificity, but would not det ...200818395220
development of a rapid and sensitive immunoassay for detection and subsequent recovery of bacillus anthracis spores in environmental samples.bacillus anthracis is considered a major threat as an agent of bioterrorism. b. anthracis spores are readily dispersed as aerosols, are very persistent, and are resistant to normal disinfection treatments. immunoassays have been developed to rapidly detect b. anthracis spores at high concentrations. however, detection of b. anthracis spores at lower concentrations is problematic due to the fact that closely related bacillus species (e.g., b. thuringiensis) can cross-react with anti-b. anthracis ...200818395279
modeling the inactivation kinetics of bacillus spores by glutaraldehyde.our goal was to develop a mathematical kinetic model to predict the sporicidal activity of glutaraldehyde, which is an active ingredient frequently used in commercial products employed for liquid disinfection and decontamination.200818397220
pyridine nucleotide complexes with bacillus anthracis coenzyme a-disulfide reductase: a structural analysis of dual nad(p)h specificity.we have recently reported that coash is the major low-molecular weight thiol in bacillus anthracis [nicely, n. i. , parsonage, d., paige, c., newton, g. l., fahey, r. c., leonardi, r., jackowski, s., mallett, t. c., and claiborne, a. (2007) biochemistry 46, 3234-3245], and we have now characterized the kinetic and redox properties of the b. anthracis coenzyme a-disulfide reductase (coadr, bacoadr) and determined the crystal structure at 2.30 a resolution. while the staphylococcus aureus and borr ...200818399646
wet and dry density of bacillus anthracis and other bacillus species.to determine the wet and dry density of spores of bacillus anthracis and compare these values with the densities of other bacillus species grown and sporulated under similar conditions.200818298528
standardized, mathematical model-based and validated in vitro analysis of anthrax lethal toxin neutralization.quantification of anthrax lethal toxin (ltx) neutralization activity (tna) is pivotal in assessing protective antibody responses to anthrax vaccines and for evaluation of immunotherapies for anthrax. we have adapted and redesigned the tna assay to establish a unifying, standardized, quantitative and validated technology platform for ltx neutralization in the j774a.1 murine cell line. critical design features of this platform are 1) the application of a free-form or constrained 4 parameter logist ...200818304568
experiments on army volunteers in israel will be overseen by the health ministry. 200818309985
inhibitors of anthrax lethal factor based upon n-oleoyldopamine.the structural features of an anthrax lethal factor inhibitor, n-oleoyldopamine (olda, 1) have been probed. the oleic acid moiety is critical, but, more interestingly, the presence of the double bond and its geometry were found to play an essential role. one compound, 5, was found to be an uncompetitive inhibitor of lethal factor (lf) with a k(i) value of 2.2microm and a cell-based ic(50) value of 4.3microm.200818314330
etest for antibiotic susceptibility testing of bacillus anthracis, bacillus cereus and bacillus thuringiensis: evaluation of a french collection. 200818316178
bacterial nitric-oxide synthases operate without a dedicated redox partner.bacterial nitric-oxide (no) synthases (bnoss) are smaller than their mammalian counterparts. they lack an essential reductase domain that supplies electrons during no biosynthesis. this and other structural peculiarities have raised doubts about whether bnoss were capable of producing no in vivo. here we demonstrate that bnos enzymes from bacillus subtilis and bacillus anthracis do indeed produce no in living cells and accomplish this task by hijacking available cellular redox partners that are ...200818316370
anamnestic protective immunity to bacillus anthracis is antibody mediated but independent of complement and fc receptors.the threat of bioterrorist use of bacillus anthracis has focused urgent attention on the efficacy and mechanisms of protective immunity induced by available vaccines. however, the mechanisms of infection-induced immunity have been less well studied and defined. we used a combination of complement depletion along with immunodeficient mice and adoptive transfer approaches to determine the mechanisms of infection-induced protective immunity to b. anthracis. b- or t-cell-deficient mice lacked the co ...200818316379
mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma.we hypothesized that signaling through multiple mitogen-activated protein kinase (mapk) kinase (mkk) pathways is essential for the growth and vascularization of soft-tissue sarcomas, which are malignant tumors derived from mesenchymal tissues. we tested this using ht-1080, nci, and shac fibrosarcoma-derived cell lines and anthrax lethal toxin (letx), a bacterial toxin that inactivates mkks. western blots confirmed that letx treatment reduced the levels of phosphorylated extracellular signal-regu ...200818319331
use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections.the ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. ketolides bind to a secondary region on domain ii of the 23s rrna subunit. telithromycin was the first ketolide to be approved by the fda in 2004 for treatment of community-acquired pneumonia (cap), acute exacerbations of chronic bronchitis (aecb) and sinusitis. however, in 2006, after repo ...200818321237
rapid point-of-care test to detect broad ranges of protective antigen-specific immunoglobulin g concentrations in recipients of the u.s.-licensed anthrax vaccine.currently, there is no routine monitoring of an immune response to the anthrax vaccine. simple on-site tests are needed to evaluate the antibody response of anthrax-vaccinated individuals in the armed forces and others at high risk. using a prototype lateral flow assay (lfa) (r. e. biagini, d. l. sammons, j. p. smith, b. a. mackenzie, c. a. f. striley, j. e. snawder, s. a. robertson, and c. p. quinn, clin. vaccine immunol. 13:541-546, 2006), we investigated the agreement between a validated anth ...200818321882
anthrax lethal toxin increases superoxide production in murine neutrophils via differential effects on mapk signaling pathways.the combination of lethal factor and its receptor-binding partner, protective ag, is termed lethal toxin (lt) and has critical pathogenic activity during infection with bacillus anthracis. we herein report that anthrax lt binds and enters murine neutrophils, leading to the cleavage of mitogen-activated protein kinase kinase/mek/mapkk 1-4 and 6, but not mitogen-activated protein kinase kinase 5 and 7. anthrax lt treatment of neutrophils disrupts signaling to downstream mapk targets in response to ...200818322225
macaque models of human infectious disease.macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. the remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. historically, macaques played a major rol ...200818323583
spin labelling of bacillus anthracis endospores: a model for in vivo tracking by epr imaging.anthrax is caused by the gram-negative bacterium, bacillus anthracis. infection by this microbe results from delivery of the endospore form of the bacillus through direct contact, either topical or inhalation. with regard to the latter route of administration, it is proposed that endospores of b. anthracis enter the lungs and are phagocytized by host alveolar macrophages. thereafter, it is unclear as to how endospores travel to distal loci and what tissues are the targets. herein, this study des ...200818324523
targeting mucosal dendritic cells with microbial antigens from probiotic lactic acid bacteria.the use of vaccines against infectious microbes has been critical to the advancement of medicine. vaccine strategies combined with, or without, adjuvants have been established to eradicate various bacterial and viral pathogens. a new generation of vaccines is being developed using specific strains of gram-positive, lactic acid bacteria and, notably, some probiotic lactobacilli. these bacteria have been safely consumed by humans for centuries in fermented foods. thus, they can be orally administe ...200818324887
inactivation kinetics of avirulent bacillus anthracis spores in milk with a combination of heat and hydrogen peroxide.the combined effect of heat and hydrogen peroxide (hp) on the inactivation of avirulent bacillus anthracis spores (sterne strain 7702; strain anr-1, an avirulent ames derivative lacking the pxo2 plasmid; and strain 9131, a plasmid-less sterne strain) was evaluated in milk. the study temperature ranged from 90 to 95 degrees c, and the concentration of added hp varied from 0.05 to 0.5%. decimal reduction times (d-values) were determined using a sealed capillary tube technique. the mean d- and z-va ...200818326183
molecular epidemiology of bacillus anthracis: determining the correct origin.we analyzed and compared strains of bacillus anthracis isolated from husbandry and industrial anthrax cases in switzerland between 1952 and 1981 with published data using multiple-locus variable-number tandem repeat analysis. strains isolated from autochthonous cases of anthrax in cattle belong to genotype b2, together with strains from continental europe, while human b. anthracis strains clustered with genotype a4. these strains could be traced back to outbreaks of human anthrax that occurred b ...200818326672
teichoic acids and related cell-wall glycopolymers in gram-positive physiology and host interactions.most gram-positive bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. such cell-wall glycopolymers (cwgs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. further important roles of cwgs in host-cell adhesion, inflammation and immune activation have also been described in recent years. identifying and harnessing highly conserved or species-specific s ...200818327271
universal liposomes: preparation and usage for the detection of mrna.dye-encapsulating liposomes can serve as signaling reagents in biosensors and biochemical assays in place of enzymes or fluorophores. detailed here is the use and preparation of streptavidin-coupled liposomes which offer a universal approach to biotinylated target detection. the universal approach provides two advantages, i.e. only one type of liposome is necessary despite varying target and probe sequences and the hybridization event can take place in the absence of potential steric hindrance o ...200818327569
the conserved pa14 domain of cell wall-associated fungal adhesins governs their glycan-binding specificity.yeast cell wall-associated, lectin-like adhesins form large families that mediate flocculation and host cell recognition. the glycan specificity of individual adhesins is largely unknown. zupancic et al. (this issue of molecular microbiology) used glycan microarrays to compare the glycan-binding characteristics of individual adhesins (epa proteins) of the pathogenic yeast candida glabrata produced in the non-adherent yeast saccharomyces cerevisiae. by sequence swapping between the conserved pa14 ...200818331471
phenylalanine-427 of anthrax protective antigen functions in both pore formation and protein translocation.the protective antigen (pa) moiety of anthrax toxin forms a heptameric pore in endosomal membranes of mammalian cells and translocates the enzymatic moieties of the toxin to the cytosol of these cells. phenylalanine-427 (f427), a solvent-exposed residue in the lumen of the pore, was identified earlier as being crucial for the transport function of pa. the seven f427 residues were shown in electrophysiological studies to form a clamp that catalyzes protein translocation through the pore. here, we ...200818334631
function, structure and regulation of the vacuolar (h+)-atpases.the vacuolar atpases (or v-atpases) are atp-driven proton pumps that function to both acidify intracellular compartments and to transport protons across the plasma membrane. intracellular v-atpases function in such normal cellular processes as receptor-mediated endocytosis, intracellular membrane traffic, prohormone processing, protein degradation and neurotransmitter uptake, as well as in disease processes, including infection by influenza and other viruses and killing of cells by anthrax and d ...200818406336
infectious agents of bioterrorism: a review for emergency physicians.the terrorist attacks on the united states in 2001 and the anthrax release soon after brought the issue of bioterrorism to the forefront in the medical community. bioterrorism is the use of a biologic weapon to create terror and panic. biologic weapons, or bioweapons, can be bacteria, fungi, viruses, or biologic toxins. because the emergency department represents the front line of defense for the recognition of agents of bioterrorism, it is essential that emergency physicians have the ability to ...200818406986
biological and biochemical characterization of anthrax lethal factor, a proteolytic inhibitor of mek signaling pathways.the secretion of factors that block critical intracellular signaling pathways is a common strategy used by pathogenic bacteria for disabling host defenses and causing disease. anthrax lethal toxin (letx) has been shown to cleave and inactivate mitogen-activated protein kinase (mapk) kinases (mkks or meks) and to inhibit mkk signaling. cleavage of mkks by letx prevents activation of their downstream substrates, the mapks. because mapk pathways regulate a variety of crucial cellular functions incl ...200818413261
petrobactin-mediated iron transport in pathogenic bacteria: coordination chemistry of an unusual 3,4-catecholate/citrate siderophore. 200818220393
rhodanine derivatives as selective protease inhibitors against bacterial toxins.in this study, we analyzed a series of rhodanine derivatives, as potential inhibitors of bacterial toxins, namely the proteases anthrax lethal factor and the botulinum neurotoxin type a. conducting an extensive structure-activity relationship study on rhodanine derivatives, we profiled their selectivity against the two bacterial toxins and two related human metalloproteases using in vitro assays. in addition, we examined initial in vitro adme-tox properties of selected compounds and their abilit ...200818221310
anthrax toxin-induced shock in rats is associated with pulmonary edema and hemorrhage.bacillus anthracis infections are frequently associated with severe and often irreversible hypotensive shock despite appropriate antibiotics and aggressive hemodynamic and pulmonary support. based on the observations that the anthrax secreted proteins-protective antigen (pa), lethal factor (lf), and edema factor (ef) also produce shock and mortality in animal models, we chose to characterize further the clinical chemistries and microscopic pathology of toxin treated rats. groups of three male sp ...200818222626
intensified biochip system using chemiluminescence for the detection of bacillus globigii spores.this paper reports the first intensified biochip system for chemiluminescence detection and the feasibility of using this system for the analysis of biological warfare agents is demonstrated. an enzyme-linked immunosorbent assay targeting bacillus globigii spores, a surrogate species for bacillus anthracis, using a chemiluminescent alkaline phosphatase substrate is combined with a compact intensified biochip detection system. the enzymatic amplification was found to be an attractive method for d ...200818224472
synthesis and biological evaluation of novel 1,3,5-triazine derivatives as antimicrobial agents.numerous studies have contributed to the development of natural and synthetic antimicrobial peptides as a prospective source of antibiotic agents. based on the concept that cationic charge, bulk, and lipophilicity are major factors determining antibacterial activity in these peptides, we designed and screened several combinatorial libraries based on 1,3,5-triazine as a template. a set of compounds were identified to show potent antimicrobial activity together with low hemolytic activity.200818226902
analysis of a novel spore antigen in bacillus anthracis that contributes to spore opsonization.the significance of bacillus anthracis as an agent of bioterrorism has been well established. an understanding of both the pathogenesis and the host response is required to elucidate approaches to more rapidly detect and effectively prevent or treat anthrax. current vaccine strategies are focused primarily on production of antibodies against the protective antigen components of the anthrax toxins, which are secreted by the bacilli. a better understanding of the dynamic morphology of the dormant ...200818227265
colloidal gold-polystyrene bead hybrid for chemiluminescent detection of sequence-specific dna.a sensitive chemiluminescent (cl) detection of sequence-specific dna has been developed by taking advantage of a magnetic separation/mixing process and the amplification feature of colloidal gold labels. in this protocol, the target oligonucleotides are hybridized with magnetic bead-linked capture probes, followed by the hybridization of the biotin-terminated amplifying dna probes and the binding of streptavidin-coated gold nanoparticles; the nanometer-sized gold tags are then dissolved and quan ...200818227945
development of an automated dna purification module using a micro-fabricated pillar chip.we present a fully automated dna purification module comprised of a micro-fabricated chip and sequential injection analysis system that is designed for use within autonomous instruments that continuously monitor the environment for the presence of biological threat agents. the chip has an elliptical flow channel containing a bed (3.5 x 3.5 mm) of silica-coated pillars with height, width and center-to-center spacing of 200, 15, and 30 microm, respectively, which provides a relatively large surfac ...200818227949
bacillus anthracis spores and lethal toxin induce il-1beta via functionally distinct signaling pathways.previous reports suggested that lethal toxin (lt)-induced caspase-1 activity and/or il-1beta accounted for bacillus anthracis (ba) infection lethality. in contrast, we now report that caspase-1-mediated il-1beta expression in response to ba spores is required for anti-ba host defenses. caspase-1(-/-) and il-1beta(-/-) mice are more susceptible than wild-type (wt) mice to lethal ba infection, are less able to kill ba both in vivo and in vitro, and addition of ril-1beta to macrophages from these m ...200818493980
in vivo efficacy of a phosphodiester tlr-9 aptamer and its beneficial effect in a pulmonary anthrax infection model.immunostimulatory oligonucleotide (iss-odn) used as adjuvants are commonly modified with phosphorothioate (ps). the ps backbone prevents nuclease degradation, but confers undesired side effects, including systemic cytokine release. previously, r10-60, a phosphodiester (po) iss-odn, was structurally optimized as an intracellular toll-like receptor-9 agonist. here intravenous, intradermal and intranasal administration of po r10-60 elicit local or adaptive immune responses with minimal systemic eff ...200818495099
first things first: a practice-academic collaboration to develop and deliver a competency-based series of applied epidemiology trainings.the florida center for public health preparedness in the university of south florida college of public health and the florida department of health (fdoh) collaborated to design, develop, and deliver two competency-based epidemiology training programs aimed at increasing the epidemiologic preparedness and response capability of the fdoh workforce. they were also designed to meet the requirements of the national incident management system and recommendations or needs identified in national studies ...200818497019
design and synthesis of 2-pyridones as novel inhibitors of the bacillus anthracis enoyl-acp reductase.enoyl-acp reductase (enr), the product of the fabi gene, from bacillus anthracis (baenr) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis. a number of novel 2-pyridone derivatives were synthesized and shown to be potent inhibitors of baenr.200818499454
adrenal gland hemorrhage in patients with fatal bacterial infections.a wide spectrum of adrenal gland pathology is seen during bacterial infections. hemorrhage is particularly associated with meningococcemia, while abscesses have been described with several neonatal infections. we studied adrenal gland histopathology of 65 patients with bacterial infections documented in a variety of tissues by using immunohistochemistry. the infections diagnosed included neisseria meningitidies, group a streptococcus, rickettsia rickettsii, streptococcus pneumoniae, staphylococc ...200818500257
substrate cleavage analysis of furin and related proprotein convertases. a comparative study.we present the data and the technology, a combination of which allows us to determine the identity of proprotein convertases (pcs) related to the processing of specific protein targets including viral and bacterial pathogens. our results, which support and extend the data of other laboratories, are required for the design of effective inhibitors of pcs because, in general, an inhibitor design starts with a specific substrate. seven proteinases of the human pc family cleave the multibasic motifs ...200818505722
anthrax-associated shock.recent events have brought attention to the potential of bacillus anthracis as an agent of bioterrorism. the shock like state of anthrax is invariably associated with high mortality, despite anti-microbial and supportive therapy. multi-system dysfunction is typical, including: enhanced vascular permeability, hemorrhage and inflammation. important questions concerning the pathophysiology of anthrax-associated shock remain unanswered, including the effects of b. anthracis infection on cardiac func ...200818508494
a nod2-nalp1 complex mediates caspase-1-dependent il-1beta secretion in response to bacillus anthracis infection and muramyl dipeptide.nod2, a nod-like receptor (nlr), is an intracellular sensor of bacterial muramyl dipeptide (mdp) that was suggested to promote secretion of the proinflammatory cytokine il-1beta. yet, the molecular mechanism by which nod2 can stimulate il-1beta secretion, and its biological significance were heretofore unknown. we found that nod2 through its n-terminal caspase recruitment domain directly binds and activates caspase-1 to trigger il-1beta processing and secretion in mdp-stimulated macrophages, whe ...200818511561
cloning and development of synthetic internal amplification control for bacillus anthracis real-time polymerase chain reaction assays.an internal amplification control (iac) was developed for bacillus anthracis rpob gene detection using taqman assay. synthetic iac oligonucleotides were subcloned using vector pdg1730 for ectopic integration into host bacillus subtilis strain 1a772 genome. differentially labeled target and iac probes were used in real-time polymerase chain reaction (pcr) assays. there was no nonspecific cross-detection in single-well reactions. limit of detection for both target and iac dna was 5 fg correspondin ...200818513914
gamma irradiation can be used to inactivate bacillus anthracis spores without compromising the sensitivity of diagnostic assays.the use of bacillus anthracis as a biological weapon in 2001 heightened awareness of the need for validated methods for the inactivation of b. anthracis spores. this study determined the gamma irradiation dose for inactivating virulent b. anthracis spores in suspension and its effects on real-time pcr and antigen detection assays. strains representing eight genetic groups of b. anthracis were exposed to gamma radiation, and it was found that subjecting spores at a concentration of 10(7) cfu/ml t ...200818515484
recent insights into the biology and biomedical applications of flock house virus.flock house virus (fhv) is a nonenveloped, icosahedral insect virus whose genome consists of two molecules of single-stranded, positive-sense rna. fhv is a highly tractable system for studies on a variety of basic aspects of rna virology. in this review, recent studies on the replication of fhv genomic and subgenomic rna are discussed, including a landmark study on the ultrastructure and molecular organization of fhv replication complexes. in addition, we show how research on fhv b2, a potent su ...200818516498
survey of nursing knowledge on bioterrorism.with the aim of identifying intervention programmes within the framework of basic and permanent nursing training, we evaluated the knowledge of 187 nurses and nursing students concerning biological emergencies. a questionnaire was used to identify their knowledge of the pathogens that may be used in a terrorist attack and measures for containing them, and their perception of the danger to public health. analysis of the responses showed that the undergraduates studying for the triennial degree we ...200818519061
an ounce of prevention is worth a pound of cure: improving communication to reduce mortality during bioterrorism responses.to identify communication needs and evaluate the effectiveness of alternative communication strategies for bioterrorism responses.200818522248
characterization of bacillus anthracis arginase: effects of ph, temperature, and cell viability on metal preference.arginase (rocf) hydrolyzes l-arginine to l-ornithine and urea. while previously characterized arginases have an alkaline ph optimum and require activation with manganese, arginase from helicobacter pylori is optimally active with cobalt at ph 6. the arginase from bacillus anthracis is not well characterized; therefore, this arginase was investigated by a variety of strategies and the enzyme was purified.200818522738
mechanisms of substrate selectivity for bacillus anthracis thymidylate kinase.bacillus anthracis is well known in connection with biological warfare. the search for new drug targets and antibiotics is highly motivated because of upcoming multiresistant strains. thymidylate kinase is an ideal target since this enzyme is at the junction of the de novo and salvage synthesis of dttp, an essential precursor for dna synthesis. here the expression and characterization of thymidylate kinase from b. anthracis (ba-tmpk) is presented. the enzyme phosphorylated deoxythymidine-5'-mono ...200818523102
unsymmetric aryl-alkyl disulfide growth inhibitors of methicillin-resistant staphylococcus aureus and bacillus anthracis.this study describes the antibacterial properties of synthetically produced mixed aryl-alkyl disulfide compounds as a means to control the growth of staphylococcus aureus and bacillus anthracis. some of these compounds exerted strong in vitro bioactivity. our results indicate that among the 12 different aryl substituents examined, nitrophenyl derivatives provide the strongest antibiotic activities. this may be the result of electronic activation of the arylthio moiety as a leaving group for nucl ...200818524602
unexplained deaths in connecticut, 2002-2003: failure to consider category a bioterrorism agents in differential diagnoses.recognition of bioterrorism-related infections by hospital and emergency department clinicians may be the first line of defense in a bioterrorist attack.200818525371
substrate specificity of the anthrax lethal factor. 200818429598
human alpha-defensins inhibit clostridium difficile toxin b.clostridium difficile toxins a and b are major virulence factors implicated in pseudomembranous colitis and antibiotic-associated diarrhea. the toxins are glucosyltransferases, which inactivate rho proteins involved in cellular signaling. human alpha-defensins as part of the innate immune system inactivate various microbial pathogens as well as specific bacterial exotoxins. here, we studied the effects of alpha-defensins human neutrophil protein (hnp)-1, hnp-3, and enteric human defensin (hd)-5 ...200818435932
selective killing of hiv-1-positive macrophages and t cells by the rev-dependent lentivirus carrying anthrolysin o from bacillus anthracis.the ability of human immunodeficiency virus (hiv) to persist in the body has proven to be a long-standing challenge to virus eradication. current antiretroviral therapy cannot selectively destroy infected cells; it only halts active viral replication. with therapeutic cessation or interruption, viral rebound occurs, and invariably, viral loads return to pre-treatment levels. the natural reservoirs harboring replication-competent hiv-1 include cd4 t cells and macrophages. in particular, cells fro ...200818439272
the bacillus cereus containing sub-branch most closely related to bacillus anthracis, have single amino acid substitutions in small acid-soluble proteins, while remaining sub-branches are more variable.hoffmaster et al. [hoffmaster ar, ravel j, rasko da, chapman gd, chute md, marston ck, et al. identification of anthrax toxin genes in bacillus cereus associated with illness resembling inhalation anthrax. proc natl acad sci u s a 2004;101:8449-54; hoffmaster ar, hill kk, gee je, marston ck, de bk, popovic t, et al. characterization of bacillus cereus isolates associated with fatal pneumonias: strains are closely related to bacillus anthracis and harbor b. anthracis virulence genes. j clin micro ...200818439962
human serum contains a protease that protects against cytotoxic activity of bacillus anthracis lethal toxin in vitro.the role of innate immunity in the host response to bacillus anthracis is poorly understood. we found that normal human serum contains an antitoxin mechanism that is capable of protecting macrophages in vitro from b. anthracis lethal toxin-mediated killing. this protective activity was limited to defined amounts of toxin and was lost by heat treatment or serum dilution. some person-to-person variation in the protective activity of serum was noted, especially with higher concentrations of lethal ...200818448623
the role of a purine-specific nucleoside hydrolase in spore germination of bacillus thuringiensis.a homologous gene (iunh) of a putative nucleoside hydrolase (nh), which had been identified from the exosporia of bacillus cereus and bacillus anthracis spores, was cloned from bacillus thuringiensis subsp. kurstaki. disruption of iunh did not affect the vegetative growth and sporulation of bacillus thuringiensis, but promoted both inosine- and adenosine-induced spore germination. the inosine- or adenosine-induced germination rate decreased when the wild-type iunh gene was overexpressed in bacil ...200818451042
structures of an alanine racemase from bacillus anthracis (ba0252) in the presence and absence of (r)-1-aminoethylphosphonic acid (l-ala-p).bacillus anthracis, the causative agent of anthrax, has been targeted by the oxford protein production facility to validate high-throughput protocols within the structural proteomics in europe project. as part of this work, the structures of an alanine racemase (ba0252) in the presence and absence of the inhibitor (r)-1-aminoethylphosphonic acid (l-ala-p) have determined by x-ray crystallography to resolutions of 2.1 and 1.47 a, respectively. difficulties in crystallizing this protein were overc ...200818453697
alpha-enolase binds to human plasminogen on the surface of bacillus anthracis.alpha-enolase of bacillus anthracis has recently been classified as an immunodominant antigen and a potent virulence factor determinant. alpha-enolase (2-phospho-d-glycerate hydrolase (ec 4.2.1.11), a key glycolytic metalloenzyme catalyzes the dehydration of d-(+)-2-phosphoglyceric acid to phosphoenolpyruvate. interaction of surface bound alpha-enolase with plasminogen has been incriminated in tissue invasion for pathogenesis. b. anthracis alpha-enolase was expressed in escherichia coli and the ...200818456007
cortex peptidoglycan lytic activity in germinating bacillus anthracis spores.bacterial endospore dormancy and resistance properties depend on the relative dehydration of the spore core, which is maintained by the spore membrane and its surrounding cortex peptidoglycan wall. during spore germination, the cortex peptidoglycan is rapidly hydrolyzed by lytic enzymes packaged into the dormant spore. the peptidoglycan structures in both dormant and germinating bacillus anthracis sterne spores were analyzed. the b. anthracis dormant spore peptidoglycan was similar to that found ...200818456807
use of an in vitro pharmacodynamic model to derive a linezolid regimen that optimizes bacterial kill and prevents emergence of resistance in bacillus anthracis.simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in bacillus anthracis. in 10-day dose-ranging studies, the average exposure for > or =700 mg of linezolid given once daily (qd) resulted in >3-log cfu/ml declines in b. anthracis without resistance selection. linezolid at < or =600 mg qd am ...200818458134
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