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binary fingerprints at fluctuation-enhanced sensing.we have developed a simple way to generate binary patterns based on spectral slopes in different frequency ranges at fluctuation-enhanced sensing. such patterns can be considered as binary "fingerprints" of odors. the method has experimentally been demonstrated with a commercial semiconducting metal oxide (taguchi) sensor exposed to bacterial odors (escherichia coli and anthrax-surrogate bacillus subtilis) and processing their stochastic signals. with a single taguchi sensor, the situations of e ...201022315545
human genetic variation altering anthrax toxin sensitivity.the outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. some host genes encode defense mechanisms, whereas others assist pathogen functions. genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 (cmg2), which encodes a host membrane protein exploited by anthrax toxin a ...201222315420
increased affinity and solubility of peptides used for direct peptide elisa on polystyrene surfaces through fusion with a polystyrene-binding peptide tag.peptide reagents can serve as alternatives or replacements to antibodies in sensing or diagnostic applications. the passive adsorption of peptides onto polystyrene surfaces can limit the target binding capability, especially for short, positively charged, or hydrophobic sequences. in this report, we show that fusing a peptide with a previously characterized 12-amino acid polystyrene binding sequence (ps-tag) improves overall peptide solubility and enzyme-linked immunosorbent assay (elisa) result ...201222313407
total decontamination cost of the anthrax letter attacks.all of the costs associated with decontamination following the 2001 anthrax letter attacks were summarized, estimated, and aggregated based on existing literature and news media reports. a comprehensive list of all affected structures was compiled. costs were analyzed by building class and decontamination type. sampling costs and costs of worker relocation were also included. our analysis indicates that the total cost associated with decontamination was about $320 million.201222313022
insights from genomic comparisons of genetically monomorphic bacterial pathogens.some of the most deadly bacterial diseases, including leprosy, anthrax and plague, are caused by bacterial lineages with extremely low levels of genetic diversity, the so-called 'genetically monomorphic bacteria'. it has only become possible to analyse the population genetics of such bacteria since the recent advent of high-throughput comparative genomics. the genomes of genetically monomorphic lineages contain very few polymorphic sites, which often reflect unambiguous clonal genealogies. some ...201222312053
on-column labeling of gram-positive bacteria with a boronic acid functionalized squarylium cyanine dye for analysis by polymer-enhanced capillary transient isotachophoresis.a new asymmetric, squarylium cyanine dye functionalized by boronic acid ("sq-ba") was designed and synthesized for on-capillary labeling of gram-positive bacteria to provide for high sensitivity detection by way of a modified form of capillary electrophoresis with laser induced fluorescence detection (ce-lif). the ce-based separation employed a polymer-enhanced buffer with capillary transient isotachophoresis in a new hybrid method dubbed "pecti." it was found that the addition of various monosa ...201222304241
binding of filamentous actin to anthrax toxin receptor 1 decreases its association with protective antigen.antxr1 is a type i membrane protein that binds the protective antigen (pa) component of anthrax toxin. the cytosolic domain of antxr1 has a novel actin-binding region that influences the interaction of the ectodomain with pa. here, we have investigated features of the cytosolic domain of antxr1 that reduce the association of the receptor with pa. we mutated a stretch of conserved acidic amino acids adjacent to the actin-binding region and found that the mutation increased the affinity for monome ...201222303962
infantile systemic hyalinosis associated with a putative splice-site mutation in the antxr2 gene.infantile systemic hyalinosis (ish) is a rare autosomal recessive genetic disorder characterized by dermal and subcutaneous fibromatosis, joint contractures and bone deformities. the condition usually presents at birth, resulting in death in infancy. ish is caused by mutations in the anthrax toxin receptor 2 gene, antxr2, also known as cmg2. we report an indian child with ish in whom we identified a homozygous acceptor splice site mutation, ivs2-4g>a. in silico analysis of this sequence showed t ...201222300424
lethality in a murine model of pulmonary anthrax is reduced by combining nuclear transport modifier with antimicrobial therapy.in the last ten years, bioterrorism has become a serious threat and challenge to public health worldwide. pulmonary anthrax caused by airborne bacillus anthracis spores is a life-threatening disease often refractory to antimicrobial therapy. inhaled spores germinate into vegetative forms that elaborate an anti-phagocytic capsule along with potent exotoxins which disrupt the signaling pathways governing the innate and adaptive immune responses and cause endothelial cell dysfunction leading to vas ...201222291977
genomic and snp analyses demonstrate a distant separation of the hospital and community-associated clades of enterococcus faecium.recent studies have pointed to the existence of two subpopulations of enterococcus faecium, one containing primarily commensal/community-associated (ca) strains and one that contains most clinical or hospital-associated (ha) strains, including those classified by multi-locus sequence typing (mlst) as belonging to the cc17 group. the ha subpopulation more frequently has is16, pathogenicity island(s), and plasmids or genes associated with antibiotic resistance, colonization, and/or virulence. supp ...201222291916
design and characterization of novel hybrid antimicrobial peptides based on cecropin a, ll-37 and magainin ii.antimicrobial peptides (amps) are a naturally occurring component of the innate immune response of many organisms and can have activity against both gram-negative and gram-positive bacterial species. in order to optimize and improve the direct antimicrobial effect of amps against a broad spectrum of bacterial species, novel synthetic hybrids were rationally designed from cecropin a, ll-37 and magainin ii. amps were selected based on their α-helical secondary structure and fragments of these were ...201222289499
serum albumin disrupts cryptococcus neoformans and bacillus anthracis extracellular vesicles.for both pathogenic fungi and bacteria, extracellular vesicles have been shown to contain many microbial components associated with virulence, suggesting a role in pathogenesis. however, there are many unresolved issues regarding vesicle synthesis and stability, including the fact that vesicular packaging for extracellular factors involved in virulence must also have a mechanism for vesicle unloading. consequently, we studied the kinetics of vesicle production and stability using [1-(14) c] palm ...201222289081
[bacillus anthracis: a molecular look at a famous pathogen].bacillus anthracis, a gram-positive rod belonging to the bacillus cereus group, has an extremely monomorphic genome, and presents high structural and physiological similarity with b. cereus and bacillus thuringiensis. in this work, the new molecular methods for the identification and typing of b. anthracis developed in the last years, based on variable number tandem repeats or on genetic differences detected through sequencing, are described. the molecular aspects of traditional virulence factor ...201322274828
effect of the mammalian arginase inhibitor 2(s)-amino-6-boronohexanoic acid on bacillus anthracis arginase.macrophages, upon phagocytosing endospores of bacillus anthracis, up-regulate the expression of the immunological isoform of nitric oxide synthase, nos 2, concomitant with production of nitric oxide (no•) from metabolism of l: -arginine. we have previously demonstrated that macrophages that secrete no• kill the bacilli of b. anthracis. to circumvent this microbicidal activity of no•, b. anthracis has evolved pathways that include the enzyme arginase, which metabolizes l: -arginine to ornithine a ...201222271269
sometimes it takes two to tango: contributions of dimerization to functions of human α-defensin hnp1.human myeloid α-defensins called hnps play multiple roles in innate host defense. the trp26 residue of hnp1 was previously shown to contribute importantly to its ability to kill s. aureus, inhibit anthrax lethal factor (lf), bind gp120 of hiv-1, dimerize, and undergo further self-association. to gain additional insights into the functional significance of dimerization, we compared wild-type hnp1 to dimerization-impaired, n-methylated hnp1 monomers and to disulfide-tethered obligate hnp1 dimers. ...201222270360
inhibition of anthrax lethal factor: lability of hydroxamate as a chelating group.the metalloprotease activity of lethal factor (lf) from bacillus anthracis (b. anthracis) is a main source of toxicity in the lethality of anthrax infection. thus, the understanding of the enzymatic activity and inhibition of b. anthracis lf is of scientific and clinical interests. we have designed, synthesized, and studied a peptide inhibitor of lf, r9lf-1, with the structure nh(2)-(d: -arg)(9)-val-leu-arg-co-nhoh in which the c-terminal hydroxamic acid is commonly used in the inhibitors of met ...201222270239
comparative analysis of virulence factors secreted by bacillus anthracis sterne at host body temperature.aims:  for the analysis of virulence factors produced and secreted by bacillus anthracis vegetative cells during mammalian host infection, we evaluated the secretome of b. anthracis sterne exposed to host-specific factors specifically to host body temperature. methods and results:  we employed a comparative proteomics-based approach to analyze the proteins secreted by b. anthracis sterne under host-specific body temperature conditions. a total of 17 proteins encoded on a single chromosome and th ...201222268495
three probable cases of cutaneous anthrax in autonomous province of vojvodina, serbia, june 2011. 201222264812
rapid detection methods for bacillus anthracis in environmental samples: a review.bacillus anthracis is a gram-positive, spore-forming bacterium, which causes anthrax, an often lethal disease of animals and humans. although the disease has been well studied since the nineteenth century, it has witnessed a renewed interest during the past decade, due to its use as a bioterrorist agent in the fall of 2001 in the usa. a number of techniques aimed at rapidly detecting b. anthracis, in environmental samples as well as in point-of-care settings for humans suspected of exposure to t ...201222262227
hiv vaccine candidates generate in vitro t cell response to putative epitopes in chinese-origin rhesus macaques.the indian rhesus macaque is the established animal model for hiv infection and vaccine research. growing evidence suggests that the more readily available chinese rhesus macaque may be a more relevant option. as increasing numbers of novel chinese rhesus mhc alleles are reported, we decided to explore potential hiv vaccine epitopes in this model. we immunized forty chinese rhesus macaques with three different hiv vaccine candidates either individually or following a prime/boost strategy. we use ...201222261410
rapid assembly of a multimeric membrane protein pore.we have observed the assembly of the staphylococcal pore-forming toxin α-hemolysin using single-molecule fluorescence imaging. surprisingly, assembly from the monomer to the complete heptamer is extremely rapid, occurring in <5 ms. no lower order oligomeric intermediates are detected. monte carlo simulation of our experiment shows that assembly is diffusion limited, and pore formation is dependent on the stability of intermediate species. there are close similarities between bacterial pore-formi ...201122261056
probing the substrate and acceptor specificity of the γ-glutamyltranspeptidase.abstract. γ-glutamyl transpeptidase (ggt) is a two-substrate enzyme that plays a central role in glutathione metabolism and is a potential target for drug design. ggt catalyze the cleavage of γ-glutamyl donor substrates, and the transfer of the γ-glutamyl moiety to an amine of an acceptor substrate or water. although structures of bacterial ggt have revealed details of the protein-ligand interactions at the donor site, the acceptor substrate site is relatively undefined. the recent identificatio ...201222257032
curing of plasmid pxo1 from bacillus anthracis using plasmid incompatibility.the large plasmid pxo1 encoding the anthrax toxin is important for the virulence of bacillus anthracis. it is essential to cure pxo1 from b. anthracis to evaluate its role in the pathogenesis of anthrax infection. because conventional methods for curing plasmids (e.g., curing agents or growth at elevated temperatures) can induce mutations in the host chromosomal dna, we developed a specific and reliable method to eliminate pxo1 from b. anthracis using plasmid incompatibility. three putative repl ...201222253811
mechanisms of nk cell-macrophage bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins.nk cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. bacillus anthracis spores can efficiently drive ifn-γ production by nk cells. the present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of nk-cell activation by b. anthracis and the bacterial strategies to subvert and evade this response. infection with non-toxigenic encapsulated b. anthracis i ...201222253596
pharmacological inhibition of the clpxp protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics.the clpxp protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. here we identified a pharmacological inhibitor of the clpxp protease, f2, and evaluated its action in bacillus anthracis and staphylococcus aureus. we found that f2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in b. anthracis and drug- ...201222252821
gc/ms method for positive detection of bacillus anthracis endospores.a simple method was developed for detection of bacillus anthracis (ba) endospores and for differentiation of them from other species in the bacillus cereus group. chemical profiles that include lipids (i.e., fatty acids), carbohydrates (i.e., sugars), and the spore-specific biomarker, dipicolinic acid, were generated by one-step thermochemolysis (tcm) at 140 °c in 5 min to provide specific biomarker signatures. anthrose, which is a biomarker characteristic of the b. cereus group of bacteria, was ...201222243393
gold nanoparticles with asymmetric polymerase chain reaction for colorimetric detection of dna sequence.we developed a novel strategy for rapid colorimetric analysis of a specific dna sequence by combining gold nanoparticles (aunps) with an asymmetric polymerase chain reaction (as-pcr). in the presence of the correct dna template, the bound oligonucleotides on the surface of aunps selectively hybridized to form complementary sequences of single-stranded dna (ssdna) target generated from as-pcr. dna hybridization resulted in self-assembly and aggregation of aunps, and a concomitant color change fro ...201222243128
biosurveillance: a review and update.since the terrorist attacks and anthrax release in 2001, almost $32 billion has been allocated to biodefense and biosurveillance in the usa alone. surveillance in health care refers to the continual systematic collection, analysis, interpretation, and dissemination of data. when attempting to detect agents of bioterrorism, surveillance can occur in several ways. syndromic surveillance occurs by monitoring clinical manifestations of certain illnesses. laboratory surveillance occurs by looking for ...201222242207
allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to bacillus anthracis.anthrax is a potentially fatal disease resulting from infection with bacillus anthracis. the outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (lt), as well as by genetic variation within the host. to identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the lt-responsive cast/ei strain introgressed on a lt-resistant c57bl/6 (b6) background was screened for ...201122241984
two independent replicons can support replication of the anthrax toxin-encoding plasmid pxo1 of bacillus anthracis.the large pxo1 plasmid (181.6kb) of bacillus anthracis encodes the anthrax toxin proteins. previous studies have shown that two separate regions of pxo1 can support replication of pxo1 miniplasmids when introduced into plasmid-less strains of this organism. no information is currently available on the ability of the above two replicons, termed repx and orfs 14/16 replicons, to support replication of the full-length pxo1 plasmid. we generated mutants of the full-length pxo1 plasmid in which eithe ...201222239982
nanohole-based spr instruments with improved spectral resolution quantify a broad range of antibody-ligand binding kinetics.we demonstrate an affordable low-noise spr instrument based on extraordinary optical transmission (eot) in metallic nanohole arrays and quantify a broad range of antibody-ligand binding kinetics with equilibrium dissociation constants ranging from 200 pm to 40 nm. this nanohole-based spr instrument is straightforward to construct, align, and operate, since it is built around a standard microscope and a portable fiber-optic spectrometer. the measured refractive index resolution of this platform i ...201222235895
kinetic characterization of a slow-binding inhibitor of bla2: thiomaltol.the increasing prevalence of drug resistant bacteria is a pandemic problem. metallo-β-lactamases (mbls) are one of the main causes of drug resistance due to hydrolysis of β-lactam antibiotics. thus, the development of effective inhibitors of mbls remains urgent. the compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-β-lactamase from bacillus anthracis (bla2), which causes anthrax. kinetic evaluation with nitrocefin as a substrate indicates that thiomalt ...201222233540
health-related quality of life in the anthrax vaccination program for workers in the laboratory response network.background: in 2002 cdc initiated the anthrax vaccination program (avp) to provide voluntary pre-exposure vaccination with anthrax vaccine adsorbed (ava) for persons at high risk of exposure to bacillus anthracis spores. there has been concern that ava could be associated with long term impairment of physical and/or mental health. objectives: to ascertain whether physical and mental functional status, as measured by the sf-36v2 health survey (medical outcomes trust, boston, ma), of ava recipient ...201222230591
bacillus anthracis-derived edema toxin (et) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway.abstract: background: a common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (pmns) in infected tissues in the face of abundant circulating pmns. a major virulence determinant of anthrax is edema toxin (et), which is formed by the combination of two proteins produced by the organism, edema factor (ef), which is an adenyl cyclase, and protective antigen (pa). since camp, a product of adenyl cyclase, is known to enhance endothelial barrier integri ...201222230035
comparison of quantitative pcr and culture-based methods for evaluating dispersal of bacillus thuringiensis endospores at a bioterrorism hoax crime scene.since the anthrax mail attacks of 2001, law enforcement agencies have processed thousands of suspicious mail incidents globally, many of which are hoax bioterrorism threats. bio-insecticide preparations containing bacillus thuringiensis (bt) spores have been involved in several such threats in australia, leading to the requirement for rapid and sensitive detection techniques for this organism, a close relative of bacillus anthracis. here we describe the development of a quantitative pcr (qpcr) m ...201222227150
protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines.background. anthrax-associated shock is closely linked to lethal toxin (lt) release and is highly lethal despite conventional hemodynamic support. we investigated whether protective antigen-directed monoclonal antibody (pa-mab) treatment further augments titrated hemodynamic support.methods and results. forty sedated, mechanically ventilated, instrumented canines challenged with anthrax lt were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinep ...201222223857
apoptosis, antimicrobial and antioxidant activities of phytochemicals from garcinia malaccensis hk.f.to study the chemical constituents of stembark of garcinia malaccensis (g. malaccensis) together with apoptotic, antimicrobial and antioxidant activities.201222221758
structural studies on antd: an n-acyltransferase involved in the biosynthesis of d-anthrose.the unusual dideoxysugar d-anthrose has been identified as an important component in the endospores of such infectious agents as bacillus anthracis and bacillus cereus. specifically, it is the terminal sugar on the bacterium's exosporium, and it provides a point of interaction between the spore and the host. the biosynthesis of d-anthrose involves numerous steps starting from α-d-glucose-1-phosphate. here we present a combined structural and functional investigation of antd from b. cereus. this ...201222220494
binding and cell intoxication studies of anthrax lethal toxin.anthrax lethal toxin (lt) is a major virulence factor of bacillus anthracis. the vast majority of the anthrax toxin-related literature describes the assembly of lt as a cell-dependent process. however, some reports have provided evidence for the existence of a fully assembled lt, either in vitro or in the bloodstream of anthrax-infected animals. to follow up on this work, we present studies on fully-assembled lt. we first demonstrate facile and cell-free assembly and purification of lt. we then ...201222219086
development of aptamer beacons for rapid presumptive detection of bacillus spores.a library of 92 dna aptamer sequences was developed against bacillus anthracis (nonpathogenic sterne strain) spores and anthrose sugar immobilized on magnetic beads. the selected dna sequences were studied for similarities and potential binding pockets between the b. anthracis spore and anthrose aptamers. several recurring loop structures were identified and tested for their potential to act as aptamer beacons when labeled with tye 665 dye on their 5' ends and iowa black quencher on their 3' end ...201222218972
the pore-forming protein cry5b elicits the pathogenicity of bacillus sp. against caenorhabditis elegans.the soil bacterium bacillus thuringiensis is a pathogen of insects and nematodes and is very closely related to, if not the same species as, bacillus cereus and bacillus anthracis. the defining characteristic of b. thuringiensis that sets it apart from b. cereus and b. anthracis is the production of crystal (cry) proteins, which are pore-forming toxins or pore-forming proteins (pfps). although it is known that pfps are important virulence factors since their elimination results in reduced virule ...201122216181
detecting anthrax in the mail by coherent raman microspectroscopy.in this report, we show the collection of spatial information through a turbid medium by coherent raman microspectroscopic imaging. in particular, the technique is capable of identifying anthrax endospores inside a sealed paper envelope.201222215594
the dark sides of capillary morphogenesis gene 2.capillary morphogenesis gene 2 (cmg2) is a type i membrane protein involved in the homeostasis of the extracellular matrix. while it shares interesting similarities with integrins, its exact molecular role is unknown. the interest and knowledge about cmg2 largely stems from the fact that it is involved in two diseases, one infectious and one genetic. cmg2 is the main receptor of the anthrax toxin, and knocking out this gene in mice renders them insensitive to infection with bacillus anthracis sp ...201122215446
inhibition of bacterial carbonic anhydrases and zinc proteases: from orphantargets to innovative new antibiotic drugs.zinc-containing enzymes, such as carbonic anhydrases (cas) and metalloproteases (mps) play critical functions in bacteria, being involved in various steps of their life cycle, which are important for survival, colonization, acquisition of nutrients for growth and proliferation, facilitation of dissemination, invasion and pathogenicity. the development of resistance to many classes of clinically used antibiotics emphasizes the need of new antibacterial drug targets to be explored. there is a weal ...201222214451
coatings capable of germinating and neutralizing bacillus anthracis endospores.endospores are formed by various bacterial families, including bacillus and clostridium, in response to environmental stresses as a means to survive conditions inhospitable to vegetative growth. although metabolically inert, the endospore must interact with its environment to determine an optimal time to return to a vegetative state, a process known as germination. germination has been shown to occur in response to a variety of chemical stimuli from specific nutrient germinants including amino a ...201222211260
rapid sample preparation method of bacillus spores in powdery and environmental matrices based on filtration separation.suspicious powders and other samples need to be analyzed frequently for biothreat agents by authorities to assess environmental safety. numerous nucleic acid detection technologies have been developed to detect and identify biowarfare agents in a timely fashion. extracting microbial nucleic acids from a wide variety of powdery and environmental samples to obtain a quality level adequate for these technologies still remains a technical challenge. we aimed to develop a rapid and versatile method t ...201122210204
anthrax and the inflammasome.anthrax lethal toxin (lt), a major virulence determinant of anthrax disease, induces vascular collapse in mice and rats. lt activates the nlrp1 inflammasome in macrophages and dendritic cells, resulting in caspase-1 activation, il-1β and il-18 maturation and a rapid cell death (pyroptosis). this review presents the current understanding of lt-induced activation of nlrp1 in cells and its consequences for toxin-mediated effects in rodent toxin and spore challenge models.201122207185
bacillus manliponensis sp. nov., a new member of the bacillus cereus group isolated from foreshore tidal flat sediment.a gram-positive, endospore-forming, new bacillus species, strain bl4-6(t), was isolated from tidal flat sediment of the yellow sea. strain bl4-6(t) is a straight rod, with motility by peritrichate flagella. the cell wall contains meso-diaminopimelic acid, and the major respiratory quinone is menaquinone-7. the major fatty acids are iso-c(15:0) and summed feature 3 (containing c(16:1) ω7c/iso-c(15:0) 2oh, and/or iso-c(15:0) 2oh/c(16:1) ω7c). cells are catalase-positive and oxidase-negative. the g ...201122203569
Reviewing the role of peptide rarity in bacterial toxin immunomics.In the past decade, renewed efforts have been made toward the development of vaccines against cancers, infectious agents, autoimmune diseases, and allergies. These efforts have led to the accumulation of numerous peptide sequences experimentally validated as epitopes. However, the factors that render a peptide immunogenic and, more generally, the nature of the antigen-antibody recognition process remain unclear. Based on the hypothesis that potential epitopes correspond to rare sequences and/or ...201222202055
validation and long term performance characteristics of a quantitative enzyme linked immunosorbent assay (elisa) for human anti-pa igg.accurate, reliable and standardized quantification of anti-protective antigen (pa) igg antibody levels is essential for comparative analyses of anti-toxin immune responses in anthrax cases, recipients of pa-based anthrax vaccines and for evaluation of anti-pa based immunotherapies. we have previously reported the early performance characteristics and application of a quantitative anti-pa igg enzyme linked immunosorbent assay. the principal application of this assay was in a phase 4 human clinica ...201122197974
Scanning surface potential microscopy of spore adhesion on surfaces.The adhesion of spores of Bacillus anthracis - the cause of anthrax and a likely biological threat - to solid surfaces is an important consideration in cleanup after an accidental or deliberate release. However, because of safety concerns, directly studying B. anthracis spores with advanced instrumentation is problematic. As a first step, we are examining the electrostatic potential of Bacillus thuringiensis (Bt), which is a closely related species that is often used as a simulant to study B. an ...201122196463
Detection of anthrax lef with DNA-based photonic crystal sensors.Bacillus anthracis has posed a threat of becoming biological weapons of mass destruction due to its virulence factors encoded by the plasmid-borne genes, such as lef for lethal factor. We report the development of a fast and sensitive anthrax DNA biosensor based on a photonic crystal structure used in a total-internal-reflection configuration. For the detection of the lef gene, a single-stranded DNA lef probe was biotinylated and immobilized onto the sensor via biotin-streptavidin interactions. ...201122191936
Phase 1 Study of a Recombinant Mutant Protective Antigen of Bacillus anthracis.A Phase 1 study of a recombinant mutant Protective Antigen (rPA) vaccine was conducted in 186 healthy adults aged 18 to 45 years. Volunteers were randomized to receive one of three formulations of rPA (formalin-treated, alum-adsorbed or both) in 10 or 20 µg dosages each, or the licensed vaccine, AVA. Three injections were given at 2 months intervals and a 4(th) one year after the third. Vaccinees were examined once at 48-72 hours following each injection at the clinic. Adverse reactions were rec ...201122190398
Identification of a lead small-molecule inhibitor of anthrax lethal toxin by using fluorescence-based high-throughput screening.Inhalational anthrax is caused by B. anthracis, a virulent sporeforming bacterium which secretes anthrax toxins consisting of protective antigen (PA ), lethal factor (LF ) and edema factor (EF ). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput scr ...201122189685
In situ gastrointestinal protection against anthrax edema toxin by single-chain antibody fragment producing lactobacilli.ABSTRACT: BACKGROUND: Anthrax is caused by the bacterium Bacillus anthracis and is regarded as one of the most prominent bioterrorism threats. Anthrax toxicity is induced by the tripartite toxin complex, composed of the receptor-binding anthrax protective antigen and the two enzymatic subunits, lethal factor and edema factor. Recombinant lactobacilli have previously been used to deliver antibody fragments directed against surface epitopes of a variety of pathogens, including Streptococcus mutan ...201122185669
[Detection and identification of highly pathogenic bacteria within the framework of the EQADeBa project--Part I: Samples containing living pathogens].Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella sp., Bulkholderia mallei are B. pseudomallei are highly pathogenic bacteria of potential bioterrorism risk. To support the early warning and rapid response capacity to ensure an effective reaction to bioterrorist attacks the international project "Establishment of Quality Assurances for Detection of Highly Pathogenic Bacteria of Potential Bioterrorism Risk" (EQADeBa) has been established. The aim of the project was establishme ...201122184939
CELLULAR IRON DISTRIBUTION IN BACILLUS ANTHRACIS.Although successful iron acquisition by pathogens within a host is a pre-requisite for the establishment of infection, surprisingly little is known about the intracellular distribution of iron within bacterial pathogens. We have used a combination of anaerobic, native liquid chromatography, inductively coupled plasma mass spectrometry, principal component analysis and peptide mass fingerprinting to investigate the cytosolic iron distribution in the pathogen Bacillus anthracis. Our studies identi ...201122178968
membrane topology of the bacillus anthracis gerh germinant receptor proteins.bacillus anthracis spores are the etiologic agent of anthrax. nutrient germinant receptors (ngrs) packaged within the inner membrane of the spore sense the presence of specific stimuli in the environment and trigger the process of germination, quickly returning the bacterium to the metabolically active, vegetative bacillus. this ability to sense the host environment and initiate germination is a required step in the infectious cycle. the ngrs are comprised of three subunits: the a-, b-, and c-ty ...201122178966
methylation-dependent dna restriction in bacillus anthracis.bacillus anthracis, the causative agent of anthrax, is poorly transformed with dna that is methylated on adenine or cytosine. here we characterize three genetic loci encoding type iv methylation-dependent restriction enzymes that target dna containing c5-methylcytosine (m5c). strains in which these genes were inactivated, either singly or collectively, showed increased transformation by methylated dna. additionally, a triple mutant with an ~30-kb genomic deletion could be transformed by dna obta ...201122178763
botulinum toxin: therapeutic agent to cosmetic enhancement to lethal biothreat.the clinical effects of clostridium botulinum and its extremely potent neurotoxin have been known for two centuries. the disease threat and the clinical uses are now well established. what's changed is the potential for botulinum neurotoxin to be used as a biological threat agent. the recent upsurge of illegal trafficking of reagent-grade toxin could, if bought in large enough quantities, be as serious a threat as other biothreat agents such as anthrax and smallpox, which have received much more ...201122178572
a longitudinal study of uk military personnel offered anthrax vaccination: informed choice, symptom reporting, uptake and pre-vaccination health.aim: to determine longer term health outcome in a cohort of uk service personnel who received the anthrax vaccination. method: we conducted a three year follow up of uk service personnel all of whom were in the armed forces at the start of the iraq war. 3206 had been offered the anthrax vaccination as part of preparations for the 2003 invasion of iraq. a further 1190 individuals who did not deploy to iraq in 2003 were subsequently offered the vaccination as part of later deployments, and in whom ...201122178523
developing an integrated proteo-genomic approach for the characterisation of biomarkers for the identification of bacillus anthracis.bacillus anthracis is the causative agent of anthrax, an acute and often fatal disease in humans. due to the high genomic relatedness within the bacillus cereus group of species it is a challenge to identify b. anthracis consistently. alternative strategies such as proteomics coupled with mass spectrometry (ms) provide a powerful approach for biomarker discovery. however, validating and evaluating these markers, particularly for genetically homogeneous species such as b. anthracis are challengin ...201122178189
S-layer homology motif is an immunogen and confers protection to mouse model against anthrax.SLH proteins bear an S-layer homology motif comprised of three S-layer homology (SLH) domains. Several SLH proteins in Bacillus anthracis have been recognized as immunogenic in recent past. We hypothesized that the SLH motif, the most common moiety amongst all the SLH proteins could be responsible for their immunogenicity. To test this hypothesis, we checked the immunogenic capacity of recombinant SLH motif. The rSLH fragment on immunization in mice led to the development of a potent humoral and ...201122178119
Antibodies against anthrax: mechanisms of action and clinical applications.B. anthracis is a bioweapon of primary importance and its pathogenicity depends on its lethal and edema toxins, which belong to the A-B model of bacterial toxins, and on its capsule. These toxins are secreted early in the course of the anthrax disease and for this reason antibiotics must be administered early, in addition to other limitations. Antibodies (Abs) may however neutralize those toxins and target this capsule to improve anthrax treatment, and many Abs have been developed in that perspe ...201122174979
Molecular epidemiology of anthrax cases associated with recreational use of animal hides and yarn in the United States.To determine potential links between the clinical isolate to animal products and their geographic origin, we genotyped (MLVA-8, MVLA-15, and canSNP analysis) 80 environmental and 12 clinical isolates and 2 clinical specimens from five cases of anthrax (California in 1976 [n?=?1], New York in 2006 [n?=?1], Connecticut in 2007 [n?=?2], and New Hampshire in 2009[n?=?1]) resulting from recreational handling of animal products. For the California case, four clinical isolates were identified as MLVA-8 ...201122174783
A Receptor-based Switch that Regulates Anthrax Toxin Pore Formation.Cellular receptors can act as molecular switches, regulating the sensitivity of microbial proteins to conformational changes that promote cellular entry. The activities of these receptor-based switches are only partially understood. In this paper, we sought to understand the mechanism that underlies the activity of the ANTXR2 anthrax toxin receptor-based switch that binds to domains 2 and 4 of the protective antigen (PA) toxin subunit. Receptor-binding restricts structural changes within the hep ...201122174672
a supramolecular sensing platform for phosphate anions and an anthrax biomarker in a microfluidic device.a supramolecular platform based on self-assembled monolayers (sams) has been implemented in a microfluidic device. the system has been applied for the sensing of two different analyte types: biologically relevant phosphate anions and aromatic carboxylic acids, which are important for anthrax detection. a eu(iii)-edta complex was bound to β-cyclodextrin monolayers via orthogonal supramolecular host-guest interactions. the self-assembly of the eu(iii)-edta conjugate and naphthalene β-diketone as a ...201122174602
comparative analysis of the responses of related pathogenic and environmental bacteria to oxidative stress.bacillus anthracis, the causative agent of anthrax, is exposed to host-mediated antibacterial activities, such as reactive oxygen species (ros), during the early stages of its disease process. the ability to resist these host-mediated insults is an essential characteristic of a successful pathogen while it is generally assumed that non-pathogenic environmental bacteria succumb to these antimicrobial activities. in order to gain insights into the underlying mechanisms that pathogens use to resist ...201122174384
Development of a hyena immunology toolbox.Animals that hunt and scavenge are often exposed to a broad array of pathogens. Theory predicts the immune systems of animals specialized for scavenging should have been molded by selective pressures associated with surviving microbial assaults from their food. Spotted hyenas (Crocuta crocuta) are capable hunters that have recently descended from carrion feeding ancestors. Hyenas have been documented to survive anthrax and rabies infections, and outbreaks of several other viral diseases that dec ...201122173276
Efficacy of a capsule conjugate vaccine against inhalational anthrax in rabbits and monkeys.Bacillus anthracis, the causative agent of anthrax, is recognized as one of the most serious bioterrorism threats. The current human vaccines are based on the protective antigen component of the anthrax toxins. Concern about possible vaccine resistant strains and reliance on a single antigen has prompted the search for additional immunogens. Bacterial capsules, as surface-expressed virulence factors, are well-established components of several licensed vaccines. In a previous study we showed that ...201122172509
occurrence, recognition, and reversion of spontaneous, sporulation-deficient bacillus anthracis mutants that arise during laboratory culture.bacillus anthracis is a spore-forming, soil-dwelling bacterium. this review describes the occurrence of spontaneous mutations leading to loss of sporulation and the selective pressures that can lead to their enrichment. we also discuss recognition of the associated phenotypes on solid medium, thereby allowing researchers to employ measures that either prevent or favor selection of sporulation-deficient mutants.201122166343
supercharging protein complexes from aqueous solution disrupts their native conformations.the effects of aqueous solution supercharging on the solution- and gas-phase structures of two protein complexes were investigated using traveling-wave ion mobility-mass spectrometry (twims-ms). low initial concentrations of m-nitrobenzyl alcohol (m-nba) in the electrospray ionization (esi) solution can effectively increase the charge of concanavalin a dimers and tetramers, but at higher m-nba concentrations, the increases in charge are accompanied by solution-phase dissociation of the dimers an ...201122161509
anthrax lethal and edema toxins fail to directly impair human platelet function.hemorrhage is a prominent clinical manifestation of systemic anthrax. therefore, we have examined the effects of anthrax lethal and edema toxins on human platelets. we find that anthrax lethal toxin fails to cleave its target, mitogen-activated protein kinase 1, and anthrax edema toxin fails to increase intracellular cyclic adenosine monophosphate. surface expression of toxin receptors tumor endothelial marker 8 and capillary morphogenesis gene 2, as well as coreceptor low density lipoprotein re ...201122158563
impact of spores on the comparative efficacies of five antibiotics for the treatment of bacillus anthracis in an in vitro hollow fiber pharmacodynamic model.background: bacillus anthracis (ba), the bacterium that causes anthrax, is an agent of bioterrorism. the most effective antimicrobial therapy for ba infections is unknown. methods: an in vitro pharmacodynamic model of ba was used to compare the efficacies of simulated clinically-prescribed regimens of moxifloxacin, linezolid, and meropenem with the "gold standards," doxycycline and ciprofloxacin. treatment outcomes for isogenic spore-forming and non-spore-forming strains of ba were compared. res ...201122155821
the iron binding protein dps2 confers peroxide stress resistance on bacillus anthracis.iron is an essential nutrient that is implicated in most of cellular oxidation reactions. however, iron is a highly reactive element that, if not appropriately chaperoned, can react with endogenously and exogenously generated oxidants such as hydrogen peroxide to generate highly toxic hydroxyl radicles. dps (dna-binding proteins from starved cells) proteins form a distinct class (the mini-ferritins) of iron-binding proteins within the ferritin superfamily. b. anthracis encodes two dps-like prote ...201122155779
structural basis of anthrax edema factor neutralization by a neutralizing antibody.fine epitope mapping of ef13d, a highly potent neutralizing monoclonal antibody specific for the anthrax edema factor (ef), was accomplished through random mutagenesis and yeast surface display. a yeast-displayed library of single point mutants of an ef domain iii (diii), comprising amino acids 624-800, was constructed by random mutagenesis and screened for reduced binding to ef13d. with this method, residues leu 667, ser 668, arg 671, and arg 672 were identified as key residues important for ef ...201122155239
Structure-based redesign of an edema toxin inhibitor.Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an ...201222154558
ecological niche modelling of the bacillus anthracis a1.a sub-lineage in kazakhstan.abstract:201122152056
small molecule inhibitors of anthrax toxin-induced cytotoxicity targeted against protective antigen.two molecular scaffolds were designed using the caveat molecular design package to inhibit the oligomerization of protective antigen (pa(63) ), a key protein component of anthrax toxin. the inhibitors were designed to prevent heptamerization of pa(63) by mimicking key residues of pa(63) needed for the intermolecular interactions that stabilize the heptamer. using the scaffolds identified by caveat, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxi ...201122146079
Screening of Peptide Libraries against Protective Antigen of Bacillus anthracis in a Disposable Microfluidic Cartridge.Bacterial surface peptide display has gained popularity as a method of affinity reagent generation for a wide variety of applications ranging from drug discovery to pathogen detection. In order to isolate the bacterial clones that express peptides with high affinities to the target molecule, multiple rounds of manual magnetic activated cell sorting (MACS) followed by multiple rounds of fluorescence activated cell sorting (FACS) are conventionally used. Although such manual methods are effective, ...201122140433
microchip capillary electrophoresis of multi-locus vntr analysis for genotyping of bacillus anthracis and yersinia pestis in microbial forensic cases.bacillus anthracis and yersinia pestis are etiological agents of anthrax and plague respectively, and are also considered among the most feared potential bioterrorism agents. these microorganisms show intraspecies genome homogeneity, making strains differentiation difficult, while strains identification and comparison with known genotypes may be crucial for naturally occurring outbreaks vs. bioterrorist events discrimination.here an mlva application for b. anthracis and y. pestis strains differe ...201222139674
unusual epidemic events: a new method of early orientation and differentiation between natural and deliberate epidemics.to develop a model for quick and accurate evaluation of unusual epidemic events (uee), based on the original model of bioterrorism risk assessment.201222136700
epidemic intelligence service investigations of respiratory illness, 1946-2005.infectious respiratory pathogens were the suspected cause of 480 outbreaks investigated by the centers for disease control and prevention's epidemic intelligence service officers during 1946-2005. all epidemic-assistance investigation reports and associated articles from scientific journals were reviewed. investigations identified 25 different infectious respiratory pathogens including, most frequently, tuberculosis, influenza, and legionellosis. other bacterial-, viral-, and fungal-related path ...201122135392
glycoconjugates prevent b. anthracis toxin-induced cell death through binding while activating macrophages.bacillus anthracis toxins may be attenuated if macrophages could neutralize toxins upon contact or exposure. glycoconjugate-bearing polymers, which have been shown to bind to bacillus spores, were tested for recognition and binding of protective antigen (pa), lethal factor (lf), and edema factor (ef) toxins. we have demonstrated modulation of macrophage activity following exposure to these toxins. without glycoconjugate (gc) activation, murine macrophages were killed by bacillus toxins. gcs were ...201122134879
bioterrorism: preparing the plastic surgeon.introduction: many medical disciplines, such as emergency medicine, trauma surgery, dermatology, psychiatry, family practice, and dentistry have documented attempts at assessing the level of bioterrorism preparedness in their communities. currently, there is neither such an assessment nor an existing review of potential bioterrorism agents as they relate to plastic surgery. therefore, the purpose of this article is to present plastic surgeons with a review of potential bioterrorism agents. metho ...201122132252
logistics modelling: improving resource management and public information strategies in florida.one of the most time-sensitive and logistically-challenging emergency response operations today is to provide mass prophylaxis to every man, woman and child in a community within 48 hours of a bioterrorism attack. to meet this challenge, federal, state and local public health departments in the usa have joined forces to develop, test and execute large-scale bioterrorism response plans. this preparedness and response effort is funded through the us centers for disease control and prevention's cit ...201122130343
A Review of Zoonotic Disease Surveillance Supported by the Armed Forces Health Surveillance Center.The Armed Forces Health Surveillance Center (AFHSC), Division of Global Emerging Infections Surveillance and Response System conducts disease surveillance through a global network of US Department of Defense research laboratories and partnerships with foreign ministries of agriculture, health and livestock development in over 90 countries worldwide. In 2010, AFHSC supported zoonosis survey efforts were organized into four main categories: (i) development of field assays for animal disease survei ...201122128834
Drug Interactions with Bacillus anthracis Topoisomerase IV: Biochemical Basis for Quinolone Action and Resistance.Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as a bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing the levels of DNA cleavage mediated by topoisomerase IV and gyrase. Quinolone resistance most often is associated with specific serine mutations in these enzymes. Therefore, to determine the basis for quinolone action and resistance, we characterized wild-type B. anthracis topoisomerase IV, the GrlA(S81F) and GrlA ...201122126453
risk factors associated with anthrax in cattle on smallholdings.summaryunprecedented high rates of anthrax outbreaks have been observed recently in cattle and humans in bangladesh, with 607 human cases in 2010. by enrolling 15 case and 15 control cattle smallholdings in the spatial zone in july-september 2010, we conducted a case-control study, data of which were analysed by matched-pair analysis and multivariable conditional logistic regression. feeding animals with uprooted and unwashed grass [odds ratio (or) 41·2, 95% confidence interval (ci) 3·7-458·8, p ...201122123521
antibodies for biodefense.potential bioweapons are biological agents (bacteria, viruses, and toxins) at risk of intentional dissemination. biodefense, defined as development of therapeutics and vaccines against these agents, has seen an increase, particularly in the us following the 2001 anthrax attack. this review focuses on recombinant antibodies and polyclonal antibodies for biodefense that have been accepted for clinical use. these antibodies aim to protect against primary potential bioweapons, or category a agents a ...201122123065
suitability of commercial transport media for biological pathogens under nonideal conditions.there is extensive data to support the use of commercial transport media as a stabilizer for known clinical samples; however, there is little information to support their use outside of controlled conditions specified by the manufacturer. furthermore, there is no data to determine the suitability of said media for biological pathogens, specifically those of interest to the us military. this study evaluates commercial off-the-shelf (cots) transport media based on sample recovery, viability, and q ...201122121364
Detection of anthrax toxin genetic sequences by the solid phase oligo-probes.Purpose: There is an urgent need to detect a rapid field-based test to detect anthrax. We have developed a rapid, highly sensitive DNA-based method to detect the anthrax toxin lethal factor gene located in pXO1, which is necessary for the pathogenicity of Bacillus anthracis. Materials and Methods: We have adopted the enzyme-linked immunosorbent assay (ELISA) so that instead of capturing antibodies we capture the DNA of the target sequence by a rapid oligo-based hybridization and then detect the ...201122120797
spectroscopic, catalytic and binding properties of bacillus subtilis no synthase-like protein: comparison with other bacterial and mammalian no synthases.genome sequencing has shown the presence of genes coding for no-synthase (nos)-like proteins in bacteria. the roles and properties of these proteins remain unclear. uv-visible spectroscopy was used to characterize the recombinant nos-like protein from bacillus subtilis (bsnos) in its ferric and ferrous states in the presence of various fe(iii)- and fe(ii)-heme-ligands and of a series of l-arginine (l-arg) analogs. bsnos exhibited several spectroscopic and binding properties in common with bacill ...201222119809
Association of the ANTXR2 gene polymorphism and ankylosing spondylitis in Chinese Han.Objective: Ankylosing spondylitis (AS) is an inflammatory disease of unknown origin. Both genetic and environmental factors are involved. A recent genome-wide association study (GWAS) found anthrax toxin receptor 2 (ANTXR2) to be associated with AS in Caucasians. We aimed to investigate whether the ANTXR2 polymorphism is also associated with AS in a Chinese Shandong Han population. Methods: From 2008 to 2009, we recruited 309 patients with AS and 384 age- and sex-matched controls of Han nation ...201122118297
Two cases of infection with Bacillus anthracis, Romania, October 2011.A cluster of two confirmed cases of anthrax were reported in October 2011 from a small village with a population of 3,400 people, in south-eastern Romania.One was a fatal case of cutaneous and anthrax meningoencephalitis, while the other had cutaneous anthrax. Both cases had been exposed to one Bacillus anthracis-infected cow via consumption of its meat or being involved in its slaughter.201122114977
Thawing of permafrost may disturb historic cattle burial grounds in East Siberia.Climate warming in the Arctic may increase the risk of zoonoses due to expansion of vector habitats, improved chances of vector survival during winter, and permafrost degradation. Monitoring of soil temperatures at Siberian cryology control stations since 1970 showed correlations between air temperatures and the depth of permafrost layer that thawed during summer season. Between 1900s and 1980s, the temperature of surface layer of permafrost increased by 2-4°C; and a further increase of 3°C is e ...201122114567
bacillus anthracis lethal toxin alters regulation of visceral sympathetic nerve discharge.bacillus anthracis infection is a pathophysiological condition that is complicated by progressive decreases in mean arterial pressure (map). lethal toxin (letx) is central to the pathogenesis of b. anthracis infection and the sympathetic nervous system plays a critical role in physiological regulation to acute stressors. however, the effect of letx on sympathetic nerve discharge (snd), a critical link between central sympathetic neural circuits and map regulation, remains unknown. we determined ...201122114180
Anthrax edema toxin impairs protein clearance in mice.Anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cAMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo. We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the pr ...201122104108
Lipoprotein biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination and full virulence of Bacillus anthracis.Bacterial lipoproteins play a crucial role in virulence in some Gram-positive bacteria. However, the role of lipoprotein biosynthesis in Bacillus anthracis is unknown. We created a B. anthracis mutant strain altered in lipoproteins by deleting the lgt gene encoding the enzyme prolipoprotein diacylglyceryl transferase, which attaches the lipid anchor to prolipoproteins. (14) C-palmitate labelling confirmed that the mutant strain lacked lipoproteins, and hydrocarbon partitioning showed it to have ...201222103323
Web interface for brownian dynamics simulation of ion transport and its applications to beta-barrel pores.Brownian dynamics (BD) based on accurate potential of mean force is an efficient and accurate method for simulating ion transport through wide ion channels. Here, a web-based graphical user interface (GUI) is presented for carrying out grand canonical Monte Carlo (GCMC) BD simulations of channel proteins: http://www.charmm-gui.org/input/gcmcbd. The webserver is designed to help users avoid most of the technical difficulties and issues encountered in setting up and simulating complex pore systems ...201222102176
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