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immuno capture pcr for rapid and sensitive identification of pathogenic bacillus anthracis.immuno capture pcr (ipcr) is a technique capable of detecting the pathogens with high specificity and sensitivity. rapid and accurate detection of bacillus anthracis was achieved using anti-ea1 antibodies to capture the cells and two primer sets targeting the virulence factors of the pathogen i.e., protective antigen (pag) and capsule (cap) in an ipcr format. monoclonal antibodies specific to b. anthracis were generated against extractable antigen 1 protein and used as capture antibody onto 96 w ...201323793942
zinc regulates the activity of kinase-phosphatase pair (basprkc/basprpc) in bacillus anthracis.bacillus anthracis ser/thr protein kinase prkc (basprkc) is important for virulence of the bacterium within the host. homologs of prkc and its cognate phosphatase prpc (basprpc) are the most conserved mediators of signaling events in diverse bacteria. basprkc homolog in bacillus subtilis regulates critical processes like spore germination and basprpc modulates the activity of basprkc by dephosphorylation. so far, biochemical and genetic studies have provided important insights into the roles of ...201323793375
protective-antigen (pa) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection.an intense effort has been launched to develop improved anthrax vaccines that confer rapid, long lasting protection preferably with an extended stability profile amenable for stockpiling. protective antigen (pa)-based vaccines are most favored as immune responses directed against pa are singularly protective, although the actual protective mechanism remains to be unraveled. herein we show that contrary to the prevailing view, an efficacious pa-based vaccine confers protection against inhalation ...201323787486
differentiation of springtime vegetation indices associated with summer anthrax epizootics in west texas, usa, deer.anthrax outbreaks in white-tailed deer, odocoileus virginianus, are frequent in west texas, usa, particularly across the edwards plateau. however, the outbreak severity varies among years. we summarize the outbreak history in white-tailed deer at a ranch north of del rio, texas, from 2001 to 2010 and compare mortality rates to remotely sensed vegetation indices derived from moderate resolution imaging spectroradiometer satellite data. it has long been posited that the occurrence of mid- to high- ...201323778625
small-molecule inhibitors of lethal factor protease activity protect against anthrax infection.bacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. the bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. we previously developed small-molecule inhibitors of lethal factor proteolytic activity (lfis) and demonstrated their in vivo efficacy in a rat lethal toxin challenge model. in this work, we show that th ...201323774434
detection of protective antigen, an anthrax specific toxin in human serum by using surface plasmon resonance.in this study, surface plasmon resonance (spr) technology was used for the sensitive detection of protective antigen (pa), an anthrax specific toxin in spiked human serum samples. a monoclonal antibody raised against bacillus anthracis pa was immobilized on carboxymethyldextran-modified gold chip, and its interaction with pa was characterized in situ by spr. by using kinetic evaluation software, kd (equilibrium constant) and bmax (maximum binding capacity of analyte) were found to be 20 fm and 1 ...201323773677
razor ex anthrax air detection system for detection of bacillus anthracis spores from aerosol collection samples: collaborative study.the razor ex anthrax air detection system was validated in a collaborative study for the detection of bacillus anthracis in aerosol collection buffer. phosphate-buffered saline was charged with 1 mg/ml standardized dust to simulate an authentic aerosol collection sample. the dust-charged buffer was spiked with either b. anthracis ames at 2000 spores/ml or bacillus cereus at 20 000 spores/ml. twelve collaborators participated in the study, with four collaborators at each of three sites. each coll ...201323767365
cross-functionalities of bacillus deacetylases involved in bacillithiol biosynthesis and bacillithiol-s-conjugate detoxification pathways.bshb, a key enzyme in bacillithiol biosynthesis, hydrolyses the acetyl group from n-acetylglucosamine malate to generate glucosamine malate. in bacillus anthracis, ba1557 has been identified as the n-acetylglucosamine malate deacetylase (bshb); however, a high content of bacillithiol (~70%) was still observed in the b. anthracis ∆ba1557 strain. genomic analysis led to the proposal that another deacetylase could exhibit cross-functionality in bacillithiol biosynthesis. in the present study, ba155 ...201323758290
characterization of bacillus anthracis persistence in vivo.pulmonary exposure to bacillus anthracis spores initiates inhalational anthrax, a life-threatening infection. it is known that dormant spores can be recovered from the lungs of infected animals months after the initial spore exposure. consequently, a 60-day course antibiotic treatment is recommended for exposed individuals. however, there has been little information regarding details or mechanisms of spore persistence in vivo. in this study, we investigated spore persistence in a mouse model. th ...201323750280
cleavage of the junb transcription factor by caspases generates a carboxyl-terminal fragment that inhibits activator protein-1 transcriptional activity.the activator protein-1 (ap-1) family transcription factor, junb, is an important regulator of proliferation, apoptosis, differentiation, and the immune response. in this report, we show that junb is cleaved in a caspase-dependent manner in apoptotic anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma cell lines and that ectopically expressed junb is cleaved in murine raw 264.7 macrophage cells treated with the nalp1b inflammasome activator, anthrax lethal toxin. in both cases, w ...201323749999
straight talk with... tom inglesby. interview by kevin jiang.when letters containing anthrax spores were mailed to several us senators and media offices in september 2001, just one week after the 9/11 attacks, bioterrorism catapulted to the national stage. political leaders and public health officials, desperate for guidance on this once-theoretical scenario, turned to experts including tom inglesby, then deputy director of the johns hopkins center for civilian biodefense strategies, a bioterrorism research and analysis think tank in baltimore. in the yea ...201323744137
thermal effects on surface structures and properties of bacillus anthracis spores on nanometer scales.bacterial spores, one of the hardiest forms of life known, can survive severe environmental stresses such as high temperature. using thermal atomic force microscopy (afm), we show that the surface structures and properties of bacillus anthracis spores when exposed to elevated temperatures undergo substantial changes on nanometer scales. thermal-blister-like nanostructures, which grow in size with increasing temperature, are formed on the spore surface when it is heated by a thermal tip. although ...201323742662
the sepsis model: an emerging hypothesis for the lethality of inhalation anthrax.inhalation anthrax is often described as a toxin-mediated disease. however, the toxaemia model does not account for the high mortality of inhalation anthrax relative to other forms of the disease or for the pathology present in inhalation anthrax. patients with inhalation anthrax consistently show extreme bacteraemia and, in contrast to animals challenged with toxin, signs of sepsis. rather than toxaemia, we propose that death in inhalation anthrax results from an overwhelming bacteraemia that l ...201323742651
mapping the epitopes of a neutralizing antibody fragment directed against the lethal factor of bacillus anthracis and cross-reacting with the homologous edema factor.the lethal toxin (lt) of bacillus anthracis, composed of the protective antigen (pa) and the lethal factor (lf), plays an essential role in anthrax pathogenesis. pa also interacts with the edema factor (ef, 20% identity with lf) to form the edema toxin (et), which has a lesser role in anthrax pathogenesis. the first recombinant antibody fragment directed against lf was scfv 2lf; it neutralizes lt by blocking the interaction between pa and lf. here, we report that scfv 2lf cross-reacts with ef an ...201323741517
genomic copy number variants: evidence for association with antibody response to anthrax vaccine adsorbed.anthrax and its etiologic agent remain a biological threat. anthrax vaccine is highly effective, but vaccine-induced igg antibody responses vary widely following required doses of vaccinations. such variation can be related to genetic factors, especially genomic copy number variants (cnvs) that are known to be enriched among genes with immunologic function. we have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination.201323741398
bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model.disseminated intravascular coagulation (dic) appears to be important in the pathogenesis of bacillus anthracis infection, but its causes are unclear. although lethal toxin (lt) and edema toxin (et) could contribute, b. anthracis cell wall peptidoglycan (pgn), not the toxins, stimulates inflammatory responses associated with dic.201323737601
bacillus anthracis peptidoglycan activates human platelets through fcγrii and complement.platelet activation frequently accompanies sepsis and contributes to the sepsis-associated vascular leakage and coagulation dysfunction. our previous work has implicated peptidoglycan (pgn) as an agent causing systemic inflammation in gram-positive sepsis. we used flow cytometry and fluorescent microscopy to define the effects of pgn on the activation of human platelets. pgn induced platelet aggregation, expression of the activated form of integrin αiibβ3, and exposure of phosphatidylserine (ps) ...201323733338
pandemic influenza planning, united states, 1978-2008.during the past century, 4 influenza pandemics occurred. after the emergence of a novel influenza virus of swine origin in 1976, national, state, and local us public health authorities began planning efforts to respond to future pandemics. several events have since stimulated progress in public health emergency planning: the 1997 avian influenza a(h5n1) outbreak in hong kong, china; the 2001 anthrax attacks in the united states; the 2003 outbreak of severe acute respiratory syndrome; and the 200 ...201323731839
competency in chaos: lifesaving performance of care providers utilizing a competency-based, multi-actor emergency preparedness training curriculum.providing comprehensive emergency preparedness training (ept) to care providers is important to the future success of disaster operations in the us. few ept programs possess both competency-driven goals and metrics to measure performance during a multi-patient simulated disaster.201323731521
bacillus anthracis co-opts nitric oxide and host serum albumin for pathogenicity in hypoxic conditions.bacillus anthracis is a dangerous pathogen of humans and many animal species. its virulence has been mainly attributed to the production of lethal and edema toxins as well as the antiphagocytic capsule. recent data indicate that the nitric oxide (no) synthase (banos) plays an important pathogenic role at the early stage of disease by protecting bacteria from the host reactive species and s-nytrosylating the mitochondrial proteins in macrophages. in this study we for the first time present eviden ...201323730627
assessment of delivery parameters with the multi-electrode array for development of a dna vaccine against bacillus anthracis.gene electrotransfer (get) enhances delivery of dna vaccines by increasing both gene expression and immune responses. our lab has developed the multi-electrode array (mea) for dna delivery to skin. the mea was used at constant pulse duration (150 ms) and frequency (6.67 hz). in this study, delivery parameters including applied voltage (5-45 v), amount of plasmid (100-300 μg), and number of treatments (2-3) were evaluated for delivery of a dna vaccine. mice were intradermally injected with plasmi ...201323727769
spatial modelling of bacillus anthracis ecological niche in zimbabwe.anthrax continues to cause significant mortalities in livestock, wildlife and humans worldwide. in zimbabwe, anthrax outbreaks have been reported almost annually over the past four decades. in this study we tested whether anthrax outbreak data and a set of environmental variables can be used to predict the ecological niche for bacillus anthracis using maximum entropy modelling for species geographical distribution (maxent). confirmed geo-referenced anthrax outbreaks data for the period 1995-2010 ...201323726015
a descriptive overview of the burden, distribution and characteristics of epidemics in uganda.although uganda is a high burden country for epidemics of infectious diseases, the pattern of epidemics has not yet been adequately documented. the purpose of this study was to describe the distribution, magnitude and characteristics of recent epidemics in uganda, as a basis for informing policy on priorities for targeted prevention of epidemics.201325130019
anthrax set protein: a potential virulence determinant that epigenetically represses nf-κb activation in infected macrophages.toxins play a major role in the pathogenesis of bacillus anthracis by subverting the host defenses. however, besides toxins, b. anthracis expresses effector proteins, whose role in pathogenesis are yet to be investigated. here we present that suppressor-of-variegation, enhancer-of-zeste, trithorax protein from b. anthracis (baset) methylates human histone h1, resulting in repression of nf-κb functions. notably, baset is secreted and undergoes nuclear translocation to enhance h1 methylation in b. ...201323720780
detection of biological warfare agents using ultra violet-laser induced fluorescence lidar.this review has been written to highlight the threat of biological warfare agents, their types and detection. bacterial biological agent bacillus anthracis (bacteria causing the disease anthrax) which is most likely to be employed in biological warfare is being discussed in detail. standoff detection of biological warfare agents in aerosol form using ultra violet-laser induced fluorescence (uv-lif) spectroscopy method has been studied. range-resolved detection and identification of biological ae ...201323719340
cct chaperonin complex is required for efficient delivery of anthrax toxin into the cytosol of host cells.bacterial toxins have evolved successful strategies for coopting host proteins to access the cytosol of host cells. anthrax lethal factor (lf) enters the cytosol through pores in the endosomal membrane formed by anthrax protective antigen. although in vitro models using planar lipid bilayers have shown that translocation can occur in the absence of cellular factors, recent studies using intact endosomes indicate that host factors are required for translocation in the cellular environment. in thi ...201323716698
structure of the chlamydia trachomatis immunodominant antigen pgp3.chlamydia trachomatis infection is the most common sexually transmitted bacterial disease. left untreated, it can lead to ectopic pregnancy, pelvic inflammatory disease, and infertility. here we present the structure of the secreted c. trachomatis protein pgp3, an immunodominant antigen and putative virulence factor. the ∼84-kda pgp3 homotrimer, encoded on a cryptic plasmid, consists of globular n- and c-terminal assemblies connected by a triple-helical coiled-coil. the c-terminal domains posses ...201323703617
randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of anthrax vaccine adsorbed plus cpg 7909 (av7909) in healthy adult volunteers.a new anthrax vaccine that could accelerate the immune response and possibly reduce the number of injections needed for protection would be desirable in a post-exposure setting. this phase 1 study compared the safety and immunogenicity of 2 im doses (days 0 and 14) of 4 formulations of av7909 (ava plus cpg 7909) with 2 im doses of biothrax(®) (anthrax vaccine adsorbed) and 2 im doses of saline placebo administered on days 0 and 14. a total of 105 healthy adults 18-50 years of age were randomized ...201323701746
anthrax threat: a review of clinical and diagnostic measures.anthrax is the plague of the ancient world and its existence is confirmed by the roman poet virgil. also it is a threat in the modern world as it can be used in biological wars and bioterrorism. anthrax is caused by bacillus anthracis an unmovable, aerobic, gram-positive rod. it forms spores, which can survive for years in the environment. three clinical forms result after exposure to anthrax spores: cutaneous, respiratory, and gastro- intestinal. the cutaneous anthrax commonly prevails among hu ...201323697023
decontamination of materials contaminated with bacillus anthracis and bacillus thuringiensis al hakam spores using pes-solid, a solid source of peracetic acid.to develop test methods and evaluate survival of bacillus anthracis ames, b. anthracis ∆sterne and b. thuringiensis al hakam spores after exposure to pes-solid (a solid source of peracetic acid), including pes-solid formulations with bacteriostatic surfactants.201323692445
[response and evaluation of the disinfection effects on an anthrax outbreak in human being and cattle in guizhou]. 201323678679
proteomic analysis of the oxidative stress response induced by low-dose hydrogen peroxide in bacillus anthracis.anthrax is a bacterial disease caused by the aerobic sporeforming bacterium bacillus anthracis, which is an important pathogen owing to its ability to be used as a terror agent. b. anthracis spores can escape phagocytosis and initiate the germination process even in antimicrobial conditions, such as oxidative stress. to analyze the oxidative stress response in b. anthracis and thereby learn how to prevent antimicrobial resistance, we performed protein expression profiling of b. anthracis strain ...201323676920
the use of colorimetric sensor arrays to discriminate between pathogenic bacteria.a colorimetric sensor array is a high-dimensional chemical sensor that is cheap, compact, disposable, robust, and easy to operate, making it a good candidate technology to detect pathogenic bacteria, especially potential bioterrorism agents like yersinia pestis and bacillus anthracis which feature on the center for disease control and prevention's list of potential biothreats. here, a colorimetric sensor array was used to continuously monitor the volatile metabolites released by bacteria in soli ...201323671629
studying the fate of non-volatile organic compounds in a commercial plasma air purifier.degradation of non-volatile organic compounds-environmental toxins (methyltriclosane and phenanthrene), bovine serum albumin, as well as bioparticles (legionella pneumophila, bacillus subtilis, and bacillus anthracis)-in a commercially available plasma air purifier based on a cold plasma was studied in detail, focusing on its efficiency and on the resulting degradation products. this system is capable of handling air flow velocities of up to 3.0m s(-1) (3200lmin(-1)), much higher than other plas ...201323669793
optimization of a novel potent and selective bacterial dna helicase inhibitor scaffold from a high throughput screening hit.benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified staphylococcus aureus (sa) and bacillus anthracis (ba) replicative helicases. chemical optimization has produced compound 59 with nanomolar potency against the dna duplex strand unwinding activities of both b. anthracis and s. aureus helicases. selectivity index (si=cc50/ic50) values for 59 were greater than 500. kinetic studies demonstrated that the benzobisthiazole-based ...201323664213
assay for peptidoglycan o-acetyltransferase: a potential new antibacterial target.the o-acetylation of peptidoglycan occurs at the c-6 hydroxyl group of muramoyl residues in many human pathogens, both gram positive and gram negative, such as staphylococcus aureus and species of campylobacter, helicobacter, neisseria, and bacillus, including bacillus anthracis. the process is a maturation event being catalyzed either by integral membrane o-acetylpeptidoglycan transferase (oat) of gram-positive bacteria or by a two-component peptidoglycan o-acetyltransferase system (pata/patb) ...201323660013
evaluation of immunogenicity and efficacy of anthrax vaccine adsorbed for postexposure prophylaxis.antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (pep). in a rabbit pep study, animals were subjected to lethal challenge with aerosolized bacillus ...201323658392
human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed.interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (hla) and other gene families. this study examined associations between hla genotypes, haplotypes, and homozygosity and protective antigen (pa)-specific cellular immune responses in healthy subjects following immunization with anthrax vaccine adsorbed (ava). while limited associations were observed between individual hla alleles or haplotypes and variable ly ...201323649091
prothera biologics, inc.: a novel immunomodulator and biomarker for life-threatening diseases.prothera biologics is a development stage bio-therapeutics company in east providence, rhode island. the company was founded in 2002 to focus on the critical role and commercial potential of inter-alpha inhibitor proteins (iaip) for treating acute life-threatening inflammatory diseases. the discovery research originated in the basic research laboratories of the co-founders, yow-pin lim, md, phd, and douglas c. hixson, phd, at rhode island hospital, a lifespan partner. the company is backed by th ...201323641420
constructing droplet interface bilayers from the contact of aqueous droplets in oil.we describe a protocol for forming an artificial lipid bilayer by contacting nanoliter aqueous droplets in an oil solution in the presence of phospholipids. a lipid monolayer forms at each oil-water interface, and when two such monolayers touch, a bilayer is created. droplet interface bilayers (dibs) are a simple way to generate stable bilayers suitable for single-channel electrophysiology and optical imaging from a wide variety of preparations, ranging from purified proteins to reconstituted eu ...201323640169
a single-dose plga encapsulated protective antigen domain 4 nanoformulation protects mice against bacillus anthracis spore challenge.bacillus anthracis, the etiological agent of anthrax, is a major bioterror agent. vaccination is the most effective prophylactic measure available against anthrax. currently available anthrax vaccines have issues of the multiple booster dose requirement, adjuvant-associated side effects and stability. use of biocompatible and biodegradable nanoparticles to deliver the antigens to immune cells could solve the issues associated with anthrax vaccines. we hypothesized that the delivery of a stable i ...201323637922
igg subclass and heavy chain domains contribute to binding and protection by mabs to the poly γ-d-glutamic acid capsular antigen of bacillus anthracis.bacterial capsules are common targets for antibody-mediated immunity. the capsule of bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-γ-d-glutamic acid (γdpga). we previously generated murine igg3 monoclonal antibodies (mabs) to γdpga that were protective in a murine model of pulmonary anthrax. igg3 antibodies are characteristic of the murine response to polysaccharide antigens. the goal of the present study was to produce subclass switch variants of the γ ...201323637599
characterization of the native form of anthrax lethal factor for use in the toxin neutralization assay.the cell-based anthrax toxin neutralization assay (tna) is used to determine functional antibody titers of sera from animals and humans immunized with anthrax vaccines. the anthrax lethal toxin is a critical reagent of the tna composed of protective antigen (pa) and lethal factor (lf), which are neutralization targets of serum antibodies. cytotoxic potency of recombinant lf (rlf) lots can vary substantially, causing a challenge in producing a renewable supply of this reagent for validated tnas. ...201323637044
anthrax toxin-mediated delivery of the pseudomonas exotoxin a enzymatic domain to the cytosol of tumor cells via cleavable ubiquitin fusions.anthrax toxin proteins from bacillus anthracis constitute a highly efficient system for delivering cytotoxic enzymes to the cytosol of tumor cells. however, exogenous proteins delivered to the cytosol of cells are subject to ubiquitination on lysines and proteasomal degradation, which limit their potency. we created fusion proteins containing modified ubiquitins with their c-terminal regions fused to the pseudomonas exotoxin a catalytic domain (peiii) in order to achieve delivery and release of ...201323631917
interactions of antimicrobial peptide chrysophsin-3 with bacillus anthracis in sporulated, germinated, and vegetative states.bacillus anthracis spores contain on their surface multilayered protein coats that provide barrier properties, mechanical strength, and elasticity that aid in protecting the sporulated state and preventing germination, outgrowth, and transition into the virulent vegetative bacterial state. in this work, the antimicrobial peptide (amp) chrysophsin-3 was tested against b. anthracis in each of the three distinct metabolic states (sporulated, germinated, and vegetative) for its bacteria-killing acti ...201323631815
anthrax lethal toxin downregulates claudin-5 expression in human endothelial tight junctions.vascular leakage pathologies such as pleural effusion and hemorrhage are hallmarks of anthrax pathogenesis. we previously reported that anthrax lethal toxin (lt), the major virulence factor of anthrax, reduces barrier function in cultured primary human microvascular endothelial cells. here, we show that lt-induced barrier dysfunction is accompanied by the reduced expression of the endothelial tight junction (tj) protein claudin-5 but no change in the expression of other tj components occludin, z ...201323626836
exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1.anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (pa) with one of three reported cell surface toxin receptors (antxr). receptor binding has been shown to influence host susceptibility to the toxins. despite this crucial role for antxr in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about antxr expression on human leucocytes. we characterized the expr ...201323607659
chemical genetics reveals a kinase-independent role for protein kinase r in pyroptosis.formation of the inflammasome, a scaffolding complex that activates caspase-1, is important in numerous diseases. pyroptotic cell death induced by anthrax lethal toxin (lt) is a model for inflammasome-mediated caspase-1 activation. we discovered 7-desacetoxy-6,7-dehydrogedunin (7dg) in a phenotypic screen as a small molecule that protects macrophages from lt-induced death. using chemical proteomics, we identified protein kinase r (pkr) as the target of 7dg and show that rnai knockdown of pkr phe ...201323603659
rapid and reliable detection of bacterial endospores in environmental samples by diagnostic electron microscopy combined with x-ray microanalysis.diagnostic negative staining electron microscopy is a front-line method for the rapid investigation of environmental and clinical samples in emergency situations caused by bioterrorism or outbreaks of an infectious disease. spores of anthrax are one of the diagnostic targets in case of bioterrorism, because they have been used as a bio-weapon in the past and their production and transmission are rather simple. with negative staining electron microscopy bacterial spores can be identified based on ...201323603002
mutations in antxr1 cause gapo syndrome.the genetic cause of gapo syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. we studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262c>t [p.arg88*] and c.505c>t [p.arg169*]) or splicing mutations (c.1435-12a>g [p.gly479phefs*119]) in antxr1, which encodes anthrax toxin receptor 1. the nonsense mutations predictably trigger nonsense-mediate ...201323602711
stereo-selective binding of monoclonal antibodies to the poly-γ-d-glutamic acid capsular antigen of bacillus anthracis.bacillus anthracis is surrounded by an anti-phagocytic capsule that is entirely composed of γ-linked d-glutamic acid (γdpga). γdpga is required for virulence and is produced in large quantities following spore germination. we have previously described the isolation of several γdpga-reactive mabs. the reagents are effective in both immunoprotection and diagnostic applications. the current work was done to further investigate the specificity of γdpga-reactive mabs. the specificity of each mab was ...201323602451
automated thermochemolysis reactor for detection of bacillus anthracis endospores by gas chromatography-mass spectrometry.an automated sample preparation system was developed and tested for the rapid detection of bacillus anthracis endospores by gas chromatography-mass spectrometry (gc-ms) for eventual use in the field. this reactor is capable of automatically processing suspected bio-threat agents to release and derivatize unique chemical biomarkers by thermochemolysis (tcm). the system automatically controls the movement of sample vials from one position to another, crimping of septum caps onto the vials, precise ...201323601976
disease-enhancing antibodies improve the efficacy of bacterial toxin-neutralizing antibodies.during infection, humoral immunity produces a polyclonal response with various immunoglobulins recognizing different epitopes within the microbe or toxin. despite this diverse response, the biological activity of an antibody (ab) is usually assessed by the action of a monoclonal population. we demonstrate that a combination of monoclonal antibodies (mabs) that are individually disease enhancing or neutralizing to bacillus anthracis protective antigen (pa), a component of anthrax toxin, results i ...201323601104
architecture and assembly of the gram-positive cell wall.the bacterial cell wall is a mesh polymer of peptidoglycan--linear glycan strands cross-linked by flexible peptides--that determines cell shape and provides physical protection. while the glycan strands in thin 'gram-negative' peptidoglycan are known to run circumferentially around the cell, the architecture of the thicker 'gram-positive' form remains unclear. using electron cryotomography, here we show that bacillus subtilis peptidoglycan is a uniformly dense layer with a textured surface. we f ...201323600697
federal legal preparedness tools for facilitating medical countermeasure use during public health emergencies.preparing for and responding to public health emergencies involving medical countermeasures (mcms) raise often complex legal challenges and questions among response stakeholders at the local, state, and federal levels. this includes concerns about emergency legal authorities, liability, emergency use of regulated medical products, and regulations that might enhance or hinder public health response goals. in this article, lawyers from the u.s. department of health and human services' (hhs) office ...201323590735
pharmaceutical approval update.cabozantinib (cometriq) for metastatic medullary thyroid cancer; ponatinib (iclusig) for two forms of leukemia; and raxibacumab for inhalational anthrax.201323599674
draft genome sequences of two bulgarian bacillus anthracis strains.bacillus anthracis strains previously isolated from bulgaria form a unique subcluster within the a1.a cluster that is typical for isolates from southeastern europe. here, we report the draft genome sequences of two bulgarian b. anthracis strains belonging to the a branch (a.br.)008/009 canonical single nucleotide polymorphism (snp) group of the major a branch.201323599294
use of a bacteriophage lysin to identify a novel target for antimicrobial development.we identified an essential cell wall biosynthetic enzyme in bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. this work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. focusing on the b. anthracis-specific plyg lysin, we first identified its unique cell wall receptor and cognate biosynthetic path ...201323593301
us delays testing anthrax vaccine for children. 201323589431
electrical graphene aptasensor for ultra-sensitive detection of anthrax toxin with amplified signal transduction.detection of the anthrax toxin, the protective antigen (pa), at the attomolar (am) level is demonstrated by an electrical aptamer sensor based on a chemically derived graphene field-effect transistor (fet) platform. higher affinity of the aptamer probes to pa in the aptamer-immobilized fet enables significant improvements in the limit of detection (lod), dynamic range, and sensitivity compared to the antibody-immobilized fet. transduction signal enhancement in the aptamer fet due to an increase ...201323589198
the papain inhibitor (spi) of streptomyces mobaraensis inhibits bacterial cysteine proteases and is an antagonist of bacterial growth.a novel papain inhibitory protein (spi) from streptomyces mobaraensis was studied to measure its inhibitory effect on bacterial cysteine protease activity (staphylococcus aureus sspb) and culture supernatants (porphyromonas gingivalis, bacillus anthracis). further, growth of bacillus anthracis, staphylococcus aureus, pseudomonas aeruginosa, and vibrio cholerae was completely inhibited by 10 μm spi. at this concentration of spi, no cytotoxicity was observed. we conclude that spi inhibits bacteria ...201323587952
b. anthracis edema toxin increases camp levels and inhibits phenylephrine-stimulated contraction in a rat aortic ring model.b. anthracis edema toxin (et) and lethal toxin (lt) are each composed of protective antigen (pa), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (ef) and lethal factor (lf). although both toxins likely contribute to shock during infection, their mechanisms are unclear. to test whether et and lt produce arterial relaxation, their effects on phenylephrine (pe)-stimulated contraction in a sprague-dawley rat aortic ring model were measured. rings were pre ...201323585140
effects of experimental exclusion of scavengers from carcasses of anthrax-infected herbivores on bacillus anthracis sporulation, survival, and distribution.scavenging of anthrax carcasses has long been hypothesized to play a critical role in the production of the infectious spore stage of bacillus anthracis after host death, though empirical studies assessing this are lacking. we compared b. anthracis spore production, distribution, and survival at naturally occurring anthrax herbivore carcasses that were either experimentally caged to exclude vertebrate scavengers or left unmanipulated. we found no significant effect of scavengers on soil spore de ...201323584788
bacillus anthracis spore decontamination in food grease.bacillus anthracis sterne strain spores were analyzed for their resistance against five disinfectants: commercial sodium hypochlorite, spor-klenz ready-to-use cold sterilant, accelerated hydrogen peroxide (ahp), virkon, and surface decontamination foam (sdf). the aim of this study was to find an effective disinfectant that would reduce the viability of b. anthracis sterne spores at ≥6 log in the presence of variables such as animal grease and fat, stainless steel, and temperature (room temperatu ...201323575137
identification of novel anthrax toxin countermeasures using in silico methods.anthrax is an acute infectious disease caused by the spore-forming, gram-positive, rod-shaped bacterium bacillus anthracis. the anthrax toxin lethal factor (lf) is the primary anthrax toxin component responsible for cytotoxicity and host death and has been a heavily researched target for design of postexposure therapeutics in the event of a bioterror attack. various computer-aided drug design methodologies have proven useful for pinpointing new antianthrax drug scaffolds, optimizing existing lea ...201323568471
modeling low-dose mortality and disease incubation period of inhalational anthrax in the rabbit.there is a need to advance our ability to conduct credible human risk assessments for inhalational anthrax associated with exposure to a low number of bacteria. combining animal data with computational models of disease will be central in the low-dose and cross-species extrapolations required in achieving this goal. the objective of the current work was to apply and advance the competing risks (cr) computational model of inhalational anthrax where data was collected from nzw rabbits exposed to a ...201323567649
evaluation of cutaneous palpebral anthrax.anthrax is a rare disease caused by bacillus anthracis. antrax is zoonotic disease and is often encountered in persons engaged in animal husbandry. cutaneous anthrax is approximately 95% of anthrax in humans. palbebral involvement is rare.201323566172
differentiation of bacillus anthracis, b. cereus, and b. thuringiensis on the basis of the csab gene reflects host source.csab gene analysis clustered 198 strains of bacillus anthracis, bacillus cereus, and bacillus thuringiensis into two groups related to mammalian and insect hosts, respectively. mammal-related group i strains also have more s-layer homology (slh) protein genes than group ii strains. this indicates that csab-based differentiation reflects selective pressure from animal hosts.201323563945
evaluation of dna extraction methods for bacillus anthracis spores isolated from spiked food samples.nine commercial dna extraction kits were evaluated for the isolation of dna from 10-fold serial dilutions of bacillus anthracis spores using quantitative real-time pcr (qpcr). the three kits determined by qpcr to yield the most sensitive and consistent detection (epicenter masterpure gram positive; mobio powerfood; abi prepseq) were subsequently tested for their ability to isolate dna from trace amounts of b. anthracis spores (approx. 6·5 × 10(1) and 1·3 × 10(2)  cfu in 25 ml or 50 g of food sam ...201323560745
anthrax among heroin users in europe possibly caused by same bacillus anthracis strain since 2000.injection anthrax was described first in 2000 in a heroin-injecting drug user in norway. new anthrax cases among heroin consumers were detected in the united kingdom (52 cases) and germany (3 cases) in 2009-10. in june 2012, a fatal case occurred in regensburg, bavaria. as of december 2012, 13 cases had been reported in this new outbreak from germany, denmark, france and the united kingdom. we analysed isolates from 2009-10 and 2012 as well as from the first injection anthrax case in norway in 2 ...201323557972
suppressive effects of anthrax lethal toxin on megakaryopoiesis.anthrax lethal toxin (lt) is a major virulence factor of bacillus anthracis. lt challenge suppresses platelet counts and platelet function in mice, however, the mechanism responsible for thrombocytopenia remains unclear. lt inhibits cellular mitogen-activated protein kinases (mapks), which are vital pathways responsible for cell survival, differentiation, and maturation. one of the mapks, the mek1/2-extracellular signal-regulated kinase pathway, is particularly important in megakaryopoiesis. thi ...201323555687
synthetic ion transporters that work with anion-π interactions, halogen bonds, and anion-macrodipole interactions.the transport of ions and molecules across lipid bilayer membranes connects cells and cellular compartments with their environment. this biological process is central to a host of functions including signal transduction in neurons and the olfactory and gustatory sensing systems, the translocation of biosynthetic intermediates and products, and the uptake of nutrients, drugs, and probes. biological transport systems are highly regulated and selectively respond to a broad range of physical and che ...201323547885
raxibacumab for anthrax. 201323545582
sporicidal efficacy of ph-adjusted bleach for control of bioburden on production facility surfaces.ph-adjusted bleach was one of the agents used to disinfect contaminated public buildings in the usa following the 2001 bioterrorist attack with bacillus anthracis spores. a usepa fact sheet describes the preparation of ph-adjusted bleach by combining diluted sodium hypochlorite (naocl) with a controlled amount of 5 % acetic acid. this paper reports a modification of this procedure to qualify the use of ph-adjusted bleach for routine disinfection of cleanroom surfaces in pharmaceutical manufactur ...201323532317
double-color fluorescence in situ hybridization (fish) for the detection of bacillus anthracis spores in environmental samples with a novel permeabilization protocol.for anti-bioterrorism measures against the use of bacillus anthracis, a double-color fluorescence in situ hybridization (fish) is proposed, for the rapid and specific detection of b. anthracis. the probes were designed based on the differences in 16s and 23s rrna genes of b. cereus group. a new permeabilization protocol was developed to enhance the permeability of fish probes into b. anthracis spores. the highest detection rate (90.8 ± 0.69) of b. anthracis spores by fish was obtained with succe ...201323523967
diversity of thermal ecotypes and potential pathotypes of bacillus thuringiensis soil isolates.ecological diversification of bacillus thuringiensis soil isolates was examined to determine whether bacteria adapted to grow at low temperature and/or potentially pathogenic correspond to genetically distinct lineages. altogether, nine phylogenetic lineages were found among bacilli originating from north-eastern poland (n = 24) and lithuania (n = 25) using multi-locus sequence typing. this clustering was chiefly confirmed by pulsed-field gel electrophoresis. one third of the bacilli were found ...201323521504
screen-printed fluorescent sensors for rapid and sensitive anthrax biomarker detection.since the 2001 anthrax attacks, efforts have focused on the development of an anthrax detector with rapid response and high selectivity and sensitivity. here, we demonstrate a fluorescence sensor for detecting anthrax biomarker with high sensitivity and selectivity using a screen-printing method. a lanthanide-ethylenediamine tetraacetic acid complex was printed on a flexible polyethersulfone film. screen-printing deposition of fluorescent detecting moieties produced fluorescent patterns that act ...201323518174
structure of the nlrp1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1.the nlrp1 inflammasome responds to microbial challenges such as bacillus anthracis infection and is implicated in autoimmune disease such as vitiligo. human nlrp1 contains both an n-terminal pyrin domain (pyd) and a c-terminal caspase recruitment domain (card), with the latter being essential for its association with the downstream effector procaspase-1. here we report a 2.0 å crystal structure of the human nlrp1 card as a fusion with the maltose-binding protein. the structure reveals the six-he ...201323508996
the importance of establishing a national health security preparedness index.natural disasters, infectious disease epidemics, terrorism, and major events like the nuclear incident at fukushima all pose major potential challenges to public health and security. events such as the anthrax letters of 2001, hurricanes katrina, irene, and sandy, severe acute respiratory syndrome (sars) and west nile virus outbreaks, and the 2009 h1n1 influenza pandemic have demonstrated that public health, emergency management, and national security efforts are interconnected. these and other ...201323506403
transcriptional analysis of the three nlrp1 paralogs in mice.signals of danger and damage in the cytosol of cells are sensed by nod-like receptors (nlrs), which are components of multiprotein complexes called inflammasomes. inflammasomes activate caspase-1, resulting in il-1-beta and il-18 secretion and an inflammatory response. to date, the only known activator of rodent nlrp1 is anthrax lethal toxin (lt), a protease secreted by the bacterial pathogen bacillus anthracis. although susceptibility of mouse macrophages to lt has been genetically linked to nl ...201323506131
three dimensional structure of the anthrax toxin translocon-lethal factor complex by cryo-electron microscopy.we have visualized by cryo-electron microscopy (cryo-em) the complex of the anthrax protective antigen (pa) translocon and the n-terminal domain of anthrax lethal factor (lf(n) inserted into a nanodisc model lipid bilayer. we have determined the structure of this complex at a nominal resolution of 16 å by single-particle analysis and three-dimensional reconstruction. consistent with our previous analysis of negatively stained unliganded pa, the translocon comprises a globular structure (cap) sep ...201323494942
the secondary cell wall polysaccharide of bacillus anthracis provides the specific binding ligand for the c-terminal cell wall-binding domain of two phage endolysins, plyl and plyg.endolysins are bacteriophage enzymes that lyse their bacterial host for phage progeny release. they commonly contain an n-terminal catalytic domain that hydrolyzes bacterial peptidoglycan (pg) and a c-terminal cell wall-binding domain (cbd) that confers enzyme localization to the pg substrate. two endolysins, phage lysin l (plyl) and phage lysin g (plyg), are specific for bacillus anthracis. to date, the cell wall ligands for their c-terminal cbd have not been identified. we recently described s ...201323493680
evidence that yycj is a novel 5'-3' double-stranded dna exonuclease acting in bacillus anthracis mismatch repair.the most important system for correcting replication errors that survive the built in editing system of dna polymerase is the mismatch repair (mmr) system. we have identified a novel mutator strain yycj in bacillus anthracis. mutations in the yycj gene result in a spontaneous mutator phenotype with a mutational frequency and specificity comparable to that of mmr-deficient strains such as those with mutations in mutl or muts. yycj was annotated as a metallo-β-lactamase (mβl) super family member w ...201323491602
not all eschars are anthrax. 201323490091
empirical valence bond simulations of the chemical mechanism of atp to camp conversion by anthrax edema factor.the two-metal catalysis by the adenylyl cyclase domain of the anthrax edema factor toxin was simulated using the empirical valence bond (evb) quantum mechanical/molecular mechanical approach. these calculations considered the energetics of the nucleophile deprotonation and the formation of a new p-o bond in aqueous solution and in the enzyme-substrate complex present in the crystal structure models of the reactant and product states of the reaction. our calculations support a reaction pathway th ...201323480863
identification of small molecules that inhibit the interaction of tem8 with anthrax protective antigen using a fret assay.tumor marker endothelial 8 (tem8) is a receptor for the protective antigen (pa) component of anthrax toxin. tem8 is upregulated on endothelial cells lining the blood vessels within tumors, compared with normal blood vessels. a number of studies have demonstrated a pivotal role for tem8 in developmental and tumor angiogenesis. we have also shown that targeting the anthrax receptors with a mutated form of pa inhibits angiogenesis and tumor formation in vivo. here we describe the development and te ...201323479355
assessment of medical reserve corps volunteers' emergency response willingness using a threat- and efficacy-based model.the goal of this study was to investigate the willingness of medical reserve corps (mrc) volunteers to participate in public health emergency-related activities by assessing their attitudes and beliefs. mrc volunteers responded to an online survey organized around the extended parallel process model (eppm). respondents reported agreement with attitude/belief statements representing perceived threat, perceived efficacy, and personal/organizational preparedness in 4 scenarios: a weather-related di ...201323477632
can one size fit all? towards a universal anthrax vaccine. 201323464366
cethromycin: a new ketolide antibiotic.to review the pharmacology, chemistry, microbiology, in vitro susceptibility, mechanism of resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, dosage, and administration of cethromycin, a new ketolide antibiotic.201323463743
enhancing bioaerosol sampling by andersen impactors using mineral-oil-spread agar plate.as a bioaerosol sampling standard, andersen type impactor is widely used since its invention in 1950s, including the investigation of the anthrax attacks in the united states in 2001. however, its related problems such as impaction and desiccation stress as well as particle bounce have not been solved. here, we improved its biological collection efficiencies by plating a mineral oil layer (100 µl) onto the agar plate. an andersen six-stage sampler and a biostage impactor were tested with mineral ...201323460818
secretory expression and efficient purification of recombinant anthrax toxin lethal factor with full biological activity in e. coli.lethal factor (lf), a virulence factor of bacillus anthracis, plays key roles in anthrax pathogenesis and host-pathogen interactions. the detailed mechanisms by which lf contributes to infection are still under investigation. while these studies require pure, homogeneous and reliable lf preparations, most methods reported for production of recombinant lf (rlf) in b. anthracis or escherichia coli either are complicated or add extra residues to the protein. in this work, we modified our previous m ...201323459291
[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
electrochemical detection of the binding of bacillus anthracis protective antigen (pa) to the membrane receptor on macrophages through release of nitric oxide.anthrax is a serious bacterial disease of man and animals whose pathogenesis involves the secretion of lethal toxins in the host. the intracellular delivery of toxic complexes involves a complex structural rearrangement of sub-domains of the exotoxin protective antigen (pa). we have used a biocompatible microelectrode array, coated with j774 mouse macrophages, to detect pa binding and intracellular signaling resulting in nitric oxide (no) release. we have found that exposure of macrophages to pa ...201322672762
genotyping of bacillus anthracis isolated from croatia and bosnia and herzegovina.anthrax is a serious disease caused by bacillus anthracis. humans can become infected by handling products from infected animals, by breathing spores and rarely by eating undercooked meat from infected animals. the genome of b. anthracis is highly monomorphic and thus shows very low dna sequence variation. we analysed the molecular characteristics of 12 b. anthracis isolates from outbreaks in croatia and bosnia and herzegovina, which have occurred during the past 10 years along with two vaccine ...201322726272
an amoeba phagocytosis model reveals a novel developmental switch in the insect pathogen bacillus thuringiensis.the bacillus cereus group bacteria contain pathogens of economic and medical importance. from security and health perspectives, the lethal mammalian pathogen bacillus anthracis remains a serious threat. in addition the potent insect pathogen bacillus thuringiensis is extensively used as a biological control agent for insect pests. this relies upon the industrial scale induction of bacterial spore formation with the associated production of orally toxic cry-toxins. understanding the ecology and p ...201322750551
the mountain meadows massacre and "poisoned springs": scientific testing of the more recent, anthrax theory.it has been recorded that one of the possible causes that eventually escalated into the 1857 manslaughter at mountain meadows in southern utah was the poisoning of an open spring by the fancher-baker party as they crossed the utah territory on their way from arkansas to california. historical accounts report that a number of cattle died, followed by human casualties from those that came in contact with the dead animals. even after the arkansas party departed, animals continued to perish and peop ...201322395921
the role of the exosporium in the environmental distribution of anthrax.to determine the contribution of the exosporium, the outer layer of the bacillus anthracis spore, to soil attachment. persistence of spores in soil and their ability to infect animals has been linked to a range of factors which include the presence of organic material and calcium (omc), ph > 6.0, temperatures above 15.5°c and cycles of local flooding which are thought to transport buried spores to the surface.201323039141
structural models used in real-time biosurveillance outbreak detection and outbreak curve isolation from noisy background morbidity levels.we discuss the use of structural models for the analysis of biosurveillance related data.201323037798
three types of human cpg motifs differentially modulate and augment immunogenicity of nonviral and viral replicon dna vaccines as built-in adjuvants.nakeddna vaccines given by intramuscular injection are efficient in mouse models, but they require improvement for human use. as the immunogenicity of dna vaccines depends, to a large extent, on the presence of cpg motifs as built-in adjuvants, we addressed this issue by inserting three types of human cpg motifs (a-type, b-type, and c-type) into the backbone of nonviral dna and viral dna replicon vectors with distinct immunostimulatory activities on human pbmcs. the adjuvant effects of cpg modif ...201323037552
insights into the drug resistance induced by the badhps mutations: molecular dynamic simulations and mm/gbsa studies.dihydropteroate synthase (dhps) is essential for the folic acid biosynthetic pathway in prokaryotes; the mutation forms for dhps are found to be relative to the urgent drug resistance problems. in our study, the bacillus anthracis dhps (badhps) was selected for molecular dynamics and binding free energy studies to investigate the biochemistry behaviors of the wild-type and mutation form badhps proteins (d184n and k220q). it is found that the conformational change of the ligand dihydropteroate su ...201323030549
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