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reverse line blot macroarray for simultaneous detection and characterization of four biological warfare agents.the need for a rapid detection and characterization of biowarfare (bw) agents cannot be over emphasized. with diverse array of potential bw pathogen available presently, rapid identification of the pathogen is crucial, so that specific therapy and control measures can be initiated. we have developed a multiplex polymerase chain reaction based reverse line blot macroarray to simultaneously detect four pathogens of bw importance viz. bacillus anthracis, yersinia pestis, brucella melitensis and bur ...201324426077
[bioterrorism and pathogenic microorganisms].in recent years the use of pathogenic microorganisms in acts of bioterrorism has been the subject of major concern in many countries. this paper presents a possible application of viruses and bacteria for warfare and terrorist purposes, as well as a laboratory diagnosis to identify those agents. the viruses of smallpox (orthopoxvirus), of hemorrhagic fever and those belonging to filovirus have been highlighted, inter alia, as agents of human infection with bioterrorist intent. among the bacteria ...201324473660
historical review of the list of occupational diseases recommended by the international labour organization (ilo).the list of occupational diseases established in the international and national legal system has played important roles in both prevention of and compensation for workers' diseases. this report reviewed the historical development in the ilo list of occupational diseases and suggested implications of the trends. since the first establishment of the ilo list of occupational diseases in 1925, the list has played a key role in harmonizing the development of policies on occupational diseases at the i ...201324472440
quantitative anti-pa igg elisa; assessment and comparability with the anthrax toxin neutralization assay in goats.presently, few data exist on the level and duration of anti-protective antigen (pa) igg in vaccinated livestock. various adaptation of enzyme-linked immunosorbent assays (elisas) have been developed in studies to assess immune response following vaccination, albeit mostly in laboratory rodent models. the quantitative anti-anthrax igg elisa in this study describes a method of enumerating the concentration of anti-pa specific igg present in sera of immunized goats, with the aid of an affinity-puri ...201324373579
allelic-dependent expression of an activating fc receptor on b cells enhances humoral immune responses.b cells are pivotal regulators of acquired immune responses, and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of b cell function can substantially alter immunological responses. the balance of negative and positive signals in maintaining an appropriate b cell activation threshold is critical in b lymphocyte immune tolerance and autoreactivity. fcγriib (cd32b), the only recognized fcγ receptor on b cells, provides immunoglobulin ...201324353158
[the experimental evaluation with flow cytofluorimetry technique of the level of cellular immunologic memory in persons vaccinated against plague and anthrax].the article deals with experimental evaluation with flow cytofluorimetry technique of the level of cellular immunologic memory in persons vaccinated with plague and anthrax live dry vaccines. it is established that the introduction of plague and anthrax live dry vaccines into organism of vaccinated persons ignites immunologic rearrangement manifested by reliable increase of level of blood concentration of th1-lymphocytes (immunologic memory cells) against the background of vaccination. the highe ...201324640112
poly(acrylic acid)-grafted fluoropolymer films for highly sensitive fluorescent bioassays.in this study, a facile and effective method for the surface functionalization of inert fluoropolymer substrates using surface grafting was demonstrated for the preparation of a new platform for fluorescence-based bioassays. the surface of perfluorinated poly(ethylene-co-propylene) (fep) films was functionalized using a 150 kev ion implantation, followed by the graft polymerization of acrylic acid, to generate a high density of carboxylic acid groups on the implanted surface. the resulting funct ...201323452270
biosurveillance in outbreak investigations.following the terrorist attacks of september 11 and the anthrax attacks in 2001, public health entities implemented automated surveillance systems based on disease syndromes for early detection of bioterror events and to increase timeliness of responses. despite widespread adoption, syndromic surveillance systems' ability to provide early notification of outbreaks is unproven, and there is little documentation on their role in outbreak response. we hypothesized that biosurveillance is used in pr ...201323448272
increased long-term immunity to bacillus anthracis protective antigen in mice immunized with a cia06b-adjuvanted anthrax vaccine.anthrax is an acute infectious disease caused by bacillus anthracis. we previously reported that the adjuvant cia06b, which consists of tlr4 agonist cia05 and aluminum hydroxide (alum), enhanced the immune response to anthrax protective antigen (pa) in mice. this study was carried out to determine whether cia06b can enhance long-term immune responses to pa in mice. balb/c mice were immunized intramuscularly three times at 2-week intervals with recombinant pa alone or pa combined with alum or cia ...201323440578
evaluation of peracetic acid fog for the inactivation of bacillus anthracis spore surrogates in a large decontamination chamber.the purpose of this study was to evaluate the sporicidal (inactivation of bacterial spores) effectiveness and operation of a fogging device utilizing peracetic acid/hydrogen peroxide (paa). experiments were conducted in a pilot-scale 24 m(3) stainless steel chamber using either biological indicators (bis) or bacterial spores deposited onto surfaces via aerosolization. wipe sampling was used to recover aerosol-deposited spores from chamber surfaces and coupon materials before and after fogging to ...201323434480
cutaneous anthrax resulting in renal failure with generalized tissue damage.anthrax is a zoonotic infection caused by bacillus anthracis which can be clinically present in a cutaneous, gastrointestinal or inhalational form depending on the entry site of the agent. the most frequent clinical type with the mildest clinical course is cutaneous anthrax. in this report, a patient with cutaneous anthrax which begins at the dorsal hand and progresses up to the proximal forearm resulting in massive tissue damage is presented. prerenal azotemia developed due to massive tissue da ...201323431997
current biodefense vaccine programs and challenges.the defense threat reduction agency's joint science and technology office manages the chemical and biological defense program's science and technology portfolio. the joint science and technology office's mission is to invest in transformational ideas, innovative people and actionable technology development for chemical and biological defense solutions, with the primary goal to deliver science and technology products and capabilities to the warfighter and civilian population that outpace the thre ...201323428906
vector-mediated selective expression of lethal factor, a toxic element of bacillus anthracis, damages a549 cells via inhibition of mapk and akt pathways.lethal factor (lf), a major toxic element of bacillus anthracis combined with its protective antigen (pa), enters the cells through the cytomembrane receptors and causes damage to the host cells, thereby leading to septicemia, toxemia, and meningitis with high mortality. lf has been identified as a potential biotech-weapon, which can impede cancer growth in vascular endothelial cells because of its cytotoxicity. however, the feasibility of lf application and further investigations has been limit ...201323423542
awareness and attitude toward zoonoses with particular reference to anthrax among cattle owners in selected rural communities of zimbabwe.we conducted a cross-sectional study to assess cattle owners' awareness, perceptions, and attitudes toward zoonoses, with particular emphasis regarding anthrax. data on awareness of zoonoses, clinical signs of anthrax in animals and human, its routes of transmission and methods of prevention, the families' consumption habits of anthrax-infected carcasses, and other family activities that increase exposure to anthrax were collected using an interviewer-administered questionnaire. a total of 41.4% ...201323421887
cytotoxicity of anthrax lethal toxin to human acute myeloid leukemia cells is nonapoptotic and dependent on extracellular signal-regulated kinase 1/2 activity.in this study, we attempt to target the mitogen-activated protein kinase (mapk) pathway in acute myeloid leukemia (aml) cells using a recombinant anthrax lethal toxin (letx). letx consists of protective antigen (prag) and lethal factor (lf). prag binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of lf, and undergoes endocytosis, releasing lf into the cytosol. lf cleaves mapk kinases, inhibiting the mapk pathway. we tested potency of letx on a panel of 11 human aml cel ...201323418614
bacillus weihenstephanensis characteristics are present in bacillus cereus and bacillus mycoides strains.the bacillus cereus group comprises seven bacterial species: bacillus cereus, bacillus anthracis, bacillus thuringiensis, bacillus mycoides, bacillus pseudomycoides, bacillus cytotoxicus, and bacillus weihenstephanensis. bacillus weihenstephanensis is distinguished based on its capability to grow at 7 °c but not at 43 °c, and the presence of specific signature sequences in the 16s rrna and cspa genes and in several housekeeping genes: glpf, gmk, purh, and tpi. bacillus weihenstephanensis-specifi ...201323413955
a genetic approach for the identification of exosporium assembly determinants of bacillus anthracis.the exosporium is the outermost layer of spores of the zoonotic pathogen bacillus anthracis. the composition of the exosporium and its functions are only partly understood. because this outer spore layer is refractive to traditional biochemical analysis, a genetic approach is needed in order to define the proteins which comprise this important spore layer and its assembly pathway. we have created a novel genetic screening system for the identification and isolation of mutants with defects in exo ...201323411372
portable, quantitative detection of bacillus bacterial spores using surface-enhanced raman scattering.portable rapid detection of pathogenic bacteria such as bacillus is highly desirable for safety in food manufacture and under the current heightened risk of biological terrorism. surface-enhanced raman scattering (sers) is becoming the preferred analytical technique for bacterial detection, due to its speed of analysis and high sensitivity. however in seeking methods offering the lowest limits of detection, the current research has tended toward highly confocal, microscopy-based analysis, which ...201323409961
genome sequence of the attenuated carbosap vaccine strain of bacillus anthracis.the bacillus anthracis carbosap genome, which includes the pxo1 and pxo2 plasmids, has been shown to encode the major b. anthracis virulence factors, yet this strain's attenuation has not yet been explained. here we report the draft genome sequence of this strain, and a comparison to fully virulent b. anthracis.201323405332
1,2,3,4,6-penta-o-galloyl-β-d-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2.capillary morphogenesis gene 2 (cmg2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. we have shown that high-affinity cmg2 binders can inhibit angiogenesis and tumor growth. we recently described a high-throughput fret assay to identify cmg2 inhibitors. we now report the serendipitous discovery that pgg (1,2,3,4,6-penta-o-galloyl-β-d-glucopyranose) is a cmg2 inhibitor with antiangiogenic activity. pgg is a gallotannin produced by a variety of medi ...201323394144
engineering anthrax toxin variants that exclusively form octamers and their application to targeting tumors.anthrax toxin protective antigen (pa) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. by screening a highly directed library of pa mutants, we identified variants that complement each other to exclusively form octamers. these pa variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. we then engineered requirements for activation by matrix ...201323393143
assembly of anthrax toxin pore: lethal-factor complexes into lipid nanodiscs.we have devised a procedure to incorporate the anthrax protective antigen (pa) pore complexed with the n-terminal domain of anthrax lethal factor (lfn ) into lipid nanodiscs and analyzed the resulting complexes by negative-stain electron microscopy. insertion into nanodiscs was performed without relying on primary and secondary detergent screens. the preparations were relatively pure, and the percentage of pa pore inserted into nanodiscs on em grids was high (∼43%). three-dimensional analysis of ...201323389868
studies in mice reveal a role for anthrax toxin receptors in matrix metalloproteinase function and extracellular matrix homeostasis.the genes encoding anthrax toxin receptors (antxrs) were originally identified based on expression in endothelial cells suggesting a role in angiogenesis. the focus of this review is to discuss what has been learned about the physiological roles of these receptors through evaluation of the antxr knockout mouse phenotypes. mice mutant in antxr genes have defects in extracellular matrix homeostasis. we discuss how knowledge of physiological antxr function relates to what is already known about ant ...201323389402
a novel homogeneous immunoassay for anthrax detection based on the alphalisa method: detection of b. anthracis spores and protective antigen (pa) in complex samples.amplified luminescent proximity homogeneous assay (alphalisa) technology is an energy-transfer-based assay, utilizing singlet oxygen as an energy donor to a fluorescent acceptor. the long singlet oxygen migration distance allows the energy transfer mechanism to go up to ~200 nm, facilitating flexible and sensitive homogeneous immunoassays. while soluble protein detection using alphalisa was previously described, the detection of particles such as bacteria and viruses was not reported. in this wo ...201323388689
concentration, detection and discrimination of bacillus anthracis spores in orange juice using aptamer based surface enhanced raman spectroscopy.herein, we developed an innovative label free platform for concentration, detection and discrimination of bacillus anthracis spores. based on aptamer capture and surface enhanced raman scattering detection, we were able to detect 10(4) cfu spores spiked in orange juice and discriminate between spores b. anthracis and b. mycoides within 40 min.201323386216
elastic and inelastic diffraction changes upon variation of the relative humidity environment of pure crystals.the different changes observed in the diffraction patterns of three different crystal forms (hexagonal, trigonal and monoclinic) of pure (ec 4.1.1.21), an enzyme from the purine-biosynthesis pathway of bacillus anthracis, upon a wide range of changes in the relative humidity environment of the crystals are documented. in addition, the changes in the unit-cell parameters, volume and bulk solvent in the three different crystal forms were systematically followed. in an attempt to explain the elasti ...201323385456
colonic immune stimulation by targeted oral vaccine.currently, sufficient data exist to support the use of lactobacilli as candidates for the development of new oral targeted vaccines. to this end, we have previously shown that lactobacillus gasseri expressing the protective antigen (pa) component of anthrax toxin genetically fused to a dendritic cell (dc)-binding peptide (dcpep) induced efficacious humoral and t cell-mediated immune responses against bacillus anthracis sterne challenge.201323383086
fatal cutaneous anthrax in a heroin user.cutaneous anthrax usually has a mortality rate of less than 1 per cent. however, since december 2009 there have been more than 13 deaths in the uk due to anthrax-contaminated heroin. we therefore wish to raise clinical awareness of this treatable disease.201323374534
the near-iron transporter (neat) domains of the anthrax hemophore isdx2 require a critical glutamine to extract heme from methemoglobin.several gram-positive pathogenic bacteria employ near-iron transporter (neat) domains to acquire heme from hemoglobin during infection. however, the structural requirements and mechanism of action for neat-mediated heme extraction remains unknown. bacillus anthracis exhibits a rapid growth rate during systemic infection, suggesting that the bacterium expresses efficient iron acquisition systems. to understand how b. anthracis acquires iron from heme sources, which account for 80% of mammalian ir ...201323364793
pathology and pathophysiology of inhalational anthrax in a guinea pig model.nonhuman primates (nhps) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the fda's "animal rule." however, a need for an alternative animal model may arise in certain cases. the development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. the guinea p ...201323357384
a simple, reliable m'fadyean stain for visualizing the bacillus anthracis capsule.the simple polychrome methylene blue (pmb) staining procedure for blood or tissue smears from dead animals (m'fadyean reaction) established in 1903 remained accepted as a highly reliable, rapid diagnostic test for anthrax for six decades while that disease was still common in livestock throughout the world. improvements in disease control led to anthrax becoming rare in industrialized countries and less frequent in developing countries with the result that quality controlled, commercially produc ...201323357124
rapid vaccination using an acetalated dextran microparticulate subunit vaccine confers protection against triplicate challenge by bacillus anthracis.a rapid immune response is required to prevent death from anthrax, caused by bacillus anthracis.201323354770
genetic tools to enhance the study of gene function and regulation in staphylococcus aureus.the bursa aurealis transposon has been used to create transposon insertion libraries of bacillus anthracis and staphylococcus aureus. to provide a set of genetic tools to enhance the utility of these libraries, we generated an allelic-exchange system that allows for the replacement of the transposon with useful genetic markers and fluorescent reporter genes. these tools were tested in the nebraska transposon mutant library (ntml), containing defined transposon insertions in 1,952 nonessential s. ...201323354696
a comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen.development of nasal immunization for human use is hindered by the lack of acceptable adjuvants. although ct is an effective adjuvant, its toxicity will likely prevent its use in nasal vaccines. this study compared non-toxin adjuvants to ct for their ability to induce protective antibody responses with nasal immunization. c3h/hen and c57bl/6 mice were immunized with rpa formulated with the following adjuvants: ct, il-1α, lps, cpg, pam3csk4, 3m-019, resiquimod/r848 or c48/80. serum and nasal wash ...201323352329
carbon microarrays for the direct impedimetric detection of bacillus anthracis using gamma phages as probes.a direct and efficient impedimetric method is presented for the detection of bacillus anthracis sterne vegetative cells, using gamma phages as probes attached to screen-printed carbon electrode microarrays. the carbon electrodes were initially functionalized through cyclic-voltammetric reduction of a nitro-aryl diazonium moiety, followed by further reduction of nitro groups to amino groups, and finally by treatment with glutaraldehyde. functionalization (probe immobilization) using gamma phages ...201323348920
bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/ raxibacumab-treated new zealand white rabbits.inhaled bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (pa) binds to cell receptors and the enzymatic moieties. antibiotics can control b. anthracis bacteremia, whereas raxibacumab binds pa and blocks lethal toxin effects. this study assessed plasma pa kinetics in rabbits following an inhaled b. anthracis spore ...201323344456
identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death.studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. we conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function ...201323343607
medical aspects of bio-terrorism.bioterrorism is a terrorist action involving the intentional release or dissemination of a biological warfare agent (bwa), which includes some bacteria, viruses, rickettsiae, fungi or biological toxins. bwa is a naturally occurring or human-modified form that may kill or incapacitate humans, animals or plants as an act of war or terrorism. bwa is a weapon of choice for mass destruction and terrorism, because of the incubation period, less effective amount than chemical warfare agents, easily dis ...201323339855
distinct functions of polysaccharide deacetylases in cell shape, neutral polysaccharide synthesis and virulence of bacillus anthracis.peptidoglycan deacetylases (pgng-dacs) belong to the carbohydrate esterase family 4 (ce4) and have been described as required for bacterial evasion to lysozyme and innate immune responses. interestingly, there is an unusual occurrence of 10 putative polysaccharide deacetylases, including five pgng-dacs, in the bacillus sp. genomes, especially b. cereus and b. anthracis. to elucidate the physiological role of these multiple deacetylases, we employed genetic analysis and protein localization studi ...201323336745
[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
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