Publications

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The effect of deletion of the edema factor on Bacillus anthracis pathogenicity in guinea pigs and rabbits.Bacillus anthracis secretes three major components, which assemble into two bipartite toxins: lethal toxin (LT), composed of lethal factor (LF) and protective antigen (PA) and edema toxin (ET), composed of edema factor (EF) and PA. EF is a potent calmodulin-dependent adenylate cyclase, which is internalized into the target cell following PA binding. Once inside the cell, EF elevates cAMP levels, interrupting intracellular signaling. Effects of ET were demonstrated on monocytes, neutrophils and T ...201222020310
Domain flexibility modulates the heterogeneous assembly mechanism of anthrax toxin protective antigen.The three protein components of anthrax toxin are nontoxic individually, but they form active holotoxin complexes upon assembly. The role of the protective antigen (PA) component of the toxin is to deliver two other enzyme components, lethal factor and edema factor, across the plasma membrane and into the cytoplasm of target cells. PA is produced as a proprotein, which must be proteolytically activated; generally, cell surface activation is mediated by a furin family protease. Activated PA can t ...201222063095
Anthrax toxin protective antigen-Insights into molecular switching from prepore to pore.The protective antigen is a key component of the anthrax toxin, as it allows entry of the enzymatic components edema factor and lethal factor into the host cell, through the formation of a membrane spanning pore. This event is absolutely critical for the pathogenesis of anthrax, and although we have yet to understand the mechanism of pore formation, recent developments have provided key insights into how this process may occur. Based on the available data, a model is proposed for the kinetic ste ...201222095644
Reviewing the role of peptide rarity in bacterial toxin immunomics.In the past decade, renewed efforts have been made toward the development of vaccines against cancers, infectious agents, autoimmune diseases, and allergies. These efforts have led to the accumulation of numerous peptide sequences experimentally validated as epitopes. However, the factors that render a peptide immunogenic and, more generally, the nature of the antigen-antibody recognition process remain unclear. Based on the hypothesis that potential epitopes correspond to rare sequences and/or ...201222202055
unusual epidemic events: a new method of early orientation and differentiation between natural and deliberate epidemics.to develop a model for quick and accurate evaluation of unusual epidemic events (uee), based on the original model of bioterrorism risk assessment.201222136700
differential role of the interleukin-17 axis and neutrophils in resolution of inhalational anthrax.the roles of interleukin-17 (il-17) and neutrophils in the lung have been described as those of two intricate but independent players. here we identify neutrophils as the primary il-17-secreting subset of cells in a model of inhalation anthrax using a/j and c57bl/6 mice. with il-17 receptor a knockout (il-17ra(-/-)) mice, we confirmed that il-17a/f signaling is instrumental in the self-recruitment of this population. we also show that the il-17a/f axis is critical for surviving pulmonary infecti ...201222025514
three probable cases of cutaneous anthrax in autonomous province of vojvodina, serbia, june 2011. 201222264812
sometimes it takes two to tango: contributions of dimerization to functions of human α-defensin hnp1.human myeloid α-defensins called hnps play multiple roles in innate host defense. the trp26 residue of hnp1 was previously shown to contribute importantly to its ability to kill s. aureus, inhibit anthrax lethal factor (lf), bind gp120 of hiv-1, dimerize, and undergo further self-association. to gain additional insights into the functional significance of dimerization, we compared wild-type hnp1 to dimerization-impaired, n-methylated hnp1 monomers and to disulfide-tethered obligate hnp1 dimers. ...201222270360
biosurveillance: a review and update.since the terrorist attacks and anthrax release in 2001, almost $32 billion has been allocated to biodefense and biosurveillance in the usa alone. surveillance in health care refers to the continual systematic collection, analysis, interpretation, and dissemination of data. when attempting to detect agents of bioterrorism, surveillance can occur in several ways. syndromic surveillance occurs by monitoring clinical manifestations of certain illnesses. laboratory surveillance occurs by looking for ...201222242207
kinetic characterization of a slow-binding inhibitor of bla2: thiomaltol.the increasing prevalence of drug resistant bacteria is a pandemic problem. metallo-β-lactamases (mbls) are one of the main causes of drug resistance due to hydrolysis of β-lactam antibiotics. thus, the development of effective inhibitors of mbls remains urgent. the compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-β-lactamase from bacillus anthracis (bla2), which causes anthrax. kinetic evaluation with nitrocefin as a substrate indicates that thiomalt ...201222233540
inhibition of bacterial carbonic anhydrases and zinc proteases: from orphantargets to innovative new antibiotic drugs.zinc-containing enzymes, such as carbonic anhydrases (cas) and metalloproteases (mps) play critical functions in bacteria, being involved in various steps of their life cycle, which are important for survival, colonization, acquisition of nutrients for growth and proliferation, facilitation of dissemination, invasion and pathogenicity. the development of resistance to many classes of clinically used antibiotics emphasizes the need of new antibacterial drug targets to be explored. there is a weal ...201222214451
protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines.background. anthrax-associated shock is closely linked to lethal toxin (lt) release and is highly lethal despite conventional hemodynamic support. we investigated whether protective antigen-directed monoclonal antibody (pa-mab) treatment further augments titrated hemodynamic support.methods and results. forty sedated, mechanically ventilated, instrumented canines challenged with anthrax lt were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinep ...201222223857
bacillus anthracis-derived edema toxin (et) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway.abstract: background: a common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (pmns) in infected tissues in the face of abundant circulating pmns. a major virulence determinant of anthrax is edema toxin (et), which is formed by the combination of two proteins produced by the organism, edema factor (ef), which is an adenyl cyclase, and protective antigen (pa). since camp, a product of adenyl cyclase, is known to enhance endothelial barrier integri ...201222230035
two independent replicons can support replication of the anthrax toxin-encoding plasmid pxo1 of bacillus anthracis.the large pxo1 plasmid (181.6kb) of bacillus anthracis encodes the anthrax toxin proteins. previous studies have shown that two separate regions of pxo1 can support replication of pxo1 miniplasmids when introduced into plasmid-less strains of this organism. no information is currently available on the ability of the above two replicons, termed repx and orfs 14/16 replicons, to support replication of the full-length pxo1 plasmid. we generated mutants of the full-length pxo1 plasmid in which eithe ...201222239982
comparative analysis of virulence factors secreted by bacillus anthracis sterne at host body temperature.aims:  for the analysis of virulence factors produced and secreted by bacillus anthracis vegetative cells during mammalian host infection, we evaluated the secretome of b. anthracis sterne exposed to host-specific factors specifically to host body temperature. methods and results:  we employed a comparative proteomics-based approach to analyze the proteins secreted by b. anthracis sterne under host-specific body temperature conditions. a total of 17 proteins encoded on a single chromosome and th ...201222268495
effect of the mammalian arginase inhibitor 2(s)-amino-6-boronohexanoic acid on bacillus anthracis arginase.macrophages, upon phagocytosing endospores of bacillus anthracis, up-regulate the expression of the immunological isoform of nitric oxide synthase, nos 2, concomitant with production of nitric oxide (no•) from metabolism of l: -arginine. we have previously demonstrated that macrophages that secrete no• kill the bacilli of b. anthracis. to circumvent this microbicidal activity of no•, b. anthracis has evolved pathways that include the enzyme arginase, which metabolizes l: -arginine to ornithine a ...201222271269
probing the substrate and acceptor specificity of the γ-glutamyltranspeptidase.abstract. γ-glutamyl transpeptidase (ggt) is a two-substrate enzyme that plays a central role in glutathione metabolism and is a potential target for drug design. ggt catalyze the cleavage of γ-glutamyl donor substrates, and the transfer of the γ-glutamyl moiety to an amine of an acceptor substrate or water. although structures of bacterial ggt have revealed details of the protein-ligand interactions at the donor site, the acceptor substrate site is relatively undefined. the recent identificatio ...201222257032
health-related quality of life in the anthrax vaccination program for workers in the laboratory response network.background: in 2002 cdc initiated the anthrax vaccination program (avp) to provide voluntary pre-exposure vaccination with anthrax vaccine adsorbed (ava) for persons at high risk of exposure to bacillus anthracis spores. there has been concern that ava could be associated with long term impairment of physical and/or mental health. objectives: to ascertain whether physical and mental functional status, as measured by the sf-36v2 health survey (medical outcomes trust, boston, ma), of ava recipient ...201222230591
gold nanoparticles with asymmetric polymerase chain reaction for colorimetric detection of dna sequence.we developed a novel strategy for rapid colorimetric analysis of a specific dna sequence by combining gold nanoparticles (aunps) with an asymmetric polymerase chain reaction (as-pcr). in the presence of the correct dna template, the bound oligonucleotides on the surface of aunps selectively hybridized to form complementary sequences of single-stranded dna (ssdna) target generated from as-pcr. dna hybridization resulted in self-assembly and aggregation of aunps, and a concomitant color change fro ...201222243128
spectroscopic, catalytic and binding properties of bacillus subtilis no synthase-like protein: comparison with other bacterial and mammalian no synthases.genome sequencing has shown the presence of genes coding for no-synthase (nos)-like proteins in bacteria. the roles and properties of these proteins remain unclear. uv-visible spectroscopy was used to characterize the recombinant nos-like protein from bacillus subtilis (bsnos) in its ferric and ferrous states in the presence of various fe(iii)- and fe(ii)-heme-ligands and of a series of l-arginine (l-arg) analogs. bsnos exhibited several spectroscopic and binding properties in common with bacill ...201222119809
Serum amyloid A protects murine macrophages from lethal toxin-mediated death.Lethal toxin, a key virulence factor produced by Bacillus anthracis, induces cell death, in part by disrupting numerous signaling pathways, in mouse macrophages. However, exposure to sublethal doses of lethal toxin allows some cells to survive. Because these pro-survival signaling events occur within a few hours after exposure to sublethal doses, we hypothesized that acute phase proteins might influence macrophage survival. Our data show that serum amyloid A (SAA) is produced in response to leth ...201222082566
Anthrax sub-unit vaccine: The structural consequences of binding rPA83 to Alhydrogel®.An anthrax sub-unit vaccine, comprising recombinant Protective Antigen (rPA83) and aluminium hydroxide adjuvant (Alhydrogel®) is currently being developed. Here, a series of biophysical techniques have been applied to free and adjuvant bound antigen. Limited proteolysis and fluorescence identified no changes in rPA83 tertiary structure following binding to Alhydrogel and the bound rPA83 retained two structurally important calcium ions. For adsorbed rPA83, differential scanning calorimetry reveal ...201221964315
in vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria.silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. here, the bactericidal activity of four silver carbene complexes (sccs) with different formulations, including nanoparticles (nps) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections.201221972270
Characterization of Type II and III Restriction-Modification Systems from Bacillus cereus Strains ATCC 10987 and ATCC 14579.The genomes of two Bacillus cereus strains (ATCC 10987 and ATCC 14579) have been sequenced. Here, we report the specificities of type II/III restriction (R) and modification (M) enzymes. Found in the ATCC 10987 strain, BceSI is a restriction endonuclease (REase) with the recognition and cut site CGAAG 24-25/27-28. BceSII is an isoschizomer of AvaII (G/GWCC). BceSIII cleaves at ACGGC 12/14. The BceSIII C terminus resembles the catalytic domains of AlwI, MlyI, and Nt.BstNBI. BceSIV is composed of ...201222037402
Antibacterial Role for Natural Killer Cells in Host Defense to Bacillus anthracis.Natural killer (NK) cells have innate antibacterial activity that could be targeted for clinical interventions for infectious disease caused by naturally occurring or weaponized bacterial pathogens. To determine a potential role for NK cells in immunity to Bacillus anthracis, we utilized primary human and murine NK cells, in vitro assays, and in vivo NK cell depletion in a murine model of inhalational anthrax. Our results demonstrate potent antibacterial activity by human NK cells against B. ant ...201222006566
Lipoprotein biosynthesis by prolipoprotein diacylglyceryl transferase is required for efficient spore germination and full virulence of Bacillus anthracis.Bacterial lipoproteins play a crucial role in virulence in some Gram-positive bacteria. However, the role of lipoprotein biosynthesis in Bacillus anthracis is unknown. We created a B. anthracis mutant strain altered in lipoproteins by deleting the lgt gene encoding the enzyme prolipoprotein diacylglyceryl transferase, which attaches the lipid anchor to prolipoproteins. (14) C-palmitate labelling confirmed that the mutant strain lacked lipoproteins, and hydrocarbon partitioning showed it to have ...201222103323
Structure-based redesign of an edema toxin inhibitor.Edema factor (EF) toxin of Bacillus anthracis (NIAID category A), and several other toxins from NIAID category B Biodefense target bacteria are adenylyl cyclases or adenylyl cyclase agonists that catalyze the conversion of ATP to 3',5'-cyclic adenosine monophosphate (cAMP). We previously identified compound 1 (3-[(9-oxo-9H-fluorene-1-carbonyl)-amino]-benzoic acid), that inhibits EF activity in cultured mammalian cells, and reduces diarrhea caused by enterotoxigenic Escherichia coli (ETEC) at an ...201222154558
occurrence, recognition, and reversion of spontaneous, sporulation-deficient bacillus anthracis mutants that arise during laboratory culture.bacillus anthracis is a spore-forming, soil-dwelling bacterium. this review describes the occurrence of spontaneous mutations leading to loss of sporulation and the selective pressures that can lead to their enrichment. we also discuss recognition of the associated phenotypes on solid medium, thereby allowing researchers to employ measures that either prevent or favor selection of sporulation-deficient mutants.201122166343
t cell targeting by anthrax toxins: two faces of the same coin.bacillus anthracis, similar to other bacterial pathogens, has evolved effective immune evasion strategies to prolong its survival in the host, thus ensuring the unchecked spread of the infection. this function is subserved by lethal (lt) and edema (et) toxins, two exotoxins produced by vegetative anthrax bacilli following germination of the spores. the structure of these toxins and the mechanism of cell intoxication are topics covered by other reviews in this issue. here we shall discuss how b. ...201122069732
ten years on from anthrax scare, analysis lags behind sequencing. 201121988965
the munich outbreak of cutaneous cowpox infection: transmission by infected pet rats.cowpox virus infection of humans is an uncommon, potentially fatal, skin disease. it is largely confined to europe, but is not found in eire, or in the usa, australasia, or the middle or far east. patients having contact with infected cows, cats, or small rodents sporadically contract the disease from these animals. we report here clinical aspects of 8 patients from the munich area who had purchased infected pet rats from a local supplier. pet rats are a novel potential source of local outbreaks ...201122041995
Detection of anthrax lef with DNA-based photonic crystal sensors.Bacillus anthracis has posed a threat of becoming biological weapons of mass destruction due to its virulence factors encoded by the plasmid-borne genes, such as lef for lethal factor. We report the development of a fast and sensitive anthrax DNA biosensor based on a photonic crystal structure used in a total-internal-reflection configuration. For the detection of the lef gene, a single-stranded DNA lef probe was biotinylated and immobilized onto the sensor via biotin-streptavidin interactions. ...201122191936
glycoconjugates prevent b. anthracis toxin-induced cell death through binding while activating macrophages.bacillus anthracis toxins may be attenuated if macrophages could neutralize toxins upon contact or exposure. glycoconjugate-bearing polymers, which have been shown to bind to bacillus spores, were tested for recognition and binding of protective antigen (pa), lethal factor (lf), and edema factor (ef) toxins. we have demonstrated modulation of macrophage activity following exposure to these toxins. without glycoconjugate (gc) activation, murine macrophages were killed by bacillus toxins. gcs were ...201122134879
Interagency Biological Restoration Demonstration (IBRD): a collaborative approach to biological incident recovery.Following the terrorist attacks in 2001, much time and effort has been put toward improving catastrophic incident response. But recovery--the period following initial response that focuses on the long-term viability of the affected area--has received less attention. Recognizing the importance of being able to recover an area following a catastrophic incident, the Department of Defense, through its Defense Threat Reduction Agency (DTRA), and the Department of Homeland Security, through its Scienc ...201121882966
Developing a regional recovery framework.A biological attack would present an unprecedented challenge for local, state, and federal agencies, the military, the private sector, and individuals on many fronts, ranging from vaccination and treatment to prioritization of cleanup actions to waste disposal. To prepare for recovery from this type of incident, the Seattle Urban Area Security Initiative (UASI) partners collaborated with military and federal agencies to develop a regional recovery framework. The goal was to identify key informat ...201121882969
S-layer homology motif is an immunogen and confers protection to mouse model against anthrax.SLH proteins bear an S-layer homology motif comprised of three S-layer homology (SLH) domains. Several SLH proteins in Bacillus anthracis have been recognized as immunogenic in recent past. We hypothesized that the SLH motif, the most common moiety amongst all the SLH proteins could be responsible for their immunogenicity. To test this hypothesis, we checked the immunogenic capacity of recombinant SLH motif. The rSLH fragment on immunization in mice led to the development of a potent humoral and ...201122178119
a novel splice site mutation in antxr2 (cmg2) gene results in systemic hyalinosis.systemic hyalinosis is a rare autosomal recessive inheritance disease characterized by accumulation of amorphous, unidentified hyaline material in skin and other organs, which leads to papulonodular skin lesions, gingival hypertrophy, flexion contractures of the joints, and large subcutaneous tumors. it is composed of 2 allelic syndromes, infantile systemic hyalinosis and juvenile hyaline fibromatosis. here we describe a patient with juvenile hyaline fibromatosis confirmed by clinical and histop ...201122042284
Adverse health consequences of US Government responses to the 2001 terrorist attacks.In response to the attacks on Sept 11, 2001 (9/11), and the related security concerns, the USA and its coalition partners began a war in Afghanistan and subsequently invaded Iraq. The wars caused many deaths of non-combatant civilians, further damaged the health-supporting infrastructure and the environment (already adversely affected by previous wars), forced many people to migrate, led to violations of human rights, and diverted resources away from important health needs. After 9/11 and the an ...201121890059
AOAC SMPR 2010.004. Standard method performance requirements for immunological-based handheld assays (HHAs) for detection of Bacillus anthracis spores in visible powders. 201121919368
Association of the ANTXR2 gene polymorphism and ankylosing spondylitis in Chinese Han.Objective: Ankylosing spondylitis (AS) is an inflammatory disease of unknown origin. Both genetic and environmental factors are involved. A recent genome-wide association study (GWAS) found anthrax toxin receptor 2 (ANTXR2) to be associated with AS in Caucasians. We aimed to investigate whether the ANTXR2 polymorphism is also associated with AS in a Chinese Shandong Han population. Methods: From 2008 to 2009, we recruited 309 patients with AS and 384 age- and sex-matched controls of Han nation ...201122118297
Thawing of permafrost may disturb historic cattle burial grounds in East Siberia.Climate warming in the Arctic may increase the risk of zoonoses due to expansion of vector habitats, improved chances of vector survival during winter, and permafrost degradation. Monitoring of soil temperatures at Siberian cryology control stations since 1970 showed correlations between air temperatures and the depth of permafrost layer that thawed during summer season. Between 1900s and 1980s, the temperature of surface layer of permafrost increased by 2-4°C; and a further increase of 3°C is e ...201122114567
[Preparation and characterization of monoclonal antibodies to Bacillus anthracis protective antigen].Anthrax is the widespread acute infection disease, affecting animals and humans, refers to the bioterrorist threat agents of category A, because of the high resistance of Bacillus anthracis spores to adverse environmental factors and the ease of receiving them. We obtain a representative panel of 20 monoclonal antibodies against the key component of pathogenic exotoxins, anthrax protective antigen. Quantitative sandwich-ELISA for protective antigen with antibody obtained was developed. Six pairs ...201121899050
small molecule inhibitors of anthrax toxin-induced cytotoxicity targeted against protective antigen.two molecular scaffolds were designed using the caveat molecular design package to inhibit the oligomerization of protective antigen (pa(63) ), a key protein component of anthrax toxin. the inhibitors were designed to prevent heptamerization of pa(63) by mimicking key residues of pa(63) needed for the intermolecular interactions that stabilize the heptamer. using the scaffolds identified by caveat, seven candidate inhibitors were synthesized and tested for their ability to inhibit anthrax toxi ...201122146079
a biological decontamination process for small, privately owned buildings.an urban wide-area recovery and restoration effort following a large-scale biological release will require extensive resources and tax the capabilities of government authorities. further, the number of private decontamination contractors available may not be sufficient to respond to the needs. these resource limitations could create the need for decontamination by the building owner/occupant. this article provides owners/occupants with a simple method to decontaminate a building or area followin ...201121882971
structure of n5-carboxyaminoimidazole ribonucleotide synthase (purk) from bacillus anthracis.the apo structure of n5-carboxyaminoimidazole ribonucleotide synthase (purk) from bacillus anthracis (bapurk) with mg2+ in the active site is reported at 1.96 å resolution. purk is an enzyme in the purine-biosynthetic pathway, unique to prokaryotes, that converts 5-aminoimidazole ribonucleotide to n5-carboxyaminoimidazole ribonucleotide and has been suggested as a potential antimicrobial drug target. two interesting features of bapurk are a flexible b-loop (residues 149/150-157) that is in close ...201121931218
[development of a killed but metabolically active anthracis vaccine candidate strain].anthrax is a zoonosis caused by bacillus anthracis, which seriously affects human health. in recent years, a special phenomenon is found that the metabolic active of a bacterium remains after it is killed. to development of a kbma (killed but metabolically active) bacillus anthracis vaccine candidate strain, a plasmid pmad and a recombinase system cre-loxp were used to knockout the uvrab gene of b. anthracis ap422 which lacks both of two plasmids pxo1 and pxo2. the results of pcr and rt-pcr show ...201121845845
humidity control can compensate for the damage induced in protein crystals by alien solutions.the use of relative humidity control of protein crystals to overcome some of the shortcomings of soaking ligands (i.e. inhibitors, substrate analogs, weak ligands) into pre-grown apoprotein crystals has been explored. crystals of pure (ec 4.1.1.21), an enzyme from the purine-biosynthesis pathway of bacillus anthracis, were used as a test case. the findings can be summarized as follows: (i) using humidity control, it is possible to improve/optimize the diffraction quality of crystals soaked in so ...201122102052
structural basis of anthrax edema factor neutralization by a neutralizing antibody.fine epitope mapping of ef13d, a highly potent neutralizing monoclonal antibody specific for the anthrax edema factor (ef), was accomplished through random mutagenesis and yeast surface display. a yeast-displayed library of single point mutants of an ef domain iii (diii), comprising amino acids 624-800, was constructed by random mutagenesis and screened for reduced binding to ef13d. with this method, residues leu 667, ser 668, arg 671, and arg 672 were identified as key residues important for ef ...201122155239
tailored ß-cyclodextrin blocks the translocation pores of binary exotoxins from c. botulinum and c. perfringens and protects cells from intoxication.clostridium botulinum c2 toxin and clostridium perfringens iota toxin are binary exotoxins, which adp-ribosylate actin in the cytosol of mammalian cells and thereby destroy the cytoskeleton. c2 and iota toxin consists of two individual proteins, an enzymatic active (a-) component and a separate receptor binding and translocation (b-) component. the latter forms a complex with the a-component on the surface of target cells and after receptor-mediated endocytosis, it mediates the translocation of ...201121887348
Persistent inhibition of oxygen-induced retinal neovascularization by anthrax lethal toxin.Purpose. To evaluate the role of mitogen-activated protein kinase kinase (MKK) signaling in a mouse model of oxygen-induced retinopathy (OIR) that mimics retinopathy of prematurity (ROP). Methods. Postnatal day 7 mice were exposed to elevated oxygen for 5 days to induce retinopathy. Anthrax lethal toxin (LeTx), an MKK inhibitor, was injected into the vitreous after restoration to normoxia, and its effects on vascular growth were analyzed by whole mount immunofluorescence and confocal microscopy ...201121989728
Drug Interactions with Bacillus anthracis Topoisomerase IV: Biochemical Basis for Quinolone Action and Resistance.Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as a bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing the levels of DNA cleavage mediated by topoisomerase IV and gyrase. Quinolone resistance most often is associated with specific serine mutations in these enzymes. Therefore, to determine the basis for quinolone action and resistance, we characterized wild-type B. anthracis topoisomerase IV, the GrlA(S81F) and GrlA ...201122126453
h2s: a universal defense against antibiotics in bacteria.many prokaryotic species generate hydrogen sulfide (h(2)s) in their natural environments. however, the biochemistry and physiological role of this gas in nonsulfur bacteria remain largely unknown. here we demonstrate that inactivation of putative cystathionine β-synthase, cystathionine γ-lyase, or 3-mercaptopyruvate sulfurtransferase in bacillus anthracis, pseudomonas aeruginosa, staphylococcus aureus, and escherichia coli suppresses h(2)s production, rendering these pathogens highly sensitive t ...201122096201
anthrax attacks: lessons learned on the 10th anniversary of the anthrax attacks. 201122003133
anthrax cleanup decisions: statistical confidence or confident response. 201122029373
Detection of anthrax toxin genetic sequences by the solid phase oligo-probes.Purpose: There is an urgent need to detect a rapid field-based test to detect anthrax. We have developed a rapid, highly sensitive DNA-based method to detect the anthrax toxin lethal factor gene located in pXO1, which is necessary for the pathogenicity of Bacillus anthracis. Materials and Methods: We have adopted the enzyme-linked immunosorbent assay (ELISA) so that instead of capturing antibodies we capture the DNA of the target sequence by a rapid oligo-based hybridization and then detect the ...201122120797
evaluation of dna extraction methods for bacillus anthracis spores spiked to food and feed matrices at biosafety level 3 conditions.the dna extraction efficiency from milk, whey, soy, corn gluten meal, wheat powders and heat-treated corn grain that were spiked with bacillus anthracis and bacillus thuringiensis spores was determined. two steps were critical: lysis of the spores and binding of the free dna to the dna binding magnetic beads in the presence of the interfering powders. for the guanidine-thiocyanate based nuclisens lysis buffer from biomerieux we found that between 15 and 30% of the spores survived the lysis step. ...201121864928
Determination of the glycation sites of Bacillus anthracis neoglycoconjugate vaccine by MALDI-TOF/TOF-CID-MS/MS and LC-ESI-QqTOF-tandem mass spectrometry.We present herein an efficient mass spectrometric method for the localization of the glycation sites of a model neoglycoconjugate vaccine formed by a construct of the tetrasaccharide side chain of the Bacillus anthracis exosporium and the protein carrier bovine serum albumin. The glycoconjugate was digested with both trypsin and GluC V8 endoproteinases, and the digests were then analyzed by MALDI-TOF/TOF-CID-MS/MS and nano-LC-ESI-QqTOF-CID-MS/MS. The sequences of the unknown peptides analyzed by ...201122012665
Mouse monoclonal antibodies to anthrax edema factor protect against infection.Bacillus anthracis is the causative agent of anthrax, and the tripartite anthrax toxin is an essential element of its pathogenesis. Edema factor (EF), a potent adenylyl cyclase, is one of the toxin components. In this work, anti-EF monoclonal antibodies (MAb) were produced following immunization of mice, and four of the antibodies were fully characterized. MAb 3F2 has an affinity of 388 pM, was most effective for EF detection, and appears to be the first antibody reported to neutralize EF by bin ...201121911463
Scanning surface potential microscopy of spore adhesion on surfaces.The adhesion of spores of Bacillus anthracis - the cause of anthrax and a likely biological threat - to solid surfaces is an important consideration in cleanup after an accidental or deliberate release. However, because of safety concerns, directly studying B. anthracis spores with advanced instrumentation is problematic. As a first step, we are examining the electrostatic potential of Bacillus thuringiensis (Bt), which is a closely related species that is often used as a simulant to study B. an ...201122196463
the iron binding protein dps2 confers peroxide stress resistance on bacillus anthracis.iron is an essential nutrient that is implicated in most of cellular oxidation reactions. however, iron is a highly reactive element that, if not appropriately chaperoned, can react with endogenously and exogenously generated oxidants such as hydrogen peroxide to generate highly toxic hydroxyl radicles. dps (dna-binding proteins from starved cells) proteins form a distinct class (the mini-ferritins) of iron-binding proteins within the ferritin superfamily. b. anthracis encodes two dps-like prote ...201122155779
[Detection and identification of highly pathogenic bacteria within the framework of the EQADeBa project--Part I: Samples containing living pathogens].Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella sp., Bulkholderia mallei are B. pseudomallei are highly pathogenic bacteria of potential bioterrorism risk. To support the early warning and rapid response capacity to ensure an effective reaction to bioterrorist attacks the international project "Establishment of Quality Assurances for Detection of Highly Pathogenic Bacteria of Potential Bioterrorism Risk" (EQADeBa) has been established. The aim of the project was establishme ...201122184939
Effects of terbium chelate structure on dipicolinate ligation and the detection of Bacillus spores.Terbium-sensitized luminescence and its applicability towards the detection of Bacillus spores such as anthrax are of significant interest to research in biodefense and medical diagnostics. Accordingly, we have measured the effects of terbium chelation upon the parameters associated with dipicolinate ligation and spore detection. Namely, the dissociation constants, intrinsic brightness, luminescent lifetimes, and biological stabilities for several Tb(chelate)(dipicolinate)(x) complexes were dete ...201122071082
Molecular epidemiology of anthrax cases associated with recreational use of animal hides and yarn in the United States.To determine potential links between the clinical isolate to animal products and their geographic origin, we genotyped (MLVA-8, MVLA-15, and canSNP analysis) 80 environmental and 12 clinical isolates and 2 clinical specimens from five cases of anthrax (California in 1976 [n?=?1], New York in 2006 [n?=?1], Connecticut in 2007 [n?=?2], and New Hampshire in 2009[n?=?1]) resulting from recreational handling of animal products. For the California case, four clinical isolates were identified as MLVA-8 ...201122174783
identification of the bacterial protein ftsx as a unique target of chemokine-mediated antimicrobial activity against bacillus anthracis.chemokines are a family of chemotactic cytokines that function in host defense by orchestrating cellular movement during infection. in addition to this function, many chemokines have also been found to mediate the direct killing of a range of pathogenic microorganisms through an as-yet-undefined mechanism. as an understanding of the molecular mechanism and microbial targets of chemokine-mediated antimicrobial activity is likely to lead to the identification of unique, broad-spectrum therapeutic ...201121949405
New Developments in Vaccines, Inhibitors of Anthrax Toxins, and Antibiotic Therapeutics for Bacillus anthracis.Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the th ...201122050756
the mechanism of dna ejection in the bacillus anthracis spore-binding phage 8a revealed by cryo-electron tomography.the structure of the bacillus anthracis spore-binding phage 8a was determined by cryo-electron tomography. the phage capsid forms a t=16 icosahedron attached to a contractile tail via a head-tail connector protein. the tail consists of a six-start helical sheath surrounding a central tail tube, and a structurally novel baseplate at the distal end of the tail that recognizes and attaches to host cells. the parameters of the icosahedral capsid lattice and the helical tail sheath suggest protein fo ...201122018785
persistence of bacillus thuringiensis subsp. kurstaki in urban environments following spraying.bacillus thuringiensis subsp. kurstaki is applied extensively in north america to control the gypsy moth, lymantria dispar. since b. thuringiensis subsp. kurstaki shares many physical and biological properties with bacillus anthracis, it is a reasonable surrogate for biodefense studies. a key question in biodefense is how long a biothreat agent will persist in the environment. there is some information in the literature on the persistence of bacillus anthracis in laboratories and historical test ...201121926205
developing an integrated proteo-genomic approach for the characterisation of biomarkers for the identification of bacillus anthracis.bacillus anthracis is the causative agent of anthrax, an acute and often fatal disease in humans. due to the high genomic relatedness within the bacillus cereus group of species it is a challenge to identify b. anthracis consistently. alternative strategies such as proteomics coupled with mass spectrometry (ms) provide a powerful approach for biomarker discovery. however, validating and evaluating these markers, particularly for genetically homogeneous species such as b. anthracis are challengin ...201122178189
biodefense: 10 years after. reinventing project bioshield. 201121885752
[analyze and compare metabolic pathways of bacillus cereus group].a large number of data and information was obtained from genome sequencing and high-throughput genomic studies, use of the information to study metabolic networks become a new hotspot in biological research. this article compared different methods to reconstruct metabolic networks and analyzed the advantages and disadvantages of each methods, and then introduced some researches about carbohydrate metabolism pathways, amino acid metabolic pathways, and energy metabolism pathways of 9 strains of b ...201121993280
The potential contributions of lethal and edema toxins to the pathogenesis of anthrax associated shock.Outbreaks of Bacillus anthracis in the US and Europe over the past 10 years have emphasized the health threat this lethal bacteria poses even for developed parts of the world. In contrast to cutaneous anthrax, inhalational disease in the US during the 2001 outbreaks and the newly identified injectional drug use form of disease in the UK and Germany have been associated with relatively high mortality rates. One notable aspect of these cases has been the difficulty in supporting patients once shoc ...201122069762
vaccination and risk of type 1 diabetes mellitus in active component u.s. military, 2002-2008.to evaluate whether vaccination increases the risk of type 1 diabetes mellitus in active component u.s. military personnel.201122075092
the challenge of determining the need for remediation following a wide-area biological release.recovering from a biological attack is a complex process requiring the successful resolution of numerous challenges. the interagency biological restoration demonstration program is one of the first multiagency efforts to develop strategies and tools that could be effective following a wide-area release of b. anthracis spores. nevertheless, several key policy issues and associated science and technology issues still need to be addressed. for example, more refined risk assessment and management ap ...201121882967
logistics modelling: improving resource management and public information strategies in florida.one of the most time-sensitive and logistically-challenging emergency response operations today is to provide mass prophylaxis to every man, woman and child in a community within 48 hours of a bioterrorism attack. to meet this challenge, federal, state and local public health departments in the usa have joined forces to develop, test and execute large-scale bioterrorism response plans. this preparedness and response effort is funded through the us centers for disease control and prevention's cit ...201122130343
CodY regulation is required for full virulence and heme iron acquisition in Bacillus anthracis.Capsule and toxin are the major virulence factors of Bacillus anthracis. The B. anthracis pleiotropic regulator CodY activates toxin gene expression by post-translationally regulating the accumulation of the global regulator AtxA. However, the role of CodY on B. anthracis capsulation and virulence of encapsulated strains has been unknown. The role of CodY in B. anthracis virulence was studied in mouse and guinea pig models. Spore outgrowth and dissemination of the vegetative cells was followed i ...201121911592
suitability of commercial transport media for biological pathogens under nonideal conditions.there is extensive data to support the use of commercial transport media as a stabilizer for known clinical samples; however, there is little information to support their use outside of controlled conditions specified by the manufacturer. furthermore, there is no data to determine the suitability of said media for biological pathogens, specifically those of interest to the us military. this study evaluates commercial off-the-shelf (cots) transport media based on sample recovery, viability, and q ...201122121364
[changing the protective properties of the receptor domain of protective antigen anthrax exotoxin, depending on the orientation of the presentation on nanoparticles].polysterene particles bearing on its surface recombinant protein receptor domain of protective antigen anthrax exotoxin, exposed in different orientations have been constructed. particles with exposed cooh region of receptor domain induced the highest protective immunity in mice anthrax model (95%). we revealed that immunization with these particles causes a specific induction of th1-response, characterized by increased levels ofcytokine tnf-alpha and il-2.201122096993
Nine years' review on preseptal and orbital cellulitis and emergence of community-acquired methicillin-resistant Staphylococus aureus in a tertiary hospital in India.Preseptal cellulitis is the commonest orbital disease which frequently needs to be differentiated from orbital cellulitis. Prompt diagnosis and treatment with appropriate antibiotics can prevent vision loss and life-threatening complications of orbital cellulitis.201122011486
monoclonal antibody therapies against anthrax.anthrax is a highly lethal infectious disease caused by the spore-forming bacterium bacillus anthracis. it not only causes natural infection in humans but also poses a great threat as an emerging bioterror agent. the lethality of anthrax is primarily attributed to the two major virulence factors: toxins and capsule. an extensive effort has been made to generate therapeutically useful monoclonal antibodies to each of the virulence components: protective antigen (pa), lethal factor (lf) and edema ...201122069754
CELLULAR IRON DISTRIBUTION IN BACILLUS ANTHRACIS.Although successful iron acquisition by pathogens within a host is a pre-requisite for the establishment of infection, surprisingly little is known about the intracellular distribution of iron within bacterial pathogens. We have used a combination of anaerobic, native liquid chromatography, inductively coupled plasma mass spectrometry, principal component analysis and peptide mass fingerprinting to investigate the cytosolic iron distribution in the pathogen Bacillus anthracis. Our studies identi ...201122178968
In situ gastrointestinal protection against anthrax edema toxin by single-chain antibody fragment producing lactobacilli.ABSTRACT: BACKGROUND: Anthrax is caused by the bacterium Bacillus anthracis and is regarded as one of the most prominent bioterrorism threats. Anthrax toxicity is induced by the tripartite toxin complex, composed of the receptor-binding anthrax protective antigen and the two enzymatic subunits, lethal factor and edema factor. Recombinant lactobacilli have previously been used to deliver antibody fragments directed against surface epitopes of a variety of pathogens, including Streptococcus mutan ...201122185669
identification of a bacillus anthracis specific indel in the yeac gene and development of a rapid pyrosequencing assay for distinguishing b. anthracis from the b. cereus group.bacillus anthracis, the causative agent of anthrax, is a potential source of bioterrorism. the existing assays for its identification lack specificity due to the close genetic relationship it exhibits to other members of the b. cereus group. our comparative analyses of protein sequences from bacillus species have identified a 24 amino acid deletion in a conserved region of the yeac protein that is uniquely present in b. anthracis. pcr primers based on conserved regions flanking this indel in the ...201121907250
Identification of a lead small-molecule inhibitor of anthrax lethal toxin by using fluorescence-based high-throughput screening.Inhalational anthrax is caused by B. anthracis, a virulent sporeforming bacterium which secretes anthrax toxins consisting of protective antigen (PA ), lethal factor (LF ) and edema factor (EF ). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput scr ...201122189685
Lethal factor toxemia and anti-protective antigen antibody activity in naturally acquired cutaneous anthrax.Cutaneous anthrax outbreaks occurred in Bangladesh from August to October 2009. As part of the epidemiological response and to confirm anthrax diagnoses, serum samples were collected from suspected case patients with observed cutaneous lesions. Anthrax lethal factor (LF), anti-protective antigen (anti-PA) immunoglobulin G (IgG), and anthrax lethal toxin neutralization activity (TNA) levels were determined in acute and convalescent serum of 26 case patients with suspected cutaneous anthrax from t ...201121908727
cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization.RhoA-inhibitory bacterial toxins, such as Staphylococcus aureus EDIN toxin, induce large transendothelial cell macroaperture (TEM) tunnels that rupture the host endothelium barrier and promote bacterial dissemination. Host cells repair these tunnels by extending actin-rich membrane waves from the TEM edges. We reveal that cyclic-AMP signaling produced by Bacillus anthracis edema toxin (ET) also induces TEM formation, which correlates with increased vascular permeability. We show that ET-induced ...201122100162
The national framework and consequence management guidance following a biological attack.Consequence management following a release of aerosolized Bacillus anthracis spores requires a high level of technical understanding and direction. National policies and regulations address the topics of preparedness goals and organizational structure, but they do not tell responders how to perform remediation. Essential considerations include determining what must be cleaned, evaluating health risks, ascertaining the priority of cleanup, and selecting appropriate decontamination technologies to ...201121882968
laboratory contributions to public health. 201121976158
Biocidal activity of plasma modified electrospun polysulfone mats functionalized with polyethyleneimine-capped silver nanoparticles.The incorporation of silver nanoparticles (AgNPs) into polymeric nanofibers has attracted a great deal of attention due to the strong antimicrobial activity that the resulting fibers exhibit. However, bactericidal efficacy of AgNP-coated electrospun fibrous mats has not yet been demonstrated. In this study, polysulfone (PSf) fibers were electrospun and surface-modified using an oxygen plasma treatment, which allowed for facile irreversible deposition of cationically charged polyethyleneimine (PE ...201121928790
coenzyme a binding to the aminoglycoside acetyltransferase (3)-iiib increases conformational sampling of antibiotic binding site.nmr spectroscopy experiments and molecular dynamics simulations were performed to describe the dynamic properties of the aminoglycoside acetyltransferase (3)-iiib (aac) in its apo and coenzyme a (coash) bound forms. the (15)n-(1)h hsqc spectra indicate a partial structural change and coupling of the coash binding site with another region in the protein upon the coash titration into the apo enzyme. molecular dynamics simulations indicate a significant structural and dynamic variation of the long ...201122026726
surface architecture of endospores of the bacillus cereus/anthracis/thuringiensis family at the subnanometer scale.bacteria of the bacillus cereus family form highly resistant spores, which in the case of the pathogen b. anthracis act as the agents of infection. the outermost layer, the exosporium, enveloping spores of the b. cereus family as well as a number of clostridia, plays roles in spore adhesion, dissemination, targeting, and germination control. we have analyzed two naturally crystalline layers associated with the exosporium, one representing the "basal" layer to which the outermost spore layer ("ha ...201121896762
transcutaneous dna immunization following waxing-based hair depilation.transcutaneous dna immunization is an attractive immunization approach. previously, we reported that transcutaneous immunization by applying plasmid dna onto a skin area wherein the hair follicles had been induced into growth stage by 'cold' waxing-based hair plucking significantly enhanced the resultant immune responses. in the present study, using a plasmid that encodes the bacillus anthracis protective antigen (pa63) gene fragment, it was shown that the anti-pa63 antibody responses induced by ...201121907253
differential requirements for clathrin endocytic pathway components in cellular entry by ebola and marburg glycoprotein pseudovirions.clathrin-mediated endocytosis was previously implicated as one of the cellular pathways involved in filoviral glycoprotein mediated viral entry into target cells. here we have further dissected the requirements for different components of this pathway in ebola versus marburg virus glycoprotein (gp) mediated viral infection. although a number of these components were involved in both cases; ebola gp-dependent viral entry specifically required the cargo recognition proteins eps15 and dab2 as well ...201121855102
persistence of non-native spore forming bacteria in drinking water biofilm and evaluation of decontamination methods.persistence of bacillus globigii spores, a surrogate for bacillus anthracis, was studied on biofouled concrete-lined slides in drinking water using biofilm annular reactors. reactors were inoculated with b. globigii spores and persistence was monitored in the bulk and biofilm phases, first in dechlorinated water and later with free chlorine concentrations of 1 and 5 mg/l. in the dechlorinated study, a steady state population of spores developed on the slides. the addition of free chlorine at 5 m ...201121879559
preparation and characterization of cobalt-substituted anthrax lethal factor.anthrax lethal factor (lf) is a zinc-dependent endopeptidase involved in the cleavage of mitogen-activated protein kinase kinases near their n-termini. the current report concerns the preparation of cobalt-substituted lf (colf) and its characterization by electronic spectroscopy. two strategies to produce colf were explored, including (i) a bio-assimilation approach involving the cultivation of lf-expressing bacillus megaterium cells in the presence of cocl(2), and (ii) direct exchange by treatm ...201122093822
ecological niche modelling of the bacillus anthracis a1.a sub-lineage in kazakhstan.abstract:201122152056
chlorine dioxide inactivation of bacterial threat agents.aims:  to evaluate the efficacy of chlorine dioxide (clo(2) ) against seven species of bacterial threat (bt) agents in water. methods and results:  two strains of bacillus anthracis spores, yersinia pestis, francisella tularensis, burkholderia pseudomallei, burkholderia mallei, and brucella species were each inoculated into a clo(2) solution with an initial concentration of 2·0 mg l(-1) (spores only) and 0·25 mg l(-1) (all other bacteria) at ph 7 or 8, 5°c or 25°c. at 0·25 mg l(-1) in potable wa ...201121623848
marked enhancement of the immune response to biothrax(®) (anthrax vaccine adsorbed) by the tlr9 agonist cpg 7909 in healthy volunteers.immunization with biothrax(®) (anthrax vaccine adsorbed) is a safe and effective means of preventing anthrax. animal studies have demonstrated that the addition of cpg dna adjuvants to biothrax can markedly increase the immunogenicity of the vaccine, increasing both serum anti-protective antigen (pa) antibody and anthrax toxin-neutralizing antibody (tna) concentrations. the immune response to cpg-adjuvanted biothrax in animals was not only stronger, but was also more rapid and led to higher leve ...201121624418
a kinetic analysis of protein transport through the anthrax toxin channel.anthrax toxin is composed of three proteins: a translocase heptameric channel, (pa(63))(7), formed from protective antigen (pa), which allows the other two proteins, lethal factor (lf) and edema factor (ef), to translocate across a host cell's endosomal membrane, disrupting cellular homeostasis. (pa(63))(7) incorporated into planar phospholipid bilayer membranes forms a channel capable of transporting lf and ef. protein translocation through the channel can be driven by voltage on a timescale of ...201121624946
colorimetric and dynamic light scattering detection of dna sequences by using positively charged gold nanospheres: a comparative study with gold nanorods.we introduce a new genosensing approach employing ctab (cetyltrimethylammonium bromide)-coated positively charged colloidal gold nanoparticles (gnps) to detect target dna sequences by using absorption spectroscopy and dynamic light scattering. the approach is compared with a previously reported method employing unmodified ctab-coated gold nanorods (gnrs). both approaches are based on the observation that whereas the addition of probe and target ssdna to ctab-coated particles results in particle ...201121625041
an unusual mechanism of isopeptide bond formation attaches the collagenlike glycoprotein bcla to the exosporium of bacillus anthracis.abstract the outermost exosporium layer of spores of bacillus anthracis, the causative agent of anthrax, is comprised of a basal layer and an external hairlike nap. the nap includes filaments composed of trimers of the collagenlike glycoprotein bcla. essentially all bcla trimers are tightly attached to the spore in a process requiring the basal layer protein bxpb (also called exsfa). both bcla and bxpb are incorporated into stable, high-molecular-mass complexes, suggesting that bcla is attached ...201121628501
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