Publications

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ratiometric fluorescent detection of an anthrax biomarker at molecular printboards. 201020629056
diversity of spore-forming bacteria in cattle manure, slaughterhouse waste and samples from biogas plants.as biowaste intended for biogas production can contain pathogenic micro-organisms, the recommended treatment is pasteurization at 70°c for 60min. this reduces pathogens such as salmonella spp., whereas spore-forming bacteria (bacillus spp. and clostridium spp.) survive. most spore-forming bacteria are harmless, but some can cause diseases such as blackleg, botulism and anthrax. in this study, the effect of the biogas process on bacillus spp. and clostridium spp. was investigated.201020629803
chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.host defence peptides (hdps) are considered to be excellent candidates for the development of novel therapeutic agents. recently, it was demonstrated that the peptide c1-15, an n-terminal segment of chicken hdp cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. in the present study, we report that c1-15 is active against bacteria such as bacillus anthracis and yersinia pestis that may potentially be used by bioterrorists. substitution of s ...201020630709
analysis of antibody responses to protective antigen-based anthrax vaccines through use of competitive assays.the licensed anthrax vaccine and many of the new anthrax vaccines being developed are based on protective antigen (pa), a nontoxic component of anthrax toxin. for this reason, an understanding of the immune response to pa vaccination is important. in this study, we examined the antibody response elicited by pa-based vaccines and identified the domains of pa that contribute to that response in humans as well as nonhuman primates (nhps) and rabbits, animal species that will be used to generate eff ...201020631338
the genome of a bacillus isolate causing anthrax in chimpanzees combines chromosomal properties of b. cereus with b. anthracis virulence plasmids.anthrax is a fatal disease caused by strains of bacillus anthracis. members of this monophyletic species are non motile and are all characterized by the presence of four prophages and a nonsense mutation in the plcr regulator gene. here we report the complete genome sequence of a bacillus strain isolated from a chimpanzee that had died with clinical symptoms of anthrax. unlike classic b. anthracis, this strain was motile and lacked the four prohages and the nonsense mutation. four replicons were ...201020634886
[progress in research on occupational anthrax]. 201020635707
analytical particle measurements in an optical microflume.in this work, microscopic particles in a fluid flow are manipulated using forces generated by a high power laser beam. the resulting manipulations on the particles are imaged using a microscope lens connected to a ccd camera. differential forces on particles of varying physical and chemical composition have been measured. the goal is to measure the optical forces on a diverse range of particles and catalog the associated chemical and physical differences to understand which properties and mechan ...201020685420
amyloid peptide pores and the beta sheet conformation.over 20 clinical syndromes have been described as amyloid diseases. pathologically, these illnesses are characterized by the deposition in various tissues of amorphous, congo red stainingdeposits, referred to as amyloid. under polarizing light microscopy, these deposits exhibit characteristic green birefringence. x-ray diffraction reveals cross-beta structure of extended amyloid fibrils. although there is always a major protein in amyloid deposits, the predominant protein differs in each ofthe c ...201020687488
confirmation of bacillus anthracis from flesh-eating flies collected during a west texas anthrax season.this case study confirms the interaction between necrophilic flies and white-tailed deer, odocoileus virginianus, during an anthrax outbreak in west texas (summer 2005). bacillus anthracis was identified by culture and pcr from one of eight pooled fly collections from deer carcasses on a deer ranch with a well-documented history of anthrax. these results provide the first known isolation of b. anthracis from flesh-eating flies associated with a wildlife anthrax outbreak in north america and are ...201020688697
activation of the latent plcr regulon in bacillus anthracis.many genes in bacillus cereus and bacillus thuringiensis are under the control of the transcriptional regulator plcr and its regulatory peptide, papr. in bacillus anthracis, the causative agent of anthrax, plcr is inactivated by truncation, and consequently genes having plcr binding sites are expressed at very low levels when compared with b. cereus. we found that activation of the plcr regulon in b. anthracis by expression of a plcr-papr fusion protein does not alter sporulation in strains cont ...201020688829
oculocutaneous anthrax: detection and treatment.anthrax, a zoonotic disease that primarily affects herbivores, has received recent attention as a potential agent of bioterrorism. we report a patient who presented with a 4-day history of pain, watering and difficulty in opening the left upper and lower eyelids, and fever. clinical examination revealed brawny nonpitting edema with serosanguinous discharge. the history of the death of his sheep 1 week prior to the illness provided the clue to the diagnosis. although standard cultures of the bloo ...201020689787
anthrax toxin receptor 1/tumor endothelial marker 8: mutation of conserved inserted domain residues overrides cytosolic control of protective antigen binding.anthrax toxin receptor 1 (antxr1)/tumor endothelial marker 8 (tem8) is one of two known proteinaceous cell surface anthrax toxin receptors. a metal ion dependent adhesion site (midas) present in the integrin-like inserted (i) domain of antxr1 mediates the binding of the anthrax toxin subunit, protective antigen (pa). here we provide evidence that single point mutations in the i domain can override regulation of antxr1 ligand-binding activity mediated by intracellular signals. a previously report ...201020690680
an anthrax subunit vaccine candidate based on protective regions of bacillus anthracis protective antigen and lethal factor.studies have confirmed the key role of bacillus anthracis protective antigen (pa) in the us and uk human anthrax vaccines. however, given the tripartite nature of the toxin, other components, including lethal factor (lf), are also likely to contribute to protection. we examined the antibody and t cell responses to pa and lf in human volunteers immunized with the uk anthrax vaccine (avp). individual lf domains were assessed for immunogenicity in mice when given alone or with pa. based on the resu ...201020691267
characterisation and evaluation of synthetic antimicrobial peptides against bacillus globigii, bacillus anthracis and burkholderia thailandensis.antimicrobial peptides (amps) are produced by all forms of living organisms and represent a novel class of antibiotics to treat infectious diseases. in this study, 29 amps of varying length and characteristics were synthesised chemically and were evaluated for their ability to inhibit the growth of bacillus globigii, bacillus anthracis and burkholderia thailandensis. amongst the peptides tested, sheep myeloid antimicrobial peptide-29 (smap-29) was the most potent, inhibiting both b. globigii and ...201020692130
issues in biosecurity and biosafety.the role of non-governmental organisations and other interested observers - civil society - has long been neglected by governments in the quest for a world secure from the threat of biological weapons or bioterrorism. new trends illustrate a greater appreciation of a strong need for a cooperative partnership. governments need to accept and embrace some of these new trends and new technologies. at least since 2001 and the amerithrax anthrax letters, the usa has had a significant focus on biosecur ...201020696555
a synthetic peptide vaccine directed against the 2ß2-2ß3 loop of domain 2 of protective antigen protects rabbits from inhalation anthrax.the current vaccines for anthrax in the united states and united kingdom are efficacious in the two most accepted animal models of inhalation anthrax, nonhuman primates and rabbits, but require extensive immunization protocols. we previously demonstrated that a linear determinant in domain 2 of bacillus anthracis protective ag (pa) is a potentially important target for an epitope-specific vaccine for anthrax, as abs specific for this site, referred to as the loop-neutralizing determinant (lnd), ...201020696862
the structure of tumor endothelial marker 8 (tem8) extracellular domain and implications for its receptor function for recognizing anthrax toxin.anthrax toxin, which is released from the gram-positive bacterium bacillus anthracis, is composed of three proteins: protective antigen (pa), lethal factor (lf), and edema factor (ef). pa binds a receptor on the surface of the target cell and further assembles into a homo-heptameric pore through which ef and lf translocate into the cytosol. two distinct cellular receptors for anthrax toxin, tem8/antxr1 and cmg2/antxr2, have been identified, and it is known that their extracellular domains bind p ...201020585457
a femtomol range fret biosensor reports exceedingly low levels of cell surface furin: implications for the processing of anthrax protective antigen.furin, a specialized endoproteinase, transforms proproteins into biologically active proteins. furin function is important for normal cells and also in multiple pathologies including malignancy and anthrax. furin is believed to cycle between the golgi compartment and the cell surface. processing of anthrax protective antigen-83 (pa83) by the cells is considered thus far as evidence for the presence of substantial levels of cell-surface furin. to monitor furin, we designed a cleavage-activated fr ...201020585585
[toxicological effects of weapons of mass destruction and noxious agents in modern warfare and terrorism].weapons of mass destruction (wmd) best portray the twisted use of technological achievements against the human species. despite arm control efforts, wmd threat continues to exist and even proliferate. this in turn calls for improvement in defensive measures against this threat. the modern soldier is exposed to a number of chemical, biological, and radiological agents in military and peace operations, while civilians are mainly exposed to terrorist attacks. regardless of origin or mode of action, ...201020587400
proteasome inhibitors prevent caspase-1-mediated disease in rodents challenged with anthrax lethal toxin.nod-like receptors (nlrs) and caspase-1 are critical components of innate immunity, yet their over-activation has been linked to a long list of microbial and inflammatory diseases, including anthrax. the bacillus anthracis lethal toxin (lt) has been shown to activate the nlr nalp1b and caspase-1 and to induce many symptoms of the anthrax disease in susceptible murine strains. in this study we tested whether it is possible to prevent lt-mediated disease by pharmacological inhibition of caspase-1. ...201020595632
high abundance and diversity of bacillus anthracis plasmid pxo1-like replicons in municipal wastewater.water from the influent of a municipal wastewater treatment plant as well as soil samples collected from the shoreline of 10 lakes were screened for the presence of the bacillus anthracis pxo1-like plasmid replicon repx using a pcr assay. specific pcr products were retrieved from all samples, indicating a widespread presence of pxo1-like plasmid replicons in various environmental settings. initial screening by restriction enzyme analysis revealed at least two forms of the repx gene in the wastew ...201020597981
the structure of yersinia pestis caf1 polymer in free and adjuvant bound states.caf1 of the plague bacterium, yersinia pestis is a polymeric virulence factor and vaccine component, formed from monomers by a donor strand exchange (dse) mechanism. here, em images of caf1 reveal flexible polymers up to 1.5 microm long (4mda). the bead-like structures along the polymer are 5.8 + or - 1 nm long and correspond to single caf1 proteins. short polymers often form circles, presumably by dse. we also provide the first images of proteins bound to alhydrogel adjuvant. caf1, hemocyanin a ...201020600492
bacillus anthracis surface-layer proteins assemble by binding to the secondary cell wall polysaccharide in a manner that requires csab and tago.bacillus anthracis, the causative agent of anthrax, requires surface (s)-layer proteins for the pathogenesis of infection. previous work characterized s-layer protein binding via the surface layer homology domain to a pyruvylated carbohydrate in the envelope of vegetative forms. the molecular identity of this carbohydrate and the mechanism of its display in the bacterial envelope are still unknown. analyzing acid-solubilized, purified carbohydrates by mass spectrometry and nmr spectroscopy, we i ...201020603129
inhibition of antibiotic-resistant staphylococcus aureus by the broad-spectrum dihydrofolate reductase inhibitor rab1.the bacterial burden on human health is quickly outweighing available therapeutics. our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. we previously reported phthalazine-based inhibitors of dihydrofolate reductase (dhfr) with potent activity against bacillus anthracis, a major component of project bioshield. the most active molecule, named rab1, performs well in vitro and, in a cocrystal structure, was found deep within the active site of b. a ...201020606069
anthrax: public health risk in india and socio-environmental determinants. 201020606952
[the return of anthrax. from bioterrorism to the zoonotic cluster of sciacca district].anthrax is a disease caused by bacillus anthracis which affects herbivorous animals. humans acquire the disease incidentally by exposure to infected animals, animal products or spores on soil. the infection is still endemic in many regions in developing countries. in italy animal clusters are very rare and human cases are exceptional. bacillus anthrax is also a potential source for acts of bioterrorism. in the natural human infection, cutaneous anthrax is the most widespread, while the other two ...201020610930
molecular analysis of carbohydrate-antibody interactions: case study using a bacillus anthracis tetrasaccharide.the process for selecting potent and effective carbohydrate antigens is not well-established. a combination of synthetic glycan microarray screening, surface plasmon resonance analysis, and saturation transfer difference nmr spectroscopy was used to dissect the antibody-binding surface of a carbohydrate antigen, revealing crucial binding elements with atomic-level detail. this analysis takes the first step toward uncovering the rules for structure-based design of carbohydrate antigens.201020614885
[treatment of the patient with anthrax complicated with gastric bleeding]. 201020524239
[henry toussaint and louis pasteur. rivalry over a vaccine].henry toussaint (1847-1890) is a veterinary who studied in veterinary school of lyon with his great master auguste chauveau the famous physiologist. this place is the first school founded in europe at the end of the xviiith century and has opened a way of thinking. his carrer brilliant and rich begins first in lyon and then when he is named professor of anatomy and physiology at the veterinary school of toulouse. doctor of science and doctor of medecine toussaint applies "the experimental method ...201020527335
biosynthesis of a new udp-sugar, udp-2-acetamido-2-deoxyxylose, in the human pathogen bacillus cereus subspecies cytotoxis nvh 391-98.we have identified an operon and characterized the functions of two genes from the severe food-poisoning bacterium, bacillus cereus subsp. cytotoxis nvh 391-98, that are involved in the synthesis of a unique udp-sugar, udp-2-acetamido-2-deoxyxylose (udp-n-acetyl-xylosamine, udp-xylnac). uglcnacdh encodes a udp-n-acetyl-glucosamine 6-dehydrogenase, converting udp-n-acetylglucosamine (udp-glcnac) to udp-n-acetyl-glucosaminuronic acid (udp-glcnaca). the second gene in the operon, uxnacs, encodes a ...201020529859
select human anthrax protective antigen epitope-specific antibodies provide protection from lethal toxin challenge.bacillus anthracis remains a serious bioterrorism concern, and the currently licensed vaccine remains an incomplete solution for population protection from inhalation anthrax and has been associated with concerns regarding efficacy and safety. thus, understanding how to generate long-lasting protective immunity with reduced immunizations or provide protection through postexposure immunotherapeutics are long-sought goals. through evaluation of a large military cohort, we characterized the levels ...201020533877
use of allostery to identify inhibitors of calmodulin-induced activation of bacillus anthracis edema factor.allostery plays a key role in the regulation of the activity and function of many biomolecules. and although many ligands act through allostery, no systematic use is made of it in drug design strategies. here we describe a procedure for identifying the regions of a protein that can be used to control its activity through allostery. this procedure is based on the construction of a plausible conformational path, which describes protein transition between known active and inactive conformations. th ...201020534570
subunit and small-molecule interaction of ribonucleotide reductases via surface plasmon resonance biosensor analyses.ribonucleotide reductase (rnr) synthesizes deoxyribonucleotides for dna replication and repair and is controlled by sophisticated allosteric regulation involving differential affinity of nucleotides for regulatory sites. we have developed a robust and sensitive method for coupling biotinylated rnrs to surface plasmon resonance streptavidin biosensor chips via a 30.5 a linker. in comprehensive studies on three rnrs effector nucleotides strengthened holoenzyme interactions, whereas substrate had n ...201020534631
activation of nf-κb pathway and tnf-α are involved in the cytotoxicity of anthrax lethal toxin in bovine bomac macrophages.anthrax lethal toxin (letx) is an important virulence factor of bacillus anthracis and causes illness and lethality for both animals and humans. because species demonstrate varied sensitivity to anthrax intoxication, we investigated signaling pathways involved in anthrax letx cytotoxicity using a bovine macrophage cell line (bomac). we found that bovine macrophages are sensitive to letx as displayed by a concentration-dependent increase in cell death. letx induced the degradation of i-κb and inc ...201020537817
validation of a nylon-flocked-swab protocol for efficient recovery of bacterial spores from smooth and rough surfaces.in order to meet planetary-protection requirements, culturable bacterial spore loads are measured representatively for the total microbial contamination of spacecraft. however, the national aeronautics and space administration's (nasa's) cotton swab protocols for spore load determination have not changed for decades. to determine whether a more efficient alternative was available, a novel swab was evaluated for recovery of different bacillus atrophaeus spore concentrations on stainless steel and ...201020543054
a novel spore protein, exsm, regulates formation of the exosporium in bacillus cereus and bacillus anthracis and affects spore size and shape.bacillus cereus spores are assembled with a series of concentric layers that protect them from a wide range of environmental stresses. the outermost layer, or exosporium, is a bag-like structure that interacts with the environment and is composed of more than 20 proteins and glycoproteins. here, we identified a new spore protein, exsm, from a beta-mercaptoethanol extract of b. cereus atcc 4342 spores. subcellular localization of an exsm-green fluorescent protein (gfp) protein revealed a dynamic ...201020543075
law in the time of anthrax: biosecurity lessons from the united states.in 2009, under the national health security act 2007 (cth), the australian government began introducing biosecurity regulations for laboratory research and other work involving certain pathogenic micro-organisms. the security-sensitive biological agents (ssba) scheme is virtually unprecedented in australia but is similar to the biological select agents and toxins (bsats) scheme which has existed in the united states since the mid-1990s. this article examines recent united states experience in us ...201020552938
detection of low numbers of bacillus anthracis spores in three soils using five commercial dna extraction methods with and without an enrichment step.to (i) compare the limits of detection of bacillus anthracis spores in three soils (one florida, one texas, and one a commercial garden product) by pcr using dna extracted with five commercial extraction kits and (ii) examine if removing organic acids or adding an enrichment step utilizing a growth medium will improve the detection limits.201020553343
key roles of dendritic cells in lung infection and improving anthrax vaccines.lung immune responses control pathogens while avoiding detrimental inflammation. the dynamics of lung homeostasis are not fully understood. primary antimicrobial defenses are orchestrated by epithelial cells (ecs), interacting in close association with dendritic cells (dcs) and other innate immune cells. however, microbes, such as bacillus anthracis use host cellular machinery, including dc-migratory capacity to reach the draining lymph nodes where they germinate and produce toxins that disrupt ...201020554248
membrane chromatography: protein purification from e. coli lysate using newly designed and commercial anion-exchange stationary phases.this contribution describes the purification of anthrax protective antigen (pa) protein from escherichia coli lysate using bind-and-elute chromatography with newly designed weak anion-exchange membranes. protein separation performance of the new aex membrane adsorber was compared with the commercial sartobind d membrane adsorber and hitrap deae ff resin column under preparative scale conditions. dynamic protein binding capacities of all three stationary phases were determined using breakthrough ...201020554285
genome-wide single nucleotide polymorphism typing method for identification of bacillus anthracis species and strains among b. cereus group species.as an issue of biosecurity, species-specific genetic markers have been well characterized. however, bacillus anthracis strain-specific information is currently not sufficient for traceability to identify the origin of the strain. by using genome-wide screening using short read mapping, we identified strain-specific single nucleotide polymorphisms (snps) among b. anthracis strains including japanese isolates, and we further developed a simplified 80-tag snp typing method for the primary investiga ...201020554827
oligochlorophens are potent inhibitors of bacillus anthracis.bacterial cytoskeletal proteins are an emerging set of targets for antibiotic development. this paper describes oligochlorophen analogs based on the monomer 4-chloro-2,6-dimethylphenol as antimicrobial agents against bacillus anthracis. the most potent analogs have a mic of 160 to 320 nm against b. anthracis and may target the cytoskeletal protein ftsz. b. anthracis develops resistance to the oligochlorophens at a rate of 4.34 x 10(-10) per generation, which is approximately 10-fold lower than t ...201020566769
adverse events following smallpox vaccination with acam2000 in a military population.generalized vaccinia and benign exanthems are 2 adverse events that have been associated with the smallpox vaccination. accurate incidence and prevalence rates of each are not readily available, but these events are thought to be uncommon. to our knowledge, this is the first case series to provide clinical as well as pathologic descriptions of multiple papulovesicular eruptions occurring after receiving the second-generation smallpox vaccine, acam2000 (acambis, canton, massachusetts), among a va ...201020566929
a novel pharmacophore model for the design of anthrax lethal factor inhibitors.this study aims at the identification of novel structural features on the surface of the zn-dependent metalloprotease lethal factor (lf) from anthrax onto which to design novel and selective inhibitors. we report that by targeting an unexplored region of lf that exhibits ligand-induced conformational changes, we could obtain inhibitors with at least 30-fold lf selectivity compared to two other most related human metalloproteases, mmp-2 and mmp-9. based on these results, we propose a novel pharma ...201020572812
essentiality and functional analysis of type i and type iii pantothenate kinases of mycobacterium tuberculosis.pantothenate kinase, an essential enzyme in bacteria and eukaryotes, is involved in catalysing the first step of conversion of pantothenate to coenzyme a (coa). three isoforms (type i, ii and iii) of this enzyme have been reported from various organisms, which can be differentiated from each other on the basis of their biochemical and structural characteristics. though most bacteria carry only one of the isoforms of pantothenate kinases, some of them possess two isoforms. the physiological relev ...201020576686
complexes of bacterial nicotinate mononucleotide adenylyltransferase with inhibitors: implication for structure-based drug design and improvement.bacterial nicotinate mononucleotide adenylyltransferase encoded by the essential gene nadd plays a central role in the synthesis of the redox cofactor nad(+). the nadd enzyme is conserved in the majority of bacterial species and has been recognized as a novel target for developing new and potentially broad-spectrum antibacterial therapeutics. here we report the crystal structures of bacillus anthracis nadd in complex with three nadd inhibitors, including two analogues synthesized in the present ...201020578699
a semisynthesis platform for investigating structure-function relationships in the n-terminal domain of the anthrax lethal factor.many bacterial toxins act by covalently altering molecular targets within the cytosol of mammalian cells and therefore must transport their catalytic moieties across a membrane. the protective-antigen (pa) moiety of anthrax toxin forms multimeric pores that transport the two enzymatic moieties, the lethal factor (lf) and the edema factor, across the endosomal membrane to the cytosol. the homologous pa-binding domains of these enzymes contain n-terminal segments of highly charged amino acids that ...201020180595
epitope-cavities generated by molecularly imprinted films measure the coincident response to anthrax protective antigen and its segments.a molecularly imprinted film was fabricated, in the presence of epitope-peptides, onto a quartz crystal microbalance (qcm) chip. these five peptides are known linear or conformational epitopes of the anthrax protective antigen pa(83). imprinting resulted in an epitope-cavity with affinity for the corresponding template. with the use of a basic monomer, the binding-effect was further enhanced increasing the affinity to nanomolar levels. the affinities of the peptide to their corresponding molecul ...201020184289
evaluation of bacillus anthracis and yersinia pestis sample collection from nonporous surfaces by quantitative real-time pcr.we will validate sample collection methods for recovery of microbial evidence in the event of accidental or intentional release of biological agents into the environment.201020184669
two cases of gastrointestinal anthrax with an unusual presentation from kermanshah (western iran).during 1988-1994 a total of 38 cases of human anthrax were admitted to sina hospital in kermanshah (western iran). there were two cases of gastrointestinal anthrax (5.3%) with culture positive ascitic fluid. among the many reported gastrointestinal signs and symptoms, unexpectedly one of our patients had only vomiting and ascites whereas the other case had only ascites. neither had abdominal pain, tenderness, diarrhea, hematemesis, melena, or other expected signs and symptoms of anthrax. therefo ...201020187673
preparedness for anthrax attack: the effect of knowledge on the willingness to treat patients.little is known about the factors that may impact on the willingness of physicians and nurses to treat patients during a bioterrorism attack. this survey was conducted among 76 randomly selected nurses and physicians in the emergency rooms of three public hospitals in order to analyse the relationship between knowledge, profession and the willingness to treat anthrax. the study finds that the willingness of physicians and nurses to come to work is 50% greater among the group with the highest kno ...201020187905
snr analysis: molecular investigation of an anthrax epidemic.in italy, anthrax is endemic but occurs sporadically. during the summer of 2004, in the pollino national park, basilicata, southern italy, an anthrax epidemic consisting of 41 outbreaks occurred; it claimed the lives of 124 animals belonging to different mammal species. this study is a retrospective molecular epidemiological investigation carried out on 53 isolates collected during the epidemic. a 25-loci multiple locus vntr analysis (mlva) mlva was initially performed to define genetic relation ...201020187980
immunostimulatory cpg oligonucleotides: effect on gene expression and utility as vaccine adjuvants.synthetic oligodeoxynucleotides (odn) containing unmethylated cpg motifs mimic the immunostimulatory activity of bacterial dna. cpg odn directly stimulate b cells and plasmacytoid dendritic cells (pdc), promote the production of th1 and pro-inflammatory cytokines, and trigger the maturation/activation of professional antigen presenting cells. cpg odn are finding use as vaccine adjuvants, where they increase the speed, magnitude and duration of vaccine-specific immune responses. for example, cpg ...201020188247
the role of anthrolysin o in gut epithelial barrier disruption during bacillus anthracis infection.gastrointestinal (gi) anthrax, caused by the bacterial infection of bacillus anthracis, posts a significant bioterrorism threat by its relatively high mortality rate in humans. different from inhalational anthrax by the route of infection, accumulating evidence indicates the bypass of vegetative bacteria across gi epithelium is required to initiate gi anthrax. previously, we reported that purified anthrolysin o (alo), instead of tripartite anthrax edema and lethal toxins, is capable of disruptin ...201020188700
transport of bacillus anthracis from the lungs to the draining lymph nodes is a rapid process facilitated by cd11c+ cells.inhalational anthrax is established after inhaled bacillus anthracis spores are transported to the lung associated lymph nodes. dendritic cells (cd11c+ cells) located in the lungs are phagocytes that maintain many capabilities consistent with transport. this study investigates the role of dendritic cells as conduits of spores from the lung to the draining lymph nodes. the intratracheally spore-challenged mouse model of inhalational anthrax was utilized to investigate in vivo activities of cd11c+ ...201020188814
exclusion of kif1c as a candidate gene for anthrax toxin susceptibility.different strains of mice possess varying degrees of susceptibility to anthrax lethal toxin (lt). previous studies have suggested a responsible locus ltxs1 that contains 10 or more known genes, but functional relevance has been reported for two genes, kif1c and nalp1b. in this study, we attempted to determine the involvement of kif1c in anthrax susceptibility using kif1c knockout mice. we established kif1c knockout mice with lt-sensitive 129/sv-derived embryonic stem cells followed by 13 backcro ...201020188815
national validation study of a swab protocol for the recovery of bacillus anthracis spores from surfaces.twelve laboratory response network (lrn) affiliated laboratories participated in a validation study of a macrofoam swab protocol for the recovery, detection, and quantification of viable b. anthracis (ba) sterne spores from steel surfaces. cdc personnel inoculated steel coupons (26cm(2)) with 1-4 log(10) ba spores and recovered them by sampling with pre-moistened macrofoam swabs. phase 1 (p1) of the study evaluated swabs containing ba only, while dust and background organisms were added to swabs ...201020193714
most-probable-number rapid viability pcr method to detect viable spores of bacillus anthracis in swab samples.a comparison of most-probable-number rapid viability (mpn rv) pcr and traditional culture methods for the quantification of bacillus anthracis sterne spores in macrofoam swabs from a multi-center validation study was performed. the purpose of the study was to compare environmental swab processing methods for recovery, detection, and quantification of viable b. anthracis spores from surfaces. results show that spore numbers provided by the mpn rv-pcr method were typically within 1-log of the valu ...201020193716
anthrax lethal toxin impairs cd1d-mediated antigen presentation by targeting the extracellular signal-related kinase 1/2 mitogen-activated protein kinase pathway.lethal toxin (lt) is a critical virulence factor of bacillus anthracis and an important means by which this bacterium evades the host's immune system. in this study, we demonstrate that cd1d-expressing cells treated with lt have reduced cd1d-mediated antigen presentation. we earlier showed an important role for the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (erk1/2) in the regulation of cd1d-mediated antigen presentation, and we report here that lt impairs antigen ...201020194602
selective and potent furin inhibitors protect cells from anthrax without significant toxicity.furin and related proprotein convertases cleave the multibasic motifs r-x-r/k/x-r in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides. furin is present both in the intracellular secretory pathway and at the cell surface. intracellular furin processes its multiple normal cellular targets in the golgi and secretory vesicle compartments while cell-surface furin appears to be essential only for the processing of certain pathogen ...201020197107
a universal, fully automated high throughput screening assay for pyrophosphate and phosphate release from enzymatic reactions.the malachite green assay is often used for measuring the presence of inorganic mono-phosphate concentrations. some studies have adapted this assay for use in monitoring enzymatic reactions and have suggested its potential use in high throughput screening (hts). with the increasing availability of laboratory automation, some studies are starting to explore the possibility of conducting limited, semi-automated versions of the assay. here we report the optimization and complete adaptation of the m ...201020201823
vaccination, squalene and anti-squalene antibodies: facts or fiction?squalene, a hydrocarbon obtained for commercial purposes primarily from shark liver oil and other botanic sources, is increasingly used as an immunologic adjuvant in several vaccines, including seasonal and the novel influenza a (h1n1) 2009 pandemic flu vaccines. nearly a decade ago, squalene was supposed to be the experimental anthrax vaccine ingredient that caused the onset of persian gulf war syndrome in many veterans, since antibodies to squalene were detected in the blood of most patients a ...201020206873
natural exposure to cutaneous anthrax gives long-lasting t cell immunity encompassing infection-specific epitopes.there has been a long history of defining t cell epitopes to track viral immunity and to design rational vaccines, yet few data of this type exist for bacterial infections. bacillus anthracis, the causative agent of anthrax, is both an endemic pathogen in many regions and a potential biological warfare threat. t cell immunity in naturally infected anthrax patients has not previously been characterized, which is surprising given concern about the ability of anthrax toxins to subvert or ablate ada ...201020208010
raman spectroscopy-compatible inactivation method for pathogenic endospores.micro-raman spectroscopy is a fast and sensitive tool for the detection, classification, and identification of biological organisms. the vibrational spectrum inherently serves as a fingerprint of the biochemical composition of each bacterium and thus makes identification at the species level, or even the subspecies level, possible. therefore, microorganisms in areas susceptible to bacterial contamination, e.g., clinical environments or food-processing technology, can be sensed. within the scope ...201020208030
us biodefense contracts continue to lure biotechs. 201020212465
soluble expression and purification of the anthrax protective antigen in e. coli and identification of a novel dominant-negative mutant n435c.the anthrax toxin is an ab-type bacterium toxin composed of the protective antigen (pa) as the cell-binding b component, and the lethal factor (lf) and edema toxin (ef) as the catalytic a components. the pa component is a key factor in anthrax-related research and recombinant pa can be produced in general in escherichia coli. however, such recombinant pa always forms inclusion bodies in the cytoplasm of e. coli, making difficult the procedure of its purification. in this study, we found that the ...201020213183
trp-26 imparts functional versatility to human alpha-defensin hnp1.we performed a comprehensive alanine scan of human alpha-defensin hnp1 and tested the ability of the resulting analogs to kill staphylococcus aureus, inhibit anthrax lethal factor, and bind human immunodeficiency virus-1 gp120. by far, the most deleterious mutation for all of these functions was w26a. the activities lost by w26a-hnp1 were restored progressively by replacing w26 with non-coded, straight-chain aliphatic amino acids of increasing chain length. the hydrophobicity of residue 26 also ...201020220136
endocytosis of the anthrax toxin is mediated by clathrin, actin and unconventional adaptors.the anthrax toxin is a tripartite toxin, where the two enzymatic subunits require the third subunit, the protective antigen (pa), to interact with cells and be escorted to their cytoplasmic targets. pa binds to cells via one of two receptors, tem8 and cmg2. interestingly, the toxin times and triggers its own endocytosis, in particular through the heptamerization of pa. here we show that pa triggers the ubiquitination of its receptors in a beta-arrestin-dependent manner and that this step is requ ...201020221438
the social context shaping bioweapons (non)proliferation.this article explores the practices behind the creation and transfer of knowledge related to biological weapons (bw) in the former soviet bw program and their implications for understanding bioweapons proliferation. using in-depth interviews collected for an ongoing oral history project of the soviet and u.s. bioweapons programs, this article shows that bw proliferation is a complex issue that involves thus far unrecognized social factors that can shape the production and proliferation of biowea ...201020230229
how to reduce the impact of "low-risk patients" following a bioterrorist incident: lessons from sars, anthrax, and pneumonic plague.a bioterrorist attack may result in a large number of people who have not been exposed coming to medical facilities in search of treatment or reassurance. in this article, we review evidence from 3 previous biological incidents that are analogous to a bioterrorist attack in order to gauge the likely incidence of such "low-risk patients" and to identify possible strategies for coping with this phenomenon. evidence from the anthrax attacks in the united states suggested that a surge of low-risk pa ...201020230231
comments from the center for biosecurity of upmc on dhs proposed guidance for responders during a wide-area anthrax attack. 201020230236
[expression and neutralizing activity analysis of humanized single-chain antibody against anthrax protective antigen].in order to reduce the human anti-mouse antibody (hama) response, anti-anthrax protective antigen scfv-5e1 has been humanized.201020230675
modeling the potential distribution of bacillus anthracis under multiple climate change scenarios for kazakhstan.anthrax, caused by the bacterium bacillus anthracis, is a zoonotic disease that persists throughout much of the world in livestock, wildlife, and secondarily infects humans. this is true across much of central asia, and particularly the steppe region, including kazakhstan. this study employed the genetic algorithm for rule-set prediction (garp) to model the current and future geographic distribution of bacillus anthracis in kazakhstan based on the a2 and b2 ipcc sres climate change scenarios usi ...201020231894
targeted proteomics approach to species-level identification of bacillus thuringiensis spores by ap-maldi-ms.anthrax infections progress at a rapid pace, making rapid detection methods of utmost importance. maldi-ms proteomics methods focused on bacillus anthracis detection have targeted chromosomally encoded proteins, which are highly conserved between closely related species, hindering species identification. presented here is an ap-maldi-ms method targeting plasmid-borne proteins from bacillus spores for species-level identification. a bioinformatics analysis revealed that 60.3% and 75.4% of tryptic ...201020236838
role of the gerp operon in germination and outgrowth of bacillus anthracis spores.germination of bacillus anthracis spores occurs when nutrients such as amino acids or purine nucleosides stimulate specific germinant receptors located in the spore inner membrane. the gerp(abcdef) operon has been suggested to play a role in facilitating the interaction between germinants and their receptors in spores of bacillus subtilis and bacillus cereus. b. anthracis mutants containing deletions in each of the six genes belonging to the orthologue of the gerp(abcdef) operon, or deletion of ...201020161744
evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of bacillus anthracis acetohydroxyacid synthase.acetohydroxyacid synthase (ahas), a potential target for antimicrobial agents, catalyzes the first common step in the biosynthesis of the branched-chain amino acids. the genes of both catalytic and regulatory subunits of ahas from bacillus anthracis (bantx), a causative agent of anthrax, were cloned, overexpressed in escherichia coli, and purified to homogeneity. to develop novel anti-anthracis drugs that inhibit ahas, a chemical library was screened, and four chemicals, avs2087, avs2093, avs238 ...201020170757
anthrax investigation. silicon mystery endures in solved anthrax case. 201020299555
lysogeny and sporulation in bacillus isolates from the gulf of mexico.eleven bacillus isolates from the surface and subsurface waters of the gulf of mexico were examined for their capacity to sporulate and harbor prophages. occurrence of sporulation in each isolate was assessed through decoyinine induction, and putative lysogens were identified by prophage induction by mitomycin c treatment. no obvious correlation between ability to sporulate and prophage induction was found. four strains that contained inducible virus-like particles (vlps) were shown to sporulate ...201020008174
a rapid multiplex assay for nucleic acid-based diagnostics.we have developed a rapid (under 4 hours), multiplex, nucleic acid assay, adapted to a microsphere array detection platform. we call this assay multiplex oligonucleotide ligation-pcr (mol-pcr). unlike other ligation-based assays that require multiple steps, our protocol consists of a single tube reaction, followed by hybridization to a luminex microsphere array for detection. we demonstrate the ability of this assay to simultaneously detect diverse nucleic acid signatures (e.g., unique sequences ...201020006656
quantitative multiplex detection of pathogen biomarkers on multichannel waveguides.no single biomarker can accurately predict disease. an ideal biodetection technology should be capable of the quantitative, reproducible, and sensitive detection of a limited suite of such molecules. to this end, we have developed a multiplex biomarker assay for protective antigen and lethal factor of the bacillus anthracis lethal toxin using semiconductor quantum dots as the fluorescence reporters on our waveguide-based biosensor platform. the platform is extendable to a wide array of biomarker ...201020000585
crystal structure of the transcriptional repressor pagr of bacillus anthracis.pagr is a transcriptional repressor in bacillus anthracis that controls the chromosomal s-layer genes eag and sap, and downregulates the protective antigen paga gene by direct binding to their promoter regions. the pagr protein sequence is similar to those of members of the arsr repressor family involved in the repression of arsenate-resistance genes in numerous bacteria. the crystal structure of pagr was solved using multi-wavelength anomalous diffraction (mad) techniques and was refined with 1 ...201019926656
contributions of four cortex lytic enzymes to germination of bacillus anthracis spores.bacterial spores remain dormant and highly resistant to environmental stress until they germinate. completion of germination requires the degradation of spore cortex peptidoglycan by germination-specific lytic enzymes (gsles). bacillus anthracis has four gsles: cwlj1, cwlj2, sleb, and slel. in this study, the cooperative action of all four gsles in vivo was investigated by combining in-frame deletion mutations to generate all possible double, triple, and quadruple gsle mutant strains. analyses o ...201019966006
anthrax lethal toxin promotes dephosphorylation of ttp and formation of processing bodies.anthrax lethal toxin (letx) is composed of protective antigen (pa) and lethal factor (lf) - pa is the receptor-binding moiety and lf is a protease that cleaves mitogen-activated protein kinase kinases (mapkks). letx subverts the immune response to bacillus anthracis in several ways, such as downregulating interleukin-8 (il-8) by increasing the rate of il-8 mrna degradation. many transcripts are regulated through cis-acting elements that bind proteins that either impede or promote degradation. so ...201019995385
inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma.patients with anaplastic thyroid carcinoma (atc) typically succumb to their disease months after diagnosis despite aggressive therapy. a large percentage of atcs have been shown to harbor the v600e b-raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. atc invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (mmp). the explicit targeting of these two tumor markers may provide a nov ...201020053778
activity of dalbavancin against bacillus anthracis in vitro and in a mouse inhalation anthrax model.bacillus anthracis, the causative agent of anthrax, can produce fatal disease when it is inhaled or ingested by humans. dalbavancin, a novel, semisynthetic lipoglycopeptide, has potent activity, greater than that of vancomycin, against gram-positive bacteria and a half-life in humans that supports once-weekly dosing. dalbavancin demonstrated potent in vitro activity against b. anthracis (mic range, < or =0.03 to 0.5 mg/liter; mic(50) and mic(90), 0.06 and 0.25 mg/liter, respectively), which led ...201020047912
sequence motifs and proteolytic cleavage of the collagen-like glycoprotein bcla required for its attachment to the exosporium of bacillus anthracis.bacillus anthracis spores are enclosed by an exosporium comprised of a basal layer and an external hair-like nap. the filaments of the nap are composed of trimers of the collagen-like glycoprotein bcla. the attachment of essentially all bcla trimers to the exosporium requires the basal layer protein bxpb, and both proteins are included in stable high-molecular-mass exosporium complexes. bcla contains a proteolytically processed 38-residue amino-terminal domain (ntd) that is essential for basal-l ...201020038593
a new prior for bayesian anomaly detection: application to biosurveillance.bayesian anomaly detection computes posterior probabilities of anomalous events by combining prior beliefs and evidence from data. however, the specification of prior probabilities can be challenging. this paper describes a bayesian prior in the context of disease outbreak detection. the goal is to provide a meaningful, easy-to-use prior that yields a posterior probability of an outbreak that performs at least as well as a standard frequentist approach. if this goal is achieved, the resulting po ...201020027381
antibacterial activity of radical scavengers against class ib ribonucleotide reductase from bacillus anthracis.bacillus anthracis is a severe mammalian pathogen. the deoxyribonucleotides necessary for dna replication and repair are provided via the ribonucleotide reductase (rnr) enzyme. rnr is also important for spore germination and cell proliferation upon infection. we show that the expression of b. anthracis class ib rnr responds to the environment that the pathogen encounters upon infection. we also show that several anti-proliferative agents (radical scavengers) specifically inhibit the b. anthracis ...201020030587
expression and regulation of antxr1 in the chick embryo.anthrax toxin receptor 1 (antxr1; also known as tumor endothelial marker 8, tem8) is one of several genes that was recently found to be up-regulated in tumor-associated endothelial cells. in vitro, the protein can link extracellular matrix components with the actin cytoskeleton to promote cell adhesion and cell spreading. both, antxr1 and the closely related antxr2 can bind anthrax toxin and interact with lipoprotein receptor-related protein 5 and 6, which also work as coreceptors in the wnt sig ...201020034073
high-throughput multiplex flow cytometry screening for botulinum neurotoxin type a light chain protease inhibitors.given their medical importance, proteases have been studied by diverse approaches and screened for small molecule protease inhibitors. here, we present a multiplexed microsphere-based protease assay that uses high-throughput flow cytometry to screen for inhibitors of the light chain protease of botulinum neurotoxin type a (bontalc). our assay uses a full-length substrate and several deletion mutants screened in parallel to identify small molecule inhibitors. the use of multiplex flow cytometry h ...201020035615
dry thermal resistance of bacillus anthracis (sterne) spores and spores of other bacillus species: implications for biological agent destruction via waste incineration.to obtain needed data on the dry thermal resistance of bacillus anthracis spores and other bacillus species for waste incinerator applications.201020015207
pemk toxin of bacillus anthracis is a ribonuclease: an insight into its active site, structure, and function.bacillus anthracis genome harbors a toxin-antitoxin (ta) module encoding pemi (antitoxin) and pemk (toxin). this study describes the rpemk as a potent ribonuclease with a preference for pyrimidines (c/u), which is consistent with our previous study that demonstrated it as a translational attenuator. the in silico structural modeling of the pemk in conjunction with the site-directed mutagenesis confirmed the role of his-59 and glu-78 as an acid-base couple in mediating the ribonuclease activity. ...201020022964
the overlap of small molecule and protein binding sites within families of protein structures.protein-protein interactions are challenging targets for modulation by small molecules. here, we propose an approach that harnesses the increasing structural coverage of protein complexes to identify small molecules that may target protein interactions. specifically, we identify ligand and protein binding sites that overlap upon alignment of homologous proteins. of the 2,619 protein structure families observed to bind proteins, 1,028 also bind small molecules (250-1000 da), and 197 exhibit a sta ...201020140189
three-dimensional structure of the anthrax toxin pore inserted into lipid nanodiscs and lipid vesicles.a major goal in understanding the pathogenesis of the anthrax bacillus is to determine how the protective antigen (pa) pore mediates translocation of the enzymatic components of anthrax toxin across membranes. to obtain structural insights into this mechanism, we constructed pa-pore membrane complexes and visualized them by using negative-stain electron microscopy. two populations of pa pores were visualized in membranes, vesicle-inserted and nanodisc-inserted, allowing us to reconstruct two vir ...201020142512
type-iia secreted phospholipase a2 is an endogenous antibiotic-like protein of the host.type-iia secreted phospholipase a(2) (spla(2)-iia) has been proposed to play a role in the development of inflammatory diseases. it has been shown to release arachidonic acid, the precursor of proinflammatory eicosanoids, to hydrolyze phospholipids of pulmonary surfactant, and to bind to specific receptors located on cell surface membranes. however, the most established biological role of spla(2)-iia is related to its potent bactericidal property in particular toward gram-positive bacteria. this ...201020144678
pharmacokinetic-pharmacodynamic assessment of faropenem in a lethal murine bacillus anthracis inhalation postexposure prophylaxis model.there are few options for prophylaxis after exposure to bacillus anthracis, especially in children and women of childbearing potential. faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. faropenem was shown to have in vitro activity against b. anthracis strains that variably express the bla1 beta-lactamase (mic range, <or=0.06 to 1 microg/ml). in this study we evaluated the pharmacok ...201020145081
a tnf-like trimeric lectin domain from burkholderia cenocepacia with specificity for fucosylated human histo-blood group antigens.the opportunistic pathogen burkholderia cenocepacia expresses several soluble lectins, among them bc2l-c. this lectin exhibits two domains: a c-terminal domain with high sequence similarity to the recently described calcium-dependent mannose-binding lectin bc2l-a, and an n-terminal domain of 156 amino acids without similarity to any known protein. the recombinant n-terminal bc2l-c domain is a new lectin with specificity for fucosylated human histo-blood group epitopes h-type 1, lewis b, and lewi ...201020152153
synthesis and biological evaluation of botulinum neurotoxin a protease inhibitors.nsc 240898 was previously identified as a botulinum neurotoxin a light chain (bont/a lc) endopeptidase inhibitor by screening the national cancer institute open repository diversity set. two types of analogues have been synthesized and shown to inhibit bont/a lc in a fret-based enzyme assay, with confirmation in an hplc-based assay. these two series of compounds have also been evaluated for inhibition of anthrax lethal factor (lf), an unrelated metalloprotease, to examine enzyme specificity of t ...201020155918
heroin contaminated with anthrax has killed 11 people. 201020156915
nano aptasensor for protective antigen toxin of anthrax.we demonstrate a highly sensitive nano aptasensor for anthrax toxin through the detection of its polypeptide entity, protective antigen (pa toxin) using a pa toxin ssdna aptamer functionalized single-walled carbon nanotubes (swnts) device. the aptamer was developed in-house by capillary electrophoresis systematic evolution of ligands by exponential enrichment (ce-selex) and had a dissociation constant (k(d)) of 112 nm. the aptasensor displayed a wide dynamic range spanning up to 800 nm with a de ...201020136122
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