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host cell cytotoxicity and cytoskeleton disruption by ceradpr, an adp-ribosyltransferase of bacillus cereus g9241.bacillus cereus g9241 was isolated from a welder suffering from an anthrax-like inhalation illness. b. cereus g9241 encodes two megaplasmids, pbcxo1 and pbc210, which are analogous to the toxin- and capsule-encoding virulence plasmids of bacillus anthracis. protein modeling predicted that the pbc210 lf homologue contained an adp-ribosyltransferase (adpr) domain. this putative bacterial adp-ribosyltransferase domain was denoted ceradpr. iterative modeling showed that ceradpr possessed several con ...201322934824
brucella as a potential agent of bioterrorism.perception on bioterrorism has changed after the deliberate release of anthrax by the postal system in the united states of america in 2001. potential bioterrorism agents have been reclassified based on their dissemination, expected rate of mortality, availability, stability, and ability to lead a public panic. brucella species can be easily cultured from infected animals and human materials. also, it can be transferred, stored and disseminated easily. an intentional contamination of food with b ...201322934672
electrochemical detection of the binding of bacillus anthracis protective antigen (pa) to the membrane receptor on macrophages through release of nitric oxide.anthrax is a serious bacterial disease of man and animals whose pathogenesis involves the secretion of lethal toxins in the host. the intracellular delivery of toxic complexes involves a complex structural rearrangement of sub-domains of the exotoxin protective antigen (pa). we have used a biocompatible microelectrode array, coated with j774 mouse macrophages, to detect pa binding and intracellular signaling resulting in nitric oxide (no) release. we have found that exposure of macrophages to pa ...201322672762
one health in mongolia.the asia pacific strategy for emerging diseases (apsed) requires collaboration, consensus, and partnership across all the different actors and sectors involved in different aspects of emerging disease. guided by apsed, mongolia has established a functional coordination mechanism between the animal and human health sectors. surveillance, information exchange and risk assessment, risk reduction, and coordinated response capacity and collaborative research have been identified as the four pillars o ...201323065105
inactivation of bacillus anthracis in water by photocatalytic, photolytic and sonochemical treatment.bacillus anthracis is one of the most dangerous and pathogenic bacterial species and its intrusion in aquatic environments is a serious threat to public health. the aim of the present study was to investigate inactivation rates of b. anthracis in water by means of photocatalytic (uva/tio2), photolytic (uvc) and sonochemical treatment. the effect of various operating conditions such as bacterial concentration, tio2 loading, uv irradiation source, ultrasound power and treatment time was examined. ...201323064250
the mountain meadows massacre and "poisoned springs": scientific testing of the more recent, anthrax theory.it has been recorded that one of the possible causes that eventually escalated into the 1857 manslaughter at mountain meadows in southern utah was the poisoning of an open spring by the fancher-baker party as they crossed the utah territory on their way from arkansas to california. historical accounts report that a number of cattle died, followed by human casualties from those that came in contact with the dead animals. even after the arkansas party departed, animals continued to perish and peop ...201322395921
cationic quaternized aminocalix[4]arenes: cytotoxicity, haemolytic and antibacterial activities.this study reports the characterization of three cationic amphiphillic aminocalix[4]arenes as potential antimicrobial agents in vitro. in cytotoxicity tests on mouse macrophage raw 264.7 cells aminocalix[4]arenes 1 and 3 showed no toxicity up to 200 and 100 μm concentrations, respectively, while 2 was non-toxic only up to 50 μm. with regard to the haemolytic activity on rabbit red blood cells, 1 was not active at concentrations up to 100 μm in contrast to the other two studied macrocycles. compo ...201324157345
[bacillus anthracis: a molecular look at a famous pathogen].bacillus anthracis, a gram-positive rod belonging to the bacillus cereus group, has an extremely monomorphic genome, and presents high structural and physiological similarity with b. cereus and bacillus thuringiensis. in this work, the new molecular methods for the identification and typing of b. anthracis developed in the last years, based on variable number tandem repeats or on genetic differences detected through sequencing, are described. the molecular aspects of traditional virulence factor ...201322274828
ground anthrax bacillus refined isolation (gabri) method for analyzing environmental samples with low levels of bacillus anthracis contamination.in this work are reported the results of a qualitative analytical method capable of detecting bacillus anthracis spores when they are present in very low concentration in the soil. the ground anthrax bacillus refined isolation (gabri) method, assessed in our laboratory, was compared with the classic method. the comparison involved artificially anthrax-contaminated soil samples (500 spores/7.5 grams soil) and naturally contaminated soil samples collected in bangladesh during a field investigation ...201323865983
constant domains influence binding of mouse-human chimeric antibodies to the capsular polypeptide of bacillus anthracis.our laboratory previously described the binding characteristics of the murine igg3 monoclonal antibody (muab) f26g3. this antibody binds the poly-glutamic acid capsule (pga) of bacillus anthracis, an essential virulence factor in the progression of anthrax. f26g3 igg3 muab binds pga with a relatively high functional affinity (10 nm), produces a distinct "rim" quellung reaction, and is protective in a murine model of pulmonary anthrax. this study engineered an igg subclass family of f26g3 mouse-h ...201323863605
a human/murine chimeric fab antibody neutralizes anthrax lethal toxin in vitro.human anthrax infection caused by exposure to bacillus anthracis cannot always be treated by antibiotics. this is mostly because of the effect of the remaining anthrax toxin in the body. lethal factor (lf) is a component of lethal toxin (letx), which is the major virulence of anthrax toxin. a murine igg monoclonal antibody (mab) against lf with blocking activity (coded lf8) was produced in a previous study. in this report, a human/murine chimeric fab mab (coded lf8-fab) was developed from lf8 by ...201323861692
inhibitors of bacillus anthracis edema factor.edema factor (ef) is a calmodulin (cam)-activated adenylyl cyclase (ac) toxin from bacillus anthracis that contributes to anthrax pathogenesis. anthrax is an important medical problem, but treatment of b. anthracis infections is still unsatisfying. thus, selective ef inhibitors could be valuable drugs in the treatment of anthrax infection, most importantly shock. the catalytic site of ef, the ef/cam interaction site and allosteric sites constitute potential drug targets. to this end, most effort ...201323850654
designed azolopyridinium salts block protective antigen pores in vitro and protect cells from anthrax toxin.several intracellular acting bacterial protein toxins of the ab-type, which are known to enter cells by endocytosis, are shown to produce channels. this holds true for protective antigen (pa), the binding component of the tripartite anthrax-toxin of bacillus anthracis. evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric pa63 binding/translocation component are r ...201323840407
high temperature unfolding of a truncated hemoglobin by molecular dynamics simulation.heme containing proteins are associated with peroxidase activity. the proteins like hemoglobin, myoglobins, cytochrome c and micro-peroxidase other than peroxidases have been shown to exhibit weak peroxidase-like activity. this weak peroxidase-like activity in hemoglobin-like molecules is due to heme moiety. we conducted molecular dynamics (md) studies to decipher the unfolding path of ba-glb (a truncated hemoglobin from bacillus anthracis) and the role of heme moiety to its unfolding path. the ...201323839248
a plant-produced protective antigen vaccine confers protection in rabbits against a lethal aerosolized challenge with bacillus anthracis ames spores.the potential use of bacillus anthracis as a bioterrorism weapon threatens the security of populations globally, requiring the immediate availability of safe, efficient and easily delivered anthrax vaccine for mass vaccination. extensive research efforts have been directed toward the development of recombinant subunit vaccines based on protective antigen (pa), the principal virulence factor of b. anthracis. among the emerging technologies for the production of these vaccine antigens is our launc ...201323324615
vaccine protection against bacillus cereus-mediated respiratory anthrax-like disease in mice.bacillus cereus strains harboring a pxo1-like virulence plasmid cause respiratory anthrax-like disease in humans, particularly in welders. we developed mouse models for intraperitoneal as well as aerosol challenge with spores of b. cereus g9241, harboring pbcxo1 and pbc218 virulence plasmids. compared to wild-type b. cereus g9241, spores with a deletion of the pbcxo1-carried protective antigen gene (paga1) were severely attenuated, whereas spores with a deletion of the pbc218-carried protective ...201323319564
effect of ph on the catalytic function and zinc content of native and immobilized anthrax lethal factor.translocation of the zinc-dependent metalloendopeptidase anthrax lethal factor (lf) from the endosome to the cytosol requires an acidic endosomal milieu. in the current study, we utilized immobilized (to prevent protein aggregation below ph 5.5) and native lf to assess the effect of ph on the function and metal content of lf. our results reveal the diminution of lf's catalytic competence under moderately acidic conditions (ph ∼6) to be uncorrelated to the metal content of the protein. however, a ...201323313942
fusion of laboratory and textual data for investigative bioforensics.chemical and biological forensic programs focus on the identification of a threat and acquisition of laboratory measurements to determine how a threat agent may have been produced. however, to generate investigative leads, it might also be useful to identify institutions where the same agent has been produced by the same or a very similar process, since the producer of the agent may have learned methods at a university or similar institution. we have developed a bayesian network framework that f ...201323313599
anthrax drug first antibacterial mab to win approval. 201323302914
study of charge distribution on the surface of biocolloids.potentiometric titration and zeta potential measurements are crucial techniques for the characterization of the surface properties of bacterial cells. in this study, we investigated the effects of two commonly used electrolytes, nano(3) and naclo(4), on the viability and acid-base properties of gram-positive bacteria bacillus subtilis. b. subtilis are non-pathogenic bacteria which are often used to model the surface properties of pathogenic microorganisms of the same genus, including bacillus an ...201323298596
identification of cody targets in bacillus anthracis by genome-wide in vitro binding analysis.in gram-positive bacteria, cody is an important regulator of genes whose expression changes under conditions of nutrient limitation. bacillus anthracis cody represses or activates directly or indirectly approximately 500 genes. affinity purification of cody-dna complexes was used to identify the direct targets of cody. of the 389 dna binding sites that were copurified with cody, 132 sites were in or near the regulatory regions governing the expression of 197 cody-controlled genes, indicating tha ...201323292769
targeting her2-positive cancer cells with receptor-redirected anthrax protective antigen.targeted therapeutics have emerged in recent years as an attractive approach to treating various types of cancer. one approach is to modify a cytocidal protein toxin to direct its action to a specific population of cancer cells. we created a targeted toxin in which the receptor-binding and pore-forming moiety of anthrax toxin, termed protective antigen (pa), was modified to redirect its receptor specificity to her2, a marker expressed at the surface of a significant fraction of breast and ovaria ...201323290417
an investigation of a cluster of parapoxvirus cases in missouri, feb-may 2006: epidemiologic, clinical and molecular aspects.in the spring of 2006, four human cases of parapoxvirus infections in missouri residents were reported to the centers for disease control and prevention (cdc), two of which were initially diagnosed as cutaneous anthrax. this investigation was conducted to determine the level of recognition of zoonotic parapoxvirus infections and prevention measures, the degree to which veterinarians may be consulted on human infections and what forces were behind this perceived increase in reported infections. i ...201326487314
fast identification of yersinia pestis, bacillus anthracis and francisella tularensis based on conventional pcr.rapid and accurate diagnostic tools for detection and identification of y pestis, b. anthracis and f. tularensis are essential for timely initial appropriate treatment of exposed individuals, which will be critical to their survival, as well as for reduction of the public health impact and the spread of the disease. the paper presents application of fast polymerases and fast dry electrophoresis in conventional pcr as an alternative for real-time pcr application for detection and identification o ...201324730142
anthrax receptors position the spindle.spindle orientation plays a pivotal role in tissue morphogenesis. an asymmetric anthrax receptor cap is revealed to promote activation of a formin to orient the spindle along the planar cell polarity (pcp) axis in zebrafish dorsal epiblast cells.201323263369
use of medical simulation to teach bioterrorism preparedness: the anthrax example.the 2001 anthrax bioterrorism attacks demonstrated vulnerability for future similar attacks. this article describes mechanisms that can be used to prepare the medical community and healthcare facilities for the diagnosis and management of a subsequent bioterrorism attack should such an event occur and the fundamentals of medical simulation and its use in teaching learners about the diagnosis of management of anthrax exposure.201323263314
preparedness of rural physicians for bioterrorist events in florida.human-induced public health emergencies such as the anthrax bioterrorism event and the terrorism events of september 11, 2001 in the united states have increased awareness of the nation's vulnerability to large-scale emergencies. scant attention has been given to preparing physicians in sparsely populated areas for public health emergencies. this study introduces a conceptual model developed from participants' responses that can be used to improve our understanding of rural physicians' preparedn ...201323263309
comparison of single domain antibody immobilization strategies evaluated by surface plasmon resonance.the use of single domain antibodies (sdabs) in place of conventional antibodies for both therapeutic and diagnostic applications continues to grow. sdabs offer a number of advantages when compared to conventional antibodies such as their small size and low structural complexity which allows them to readily be produced as fusions in a variety formats. in this work we compared the utility of various c-terminal fusions and immobilization strategies for two sdabs; one which recognizes ricin and the ...201323261918
infections with spore-forming bacteria in persons who inject drugs, 2000-2009.since 2000 in the united kingdom, infections caused by spore-forming bacteria have been associated with increasing illness and death among persons who inject drugs (pwid). to assess temporal and geographic trends in these illnesses (botulism, tetanus, clostridium novyi infection, and anthrax), we compared rates across england and scotland for 2000-2009. overall, 295 infections were reported: 1.45 per 1,000 pwid in england and 4.01 per 1,000 pwid in scotland. the higher rate in scotland was mainl ...201323260795
a field usable qualitative anti-protective antigen enzyme-linked immunosorbent assay for serodiagnosis of human anthrax.although all mammals, including humans, are vulnerable when they come into direct contact with infected animals, anthrax is primarily a disease of herbivorous animals. in countries like india, cutaneous anthrax is a public health problem in several regions. hence, a simple and efficacious serodiagnostic assay for large scale surveillance of endemic populations is required. in the present study, a field-usable, qualitative elisa was developed for serodiagnosis of human anthrax. results are assess ...201323252995
serodiagnosis of human cutaneous anthrax in india using an indirect anti-lethal factor igg enzyme-linked immunosorbent assay.anthrax, caused by bacillus anthracis, is primarily a zoonotic disease. being a public health problem also in several developing countries, its early diagnosis is very important in human cases. in this study, we describe the use of an indirect enzyme-linked immunosorbent assay (elisa) for detection of anti-lethal factor (anti-lf) igg in human serum samples. a panel of 203 human serum samples consisting of 50 samples from patients with confirmed cutaneous anthrax, 93 samples from healthy controls ...201323269414
plasma bacterial and mitochondrial dna distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates.systemic inflammatory response syndrome (sirs) is a fundamental host response common to bacterial infection and sterile tissue injury. systemic inflammatory response syndrome can cause organ dysfunction and death, but its mechanisms are incompletely understood. moreover, sirs can progress to organ failure or death despite being sterile or after control of the inciting infection. biomarkers discriminating between sepsis, sterile sirs, and postinfective sirs would therefore help direct care. circu ...201323247122
bacillus anthracis acetyltransferases pata1 and pata2 modify the secondary cell wall polysaccharide and affect the assembly of s-layer proteins.the envelope of bacillus anthracis encompasses a proteinaceous s-layer with two s-layer proteins (sap and ea1). protein assembly in the envelope of b. anthracis requires s-layer homology domains (slh) within s-layer proteins and s-layer-associated proteins (bsls), which associate with the secondary cell wall polysaccharide (scwp), an acetylated carbohydrate that is tethered to peptidoglycan. here, we investigated the contributions of two putative acetyltransferases, pata1 and pata2, on scwp acet ...201323243307
rapid deamidation of recombinant protective antigen when adsorbed on aluminum hydroxide gel correlates with reduced potency of vaccine.deamidation of the recombinant protective antigen (rpa) correlates with decreased effectiveness of the vaccine in protecting against infection by bacillus anthracis. we present data demonstrating dramatic deamidation of amino acid positions 713 and 719 of rpa adsorbed onto aluminum hydroxide gel, an adjuvant, relative to rpa stored in solution without adjuvant. although deamidation did not impact total levels of rpa-specific antibodies in a mouse model, it did correlate with a decrease in toxin- ...201323242822
activation of the nlrp1b inflammasome by reduction of cytosolic atp.the efficacy of the innate immune system depends on its ability to mount an appropriate response to diverse infections and damaging agents. key components of this system are pattern recognition receptors that detect pathogen-associated and damage-associated molecular patterns (pamps and damps). nlrp1b is a pattern recognition receptor that forms a caspase-1 activation platform, known as an inflammasome, upon sensing the proteolytic activity of anthrax lethal toxin. the activation of caspase-1 le ...201323230290
anthrax infection in an intravenous drug user. 201323229347
cyclopentane-peptide nucleic acids for qualitative, quantitative, and repetitive detection of nucleic acids.we report the development of chemically modified peptide nucleic acids (pnas) as probes for qualitative and quantitative detection of dna. the remarkable stability of pnas toward enzymatic degradation makes this class of molecules ideal to develop as part of a diagnostic device that can be used outside of a laboratory setting. using an enzyme-linked reporter assay, we demonstrate that excellent levels of detection and accuracy for anthrax dna can be achieved using pna probes with suitable chemic ...201323214925
recovery balance: a method for estimating losses in a bacillus anthracis spore sampling protocol.the aim of this study was to develop a method to calculate the performance, and isolate error contributions occurring in a microbial surface sampling protocol.201323210624
poly(acrylic acid)-grafted fluoropolymer films for highly sensitive fluorescent bioassays.in this study, a facile and effective method for the surface functionalization of inert fluoropolymer substrates using surface grafting was demonstrated for the preparation of a new platform for fluorescence-based bioassays. the surface of perfluorinated poly(ethylene-co-propylene) (fep) films was functionalized using a 150 kev ion implantation, followed by the graft polymerization of acrylic acid, to generate a high density of carboxylic acid groups on the implanted surface. the resulting funct ...201323452270
biosurveillance in outbreak investigations.following the terrorist attacks of september 11 and the anthrax attacks in 2001, public health entities implemented automated surveillance systems based on disease syndromes for early detection of bioterror events and to increase timeliness of responses. despite widespread adoption, syndromic surveillance systems' ability to provide early notification of outbreaks is unproven, and there is little documentation on their role in outbreak response. we hypothesized that biosurveillance is used in pr ...201323448272
increased long-term immunity to bacillus anthracis protective antigen in mice immunized with a cia06b-adjuvanted anthrax vaccine.anthrax is an acute infectious disease caused by bacillus anthracis. we previously reported that the adjuvant cia06b, which consists of tlr4 agonist cia05 and aluminum hydroxide (alum), enhanced the immune response to anthrax protective antigen (pa) in mice. this study was carried out to determine whether cia06b can enhance long-term immune responses to pa in mice. balb/c mice were immunized intramuscularly three times at 2-week intervals with recombinant pa alone or pa combined with alum or cia ...201323440578
evaluation of peracetic acid fog for the inactivation of bacillus anthracis spore surrogates in a large decontamination chamber.the purpose of this study was to evaluate the sporicidal (inactivation of bacterial spores) effectiveness and operation of a fogging device utilizing peracetic acid/hydrogen peroxide (paa). experiments were conducted in a pilot-scale 24 m(3) stainless steel chamber using either biological indicators (bis) or bacterial spores deposited onto surfaces via aerosolization. wipe sampling was used to recover aerosol-deposited spores from chamber surfaces and coupon materials before and after fogging to ...201323434480
cutaneous anthrax resulting in renal failure with generalized tissue damage.anthrax is a zoonotic infection caused by bacillus anthracis which can be clinically present in a cutaneous, gastrointestinal or inhalational form depending on the entry site of the agent. the most frequent clinical type with the mildest clinical course is cutaneous anthrax. in this report, a patient with cutaneous anthrax which begins at the dorsal hand and progresses up to the proximal forearm resulting in massive tissue damage is presented. prerenal azotemia developed due to massive tissue da ...201323431997
current biodefense vaccine programs and challenges.the defense threat reduction agency's joint science and technology office manages the chemical and biological defense program's science and technology portfolio. the joint science and technology office's mission is to invest in transformational ideas, innovative people and actionable technology development for chemical and biological defense solutions, with the primary goal to deliver science and technology products and capabilities to the warfighter and civilian population that outpace the thre ...201323428906
vector-mediated selective expression of lethal factor, a toxic element of bacillus anthracis, damages a549 cells via inhibition of mapk and akt pathways.lethal factor (lf), a major toxic element of bacillus anthracis combined with its protective antigen (pa), enters the cells through the cytomembrane receptors and causes damage to the host cells, thereby leading to septicemia, toxemia, and meningitis with high mortality. lf has been identified as a potential biotech-weapon, which can impede cancer growth in vascular endothelial cells because of its cytotoxicity. however, the feasibility of lf application and further investigations has been limit ...201323423542
awareness and attitude toward zoonoses with particular reference to anthrax among cattle owners in selected rural communities of zimbabwe.we conducted a cross-sectional study to assess cattle owners' awareness, perceptions, and attitudes toward zoonoses, with particular emphasis regarding anthrax. data on awareness of zoonoses, clinical signs of anthrax in animals and human, its routes of transmission and methods of prevention, the families' consumption habits of anthrax-infected carcasses, and other family activities that increase exposure to anthrax were collected using an interviewer-administered questionnaire. a total of 41.4% ...201323421887
cytotoxicity of anthrax lethal toxin to human acute myeloid leukemia cells is nonapoptotic and dependent on extracellular signal-regulated kinase 1/2 activity.in this study, we attempt to target the mitogen-activated protein kinase (mapk) pathway in acute myeloid leukemia (aml) cells using a recombinant anthrax lethal toxin (letx). letx consists of protective antigen (prag) and lethal factor (lf). prag binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of lf, and undergoes endocytosis, releasing lf into the cytosol. lf cleaves mapk kinases, inhibiting the mapk pathway. we tested potency of letx on a panel of 11 human aml cel ...201323418614
bacillus weihenstephanensis characteristics are present in bacillus cereus and bacillus mycoides strains.the bacillus cereus group comprises seven bacterial species: bacillus cereus, bacillus anthracis, bacillus thuringiensis, bacillus mycoides, bacillus pseudomycoides, bacillus cytotoxicus, and bacillus weihenstephanensis. bacillus weihenstephanensis is distinguished based on its capability to grow at 7 °c but not at 43 °c, and the presence of specific signature sequences in the 16s rrna and cspa genes and in several housekeeping genes: glpf, gmk, purh, and tpi. bacillus weihenstephanensis-specifi ...201323413955
a genetic approach for the identification of exosporium assembly determinants of bacillus anthracis.the exosporium is the outermost layer of spores of the zoonotic pathogen bacillus anthracis. the composition of the exosporium and its functions are only partly understood. because this outer spore layer is refractive to traditional biochemical analysis, a genetic approach is needed in order to define the proteins which comprise this important spore layer and its assembly pathway. we have created a novel genetic screening system for the identification and isolation of mutants with defects in exo ...201323411372
portable, quantitative detection of bacillus bacterial spores using surface-enhanced raman scattering.portable rapid detection of pathogenic bacteria such as bacillus is highly desirable for safety in food manufacture and under the current heightened risk of biological terrorism. surface-enhanced raman scattering (sers) is becoming the preferred analytical technique for bacterial detection, due to its speed of analysis and high sensitivity. however in seeking methods offering the lowest limits of detection, the current research has tended toward highly confocal, microscopy-based analysis, which ...201323409961
genome sequence of the attenuated carbosap vaccine strain of bacillus anthracis.the bacillus anthracis carbosap genome, which includes the pxo1 and pxo2 plasmids, has been shown to encode the major b. anthracis virulence factors, yet this strain's attenuation has not yet been explained. here we report the draft genome sequence of this strain, and a comparison to fully virulent b. anthracis.201323405332
1,2,3,4,6-penta-o-galloyl-β-d-glucopyranose inhibits angiogenesis via inhibition of capillary morphogenesis gene 2.capillary morphogenesis gene 2 (cmg2) is a transmembrane extracellular matrix binding protein that is also an anthrax toxin receptor. we have shown that high-affinity cmg2 binders can inhibit angiogenesis and tumor growth. we recently described a high-throughput fret assay to identify cmg2 inhibitors. we now report the serendipitous discovery that pgg (1,2,3,4,6-penta-o-galloyl-β-d-glucopyranose) is a cmg2 inhibitor with antiangiogenic activity. pgg is a gallotannin produced by a variety of medi ...201323394144
engineering anthrax toxin variants that exclusively form octamers and their application to targeting tumors.anthrax toxin protective antigen (pa) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. by screening a highly directed library of pa mutants, we identified variants that complement each other to exclusively form octamers. these pa variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. we then engineered requirements for activation by matrix ...201323393143
assembly of anthrax toxin pore: lethal-factor complexes into lipid nanodiscs.we have devised a procedure to incorporate the anthrax protective antigen (pa) pore complexed with the n-terminal domain of anthrax lethal factor (lfn ) into lipid nanodiscs and analyzed the resulting complexes by negative-stain electron microscopy. insertion into nanodiscs was performed without relying on primary and secondary detergent screens. the preparations were relatively pure, and the percentage of pa pore inserted into nanodiscs on em grids was high (∼43%). three-dimensional analysis of ...201323389868
studies in mice reveal a role for anthrax toxin receptors in matrix metalloproteinase function and extracellular matrix homeostasis.the genes encoding anthrax toxin receptors (antxrs) were originally identified based on expression in endothelial cells suggesting a role in angiogenesis. the focus of this review is to discuss what has been learned about the physiological roles of these receptors through evaluation of the antxr knockout mouse phenotypes. mice mutant in antxr genes have defects in extracellular matrix homeostasis. we discuss how knowledge of physiological antxr function relates to what is already known about ant ...201323389402
a novel homogeneous immunoassay for anthrax detection based on the alphalisa method: detection of b. anthracis spores and protective antigen (pa) in complex samples.amplified luminescent proximity homogeneous assay (alphalisa) technology is an energy-transfer-based assay, utilizing singlet oxygen as an energy donor to a fluorescent acceptor. the long singlet oxygen migration distance allows the energy transfer mechanism to go up to ~200 nm, facilitating flexible and sensitive homogeneous immunoassays. while soluble protein detection using alphalisa was previously described, the detection of particles such as bacteria and viruses was not reported. in this wo ...201323388689
concentration, detection and discrimination of bacillus anthracis spores in orange juice using aptamer based surface enhanced raman spectroscopy.herein, we developed an innovative label free platform for concentration, detection and discrimination of bacillus anthracis spores. based on aptamer capture and surface enhanced raman scattering detection, we were able to detect 10(4) cfu spores spiked in orange juice and discriminate between spores b. anthracis and b. mycoides within 40 min.201323386216
elastic and inelastic diffraction changes upon variation of the relative humidity environment of pure crystals.the different changes observed in the diffraction patterns of three different crystal forms (hexagonal, trigonal and monoclinic) of pure (ec 4.1.1.21), an enzyme from the purine-biosynthesis pathway of bacillus anthracis, upon a wide range of changes in the relative humidity environment of the crystals are documented. in addition, the changes in the unit-cell parameters, volume and bulk solvent in the three different crystal forms were systematically followed. in an attempt to explain the elasti ...201323385456
colonic immune stimulation by targeted oral vaccine.currently, sufficient data exist to support the use of lactobacilli as candidates for the development of new oral targeted vaccines. to this end, we have previously shown that lactobacillus gasseri expressing the protective antigen (pa) component of anthrax toxin genetically fused to a dendritic cell (dc)-binding peptide (dcpep) induced efficacious humoral and t cell-mediated immune responses against bacillus anthracis sterne challenge.201323383086
fatal cutaneous anthrax in a heroin user.cutaneous anthrax usually has a mortality rate of less than 1 per cent. however, since december 2009 there have been more than 13 deaths in the uk due to anthrax-contaminated heroin. we therefore wish to raise clinical awareness of this treatable disease.201323374534
the near-iron transporter (neat) domains of the anthrax hemophore isdx2 require a critical glutamine to extract heme from methemoglobin.several gram-positive pathogenic bacteria employ near-iron transporter (neat) domains to acquire heme from hemoglobin during infection. however, the structural requirements and mechanism of action for neat-mediated heme extraction remains unknown. bacillus anthracis exhibits a rapid growth rate during systemic infection, suggesting that the bacterium expresses efficient iron acquisition systems. to understand how b. anthracis acquires iron from heme sources, which account for 80% of mammalian ir ...201323364793
pathology and pathophysiology of inhalational anthrax in a guinea pig model.nonhuman primates (nhps) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the fda's "animal rule." however, a need for an alternative animal model may arise in certain cases. the development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. the guinea p ...201323357384
a simple, reliable m'fadyean stain for visualizing the bacillus anthracis capsule.the simple polychrome methylene blue (pmb) staining procedure for blood or tissue smears from dead animals (m'fadyean reaction) established in 1903 remained accepted as a highly reliable, rapid diagnostic test for anthrax for six decades while that disease was still common in livestock throughout the world. improvements in disease control led to anthrax becoming rare in industrialized countries and less frequent in developing countries with the result that quality controlled, commercially produc ...201323357124
rapid vaccination using an acetalated dextran microparticulate subunit vaccine confers protection against triplicate challenge by bacillus anthracis.a rapid immune response is required to prevent death from anthrax, caused by bacillus anthracis.201323354770
genetic tools to enhance the study of gene function and regulation in staphylococcus aureus.the bursa aurealis transposon has been used to create transposon insertion libraries of bacillus anthracis and staphylococcus aureus. to provide a set of genetic tools to enhance the utility of these libraries, we generated an allelic-exchange system that allows for the replacement of the transposon with useful genetic markers and fluorescent reporter genes. these tools were tested in the nebraska transposon mutant library (ntml), containing defined transposon insertions in 1,952 nonessential s. ...201323354696
a comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen.development of nasal immunization for human use is hindered by the lack of acceptable adjuvants. although ct is an effective adjuvant, its toxicity will likely prevent its use in nasal vaccines. this study compared non-toxin adjuvants to ct for their ability to induce protective antibody responses with nasal immunization. c3h/hen and c57bl/6 mice were immunized with rpa formulated with the following adjuvants: ct, il-1α, lps, cpg, pam3csk4, 3m-019, resiquimod/r848 or c48/80. serum and nasal wash ...201323352329
carbon microarrays for the direct impedimetric detection of bacillus anthracis using gamma phages as probes.a direct and efficient impedimetric method is presented for the detection of bacillus anthracis sterne vegetative cells, using gamma phages as probes attached to screen-printed carbon electrode microarrays. the carbon electrodes were initially functionalized through cyclic-voltammetric reduction of a nitro-aryl diazonium moiety, followed by further reduction of nitro groups to amino groups, and finally by treatment with glutaraldehyde. functionalization (probe immobilization) using gamma phages ...201323348920
bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/ raxibacumab-treated new zealand white rabbits.inhaled bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (pa) binds to cell receptors and the enzymatic moieties. antibiotics can control b. anthracis bacteremia, whereas raxibacumab binds pa and blocks lethal toxin effects. this study assessed plasma pa kinetics in rabbits following an inhaled b. anthracis spore ...201323344456
identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death.studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. we conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function ...201323343607
medical aspects of bio-terrorism.bioterrorism is a terrorist action involving the intentional release or dissemination of a biological warfare agent (bwa), which includes some bacteria, viruses, rickettsiae, fungi or biological toxins. bwa is a naturally occurring or human-modified form that may kill or incapacitate humans, animals or plants as an act of war or terrorism. bwa is a weapon of choice for mass destruction and terrorism, because of the incubation period, less effective amount than chemical warfare agents, easily dis ...201323339855
distinct functions of polysaccharide deacetylases in cell shape, neutral polysaccharide synthesis and virulence of bacillus anthracis.peptidoglycan deacetylases (pgng-dacs) belong to the carbohydrate esterase family 4 (ce4) and have been described as required for bacterial evasion to lysozyme and innate immune responses. interestingly, there is an unusual occurrence of 10 putative polysaccharide deacetylases, including five pgng-dacs, in the bacillus sp. genomes, especially b. cereus and b. anthracis. to elucidate the physiological role of these multiple deacetylases, we employed genetic analysis and protein localization studi ...201323336745
[response and evaluation of the disinfection effects on an anthrax outbreak in human being and cattle in guizhou]. 201323678679
proteomic analysis of the oxidative stress response induced by low-dose hydrogen peroxide in bacillus anthracis.anthrax is a bacterial disease caused by the aerobic sporeforming bacterium bacillus anthracis, which is an important pathogen owing to its ability to be used as a terror agent. b. anthracis spores can escape phagocytosis and initiate the germination process even in antimicrobial conditions, such as oxidative stress. to analyze the oxidative stress response in b. anthracis and thereby learn how to prevent antimicrobial resistance, we performed protein expression profiling of b. anthracis strain ...201323676920
the use of colorimetric sensor arrays to discriminate between pathogenic bacteria.a colorimetric sensor array is a high-dimensional chemical sensor that is cheap, compact, disposable, robust, and easy to operate, making it a good candidate technology to detect pathogenic bacteria, especially potential bioterrorism agents like yersinia pestis and bacillus anthracis which feature on the center for disease control and prevention's list of potential biothreats. here, a colorimetric sensor array was used to continuously monitor the volatile metabolites released by bacteria in soli ...201323671629
studying the fate of non-volatile organic compounds in a commercial plasma air purifier.degradation of non-volatile organic compounds-environmental toxins (methyltriclosane and phenanthrene), bovine serum albumin, as well as bioparticles (legionella pneumophila, bacillus subtilis, and bacillus anthracis)-in a commercially available plasma air purifier based on a cold plasma was studied in detail, focusing on its efficiency and on the resulting degradation products. this system is capable of handling air flow velocities of up to 3.0m s(-1) (3200lmin(-1)), much higher than other plas ...201323669793
optimization of a novel potent and selective bacterial dna helicase inhibitor scaffold from a high throughput screening hit.benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified staphylococcus aureus (sa) and bacillus anthracis (ba) replicative helicases. chemical optimization has produced compound 59 with nanomolar potency against the dna duplex strand unwinding activities of both b. anthracis and s. aureus helicases. selectivity index (si=cc50/ic50) values for 59 were greater than 500. kinetic studies demonstrated that the benzobisthiazole-based ...201323664213
assay for peptidoglycan o-acetyltransferase: a potential new antibacterial target.the o-acetylation of peptidoglycan occurs at the c-6 hydroxyl group of muramoyl residues in many human pathogens, both gram positive and gram negative, such as staphylococcus aureus and species of campylobacter, helicobacter, neisseria, and bacillus, including bacillus anthracis. the process is a maturation event being catalyzed either by integral membrane o-acetylpeptidoglycan transferase (oat) of gram-positive bacteria or by a two-component peptidoglycan o-acetyltransferase system (pata/patb) ...201323660013
evaluation of immunogenicity and efficacy of anthrax vaccine adsorbed for postexposure prophylaxis.antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (pep). in a rabbit pep study, animals were subjected to lethal challenge with aerosolized bacillus ...201323658392
human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed.interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (hla) and other gene families. this study examined associations between hla genotypes, haplotypes, and homozygosity and protective antigen (pa)-specific cellular immune responses in healthy subjects following immunization with anthrax vaccine adsorbed (ava). while limited associations were observed between individual hla alleles or haplotypes and variable ly ...201323649091
prothera biologics, inc.: a novel immunomodulator and biomarker for life-threatening diseases.prothera biologics is a development stage bio-therapeutics company in east providence, rhode island. the company was founded in 2002 to focus on the critical role and commercial potential of inter-alpha inhibitor proteins (iaip) for treating acute life-threatening inflammatory diseases. the discovery research originated in the basic research laboratories of the co-founders, yow-pin lim, md, phd, and douglas c. hixson, phd, at rhode island hospital, a lifespan partner. the company is backed by th ...201323641420
constructing droplet interface bilayers from the contact of aqueous droplets in oil.we describe a protocol for forming an artificial lipid bilayer by contacting nanoliter aqueous droplets in an oil solution in the presence of phospholipids. a lipid monolayer forms at each oil-water interface, and when two such monolayers touch, a bilayer is created. droplet interface bilayers (dibs) are a simple way to generate stable bilayers suitable for single-channel electrophysiology and optical imaging from a wide variety of preparations, ranging from purified proteins to reconstituted eu ...201323640169
a single-dose plga encapsulated protective antigen domain 4 nanoformulation protects mice against bacillus anthracis spore challenge.bacillus anthracis, the etiological agent of anthrax, is a major bioterror agent. vaccination is the most effective prophylactic measure available against anthrax. currently available anthrax vaccines have issues of the multiple booster dose requirement, adjuvant-associated side effects and stability. use of biocompatible and biodegradable nanoparticles to deliver the antigens to immune cells could solve the issues associated with anthrax vaccines. we hypothesized that the delivery of a stable i ...201323637922
igg subclass and heavy chain domains contribute to binding and protection by mabs to the poly γ-d-glutamic acid capsular antigen of bacillus anthracis.bacterial capsules are common targets for antibody-mediated immunity. the capsule of bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-γ-d-glutamic acid (γdpga). we previously generated murine igg3 monoclonal antibodies (mabs) to γdpga that were protective in a murine model of pulmonary anthrax. igg3 antibodies are characteristic of the murine response to polysaccharide antigens. the goal of the present study was to produce subclass switch variants of the γ ...201323637599
characterization of the native form of anthrax lethal factor for use in the toxin neutralization assay.the cell-based anthrax toxin neutralization assay (tna) is used to determine functional antibody titers of sera from animals and humans immunized with anthrax vaccines. the anthrax lethal toxin is a critical reagent of the tna composed of protective antigen (pa) and lethal factor (lf), which are neutralization targets of serum antibodies. cytotoxic potency of recombinant lf (rlf) lots can vary substantially, causing a challenge in producing a renewable supply of this reagent for validated tnas. ...201323637044
anthrax toxin-mediated delivery of the pseudomonas exotoxin a enzymatic domain to the cytosol of tumor cells via cleavable ubiquitin fusions.anthrax toxin proteins from bacillus anthracis constitute a highly efficient system for delivering cytotoxic enzymes to the cytosol of tumor cells. however, exogenous proteins delivered to the cytosol of cells are subject to ubiquitination on lysines and proteasomal degradation, which limit their potency. we created fusion proteins containing modified ubiquitins with their c-terminal regions fused to the pseudomonas exotoxin a catalytic domain (peiii) in order to achieve delivery and release of ...201323631917
interactions of antimicrobial peptide chrysophsin-3 with bacillus anthracis in sporulated, germinated, and vegetative states.bacillus anthracis spores contain on their surface multilayered protein coats that provide barrier properties, mechanical strength, and elasticity that aid in protecting the sporulated state and preventing germination, outgrowth, and transition into the virulent vegetative bacterial state. in this work, the antimicrobial peptide (amp) chrysophsin-3 was tested against b. anthracis in each of the three distinct metabolic states (sporulated, germinated, and vegetative) for its bacteria-killing acti ...201323631815
anthrax lethal toxin downregulates claudin-5 expression in human endothelial tight junctions.vascular leakage pathologies such as pleural effusion and hemorrhage are hallmarks of anthrax pathogenesis. we previously reported that anthrax lethal toxin (lt), the major virulence factor of anthrax, reduces barrier function in cultured primary human microvascular endothelial cells. here, we show that lt-induced barrier dysfunction is accompanied by the reduced expression of the endothelial tight junction (tj) protein claudin-5 but no change in the expression of other tj components occludin, z ...201323626836
exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1.anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (pa) with one of three reported cell surface toxin receptors (antxr). receptor binding has been shown to influence host susceptibility to the toxins. despite this crucial role for antxr in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about antxr expression on human leucocytes. we characterized the expr ...201323607659
chemical genetics reveals a kinase-independent role for protein kinase r in pyroptosis.formation of the inflammasome, a scaffolding complex that activates caspase-1, is important in numerous diseases. pyroptotic cell death induced by anthrax lethal toxin (lt) is a model for inflammasome-mediated caspase-1 activation. we discovered 7-desacetoxy-6,7-dehydrogedunin (7dg) in a phenotypic screen as a small molecule that protects macrophages from lt-induced death. using chemical proteomics, we identified protein kinase r (pkr) as the target of 7dg and show that rnai knockdown of pkr phe ...201323603659
rapid and reliable detection of bacterial endospores in environmental samples by diagnostic electron microscopy combined with x-ray microanalysis.diagnostic negative staining electron microscopy is a front-line method for the rapid investigation of environmental and clinical samples in emergency situations caused by bioterrorism or outbreaks of an infectious disease. spores of anthrax are one of the diagnostic targets in case of bioterrorism, because they have been used as a bio-weapon in the past and their production and transmission are rather simple. with negative staining electron microscopy bacterial spores can be identified based on ...201323603002
mutations in antxr1 cause gapo syndrome.the genetic cause of gapo syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. we studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262c>t [p.arg88*] and c.505c>t [p.arg169*]) or splicing mutations (c.1435-12a>g [p.gly479phefs*119]) in antxr1, which encodes anthrax toxin receptor 1. the nonsense mutations predictably trigger nonsense-mediate ...201323602711
stereo-selective binding of monoclonal antibodies to the poly-γ-d-glutamic acid capsular antigen of bacillus anthracis.bacillus anthracis is surrounded by an anti-phagocytic capsule that is entirely composed of γ-linked d-glutamic acid (γdpga). γdpga is required for virulence and is produced in large quantities following spore germination. we have previously described the isolation of several γdpga-reactive mabs. the reagents are effective in both immunoprotection and diagnostic applications. the current work was done to further investigate the specificity of γdpga-reactive mabs. the specificity of each mab was ...201323602451
automated thermochemolysis reactor for detection of bacillus anthracis endospores by gas chromatography-mass spectrometry.an automated sample preparation system was developed and tested for the rapid detection of bacillus anthracis endospores by gas chromatography-mass spectrometry (gc-ms) for eventual use in the field. this reactor is capable of automatically processing suspected bio-threat agents to release and derivatize unique chemical biomarkers by thermochemolysis (tcm). the system automatically controls the movement of sample vials from one position to another, crimping of septum caps onto the vials, precise ...201323601976
disease-enhancing antibodies improve the efficacy of bacterial toxin-neutralizing antibodies.during infection, humoral immunity produces a polyclonal response with various immunoglobulins recognizing different epitopes within the microbe or toxin. despite this diverse response, the biological activity of an antibody (ab) is usually assessed by the action of a monoclonal population. we demonstrate that a combination of monoclonal antibodies (mabs) that are individually disease enhancing or neutralizing to bacillus anthracis protective antigen (pa), a component of anthrax toxin, results i ...201323601104
architecture and assembly of the gram-positive cell wall.the bacterial cell wall is a mesh polymer of peptidoglycan--linear glycan strands cross-linked by flexible peptides--that determines cell shape and provides physical protection. while the glycan strands in thin 'gram-negative' peptidoglycan are known to run circumferentially around the cell, the architecture of the thicker 'gram-positive' form remains unclear. using electron cryotomography, here we show that bacillus subtilis peptidoglycan is a uniformly dense layer with a textured surface. we f ...201323600697
federal legal preparedness tools for facilitating medical countermeasure use during public health emergencies.preparing for and responding to public health emergencies involving medical countermeasures (mcms) raise often complex legal challenges and questions among response stakeholders at the local, state, and federal levels. this includes concerns about emergency legal authorities, liability, emergency use of regulated medical products, and regulations that might enhance or hinder public health response goals. in this article, lawyers from the u.s. department of health and human services' (hhs) office ...201323590735
pharmaceutical approval update.cabozantinib (cometriq) for metastatic medullary thyroid cancer; ponatinib (iclusig) for two forms of leukemia; and raxibacumab for inhalational anthrax.201323599674
draft genome sequences of two bulgarian bacillus anthracis strains.bacillus anthracis strains previously isolated from bulgaria form a unique subcluster within the a1.a cluster that is typical for isolates from southeastern europe. here, we report the draft genome sequences of two bulgarian b. anthracis strains belonging to the a branch (a.br.)008/009 canonical single nucleotide polymorphism (snp) group of the major a branch.201323599294
use of a bacteriophage lysin to identify a novel target for antimicrobial development.we identified an essential cell wall biosynthetic enzyme in bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. this work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. focusing on the b. anthracis-specific plyg lysin, we first identified its unique cell wall receptor and cognate biosynthetic path ...201323593301
us delays testing anthrax vaccine for children. 201323589431
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