Publications

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public response to an anthrax attack: a multiethnic perspective.the 2001 anthrax attacks emphasized the need to develop outreach that would more effectively support racial/ethnic minority populations during a bioterrorism incident. given the importance of antibiotic prophylaxis in a future anthrax attack, it should be a priority to better support racial/ethnic minorities in mass dispensing programs. to examine the needs and perspectives of racial/ethnic minorities, this study used a nationally representative poll of 1,852 adults, including 1,240 whites, 261 ...201223244501
anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages.anthrax lethal factor (lf) is the protease component of anthrax lethal toxin (lt). lt induces pyroptosis in macrophages of certain inbred mouse and rat strains, while macrophages from other inbred strains are resistant to the toxin. in rats, the sensitivity of macrophages to toxin-induced cell death is determined by the presence of an lf cleavage sequence in the inflammasome sensor nlrp1. lf cleaves rat nlrp1 of toxin-sensitive macrophages, activating caspase-1 and inducing cell death. toxin-res ...201223152930
analysing the spatial patterns of livestock anthrax in kazakhstan in relation to environmental factors: a comparison of local (gi*) and morphology cluster statistics.we compared a local clustering and a cluster morphology statistic using anthrax outbreaks in large (cattle) and small (sheep and goats) domestic ruminants across kazakhstan. the getis-ord (gi*) statistic and a multidirectional optimal ecotope algorithm (amoeba) were compared using 1st, 2nd and 3rd order rook contiguity matrices. multivariate statistical tests were used to evaluate the environmental signatures between clusters and non-clusters from the amoeba and gi* tests. a logistic regression ...201223242686
critical challenges and impediments affecting rural physicians during a public health emergency.disaster preparedness has become a health policy priority for the united states in the aftermath of the anthrax attacks, 9/11, and other calamities. it is important for rural health care professionals to be prepared for a bioterrorist attack or other public health emergency. we sought to determine the barriers impeding rural physicians from being prepared for a human-induced disaster such as a bioterrorist attack.201223241464
the differential susceptibility of spores from virulent and attenuated bacillus anthracis strains to aldehyde- and hypochlorite-based disinfectants.this study compared the sensitivity of spores from virulent and attenuated bacillus anthracis strains in suspension to inactivation by various chemical disinfectants. spore suspensions from two virulent strains (a0256 and a0372) and two attenuated strains (sterne and a0141) of b. anthracis were tested against two aldehyde-based disinfectants and one hypochlorite-based disinfectant. a novel statistical model was used to estimate 4-log(10) reduction times for each disinfectant/strain combination. ...201223233190
coumarin-based inhibitors of bacillus anthracis and staphylococcus aureus replicative dna helicase: chemical optimization, biological evaluation, and antibacterial activities.the increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely the replicative helicase. here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9-18-fold increased potency against staphylococcus aureus (sa) and bacillus anthracis (ba) helicases. compounds 20 and ...201223231076
[detection and identification of highly pathogenic bacteria within the framework of the eqadeba project--part ii: samples containing inactivated pathogens].the aim of the studies was analysis of methods applied and results of detection and identification of bacillus anthracis, yersinia pestis, francisella tularensis, brucella sp., bulkholderia mallei and b. pseudomallei in inactivated samples obtained within the framework of the third external quality assessment exercise (eqae) in the project ,,establishment of quality assurances for detection of highly pathogenic bacteria of potential bioterrorism risk (eqadeba)".201223230707
relacin, a novel antibacterial agent targeting the stringent response.finding bacterial cellular targets for developing novel antibiotics has become a major challenge in fighting resistant pathogenic bacteria. we present a novel compound, relacin, designed to inhibit (p)ppgpp production by the ubiquitous bacterial enzyme rela that triggers the stringent response. relacin inhibits rela in vitro and reduces (p)ppgpp production in vivo. moreover, relacin affects entry into stationary phase in gram positive bacteria, leading to a dramatic reduction in cell viability. ...201223028324
cellular adaptation to anthrax lethal toxin-induced mitochondrial cholesterol enrichment, hyperpolarization, and reactive oxygen species generation through downregulating mln64 in macrophages.cellular adaptation to different stresses related to survival and function has been demonstrated in several cell types. anthrax lethal toxin (letx) induces rapid cell death, termed "pyroptosis," by activating nlrp1b/caspase-1 in murine macrophages. we and others (s. d. ha et al., j. biol. chem. 282:26275-26283, 2007; i. i. salles et al., proc. natl. acad. sci. u. s. a. 100:12426 -12431, 2003) have shown that raw264.7 cells preexposed to sublethal doses of letx become resistant to subsequent high ...201223028046
bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.the lung is the site of entry for bacillus anthracis in inhalation anthrax, the deadliest form of the disease. bacillus anthracis produces virulence toxins required for disease. alveolar macrophages were considered the primary target of the bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of mek signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. our current results s ...201223027535
bacillus anthracis thioredoxin systems, characterization and role as electron donors for ribonucleotide reductase.bacillus anthracis is the causative agent of anthrax, which is associated with a high mortality rate. like several medically important bacteria, b. anthracis lacks glutathione but encodes many genes annotated as thioredoxins, thioredoxin reductases, and glutaredoxin-like proteins. we have cloned, expressed, and characterized three potential thioredoxins, two potential thioredoxin reductases, and three glutaredoxin-like proteins. of these, thioredoxin 1 (trx1) and nrdh reduced insulin, 5,5'-dithi ...201223012357
bioterrorism: pathogens as weapons.biowarfare has been used for centuries. the use of biological weapons in terrorism remains a threat. biological weapons include infectious agents (pathogens) and toxins. the most devastating bioterrorism scenario would be the airborne dispersal of pathogens over a concentrated population area. characteristics that make a specific pathogen a high-risk for bioterrorism include a low infective dose, ability to be aerosolized, high contagiousness, and survival in a variety of environmental condition ...201223011963
genetic barcodes for improved environmental tracking of an anthrax simulant.the development of realistic risk models that predict the dissemination, dispersion and persistence of potential biothreat agents have utilized nonpathogenic surrogate organisms such as bacillus atrophaeus subsp. globigii or commercial products such as bacillus thuringiensis subsp. kurstaki. comparison of results from outdoor tests under different conditions requires the use of genetically identical strains; however, the requirement for isogenic strains limits the ability to compare other desira ...201223001658
the effect of seasonal variation on anthrax epidemiology in the upper zambezi floodplain of western zambia.anthrax has become endemic throughout the upper zambezi floodplain located in the western province of zambia over the recent years. to date, no comprehensive study has been carried out to determine whether recurrence of anthrax outbreaks may be linked to differences in precipitation and human activities. retrospective data for the period 1999 to 2007 showed that a total of 1,216 bovine cases of anthrax were reported. during the same period, 1,790 human anthrax cases and a corresponding case fata ...201223000586
role of n-terminal his6-tags in binding and efficient translocation of polypeptides into cells using anthrax protective antigen (pa).it is of interest to define bacterial toxin biochemical properties to use them as molecular-syringe devices in order to deliver enzymatic activities into host cells. binary toxins of the ab(7/8)-type are among the most potent and specialized bacterial protein toxins. the b subunits oligomerize to form a pore that binds with high affinity host cell receptors and the enzymatic a subunit. this allows the endocytosis of the complex and subsequent injection of the a subunit into the cytosol of the ho ...201223056543
draft genome sequence of bacillus anthracis ur-1, isolated from a german heroin user.we report the draft genome sequence of bacillus anthracis ur-1, isolated from a fatal case of injectional anthrax in a german heroin user. analysis of the genome sequence of strain ur-1 may aid in describing phylogenetic relationships between virulent heroin-associated isolates of b. anthracis isolated in the united kingdom, germany, and other european countries.201223045504
recent outbreak of cutaneous anthrax in bangladesh: clinico-demographic profile and treatment outcome of cases attended at rajshahi medical college hospital.human cutaneous anthrax results from skin exposure to b. anthracis, primarily due to occupational exposure. bangladesh has experienced a number of outbreaks of cutaneous anthrax in recent years. the last episode occurred from april to august, 2011 and created mass havoc due to its dreadful clinical outcome and socio-cultural consequences. we report here the clinico-demographic profile and treatment outcome of 15 cutaneous anthrax cases attended at the dermatology outpatient department of rajshah ...201222929128
[type i interferon and bacterial infection].interferons (ifns) are cytokines playing an important role in immune responses. interferons are classified into two distinct types according to specific interferon receptors(ifnr). type i ifns include ifn-α and ifn-β, whereas ifn-γ is type ii ifn. it is well known that type i ifns have important roles in the host defense against viruses through activation of interferon receptor a (ifnar). however, many recent studies have also demonstrated that type i ifns have effects on immune responses to bac ...201222927085
light-activated porphyrin-based formulations to inactivate bacterial spores.the objective of this study was to develop porphyrin-based formulations to inactivate bacillus spores. we probed the effect of porphyrins alone and in combination with germinants against both bacillus cereus and bacillus anthracis spores in the presence of light.201222925067
effect of the bacillus atrophaeus subsp. globigii spo0f h101r mutation on strain fitness.sporulation is a critical developmental process in bacillus spp. that, once initiated, removes the possibility of further growth until germination. therefore, the threshold conditions triggering sporulation are likely to be subject to evolutionary constraint. our previous studies revealed two spontaneous hypersporulating mutants of bacillus atrophaeus subsp. globigii, both containing point mutations in the spo0f gene. one of these strains (detrick-2; contains the spo0f101 allele with a c:t [his1 ...201223042165
achieving consistent multiple daily low-dose bacillus anthracis spore inhalation exposures in the rabbit model.repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. this is especially true for persistent agents such as b. anthracis spores, the causative agent of anthrax. studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 10(6) colony forming units (cfu) of b. anthracis spores) and included a pilot feasibility characterization study, acute exposure stu ...201222919662
combined bacillus licheniformis and bacillus subtilis infection in a patient with oesophageal perforation.species of the genus bacillus are a common laboratory contaminant, therefore, isolation of these organisms from blood cultures does not always indicate infection. in fact, except for bacillus anthracis and bacillus cereus, most species of the genus bacillus are not considered human pathogens, especially in immunocompetent individuals. here, we report an unusual presentation of bacteraemia and mediastinitis due to co-infection with bacillus subtilis and bacillus licheniformis, which were identifi ...201222918867
cutaneous infection caused by bacillus anthracis in larissa, thessaly, central greece, july 2012.in july 2012, a confirmed case of cutaneous anthraxinfection in a stockbreeder in the prefecture of larissa, thessaly, central greece was reported. the investigation revealed five related deaths in animals (two dogs and three sheep). control measures have been taken immediately in order to prevent further spread in humans and animals.201222913937
interactions of high-affinity cationic blockers with the translocation pores of b. anthracis, c. botulinum, and c. perfringens binary toxins.cationic β-cyclodextrin derivatives were recently introduced as highly effective, potentially universal blockers of three binary bacterial toxins: anthrax toxin of bacillus anthracis, c2 toxin of clostridium botulinum, and iota toxin of clostridium perfringens. the binary toxins are made of two separate components: the enzymatic a component, which acts on certain intracellular targets, and the binding/translocation b component, which forms oligomeric channels in the target cell membrane. here we ...201222995493
structural characterization and comparison of three acyl-carrier-protein synthases from pathogenic bacteria.some bacterial type ii fatty-acid synthesis (fas ii) enzymes have been shown to be important candidates for drug discovery. the scientific and medical quest for new fas ii protein targets continues to stimulate research in this field. one of the possible additional candidates is the acyl-carrier-protein synthase (acps) enzyme. its holo form post-translationally modifies the apo form of an acyl carrier protein (acp), which assures the constant delivery of thioester intermediates to the discrete e ...201222993090
certhrax toxin, an anthrax-related adp-ribosyltransferase from bacillus cereus.we identified certhrax, the first anthrax-like mart toxin from the pathogenic g9241 strain of bacillus cereus. certhrax shares 31% sequence identity with anthrax lethal factor from bacillus anthracis; however, we have shown that the toxicity of certhrax resides in the mart domain, whereas anthrax uses a metalloprotease mechanism. like anthrax lethal factor, certhrax was found to require protective antigen for host cell entry. this two-domain enzyme was shown to be 60-fold more toxic to mammalian ...201222992735
reversible blindness in bilateral optic neruritis associated with nasal flu vaccine.various case reports have shown possible associations between optic neuritis and different vaccines. some of the vaccines include influenza, hepatitis b and anthrax201222989339
assembly of the bclb glycoprotein into the exosporium and evidence for its role in the formation of the exosporium 'cap' structure in bacillus anthracis.the outermost layer of the bacillus anthracis spore consists of an exosporium comprised of an outer hair-like nap layer and an internal basal layer. a major component of the hair-like nap is the glycosylated collagen-like protein bcla. a second collagen-like protein, bclb, is also present in the exosporium. bclb possesses an n-terminal sequence that targets it to the exosporium and is similar in sequence to a cognate targeting region in bcla. bclb lacks, however, sequence similarity to the regio ...201222989026
isolation of bacillus anthracis from soil in selected high-risk areas of zimbabwe.to isolate bacillus anthracis from cattle carcass burial sites from high-risk districts in zimbabwe.201222984812
multi-platform comparison of ten commercial master mixes for probe-based real-time polymerase chain reaction detection of bioterrorism threat agents for surge preparedness.the centers for disease control and prevention and united states army research institute for infectious diseases have developed real-time pcr assays for the detection of bioterrorism threat agents. these assays all rely on a limited number of approved real-time pcr master mixes. because the availability of these reagents is a critical element of bioterrorism preparedness, we undertook a joint national preparedness exercise to address the potential surge needs resulting from a large-scale bio-eme ...201223107058
draft genome sequence of bacillus anthracis bf-1, isolated from bavarian cattle.bacillus anthracis bf-1 was isolated from a cow in bavaria (germany) that had succumbed to anthrax. here, we report the draft genome sequence of this strain, which belongs to the european b2 subclade of b. anthracis. the closest phylogenetic neighbor of strain bf-1 is a strain isolated from cattle in france.201223105087
solution structure of the sortase required for efficient production of infectious bacillus anthracis spores.bacillus anthracis forms metabolically dormant endospores that upon germination can cause lethal anthrax disease in humans. efficient sporulation requires the activity of the srtc sortase (basrtc), a cysteine transpeptidase that covalently attaches the bash and basi proteins to the peptidoglycan of the forespore and predivisional cell, respectively. to gain insight into the molecular basis of protein display, we used nuclear magnetic resonance to determine the structure and backbone dynamics of ...201222974341
anthrax vaccine-induced antibodies provide cross-species prediction of survival to aerosol challenge.because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the food and drug administration's "animal rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. u.s. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. we examined data from 21 of ...201222972844
d-proline-based peptidomimetic inhibitors of anthrax lethal factor.in this work we reported the generation of d-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (lf), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the zn(2+) chelating agent. the introduction of two hydrophobic groups addressing the s1' subsite and a long substrate-binding groove was conceived by overlapping the bioactive conformations of two reported lf inhibitors. micromolar affinity of compound 38 suggested cis-3-substituted-1- ...201222960696
synthesis of bacillithiol and the catalytic selectivity of fosb-type fosfomycin resistance proteins.bacillithiol (bsh) has been prepared on the gram scale from the inexpensive starting material, d-glucosamine hydrochloride, in 11 steps and 8-9% overall yield. the bsh was used to survey the substrate and metal-ion selectivity of fosb enzymes from four gram-positive microorganisms associated with the deactivation of the antibiotic fosfomycin. the in vitro results indicate that the preferred thiol substrate and metal ion for the fosb from staphylococcus aureus are bsh and ni(ii), respectively. ho ...201223030527
[analysis of outbreak of anthrax in omsk region in 2010].carrying out analysis of epizootologic-epidemiologic situation on anthrax that had emerged in omsk region in 2010 when horse meat from epizootic focus of anthrax was used in production of meat semi-finished products.201223163033
development of an inhalational bacillus anthracis exposure therapeutic model in cynomolgus macaques.appropriate animal models are required to test medical countermeasures to bioterrorist threats. to that end, we characterized a nonhuman primate (nhp) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the u.s. food and drug administration animal rule. a clinical profile was recorded for each nhp exposed to a lethal dose of bacillus anthracis ames spores. specific diagnostic parameters were detected relatively early in disease progr ...201222956657
outbreak of cutaneous anthrax in musalimadugu village, chittoor district, andhra pradesh, india, july-august 2011.in august 2011, chittoor district authorities reported a cluster of suspected human anthrax cases to the andhra pradesh state surveillance unit. we investigated this cluster to confirm its etiology, describe its magnitude, identify potential risk factors, and make recommendations for preventing similar outbreaks in the future.201223103890
kinetics and thermodynamics of binding reactions as exemplified by anthrax toxin channel blockage with a cationic cyclodextrin derivative.the thermodynamics of binding reactions is usually studied in the framework of the linear van't hoff analysis of the temperature dependence of the equilibrium constant. the logarithm of the equilibrium constant is plotted versus inverse temperature to discriminate between two terms: an enthalpic contribution that is linear in the inverse temperature, and a temperature-independent entropic contribution. when we apply this approach to a particular case-blockage of the anthrax pa(63) channel by a m ...201223100532
effects of over-expression of tlr2 in transgenic goats on pathogen clearance and role of up-regulation of lysozyme secretion and infiltration of inflammatory cells.toll-like receptor 2 (tlr2) is important to host recognition of invading gram-positive microbes. in goats, these microbes can cause serious mastitis, anthrax, tetanus, and other problems. transgenic goats constitutively over-expressing tlr2 in many tissues serve as a suitable model for the study of the role of tlr2 over-expression in bacterial clearance.201223082910
maximal adjuvant activity of nasally delivered il-1α requires adjuvant-responsive cd11c(+) cells and does not correlate with adjuvant-induced in vivo cytokine production.il-1 has been shown to have strong mucosal adjuvant activities, but little is known about its mechanism of action. we vaccinated il-1r1 bone marrow (bm) chimeric mice to determine whether il-1r1 expression on stromal cells or hematopoietic cells was sufficient for the maximal adjuvant activity of nasally delivered il-1α as determined by the acute induction of cytokine responses and induction of bacillus anthracis lethal factor (lf)-specific adaptive immunity. cytokine and chemokine responses ind ...201222345651
mechanisms of nk cell-macrophage bacillus anthracis crosstalk: a balance between stimulation by spores and differential disruption by toxins.nk cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. bacillus anthracis spores can efficiently drive ifn-γ production by nk cells. the present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of nk-cell activation by b. anthracis and the bacterial strategies to subvert and evade this response. infection with non-toxigenic encapsulated b. anthracis i ...201222253596
anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria.a variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (mapk) signaling pathways, including bacillus anthracis. anthrax lethal toxin (lt) has specific proteolytic activity against the upstream regulators of mapks, the mapk kinases (mkks). using a murine model of intoxication, we show that lt causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. this pathology correlates w ...201222438953
standoff detection of biological agents using laser induced fluorescence-a comparison of 294 nm and 355 nm excitation wavelengths.standoff detection measuring the fluorescence spectra of seven different biological agents excited by 294 nm as well as 355 nm wavelength laser pulses has been undertaken. the biological warfare agent simulants were released in a semi-closed aerosol chamber at 210 m standoff distance and excited by light at either of the two wavelengths using the same instrument. significant differences in several of the agents' fluorescence response were seen at the two wavelengths. the anthrax simulants' fluor ...201223162732
identification of novel and cross-species seroreactive proteins from bacillus anthracis using a ligation-independent cloning-based, sos-inducible expression system.the current standard for bacillus anthracis vaccination is the anthrax vaccine adsorbed (ava, biothrax). while effective, the licensed vaccine schedule requires five intramuscular injections in the priming series and yearly boosters to sustain protection. one potential approach to maintain or improve the protection afforded by an anthrax vaccine, but requiring fewer doses, is through the use of purified proteins to enhance an antibody response, which could be used on their own or in combination ...201222975444
molecular motions as a drug target: mechanistic simulations of anthrax toxin edema factor function led to the discovery of novel allosteric inhibitors.edema factor (ef) is a component of bacillus anthracis toxin essential for virulence. its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (cam). ef and its complexes with cam, nucleotides and/or ions, have been extensively characterized by x-ray crystallography. those structural data allowed molecular simulations analysis of various aspects of ef action mechanism, including the delineation of ef and cam domains through their associ ...201223012649
binding of regulatory subunits of cyclic amp-dependent protein kinase to cyclic cmp agarose.the bacterial adenylyl cyclase toxins cyaa from bordetella pertussis and edema factor from bacillus anthracis as well as soluble guanylyl cyclase α(1)β(1) synthesize the cyclic pyrimidine nucleotide ccmp. these data raise the question to which effector proteins ccmp binds. recently, we reported that ccmp activates the regulatory subunits riα and riiα of camp-dependent protein kinase. in this study, we used two ccmp agarose matrices as novel tools in combination with immunoblotting and mass spect ...201222808067
functional and structural analysis of the siderophore synthetase asbb through reconstitution of the petrobactin biosynthetic pathway from bacillus anthracis.petrobactin, a mixed catechol-carboxylate siderophore, is required for full virulence of bacillus anthracis, the causative agent of anthrax. the asbabcdef operon encodes the biosynthetic machinery for this secondary metabolite. here, we show that the function of five gene products encoded by the asb operon is necessary and sufficient for conversion of endogenous precursors to petrobactin using an in vitro system. in this pathway, the siderophore synthetase asbb catalyzes formation of amide bonds ...201222408253
bacillus anthracis edema factor substrate specificity: evidence for new modes of action.since the isolation of bacillus anthracis exotoxins in the 1960s, the detrimental activity of edema factor (ef) was considered as adenylyl cyclase activity only. yet the catalytic site of ef was recently shown to accomplish cyclization of cytidine 5'-triphosphate, uridine 5'-triphosphate and inosine 5'-triphosphate, in addition to adenosine 5'-triphosphate. this review discusses the broad ef substrate specificity and possible implications of intracellular accumulation of cyclic cytidine 3':5'-mo ...201222852066
cellular and physiological effects of anthrax exotoxin and its relevance to disease.bacillus anthracis, the causative agent of anthrax, secretes a tri-partite exotoxin that exerts pleiotropic effects on the host. the purification of the exotoxin components, protective antigen, lethal factor, and edema factor allowed the rapid characterization of their physiologic effects on the host. as molecular biology matured, interest focused on the molecular mechanisms and cellular alterations induced by intoxication. only recently have researchers begun to connect molecular and cellular k ...201222919667
pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor.antibiotic treatment may fail to protect individuals, if not started early enough, after infection with bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. stable and easily stored inhibitors of the edema factor toxin (ef), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. the toxin's basic activity is to convert atp to camp, and it is thus in principle a simple phosphatase, which means that many ...201223202316
unusual bacterial infections and the pleura.rickettsiosis, q fever, tularemia, and anthrax are all bacterial diseases that can affect the pleura. rocky mountain spotted fever (rmsf) and mediterranean spotted fever (msf) are caused by rickettsia rickettsii and rickettsia conorii, respectively. pleural fluid from a patient with msf had a neutrophil-predominant exudate. coxiellaburnetii is the causative agent of q fever. of the two cases described in the literature, one was an exudate with a marked eosinophilia while the other case was a tra ...201222977649
rapid vascular responses to anthrax lethal toxin in mice containing a segment of chromosome 11 from the cast/ei strain on a c57bl/6 genetic background.host allelic variation controls the response to b. anthracis and the disease course of anthrax. mouse strains with macrophages that are responsive to anthrax lethal toxin (lt) show resistance to infection while mouse strains with lt non-responsive macrophages succumb more readily. b6.cast.11m mice have a region of chromosome 11 from the cast/ei strain (a lt responsive strain) introgressed onto a lt non-responsive c57bl/6j genetic background. previously, b6.cast.11m mice were found to exhibit a r ...201222792226
the potential of taqman array cards for detection of multiple biological agents by real-time pcr.the taqman array card architecture, normally used for gene expression studies, was evaluated for its potential to detect multiple bacterial agents by real-time pcr. ten pcr assays targeting five biological agents (bacillus anthracis, burkholderia mallei, burkholderia pseudomallei, francisella tularensis, and yersinia pestis) were incorporated onto array cards. a comparison of pcr performance of each pcr in array card and singleplex format was conducted using dna extracted from pure bacterial cul ...201222540014
germination and amplification of anthrax spores by soil-dwelling amoebas.while anthrax is typically associated with bioterrorism, in many parts of the world the anthrax bacillus (bacillus anthracis) is endemic in soils, where it causes sporadic disease in livestock. these soils are typically rich in organic matter and calcium that promote survival of resilient b. anthracis spores. outbreaks of anthrax tend to occur in warm weather following rains that are believed to concentrate spores in low-lying areas where runoff collects. it has been concluded that elevated spor ...201222983962
cytoskeleton as an emerging target of anthrax toxins.bacillus anthracis, the agent of anthrax, has gained virulence through its exotoxins produced by vegetative bacilli and is composed of three components forming lethal toxin (lt) and edema toxin (et). so far, little is known about the effects of these toxins on the eukaryotic cytoskeleton. here, we provide an overview on the general effects of toxin upon the cytoskeleton architecture. thus, we shall discuss how anthrax toxins interact with their receptors and may disrupt the interface between ext ...201222474568
θ-defensins: cyclic peptides with endless potential.θ-defensins, the only cyclic peptides of animal origin, have been isolated from the leukocytes of rhesus macaques and baboons. their biogenesis is unusual because each peptide is an 18-residue chimera formed by the head-to-tail splicing of nonapeptides derived from two separate precursors. θ-defensins have multiple arginines and a ladder-like tridisulfide array spanning their two antiparallel β-strands. human θ-defensin genes contain a premature stop codon that prevents effective translation of ...201222700960
activation of the classical complement pathway by bacillus anthracis is the primary mechanism for spore phagocytosis and involves the spore surface protein bcla.interactions between spores of bacillus anthracis and macrophages are critical for the development of anthrax infections, as spores are thought to use macrophages as vehicles to disseminate in the host. in this study, we report a novel mechanism for phagocytosis of b. anthracis spores. murine macrophage-like cell line raw264.7, bone marrow-derived macrophages, and primary peritoneal macrophages from mice were used. the results indicated that activation of the classical complement pathway (ccp) w ...201222442442
coatings capable of germinating and neutralizing bacillus anthracis endospores.endospores are formed by various bacterial families, including bacillus and clostridium, in response to environmental stresses as a means to survive conditions inhospitable to vegetative growth. although metabolically inert, the endospore must interact with its environment to determine an optimal time to return to a vegetative state, a process known as germination. germination has been shown to occur in response to a variety of chemical stimuli from specific nutrient germinants including amino a ...201222211260
detecting anthrax in the mail by coherent raman microspectroscopy.in this report, we show the collection of spatial information through a turbid medium by coherent raman microspectroscopic imaging. in particular, the technique is capable of identifying anthrax endospores inside a sealed paper envelope.201222215594
protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines.background. anthrax-associated shock is closely linked to lethal toxin (lt) release and is highly lethal despite conventional hemodynamic support. we investigated whether protective antigen-directed monoclonal antibody (pa-mab) treatment further augments titrated hemodynamic support.methods and results. forty sedated, mechanically ventilated, instrumented canines challenged with anthrax lt were assigned to no treatment (controls), hemodynamic support alone (protocol-titrated fluids and norepinep ...201222223857
bacillus anthracis-derived edema toxin (et) counter-regulates movement of neutrophils and macromolecules through the endothelial paracellular pathway.abstract: background: a common finding amongst patients with inhalational anthrax is a paucity of polymorphonuclear leukocytes (pmns) in infected tissues in the face of abundant circulating pmns. a major virulence determinant of anthrax is edema toxin (et), which is formed by the combination of two proteins produced by the organism, edema factor (ef), which is an adenyl cyclase, and protective antigen (pa). since camp, a product of adenyl cyclase, is known to enhance endothelial barrier integri ...201222230035
curing of plasmid pxo1 from bacillus anthracis using plasmid incompatibility.the large plasmid pxo1 encoding the anthrax toxin is important for the virulence of bacillus anthracis. it is essential to cure pxo1 from b. anthracis to evaluate its role in the pathogenesis of anthrax infection. because conventional methods for curing plasmids (e.g., curing agents or growth at elevated temperatures) can induce mutations in the host chromosomal dna, we developed a specific and reliable method to eliminate pxo1 from b. anthracis using plasmid incompatibility. three putative repl ...201222253811
comparison of two suspension arrays for simultaneous detection of five biothreat bacterial in powder samples.we have developed novel bio-plex assays for simultaneous detection of bacillus anthracis, yersinia pestis, brucella spp., francisella tularensis, and burkholderia pseudomallei. universal primers were used to amplify highly conserved region located within the 16s rrna amplicon, followed by hybridized to pathogen-specific probes for identification of these five organisms. the other assay is based on multiplex pcr to simultaneously amplify five species-specific pathogen identification-targeted regi ...201222690123
anthrax and the taiga. 201223543935
the receptors that mediate the direct lethality of anthrax toxin.tumor endothelium marker-8 (tem8) and capillary morphogenesis protein-2 (cmg2) are the two well-characterized anthrax toxin receptors, each containing a von willebrand factor a (vwa) domain responsible for anthrax protective antigen (pa) binding. recently, a cell-based analysis was used to implicate another vwa domain-containing protein, integrin β1 as a third anthrax toxin receptor. to explore whether proteins other than tem8 and cmg2 function as anthrax toxin receptors in vivo, we challenged m ...201223271637
recombinant groel enhances protective antigen-mediated protection against bacillus anthracis spore challenge.the fatal inhalation infection caused by bacillus anthracis results from a complex pathogenic cycle involving release of toxins by bacteria that germinate from spores. currently available vaccines against anthrax consist of protective antigen (pa), one of the anthrax toxin components. however, these pa-based vaccines are only partially protective against spore challenge in mice. this shows that exclusive elicitation of high anti-pa titer does not directly correlate with protection. here, we demo ...201223263010
zoonotic infections among employees from great smoky mountains and rocky mountain national parks, 2008-2009.u.s. national park service employees may have prolonged exposure to wildlife and arthropods, placing them at increased risk of infection with endemic zoonoses. to evaluate possible zoonotic risks present at both great smoky mountains (grsm) and rocky mountain (romo) national parks, we assessed park employees for baseline seroprevalence to specific zoonotic pathogens, followed by evaluation of incident infections over a 1-year study period. park personnel showed evidence of prior infection with a ...201222835153
mhc class ii and non-mhc class ii genes differentially influence humoral immunity to bacillus anthracis lethal factor and protective antigen.anthrax lethal toxin consists of protective antigen (pa) and lethal factor (lf), and current vaccination strategies focus on eliciting antibodies to pa. in human vaccination, the response to pa can vary greatly, and the response is often directed toward non-neutralizing epitopes. variable vaccine responses have been shown to be due in part to genetic differences in individuals, with both mhc class ii and other genes playing roles. here, we investigated the relative contribution of mhc class ii v ...201223342680
swab protocol for rapid laboratory diagnosis of cutaneous anthrax.the clinical laboratory diagnosis of cutaneous anthrax is generally established by conventional microbiological methods, such as culture and directly straining smears of clinical specimens. however, these methods rely on recovery of viable bacillus anthracis cells from swabs of cutaneous lesions and often yield negative results. this study developed a rapid protocol for detection of b. anthracis on clinical swabs. three types of swabs, flocked-nylon, rayon, and polyester, were evaluated by 3 ext ...201223035192
panning of a phage display library against a synthetic capsule for peptide ligands that bind to the native capsule of bacillus anthracis.bacillus anthracis is the causative agent of anthrax with the ability to not only produce a tripartite toxin, but also an enveloping capsule comprised primarily of γ-d-glutamic acid residues. the purpose of this study was to isolate peptide ligands capable of binding to the native capsule of b. anthracis from a commercial phage display peptide library using a synthetic form of the capsule consisting of 12 γ-d-glutamic acid residues. following four rounds of selection, 80 clones were selected ran ...201223029033
anthrax toxin protective antigen integrates poly-γ-d-glutamate and ph signals to sense the optimal environment for channel formation.many toxins assemble into oligomers on the surface of cells. local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state. bacillus anthracis secretes two virulence factors: a tripartite toxin and a poly-γ-d-glutamic acid capsule (γ-dpga). the toxin's channel-forming component, protective antigen (pa), oligomerizes to create a prechannel that forms toxic complexes upon binding the two other enzyme components, lethal f ...201223100533
rapid induction of inflammatory lipid mediators by the inflammasome in vivo.detection of microbial products by host inflammasomes is an important mechanism of innate immune surveillance. inflammasomes activate the caspase-1 (casp1) protease, which processes the cytokines interleukin (il)-1β and il-18, and initiates a lytic host cell death called pyroptosis. to identify novel casp1 functions in vivo, we devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the naip5 (nlr family, apoptosis inhibitory protein 5)/nlrc4 (nlr family, card-dom ...201222902502
the structure of mlc titration factor a (mtfa/yeei) reveals a prototypical zinc metallopeptidase related to anthrax lethal factor.mtfa of escherichia coli (formerly yeei) was previously identified as a regulator of the phosphoenolpyruvate (pep)-dependent:glucose phosphotransferase system. mtfa homolog proteins are highly conserved, especially among beta- and gammaproteobacteria. we determined the crystal structures of the full-length mtfa apoenzyme from klebsiella pneumoniae and its complex with zinc (holoenzyme) at 2.2 and 1.95 å, respectively. mtfa contains a conserved h(149)e(150)xxh(153)+e(212)+y(205) metallopeptidase ...201222467785
peptide conjugated phosphorodiamidate morpholino oligomers increase survival of mice challenged with ames bacillus anthracis.targeting bacterial essential genes using antisense phosphorodiamidate morpholino oligomers (pmos) represents an important strategy in the development of novel antibacterial therapeutics. pmos are neutral dna analogues that inhibit gene expression in a sequence-specific manner. in this study, several cationic, membrane-penetrating peptides were conjugated to pmos (ppmos) that target 2 bacterial essential genes: acyl carrier protein (acpp) and gyrase a (gyra). these were tested for their ability ...201222978365
genomic characterization of the bacillus cereus sensu lato species: backdrop to the evolution of bacillus anthracis.the key genes required for bacillus anthracis to cause anthrax have been acquired recently by horizontal gene transfer. to understand the genetic background for the evolution of b. anthracis virulence, we obtained high-redundancy genome sequences of 45 strains of the bacillus cereus sensu lato (s.l.) species that were chosen for their genetic diversity within the species based on the existing multilocus sequence typing scheme. from the resulting data, we called more than 324,000 new genes repres ...201222645259
sortase-conjugation generates a capsule vaccine that protects guinea pigs against bacillus anthracis.capsules protect bacteria against phagocytic clearance. capsular polysaccharides or polyglutamates have evolved also to resist antigen presentation by immune cells, thereby interfering with the production of opsonophagocytic antibodies. linking capsular material to a carrier protein stimulates its presentation to the immune system. for many conjugate vaccines this is achieved by a process of random chemical cross-linking. here we describe a new technology, designated sortase-conjugation, which g ...201222449424
zoonoses: a potential obstacle to the growing wildlife industry of namibia.zoonoses, which account for approximately 75% of emerging human infectious diseases worldwide, pose a re-emerging threat to public health. with an ever-increasing interrelationship between humans, livestock and wildlife species, the threat to human health will rise to unprecedented levels. wildlife species contribute to the majority of emerging diseases; therefore, there is an urgent need to define control systems of zoonoses of wildlife origin but very little information exists. in this review, ...201223077724
a new generation microarray for the simultaneous detection and identification of yersinia pestis and bacillus anthracis in food.the use of microarrays as a multiple analytic system has generated increased interest and provided a powerful analytical tool for the simultaneous detection of pathogens in a single experiment. a wide array of applications for this technology has been reported. a low density oligonucleotide microarray was generated from the genetic sequences of y. pestis and b. anthracis and used to fabricate a microarray chip. the new generation chip, consisting of 2,240 spots in 4 quadrants with the capability ...201223125935
insights from genomic comparisons of genetically monomorphic bacterial pathogens.some of the most deadly bacterial diseases, including leprosy, anthrax and plague, are caused by bacterial lineages with extremely low levels of genetic diversity, the so-called 'genetically monomorphic bacteria'. it has only become possible to analyse the population genetics of such bacteria since the recent advent of high-throughput comparative genomics. the genomes of genetically monomorphic lineages contain very few polymorphic sites, which often reflect unambiguous clonal genealogies. some ...201222312053
crystal structures of putative phosphoglycerate kinases from b. anthracis and c. jejuni.phosphoglycerate kinase (pgk) is indispensable during glycolysis for anaerobic glucose degradation and energy generation. here we present comprehensive structure analysis of two putative pgks from bacillus anthracis str. sterne and campylobacter jejuni in the context of their structural homologs. they are the first pgks from pathogenic bacteria reported in the protein data bank. the crystal structure of pgk from bacillus anthracis str. sterne (bapgk) has been determined at 1.68 å while the struc ...201222403005
bacillus anthracis inosine 5'-monophosphate dehydrogenase in action: the first bacterial series of structures of phosphate ion-, substrate-, and product-bound complexes.inosine 5'-monophosphate dehydrogenase (impdh) catalyzes the first unique step of the gmp branch of the purine nucleotide biosynthetic pathway. this enzyme is found in organisms of all three kingdoms. impdh inhibitors have broad clinical applications in cancer treatment, as antiviral drugs and as immunosuppressants, and have also displayed antibiotic activity. we have determined three crystal structures of bacillus anthracis impdh, in a phosphate ion-bound (termed "apo") form and in complex with ...201222788966
climate change and zoonotic infections in the russian arctic.climate change in the russian arctic is more pronounced than in any other part of the country. between 1955 and 2000, the annual average air temperature in the russian north increased by 1.2°c. during the same period, the mean temperature of upper layer of permafrost increased by 3°c. climate change in russian arctic increases the risks of the emergence of zoonotic infectious diseases. this review presents data on morbidity rates among people, domestic animals and wildlife in the russian arctic, ...201222868189
quantitative assessment of anthrax vaccine immunogenicity using the dried blood spot matrix.the collection, processing and transportation to a testing laboratory of large numbers of clinical samples during an emergency response situation present significant cost and logistical issues. blood and serum are common clinical samples for diagnosis of disease. serum preparation requires significant on-site equipment and facilities for immediate processing and cold storage, and significant costs for cold-chain transport to testing facilities. the dried blood spot (dbs) matrix offers an alterna ...201223266055
soft-x-ray-enhanced electrostatic precipitation for protection against inhalable allergens, ultrafine particles, and microbial infections.protection of the human lung from infectious agents, allergens, and ultrafine particles is difficult with current technologies. high-efficiency particulate air (hepa) filters remove airborne particles of >0.3 μm with 99.97% efficiency, but they are expensive to maintain. electrostatic precipitation has been used as an inexpensive approach to remove large particles from airflows, but it has a collection efficiency minimum in the submicrometer size range, allowing for a penetration window for some ...201223263945
investigation of an outbreak of cutaneous anthrax in banlu village, lianyungang, china, 2012.after notification of a suspected case of anthrax following the slaughtering of a sick cow in banlu village, an area that has not had any anthrax cases for decades, we aimed to confirm the outbreak, determine the transmission mechanism and implement control measures.201223908932
bacillus anthracis factors for phagosomal escape.the mechanism of phagosome escape by intracellular pathogens is an important step in the infectious cycle. during the establishment of anthrax, bacillus anthracis undergoes a transient intracellular phase in which spores are engulfed by local phagocytes. spores germinate inside phagosomes and grow to vegetative bacilli, which emerge from their resident intracellular compartments, replicate and eventually exit from the plasma membrane. during germination, b. anthracis secretes multiple factors th ...201222852067
rapid and high-throughput detection of highly pathogenic bacteria by ibis plex-id technology.in this manuscript, we describe the identification of highly pathogenic bacteria using an assay coupling biothreat group-specific pcr with electrospray ionization mass spectrometry (pcr/esi-ms) run on an ibis plex-id high-throughput platform. the biothreat cluster assay identifies most of the potential bioterrorism-relevant microorganisms including bacillus anthracis, francisella tularensis, yersinia pestis, burkholderia mallei and pseudomallei, brucella species, and coxiella burnetii. dna from ...201222768173
unusual epidemic events: a new method of early orientation and differentiation between natural and deliberate epidemics.to develop a model for quick and accurate evaluation of unusual epidemic events (uee), based on the original model of bioterrorism risk assessment.201222136700
three probable cases of cutaneous anthrax in autonomous province of vojvodina, serbia, june 2011. 201222264812
biosurveillance: a review and update.since the terrorist attacks and anthrax release in 2001, almost $32 billion has been allocated to biodefense and biosurveillance in the usa alone. surveillance in health care refers to the continual systematic collection, analysis, interpretation, and dissemination of data. when attempting to detect agents of bioterrorism, surveillance can occur in several ways. syndromic surveillance occurs by monitoring clinical manifestations of certain illnesses. laboratory surveillance occurs by looking for ...201222242207
kinetic characterization of a slow-binding inhibitor of bla2: thiomaltol.the increasing prevalence of drug resistant bacteria is a pandemic problem. metallo-β-lactamases (mbls) are one of the main causes of drug resistance due to hydrolysis of β-lactam antibiotics. thus, the development of effective inhibitors of mbls remains urgent. the compound thiomaltol was used as a lead compound to investigate its ability to inhibit metallo-β-lactamase from bacillus anthracis (bla2), which causes anthrax. kinetic evaluation with nitrocefin as a substrate indicates that thiomalt ...201222233540
two independent replicons can support replication of the anthrax toxin-encoding plasmid pxo1 of bacillus anthracis.the large pxo1 plasmid (181.6kb) of bacillus anthracis encodes the anthrax toxin proteins. previous studies have shown that two separate regions of pxo1 can support replication of pxo1 miniplasmids when introduced into plasmid-less strains of this organism. no information is currently available on the ability of the above two replicons, termed repx and orfs 14/16 replicons, to support replication of the full-length pxo1 plasmid. we generated mutants of the full-length pxo1 plasmid in which eithe ...201222239982
anthrax lethal toxin and the induction of cd4 t cell immunity.bacillus anthracis secretes exotoxins which act through several mechanisms including those that can subvert adaptive immunity with respect both to antigen presenting cell and t cell function. the combination of protective antigen (pa) and lethal factor (lf) forming lethal toxin (lt), acts within host cells to down-regulate the mitogen activated protein kinase (mapk) signaling cascade. until recently the mapk kinases were the only known substrate for lt; over the past few years it has become evid ...201223162703
comparative analysis of virulence factors secreted by bacillus anthracis sterne at host body temperature.aims:  for the analysis of virulence factors produced and secreted by bacillus anthracis vegetative cells during mammalian host infection, we evaluated the secretome of b. anthracis sterne exposed to host-specific factors specifically to host body temperature. methods and results:  we employed a comparative proteomics-based approach to analyze the proteins secreted by b. anthracis sterne under host-specific body temperature conditions. a total of 17 proteins encoded on a single chromosome and th ...201222268495
effect of the mammalian arginase inhibitor 2(s)-amino-6-boronohexanoic acid on bacillus anthracis arginase.macrophages, upon phagocytosing endospores of bacillus anthracis, up-regulate the expression of the immunological isoform of nitric oxide synthase, nos 2, concomitant with production of nitric oxide (no•) from metabolism of l: -arginine. we have previously demonstrated that macrophages that secrete no• kill the bacilli of b. anthracis. to circumvent this microbicidal activity of no•, b. anthracis has evolved pathways that include the enzyme arginase, which metabolizes l: -arginine to ornithine a ...201222271269
health-related quality of life in the anthrax vaccination program for workers in the laboratory response network.background: in 2002 cdc initiated the anthrax vaccination program (avp) to provide voluntary pre-exposure vaccination with anthrax vaccine adsorbed (ava) for persons at high risk of exposure to bacillus anthracis spores. there has been concern that ava could be associated with long term impairment of physical and/or mental health. objectives: to ascertain whether physical and mental functional status, as measured by the sf-36v2 health survey (medical outcomes trust, boston, ma), of ava recipient ...201222230591
phage-based platforms for the clinical detection of human bacterial pathogens.bacteriophages (phages) have been utilized for decades as a means for uniquely identifying their target bacteria. due to their inherent natural specificity, ease of use, and straightforward production, phage possess a number of desirable attributes which makes them particularly suited as bacterial detectors. as a result, extensive research has been conducted into the development of phage, or phage-derived products to expedite the detection of human pathogens. however, very few phage-based diagno ...201223050221
prioritizing risks and uncertainties from intentional release of selected category a pathogens.this paper synthesizes available information on five category a pathogens (bacillus anthracis, yersinia pestis, francisella tularensis, variola major and lassa) to develop quantitative guidelines for how environmental pathogen concentrations may be related to human health risk in an indoor environment. an integrated model of environmental transport and human health exposure to biological pathogens is constructed which 1) includes the effects of environmental attenuation, 2) considers fomite cont ...201222412915
development and comparison of two assay formats for parallel detection of four biothreat pathogens by using suspension microarrays.microarrays provide a powerful analytical tool for the simultaneous detection of multiple pathogens. we developed diagnostic suspension microarrays for sensitive and specific detection of the biothreat pathogens bacillus anthracis, yersinia pestis, francisella tularensis and coxiella burnetii. two assay chemistries for amplification and labeling were developed, one method using direct hybridization and the other using target-specific primer extension, combined with hybridization to universal arr ...201222355407
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