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amphiphilic polyanhydride nanoparticles stabilize bacillus anthracis protective antigen.advancements toward an improved vaccine against bacillus anthracis, the causative agent of anthrax, have focused on formulations composed of the protective antigen (pa) adsorbed to aluminum hydroxide. however, due to the labile nature of pa, antigen stability is a primary concern for vaccine development. thus, there is a need for a delivery system capable of preserving the immunogenicity of pa through all the steps of vaccine fabrication, storage, and administration. in this work, we demonstrate ...201222380593
ratcheting up protein translocation with anthrax toxin.energy-consuming nanomachines catalyze the directed movement of biopolymers in the cell. they are found both dissolved in the aqueous cytosol as well as embedded in lipid bilayers. inquiries into the molecular mechanism of nanomachine-catalyzed biopolymer transport have revealed that these machines are equipped with molecular parts, including adjustable clamps, levers, and adaptors, which interact favorably with substrate polypeptides. biological nanomachines that catalyze protein transport, kno ...201222374876
sverdlovsk revisited: pulmonary pathology of inhalational anthrax versus anthraxlike bacillus cereus pneumonia. 201222372894
finding the smoking gun: protein tyrosine phosphatases as tools and targets of unicellular microorganisms and viruses.protein tyrosine phosphatases (ptps) are increasingly recognized as important effectors of host-pathogen interactions. since guan and dixon reported in 1990 that phosphatase yoph serves as an essential virulence determinant of yersinia, the field shifted significantly forward, and dozens of ptps were identified in various microorganisms and even in viruses. the discovery of extensive tyrosine signaling networks in non-metazoan organisms refuted the moth-eaten paradigm claiming that these organis ...201222360485
impaired function of the tie-2 receptor contributes to vascular leakage and lethality in anthrax.the anthrax lethal toxin (lt) enters host cells and enzymatically cleaves mapkks or meks. how these molecular events lead to death from anthrax remains poorly understood, but published reports suggest a direct effect of lt on vascular permeability. we have found that lt challenge in mice disrupts signaling through tie-2, a tonically activated receptor tyrosine kinase in the endothelium. genetic manipulations favoring tie-2 activation enhanced interendothelial junctional contacts, prevented vascu ...201222665799
hiv-1 integrase inhibitor-inspired antibacterials targeting isoprenoid biosynthesis.we report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (upps) and dehydrosqualene synthase (crtm). the leads were suggested by the observation that keto- and diketo-acids bind to the active site mg(2+)/asp domain in hiv-1 integrase, and similar domains are present in prenyl transferases. we report the x-ray crystallographic structures of one diketo-acid and one keto-acid bound to crtm, which supports the mg(2+) ...201222662288
a genome-wide association study of host genetic determinants of the antibody response to anthrax vaccine adsorbed.several lines of evidence have supported a host genetic contribution to vaccine response, but genome-wide assessments for specific determinants have been sparse. here we describe a genome-wide association study (gwas) of protective antigen-specific antibody (abpa) responses among 726 european-americans who received anthrax vaccine adsorbed (ava) as part of a clinical trial. after quality control, 736,996 snps were tested for association with the abpa response to 3 or 4 ava vaccinations given ove ...201222658931
interleukin-1, inflammasomes, autoinflammation and the skin.interleukin 1, one of the first cytokines discovered in the 1980s, and a potent mediator of fever, pain and inflammation, is at present experiencing a revival in biology and medicine. whereas the mechanism of activation and secretion of interleukin 1β, which critically regulates the function of this molecule, has remained mysterious for some 30 years following its discovery, the identification of a new cytoplasmic complex of proteins regulating il-1β activation and secretion has carried our unde ...201222653747
electrostatically embedded many-body expansion for neutral and charged metalloenzyme model systems.the electrostatically embedded many-body (ee-mb) method has proven accurate for calculating cohesive and conformational energies in clusters, and it has recently been extended to obtain bond dissociation energies for metal-ligand bonds in positively charged inorganic coordination complexes. in the present paper, we present four key guidelines that maximize the accuracy and efficiency of ee-mb calculations for metal centers. then, following these guidelines, we show that the ee-mb method can also ...201222639556
cis-acting elements that control expression of the master virulence regulatory gene atxa in bacillus anthracis.transcription of the bacillus anthracis structural genes for the anthrax toxin proteins and biosynthetic operon for capsule is positively regulated by atxa, a transcription regulator with unique properties. consistent with the role of atxa in virulence factor expression, a b. anthracis atxa-null mutant is avirulent in a murine model for anthrax. in culture, multiple signals impact atxa transcript levels, and the timing and steady-state level of atxa expression are critical for optimal toxin and ...201222636778
electroporation of a multivalent dna vaccine cocktail elicits a protective immune response against anthrax and plague.electroporation of dna vaccines represents a platform technology well positioned for the development of multivalent biodefense vaccines. to evaluate this hypothesis, three vaccine constructs were produced using codon-optimized genes encoding bacillus anthracis protective antigen (pa), and the yersinia pestis genes lcrv and f1, cloned into pvax1. a/j mice were immunized on a prime-boost schedule with these constructs using the electroporation-based trigrid delivery system. immunization with the i ...201222633906
anthrax infection among heroin users in scotland during 2009-2010: a case-control study by linkage to a national drug treatment database.using a data-linkage approach, we conducted a case-control study to investigate risk factors in an outbreak of anthrax infection among scottish heroin users. factors associated with an increased risk of infection included longer injecting history, receiving opioid substitution therapy, and alcohol consumption. smoking heroin was associated with lower risk of infection.201222618565
toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy.anthrax lethal toxin (letx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. this study was designed to evaluate the role of toll-like receptor 4 (tlr4) in anthrax lethal toxin-induced cardiac contractile dysfunction.201222612289
multiple abc transporters are involved in the acquisition of petrobactin in bacillus anthracis.in bacillus anthracis the siderophore petrobactin is vital for iron acquisition and virulence. the petrobactin-binding receptor fpua is required for these processes. here additional components of petrobactin reacquisition are described. to identify these proteins, mutants of candidate permease and atpase genes were generated allowing for characterization of multiple petrobactin atp-binding cassette (abc)-import systems. either of two distinct permeases, fpub or fatcd, is required for iron acquis ...201222429808
human monoclonal antibodies generated following vaccination with ava provide neutralization by blocking furin cleavage but not by preventing oligomerization.in order to identify the combination of antibody-mediated mechanisms of neutralization that result from vaccination with anthrax vaccine adsorbed (ava), we isolated antibody secreting cells from a single donor seven days after booster vaccination with ava and generated nine fully human monoclonal antibodies (hmab) with high specificity for protective antigen (pa). two of the antibodies were able to neutralize lethal toxin in vitro at low concentrations (ic(50): p6c01, 0.12 μg/ml and p6f01, 0.45 ...201222425791
structure, assembly, and dna packaging of the bacteriophage t4 head.the bacteriophage t4 head is an elongated icosahedron packed with 172 kb of linear double-stranded dna and numerous proteins. the capsid is built from three essential proteins: gp23*, which forms the hexagonal capsid lattice; gp24*, which forms pentamers at 11 of the 12 vertices; and gp20, which forms the unique dodecameric portal vertex through which dna enters during packaging and exits during infection. intensive work over more than half a century has led to a deep understanding of the phage ...201222420853
structure-based design of novel pyrimido[4,5-c]pyridazine derivatives as dihydropteroate synthase inhibitors with increased affinity.dihydropteroate synthase (dhps) is the validated drug target for sulfonamide antimicrobial therapy. however, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. the pterin binding pocket in dhps is highly conserved and is distinct from the sulfonamide binding site. it therefore represents an attractive alternative target for the design of novel antibacterial agents. we previously carried out the structural characterization of a known pyridazin ...201222416048
distribution and molecular evolution of bacillus anthracis genotypes in namibia.the recent development of genetic markers for bacillus anthracis has made it possible to monitor the spread and distribution of this pathogen during and between anthrax outbreaks. in namibia, anthrax outbreaks occur annually in the etosha national park (enp) and on private game and livestock farms. we genotyped 384 b. anthracis isolates collected between 1983-2010 to identify the possible epidemiological correlations of anthrax outbreaks within and outside the enp and to analyze genetic relation ...201222413024
rugged single domain antibody detection elements for bacillus anthracis spores and vegetative cells.significant efforts to develop both laboratory and field-based detection assays for an array of potential biological threats started well before the anthrax attacks of 2001 and have continued with renewed urgency following. while numerous assays and methods have been explored that are suitable for laboratory utilization, detection in the field is often complicated by requirements for functionality in austere environments, where limited cold-chain facilities exist. in an effort to overcome these ...201222412927
differential function of lip residues in the mechanism and biology of an anthrax hemophore.to replicate in mammalian hosts, bacterial pathogens must acquire iron. the majority of iron is coordinated to the protoporphyrin ring of heme, which is further bound to hemoglobin. pathogenic bacteria utilize secreted hemophores to acquire heme from heme sources such as hemoglobin. bacillus anthracis, the causative agent of anthrax disease, secretes two hemophores, isdx1 and isdx2, to acquire heme from host hemoglobin and enhance bacterial replication in iron-starved environments. both proteins ...201222412371
ultra-fast pg/ml anthrax toxin (protective antigen) detection assay based on microwave-accelerated metal-enhanced fluorescence.rapid presymptomatic diagnosis of bacillus anthracis at early stages of infection plays a crucial role in prompt medical intervention to prevent rapid disease progression and accumulation of lethal levels of toxin. to detect low levels of the anthrax protective antigen (pa) exotoxin in biological fluids, we have developed a metal-enhanced fluorescence (mef)-pa assay using a combination of the mef effect and microwave-accelerated pa protein surface absorption. the assay is based on a modified ver ...201222406431
variable lymphocyte receptor recognition of the immunodominant glycoprotein of bacillus anthracis spores.variable lymphocyte receptors (vlrs) are the adaptive immune receptors of jawless fish, which evolved adaptive immunity independent of other vertebrates. in lieu of the immunoglobulin fold-based t and b cell receptors, lymphocyte-like cells of jawless fish express vlrs (vlra, vlrb, or vlrc) composed of leucine-rich repeats and are similar to toll-like receptors (tlrs) in structure, but antibodies (vlrb) and t cell receptors (vlra and vlrc) in function. here, we present the structural and biochem ...201222405006
determinants of emergency response willingness in the local public health workforce by jurisdictional and scenario patterns: a cross-sectional survey.the all-hazards willingness to respond (wtr) of local public health personnel is critical to emergency preparedness. this study applied a threat-and efficacy-centered framework to characterize these workers' scenario and jurisdictional response willingness patterns toward a range of naturally-occurring and terrorism-related emergency scenarios.201222397547
updating perspectives on the initiation of bacillus anthracis growth and dissemination through its host.since 1957, it has been proposed that the dissemination of inhalational anthrax required spores to be transported from the lumena of the lungs into the lymphatic system. in 2002, this idea was expanded to state that alveolar macrophages act as a "trojan horse" capable of transporting spores across the lung epithelium into draining mediastinal lymph nodes. since then, the trojan horse model of dissemination has become the most widely cited model of inhalational infection as well as the focus of t ...201222354031
sporicidal/bactericidal textiles via the chlorination of silk.bacterial spores, such as those of the bacillus genus, are extremely resilient, being able to germinate into metabolically active cells after withstanding harsh environmental conditions or aggressive chemical treatments. the toughness of the bacterial spore in combination with the use of spores, such as those of bacillus anthracis, as a biological warfare agent necessitates the development of new antimicrobial textiles. in this work, a route to the production of fabrics that kill bacterial spore ...201222352921
decontamination after a release of b. anthracis spores.decontaminating civilian facilities or large urban areas following an attack with bacillus anthracis poses daunting challenges because of the lack of resources and proven technologies. nevertheless, lessons learned from the 2001 cleanups together with advances derived from recent research have improved our understanding of what is required for effective decontamination. this article reviews current decontamination technologies appropriate for use in outdoor environments, on material surfaces, wi ...201222352747
identification of the first known inhibitors of o-acetylpeptidoglycan esterase: a potential new antibacterial target.the o-acetylation of peptidoglycan (pg) is now known to occur in 53 species, including numerous human pathogens such as, staphylococcus aureus, bacillus anthracis, species of enterococcus, campylobacter jejuni, helicobacter pylori, neisseria gonorrhoeae and n. meningitidis. this modification, which occurs at the c-6 hydroxyl of n-acetylmuramoyl residues within pg, serves to regulate autolytic activity during pg metabolism and contributes to pathogenesis and persistence within a host. o-acetylpep ...201222351512
development of an in vitro potency assay for anti-anthrax lethal toxin neutralizing antibodies.lethal toxin (lt) of bacillus anthracis reduces the production of a number of inflammatory mediators, including transcription factors, chemokines and cytokines in various human cell lines, leading to down-regulation of the host inflammatory response. previously we showed that the reduction of interleukin-8 (il-8) is a sensitive marker of lt-mediated intoxication in human neutrophil-like nb-4 cells and that il-8 levels are restored to normality when therapeutic monoclonal antibodies (mab) with to ...201222347621
characterization of a novel lytic protein encoded by the bacillus cereus e33l gene ampd as a bacillus anthracis antimicrobial protein.lytic proteins encoded by bacterial genomes have been implicated in cell wall biosynthesis and recycling. the bacillus cereus e33l ampd gene encodes a putative n-acetylmuramoyl-l-alanine amidase. this gene, expressed in vitro, produced a very stable, highly active lytic protein. very low concentrations rapidly and efficiently lyse vegetative bacillus anthracis cells.201222344637
naturally occurring cutaneous anthrax: antibiotic treatment and outcome.cutaneous anthrax (ca) is the most common clinical presentation in human anthrax, but the duration of antibiotic therapy in naturally occurring ca is controversial. the aim of this study was to compare the clinical outcomes of patients receiving antibiotic treatment for either 3-5 days (group 1) or 7-10 days (group 2) in uncomplicated ca.201222343361
in vitro and in vivo analyses of the bacillus anthracis spore cortex lytic protein slel.the bacterial endospore is the most resilient biological structure known. multiple protective integument layers shield the spore core and promote spore dehydration and dormancy. dormancy is broken when a spore germinates and becomes a metabolically active vegetative cell. germination requires the breakdown of a modified layer of peptidoglycan (pg) known as the spore cortex. this study reports in vitro and in vivo analyses of the bacillus anthracis slel protein. slel is a spore cortex lytic enzym ...201222343356
antidotes to anthrax lethal factor intoxication. part 3: evaluation of core structures and further modifications to the c2-side chain.four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (lf) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro adme profiles, and relative efficacy in a rat lethal toxin (lt) model of lf intoxication. poor efficacy in the rat lt model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. specific molecular interactions contributing to the high affinity of inhibitors wit ...201222342144
tem8/antxr1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types.current antiangiogenic agents used to treat cancer only partially inhibit neovascularization and cause normal tissue toxicities, fueling the need to identify therapeutic agents that are more selective for pathological angiogenesis. tumor endothelial marker 8 (tem8), also known as anthrax toxin receptor 1 (antxr1), is a highly conserved cell-surface protein overexpressed on tumor-infiltrating vasculature. here we show that genetic disruption of tem8 results in impaired growth of human tumor xenog ...201222340594
bacteria and their toxins tamed for immunotherapy.bacterial toxins share the ability to enter host cells to target various intracellular proteins and to modulate host immune responses. over the last 20 years, toxins and their mutated variants, as well as live attenuated bacteria, have been exploited for vaccination and immunotherapy of various infectious, malignant and autoimmune diseases. the ability of bordetella pertussis adenylate cyclase toxin to translocate its adenylate cyclase domain across the host cell membrane, as well as the pathway ...201222339216
human genetic variation altering anthrax toxin sensitivity.the outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. some host genes encode defense mechanisms, whereas others assist pathogen functions. genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 (cmg2), which encodes a host membrane protein exploited by anthrax toxin a ...201222315420
increased affinity and solubility of peptides used for direct peptide elisa on polystyrene surfaces through fusion with a polystyrene-binding peptide tag.peptide reagents can serve as alternatives or replacements to antibodies in sensing or diagnostic applications. the passive adsorption of peptides onto polystyrene surfaces can limit the target binding capability, especially for short, positively charged, or hydrophobic sequences. in this report, we show that fusing a peptide with a previously characterized 12-amino acid polystyrene binding sequence (ps-tag) improves overall peptide solubility and enzyme-linked immunosorbent assay (elisa) result ...201222313407
total decontamination cost of the anthrax letter attacks.all of the costs associated with decontamination following the 2001 anthrax letter attacks were summarized, estimated, and aggregated based on existing literature and news media reports. a comprehensive list of all affected structures was compiled. costs were analyzed by building class and decontamination type. sampling costs and costs of worker relocation were also included. our analysis indicates that the total cost associated with decontamination was about $320 million.201222313022
on-column labeling of gram-positive bacteria with a boronic acid functionalized squarylium cyanine dye for analysis by polymer-enhanced capillary transient isotachophoresis.a new asymmetric, squarylium cyanine dye functionalized by boronic acid ("sq-ba") was designed and synthesized for on-capillary labeling of gram-positive bacteria to provide for high sensitivity detection by way of a modified form of capillary electrophoresis with laser induced fluorescence detection (ce-lif). the ce-based separation employed a polymer-enhanced buffer with capillary transient isotachophoresis in a new hybrid method dubbed "pecti." it was found that the addition of various monosa ...201222304241
binding of filamentous actin to anthrax toxin receptor 1 decreases its association with protective antigen.antxr1 is a type i membrane protein that binds the protective antigen (pa) component of anthrax toxin. the cytosolic domain of antxr1 has a novel actin-binding region that influences the interaction of the ectodomain with pa. here, we have investigated features of the cytosolic domain of antxr1 that reduce the association of the receptor with pa. we mutated a stretch of conserved acidic amino acids adjacent to the actin-binding region and found that the mutation increased the affinity for monome ...201222303962
infantile systemic hyalinosis associated with a putative splice-site mutation in the antxr2 gene.infantile systemic hyalinosis (ish) is a rare autosomal recessive genetic disorder characterized by dermal and subcutaneous fibromatosis, joint contractures and bone deformities. the condition usually presents at birth, resulting in death in infancy. ish is caused by mutations in the anthrax toxin receptor 2 gene, antxr2, also known as cmg2. we report an indian child with ish in whom we identified a homozygous acceptor splice site mutation, ivs2-4g>a. in silico analysis of this sequence showed t ...201222300424
lethality in a murine model of pulmonary anthrax is reduced by combining nuclear transport modifier with antimicrobial therapy.in the last ten years, bioterrorism has become a serious threat and challenge to public health worldwide. pulmonary anthrax caused by airborne bacillus anthracis spores is a life-threatening disease often refractory to antimicrobial therapy. inhaled spores germinate into vegetative forms that elaborate an anti-phagocytic capsule along with potent exotoxins which disrupt the signaling pathways governing the innate and adaptive immune responses and cause endothelial cell dysfunction leading to vas ...201222291977
genomic and snp analyses demonstrate a distant separation of the hospital and community-associated clades of enterococcus faecium.recent studies have pointed to the existence of two subpopulations of enterococcus faecium, one containing primarily commensal/community-associated (ca) strains and one that contains most clinical or hospital-associated (ha) strains, including those classified by multi-locus sequence typing (mlst) as belonging to the cc17 group. the ha subpopulation more frequently has is16, pathogenicity island(s), and plasmids or genes associated with antibiotic resistance, colonization, and/or virulence. supp ...201222291916
design and characterization of novel hybrid antimicrobial peptides based on cecropin a, ll-37 and magainin ii.antimicrobial peptides (amps) are a naturally occurring component of the innate immune response of many organisms and can have activity against both gram-negative and gram-positive bacterial species. in order to optimize and improve the direct antimicrobial effect of amps against a broad spectrum of bacterial species, novel synthetic hybrids were rationally designed from cecropin a, ll-37 and magainin ii. amps were selected based on their α-helical secondary structure and fragments of these were ...201222289499
serum albumin disrupts cryptococcus neoformans and bacillus anthracis extracellular vesicles.for both pathogenic fungi and bacteria, extracellular vesicles have been shown to contain many microbial components associated with virulence, suggesting a role in pathogenesis. however, there are many unresolved issues regarding vesicle synthesis and stability, including the fact that vesicular packaging for extracellular factors involved in virulence must also have a mechanism for vesicle unloading. consequently, we studied the kinetics of vesicle production and stability using [1-(14) c] palm ...201222289081
anthrax: has the clinical milieu changed since 2001?since the anthrax attacks of 2001 (amerithrax), several important improvements in the knowledge of bacillus anthracis and the clinical condition it causes have occurred. while much remains to be known about the optimal management of anthrax patients, several approaches that were not widely utilized, available, or known in 2001 would be used in the treatment of critically ill anthrax patients in 2012.201223882372
surface-layer (s-layer) proteins sap and ea1 govern the binding of the s-layer-associated protein bslo at the cell septa of bacillus anthracis.the gram-positive pathogen bacillus anthracis contains 24 genes whose products harbor the structurally conserved surface-layer (s-layer) homology (slh) domain. proteins endowed with the slh domain associate with the secondary cell wall polysaccharide (scwp) following secretion. two such proteins, sap and ea1, have the unique ability to self-assemble into a paracrystalline layer on the surface of bacilli and form s layers. other slh domain proteins can also be found within the s layer and have be ...201222609927
secretion genes as determinants of bacillus anthracis chain length.bacillus anthracis grows in chains of rod-shaped cells, a trait that contributes to its escape from phagocytic clearance in host tissues. using a genetic approach to search for determinants of b. anthracis chain length, we identified mutants with insertional lesions in seca2. all isolated seca2 mutants exhibited an exaggerated chain length, whereas the dimensions of individual cells were not changed. complementation studies revealed that slap (s-layer assembly protein), a gene immediately downst ...201222609926
cluster analysis of host cytokine responses to biodefense pathogens in a whole blood ex vivo exposure model (weem).rapid detection and therapeutic intervention for infectious and emerging diseases is a major scientific goal in biodefense and public health. toward this end, cytokine profiles in human blood were investigated using a human whole blood ex vivo exposure model, called weem.201222607329
differential contribution of bacillus anthracis toxins to pathogenicity in two animal models.the virulence of bacillus anthracis, the causative agent of anthrax, stems from its antiphagocytic capsule, encoded by pxo2, and the tripartite toxins encoded by pxo1. the accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play major roles in pathogenicity. we tested this assumption by a systematic study of mutants with combined deletions of the pag, lef, and cya genes, encoding protective antigen (pa), lethal factor (lf), and edema factor (ef), ...201222585968
presumed guilt in the anthrax case. 201222582244
shelf-life extension program (slep) as a significant contributor to strategic national stockpile maintenance: the israeli experience with ciprofloxacin.in the past decade, the 2001 anthrax incident in the u.s. and the 2003 sars epidemic have highlighted the biological threat to civilian populations. the risk posed by the natural or manmade spread of biological agents among the population dictates a need for better national preparedness. one key component of this preparation is the establishment of a strategic national stockpile (sns) of pharmaceuticals that would provide appropriate medical countermeasures in case of an outbreak. however, to re ...201222578017
molecular epidemiology of the bacillus anthracis isolates collected throughout turkey from 1983 to 2011.the main perspective of this study was to determine cross-transmissions amongst anthrax cases and provide detailed information regarding the genotypes of bacillus anthracis isolates circulating in turkey. a total of 251 b. anthracis isolates were obtained from human (93 isolates), animal (155 isolates), and environmental (three isolates) samples in various provinces of turkey. all isolates were susceptible to quinolones, vancomycin, tigecycline, and linezolid, but not to ceftriaxone. excluding h ...201222576652
capillary morphogenesis protein-2 is required for mouse parturition by maintaining uterine collagen homeostasis.capillary morphogenesis protein-2 (cmg2) functions as an anthrax toxin receptor that plays an essential role in anthrax pathogenesis. although mutations in cmg2 have been identified to cause two human autosomal recessive disorders, juvenile hyaline fibromatosis and infantile systemic hyalinosis, both characterized by excess hyaline material deposition in connective tissues, the physiologic function of cmg2 remains elusive. to study the roles of cmg2 in normal physiology, here we performed detail ...201222575514
functional determinants of human enteric α-defensin hd5: crucial role for hydrophobicity at dimer interface.human α-defensins are cationic peptides that self-associate into dimers and higher-order oligomers. they bind protein toxins, such as anthrax lethal factor (lf), and kill bacteria, including escherichia coli and staphylococcus aureus, among other functions. there are six members of the human α-defensin family: four human neutrophil peptides, including hnp1, and two enteric human defensins, including hd5. we subjected hd5 to comprehensive alanine scanning mutagenesis. we then assayed lf binding b ...201222573326
monte carlo n-particle simulation of neutron-based sterilisation of anthrax contamination.to simulate the neutron-based sterilisation of anthrax contamination by monte carlo n-particle (mcnp) 4c code.201222573293
louis pasteur, the father of immunology?louis pasteur is traditionally considered as the progenitor of modern immunology because of his studies in the late nineteenth century that popularized the germ theory of disease, and that introduced the hope that all infectious diseases could be prevented by prophylactic vaccination, as well as also treated by therapeutic vaccination, if applied soon enough after infection. however, pasteur was working at the dawn of the appreciation of the microbial world, at a time when the notion of such a t ...201222566949
proteolytic assay-based screening identifies a potent inhibitor of anthrax lethal factor.anthrax lethal factor (lf), a zn(2+)-dependent metalloprotease, is a key virulence component of anthrax toxin. here, we used proteolytic assay-based screening to identify novel lf inhibitors from a naturally extracted chemical library. the screening identified four compounds that inhibited in vitro proteolytic activity of lf with an ic(50) of low micromolar range (11-20 μm). three of these compounds were toxic to the mouse macrophage-like cell line, raw 264.7. compound 200 was non-toxic, however ...201222561400
localization and structural analysis of a conserved pyruvylated epitope in bacillus anthracis secondary cell wall polysaccharides and characterization of the galactose-deficient wall polysaccharide from avirulent b. anthracis cdc 684.bacillus anthracis cdc 684 is a naturally occurring, avirulent variant and close relative of the highly pathogenic b. anthracis vollum. bacillus anthracis cdc 684 contains both virulence plasmids, pxo1 and pxo2, yet is non-pathogenic in animal models, prompting closer scrutiny of the molecular basis of attenuation. we structurally characterized the secondary cell wall polysaccharide (scwp) of b. anthracis cdc 684 (ba684) using chemical and nmr spectroscopy analysis. the scwp consists of a hexnac ...201222556058
changing the receptor specificity of anthrax toxin.the actions of many bacterial toxins depend on their ability to bind to one or more cell-surface receptors. anthrax toxin acts by a sequence of events that begins when the protective-antigen (pa) moiety of the toxin binds to either one of two cell-surface proteins, antxr1 and antxr2, and is proteolytically activated. the activated pa self-associates to form oligomeric pore precursors, which, in turn, bind the enzymatic moieties of the toxin and transport them to the cytosol. we introduced a doub ...201222550037
development of metal-chelating inhibitors for the class ii fructose 1,6-bisphosphate (fbp) aldolase.it has long been suggested that the essential and ubiquitous enzyme fructose 1,6-bisphosphate (fbp) aldolase could be a good drug target against bacteria and fungi, since lower organisms possess a metal-dependant (class ii) fbp aldolase, as opposed to higher organisms which possess a schiff-base forming (class i) fbp aldolase. we have tested the capacity of derivatives of the metal-chelating compound dipicolinic acid (dpa), as well a thiol-containing compound, to inhibit purified recombinant cla ...201222546686
increased membrane turnover in the brain in cutaneous anthrax without central nervous system disorder: a magnetic resonance spectroscopy study.cutaneous anthrax, caused by bacillus anthracis contacting the skin, is the most common form of human anthrax. recent studies implicate the presence of additional, possibly toxin-related subtle changes, even in patients without neurological or radiological findings. in this study, the presence of subtle changes in cutaneous anthrax was investigated at the metabolite level using magnetic resonance spectroscopy. study subjects were consisted of 10 patients with cutaneous anthrax without co-morbid ...201222543072
trace detection of meglumine and diatrizoate from bacillus spore samples using liquid chromatography/mass spectrometry.following the september 11, 2001 terrorist attacks, letters containing bacillus anthracis were distributed through the united states postal system killing five people. a complex forensic investigation commenced to identify the perpetrator of these mailings. a novel liquid chromatography/mass spectrometry protocol for the qualitative detection of trace levels of meglumine and diatrizoate in dried spore preparations of b. anthracis was developed. meglumine and diatrizoate are components of radiogr ...201222537353
proteolytic processing of nlrp1b is required for inflammasome activity.nlrp1b is a nod-like receptor that detects the catalytic activity of anthrax lethal toxin and subsequently co-oligomerizes into a pro-caspase-1 activation platform known as an inflammasome. nlrp1b has two domains that promote oligomerization: a nacht domain, which is a member of the aaa+ atpase family, and a poorly characterized function to find domain (fiind). here we demonstrate that proteolytic processing within the fiind generates n-terminal and c-terminal cleavage products of nlrp1b that re ...201222536155
functional hybrid nickel nanostructures as recyclable sers substrates: detection of explosives and biowarfare agents.we present the synthesis of highly anisotropic nickel nanowires (nws) and large area, free-standing carpets extending over cm(2) area by simple solution phase chemistry. the materials can be post-synthetically manipulated to produce hybrid tubes, wires, and carpets by galvanic exchange reactions with au(3+), ag(+), pt(2+), and pd(2+). all of these structures, especially the hybrid carpets and tubes, have been prepared in bulk and are surface enhanced raman scattering (sers) active substrates. mo ...201222535435
anthrax toxin receptor 2 functions in ecm homeostasis of the murine reproductive tract and promotes mmp activity.anthrax toxin receptor proteins function as receptors for anthrax toxin, however physiological activity remains unclear. to evaluate the biological role of antxr2, we generated antxr2-/- mice. antxr2-/- mice were viable, however antxr2 is required for parturition in young females and for preserving fertility in older female mice. histological analysis of the uterus and cervix revealed aberrant deposition of extracellular matrix proteins such as type i collagen, type vi collagen and fibronectin. ...201222529944
real-time polymerase chain reaction assay for rapid and sensitive detection of anthrax spores in spiked soil and talcum powder.real-time polymerase chain reaction (real-time pcr) is a laboratory technique based on pcr. this technique is able to detect sequence-specific pcr products as they accumulate in "real time" during the pcr amplification, and also to quantify the number of substrates present in the initial pcr mixture before amplification begins. in the present study, real-time pcr assay was employed for rapid and real-time detection of bacillus anthracis spores spiked in 0.1 g of soil and talcum powder ranging fr ...201222528297
an overview of anthrax infection including the recently identified form of disease in injection drug users.bacillus anthracis infection (anthrax) can be highly lethal. two recent outbreaks related to contaminated mail in the usa and heroin in the uk and europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world.201222527064
expression of either lethal toxin or edema toxin by bacillus anthracis is sufficient for virulence in a rabbit model of inhalational anthrax.the development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. the rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics against bacillus anthracis. we investigated the roles of b. anthracis capsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the ames strain versus isogenic mutants with deletions of the genes for the capsule ...201222526673
structural and functional characterization of microcin c resistance peptidase mccf from bacillus anthracis.microcin c (mcc) is heptapeptide adenylate antibiotic produced by escherichia coli strains carrying the mccabcdef gene cluster encoding enzymes, in addition to the heptapeptide structural gene mcca, necessary for mcc biosynthesis and self-immunity of the producing cell. the heptapeptide facilitates mcc transport into susceptible cells, where it is processed releasing a non-hydrolyzable aminoacyl adenylate that inhibits an essential aminoacyl-trna synthetase. the self-immunity gene mccf encodes a ...201222516613
immunogenicity and efficacy of an anthrax/plague dna fusion vaccine in a mouse model.the efficacy of multi-agent dna vaccines consisting of a truncated gene encoding bacillus anthracis lethal factor (lfn) fused to either yersinia pestis v antigen (v) or y . pestis f1 was evaluated. a/j mice were immunized by gene gun and developed predominantly igg1 responses that were fully protective against a lethal aerosolized b. anthracis spore challenge but required the presence of an additional dna vaccine expressing anthrax protective antigen to boost survival against aerosolized y. pest ...201222515653
effect of animal sera on bacillus anthracis sterne spore germination and vegetative cell growth.the aims of this work were to investigate the effects of sera on b. anthracis sterne germination and growth. sera examined included human, monkey and rabbit sera, as well as sera from eight other species.201222515644
variance in bacillus anthracis virulence assessed through bayesian hierarchical dose-response modelling.to develop a predictive dose-response model for describing the survival of animals exposed to bacillus anthracis to support risk management options.201222515543
evaluation of sample preparation methods for maldi-tof ms identification of highly dangerous bacteria.to propose a universal workflow of sample preparation method for the identification of highly pathogenic bacteria by maldi-tof ms.201222512320
delayed toxicity associated with soluble anthrax toxin receptor decoy-ig fusion protein treatment.soluble receptor decoy inhibitors, including receptor-immunogloubulin (ig) fusion proteins, have shown promise as candidate anthrax toxin therapeutics. these agents act by binding to the receptor-interaction site on the protective antigen (pa) toxin subunit, thereby blocking toxin binding to cell surface receptors. here we have made the surprising observation that co-administration of receptor decoy-ig fusion proteins significantly delayed, but did not protect, rats challenged with anthrax letha ...201222511955
protective effect of bacillus anthracis surface protein ea1 against anthrax in mice.bacillus anthracis spores germinate to vegetative forms in host cells, and produced fatal toxins. a toxin-targeting prophylaxis blocks the effect of toxin, but may allow to grow vegetative cells which create subsequent toxemia. in this study, we examined protective effect of extractable antigen 1 (ea1), a major s-layer component of b. anthracis, against anthrax. mice were intranasally immunized with recombinant ea1, followed by a lethal challenge of b. anthracis spores. mucosal immunization with ...201222507985
biosecurity aspects and pathogen inactivation in acidified high risk animal by-products.the aim of the study was to investigate the effects of formic acid addition to ground high risk animal by-products (abp 1) in terms of stabilization and pathogen inactivation and to evaluate the biosecurity risk connected with the abp 1 based combustion fuel biomal. laboratory studies were performed on the persistence of salmonella typhimurium, bacillus cereus spores, porcine herpes virus, avian influenza virus, bovine viral diarrhea virus, equine rhinitis a virus and porcine parvovirus in bioma ...201222506709
raman spectroscopic detection of anthrax endospores in powder samples. 201222505355
gerhard hansen: discoverer of the organism of leprosy.this year marks the hundredth anniversary of the death, on 12 february 1912, of the norwegian leprologist, gerhard hansen, who was the first to describe the mycobacterium leprae (hansen's bacillus). it was, in fact, only the second specific disease-causing organism to be discovered, the first being the bacillus of anthrax.201222504759
role of chondroitin sulfate c in the action of anthrax toxin.anthrax toxin is produced by bacillus anthracis, the causative agent of anthrax, and is responsible for the majority of disease symptoms. the toxin consists of 3 proteins, protective antigen (pa), lethal factor (lf), and edema factor (ef), which combine to form lethal and edema toxin. glycosaminoglycans, which are present on the surface of cells, were investigated with regard to their role in toxicity resulting from anthrax toxin exposure. lethal toxin-induced cytotoxicity of the raw 264.7 cells ...201222503668
laccase- and chloroperoxidase-nanotube paint composites with bactericidal and sporicidal activity.laccase and chloroperoxidase (cpo) were separately immobilized onto multi-walled carbon nanotubes (mwnts) and subsequently mixed with a commercial eco-friendly paint to generate biocatalytic coatings. the laccase-nanotube based paints showed >99% bactericidal activity against escherichia coli and staphylococcus aureus (both challenged with 10⁶ cfu/ml) within 30 min and >98% sporicidal activity against bacillus cereus and bacillus anthracis-δsterne (initially challenged with 10⁴ cfu/ml) within 12 ...201222500892
bounds on the effect of vaccine induced immune response on outcome.a major goal of vaccine development is the identification of immune responses that are responsible for vaccine efficacy. in theory, modest vaccines could be successfully improved by increasing such immune responses. and for a vaccine with a great benefit in one population, inducing such immune response in a different population could help one conclude the vaccine would have great benefit there. such identification is tricky because the immune response to vaccination can only be measured in the v ...201222499733
invariant gly residue is important for α-defensin folding, dimerization, and function: a case study of the human neutrophil α-defensin hnp1.the human α-defensins (hnp) are synthesized in vivo as inactive prodefensins, and contain a conserved glycine, gly(17), which is part of a β-bulge structure. it had previously been shown that the glycine main chain torsion angles are in a d-configuration, and that d-amino acids but not l-alanine could be substituted at that position to yield correctly folded peptides without the help of a prodomain. in this study, the glycine to l-alanine mutant defensin was synthesized in the form of a prodefen ...201222496447
black-backed jackal exposure to rabies virus, canine distemper virus, and bacillus anthracis in etosha national park, namibia.canine distemper virus (cdv) and rabies virus (rabv) occur worldwide in wild carnivore and domestic dog populations and pose threats to wildlife conservation and public health. in etosha national park (enp), namibia, anthrax is endemic and generates carcasses frequently fed on by an unusually dense population of black-backed jackals (canis mesomelas). using serology, phylogenetic analyses (on samples obtained from february 2009-july 2010), and historical mortality records (1975-2011), we assesse ...201222493112
anthrax outbreaks in bangladesh, 2009-2010.during august 2009-october 2010, a multidisciplinary team investigated 14 outbreaks of animal and human anthrax in bangladesh to identify the etiology, pathway of transmission, and social, behavioral, and cultural factors that led to these outbreaks. the team identified 140 animal cases of anthrax and 273 human cases of cutaneous anthrax. ninety one percent of persons in whom cutaneous anthrax developed had history of butchering sick animals, handling raw meat, contact with animal skin, or were ...201222492157
distributed and grid computing projects with research focus in human health.distributed systems and grid computing systems are used to connect several computers to obtain a higher level of performance, in order to solve a problem. during the last decade, projects use the world wide web to aggregate individuals' cpu power for research purposes. this paper presents the existing active large scale distributed and grid computing projects with research focus in human health. there have been found and presented 11 active projects with more than 2000 processing units (pus) eac ...201222491123
[two new sequence type isolates of bacillus anthracis by multilocus sequence typing].to define the sequence type (st) isolates of bacillus anthracis by multilocus sequence typing (mlst).201222489469
production of protocatechuic acid in bacillus thuringiensis atcc33679.protocatechuic acid, or 3,4-dihydroxybenzoic acid, is produced by both soil and marine bacteria in the free form and as the iron binding component of the siderophore petrobactin. the soil bacterium, bacillus thuringiensis kurstaki atcc 33679, contains the asb operon, but does not produce petrobactin. iron restriction resulted in diminished b. thuringiensis kurstaki atcc 33679 growth and the production of catechol(s). the gene product responsible for protocatechuic acid (asbf) and its receptor (f ...201222489181
membrane pores in the pathogenesis of neurodegenerative disease.the neurodegenerative diseases described in this volume, as well as many nonneurodegenerative diseases, are characterized by deposits known as amyloid. amyloid has long been associated with these various diseases as a pathological marker and has been implicated directly in the molecular pathogenesis of disease. however, increasing evidence suggests that these proteinaceous congo red staining deposits may not be toxic or destructive of tissue. recent studies strongly implicate smaller aggregates ...201222482454
anthrax lethal factor cleavage of nlrp1 is required for activation of the inflammasome.nod-like receptor (nlr) proteins (nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of il-1β and il-18. anthrax lethal toxin (lt) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from cer ...201222479187
lung b cells promote early pathogen dissemination and hasten death from inhalation anthrax.sampling of mucosal antigens regulates immune responses but may also promote dissemination of mucosal pathogens. lung dendritic cells (ldcs) capture antigens and traffic them to lung-draining lymph nodes (ldlns) dependent on the chemokine receptor ccr7 (chemokine (c-c motif) receptor 7). ldcs also capture lung pathogens such as bacillus anthracis (ba). however, we show here that the initial traffic of ba spores from lungs to ldlns is largely independent of ldcs and ccr7, occurring instead in ass ...201222472773
human-animal anthrax outbreak in the luangwa valley of zambia in 2011.there has been a reduction of incidences of anthrax in the developed countries but it is still a public health problem in the developing countries where communities live in interface areas with wildlife. an outbreak of anthrax in hippopotamus amphibious was observed in zambia. following the death of hippopotamuses, suspected human cases were reported. the objective of this study was to isolate and confirm bacillus anthracis and to determine the antimicrobial susceptibility for the management of ...201222472314
benchmark dose analysis for bacillus anthracis inhalation exposures in the nonhuman primate.there is considerable variability in the published lethality values for inhalation exposures of bacillus anthracis. the lack of consensus on an acceptable dose-response relationship poses a significant challenge in the development of risk-based management approaches for use following a terrorist release of b. anthracis spores. this article reviewed available b. anthracis dose-response modeling and literature for the nonhuman primate, evaluated the use of the u.s. environmental protection agency' ...201222469218
active control of silver nanoparticles spacing using dielectrophoresis for surface-enhanced raman scattering.we demonstrate an active microfluidic platform that integrates dielectrophoresis for the control of silver nanoparticles spacing, as they flow in a liquid channel. by careful control of the nanoparticles spacing, we can effectively increase the surface-enhanced raman scattering (sers) signal intensity based on augmenting the number of sers-active hot-spots, while avoiding irreversible aggregation of the particles. the system is benchmarked using dipicolinate (2,6-pyridinedicarboxylic acid) (dpa) ...201222468827
ultrafast kinetic dna hybridization assay based on the visualization of threshold turbidity.we report herein the development of an ultrafast kinetic dna hybridization assay system based on the visualization of threshold turbidity associated with the assembly of polystyrene nanospheres. initial testing of our diagnostic protocol on a sequence associated with the anthrax lethal factor indicates that a visually identifiable, turbidity-definitive, and kinetic threshold state could be reached at a time as short as 1 min. the assay scheme allows for both target concentration quantification a ...201222458673
assessing a decade of public health preparedness: progress on the precipice?september 11 and the subsequent anthrax attacks marked the beginning of significant investment by the federal government to develop a national public health emergency response capability. recognizing the importance of the public health sector's contribution to the burgeoning homeland security enterprise, this investment was intended to convey a "dual benefit" by strengthening the overall public health infrastructure while building preparedness capabilities. in many instances, federal funds were ...201222455679
a decade of countering bioterrorism: incremental progress, fundamental failings.the fear and disruption caused by the 2001 anthrax attacks understandably led americans to seek enhanced biodefenses. however, the path followed since those attacks has left the country inadequately prepared to face further risks from biological attacks. why has security against these threats been only partially achieved? this article suggests that our responses over the past decade can be sorted into 4 levels in order of increasing difficulty. first, we rapidly appropriated funds, augmented per ...201222455678
the evolution of law in biopreparedness.the decade following the terrorist attacks on september 11, 2001, and ensuing anthrax exposures that same fall has seen significant legal reforms designed to improve biopreparedness nationally. over the past 10 years, a transformative series of legal changes have effectively (1) rebuilt components of federal, state, and local governments to improve response efforts; (2) created an entire new legal classification known as "public health emergencies"; and (3) overhauled existing legal norms defini ...201222455677
public health surveillance and infectious disease detection.emerging infectious diseases, such as hiv/aids, sars, and pandemic influenza, and the anthrax attacks of 2001, have demonstrated that we remain vulnerable to health threats caused by infectious diseases. the importance of strengthening global public health surveillance to provide early warning has been the primary recommendation of expert groups for at least the past 2 decades. however, despite improvements in the past decade, public health surveillance capabilities remain limited and fragmented ...201222455675
fluoroquinolone-induced tendinopathy: etiology and preventive measures.tendinopathy is a serious health problem and its etiology is not fully elucidated. among intrinsic and extrinsic predisposing factors of tendinopathy, the impact of therapeutic agents, especially fluoroquinolone (fq) group antibiotics, is recently being recognized. fqs are potent bactericidal agents widely used in various infectious diseases, including community acquired pneumonia and bronchitis, chronic osteomyelitis, traveler's diarrhea, typhoid fever, shigellosis, chronic bacterial prostatiti ...201222452935
bacillus anthracis protease inha regulates bsla-mediated adhesion in human endothelial cells.to achieve widespread dissemination in the host, bacillus anthracis cells regulate their attachment to host endothelium during infection. previous studies identified bsla (bacillus anthracis s-layer protein a), a virulence factor of b. anthracis, as necessary and sufficient for adhesion of vegetative cells to human endothelial cells. while some factors have been identified, bacteria-specific contributions to bsla mediated adhesion remain unclear. using the attenuated vaccine sterne 7702 strain o ...201222452315
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