| Process Research and Development of Antibodies as Countermeasures for C. botulinum |
Feb-2009 |
41 pages |
| Authors:
Michael Meagher; NEBRASKA UNIV LINCOLN
|
 | This final report describes the design and construction of a CGMP facility for yeast and bacteria on the first floor and basement of Othmer Hall, the home for the University of Nebraska-Lincoln Biological Process Development Facility. Total cost for construction was $11,165,740, with the University of Nebraska-Lincoln providing $5,179,226 (46%) of the funding, USAMRMC providing $4,958,049 (45%), and JVAP providing $1,028,465 (9 %). This final report also describes the expression, ... |
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| Defining B. Anthracis Protective Antigen Antigenic Domains |
01-Dec-2008 |
6 pages |
| Authors:
Arturo Casadevall; ALBERT EINSTEIN SCHOOL OF MEDICINE BRONX NY
|
| The US Army faces the threat of biological warfare with Bacillus anthracis spores. Although there is a vaccine available (AVA vaccine) this formulation is poorly immunogenic, has questionable efficacy in some hosts, and is associated with significant side effects. The most important antigen in this vaccine is a component of anthrax toxin known as protective antigen (PA). However, this protein can also elicit potentially deleterious antibodies. This research program seeks ... |
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| Laboratory-Scale Study in Determining the Decontamination Standards for Personnel Protective Equipment Used by Homeland Defense Personnel: Evaluation of Commercial Off-the-Shelf Technologies for Decontamination of Personnel Protective Equipment-Relevant S |
01-Jun-2008 |
19 pages |
| Authors:
Lalena Wallace; Vipin K Rastogi; Lisa S Smith; Saumil S Shah; Jonathan Sabol; EDGEWOOD CHEMICAL BIOLOGICAL CENTER ABERDEEN PROVING GROUND MD
|
| In 2001, dissemination of letters tainted with anthrax-causing spores through USPS led to a limited number of deaths and contamination of several hundred thousand cubic feet of surface space within government and commercial buildings. In the context of homeland security, these and other cases involving ricin toxin demonstrated the urgent need to develop countermeasures for cleaning up complex surfaces relevant to personnel protective equipment (PPE). Four relevant surface materials (polycarbonate, ... |
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| Project BioShield: Appropriations, Acquisitions, and Policy Implementation Issues for Congress |
08 MAR 2007 |
|
| Authors:
Frank Gottron; LIBRARY OF CONGRESS WASHINGTON DC CONGRESSIONAL RESEARCH SERVICE
|
 | The Project BioShield Act of 2004 (P.L. 108-276) established a 10-year program to acquire civilian medical countermeasures to chemical, biological, radiological and nuclear (CBRN) agents for the Strategic National Stockpile. Provisions of this act were designed to encourage private companies to develop these countermeasures by guaranteeing a government market for successfully developed countermeasures. Both the Department of Homeland Security (DHS) and the Department of Health and Human Services (HHS) have ... |
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| Coatings and Biodegradable and Bioasorbable Films |
28 DEC 2006 |
59 pages |
| Authors:
Shelby F. Thames; James W. Rawlins; UNIVERSITY OF SOUTHERN MISSISSIPPI HATTIESBURG
|
| Research and development activities focused on environmentally friendly monomer, polymer and composite materials for Navy coating and packaging needs. Specifically focusing on the plasticizing effects of vegetable oil macromonomers as incorporated into emulsion polymers for efficient almost zero VOC film formation and the additional benefit of auto-oxidative polymerization after application. The resulting formulated coatings met or exceeded each of the specified Military specifications and are currently being evaluated for larger ... |
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| Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to the Channel of Botulinum Neurotoxin |
01 SEP 2006 |
16 pages |
| Authors:
Mauricio Montal; CALIFORNIA UNIV SAN DIEGO LA JOLLA
|
| The ultimate goal of this program is to discover selective and potent drugs targeted to prevent or relieve the neurotoxic actions of botulinum neurotoxin (BoNT) A. A major goal of this program is the identification of open channel blockers as a single class of drugs that would be effective against all BoNT isoforms. We consider the BoNT channel as a validated target for intervention aimed to inhibit the translocation of ... |
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| Macrophage Responses to B. Anthracis |
14 AUG 2006 |
16 pages |
| Authors:
Philip C. Hanna; MICHIGAN UNIV ANN ARBOR SCHOOL OF MEDICINE
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| The goal of these studies is to monitor changes occurring in host macrophages using a cell culture model of the early establishment stage of anthrax. Global changes in cultured murine macrophage expression of mRNA and protein, in response to B. anthracis and anthrax lethal toxin challenges, were assessed for 8 hours via microarray and MudPIT technologies and compared to mock-challenged cells. While most host genes/proteins did not change expression levels ... |
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| Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival |
14 JUN 2006 |
7 pages |
| Authors:
Wilson J. Ribot; Rekha G. Panchal; Katherine C. Brittingham; Gordon Ruthel; Tara A. Kenny; Douglas Lane; Bob Curry; Timothy A. Hoover; Arthur M. Friedlander; Sina Bavari; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the ... |
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| Conversion of a Mouse Fab into a Whole Humanized IgG Antibody for Detecting Botulinum Toxin |
APR 2006 |
10 pages |
| Authors:
Thomas J. Palys; Kara E. Schmid; John M. Scherer; Randal J. Schoepp; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| Antibodies serve as the gold standard in most immunodiagnostic assays. Recent advances in recombinant DNA technology have offered the production of antibody fragments or Fabs as promising alternatives. However, the lack of the Fc region of the antibody can be difficult in many standard diagnostic platforms. Therefore we sought to convert a murine Fab into a whole humanized IgG. The variable regions from an anti-botulinum Fab were cloned into human ... |
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| Rapid Detection of Clostridium botulinum Toxins A, B, E, and F in Clinical Samples, Selected Food Matrices, and Buffer Using Paramagnetic Bead-Based Electrochemiluminescence Detection |
20 MAR 2006 |
11 pages |
| Authors:
Victor R. Rivera; Frank J. Gamez; William K. Keener; Jill A. White; Mark A. Poli; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| Sensitive and specific electrochemiluminescence (ECL) assays were used to detect Clostridium botulinum neurotoxins serotypes A, B, E, and F in undiluted human serum, undiluted human urine, assay buffer, and selected food matrices (whole milk, apple juice, ground beef, pastry, and raw eggs). These novel assays used paramagnetic bead-based electrochemiluminescent technology in which biotinylated serotype-specific antibodies were bound to streptavidin-coated paramagnetic beads. The beads acted as the solid support and captured ... |
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| Process Research and Development of Antibodies as Countermeasures for C. Botulinum |
MAR 2006 |
37 pages |
| Authors:
Michael Meagher; NEBRASKA UNIV LINCOLN
|
| This report describes the design of a CGMP facility for yeast and bacteria on the first floor and basement of Othmer Hall, the home for the University of Nebraska-Lincoln Biological Process Development Facility. Design and a preliminary cost estimate is completed and the Program statement for the project is being submitted to the University of Nebraska Board of Reagents for approval. This report also describes research on the expression of ... |
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| Expression and Purification of Clostridium botulinum Type B Light Chain |
26 OCT 2005 |
14 pages |
| Authors:
Janice Gilsdorf; Nizamettin Gul; Leonard A. Smith; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| A full-length synthetic gene encoding the light chain of botulinum neurotoxin serotype B, approximately 50kDa (BoNT/B LC), has been cloned into a bacterial expression vector pET24a+. BoNT/B LC was expressed in Escherichia coli BL21.DE3.pLysS and isolated from the soluble fraction. The resultant protein was purified to homogeneity by cation chromatography and was determined to be >98% pure as assessed by SDS-polyacrylamide gel stained with SilverXpress and analyzed by densitometry. Mass ... |
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| Molecular Analysis of Olfactory Neural Circuits |
21 SEP 2005 |
4 pages |
| Authors:
Linda Buck; FRED HUTCHINSON RESEARCH CENTER WASHINGTON DC
|
| The olfactory system detects odorants that elicit diverse odor perceptions as well as pheromones that stimulate instinctive behaviors. We previously identified a large family of odorant receptors and determined how signals derived from those receptors are organized in the nose and then the olfactory bulb and cortex. To explore neural circuits in higher brain areas that control olfactory perception and behavior, new technologies are needed. We took the first steps ... |
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| The Thermal Stabilization of Vaccines Against Agents of Bioterrorism |
SEP 2005 |
292 pages |
| Authors:
C. R. Middaugh; KANSAS UNIV CENTER FOR RESEARCH INC LAWRENCE
|
| Vaccines are without doubt the most powerful approach currently available for the prevention of the deleterious effects of toxins and infectious agents that might be used in a bioterrorism against civilians or military personnel. Recent disclosures have indicated that numerous countries/or terrorists organizations may possess biological weapons that could indeed be used for this purpose. Likely, agents include anthrax, botulinum toxin, smallpox, tularemia, plague, and Venezuelan equine encephalitis. With the ... |
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| Characterization of Botulinum Progenitor Toxins by Mass Spectrometry |
AUG 2005 |
11 pages |
| Authors:
Harry B. Hines; Frank Lebeda; Martha Hale; Ernst E. Brueggemann; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD DIV OF TOXINOLOGY AND AEROBIOLOGY
|
| Botulinum toxin analysis has renewed importance. This study included the use of nanochromatography-nanoelectrospray-mass spectrometry/mass spectrometry to characterize the protein composition of botulinum progenitor toxins and to assign botulinum progenitor toxins to their proper serotype and strain by using currently available sequence information. Clostridium botulinum progenitor toxins from strains Hall, Okra, Stockholm, MDPH, Alaska, Langeland, and 89 representing serotypes A through G, respectively, were reduced, alkylated, digested with trypsin, and identified ... |
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| Stable Carbon Isotope Ratios and Biodegradation Rates of BTEX Compounds at the Tranguch Gasoline Site, Hazelton, Pennsylvania |
03 MAR 2005 |
41 pages |
| Authors:
Thomas J. Boyd; Michael T. Montgomery; Richard B. Coffin; NAVAL RESEARCH LAB WASHINGTON DC
|
| In April 2002, NRL sampled groundwater at the Tranguch Gasoline Site (TGS), located in Hazelton, Pennsylvania. The goal of this study was to determine the rates and efficacy of on-site bacterial fuel hydrocarbon biodegradation; measure the overall metabolic activity and state of the on-site bacterial consortia; and determine fuel hydrocarbon stable isotope ratios. Mineralization rates were relatively high, and calculated turnover (removal of ambient pool) times for benzene and toluene ... |
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| Structural Studies on Intact Clostridium Botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design |
FEB 2005 |
54 pages |
| Authors:
Subramanyam Swaminathan; BROOKHAVEN NATIONAL LAB UPTON NY
|
| In this third annual report we present our progress on two different areas. We have identified two ganglioside binding sites in tetanus toxin. While one is common to botulinum toxins, the other is unique for tetanus. The second unique site also binds a tri-peptide which suggests that this peptide could be used as an inhibitor for tetanus, at least. We have determined the structure of the C fragment of botulinum ... |
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| Botulinum Neurotoxin Serotype F: Identification of Substrate Recognition Requirements and Development of Inhibitors with Low Nanomolar Affinity |
06 JAN 2005 |
8 pages |
| Authors:
James J. Schmidt; R. G. Stafford; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD DIV OF TOXINOLOGY AND AEROBIOLOGY
|
| Botulinum neurotoxins (BoNTs A-G) are zinc metalloendoproteases that exhibit extraordinary specificities for proteins involved in neurotransmitter release. In view of the extreme toxicities of these molecules, their applications in human medicine, and potential for misuse, it is of considerable importance to elucidate the mechanisms underlying substrate recognition and to develop inhibitors, with the ultimate goal of obtaining anti-botulinum drugs. We synthesized peptides based on vesicle-associated membrane protein (VAMP) to investigate ... |
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| Protein Receptor(s) of Botulinum Neurotoxin |
JAN 2005 |
361 pages |
| Authors:
Bal R. Singh; MASSACHUSETTS UNIV NORTH DARTMOUTH
|
| Seven serotypes of botulinum neurotoxin (BoNT) are a group of water-soluble large proteins that act on the presynaptic nerve cells of the neuro-muscular junctions. BoNTs act intracellulary to block acetylcholine neurotransmitter release leading to the flaccid muscle paralysis in the dreaded botulism disease. In order to enter the neuronal cells, BoNTs bind to as yet to be clearly identified protein receptor(s), which could be targeted to develop proper antidotes. The ... |
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| Primary Cell Culture for Evaluation of Botulinum Neurotoxin Antagonists |
2005 |
7 pages |
| Authors:
Robert E. Sheridan; Theresa J. Smith; Michael Adler; ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
|
| The actions of botulinum neurotoxin (BoNT) were studied on evoked release of the neurotransmitter glycine in primary mouse spinal cord cells. 3[H]-glycine was taken up by cells in physiological solution and released by depolarization with 56 mM K + in the presence of 2 mM Ca2+. Release of 3 [H]-glycine was found to be inhibited by BoNT serotypes A, B and E with similar potency ratios to those observed in ... |
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| The Structure of the Neurotoxin- Associated Protein HA33/A from Clostridium botulinum Suggests a Reoccurring Beta-Trefoil Fold in the Progenitor Toxin Complex |
16 DEC 2004 |
12 pages |
| Authors:
Joseph W. Arndt; Jenny Gu; Lukasz Jaroszewski; Robert Schwarzenbacher; Michael A. Hanson; Frank L. Lebeda; Raymond C. Stevens; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| The hemagglutinating protein HA33 from Clostridium botulinum is associated with the large botulinum neurotoxin secreted complexes and is critical in toxin protection, internalization, and possibly activation. We report the crystal structure of serotype A HA33 (HA33/A) at 1.5 A resolution that contains a unique domain organization and a carbohydrate recognition site. In addition, sequence alignments of the other toxin complex components, including the neurotoxin BoNT/A, hemagglutinating protein HA17/A, and non-toxic ... |
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| Molecular Database Construction and Mining: A General Approach to Unconventional Pathogen Countermeasures |
14 DEC 2004 |
4 pages |
| Authors:
Yuan-Ping Pang; MAYO FOUNDATION ROCHESTER MN
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| One general approach to unconventional pathogen countermeasures is to use specific inhibitors to cripple enzymes such as proteases that are pivotal to pathogen invasions. For example, botulinum toxins can be detoxified by inhibitors targeting the zinc endopeptidase located in the light-chain region of botulinum toxins, and anthrax can be detoxified by inhibitors targeting anthrax's lethal factor which is a zinc protease. The generality of this approach rests on the fact ... |
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| Anthrax: Gene Expression Analysis of the Early Stages of Infection |
08 DEC 2004 |
4 pages |
| Authors:
Scott N. Peterson; INSTITUTE FOR GENOMIC RESEARCH ROCKVILLE MD
|
| Control of anthrax toxin and capsule synthesis, the two major virulence factors of Bacillus anthracis, has been associated with two regulatory genes, atxA and acpA, located on virulence plasmids pXO I and pXO2, respectively. We used DNA microarrays to determine which genes in the B. anthracis genome are controlled by atxA and/or acpA. The regulation of numerous genes present on the virulence plasmids was documented and both positive and negative ... |
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| Botulinum Toxin Type A Targets RhoB to Inhibit Lysophosphatidic Acid-Stimulated Actin Reorganization and Acetylcholine Release in PC12 Cells: A Possible Mechanism For Intervention |
16 NOV 2004 |
7 pages |
| Authors:
Hiroshi Ishida; Zhillin Liao; Prabhati Ray; WALTER REED ARMY INST OF RESEARCH WASHINGTON DC DIV OF EXPERIMENTAL THERAPEUTICS
|
| We showed that the G-protein activator lysophosphatidic acid (LPA) triggered actin reorganization followed by ACh release in nerve growth factor treated PC12 cells, and that BoNT/A blocked both events through degradation of RhoB by the proteasome. Overexpression of wild-type RhoB caused to overcome toxin s inhibitory effect on actin reorganization/exocytosis stimulated by LPA. A knockdown of the RhoB gene via targeted siRNA transfection resulted in total inhibition of both actin ... |
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| Quorum Sensing: A Transcriptional Regulatory System Involved in the Pathogenicity of Burkholderia mallei |
NOV 2004 |
9 pages |
| Authors:
Ricky L. Ulrich; David DeShazer; Harry B. Hines; Jeffrey A. Jeddeloh; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| Numerous gram-negative bacterial pathogens regulate virulence factor expression by using a cell density mechanism termed quorum sensing (QS). An in silico analysis of the Burkholderia mallei ATCC 23344 genome revealed that it encodes at least two luxI and four luxR homologues. Using mass spectrometry, we showed that wild-type B. mallei produces the signaling molecules N-octanoyl- homoserine lactone and N-decanoyl-homoserine lactone. To determine if QS is involved in the virulence of ... |
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| DNA Vaccines Against Anthrax |
OCT 2004 |
8 pages |
| Authors:
Darrell R. Galloway; Les Baillie; NAVAL MEDICAL RESEARCH CENTER SILVER SPRING MD
|
| DNA vaccination is vaccination at its simplest. Due to renewed interest in vaccination against anthrax and other biothreat agents, a genetic immunisation approach offers attractive possibilities for rapid, responsive vaccine development. DNA vaccination against anthrax is an active area of research showing promising results at present, which in the short-term and in the future could form the basis for new advances in multi-agent vaccine development. The anthrax model constitutes an ... |
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| Combinatorial Strategies and High Throughput Screening in Drug Discovery Targeted to Channel of Botulinum |
SEP 2004 |
17 pages |
| Authors:
Mauricio Montel; CALIFORNIA UNIV SAN DIEGO LA JOLLA
|
| This program examines innovative approaches and powerful new technologies to identify selective and potent agents directed to prevent or relieve the neuroparalytic toxic actions of botulinum toxin A (BoNTA)1. The focus is on the ion channel forming activity pf BoNTs as a validated target to screen for inhibitors of the translocation of the light chain into the cytosol and therefore to attenuate the BoNT neurotoxicity. The key of the program ... |
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| Needed Now: The "85% Quick Fix" in Bio-Defense |
SEP 2004 |
39 pages |
| Authors:
Jim A. Davis; Bruce W. Bennett; AIR UNIV MAXWELL AFB AL
|
| The search for the best solution for bio-defense is proving to be an obstacle to finding the more immediate good solution. In the day when Americans have grown used to fast food, instant access to the Internet, and minimal United States casualties during war, many have come to expect a silver bullet solution for almost any problem. The military, like the rest of America, is often in quest for the ... |
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| Expression of Bacillus anthracis Protective Antigen in Bacillus megaterium |
MAR 2004 |
|
| Authors:
B. J. Berger; K. E. Schwandt; C. L. Radford; DEFENCE RESEARCH AND DEVELOPMENT SUFFIELD (ALBERTA)
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| Bacillus anthracis protective antigen is the central component of the anthrax toxin complexes that facilitates entry of lethal factor and edema factor into host cells. Protective antigen is also the major immunogenic component present in the currently licensed anthrax vaccine. In order to produce full-length, soluble protective antigen, the gene has been cloned and expressed using Bacillus megaterium and a xylose-inducible heterologous expression system. After only 3.5 hours growth post-induction ... |
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| Structural Studies on Intact Clostridium Botulinum Neurotoxins Complexes with Inhibitors Leading to Drug Design |
FEB 2004 |
28 pages |
| Authors:
Subramanyam Swaminathan; BROOKHAVEN NATIONAL LAB UPTON NY
|
| In this second annual report we present our progress on three different areas. We are working on intact BoNT/B to identify small molecules that could be used to block the toxic activity. In this respect, we have discovered that two calcium ions are bound to BoNT/B and that at least one of them plays an important role in the translocation of the catalytic domain into the cytosol. We propose that ... |
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| Multiscale Modeling of Complex Physics: Fluids Solids and Optics |
2004 |
18 pages |
| Authors:
James Glimm; STATE UNIV OF NEW YORK AT STONY BROOK RESEARCH FOUNDATION
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| Algorithms, simulations and modeling for fluid mixing and complex flow were developed. Our front tracking algorithm was improved for its accuracy and conservation properties. Local mesh refinement was added. Simulations in agreement with experiment were obtained. New models of the fluid mixing process were derived, which were also compared to experimental data. |
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| Testimony: Statement of Shelton Young, Director, Readiness and Logistics Support Directorate, Office of the Inspector General, Department of Defense, before the Subcommittee on National Security, Emerging Threats and International Relations, House Committ |
07 OCT 2003 |
9 pages |
| Authors:
INSPECTOR GENERAL DEPT OF DEFENSE ARLINGTON VA
|
| This testimony presents the results of an Interagency Summary Report on Security Controls Over Biological Agents. The August 27, 2003, report consolidates issues identified in 27 reports published by the Offices of the Inspectors General of the Departments of Agriculture, Army, Defense, Energy, Health and Human Services, and Veterans Affairs. The summary report identified nine systemic problems: physical security, personnel access controls, inventory accountability and controls, contingency plans, registration with ... |
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| Process Research and Development of Antibodies as Countermeasures for C. botulinum |
MAR 2003 |
30 pages |
| Authors:
Michael M. Meagher; NEBRASKA UNIV LINCOLN
|
| This report describes the ongoing project to fill out shell space on the third floor and basement of Othmer Hall, the new home for the University of Nebraska-Lincoln Biological Process Development Facility. At the detailed design is completed and construction is nearly half completed with the expected completion date being December 2003. The third floor will house all of the process research capabilities, i.e. molecular biology, fermentation, cell culture, analytical ... |
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| X-Ray Crystallography of Botulinum Neurotoxin Type E and Its Functional Subunits |
DEC 2002 |
12 pages |
| Authors:
William Furey; Martin Sax; S. Swaminathan; DEPARTMENT OF VETERANS AFFAIRS PITTSBURGH PA
|
| Botulinum Neurotoxin type E was crystallized and an electron density map was analyzed at 3 alpha resolution. A new crystal form was also obtained, and may be helpful in improving the phasing. Co-crystallization experiments with gangliosides have also been undertaken. The structure of a complex between tetanus toxin C-fragment and doxorubicin has been determined, and drug binding occurs at the ganglioside binding site. Structure determination of a complex between tetanus ... |
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| Characterization of Bc1-2, Bc1-xL, and Bax Pore Formation and Their Role in Apoptosis Regulation |
28 AUG 2002 |
33 pages |
| Authors:
Frank Stenner-Liewen; Sharon Schendel; John C. Reed; BURNHAM INST LA JOLLA CA
|
| Bcl-2-family proteins are central regulators of apoptosis and their expression often becomes deregulated in breast cancers. The biochemical mechanisms by which Bcl-2 family proteins control cell life and death decisions are unknown. Recent evidence that certain Bcl-2 family proteins bear structural similarity to the pore-forming domains of bacterial toxin proteins suggest a function for these apoptosis regulators as ion-channels. Using eletrophysiological techniques, we demonstrated that the cytoprotective protein Bcl-2 and ... |
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| Recombinant Antibodies for Biological Warfare Detection |
13 AUG 2002 |
3 pages |
| Authors:
Amanda Dim-Schultz; Joan S. Gebhardt; NAVAL MEDICAL RESEARCH CENTER BETHESDAMD
|
| Recombinant antibodies to biological warfare threat agents including F. tularensis, Y. pestis, Brucella spp., V. cholerae O1 and O139, ricin, staphylococcal enterotoxins B and C, botulinum toxins A, B, and E and cholera toxin have been developed through the use of phage display technology. Both recombinant scFvs and Fabs have been produced. Substitutions of currently available monoclonal antibodies with these recombinant antibodies in immunological based detection systems have been successful. ... |
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| Combinatorial Strategies and Hypothesis-Based Drug Design in Drug Discovery Targeted to the Protease and Channel Activities of Botulinum Toxin A |
JAN 2002 |
83 pages |
| Authors:
Mauricio Montal; CALIFORNIA UNIV SAN DIEGO LA JOLLA
|
| The ultimate goal of this program is to understand in detail the mechanisms by which botulinum neurotoxins (BoNT) abrogate neurotransmitter release. One facet is focused on the channel-forming domain of the heavy chain (HC). The aim is to identify open channel blockers as a single class of drugs that would be effective against all BoNT isoforms. A major objective is to seek direct demonstration that the HC acts as the ... |
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| Gene Delivery for Metastatic Prostate Cancer Cells |
OCT 2001 |
30 pages |
| Authors:
Shen Pang; CALIFORNIA UNIV LOS ANGELES
|
| We have constructed a diphtheria toxin A (DTA) gene expression vector driven by the PSAR-PSAR promoter. The prostate-specific expression of the DTA gene specifically destroyed prostate cancer cell line LNCaP in vitro. Enhanced by the bystander effect, the specific expression of the DTA gene causes significant cell death in prostate cancer cell cultures, with very low background cell eradication in control cell lines. The highly specific and efficient cytopathicity of ... |
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| Protection Against Anthrax Lethal Toxin Challenge by Genetic Immunization with a Plasmid Encoding the Lethal Factor Protein |
Jul-2001 |
8 pages |
| Authors:
Alfred Mateczun; Brian M Price; Adriane L Liner; Sukjoon Park; Stephen H Leppla; Darrell R Galloway; OHIO STATE UNIV COLUMBUS DEPT OF MICROBIOLOGY
|
| The ability of genetic vaccination to protect against a lethal challenge of anthrax toxin was evaluated. BALB/c mice were immunized via gene gun inoculation with eucaryotic expression vector plasniids encoding either a fragnient of the protective antigen (PA) or a fragnient of lethal factor (LF). Plasniid pCLF4 contains the N-terniinal region (aniino acids [aa] 10 to 254) of Baclllus anthracis LF cloned into the pCI expression plasniid. Plasniid pCPA contains ... |
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| Polarized Light Scattering as a Rapid and Sensitive Assay for Metal Toxicity to Bacteria |
JUL 2001 |
12 pages |
| Authors:
Z. Z. Li; J. Czege; B. V. Bronk; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD
|
| A new method that utilizes the scattering of polarized light from a suspension of bacteria to assay the effect of toxins is evaluated. The method compares the time dependence of changes in an angular scattering pattern obtained from a suspension of Escherichia coli bacteria with no toxin exposure to the corresponding, but reduced, changes that occur when there is exposure to a small concentration of certain toxicants. The changes are ... |
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| Mechanisms of Altered Control of Proliferation by Cyclic Amp/Protein Kinase A During Mammary Tumor Progression |
JUN 2001 |
29 pages |
| Authors:
Walter Imagawa; KANSAS CITY UNIV MO
|
| Changes in signal transduction networks occur during mammary tumor progression that affect the proliferative response of the cells to exogenous factors. These alterations may be related to the loss of hormonal regulation of breast cancer which has a major impact on prognosis and therapy of breast cancer. The goal of this research was to identity the mechanisms underlying the difference in the proliferative response to 3'-5' cyclic adenosine monophosphate (cAMP) ... |
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| Elucidation of Pertussis Toxin-Sensitive Migration Signaling in Human Breast Cancer Cells |
MAY 2001 |
15 pages |
| Authors:
William L. Rust; NEVADA UNIV LAS VEGAS
|
| The long range goal of this laboratory is to identify integrin- associated signaling events that contribute to the constitutive migration of human breast cancer cells on the laminin extracellular matrix proteins. This project has shown that the heterotrimeric G-protein G alpha i3 may link integrin activation and migration of MCF-10A cells via a cAMP signaling pathway. The focus of the remaining work on this project is to identify how each ... |
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| Development of Targeted Therapeutic Agents for Botulism |
FEB 2001 |
|
| Authors:
Oliver J. Dolly; Patrick G. Foran; Nadiem Mohammed; LONDON UNIV (UNITED KINGDOM)
|
| The neuroparalytic symptoms of human botulism, resulting from inhibition of acetylcholine release by type A botulinum neurotoxin (BoNTIA), are life threatening and last for up to 2 years. Thus, development of a fast and effective treatment for the forces exposed to this threat warrants the highest priority. Initial experiments focussed on developing an avid inhibitor of the BoNTIA protease that cleaves SNAP-25 - a SNARE essential for transmitter release. The ... |
|
| USAMRIID's Medical Management of Biological Casualties Handbook, Fourth Edition |
FEB 2001 |
136 pages |
| Authors:
Mark Kortepeter; George Christopher; Ted Cieslak; Randall Culpepper; Robert Darling; ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
|
| Medical defense against biological warfare or terrorism is an area of study unfamiliar to most military and civilian health care providers during peacetime. In the aftermath of Operations Desert Shield/Desert Storm, it became obvious that the threat of biological attacks against U.S. soldiers was real. Increased incidents and threats of domestic terrorism (e.g., New York City World Trade Center bombing), as well as numerous anthrax hoaxes around the country have ... |
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| Phaseolotoxin Biosynthesis: Molecular Mechanisms of Thermoregulation |
20 JAN 2001 |
18 pages |
| Authors:
Suresh S. Patil; HAWAII UNIV HONOLULU
|
| The production phaseolotoxin (PT) and PT-resistant ornithine carbamoyl-transferase (encoded by argK of Pseudomonas syringae pv. phaseolicola are thermoregulated; both are produced at 1 18 C, but neither is produced at 30 C. At 30 C (but not at 18 C) the bacterium produces a DNA-binding protein that binds (in vitro) to sites in the upstream region of argK. Our hypothesis is that this protein is a transcription factor (TP) which ... |
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| A Medical Research and Evaluation Facility (MREF) and Studies Supporting the Medical Chemical Defense Program. Protection of Guinea Pigs by Passive Immunization With Human Botulinum Immune Globulin Obtained Post Primary Series and Post Six-Month Booster I |
OCT 2000 |
383 pages |
| Authors:
Carl T. Olson; Robert E. Hunt; Rebekah A. Starner; Michelle L. Clagett; Nancy A. Niemuth; BATTELLE MEMORIAL INST COLUMBUS OH
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| Studies (MREF Tasks 95-39, 96-45, 97-51, and 97-52) have previously demonstrated a high degree of correlation between circulating neutralizing antibody titers and protection against high doses of all botulinum toxin serotypes in the guinea pig model. Neutralizing antibodies have been proposed to the FDA as a serological marker for human protection since efficacy for This vaccine cannot be directly demonstrated in traditional human clinical trials. Task 97-53 establishes the level ... |
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| Fermentation, Recovery, and Purification of the HC Fragments of the Botulinum Neurotoxin from Pichia Pastoris |
JUN 2000 |
78 pages |
| Authors:
Michael M. Meagher; NEBRASKA UNIV LINCOLN
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| The report documents the research and development activities on BoNTC Hc, BoNTF Hc, and BoNTE Hc. BoNTC Hc research focused on characterizing the capture of the BoNTC Hc from P. pastoris lysate and the interference of DNA-type material on the binding of BoNTC Hc to a anion exchange column. BoNTF Hc process development was concerned with confirmation of a process developed by USARMIID transferred to Covance and tested ... |
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| Biodegradable Vaccine Microspheres for System and Mucosal Immunization Against Equine Encephalitis |
APR 2000 |
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| Authors:
Suzanne M. Michalek; ALABAMA UNIV IN BIRMINGHAM
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| The goals of the proposed studies are to show that pulse-release microsphere vaccines consisting of antigen and adjuvant is an effective and efficacious method for inducing protective immune responses, that the approach will require less antigen, fewer immunizations and convenient, safe methods for delivery, and that a single multivalent vaccine will be effective in inducing a protective response against the EE viruses. The specific aims ... |
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| X-Ray Crystallography of Botulinum Neurotoxins |
MAR 2000 |
10 pages |
| Authors:
Martin Sax; W. Furey; S. Swaminathan; VETERANS ADMINISTRATION MEDICAL CENTER PITTSBURGH PA
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| Botulinum Neurotoxin type E was purchased, and the protein was crystallized. The best diffracting crystals were obtained when the toxin was crystallized in the presence of a peptide from SNAP-25. An isomorphous tungsten derivative has been prepared and data have been collected to 3.2A resolution. Three heavy atom sites were identified and used in phasing by the single isomorphous replacement with anomalous scattering method. The ... |
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| Combinatorial Strategies and Hypothesis-Based Drug Design in Drug Discovery Targeted to the Protease and Channel Activities of Botulinum Toxin A |
FEB 2000 |
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| Authors:
Mauricio Montal; CALIFORNIA UNIV SAN DIEGO LA JOLLA
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| The ultimate goal of this program is to understand in detail the mechanisms by which botulinum neurotoxins (BoNT) abrogate neurotransmitter release. One facet is focused on the channel-forming domain of the heavy chain (HC). The aim is to identify open channel blockers as a single class of drugs that would be effective against all BoNT isoforms. A major objective is to seek direct demonstration that the HC acts as the ... |
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Reports by Keyword(s)
BACTERIAL TOXINS
