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EXPLORE RESEARCH AND TECHNOLOGY INNOVATIONS IN BIODEFENSE
Knowledge and understanding gained through advances in biotechnology can be leveraged in biodefense research to protect humans and animals against intentional use of pathogens. This conference will present the latest research and technologies to improve specificity, sensitivity, and speed for detecting, identifying, and characterizing pathogens. It will also address efforts to create novel vaccines and therapeutics, to characterize host cell response and stimulate innate immunity, and to develop effective decontamination methods.
SCIENTIFIC ADVISORS AND CHAIRS
Dr. Steven Kornguth, University of Texas at Austin
Dr. Arthur M. Krieg, Coley Pharmaceutical Group
Dr. James D. Marks, University of California, San Francisco
Dr. Lloyd J. Whitman, U.S. Naval Research LaboratoryOVERVIEW
Dr. J. Patrick Fitch, Lawrence Livermore National Laboratory
Dr. Steven Kornguth, University of Texas at Austin
Dr. Gerald McDonnell, STERIS Corporation
Dr. Willem (Pim) Stemmer, Maxygen, Inc.
Colonel John Wilcox, U.S. Department of DefenseDETECTING AND CHARACTERIZING BIOLOGICAL AGENTS
Dr. Ronald R. Breaker, Yale University
Dr. Yi Cui, Harvard University
Dr. Alan Louie, TIAX LLC
Dr. Valery A. Petrenko, Auburn University
Dr. Linda Powers, Utah State University
Dr. Lloyd J. Whitman, U.S. Naval Research LaboratoryCHARACTERIZING HOST CELL RESPONSE AND STIMULATING INNATE IMMUNITY
Dr. Emilio Garcia, Lawrence Livermore National Research Laboratory
Dr. C. Fred Battrell, Micronics, Inc.
Dr. Dennis Klinman, U.S. Food and Drug Administration
Dr. Arthur M. Krieg, Coley Pharmaceutical Group
Dr. Kurt Petersen, Cepheid
Dr. Anders Sjöstedt, Umeå UniversityDEVELOPING VACCINES AND THERAPEUTICS
Dr. Karl Y. Hostetler, San Diego VA Healthcare System and University of California, San Diego
Dr. David M. Kranz, University of Illinois
Dr. James D. Marks, University of California, San Francisco
Dr. Davin M. Potts, United Devices, Inc.
Dr. Kathryn Sykes, MacroGenics, Inc.
SUNDAY, NOVEMBER 3
5:00-7:00pm Early Registration and Poster Set-up
MONDAY, NOVEMBER 4
7:30am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast
Overview
8:30 Chairperson's Opening Remarks
Dr. Steven Kornguth, Director, Biological and Chemical Defense,
Institute for Advanced Technology, University of Texas at Austin
8:40 The Advanced Concept Technology Demonstration (ACTD)
Program
Colonel John Wilcox, U.S. Department of Defense
An overview of the Advanced Systems & Concepts Demonstration (ACTD)
program will be presented. An ACTD is an advanced technology concept, which
exploits mature and maturing technologies to solve important military
problems. ACTDs are taken to the Commanders in Chief (CINCs), services, and
warfighters to rapidly transition new capabilities from the developer to the
user.
9:10 Commercial Development of Biosensors: The
Business of Science
Dr. Alan Louie, Senior Manager, Applied Biotechnology Programs,TIAX LLC
Owning a novel technology capable of rapid, specific, and real-time
detection of biological warfare agent pathogens is only one of the key
elements necessary to providing solutions to the terrorist threat. As concerns
over the potential for an attack expands beyond the military to first
responders and the general public, additional commercial constraints become
critical to both meeting the needs of the public and success as a business. In
this presentation, we will consider both the technical and market parameters
that must be considered to successfully respond to the threat and hopefully
provide insights that could reduce the overall time to fieldable solutions and
commercial reality.
9:40 Biological Countermeasures Program at the
University of Texas
Dr. Steven Kornguth
Developments in the continental U.S. (anthrax letters disseminated October
2001 CONUS) have alerted the defense community to the threat of biological and
chemical agents on civilian and military populations. The Countermeasures
Program serves as the comprehensive model to provide real solutions to meet
national needs in preventing and mitigating biological and chemical terrorist
threats. The program addresses all of the following areas-agent detection,
identification and treatment, and early disease detection via electronic
biosurveillance systems-and interacts directly with Civil Support Teams of the
National Guard and state Departments of Health. The University of Texas at
Austin Countermeasures Program has made significant progress in sensor
(high-affinity antibodies, polynucleotide probes and aptamers for the sensors
and platforms, MEMS, electronic tongue, hand-held redox system, for these
sensor systems) therapeutic responses to biothreats and communication
(including presentation and iconography) technology.
10:10 Poster Viewing, Refreshment Break
10:45 Civilian Biodefense: Systems That Can Be
Incorporated into Special Events and Public Health Responses
Dr. J. Patrick Fitch, Program Leader, Chemical and Biological National
Security, Lawrence Livermore National Laboratory
In the summer of 2000, the National Nuclear Security Administration (NNSA)
Chemical and Biological National Security Program (CBNP) initiated a project
at Lawrence Livermore (LLNL) and Los Alamos (LANL) National Laboratories to
create a Biological Aerosol Sentry Information System (BASIS) that was to be
deployed for biodefense at the 2002 Winter Olympic Games in Salt Lake City,
Utah. The system was designed to meet needs articulated by local, state, and
federal public health experts. The particular motivation was "detect to
treat." This allowed trade-offs for sample collection and processing that
increased the probability of detection within budgetary constraints.
Environmental samples were collected on dry filters and brought to a central
laboratory where the filters were segmented and biochemically processed to
release nucleic acids from the bacteria and viruses on the filter segment, and
then PCR was used to determine if specific pathogens were present. Some of
LLNL's responsibilities for BASIS at the Olympics were to implement a field
laboratory for processing environmental samples and establishing validated
assays for the laboratory. This system was designed to detect a number of
pathogens on the Center for Disease Control and Prevention (CDC) disease and
agent lists and often required development of nucleic acid signatures. The
BASIS deployment at the Olympic Games will be presented as well as the nucleic
acid signature pipeline we implemented with CDC collaborators. Highly
multiplexed emerging technologies for building monitoring and medical triage
will also be presented.
11:15 Room and Enclosed-Area Decontamination with
Vaporized Hydrogen Peroxide
Dr. Gerald McDonnell, Director, Research and Development, STERIS
Corporation
Vaporized Hydrogen Peroxide (VHP) is widely used for decontaminating
critical environment rooms and enclosed areas for a variety of scientific,
research, and pharmaceutical applications. VHP biodecontamination is a unique
dry, low-temperature process, which demonstrates broad-spectrum antimicrobial
efficacy and material compatibility. Further, in comparison to other
fumigation methods, VHP has the best safety and environmental profile. The VHP
process, control systems, and advantages/disadvantages will be discussed. The
VHP 1000 series are used as mobile or modular systems to generate, deliver,
control, and remove VHP for an enclosed environment in an automated process. A
major limitation is the area size that one unit can routinely decontaminate
(generally up to 8,000 ft.3). In this report, a high-capacity VHP
decontamination system was designed and tested for its ability to
decontaminate larger areas. Decontamination cycles were conducted in two areas
(up to 130,000 ft.3) and the efficacy of the process monitored with chemical
and biological indicators. The system was successful in decontaminating both
areas for a minimum 6 log reduction of Bacillus stearothermophilus and/or
Bacillus subtilis var. globigii spores over an overall process time of four to
eight hours. No material effects were observed, including exposure to
sensitive room fixtures like paintwork, furniture, artwork, and computers. The
large-capacity VHP system was practical for the bioremediation or routine
decontamination of large enclosed areas.
11:45 Development of Vaccines and Pharmaceuticals by
Molecular Breeding
Dr. Willem (Pim) Stemmer, Vice President of Research, Maxygen, Inc.
We have used molecular breeding to rapidly develop powerful vaccines and
protein pharmaceuticals for biodefense applications. We take multiple related
genes from natural diversity and recombine them homologously, creating a
library of chimeric genes. Because the diversity that is used is functional,
these chimeras tend to be very high quality such that we can screen them
directly in complex assays (i.e., for immunogenicity, one mouse per clone).
This approach is rapid and reliably yields dramatic improvements in activity,
which we will demonstrate with examples including Dengue, HBV, HIV, and IL-12.
12:15 Lunch (on your own)
DETECTING AND CHARACTERIZING
BIOLOGICAL AGENTS
1:45 Chairperson's Remarks
Dr. Lloyd J. Whitman, Head, Surface Nanoscience and Sensor Technology
Section, U.S. Naval Research Laboratory
1:50 Engineering Allosteric RNAs for Biosensor
Applications
Dr. Ronald R. Breaker, Department of Molecular, Cellular and
Developmental Biology, Yale University
RNA and DNA molecules can be engineered to perform as precision allosteric
enzymes, or "molecular switches", that are modulated by specific
effectors. These designer sensor elements have numerous applications ranging
from the construction of biosensors to the development of novel genetic
switches. We have embarked on a program to establish effective molecular
engineering strategies for switch construction, and to establish the
fundamental principles that dictate the performance characteristics of these
molecules. In pursuing our objectives, we have created a variety of RNA
molecular switches that are modulated by specific target molecules that range
from nucleotides and oligonucleotides to drug compounds, metabolites and
toxins. In addition, we have begun to explore the use of immobilized RNA
switches for the construction of advanced biosensor arrays. Our findings
suggest that RNA and DNA have a significant untapped potential for functioning
as precision molecular switches in both industrial and natural settings.
2:20 Phage as a Biospecific Probe for Detection of
Biological Threat Agents
Dr. Valery A. Petrenko, Professor, College of Veterinary Medicine,
Auburn University
Filamentous phage can serve as a scaffold, able to form on its surface an
indefinite number of potential antigen-binding sites by displaying random
peptides fused to major coat protein pVIII. We constructed libraries with
random peptides fused to pVIII in various formats (landscape libraries) and
selected phages that act as substitute antibodies specific for a panel of test
antigens and threat agents. We demonstrated that page-derived probes bind
biological agents and, as a part of analytical platforms, generate a
detectable signal. Phages are prospective probes in a new generation of
sensors for food safety control and environmental in-a-real-time monitoring.
As elements of field-use detectors, they are superior to monoclonal
antibodies, since they are inexpensive, highly specific, and strong binders,
resistant to unfavorable environmental conditions.
2:50 Detection and Identification of Biological
Threat Agents Using a Unique Combination of Leading-Edge Technologies
Dr. Linda Powers, Director, National Center for the Design of Molecular
Function; Professor of Electrical and Computer Engineering, Professor of
Biological Engineering, and Adjunct Professor of Physics; Utah State
University
Using a unique combination of leading-edge technologies, a hand-held prototype
detector has been developed that is capable of determining the presence of no
microbial agents and viability of microbial cells. It requires no reagents or
sample contact and provides this information in essentially real time
(seconds). Together with microbe capture technology on a "chip" that
is based on the molecular recognition and pathogenesis, specific pathogens/exotoxins/viruses
and functionally related groups of pathogens are identified through
statistically sampling of the environment. This system is sensitive enough to
detect very low levels (~20 cells/cm2 on surfaces or ~100 cells/50 mL
solution) of infectious bacteria in minutes.
3:20 Poster Viewing, Refreshment Break
4:00 Micromagnetic Labeling and Detection of
Biowarfare Agents
Dr. Lloyd J. Whitman
The Bead ARray Counter (BARC) biosensor system uniquely combines a DNA
microarray, magnetic microbeads, giant magnetoresistive (GMR) magnetic field
sensors, and microfluidics to detect and identify biological molecules. Our
initial focus is on detection of biological warfare agents. The core of the
current sensor is a microchip containing an array of 64 GMR magnetic field
sensors. Distinct single-stranded DNA capture probes are immobilized above
each sensor, as in a conventional DNA microarray. Complementary DNA in a
sample is allowed to hybridize on the chip and is then labeled with magnetic
microbeads. A GMR sensor measures the number of magnetic reporters in each
element of the DNA array. The assay is performed in a flow cell using a hybrid
macro-microfluidics system. The overall system sensitivity is a convolution of
the chemical and instrumental sensitivities. The chemical sensitivity is
determined by the effectiveness of the hybridization and labeling assay, and
the instrumental sensitivity by the micromagnetics of the bead-sensor
interaction. We have been able to achieve an optimal chemical sensitivity of
0.1 fM, and our current sensors can detect as few as ten 2.8 µm-diameter
Dynabeads (covering only 0.2% of a sensor s area). We have demonstrated an
overall system sensitivity per sensor of 10 fM using only 30 µl of sample, 15
min. of room temperature hybridization, and a total assay time of about 30
minutes. We are now exploring the use of peptide nucleic acid (PNA) capture
probes to enhance the chemical sensitivity, adapting the system for use with
immunoassays, and working to develop high-magnetization microbeads to increase
the instrumental sensitivity.
4:30 Highly Sensitive, Real-Time Detection of
Biological and Chemical Species Using Integrated Nanowire Sensors
Dr. Yi Cui, Graduate Student, Harvard
University
Summary unavailable at time of printing.
5:00 Panel Discussion
5:30 Reception
6:30 Close of Day One
TUESDAY, NOVEMBER 5
8:00am Poster Viewing and Light Continental Breakfast
CHARACTERIZING HOST CELL RESPONSE AND STIMULATING INNATE IMMUNITY
8:30 Chairperson's Remarks
Dr. Arthur M. Krieg, Chief Scientific Officer, Coley Pharmaceutical
Group
8:35 Characterizing Host Cell Response to the
Prototypic Intracellular Infections: Tularemia and Plague
Dr. Anders Sjöstedt, Defense Research Establishment; and Professor,
Department of Clinical Microbiology, Division of Clinical Bacteriology, Umeå
University
Several microorganisms considered as potential biological warfare agents
are capable of surviving intracellularly. Treating such intracellular
infections poses a great challenge to the medical community since these
infections may be lethal and their intracellular habitat renders these
microbes relatively inaccessible. Our ongoing project aims to characterize
host cell response to the prototypic intracellular infections tularemia and
plague. Characterization of the host cell responses is performed by
large-scale cDNA microarray analysis. These studies will elucidate
interactions and identify genes regulated by eukaryotic cells in response to
intracellular infections.
9:05 Defending against Bioterror by Activation of
Innate Immunity with CpG DNA
Dr. Arthur M. Krieg
To detect invading infectious organisms, the innate immune system uses
receptors called Toll-like receptors (TLRs), which detect molecular patterns
characteristic of microbes. TLR9 detects unmethylated CpG dinucleotides, which
are common in bacterial DNA but not common in vertebrate DNA. Synthetic CpG
DNA molecules bind TLR9 and activate innate immune defenses that can protect
rodents against viral, bacterial, and parasitic pathogens. One CpG molecule,
7909, has entered human clinical trials as an enhancer of vaccination, and for
cancer and allergy immunotherapy, and may have applications in bioterror
defense.
9:35 Induction of Protective Immune Responses by CpG
Oligodeoxynucleotides
Dr. Dennis Klinman, Section Chief, Center for Biologics Evaluation and
Research, U.S. Food and Drug Administration
The ability of synthetic oligodeoxynucleotides (ODN) containing
immunostimulatory "CpG" motifs to trigger an innate immune response
capable of improving host survival following bacterial, viral, and parasitic
infection was investigated. In animal models, CpG ODN provided complete or
partial protection from infection by a variety of pathogens, including
Listeria monocytogenes, Francisella tularensis, leishmania, Ebola, and
anthrax.
10:05 Poster Viewing, Refreshment Break
10:35 Handheld Biological Detector Using a Disposable
Microfluidic Cartridge
Dr. Fred Battrell, Ph.D., Vice president, Operations, Micronics, Inc.
This talk will present lab-on-a-chip tools/integrated systems for cost
effective, portable systems with disposable lab cards for applications to meet
the needs of early-warning systems. We will demonstrate designs and
experimental results for a number of microfluidic lab cards developed for
applications in biodefense. Micronics' H-Filter® and T-Sensor® lab cards are
microfluidic devices based on Laminar Fluid Diffusion Interfaces (LFDIs).
LFDIs are generated when two or more streams flow in parallel in a single
microfluidic structure. These structures can be used for diffusion-based
separation and detection applications. The method is broadly applicable to
on-card sampling and detecting raw samples, including whole blood, urine and
sputum for determination of exposure to bacterial and viral biological warfare
agents. We will also present proposed instrumentation for a handheld air
sampling detector that uses such microfluidic lab cards in combination with
air sampling solutions that are currently being introduced to the market.
11:05 Profiling the Transcriptional Response of Human
Cells during Bacterial Infection: Can We Develop Early-Warning Approaches for
Biothreat Agents?
Dr. Emilio Garcia, Team Leader, Microbial Studies, Biology and
Biotechnology Research Program, Lawrence Livermore National Laboratory
We are using DNA microarray chips (Affymetrix) to follow the temporal
events triggered immediately after Yersinia pestis infection. Bacterial
pathogens have evolved in a number of strategies to defeat the immunological
response launched by their target host. Whereas the Yersinia group possesses a
type III secretion-based apparatus to inject a number of cytotoxins and
effectors to overcome the host cell without necessarily invading the host,
other organisms such as Brucella and Francisella have developed mechanisms to
actually survive in the intracellular milieu of the host. Studies using Y.
pestis to infect dendritic cells show a pattern of gene expression that can be
easily distinguished from that of similar infection from E. coli, for example.
In particular, early- and late-response sets of genes can be clearly
discerned. Similar studies are being performed using bacterial pathogens with
a different route of infection and/or mechanism of pathogenicity. This type of
work may enable the development of early warning methods useful in
bioterrorism.
11:35 Rapid, Reliable, Confident PCR for
Bio-Detection
Dr. Kurt Petersen, President, Chief Operations Officer and Director,
Cepheid
Some controversy has recently surrounded the use of PCR for detection and
identification of bio-threat agents. Disadvantages that have been cited are 1)
sensitivity to inhibitors, 2) operator errors, 3) unverified, unvalidated DNA
target sequences, 4) unstable reagents, and 5) overall complexity of the PCR
procedure. These problems have resulted in false positives and false negatives
when PCR is used in a a casual and thoughtless manner. This presentation will
show how all these issues can be addressed and solved through a careful and
thorough system design and implementation. Application of meticulous sample
preparation methodologies, internal reaction controls, multiple target
sequences before calling a positive, lyophilized, single-dose reagents, and
complete protocol automation to eliminate operator errors is now allowing
rapid PCR to be used reliably and confidently for detection and identification
of bio-threat organisms.
12:05 Panel Discussion
Opportunity for Audience Members to Ask the Session Speakers Questions
12:30 Lunch
Developing Vaccines and Therapeutics
1:45 Chairperson's Remarks
Dr. James D. Marks, Professor of Anesthesia, Pharmaceutical Chemistry
and Comprehensive Cancer Center, University of California, San Francisco
1:50 Comprehensive Vaccine Discovery for Public
Health Preparedness
Dr. Kathryn Sykes, Senior Scientist and Scientific Director,
MacroGenics, Inc.
Eliance uses advanced expression library technologies and genetic
immunization to comprehensively screen pathogen genomes for protective
sequences. This proprietary process identifies, from any genome, effective
genes and encoded proteins for vaccine development. We consider the resulting
products and information necessary preparation for the threats of bioterrorism
and essential to deter development of genetically engineered agents. In
addition to identifying components for future vaccines, we anticipate that
these protective antigens will also reveal immune markers of protection and
thereby facilitate clinical validation of these and other vaccines. Examples
of defense vaccines under research and development at Eliance illustrate the
utility of this approach.
2:20 The Virtual Screening Project: Collaborators on
the Anthrax Research Project
Dr. Davin M. Potts, Senior Scientist, Bioinformatics, and Senior
Applications Developer, United Devices, Inc.
The ability to aggregate and harness idle computer resources in a
pharmaceutical corporation, on an academic campus, or on the Internet offers a
potentially massive computing resource to life sciences researchers. Given the
algorithms used, a large number of classes of applications in bioinformatics,
cheminformatics, and genomics lend themselves well to this kind of distributed
computing on a desktop grid. With the realization of the combined compute
power from thousands to a million or more PCs comes a new set of challenges
for researchers. Should we continue to perform the same kinds of computations
as in the past only on a much larger scale, or are there new ways to use
existing applications with edge distributed computing to yield deeper insight
into our results? Are there computational methodologies, which were dismissed
in the past as too expensive, now computationally feasible? We will examine
these challenges and discuss several specific examples, including the much
publicized screen-saver projects initiated by the University of Oxford
(anthrax) and the National Foundation for Cancer Research.
2:50 Engineering Soluble Receptors to Neutralize
Toxin Activity
Dr. David M. Kranz, Department of Biochemistry, University of Illinois,
Urbana-Champaign
Toxins typically bind to a cell surface receptor that mediates the uptake
of the molecule or that stimulates detrimental cell activation. Massive T cell
activation accounts for the lethal activity of a class of toxins known as
superantigens, that include 21 known enterotoxins from Staphylococcus
aureus and Streptococcus pyrogenes. These toxins bind to and bridge
two different cell surface molecules on different cells, a class II major
histocompatibility complex product and a T cell receptor. Despite the
relatively low binding affinity of these events (SAg:MHC and SAg:TCR),
extensive T cell activation can occur leading to release of inflammatory
mediators of shock, such as TNF and IL-1. In order to develop treatments for
these agents, we have engineered soluble forms of the T cell receptor. The
principles and strategies we have used for engineering high-affinity soluble
receptors will be discussed, along with the development of antagonists for two
enterotoxins, Staphylococcal enterotoxins B and C3.
3:20 Poster Viewing, Refreshment Break
3:45 Design and Development of Drugs for Smallpox
Dr. Karl Y. Hostetler, San Diego VA Healthcare System; and Professor of
Medicine, University of California, San Diego
Orally active ether lipid analogs of cidofovir have been shown to be
highly active and selective against smallpox, cowpox, monkeypox and other
viruses in cell culture assays. In collaboration with Dr. John Huggins at
USAMRIID and Dr. Earl Kern at the University of Alabama, Birmingham, these
drugs, administered orally, have been shown to prevent death from cowpox
infection in a rodent disease model.
4:15 Deciphering the Immune Response: Potent
Neurotoxin Neutralization by Oligoclonal Antibody
Dr. James D. Marks
The Botulinum neurotoxins (BoNTs) cause the paralytic human disease
botulism and are also one of the highest-risk threat agents for bioterrorism.
We have utilized immune phage antibody libraries constructed from humans,
mice, and mice transgenic for the human Ig locus to dissect the immune
response to toxin and to identify the requirements for potent toxin
neutralization. While no single antibody potently neutralized toxin in vivo,
combining two to three antibodies (oligoclonal antibody) led to extremely
potent toxin neutralization. Potency results from a large increase in the
functional binding constant of the oligoclonal antibody, as well as increased
blockade of the receptor-binding surface. This effect is likely general and
applicable to achieve potent neutralization of many toxins, pathogens, or
soluble mediators. The specific antibodies described can be used for treatment
and prevention of botulism resulting from natural exposure or bioterrorism.
4:45 Panel Discussion
Opportunity for Audience Members to Ask the Session Speakers Questions
5:15 Close of Conference
Hotel Information
Hilton McLean Tysons Corner
7920 Jones Branch Drive
McLean, VA 22102
T: 703-847-5000
F: 703-761-5100
Room Rate: $199 S/D
Cut-off Date: October 14, 2002
Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.
Travel Information
Special Zone and Discount Fares have been established for this conference
with United Airlines. Please call United Airlines Meeting Reservation Desk at
800-521-4041 and reference ID #579YS.
Call for Sponsors and Exhibitors
This is an outstanding opportunity to network with scientists in biodefense
from the biotechnology and pharmaceutical industries, and government and
academia. Cambridge Healthtech Institute offers an array of sponsorship packages
for you to reach this select audience. Make a lasting impression as a thought
leader in biodefense by taking advantage of these marketing tools.
For additional information, please contact Angela Parsons at 781-972-5467 or email at her at aparsons@healthtech.com.
Call for Posters
Cambridge Healthtech Institute encourages attendees to gain further exposure
by presenting their work in the poster sessions. Please fill out the
registration form, with the poster title and primary author. To ensure inclusion
in the conference binder, a one-page summary must be submitted and registration
must be paid in full by October 4, 2002. Click
here for poster instructions
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