Progress 12/10/04 to 11/19/09
Outputs
Progress Report Objectives (from AD-416) Objective 1: Discover and develop next generation topical skin repellents, spatial repellents, contact irritants, and toxicants against mosquitoes and other arthropod disease vectors. Research toward this objective will primarily involve a consortium of military, government, academic, and private industry research groups using high throughput bioassays to test model compounds selected via computational chemistry from the large chemical library maintained by the BASF Corporation. Objective 2: Develop new technology for preparation of fabrics having insect controlling and/or repelling properties. Repellent compounds will be covalently bonded to fabric polymers, and the resulting polymers will be tested to determine if repellent activity against mosquitoes is retained; if these derivatized polymers are repellent, then research will continue to optimize conditions required to produce insect repellent fabrics. Objective 3: Identify the mechanisms underlying the activity of key mosquito repellents and attractants, and develop ways to exploit the mechanisms for commercial use. This objective will focus on state-of-the- art application of odorant binding protein (OBP) research by covalently bonding cloned mosquito OBPs to HPLC columns for use in screening natural product and synthetic chemical libraries for binding activity. Bound compounds will be identified and tested in conventional behavioral bioassays for activity against mosquitoes. Also, the mechanisms of action for selected compounds will be investigated electrophysiologically, including single cell recording experimentation to pinpoint the sites of receptors involved in the perception of bioactive compounds. Approach (from AD-416) Discover and develop next generation topical skin repellents, spatial repellents, contact irritants, and toxicants against mosquitoes and other arthropod disease vectors. Develop new technology for preparation of fabrics having insect controlling and/or repelling properties. Identify the mechanisms underlying the activity of key mosquito repellents and attractants, and develop ways to exploit the mechanisms for commercial use. Significant Activities that Support Special Target Populations The focus of our research is the discovery and development of methods to protect people from medically important insects and other blood-sucking arthropods that transmit disease agents or are a public health issue. Scientists have identified and tested new, fast-acting insecticides for public health use. These candidate pyrethroid-based compounds were shown to be effective against numerous resistance species of mosquitoes. An invention disclosure for a patent application entitled, �Identification of key ligand in the development of more effective deterrents and repellents of arthropod vectors,� has been submitted. We believe that these compounds induce desirable toxic effects against vectors of disease pathogens in minutes due to their high vapor pressure. Fundamental research involving the yellow fever mosquito, Aedes aegypti, demonstrated that specific receptors located in the antennae responded to odors produced by the host. This research provides a better understanding of the elements that affect mosquito attraction to a vertebrate host and will hopefully lead to novel methods of mosquito control. Research with bed bugs revealed that the glands of immature bed bugs produce two compounds that have never been associated with these blood- sucking insects. Considered �alerting scents� or alarm pheromones, these compounds comprised more than 15% of the gland�s composition, and they may be important in attractants and traps designed to monitor and control bed bugs. Additional research with bed bugs showed that adult males had a preference for harborages (hiding places) that were treated with an extract of immature shed skins. This research may also be valuable in designing traps and lures meant to control bed bugs.
Impacts
(N/A)
Publications
- Grieco, J.P., Achee, N.L., Chareonviriyaphap, T., Suwonkerd, W., Chauhan, K.R., Sardelis, M., Roberts, D. 2007. A new classification system for the actions of IRS chemicals traditionally used for malaria control. PLoS ONE 2(8):e716.
- Vogt, R. G., Miller, N. E., Litvack, R., Fandino, R. A., Sparks, J., Staples, J., Friedman, R. and Dickens, J. C. 2009. The insect SNMP gene family. Insect Biochemistry and Molecular Biology. 39(7):448-456.
- Zhang, A., Wang, S., Klun, J.A., Carroll, J.F., and Debboun, M. 2009. Isolongifolenone: A natural sesquiterpene repellent of ticks and mosquitoes Journal of Medical Entomology. 46(1):100-106
- Polsomboon S., Grieco, J., Chauhan, K. R., Tanasinchayakul, S., Chareonviriyaphap T. 2008. Behavioral responses of catnip (Nepeta cataria L.) by two species of mosquitoes, Aedes aegypti (L.) and Anopheles harrisoni Harbach and Manguin, in Thailand. Journal of the American Mosquito Control Association. 24(4):513�519.
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Progress 10/01/06 to 09/30/07
Outputs
Progress Report Objectives (from AD-416) Objective 1: Discover and develop next generation topical skin repellents, spatial repellents, contact irritants, and toxicants against mosquitoes and other arthropod disease vectors. Research toward this objective will primarily involve a consortium of military, government, academic, and private industry research groups using high throughput bioassays to test model compounds selected via computational chemistry from the large chemical library maintained by the BASF Corporation. Objective 2: Develop new technology for preparation of fabrics having insect controlling and/or repelling properties. Repellent compounds will be covalently bonded to fabric polymers, and the resulting polymers will be tested to determine if repellent activity against mosquitoes is retained; if these derivatized polymers are repellent, then research will continue to optimize conditions required to produce insect repellent fabrics. Objective 3: Identify the mechanisms underlying the activity of key mosquito repellents and attractants, and develop ways to exploit the mechanisms for commercial use. This objective will focus on state-of-the- art application of odorant binding protein (OBP) research by covalently bonding cloned mosquito OBPs to HPLC columns for use in screening natural product and synthetic chemical libraries for binding activity. Bound compounds will be identified and tested in conventional behavioral bioassays for activity against mosquitoes. Also, the mechanisms of action for selected compounds will be investigated electrophysiologically, including single cell recording experimentation to pinpoint the sites of receptors involved in the perception of bioactive compounds. Approach (from AD-416) Discover and develop next generation topical skin repellents, spatial repellents, contact irritants, and toxicants against mosquitoes and other arthropod disease vectors. Develop new technology for preparation of fabrics having insect controlling and/or repelling properties. Identify the mechanisms underlying the activity of key mosquito repellents and attractants, and develop ways to exploit the mechanisms for commercial use. Significant Activities that Support Special Target Populations Behavioral assays to quantitatively measure mosquito responses to stimuli involved in host seeking and feeding were developed in the laboratory. Accomplishments New mosquito and tick repellent. There is a need for novel arthropod repellents with new chemical composition. A patent, Methods For Preparing Isolongifolenone And Its Use In Repelling Arthropods, has been applied for. It is expected that isolongifolenone will become available in large quantities for use in the perfume and arthropod repellent industries. National Program Component: NP104, goal 4.1.3 (Identify and test new classes of topical and area repellents for previously synthesized or natural volatiles.) Oviposition attractants for the arthropod disease vectors -The accomplishment concerns identification and patenting of a new mosquito oviposition attractant. There is a need for commercially viable oviposition attractants to utilize attract and kill technology in disease vector control. A patent, Novel biorational oviposition attractants to disease vector mosquitoes, has been applied for. It is expected that newly developed oviposition attractants would be used in strategies to curb the mosquito surveillance as well as control. National Program Component: NP104, goal 2.2.3 (Identify and synthesize host specific attractants for use in traps). Technology Transfer Number of New CRADAS and MTAS: 3 Number of Active CRADAS and MTAS: 6 Number of Invention Disclosures submitted: 3 Number of Patent Applications filed: 2 Number of Non-Peer Reviewed Presentations and Proceedings: 7
Impacts
(N/A)
Publications
- Klun, J.A., Khrimian, A., Rowton, E., Kramer, M.H., Debboun, M. 2006. Biting-deterrent activity of a deet analog, two depa analogs and ss220 applied topically to human volunteers compared with deet against three species of blood-feeding flies. Journal of Medical Entomology. 43:1248- 1251.
- Tran, K., Chauhan, K.R. 2007. Structural activity of bovidic acid and related compounds as feeding deterrents against Aedes aegypti. Biopestic. Int. 3(1):53-57.
- Chauhan, K.R., Raina, A. 2007. Effect of catnip oil and its major components on the Formosan subterranean termites. Biopesticides International 2(2):137-143.
- Zhu, J., Zeng, X., Ma, Y., Liu, T., Qian, K., Han, Y., Xue, S., Tucker, B., Schultz, G., Coats, J. 2006. Comparisons of adult repellency and larvicidal activity of plant essential oils against mosquitoes. Journal of the Mosquito Control Association. 35:249-257
- Carroll, J.F., Cantrell, C.L., Klun, J.A., Kramer, M.H. 2007. Repellency of two terpenoid compounds isolated from Callicarpa americana (Lamiaceae) against Ixodes scapularis and Amblyomma americanum ticks. Experimental and Applied Acarology. 41:215-224.
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Progress 10/01/05 to 09/30/06
Outputs
Progress Report 1. What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? Why does it matter? New chemical tools are urgently needed for the protection of humans against existing and emerging diseases transmitted by blood-sucking insects and other arthropods. Chemicals detrimental to disease-vectoring arthropod behavior and/or physiology will be identified, providing a means to reduce risks of disease transmission to humans. Discovery of topical repellents active at lower levels of active ingredient than contained in current repellents will enable more acceptable repellent formulations to be developed, thereby increasing human usage. Emphasis will be on exploratory chemical testing of compounds obtained from existing chemical libraries, and from model synthetic compounds generated by rational chemical design. New fabric-bound chemicals will be explored for vector control. Compounds
will be evaluated against vectors of malaria, dengue, and West Nile virus using optimized high through put assays to compare different chemicals for levels of repellent, irritant and pesticide activity. These assays will identify new compounds having behavioral and/or insecticidal modes of action. In addition, new chemical attractants will be sought for improved mosquito surveillance, and spatial repellent compounds will be sought to guard against biting arthropods entering areas of human habitation. In all of the research, there will be an underlying effort to understand the mechanisms and modes of action of new and existing chemicals. In part, the proposed research involves a consortium of military, government, academic, and private industry groups. The new medically important chemical tools will be introduced into existing pest management programs related to public health protection. This program falls within the National Program 104 Mission to develop effective means to prevent or
suppress insects and other arthropods that affect human well being and to enhance the safety and quality of life for the U.S. public. The research involves a multidisciplinary approach involving entomology, insect behavior, vector biology, and organic, analytical and computational chemistry. The project focuses on NP104 goals 2.2.1 (Develop species-specific traps and traps that will automatically register and transmit collection information), 2.2.3 (Identify and synthesize host specific attractants for use in traps), 3.2. 2 (Characterize and isolate pheromones and other cues used by Diptera in mating and host finding), 3.2.3 (Develop measurements of electrophysiological activation for use in selecting vector repellents.), 4.1.1 (Develop and use computational models for rapidly screening and predicting efficacy of available compounds from configurational extrapolation), 4.1.2 (Develop and test novel means of applying pesticides and repellents that are more efficient, methods to bond
agents to material, and area repellents), and 4.1.3 (Identify and test new classes of topical and area repellents for previously synthesized or natural volatiles. Develop carrier formulations). 2. List by year the currently approved milestones (indicators of research progress) Year 1 (FY2005) Insects rearing optimized using blood-membrane feeding. Standardized high through put screening (HTS) assay system in place. A Computational methodology for compound selection from BASF library in place. Design and synthesis of 3 pyrethroids containing molecular spacers complete. Design and synthesis of several polymers with functional groups suitable for attaching repellent units studied. Candidate compounds bioassayed against a mosquito. Method for chemically attaching the modified pyrethroids to polymer studied. Known repellent compounds studied using Culex quinquifaciatus odorant binding proteins (OBPs) affinity columns. Preliminary single cell electrophysiological screening recording (SCR)
experiments conducted on Culex pipiens. Cloning of OBP from Anopheles stephensi and Aedes aegypti initiated. Year 2 (FY2006) HTS-evaluated 3,000 BASF library compounds and two new model compounds identified. Computational chemistry models optimized. EPA requirements for product registration determined. Synthetic polymers containing chemically bonded pyrethroids obtained and bioassayed. Most promising polymers are spun into fibers. Affinity columns prepared using cloned Anopheles stephensi and Aedes aegypti OBPs and SCR started with the two species. Year 3 (FY2007) Synthetic methods for preparation of model compounds for field tests developed. Field tests experimental designs complete. Fabric development studied. Complete experimental designs for field tests. Compound screening started using CquiOBP affinity columns. Year 4 (FY2008) Final evaluation studies of most promising compounds completed. New refined and efficient computational chemistry strategies identified and published. New
fabrics developed. Complete SCR comparisons in three mosquito species. Year 5 (FY2009) EPA registration and technology transfer of new products in final stages. Finish field tests to test vector-control efficacy. Finish Quantitative Structure Activity Relationship (QSAR) studies using synthetic model compounds having optimized OBP affinity. 5. Describe the major accomplishments to date and their predicted or actual impact. Screening program established to identify new mosquito repellents We have designed and established an extensive chemical screening program to identify new mosquito repellents and toxicants. Our customers include industry partners interested in developing and marketing new topical skin repellents, the U.S. public interested in protecting themselves from the insects and other arthropods that transmit Lyme disease and West Nile virus, and the U.S. military that require new topical skin repellents to protect deployed forces from disease-transmitting, blood-sucking
arthropods. To date, we have published a series of articles on new screening procedures that will be used by the scientific community interested in developing new repellents. The potential impact is the availability of new, E.P.A.- registered repellents. This accomplishment aligns with Component 4 (Control Technology) of National Program 104 (Veterinary, Medical and Urban Entomology). 6. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? Techniques for using in vitro bioassays to test compounds for repellent activity have been transferred to the scientific community in publications. A CRADA has been developed as well as several cooperative agreements. Our customers are the U.S. Military, public health-care industries, and pest management industries, other
scientists and the consumer public. Constraints include the ability to conduct human repellent testing and changing guidelines for repellent approval by the EPA. 7. List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). Klun, J.A. 2006. SS220-a new compound to fend off blood-feeding arthropods. Presentation to 2006 Pesticide Recertification Program and Agriculture Trade Show, March 3, 2006, USDA-ARS, BARC-West, Beltsville, MD. Klun, J.A. 2006. A new compound for personal protection against blood- feeding arthropods. Presentation to The 2006 Pesticide Safety Conference for Forest, Aquatic, and Right-of-Way Pest Control and Industrial Weed Control, March, 23, 2006. BWI Airport Marriot Hotel.. Cantrell, C. 2006. "Folk Remedy Yields Mosquito-thwarting Compound. International Pest Control news article, May/June 2006, 48(3):153-154. Krajick, K. 2006. Keeping
the bugs at bay. Science. 313:36-38. Klun, J.A. 2006. Upwind flight and feeding engorgement of Aedes aegypti in a flight tunnel. Presentation to the Armed Forces Pest Management Board, Repellents Committee, July 25, 2006, Forest Glenn, MD.
Impacts
(N/A)
Publications
- Natarajan, R., Basak, S., Balaban, A., Klun, J.A., Schmidt, W.F. 2005. Chirality index, molecurlar overlay and the activity of stereoisomeric topical mosquito repellents. Pesticide Management Science. 61:1193-1201.
- Klun, J.A., Khrimian, A., Debboun, M. 2006. The repellent and deterrent effects of ss220, bayrepel and deet against aedes aegypti, anopheles stephensi and phlebotomus papatasi. Journal of Medical Entomology. 43: 34- 39.
- Debboun, M., Klun, J.A., Strickman, D.A. 2005. Repellents and the military: our first line of defense.. Journal of the Mosquito Control Association. 21:4-6.
- Houpt, J.T., Debboun, M., Michie, M.W., Paulus, H.I., Thompson, M.I., Lee, R.B., Klun, J.A. 2005. The 90-day dermal toxicity of the repellent ss-220 in rats. U.S. Army Center for Health Promotion and Preventative Medicine. Toxicology Study No. 85-XC-3929-04.
- Tran, K., Chauhan, K.R. 2006. Structural activity of bovidic acid and related compounds as feeding deterrents against aedes aegypti. American Mosquito Control Association. Addendum 07/27/06.
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Progress 10/01/04 to 09/30/05
Outputs
1. What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? New chemical tools are urgently needed to protect humans from blood- sucking arthropods that can transmit diseases like West Nile virus, malaria, and leishmaniasis. Using a multidisciplinary approach involving entomology, insect behavior, vector biology, and organic, analytical and computational chemistry, the Chemicals Affecting Insect Behavior Laboratory (CAIBL) has developed novel bioassay systems in an attempt to identify new arthropod repellents and compounds having behavioral and/or insecticidal modes of action. In addition, new chemical attractants will be sought for improved mosquito surveillance, and spatial repellent compounds will be sought to guard against biting arthropods entering areas of human habitation. The ultimate goal is to provide safe and effective means to reduce risks of
disease transmission to humans. This program falls within the National Program 104 Mission to develop effective means to prevent or suppress insects and other arthropods that affect human well being and to enhance the safety and quality of life for the U.S. public. 2. List the milestones (indicators of progress) from your Project Plan. Year 1 (FY2005) Insects rearing optimized using blood-membrane feeding. Standardized high through put screening (HTS) assay system in place. Computational methodology for compound selection from BASF library in place. Design and synthesis of 3 pyrethroids containing molecular spacers complete. Design and synthesis of several polymers with functional groups suitable for attaching repellent units studied. Candidate compounds bioassayed against a mosquito. Method for chemically attaching the modified pyrethroids to polymer studied. Known repellent compounds studied using Culex quinquifaciatus odorant binding proteins (OBPs) affinity columns. Preliminary
single cell electrophysiological screening recording (SCR) experiments conducted on Culex pipiens. Cloning of OBP from Anopheles stephensi and Aedes aegypti initiated. Year 2 (FY2006) HTS-evaluated 3,000 BASF library compounds and two new model compounds identified. Computational chemistry models optimized. EPA requirements for product registration determined. Synthetic polymers containing chemically bonded pyrethroids obtained and bioassayed. Most promising polymers are spun into fibers. Affinity columns prepared using cloned Anopheles stephensi and Aedes aegypti OBPs and SCR started with the two species Year 3 (FY2007) Synthetic methods for preparation of model compounds for field tests developed. Field tests experimental designs complete. Fabric development studied. Complete experimental designs for field tests. Compound screening started using CquiOBP affinity columns. Year 4 (FY2008) Final evaluation studies of most promising compounds completed. New refined and efficient
computational chemistry strategies identified and published. New fabrics developed. Complete SCR comparisons in three mosquito species. Year 5 (FY2009) EPA registration and technology transfer of new products in final stages. Finish field tests to test vector-control efficacy. Finish QSAR studies using synthetic model compounds having optimized OBP affinity. 3a List the milestones that were scheduled to be addressed in FY 2005. For each milestone, indicate the status: fully met, substantially met, or not met. If not met, why. 1. Insects rearing optimized using blood-membrane feeding. Milestone Substantially Met 2. Standardized high through put screening (HTS) assay system in place. Milestone Fully Met 3. A Computational methodology for compound selection from BASF library in place. Milestone Substantially Met 4. Design and synthesis of 3 pyrethroids containing molecular spacers complete. Milestone Substantially Met 5. Design and synthesis of several polymers with functional groups
suitable for attaching repellent units studied. Milestone Substantially Met 6. Candidate compounds bioassayed against a mosquito. Milestone Substantially Met 7. Method for chemically attaching the modified pyrethroids to polymer studied. Milestone Not Met Other 8. Known repellent compounds studied using Culex quinquifaciatus odorant binding proteins (OBPs) affinity columns. Milestone Substantially Met 9. Preliminary single cell electrophysiological screening recording (SCR) experiments conducted on Culex pipiens. Milestone Not Met Progress slowed by resource limitation (human,fiscal,equipment, etc. 10. Cloning of OBP from Anopheles stephensi and Aedes aegypti initiated. Milestone Substantially Met 3b List the milestones that you expect to address over the next 3 years (FY 2006, 2007, and 2008). What do you expect to accomplish, year by year, over the next 3 years under each milestone? FY2006 HTS-evaluated 3,000 BASF library compounds and two new model compounds identified. We have
evaluated nearly 500 compounds in the past year yielding 18 active lead compounds. It is anticipated that the targeted number of tested compounds will be achieved as our testing efficiency improves. Computational chemistry models optimized. Through an iterative process, computational chemistry yield models with enhanced predictive power. EPA will begin development of initiatives that will ease registration requirements for public health insecticides. Synthetic polymers containing chemically bonded pyrethroids obtained and bioassayed. This milestone has been deleted due to the retirement of the scientist in charge, and will not be reported in future annual reports. Most promising polymers are spun into fibers. This milestone has been deleted due to the retirement of the scientist in charge, and will not be reported in future annual reports. Affinity columns prepared using cloned Anopheles stephensi and Aedes aegypti OBPs and single cell electrophysiological recording (SCR) started
with the two species. We expect that having OBP columns of two species and SCR study will provide insight into the differences and similarities that may exist in their perception of odors. FY2007 Synthetic methods for preparation of model compounds for field tests developed. Field tests experimental designs complete. We intend to scale up our synthetic capabilities so new model compounds are available in sufficient quantity for field testing. Fabric development studied. This milestone has been deleted due to the retirement of the scientist in charge, and will not be reported in future annual reports. Complete experimental designs for field tests. This milestone has been deleted due to the retirement of the scientist in charge, and will not be reported in future annual reports. Compound screening started using CquiOBP affinity columns. We expect biologically relevant compounds which show highest affinity for the bound protein to be available for testing in Culex quinquefasciatus.
FY2008 Final evaluation studies of most promising compounds completed. We will be able to determine which of the newly discovered compounds will most likely be of practical utility for public health protection against disease vectors. New refined and efficient computational chemistry strategies identified and published. The new strategies will contribute significantly to the field of computational chemistry. New fabrics developed. This milestone has been deleted due to the retirement of the scientist in charge, and will not be reported in future annual reports. Complete SCR comparisons in three mosquito species. The electrophysiological studies of Anopheles stephensi, Aedes aegypti and C. pipiens are expected to correlate specific sensilla with the specific odors they detect with highest sensitivity. 4a What was the single most significant accomplishment this past year? A walk-in mosquito rearing facility was developed to permit the rearing of thousands of mosquitoes for use in
behavioral research and in a chemical screening program for discovery of new mosquito feeding deterrent compounds and knock down toxicants. 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. This research project started 12/10/04 and replaced Project number 1275- 22000-192-00D, MANIPULATION OF ARTHROPOD BEHAVIOR FOR PROTECTION OF LIVESTOCK AND HUMANS. 6. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? None. It is anticipated it will take at approximately 5-10 years to deliver the technology to our customers that include the U. S. military, public health-care industries, and pest management industries. Constraints include the identification of new and safe repellents and registration
requirements of the Environmental Protection Agency (EPA). 7. List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). "From the back yard to the bloodstream: The summer bug battle is rejoined" by Dennis Obrien, Baltimore Sun June 13, 2005. "If you go down to the woods today, rub some leaves on yourself" by Peter Calamai, Toronto Star July 2, 2005.
Impacts
(N/A)
Publications
- Chauhan, K.R., Klun, J.A., Debboun, M., Kramer, M. 2005. Feeding Deterrent Effects of Catnip Oil Components Compared with Two Synthetic Amides Against Aedes aegypti. Journal of Medical Entomology. 42:643-646.
- Norden, B.B., Webb, R.E., Mccardle, P.W., White, G.B. 2005. A new fixing technique using rice vinegar prior to mosquito dissection.. Journal of Kansas Entomological Society. 78:189-191.
- Klun, J.A., Kramer, M., Debboun, M. 2005. A new in vitro bioassay system for discovery of novel human-use mosquito repellents.. American Mosquito Control Association. 21:64-70.
- Cantrell, C.L., Klun, J.A., Duke, S.O., Bryson, C.T., Kobaisy, M.M. 2005. Isolation and identification of mosquito-repellent terpenoids from leaves of american (callicarpa americana) and japanese (callicarpa japonica) beautyberry. Journal of Agricultural and Food Chemistry. 53:5948-5953.
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