Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer

Las enfermedades catalogadas como demencia, entre ellas la enfermedad de Alzheimer, afecta cada vez más a las personas en el mundo, afectando su cognición. Poco se sabe de la fisiopatología de la enfermedad, hasta el momento existen dos hipótesis, la hipótesis amiloide y la hipótesis colinérgica, el...

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Autores:
Osorio Caviedes, Jammie Camila
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2024
Institución:
Universidad Distrital Francisco José de Caldas
Repositorio:
RIUD: repositorio U. Distrital
Idioma:
spa
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oai:repository.udistrital.edu.co:11349/93710
Acceso en línea:
http://hdl.handle.net/11349/93710
Palabra clave:
Acoplamiento molecular
Tratamiento
Enfermedad de Alzheimer
Herramientas computacionales
Licenciatura en Biología -- Tesis y disertaciones académicas
Molecular docking computational tools
Treatment
Alzheimer's disease
Computational tools
Rights
License
Abierto (Texto Completo)
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dc.title.none.fl_str_mv Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
dc.title.titleenglish.none.fl_str_mv Bioinformatic analysis of four flavonoids (3,5-dihydroxi-6,7,8-timethovyflavone, alpinone-izalpinine and rhamnocitrine) as possible treatment for Alzheimer's disease
title Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
spellingShingle Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
Acoplamiento molecular
Tratamiento
Enfermedad de Alzheimer
Herramientas computacionales
Licenciatura en Biología -- Tesis y disertaciones académicas
Molecular docking computational tools
Treatment
Alzheimer's disease
Computational tools
title_short Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
title_full Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
title_fullStr Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
title_full_unstemmed Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
title_sort Análisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el Alzheimer
dc.creator.fl_str_mv Osorio Caviedes, Jammie Camila
dc.contributor.advisor.none.fl_str_mv Mahecha Jiménez, Oscar Javier
Rodríguez López, Edwin Alexander
dc.contributor.author.none.fl_str_mv Osorio Caviedes, Jammie Camila
dc.contributor.orcid.none.fl_str_mv Mahecha Jiménez, Oscar Javier [0000-0002-8682-0020]
dc.subject.none.fl_str_mv Acoplamiento molecular
Tratamiento
Enfermedad de Alzheimer
Herramientas computacionales
topic Acoplamiento molecular
Tratamiento
Enfermedad de Alzheimer
Herramientas computacionales
Licenciatura en Biología -- Tesis y disertaciones académicas
Molecular docking computational tools
Treatment
Alzheimer's disease
Computational tools
dc.subject.lemb.none.fl_str_mv Licenciatura en Biología -- Tesis y disertaciones académicas
dc.subject.keyword.none.fl_str_mv Molecular docking computational tools
Treatment
Alzheimer's disease
Computational tools
description Las enfermedades catalogadas como demencia, entre ellas la enfermedad de Alzheimer, afecta cada vez más a las personas en el mundo, afectando su cognición. Poco se sabe de la fisiopatología de la enfermedad, hasta el momento existen dos hipótesis, la hipótesis amiloide y la hipótesis colinérgica, el desconocimiento de esto ha llevado a que los tratamientos actuales para la enfermedad, sólo sean tratamientos sintomáticos. Esta investigación se centró en el análisis in silico de cuatro flavonoides para evaluar su actividad inhibitoria sobre las enzimas Acetilcolinesterasa y Butirilcolinesterasa, esto se hizo utilizando herramientas computacionales, como AutoDock tools y servidores en línea. Los resultados mostraron que los ligandos tuvieron mayor interacción con la Acetylcolinestera, en cuanto al tipo de interacciones se evidenció la que la mayoría de interacciones fueron de tipo Pi-Pi Stacked.
publishDate 2024
dc.date.created.none.fl_str_mv 2024-08-06
dc.date.accessioned.none.fl_str_mv 2025-03-16T21:19:00Z
dc.date.available.none.fl_str_mv 2025-03-16T21:19:00Z
dc.type.none.fl_str_mv bachelorThesis
dc.type.degree.none.fl_str_mv Investigación-Innovación
dc.type.driver.none.fl_str_mv info:eu-repo/semantics/bachelorThesis
dc.type.coar.none.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
format http://purl.org/coar/resource_type/c_7a1f
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/11349/93710
url http://hdl.handle.net/11349/93710
dc.language.iso.none.fl_str_mv spa
language spa
dc.relation.references.none.fl_str_mv Bekdash, A. Rola. (2021). The Cholinergic System, the Adrenergic System and the Neuropathology of Alzhermer´s disease. Int. J. Mol. Sci. 22(3), 1273; https://doi.org/10.3390/ijms22031273
Calabrò M, Rinaldi C, Santoro G, Crisafulli C. (2020). The biological pathways of Alzheimer disease: a review. AIMS Neurosci. doi: 10.3934/Neuroscience.2021005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815481/#box1
Chen, Deliang., Oezguen, Numan., Urvill, Petri., Ferguson, Colin., Dann, M. Sara & Savidge, C. Tor (2016). Regulation of protein-ligand binding affinity by hydrogen bond pairing
Cox, B. Philip & Grupta Rishi. (2022). Contemporary Computational Applications and Tools in Drug Discovery. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.1c00662.
Daina, Antoine., Michielin, Oliver & Zoete, Vicent. (2017). SwissADME: a free web tools to evaluate pharmacokinetiics, druglikeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 7 (1). doi:10.1038/srep42717
Dhakal, Ashwin., McKay, Cole., Tanner, J. Jhon & Cheng, Jianlin. (2021). Artificial intelligence in the prediction of protein-ligand interaction: recent advances and future directions. Briefings in Bioinformatics.
Darvesh, Suktan., Hopkins, A, David & Geula, Changiz. (2003). Neurobiology of Butyrylcholinesterase. DOI: 10.1038/nrn1035
Dwomoh, Louis., Tejada, S. Gonzalo & Tobin, B. Andrew. (2022). Targeting the M1 muscarinic acetylcholine receptor in Alzheimer´s disease. Neuronal Signaling. 6 NS20210004 https://doi.org/10.1042/NS20210004
Ferreira-Vieira., Guimaraes, M. Isabella., Silva, R. Flavia & Ribeiro, M. Fabiola. (2016). Alzheimer´s disease: targeting the cholinergic system. Current neuropharmacology 4(1): 101–115. doi: 10.2174/1570159X13666150716165726
Fontana, C. Igor., Zimmer, R. Aline., Rocha, S. Andreia., Gossman, Grace., Souza, O. Diogo., Lourenco, V. Mychael., Ferreira, T. Sergio & Zimmer, R. Eduardo. (2020). Amyloid-β oligomers in celular models of Alzheimer´s disease. Journal of Neurochemistry. DOI: 10.1111/jnc.15030
Gauthier, Serge., Webster, Claire., Stjjn, Servaes., Morais, A. José & Rosa-Neto, Pedro. (2022). World Alzheimer Report. Life after diagnosis: Navigating treatment, care and support. Alzheimer´s Disease International. https://www.alzint.org/u/World-Alzheimer Report-2022.pdf
Gonzáles, Eduardo., Ramirez, Jesús., Hernández, Jorge & Carballo, Alna. (2023). Ginkgo biloba: Antioxidant Activity and In Silico Central Nerveus System Potential. Curr. Issues Mol. Bio.
Guo, Yanjun., Wang, Qinqiu & Xu, Chengfu. (2020). Functions of amyloid precursor in metabolic disease. Metabolics 154454. DOI: https://doi.org/10.1016/j.metabol.2020.154454
Hall, M. Chloe., Moeendarbary, Emad & Sheridan, K. Sheridan. (2020). Mechanobiology of the brain in ageing and Alzheimer´s disease. European Journal of Neuroscience. DOI: 10.1111/ejn.14766
Kim, W. Gwang, Park, Kwangsung., Kim, Yun-Hyeon & Jeong, Woo-Gwang. (2023). Increased Hippocampal-Inferior Temporal Gyrus White Matter Connectivity following Donepezil Treatment in Patients with early Alzheimer´s Disease: A difusión Tensor probabilistic Tractography study. Journal of Clinical Medicine. p 2.
Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., … Jones, D. T. (2021). Alzheimer disease. Nature Reviews Disease Primers, 7(1). doi:10.1038/s41572-021-00269-y https://sci-hub.se/https://doi.org/10.1038/s41572- 021-00269-y
Li, Hong Chun., Luo, Ke-Xue., Wang, Jie-Sheng & Wang, Quin-Xian. (2020). Extrapyramidal side effect of donepezil hydrochloride in an elderly patient. Medicine. doi:10.1097/md.0000000000019443
Li, Jiao., Sun, Min & Li, Chen. (2022). Protective Effects of Flavonoids against Alzheimer´s Disease: Pathological Hypothesis, Potential Targets, and Structure-Activity Relationship. Int J Mol Sci. doi: 10.3390/ijms231710020
Liu, Jinping., Chang, Lirong.,Song, Yizhi., Li, Hui & Wu, Yan. (2019). The role of NMDA receptor in Alzheimer´s disease. Frintiers in Neuroscience. 13. https://doi.org/10.3389/fnins.2019.00043
López, Juana Andrea., Luque, Miriam., Campos, Cynthia., Gutierres, Antonia & Vargas, David. (2023). Agregación y propagación de Aβ en modelos transgénicos de la enfermedad de Alzheimer. Anales Ranm. DOI: 10.32440/ar.2023.140.01.rev05
Makarian, Makar., Gonzales, Michael., Salvador, M. Stephanie., Lorzadeh, Shahrok., Hudson, K. Paula & Pecic, Stevan. (2022). Synthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitor. Journal of Molecular Structure. P 1.
Marucci, Gabriella., Buccioni, Michela., Ben, D. Diego., Lambertucci., Volpini, Rosaria & Amenta, Francesco. (2021). Effucacy of acetylcholinesterase inhibitors in Alzheimer´s disease. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2020.108352
McNutt, T. Andrew., Francoeur, Paul., Aggarwal, Rishal., Masuda, Tomohide., Meli, Rocco., Ragoza, Matthew., Sunseri, Jocelyn & Koes, Ryan David. (2021). GNINA 1.0: 36 molecular docking with Deep learning. J Cheminform 13, 43. https://doi.org/10.1186/s13321-021-00522-2
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Pardo, Terasa., Gonzales, Anabel., Rivas, Antonio., García, Victoria., García, Francisco., Ramos, Juan & Melguizo, Lucía. (2022). Therapeutic approach to Alzheimer´s Disease: Current Treatments and new perspective. Pharmaceutics. https://doi.org/10.3390/pharmaceutics14061117
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Peitzika, Chrysovalanti-Stergiani & Pontiki, Eleni. (2023). A review on recent approaches on molecular docking of novel compounds targeting Acetylcholinesterase in Alzheimer´s disease. Molecules. 1084. https://doi.org/10.3390/molecules28031084
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Sadeghi, Morteza., Seyedebrahimi, Seyedehmasoumeth., Ghanadian, Mustafa & Miroliaeli, Mehran. (2024). Identification of cholinesterases inhibitors from flavonoids for posible treatment of Alzheimer´s disease: In silico and in vitro approaches. Current Research in Structural Biology. 2665-928X, https://doi.org/10.1016/j.crstbi.2024.100146
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Stanzione, Francesca., Giangreco, Ilenia & Cole, Jason. (2021). Use of molecular docking computational tools in drug Discovery. Progress in medical chemistry. 273-343. doi:10.1016/bs.pmch.2021.01.004
Suprijino, Maria., Sujuti, Hidayat., Kurnia, D. & Widjanarko, Banbang. (2020). Absorption, distribution, metabolism, excretion and toxicity evaluation of Papua red fruit flavonoids through a computational study. IOP Conference Series: Earth and Enviromental Science. 475 012078. DOI 10.1088/1755-1315/475/1/012078
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spelling Mahecha Jiménez, Oscar JavierRodríguez López, Edwin AlexanderOsorio Caviedes, Jammie CamilaMahecha Jiménez, Oscar Javier [0000-0002-8682-0020]2025-03-16T21:19:00Z2025-03-16T21:19:00Z2024-08-06http://hdl.handle.net/11349/93710Las enfermedades catalogadas como demencia, entre ellas la enfermedad de Alzheimer, afecta cada vez más a las personas en el mundo, afectando su cognición. Poco se sabe de la fisiopatología de la enfermedad, hasta el momento existen dos hipótesis, la hipótesis amiloide y la hipótesis colinérgica, el desconocimiento de esto ha llevado a que los tratamientos actuales para la enfermedad, sólo sean tratamientos sintomáticos. Esta investigación se centró en el análisis in silico de cuatro flavonoides para evaluar su actividad inhibitoria sobre las enzimas Acetilcolinesterasa y Butirilcolinesterasa, esto se hizo utilizando herramientas computacionales, como AutoDock tools y servidores en línea. Los resultados mostraron que los ligandos tuvieron mayor interacción con la Acetylcolinestera, en cuanto al tipo de interacciones se evidenció la que la mayoría de interacciones fueron de tipo Pi-Pi Stacked.Diseases categorised as dementia, including Alzheimer's disease, increasingly affects people around the world, affecting their cognition. Little is known about the pathophysiology of the disease, so far there are two hypotheses, the amyloid hypothesis and the cholinergic hypothesis, which are amyloid hypothesis and the cholinergic hypothesis current treatments for the disease are only symptomatic treatments. This research focused on the in silico analysis of four flavonoids to evaluate their inhibitory activity on the inhibitory activity on acetylcholinesterase and butyrylcholinesterase enzymes. This was done using computational tools, such as AutoDock tools and online servers. The results showed that the ligands had the strongest interaction with the Acetylcholinesterase, in terms of the type of interactions, it was found that the majority of the interactions were of the Pi-Pi interactions were of the Pi-Pi Stacked type.pdfspaUniversidad Distrital Francisco José de CaldasAcoplamiento molecularTratamientoEnfermedad de AlzheimerHerramientas computacionalesLicenciatura en Biología -- Tesis y disertaciones académicasMolecular docking computational toolsTreatmentAlzheimer's diseaseComputational toolsAnálisis bioinformático de cuatro flavonoides (3,5 dihidroxi-6,7,8-trimetoxiflavona, alpinona-izalpinina y rhamnocitrina) como posible tratamiento para el AlzheimerBioinformatic analysis of four flavonoids (3,5-dihydroxi-6,7,8-timethovyflavone, alpinone-izalpinine and rhamnocitrine) as possible treatment for Alzheimer's diseasebachelorThesisInvestigación-Innovacióninfo:eu-repo/semantics/bachelorThesishttp://purl.org/coar/resource_type/c_7a1fAbierto (Texto Completo)http://purl.org/coar/access_right/c_abf2Bekdash, A. Rola. (2021). The Cholinergic System, the Adrenergic System and the Neuropathology of Alzhermer´s disease. Int. J. Mol. Sci. 22(3), 1273; https://doi.org/10.3390/ijms22031273Calabrò M, Rinaldi C, Santoro G, Crisafulli C. (2020). The biological pathways of Alzheimer disease: a review. AIMS Neurosci. doi: 10.3934/Neuroscience.2021005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815481/#box1Chen, Deliang., Oezguen, Numan., Urvill, Petri., Ferguson, Colin., Dann, M. Sara & Savidge, C. Tor (2016). Regulation of protein-ligand binding affinity by hydrogen bond pairingCox, B. Philip & Grupta Rishi. (2022). Contemporary Computational Applications and Tools in Drug Discovery. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.1c00662.Daina, Antoine., Michielin, Oliver & Zoete, Vicent. (2017). SwissADME: a free web tools to evaluate pharmacokinetiics, druglikeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 7 (1). doi:10.1038/srep42717Dhakal, Ashwin., McKay, Cole., Tanner, J. Jhon & Cheng, Jianlin. (2021). Artificial intelligence in the prediction of protein-ligand interaction: recent advances and future directions. Briefings in Bioinformatics.Darvesh, Suktan., Hopkins, A, David & Geula, Changiz. (2003). Neurobiology of Butyrylcholinesterase. DOI: 10.1038/nrn1035Dwomoh, Louis., Tejada, S. Gonzalo & Tobin, B. Andrew. (2022). Targeting the M1 muscarinic acetylcholine receptor in Alzheimer´s disease. Neuronal Signaling. 6 NS20210004 https://doi.org/10.1042/NS20210004Ferreira-Vieira., Guimaraes, M. Isabella., Silva, R. Flavia & Ribeiro, M. Fabiola. (2016). Alzheimer´s disease: targeting the cholinergic system. Current neuropharmacology 4(1): 101–115. doi: 10.2174/1570159X13666150716165726Fontana, C. Igor., Zimmer, R. Aline., Rocha, S. Andreia., Gossman, Grace., Souza, O. Diogo., Lourenco, V. Mychael., Ferreira, T. Sergio & Zimmer, R. Eduardo. (2020). Amyloid-β oligomers in celular models of Alzheimer´s disease. Journal of Neurochemistry. DOI: 10.1111/jnc.15030Gauthier, Serge., Webster, Claire., Stjjn, Servaes., Morais, A. José & Rosa-Neto, Pedro. (2022). World Alzheimer Report. Life after diagnosis: Navigating treatment, care and support. Alzheimer´s Disease International. https://www.alzint.org/u/World-Alzheimer Report-2022.pdfGonzáles, Eduardo., Ramirez, Jesús., Hernández, Jorge & Carballo, Alna. (2023). Ginkgo biloba: Antioxidant Activity and In Silico Central Nerveus System Potential. Curr. Issues Mol. Bio.Guo, Yanjun., Wang, Qinqiu & Xu, Chengfu. (2020). Functions of amyloid precursor in metabolic disease. Metabolics 154454. DOI: https://doi.org/10.1016/j.metabol.2020.154454Hall, M. Chloe., Moeendarbary, Emad & Sheridan, K. Sheridan. (2020). Mechanobiology of the brain in ageing and Alzheimer´s disease. European Journal of Neuroscience. DOI: 10.1111/ejn.14766Kim, W. Gwang, Park, Kwangsung., Kim, Yun-Hyeon & Jeong, Woo-Gwang. (2023). Increased Hippocampal-Inferior Temporal Gyrus White Matter Connectivity following Donepezil Treatment in Patients with early Alzheimer´s Disease: A difusión Tensor probabilistic Tractography study. Journal of Clinical Medicine. p 2.Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., … Jones, D. T. (2021). Alzheimer disease. Nature Reviews Disease Primers, 7(1). doi:10.1038/s41572-021-00269-y https://sci-hub.se/https://doi.org/10.1038/s41572- 021-00269-yLi, Hong Chun., Luo, Ke-Xue., Wang, Jie-Sheng & Wang, Quin-Xian. (2020). Extrapyramidal side effect of donepezil hydrochloride in an elderly patient. Medicine. doi:10.1097/md.0000000000019443Li, Jiao., Sun, Min & Li, Chen. (2022). Protective Effects of Flavonoids against Alzheimer´s Disease: Pathological Hypothesis, Potential Targets, and Structure-Activity Relationship. Int J Mol Sci. doi: 10.3390/ijms231710020Liu, Jinping., Chang, Lirong.,Song, Yizhi., Li, Hui & Wu, Yan. (2019). 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FsLCBBY3VlcmRvIDAyNiAgZGVsIDMxIGRlIGp1bGlvIGRlIDIwMTIgc29icmUgZWwgcHJvY2VkaW1pZW50byBwYXJhIGxhIHB1YmxpY2FjacOzbiBkZSB0ZXNpcyBkZSBwb3N0Z3JhZG8gZGUgbG9zIGVzdHVkaWFudGVzIGRlIGxhIFVuaXZlcnNpZGFkIERpc3RyaXRhbCBGcmFuY2lzY28gSm9zw6kgZGUgQ2FsZGFzLCAgQWN1ZXJkbyAwMzAgZGVsIDAzIGRlIGRpY2llbWJyZSBkZSAyMDEzIHBvciBtZWRpbyBkZWwgY3VhbCBzZSBjcmVhIGVsIFJlcG9zaXRvcmlvIEluc3RpdHVjaW9uYWwgZGUgbGEgVW5pdmVyc2lkYWQgRGlzdHJpdGFsIEZyYW5jaXNjbyBKb3PDqSBkZSBDYWxkYXMsIEFjdWVyZG8gMDM4IGRlIDIwMTUgMjAxNSDigJxwb3IgZWwgY3VhbCBzZSBtb2RpZmljYSBlbCBBY3VlcmRvIDAzMSBkZSAyMDE0IGRlIDIwMTQgcXVlIHJlZ2xhbWVudGEgZWwgdHJhYmFqbyBkZSBncmFkbyBwYXJhIGxvcyBlc3R1ZGlhbnRlcyBkZSBwcmVncmFkbyBkZSBsYSBVbml2ZXJzaWRhZCBEaXN0cml0YWwgRnJhbmNpc2NvIEpvc8OpIGRlIENhbGRhcyB5IHNlIGRpY3RhbiBvdHJhcyBkaXJlY3RyaWNlc+KAnSB5IGxhcyBkZW3DoXMgbm9ybWFzIGNvbmNvcmRhbnRlIHkgY29tcGxlbWVudGFyaWFzIHF1ZSByaWdlbiBhbCByZXNwZWN0bywgZXNwZWNpYWxtZW50ZSBsYSBsZXkgMjMgZGUgMTk4MiwgbGEgbGV5IDQ0IGRlIDE5OTMgeSBsYSBkZWNpc2nDs24gQW5kaW5hIDM1MSBkZSAxOTkzLiBFc3RvcyBkb2N1bWVudG9zIHBvZHLDoW4gc2VyIGNvbnN1bHRhZG9zIHkgZGVzY2FyZ2Fkb3MgZW4gZWwgcG9ydGFsIHdlYiBkZSBsYSBiaWJsaW90ZWNhIGh0dHA6Ly9zaXN0ZW1hZGViaWJsaW90ZWNhcy51ZGlzdHJpdGFsLmVkdS5jby8KCmspCUFjZXB0byhhbW9zKSBxdWUgTEEgVU5JVkVSU0lEQUQgbm8gc2UgcmVzcG9uc2FiaWxpemEgcG9yIGxhcyBpbmZyYWNjaW9uZXMgYSBsYSBwcm9waWVkYWQgaW50ZWxlY3R1YWwgbyBEZXJlY2hvcyBkZSBBdXRvciBjYXVzYWRhcyBwb3IgbG9zIHRpdHVsYXJlcyBkZSBsYSBwcmVzZW50ZSBMaWNlbmNpYSB5IGRlY2xhcmFtb3MgcXVlIG1hbnRlbmRyw6kgKGVtb3MpIGluZGVtbmUgYSBMQSBVTklWRVJTSURBRCBwb3IgbGFzIHJlY2xhbWFjaW9uZXMgbGVnYWxlcyBkZSBjdWFscXVpZXIgdGlwbyBxdWUgbGxlZ2FyZW4gYSBwcmVzZW50YXJzZSBwb3IgdmlvbGFjacOzbiBkZSBkZXJlY2hvcyBhIGxhIHByb3BpZWRhZCBpbnRlbGVjdHVhbCBvIGRlIEF1dG9yIHJlbGFjaW9uYWRvcyBjb24gbG9zIGRvY3VtZW50b3MgcmVnaXN0cmFkb3MgZW4gZWwgUklVRC4KCmwpCUVsIChsb3MpIGF1dG9yKGVzKSBtYW5pZmllc3RhKG1vcykgcXVlIGxhIG9icmEgb2JqZXRvIGRlIGxhIHByZXNlbnRlIGF1dG9yaXphY2nDs24gZXMgb3JpZ2luYWwsIGRlIGV4Y2x1c2l2YSBhdXRvcsOtYSwgeSBzZSByZWFsaXrDsyBzaW4gdmlvbGFyIG8gdXN1cnBhciBkZXJlY2hvcyBkZSBhdXRvciBkZSB0ZXJjZXJvczsgZGUgdGFsIHN1ZXJ0ZSwgZW4gY2FzbyBkZSBwcmVzZW50YXJzZSBjdWFscXVpZXIgcmVjbGFtYWNpw7NuIG8gYWNjacOzbiBwb3IgcGFydGUgZGUgdW4gdGVyY2VybyBlbiBjdWFudG8gYSBsb3MgZGVyZWNob3MgZGUgYXV0b3Igc29icmUgbGEgb2JyYSwgZWwgKGxvcykgZXN0dWRpYW50ZShzKSDigJMgYXV0b3IoZXMpIGFzdW1pcsOhKG4pIHRvZGEgbGEgcmVzcG9uc2FiaWxpZGFkIHkgc2FsZHLDoShuKSBlbiBkZWZlbnNhIGRlIGxvcyBkZXJlY2hvcyBhcXXDrSBhdXRvcml6YWRvcy4gUGFyYSB0b2RvcyBsb3MgZWZlY3RvcywgTEEgVU5JVkVSU0lEQUQgYWN0w7phIGNvbW8gdW4gdGVyY2VybyBkZSBidWVuYSBmZS4KCgptKQlFbCAobG9zKSBhdXRvcihlcykgbWFuaWZpZXN0YShtb3MpIHF1ZSBjb25vemNvKGNlbW9zKSBsYSBhdXRvbm9tw61hIHkgbG9zIGRlcmVjaG9zLCBxdWUgcG9zZWUobW9zKSBzb2JyZSBsYSBvYnJhIHksIGNvbW8gdGFsLCBlcyAoc29tb3MpIHJlc3BvbnNhYmxlKHMpIGRlbCBhbGNhbmNlIGp1csOtZGljbyB5IGxlZ2FsLCBkZSBlc2NvZ2VyIGxhIG9wY2nDs24gZGUgbGEgcHVibGljYWNpw7NuIG8gZGUgcmVzdHJpY2Npw7NuIGRlIGxhIHB1YmxpY2FjacOzbiBkZWwgZG9jdW1lbnRvIHJlZ2lzdHJhZG8gZW4gZWwgUklVRC4KCgoKCgoKU0kgRUwgRE9DVU1FTlRPIFNFIEJBU0EgRU4gVU4gVFJBQkFKTyBRVUUgSEEgU0lETyBQQVRST0NJTkFETyBPIEFQT1lBRE8gUE9SIFVOQSBBR0VOQ0lBIE8gVU5BIE9SR0FOSVpBQ0nDk04sIENPTiBFWENFUENJw5NOIERFIExBIFVOSVZFUlNJREFEIERJU1RSSVRBTCBGUkFOQ0lTQ08gSk9TRSBERSBDQUxEQVMsIExPUyBBVVRPUkVTIEdBUkFOVElaQU4gUVVFIFNFIEhBIENVTVBMSURPIENPTiBMT1MKREVSRUNIT1MgWSBPQkxJR0FDSU9ORVMgUkVRVUVSSURPUyBQT1IgRUwgUkVTUEVDVElWTyBDT05UUkFUTyBPIEFDVUVSRE8uCgoKCgoKCgoKCgoKCgoKCgoKCgoKCkVuIGNvbnN0YW5jaWEgZGUgbG8gYW50ZXJpb3IsIGZpcm1vKGFtb3MpIGVsIHByZXNlbnRlIGRvY3VtZW50bywgZW4gbGEgY2l1ZGFkIGRlIEJvZ290w6EsIEQuQy4sIGEgbG9zCgoKRklSTUEgREUgTE9TIFRJVFVMQVJFUyBERSBERVJFQ0hPUyBERSBBVVRPUgoKX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fICAgQy5DLiBOby4gX19fX19fX19fX19fX19fX19fCgpfX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX18gICBDLkMuIE5vLiBfX19fX19fX19fX19fX19fX18KCl9fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fX19fXyAgIEMuQy4gTm8uIF9fX19fX19fX19fX19fX19fXwoKCgpDb3JyZW8gRWxlY3Ryw7NuaWNvIEluc3RpdHVjaW9uYWwgZGVsIChkZSBsb3MpIEF1dG9yKGVzKToKCkF1dG9yCSAgICAgIENvcnJlbyBFbGVjdHLDs25pY28KCjEKCjIKCjMKCk5vbWJyZSBkZSBEaXJlY3RvcihlcykgZGUgR3JhZG86CgoxCgoyCgozCgpOb21icmUgRmFjdWx0YWQgeSBQcm95ZWN0byBDdXJyaWN1bGFyOgoKRmFjdWx0YWQJUHJveWVjdG8gQ3VycmljdWxhcgoKCgoKCgoKCk5vdGE6IEVuIGNhc28gcXVlIG5vIGVzdMOpIGRlIGFjdWVyZG8gY29uIGxhcyBjb25kaWNpb25lcyBkZSBsYSBwcmVzZW50ZSBsaWNlbmNpYSwgeSBtYW5pZmllc3RlIGFsZ3VuYSByZXN0cmljY2nDs24gc29icmUgbGEgb2JyYSwganVzdGlmaXF1ZSBsb3MgbW90aXZvcyBwb3IgbG9zIGN1YWxlcyBlbCBkb2N1bWVudG8geSBzdXMgYW5leG9zIG5vIHB1ZWRlbiBzZXIgcHVibGljYWRvcyBlbiBlbCBSZXBvc2l0b3JpbyBJbnN0aXR1Y2lvbmFsIGRlIGxhIFVuaXZlcnNpZGFkIERpc3RyaXRhbCBGcmFuY2lzY28gSm9zw6kgZGUgQ2FsZGFzIFJJVUQuCgoKU2kgcmVxdWllcmUgbcOhcyBlc3BhY2lvLCBwdWVkZSBhbmV4YXIgdW5hIGNvcGlhIHNpbWlsYXIgYSBlc3RhIGhvamEK

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