199 results on '"Martinez DR"'
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2. El mundo integral y complejo del sujeto de la educación
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Ivan Javier Valencia Martinez, Dr. and Cecilia Dolores Correa De Molina, Dra.
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Método ,Etnografía ,Formación Integral ,Complejidad ,Educación ,Praxis ,Education ,Education (General) ,L7-991 - Abstract
La adopción de un método etnográfico para la formación integral desde la complejidad centra su análisis en la educación, escenario significativo para interpretar e identificar nuevas formas de comprensión del acto educativo, donde la pedagogía y la didáctica admitida por el docente son fundamentales para religar los procesos académicos. Comprender desde la escuela que el sujeto de la educación es un ser humano multidimensional, sumergido en una diáspora de incertidumbres, certezas, dudas y utopías, situaciones que requieren miradas complejas para reconocer conexiones que dinamizan el tejido social del conocimiento. El método investigativo implementado, privilegia el análisis hermenéutico de los procesos que intervienen en la formación integral y asume su comprensión e interpretación en el contexto de la escuela, buscando penetrar en las simbologías e imaginarios de la comunidad durante del acto educativo. Para ello, la apropiación de un método etnográfico de investigación acción compleja para la transformación, constituye una vía metodológica emergente identificadora de realidades, para avanzar hacia procesos de integralidad, validar percepciones y reconceptualizaciones de la formación integral y generar actitudes de transformación en la comunidad docente y discente. Una práctica docente integral desde la complejidad propicia comprensión y valoración del estudiante en su condición de ser humano, otorga reconocimiento en el aula, necesario para un contexto social que reclama inclusión, dialogicidad y profunda sensibilidad ecológica y humana.
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- 2018
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3. Evaluating Two Antenatal Depression Screening Tools and Determining the Need for More Routine Administration in Adult Pregnant Women
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Philip, Drew Adrienne, Martinez, Dr. Nicole1, Lazenby, Dr. Mark, Philip, Drew Adrienne, Philip, Drew Adrienne, Martinez, Dr. Nicole1, Lazenby, Dr. Mark, and Philip, Drew Adrienne
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Antenatal depression is a non-psychotic depressive disorder that can occur during pregnancy and advance into the postpartum period if not addressed (Verreault et al., 2014). This type of depression can lead to poor maternal and fetal outcomes including and not limited to: gestational hypertension, prematurity, low birth weight, preeclampsia, and mental health problems (Dadi et al., 2020; Sidebottom et al., 2012). Antenatal depression is not routinely screened as evidenced by the clinical guidelines outlined by The American College of Obstetricians-Gynecologists (ACOG) (2018) who recommends screening for depression once perinatally with an emphasis on the postpartum period. In addition, ACOG (2018) offers several different depression screening tools to choose from when screening perinatally including but not limited to: the Edingburgh Depression Scale (EDS) and the Patient Health Questionnaire-9 (PHQ-9). These two depression screening tools are proven to have strong validity and reliability (Bergnik et al., 2011; Brancaglion et al., 2013; Flynn et al., 2011; Heyningen et al., 2018; Kozinsky & Dudas, 2015; Levis et al., 2020; Stewart et al., 2013; Sidebottom et al., 2012; Wang et al., 2021; Woldentensay et al. 2018; Zhong et al., 2014). Inadequate recognition of antenatal depression could be largely due to the fact pregnant women are not routinely screened throughout pregnancy in accordance with the 2018 national clinical guidelines. The purpose of this quality improvement project is to increase the frequency of screening for antenatal depression, determine if both the EDS and PHQ-9 capture antenatal depression similarly across the three trimesters of pregnancy, and to determine how many pregnant women screen positive with the utilization of these two depression screening tools. Pregnant women who were 18 years or older were screened for antenatal depression in two different trimesters (i.e., first and second or second and third trimester) using both the EDS and P
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- 2022
4. Comparing the reliability of two soil moisture probes for high clay content NSW soils
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Bretreger, David, primary, Hancock, Greg, additional, Yeo, In-Young, additional, Martinez, Dr Cristina, additional, Wells, Dr Tony, additional, Cox, Tristan, additional, Kunkel, Veikko, additional, and Gibson, Abraham, additional
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- 2022
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5. 'Plug and play' modular façade construction system for building renovation to achieve nearly Zero Energy Building (nZEB)
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Jorge, Torres, Roberto Garay Martinez, Dr., Ignacio Torrens-Galdiz, J., Amaia, Uriarte, Pracucci, Alessandro, Oscar, Casadei, Sara, Magnani, Noemi, Arroyo, and Cea, Angel M.
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Building retrofit ,Economica ,Building envelope ,Building envelope, Building retrofit, Energy performance ,Socio-culturale ,Ambientale ,Energy performance - Published
- 2020
6. The use of E-Cigarettes among Adolescents in the United States
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O’lawrence, Dr. Henry, primary, Martinez, Dr. Linda, additional, Garcia, Andre, additional, Ramos, Patricia, additional, Pequillo, Dejay, additional, and Marquez, Carina, additional
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- 2020
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7. Efficacy and safety of radial wave therapy for erectile dysfunction.
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Sandoval-Salinas, Carolina, Martínez, Dr. Juan M., Corredor, Dr. Héctor A., Gallego, Dr. Andrés F., Saffon, Dr. José P., and Primera, Dr. Néstor
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- 2022
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8. Evaluation of three shock wave schemes for treatment of erectile dysfunction
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Corredor, Dr. Hector A., Sandoval-Salinas, Carolina, Martínez, Dr. Juan M., Barba, Dr. Jorge, Gallego, Dr. Andrés F., and Primera, Dr. Néstor
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- 2022
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9. ACTIVE DECOMPRESSION AND DISTRACTION SUGOSTEOGENESIS AS A NOVEL TREATMENT FOR ODONTOGENIC KERATOCYST: A CASE REPORT
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Sifuentes-Cervantes, Dr. Jose, Autran-Martínez, Dr. Jorge, Castro-Núñez, Dr. Jaime, and Guerrero, Dr. Lidia
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- 2022
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10. A Case of Von Recklinghausens Neurofibromatosis
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Descalzo, Dr. Salvador Labrador, primary and Salas-Martinez, Dr. Ana Maria, additional
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- 2019
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11. The MindBody Self : How Longevity Is Culturally Learned and the Causes of Health Are Inherited
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Mario Martinez, Dr and Mario Martinez, Dr
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- Mind and body, Health behavior
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Best-selling author of The MindBody CodeIn these turbulent times, just about every solution you can think of has been put forth by someone, somewhere, as a way to calm the waters and live with more happiness and ease. But the fact is you cannot think your way to a better life. Change isn't something your mind can accomplish alone. It calls for mind and body to work together in a deeper unity than you may ever have imagined.Neuropsychologist Mario Martinez is a pioneer in the science of the mindbody —his term for that essential oneness of cognition and biology —and a passionate advocate for its power to reshape our lives, if we work with it consciously. In The MindBody Self, he builds on the foundation he laid in the critically acclaimed MindBody Code to explore the cultural conditions that coauthor our reality and shape every aspect of our lives, from health and longevity to relationships and self-esteem. Then he offers practical tools we can use to shed outworn patterns and create sustainable change.You'll read about: • How our cultural beliefs affect the diagnosis, prognosis, and treatment of disease • The difference between growing older (which we all do) and “aging” by our culture's standards (which we can learn not to do) • What happens when we move “beyond the pale” of our tribe's expectations • How to navigate adversity using uncertainty as a guide • Biocognitive tools for a healthy lifeThe MindBody Self presents groundbreaking ideas derived from rigorous scholarship —but you don't need a background in science to use what you find here. Each chapter concludes with exercises and experiential processes that make complex scientific discoveries not only accessible, but applicable. The result is a paradigm shift in which the myths of doom are shattered by the science of hope, survival takes a back seat to meaning, and fear gives way to love.
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- 2017
12. In a World of Social Media: A Case Study Analysis of Instagram
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D. Green, Dr. Daryl, primary and Martinez, Dr. Richard, additional
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- 2018
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13. HYMENOPTERA PARASITICA EN EL CULTIVO DE LA PAPA (Solanum tuberosum L.) Y MALEZ ALEDAÑA EN HUACHICHIL, ARTEAGA COAHUILA
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HERRERA PEREZ, PATRICIA and GARCIA MARTINEZ, Dr. OSWALDO ASESOR
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- 2014
14. SOMATIC DRIVER MUTATIONS IN ORAL AND SINONASAL MUCOSAL MELANOMA. A REFERRAL CENTRE EXPERIENCE IN MEXICO CITY
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Mendoza, Dr. Jessica Lissete Maldonado, Ramirez-Amador, Dr. Velia, Saavedra, Dr. Gabriela Anaya, GarcÍa, Dr. Erika RuÍz, MartÍnez, Dr. HÉctor Maldonado, Figueroa, Dr. Edith FernÁndez, and GarcÍa, Dr. Abelardo Meneses
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- 2019
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15. Predictive Modelling for Iron Ore Exploration Targeting: Case Study: 57 Bt Xaudum Iron Ore Exploration Target (Botswana).
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Martinez, Dr Iuma, primary, Jeffcoate, Dr Alistair, additional, Fuss, Gaetan, additional, de Wit, Dr Mike, additional, Kahari, McDonald, additional, and Ntshasang, Omphile, additional
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- 2015
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16. Spanish Caciquism: Chronicle of an Underdevelopment Foretold?
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Martinez, Dr. J. Agustin Franco, primary
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- 2014
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17. Comité científico de la edición española
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Braojos, Dr. Gustavo Barroso, Campaña, Dra. M.ª Mercedes Bueno, Marcos, Dr. David Crespo, Gómez, Dra. Cristina de Manuel, Martínez, Dr. Pedro del Río, Neyra, Dr. Alejandro López, Fernández, Dra. Cristina Mata, Ajami, Dra. Rasha Isabel Pérez, Picarzo, Dr. Javier Pérez-Lescure, and Asensi, Dr. José Ramón Villa
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- 2020
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18. Fly Me to the Moon: Legal Considerations of Space Exploration Initiatives from the European and US Perspectives
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Bohlmann, Dr. Ulrike M., primary and Martinez, Dr. Larry F., additional
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- 2006
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19. Rectorragia Como Complicación del Síndrome de Klippel Trenaunay.
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Garteiz Martinez, Dr. Denzil, Robledo Ogazon, Dr. Felipe, de La Fuente Lira, Dr. Mauricio, del Carmen Mejia Hernandez, Dra. Maria, and Blanco Buenavides, Dr. Roberto
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- 1999
20. Cambios en la reserva de hierro en mujeres no anémicas entre los 18 y 58 años de edad.
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Baptista Gonzalez, Dr. Hector Alfredo, Peñuela Olaya, Dr. Marco Antonio, Sorroza Martinez, Dr. Miguel Angel, Fanny Rosenfeld, Qfb Mann, and Tello Nielsen, Dr. Juan
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- 1999
21. Presencia de fibronectina fetal en secreción cérvico-vaginal como predictor de parto pretérmino.
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Garcia Alonso L., Dr. Angel, Ayala Mendez, Dr. Jose A., Jimenez Solis, Dr. Guillermo, Sanchez Martinez, Dr. Manuel, and Izquierdo Puente, Dr. Juan C.
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- 1999
22. Seudoquiste abdominal gigante en pacientes con derivación ventriculoperitoneal.
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Aguirre Rivero, Dr. Rafael, Perez Salcedo, Dr. Carlos, Meza Martinez, Dr. Hector, Kuri Guinto, Dr. Javit, and Vazquez Cruz, Dra. Irma
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- 1998
23. Acalasia, alacrima sin insuficiencia suprarrenal, con disfunción neurológica periférica y autonómica (síndrome de Allgrove).
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Garcia-Compean, Dr. Diego, Villegas-Gonzalez, Dr. Mario Jesus, Gonzalez Y Cols., Dr. Jorge Alberto, Ramon Martinez, Dr. Hector, Montes, Dr. Juan, and Garcia Quintanilla, Dr. Francisco
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- 1998
24. Role-Effectiveness of the Pharmacist in the Treatment of Hemodialysis Patients
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Lorisch D, Acchiardo, George C. Wood, Martinez Dr, and Skoutakis Va
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Pharmacology ,medicine.medical_specialty ,Text mining ,business.industry ,Health Policy ,medicine.medical_treatment ,Pharmacist ,Medicine ,Hemodialysis ,business ,Intensive care medicine - Published
- 1978
25. Evaluation of the Usefulness of Echocardiography in Patients With Staphylococcus Aureus Bacteremia (ET-AUREUS Study). (ET-AUREUS)
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Hospital Rafael Mendez, Gregorio Marañón Hospital, University Hospital Virgen de las Nieves, Hospital Universitario La Paz, Hospital Mutua de Terrassa, Hospital Universitario Virgen de la Arrixaca, Hospital Infanta Sofia, Hospitales Universitarios Virgen del Rocío, Hospital de Alava, Hospital de Donosti, Hospital de Basurto, Hospital Universitario Virgen Macarena, Hospital Santa Cruz de Tenerife, and Antonio Ramos Martinez, Dr.
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- 2023
26. Le juif, voilà l'ennemi ! : appel aux catholiquesf / Dr Martinez,...
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Martinez, Dr (professeur de théologie). Auteur du texte and Martinez, Dr (professeur de théologie). Auteur du texte
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Contient une table des matières, Avec mode texte
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- 1890
27. EFECTO DE LA SUPLEMENTACION ALIMENTICIA 15 O 30 DIAS PREPARTO SOBRE EL PESO DE LOS CABRITOS Y PRODUCCION LACTEA EN CABRAS EN AGOSTADERO
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CONTRERAS VILLARREAL, VIRIDIANA and GARCIA MARTINEZ, DR. JOSE EDUARDO
28. Food habits and hunting ranges of short-eared owls (Asio flammeus) in agricultural landscapes of southern Chile
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Martinez, Dr, Figueroa, Ra, Ocampo, Cl, and Fabian M. Jaksic
29. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans
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Alter, G, primary, Yu, J, additional, Liu, J, additional, Chandrashekar, A, additional, Borducchi, EN, additional, Tostanoski, LT, additional, McMahan, K, additional, Jacob-Dolan, C, additional, Martinez, DR, additional, Chang, A, additional, Anioke, T, additional, Lifton, M, additional, Nkolola, J, additional, Stephenson, KE, additional, Atyeo, C, additional, Shin, S, additional, Fields, P, additional, Kaplan, I, additional, Robins, H, additional, Amanat, F, additional, Krammer, F, additional, Baric, RS, additional, Le Gars, M, additional, Sadoff, J, additional, de Groot, AM, additional, Heerwegh, D, additional, Struyf, F, additional, Douoguih, M, additional, van Hoof, J, additional, Schuitemaker, H, additional, and Barouch, DH, additional
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30. Analisis del proceso de gestion y desarrollo del trabajador de la empresa prestadora de servicio de agua potable y alcantarillado de chincha- ica
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Rojas Campos, Ladislao Enrique and Campos Martinez, Dr. José Jorge
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Analisis del proceso de gestion y desarrollo del trabajador de la empresa prestadora de servicio de agua potable y alcantarillado de chincha- ica - Abstract
La tesis tuvo como propósito analizar el proceso de gestión en relación al desarrollo del trabajador de la empresa prestadora de servicio de agua potable y alcantarillado de Chincha- Ica (SEMAPACH S.A.), periodo 2016-2017, problemática que se sustenta con el conocimiento teórico suficiente acerca del estudio. Por tal motivo, debe comprenderse al proceso de gestión, como: clasificación y ordenamiento de las fases y recursos de la organización, tendiente a desarrollar personas acorde con su capacidad, proceso técnicos de rotación, entre otros aspectos que lleva a intercambiar experiencias, vivencias y conocimiento sobre la función asignada. En tal sentido, el mejoramiento del trabajo y servicio en las empresas permite que sean cada vez más competitivas, realidad que se refleja en las habilidades y destrezas de los trabajadores. Por lo tanto, para recolectar y procesar los datos se aplicó técnicas tales como: análisis documental, la encuesta, organización y tabulación de datos. En la comprobación estadística de la hipótesis se aplicó un cuestionario de 14 preguntas con alternativas medibles, realidad que fue comprobada en el lugar de los hechos. La población de estudio estuvo integrada por los trabajadores de SEMAPACH S.A. que operan a nivel de la provincia de Chincha - Ica, teniendo como muestra de estudio a 86 trabajadores, la misma que se calculó a un nivel de confianza del 95% y un margen de error permisible del 5% En consecuencia, según resultados se llegó a la siguiente conclusión general: Que el proceso de gestión afecta el desarrollo del trabajador en la medida que se especifiquen las actividades y el logro de metas u objetivos empresariales, específicamente de la Empresa Prestadora de Servicio de Agua Potable y Alcantarillado de la provincia de Chincha – Ica. Tesis
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- 2018
31. Global genetic diversity of Aedes aegypti
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Joshua B. Richardson, Ambicadutt Bheecarry, Alma Lopez-Solis, Gonçalo Seixas, Maureen Coetzee, Marina B. Chiappero, Amag A. Saleh, Syed Basit Rasheed, Vicki L. Kramer, Olger Calderón-Arguedas, Rosa M. Sanchez-Casas, Basile Kamgang, Carla A. Sousa, Walter J. Tabachnick, Hany A. Kamal, María Victoria Micieli, Alongkot Ponlawat, Emad I.M. Khater, Nil Rahola, Ademir Jesus Martins, Khouaildi Bin Elahee, Adriana Troyo, Joel Lutomiah, Diego Ayala, Ildefonso Fernández-Salas, Jeffrey R. Powell, Andrea Gloria-Soria, Christophe Paupy, Laura D. Kramer, Dave D. Chadee, Yale University [New Haven], Diversity, ecology, evolution & Adaptation of arthropod vectors (MIVEGEC-DEEVA), Evolution des Systèmes Vectoriels (ESV), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Ministry of Health and Quality of Life, Centro de Investigación en Enfermedades Tropicales, Universidad Nacional de Costa Rica, The University of the West Indies, Universidad Nacional de Córdoba [Argentina], University of the Witwatersrand [Johannesburg] (WITS), Centro Regional de Investigación en Salud Pública = Regional Centre of Research in Public Health [Tapachula, Mexique] (CRISP), National Institute of Public Health = Instituto Nacional de Salud Pública [Cuernavaca, Mexique] (INSP), Centre for Research in Infectious Diseases [Yaoundé] (CRID), King Saud University [Riyadh] (KSU), Wadsworth Center, New York State Department of Health [Albany], Kenya Medical Research Institute (KEMRI), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Centro de Estudios Parasitologicos y de Vectores [La Plata] (CEPAVE), Universidad Nacional de la Plata [Argentine] (UNLP)-Comisión de Investigaciones Científicas [Buenos Aires] (CIC)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), University of Peshawar (UOP), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), University of Florida [Gainesville] (UF), Universidad de Costa Rica (UCR), Financial support was provided by NIAID RO1 AI101112 awarded to JRP. A. Gloria‐Soria was supported by NIAID 3R01AI091646‐04S1. G. Seixas was funded by a PhD fellowship of Fundação para a Ciência e Tecnologia/MCTES (SFRH/BD/98873/2013). EIK and AAS were funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia (Award Number BIO1483), to EIK., We thank generous colleagues who assisted in providing the samples for this study, and we thank J. Pinto, R. Butlin, M. Boots, D. Severson, R. Kelly, K. McCarley, Y. Lourenco, R. Martinez, Dr E. Nchoutpouen, S. Kluh, L. Irby, M. Garcia, A. Scalzo, S. Mulligan, J. Holeman, R. Gay, N. Zahiri, B. Weber and D. J. Gubler. We thank David A. Kellner and Robert Hallberg who provided technical assistance in the laboratory.
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0301 basic medicine ,History ,Asia ,Otras Ciencias Biológicas ,030231 tropical medicine ,[SDV.BID]Life Sciences [q-bio]/Biodiversity ,Biology ,Subspecies ,Invasive species ,microsatellites ,Article ,purl.org/becyt/ford/1 [https] ,Ciencias Biológicas ,03 medical and health sciences ,Monophyly ,0302 clinical medicine ,Aedes aegypti ,Invasion ,Aedes ,Aedes mascarensis ,Genetic variation ,Genetics ,Ciencias Naturales ,Animals ,purl.org/becyt/ford/1.6 [https] ,Microsatellites ,Ecology, Evolution, Behavior and Systematics ,Genetic diversity ,Ecology ,fungi ,Genetic Variation ,biology.organism_classification ,invasion ,Kenya ,Senegal ,030104 developmental biology ,Genetics, Population ,Habitat ,history ,CIENCIAS NATURALES Y EXACTAS ,Founder effect ,Microsatellite Repeats - Abstract
Mosquitoes, especially Aedes aegypti, are becoming important models for studying invasion biology. We characterized genetic variation at 12 microsatellite loci in 79 populations of Ae. aegypti from 30 countries in six continents, and used them to infer historical and modern patterns of invasion. Our results support the two subspecies Ae. aegypti formosus and Ae. aegypti aegypti as genetically distinct units. Ae. aegypti aegypti populations outside Africa are derived from ancestral African populations and are monophyletic. The two subspecies co-occur in both East Africa (Kenya) and West Africa (Senegal). In rural/forest settings (Rabai District of Kenya), the two subspecies remain genetically distinct, whereas in urban settings, they introgress freely. Populations outside Africa are highly genetically structured likely due to a combination of recent founder effects, discrete discontinuous habitats and low migration rates. Ancestral populations in sub-Saharan Africa are less genetically structured, as are the populations in Asia. Introduction of Ae. aegypti to the New World coinciding with trans-Atlantic shipping in the 16th to 18th centuries was followed by its introduction to Asia in the late 19th century from the New World or from now extinct populations in the Mediterranean Basin. Aedes mascarensis is a genetically distinct sister species to Ae. aegypti s.l. This study provides a reference database of genetic diversity that can be used to determine the likely origin of new introductions that occur regularly for this invasive species. The genetic uniqueness of many populations and regions has important implications for attempts to control Ae. aegypti, especially for the methods using genetic modification of populations., Centro de Estudios Parasitológicos y de Vectores
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- 2016
32. Liquid droplets and gas interactions in two-phase flow
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Zoby, Maria Regina Gomes, Kronenburg, Professor Andreas, Marquis, Dr. Fred, Navarro-Martinez, Dr. Salvador, and CNPQ - Ministery of Science and Technology of Brazil
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Physics::Fluid Dynamics - Abstract
The work focuses on the interactions of the two phases (liquid and gas) in droplet flows. Most studies of sprays do not resolve the liquid phase nor the near field and droplets are treated as point sources of mass, momentum, energy and species. In the present work, two- and three-dimensional Direct Numerical Simulations of fully resolved droplet arrays are analysed. Simulations of droplets arrays in inert and reacting environments are performed and evaporation rates and fuel vapour mixing in laminar and turbulent flows are assessed. The novel model developed in this work combines the one- and two-fluid formulations for multiphase flows. The energy transport equation is solved based on a one-fluid formulation while the species, velocities and pressure equations are solved with a two-fluid formulation. In addition, a Level Set technique is combined with the Ghost Fluid method in a mass conserving approach in order to track the liquid interfaces. The numerical algorithm was parallelised in order to satisfy the computational demand of the simulations. The validation tests performed show that the model implemented is able to capture the dynamic behavior of droplet interactions and heat and mass transfer across interfaces. The effects of turbulence and droplet density on droplet evaporation rates in reacting flows is investigated for n-heptane and kerosene droplet arrays. The evaporation rates are compared to existing models commonly used in Large Eddy Simulations and Reynolds-averaged Navier-Stokes computations. A shell around the droplet approach is proposed in order to estimate the gas properties used in these models. It is noted that this approach allows the models to capture transients and provides predictions of the evaporation rates with errors around 2%. The gas phase mixing is assessed by examining the distribution of scalar dissipation. Novel multi-conditional models are proposed that use mixture fraction, distance to previous droplet and zone of location as the conditioning variables for the scalar dissipation. The scalar dissipation is found to be well predicted in terms of magnitude and distribution. The accurate representation of the mean scalar dissipation is achieved. The b-PDF description of the mixture fraction seems to capture well the global behaviour for a laminar environment and for time averaged results in the turbulent cases. Open access
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- 2010
33. Decoding reveals the neural representation of perceived and imagined musical sounds.
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Quiroga-Martinez DR, Rubio GF, Bonetti L, Achyutuni KG, Tzovara A, Knight RT, and Vuust P
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Vividly imagining a song or a melody is a skill that many people accomplish with relatively little effort. However, we are only beginning to understand how the brain represents, holds, and manipulates these musical "thoughts." Here, we decoded perceived and imagined melodies from magnetoencephalography (MEG) brain data (N = 71) to characterize their neural representation. We found that, during perception, auditory regions represent the sensory properties of individual sounds. In contrast, a widespread network including fronto-parietal cortex, hippocampus, basal nuclei, and sensorimotor regions hold the melody as an abstract unit during both perception and imagination. Furthermore, the mental manipulation of a melody systematically changes its neural representation, reflecting volitional control of auditory images. Our work sheds light on the nature and dynamics of auditory representations, informing future research on neural decoding of auditory imagination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
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- 2024
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34. Decoding reveals the neural representation of perceived and imagined musical sounds.
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Quiroga Martinez DR, Fernández Rubio G, Bonetti L, Achyutuni KG, Tzovara A, Knight RT, and Vuust P
- Abstract
Vividly imagining a song or a melody is a skill that many people accomplish with relatively little effort. However, we are only beginning to understand how the brain represents, holds, and manipulates these musical "thoughts". Here, we decoded perceived and imagined melodies from magnetoencephalography (MEG) brain data (N = 71) to characterize their neural representation. We found that, during perception, auditory regions represent the sensory properties of individual sounds. In contrast, a widespread network including fronto-parietal cortex, hippocampus, basal nuclei, and sensorimotor regions hold the melody as an abstract unit during both perception and imagination. Furthermore, the mental manipulation of a melody systematically changes its neural representation, reflecting volitional control of auditory images. Our work sheds light on the nature and dynamics of auditory representations, informing future research on neural decoding of auditory imagination., Competing Interests: Competing interests The authors declare no competing interests.
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- 2024
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35. SARS-CoV-2-related bat viruses evade human intrinsic immunity but lack efficient transmission capacity.
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Peña-Hernández MA, Alfajaro MM, Filler RB, Moriyama M, Keeler EL, Ranglin ZE, Kong Y, Mao T, Menasche BL, Mankowski MC, Zhao Z, Vogels CBF, Hahn AM, Kalinich CC, Zhang S, Huston N, Wan H, Araujo-Tavares R, Lindenbach BD, Homer R, Pyle AM, Martinez DR, Grubaugh ND, Israelow B, Iwasaki A, and Wilen CB
- Subjects
- Animals, Humans, Mice, Cricetinae, Immune Evasion, Epithelial Cells virology, Epithelial Cells immunology, Coronavirus Infections transmission, Coronavirus Infections immunology, Coronavirus Infections virology, Coronavirus immunology, Coronavirus genetics, Coronavirus classification, Coronavirus physiology, Coronavirus pathogenicity, Cell Line, Female, SARS-CoV-2 immunology, SARS-CoV-2 genetics, SARS-CoV-2 physiology, Chiroptera virology, Chiroptera immunology, COVID-19 transmission, COVID-19 virology, COVID-19 immunology, Virus Replication, Immunity, Innate
- Abstract
Circulating bat coronaviruses represent a pandemic threat. However, our understanding of bat coronavirus pathogenesis and transmission potential is limited by the lack of phenotypically characterized strains. We created molecular clones for the two closest known relatives of SARS-CoV-2, BANAL-52 and BANAL-236. We demonstrated that BANAL-CoVs and SARS-CoV-2 have similar replication kinetics in human bronchial epithelial cells. However, BANAL-CoVs have impaired replication in human nasal epithelial cells and in the upper airway of mice. We also observed reduced pathogenesis in mice and diminished transmission in hamsters. Further, we observed that diverse bat coronaviruses evade interferon and downregulate major histocompatibility complex class I. Collectively, our study demonstrates that despite high genetic similarity across bat coronaviruses, prediction of pandemic potential of a virus necessitates functional characterization. Finally, the restriction of bat coronavirus replication in the upper airway highlights that transmission potential and innate immune restriction can be uncoupled in this high-risk family of emerging viruses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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36. mRNA-LNP vaccine-induced CD8 + T cells protect mice from lethal SARS-CoV-2 infection in the absence of specific antibodies.
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Montoya B, Melo-Silva CR, Tang L, Kafle S, Lidskiy P, Bajusz C, Vadovics M, Muramatsu H, Abraham E, Lipinszki Z, Chatterjee D, Scher G, Benitez J, Sung MMH, Tam YK, Catanzaro NJ, Schäfer A, Andino R, Baric RS, Martinez DR, Pardi N, and Sigal LJ
- Subjects
- Animals, Mice, Female, Male, Mice, Inbred C57BL, Humans, Disease Models, Animal, CD8-Positive T-Lymphocytes immunology, SARS-CoV-2 immunology, COVID-19 immunology, COVID-19 prevention & control, Spike Glycoprotein, Coronavirus immunology, Spike Glycoprotein, Coronavirus genetics, COVID-19 Vaccines immunology, Antibodies, Viral immunology
- Abstract
The role of CD8
+ T cells in SARS-CoV-2 pathogenesis or mRNA-LNP vaccine-induced protection from lethal COVID-19 is unclear. Using mouse-adapted SARS-CoV-2 virus (MA30) in C57BL/6 mice, we show that CD8+ T cells are unnecessary for the intrinsic resistance of female or the susceptibility of male mice to lethal SARS-CoV-2 infection. Also, mice immunized with a di-proline prefusion-stabilized full-length SARS-CoV-2 Spike (S-2P) mRNA-LNP vaccine, which induces Spike-specific antibodies and CD8+ T cells specific for the Spike-derived VNFNFNGL peptide, are protected from SARS-CoV-2 infection-induced lethality and weight loss, while mice vaccinated with mRNA-LNPs encoding only VNFNFNGL are protected from lethality but not weight loss. CD8+ T cell depletion ablates protection in VNFNFNGL but not in S-2P mRNA-LNP-vaccinated mice. Therefore, mRNA-LNP vaccine-induced CD8+ T cells are dispensable when protective antibodies are present but essential for survival in their absence. Hence, vaccine-induced CD8+ T cells may be critical to protect against SARS-CoV-2 variants that mutate epitopes targeted by protective antibodies., Competing Interests: Declaration of interests L.J.S. is a member of the Scientific Advisory Board of RNA Advanced Technologies member. N.P. is named on patents describing the use of nucleoside-modified mRNA in LNPs as a vaccine platform. He has disclosed those interests fully to the University of Pennsylvania and has an approved plan for managing potential conflicts arising from licensing those patents. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022 and Pfizer in 2023–2024, and is a member of the Scientific Advisory Board of AldexChem and BioNet and has consulted for Vaccine Company Inc. and Pasture Bio. R.S.B. is a member of the Scientific Advisory Board of Invivyd and VaxArt and has consulted on virus-related countermeasures with Gilead, Moderna, Takeda, BioNet, and Jenssen Bio unrelated to this project. Y.K.T. and M.M.H. Sung are employees of Acuitas Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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37. Mapping of susceptibility loci for Ebola virus pathogenesis in mice.
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Schäfer A, Marzi A, Furuyama W, Catanzaro NJ, Nguyen C, Haddock E, Feldmann F, Meade-White K, Thomas T, Hubbard ML, Gully KL, Leist SR, Hock P, Bell TA, De la Cruz GE, Midkiff BR, Martinez DR, Shaw GD, Miller DR, Vernon MJ, Graham RL, Cowley DO, Montgomery SA, Schughart K, de Villena FPM, Wilkerson GK, Ferris MT, Feldmann H, and Baric RS
- Subjects
- Animals, Mice, Mice, Knockout, Chromosome Mapping, Liver pathology, Liver metabolism, Humans, Mice, Inbred C57BL, Female, Male, Hemorrhagic Fever, Ebola virology, Hemorrhagic Fever, Ebola genetics, Hemorrhagic Fever, Ebola pathology, Quantitative Trait Loci genetics, Ebolavirus pathogenicity, Ebolavirus genetics, Genetic Predisposition to Disease
- Abstract
Ebola virus (EBOV), a major global health concern, causes severe, often fatal EBOV disease (EVD) in humans. Host genetic variation plays a critical role, yet the identity of host susceptibility loci in mammals remains unknown. Using genetic reference populations, we generate an F2 mapping cohort to identify host susceptibility loci that regulate EVD. While disease-resistant mice display minimal pathogenesis, susceptible mice display severe liver pathology consistent with EVD-like disease and transcriptional signatures associated with inflammatory and liver metabolic processes. A significant quantitative trait locus (QTL) for virus RNA load in blood is identified in chromosome (chr)8, and a severe clinical disease and mortality QTL is mapped to chr7, which includes the Trim5 locus. Using knockout mice, we validate the Trim5 locus as one potential driver of liver failure and mortality after infection. The identification of susceptibility loci provides insight into molecular genetic mechanisms regulating EVD progression and severity, potentially informing therapeutics and vaccination strategies., Competing Interests: Declaration of interests D.O.C. is employed by, has equity ownership in, and serves on the board of directors of TransViragen, the company that has been contracted by UNC-Chapel Hill to manage its Animal Models Core Facility. R.S.B. is a member of advisory boards for VaxArt, Takeda, and Invivyd, focused on unrelated projects., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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38. The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.
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Martinez DR, Moreira FR, Catanzaro NJ, Diefenbacher MV, Zweigart MR, Gully KL, De la Cruz G, Brown AJ, Adams LE, Yount B, Baric TJ, Mallory ML, Conrad H, May SR, Dong S, Scobey DT, Nguyen C, Montgomery SA, Perry JK, Babusis D, Barrett KT, Nguyen AH, Nguyen AQ, Kalla R, Bannister R, Feng JY, Cihlar T, Baric RS, Mackman RL, Bilello JP, Schäfer A, and Sheahan TP
- Subjects
- Animals, Humans, Mice, Administration, Oral, Chlorocebus aethiops, Vero Cells, COVID-19 Drug Treatment, COVID-19 virology, Virus Replication drug effects, Nucleosides pharmacology, Nucleosides therapeutic use, Nucleosides chemistry, Coronavirus Infections drug therapy, Coronavirus Infections virology, Female, Disease Models, Animal, SARS-CoV-2 drug effects, Prodrugs pharmacology, Prodrugs therapeutic use, Antiviral Agents pharmacology, Antiviral Agents therapeutic use
- Abstract
Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M
pro ) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.- Published
- 2024
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39. Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.
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Dillard JA, Taft-Benz SA, Knight AC, Anderson EJ, Pressey KD, Parotti B, Martinez SA, Diaz JL, Sarkar S, Madden EA, De la Cruz G, Adams LE, Dinnon KH 3rd, Leist SR, Martinez DR, Schäfer A, Powers JM, Yount BL Jr, Castillo IN, Morales NL, Burdick J, Evangelista MKD, Ralph LM, Pankow NC, Linnertz CL, Lakshmanane P, Montgomery SA, Ferris MT, Baric RS, Baxter VK, and Heise MT
- Subjects
- Animals, Female, Mice, Disease Models, Animal, Adjuvants, Immunologic administration & dosage, Adjuvants, Vaccine, Antibodies, Viral immunology, Mice, Inbred BALB C, Humans, Severe acute respiratory syndrome-related coronavirus immunology, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, COVID-19 prevention & control, COVID-19 immunology, COVID-19 virology, Vaccines, Inactivated immunology, SARS-CoV-2 immunology, Aluminum Hydroxide administration & dosage
- Abstract
Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection., (© 2024. The Author(s).)
- Published
- 2024
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40. Provider Perspectives: Identification and Follow-up of Infants who Are Deaf or Hard of Hearing.
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Cree RA, Bitsko R, Grimm C, Nash A, Cahill ES, Dunham E, Logan N, McKay SL, Martinez DR, and Gaffney M
- Subjects
- Humans, Texas, Infant, Newborn, Qualitative Research, Female, Male, Hearing Loss diagnosis, Hearing Loss therapy, Health Services Accessibility, Lost to Follow-Up, Deafness diagnosis, Interviews as Topic, Infant, Attitude of Health Personnel, Neonatal Screening
- Abstract
Objective: Without timely screening, diagnosis, and intervention, hearing loss can cause significant delays in a child's speech, language, social, and emotional development. In 2019, Texas had nearly twice the average rate of loss to follow-up (LFU) or loss to documentation (LTD; i.e., missing documentation of services received) among infants who did not pass their newborn hearing screening compared to the United States overall (51.1 vs. 27.5%). We aimed to identify factors contributing to LFU/LTD among infants who do not pass their newborn hearing screening in Texas., Study Design: Data were collected through semistructured qualitative interviews with 56 providers along the hearing care continuum, including hospital newborn hearing screening program staff, audiologists, primary care physicians, and early intervention (EI) program staff located in three rural and urban public health regions in Texas. Following recording and transcription of the interviews, we used qualitative data analysis software to analyze themes using a conventional content analysis approach., Results: Frequently cited barriers included problems with family access to care, difficulty contacting patients, problems with communication between providers and referrals, lack of knowledge among providers and parents, and problems using the online reporting system. Providers in rural areas more often mentioned problems with family access to care and contacting families compared to providers in urban areas., Conclusion: These findings provide insight into strategies that public health professionals and health care providers can use to work together to help further increase the number of children identified early who may benefit from EI services., Key Points: · Infants with suspected hearing loss may not receive timely diagnosis or early intervention.. · We interviewed healthcare providers in Texas along the hearing care continuum.. · Findings suggest strategies to increase the number of children with hearing loss identified early.., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2024
- Full Text
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41. Mutations spike in a reservoir of compromised immunity.
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Seo J and Martinez DR
- Subjects
- Mutation, Kinetics, Immunosuppression Therapy, SARS-CoV-2
- Abstract
The hierarchy of immunosuppression predicts SARS-CoV-2 time to clearance and intrahost viral evolution.
- Published
- 2024
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42. A nano-luciferase expressing human coronavirus OC43 for countermeasure development.
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Diefenbacher MV, Baric TJ, Martinez DR, Baric RS, Catanzaro NJ, and Sheahan TP
- Subjects
- Humans, Viral Proteins, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Coronavirus OC43, Human genetics, Coronavirus genetics, Coronavirus Infections
- Abstract
The genetic diversity of the coronavirus (CoV) family poses a significant challenge for drug discovery and development. Traditional antiviral drugs often target specific viral proteins from specific viruses which limits their use, especially against novel emerging viruses. Antivirals with broad-spectrum activity overcome this limitation by targeting highly conserved regions or catalytic domains within viral proteins that are essential for replication. For rapid identification of small molecules with broad antiviral activity, assays with viruses representing family-wide genetic diversity are needed. Viruses engineered to express a reporter gene (i.e. luminescence, fluorescence, etc.) can increase the efficiency, sensitivity or precision of drug screening over classical measures of replication like observation of cytopathic effect or measurement of infectious titers. We have previously developed reporter virus systems for multiple other endemic, pandemic, epidemic and enzootic CoV. Human CoV OC43 (HCoV-OC43) is a human endemic CoV that causes respiratory infection with age-related exacerbations of pathogenesis. Here, we describe the development of a novel recombinant HCoV-OC43 reporter virus that expresses nano-luciferase (HCoV-OC43 nLuc), and its potential application for screening of antivirals against CoV., Competing Interests: Declaration of Competing Interest T.P.S. has received funding from ViiV Healthcare and GlaxoSmithKline and has collaboratins with Ridgeback Biosciences and Gilead. R.S.B. is a member of the advisory board of VaxArt and Inviyd, and has collaborations with Takeda, Pfizer, Moderna, Ridgeback Biosciences, Gilead, and Eli Lily., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
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- View/download PDF
43. Asymmetric coding of reward prediction errors in human insula and dorsomedial prefrontal cortex.
- Author
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Hoy CW, Quiroga-Martinez DR, Sandoval E, King-Stephens D, Laxer KD, Weber P, Lin JJ, and Knight RT
- Subjects
- Humans, Prefrontal Cortex physiology, Brain physiology, Learning, Reward, Reinforcement, Psychology
- Abstract
The signed value and unsigned salience of reward prediction errors (RPEs) are critical to understanding reinforcement learning (RL) and cognitive control. Dorsomedial prefrontal cortex (dMPFC) and insula (INS) are key regions for integrating reward and surprise information, but conflicting evidence for both signed and unsigned activity has led to multiple proposals for the nature of RPE representations in these brain areas. Recently developed RL models allow neurons to respond differently to positive and negative RPEs. Here, we use intracranially recorded high frequency activity (HFA) to test whether this flexible asymmetric coding strategy captures RPE coding diversity in human INS and dMPFC. At the region level, we found a bias towards positive RPEs in both areas which paralleled behavioral adaptation. At the local level, we found spatially interleaved neural populations responding to unsigned RPE salience and valence-specific positive and negative RPEs. Furthermore, directional connectivity estimates revealed a leading role of INS in communicating positive and unsigned RPEs to dMPFC. These findings support asymmetric coding across distinct but intermingled neural populations as a core principle of RPE processing and inform theories of the role of dMPFC and INS in RL and cognitive control., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
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44. Broadly neutralizing antibody induction by non-stabilized SARS-CoV-2 Spike mRNA vaccination in nonhuman primates.
- Author
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Malewana RD, Stalls V, May A, Lu X, Martinez DR, Schäfer A, Li D, Barr M, Sutherland LL, Lee E, Parks R, Beck WE, Newman A, Bock KW, Minai M, Nagata BM, DeMarco CT, Denny TN, Oguin TH 3rd, Rountree W, Wang Y, Mansouri K, Edwards RJ, Sempowski GD, Eaton A, Muramatsu H, Henderson R, Tam Y, Barbosa C, Tang J, Cain DW, Santra S, Moore IN, Andersen H, Lewis MG, Golding H, Seder R, Khurana S, Montefiori DC, Pardi N, Weissman D, Baric RS, Acharya P, Haynes BF, and Saunders KO
- Abstract
Immunization with mRNA or viral vectors encoding spike with diproline substitutions (S-2P) has provided protective immunity against severe COVID-19 disease. How immunization with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike elicits neutralizing antibodies (nAbs) against difficult-to-neutralize variants of concern (VOCs) remains an area of great interest. Here, we compare immunization of macaques with mRNA vaccines expressing ancestral spike either including or lacking diproline substitutions, and show the diproline substitutions were not required for protection against SARS-CoV-2 challenge or induction of broadly neutralizing B cell lineages. One group of nAbs elicited by the ancestral spike lacking diproline substitutions targeted the outer face of the receptor binding domain (RBD), neutralized all tested SARS-CoV-2 VOCs including Omicron XBB.1.5, but lacked cross-Sarbecovirus neutralization. Structural analysis showed that the macaque broad SARS-CoV-2 VOC nAbs bound to the same epitope as a human broad SARS-CoV-2 VOC nAb, DH1193. Vaccine-induced antibodies that targeted the RBD inner face neutralized multiple Sarbecoviruses, protected mice from bat CoV RsSHC014 challenge, but lacked Omicron variant neutralization. Thus, ancestral SARS-CoV-2 spike lacking proline substitutions encoded by nucleoside-modified mRNA can induce B cell lineages binding to distinct RBD sites that either broadly neutralize animal and human Sarbecoviruses or recent Omicron VOCs., Competing Interests: Competing interests: DW and NP are inventors on patents regarding nucleoside modified mRNA. Ying Tam and Christopher Barbosa are employees of Acuitas Therapeutics. Rory Henderson has patents regarding engineered forms of Spike proteins. Barton Haynes, Kevin Saunders, Dapeng Li, Priyamvada Acharya, and Xiaozhi Lu have patents regarding human antibodies and their uses. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022. N.P. is a member of the Scientific Advisory Board of AldexChem.
- Published
- 2023
- Full Text
- View/download PDF
45. "Training immunity" against nosocomial pathogens.
- Author
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Schäfer A and Martinez DR
- Subjects
- Humans, Trained Immunity, Immunity, Innate, Hospitals, Cross Infection, Vaccines
- Abstract
Non-antigen vaccines that broadly activate innate immune responses reduce mortality against hospital-acquired bacterial and fungal pathogens.
- Published
- 2023
- Full Text
- View/download PDF
46. Vaccine-mediated protection against Merbecovirus and Sarbecovirus challenge in mice.
- Author
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Martinez DR, Schäfer A, Gavitt TD, Mallory ML, Lee E, Catanzaro NJ, Chen H, Gully K, Scobey T, Korategere P, Brown A, Smith L, Parks R, Barr M, Newman A, Bowman C, Powers JM, Soderblom EJ, Mansouri K, Edwards RJ, Baric RS, Haynes BF, and Saunders KO
- Subjects
- Animals, Humans, Mice, COVID-19 Vaccines, Antibodies, Viral, Antibodies, Neutralizing, SARS-CoV-2, Middle East Respiratory Syndrome Coronavirus, Severe acute respiratory syndrome-related coronavirus
- Abstract
The emergence of three highly pathogenic human coronaviruses-severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, Middle Eastern respiratory syndrome (MERS)-CoV in 2012, and SARS-CoV-2 in 2019-underlines the need to develop broadly active vaccines against the Merbecovirus and Sarbecovirus betacoronavirus subgenera. While SARS-CoV-2 vaccines protect against severe COVID-19, they do not protect against other sarbecoviruses or merbecoviruses. Here, we vaccinate mice with a trivalent sortase-conjugate nanoparticle (scNP) vaccine containing the SARS-CoV-2, RsSHC014, and MERS-CoV receptor-binding domains (RBDs), which elicited live-virus neutralizing antibody responses. The trivalent RBD scNP elicited serum neutralizing antibodies against bat zoonotic Wuhan Institute of Virology-1 (WIV-1)-CoV, SARS-CoV, SARS-CoV-2 BA.1, SARS-CoV-2 XBB.1.5, and MERS-CoV live viruses. The monovalent SARS-CoV-2 RBD scNP vaccine only protected against Sarbecovirus challenge, whereas the trivalent RBD scNP vaccine protected against both Merbecovirus and Sarbecovirus challenge in highly pathogenic and lethal mouse models. This study demonstrates proof of concept for a single pan-sarbecovirus/pan-merbecovirus vaccine that protects against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera., Competing Interests: Declaration of interests B.F.H. and K.O.S. have filed US patents regarding the nanoparticle vaccine. R.S.B. is on the scientific advisory boards of VaxArt, Invivyd, and Takeda., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
47. Host range, transmissibility and antigenicity of a pangolin coronavirus.
- Author
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Hou YJ, Chiba S, Leist SR, Meganck RM, Martinez DR, Schäfer A, Catanzaro NJ, Sontake V, West A, Edwards CE, Yount B, Lee RE, Gallant SC, Zost SJ, Powers J, Adams L, Kong EF, Mattocks M, Tata A, Randell SH, Tata PR, Halfmann P, Crowe JE Jr, Kawaoka Y, and Baric RS
- Subjects
- Cricetinae, Humans, Animals, Mice, Host Specificity, Pangolins, SARS-CoV-2 genetics, Antibodies, Viral, COVID-19 Vaccines, Mice, Inbred BALB C, COVID-19 prevention & control, Severe acute respiratory syndrome-related coronavirus
- Abstract
The pathogenic and cross-species transmission potential of SARS-CoV-2-related coronaviruses (CoVs) remain poorly characterized. Here we recovered a wild-type pangolin (Pg) CoV GD strain including derivatives encoding reporter genes using reverse genetics. In primary human cells, PgCoV replicated efficiently but with reduced fitness and showed less efficient transmission via airborne route compared with SARS-CoV-2 in hamsters. PgCoV was potently inhibited by US Food and Drug Administration approved drugs, and neutralized by COVID-19 patient sera and SARS-CoV-2 therapeutic antibodies in vitro. A pan-Sarbecovirus antibody and SARS-CoV-2 S2P recombinant protein vaccine protected BALB/c mice from PgCoV infection. In K18-hACE2 mice, PgCoV infection caused severe clinical disease, but mice were protected by a SARS-CoV-2 human antibody. Efficient PgCoV replication in primary human cells and hACE2 mice, coupled with a capacity for airborne spread, highlights an emergence potential. However, low competitive fitness, pre-immune humans and the benefit of COVID-19 countermeasures should impede its ability to spread globally in human populations., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
48. A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
- Author
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Tse LV, Hou YJ, McFadden E, Lee RE, Scobey TD, Leist SR, Martinez DR, Meganck RM, Schäfer A, Yount BL, Mascenik T, Powers JM, Randell SH, Zhang Y, Wang L, Mascola J, McLellan JS, and Baric RS
- Subjects
- Humans, Animals, Mice, Dipeptidyl Peptidase 4 genetics, Dipeptidyl Peptidase 4 metabolism, Cryoelectron Microscopy, Antibodies, Monoclonal metabolism, Middle East Respiratory Syndrome Coronavirus, Chiroptera, Coronavirus Infections
- Abstract
The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)-related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV/ li /GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/M
pro protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV-neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo-electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.- Published
- 2023
- Full Text
- View/download PDF
49. Targeting spike glycans to inhibit SARS-CoV2 viral entry.
- Author
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Guseman AJ, Rennick LJ, Nambulli S, Roy CN, Martinez DR, Yang DT, Bhinderwala F, Vergara S, Schaefer A, Baric RS, Ambrose Z, Duprex WP, and Gronenborn AM
- Subjects
- Humans, RNA, Viral, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Virus Internalization, Agglutinins, Lectins, Polysaccharides pharmacology, COVID-19
- Abstract
SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors.
- Published
- 2023
- Full Text
- View/download PDF
50. Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential.
- Author
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Martinez DR, Moreira FR, Zweigart MR, Gully KL, De la Cruz G, Brown AJ, Adams LE, Catanzaro N, Yount B, Baric TJ, Mallory ML, Conrad H, May SR, Dong S, Scobey DT, Montgomery SA, Perry J, Babusis D, Barrett KT, Nguyen AH, Nguyen AQ, Kalla R, Bannister R, Bilello JP, Feng JY, Cihlar T, Baric RS, Mackman RL, Schäfer A, and Sheahan TP
- Abstract
Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (M
pro ) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions., Competing Interests: DECLARATION OF INTERESTS These authors are employees of Gilead Sciences and hold stock in Gilead Sciences: D.B., A.N., K.T.B., R.B, J.P.B., J.Y.F., T.C., R.L.M.- Published
- 2023
- Full Text
- View/download PDF
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