Proyectos

One goal is to enhance the methods being currently developed by Espı́ndola (Physics), Krause (Physiology), and Xavier (Biomedical Engineering) for reconstructing capillary networks with ultrasound. The super-resolution is needed for early detection diseases such as cognitive decline, cancer, or liver fibrosis. They perfuse lipid-encapsulated microbubbles as contrast agents and then localize the bubbles in the ultrasound images with the singular value filter. However, that method leaves a non-negligible percentage of bubbles undetected. Here we propose to complement the singular value filter for the detection and tracking of microbubbles with the sophisticated and mathematically sound Mumford-Shah method for image contour detection, which stems from the conceptually-insightful and numerically-robust perspective of the minimization of energies. In the reconstruction of the capillary network from ultrasound, it is impossible to directly distinguish the microbubbles, or even the blood vessels, in each frame separately, due to the attentuation and degradation in this imaging technique. It is essential to take into account the dynamic nature of the problem, distinguishing the slowly-varying signals emitted by the tissue from those emitted by the microbubbles, which flow rapidly, behave nonlinearly, and have a much shorter coherence length. We therefore propose to regard the collection of two-dimensional frames as a single three-dimensional image, where a moving bubble becomes a tubular neighbourhood of a filament, which the Mumford-Shah model is expected to recover. From these filaments, bubbles can be detected and tracked, and the vertical inclinations of theses filaments will yield the microbubbles velocities. From the velocity profiles it is possible to estimate the shear wall stresses (their ‘tangential elastic rigidities’) of the blood vessels, and anomalies in these stresses are commonly good indicators of the presence of specific diseases. A fortunate encounter between mathematics and mechanics led to the observation that the problem of finding the path that the propagation of a crack will follow inside a structure upon loading could be solved with the mathematical theory (the analysis of free-discontinuity problems) developed for the apparently unrelated image segmentation Mumford-Shah model. The variational fracture theory initiated by Francfort and Marigo is by now (20 years after) very well established. The second goal of this proposal is to further develop the ongoing collaboration between Song (Pharmaceutics), Siegel (Pharmaceutics), Sánchez (Numerical analysis), Calderer (Applied mathematics), and the PI on the study of the debonding of polymer gels from rigid substrates (relevant in the design of the synthetic polymers coating the metallic parts of pacemakers and other medical prostheses) from this variational fracture theory perspective. The third main goal is to apply the mathematical analysis of free-discontinuity problems to the modelling of the evolution of the cavity in the block caving technique in underground rock mining. This has been pursued by Ortega, Lecaros, and coworkers from the side of applied mathematics in academia, in collaboration with Gaete from the Geomechanics Research Department at El Teniente, research group to which Gutiérrez and the PI have joined in the last months. We propose to study the seismic activity induced by the fracture of the rock mass due to gravity, following the works in the last decade within the variational fracture theory that incorporate the inertia effects. The final aim is to optimize the injection of water jets for the aminoration of the seismic events near the operation sites. The three research lines are applications of the phase-field regularization by Ambrosio and Tortorelli of the Mumford-Shah free-discontinuity model, a different variant being required in each of the three contexts. The first stage of the implementation is of mathematical modelling and high-level numerical simulation abilities, in which the intuition and first-hand knowledge from the members of the research team that are experts in vascular function, ultrasound imaging, polymer chemistry, and mining geomechanics is translated into particular mathematical concepts and concrete computational methods. This is followed by a stage of calibration and validation, where the full interplay with experiments is required. The product of a robust and validated computational method will constitute then an advancement in the capabilities, available resources, and understanding in each of the applied disciplines.

One goal is to enhance the methods being currently developed by Espı́ndola (Physics), Krause (Physiology), and Xavier (Biomedical Engineering) for reconstructing capillary networks with ultrasound. The super-resolution is needed for early detection diseases such as cognitive decline, cancer, or liver fibrosis. They perfuse lipid-encapsulated microbubbles as contrast agents and then localize the bubbles in the ultrasound images with the singular value filter. However, that method leaves a non-negligible percentage of bubbles undetected. Here we propose to complement the singular value filter for the detection and tracking of microbubbles with the sophisticated and mathematically sound Mumford-Shah method for image contour detection, which stems from the conceptually-insightful and numerically-robust perspective of the minimization of energies. In the reconstruction of the capillary network from ultrasound, it is impossible to directly distinguish the microbubbles, or even the blood vessels, in each frame separately, due to the attentuation and degradation in this imaging technique. It is essential to take into account the dynamic nature of the problem, distinguishing the slowly-varying signals emitted by the tissue from those emitted by the microbubbles, which flow rapidly, behave nonlinearly, and have a much shorter coherence length. We therefore propose to regard the collection of two-dimensional frames as a single three-dimensional image, where a moving bubble becomes a tubular neighbourhood of a filament, which the Mumford-Shah model is expected to recover. From these filaments, bubbles can be detected and tracked, and the vertical inclinations of theses filaments will yield the microbubbles velocities. From the velocity profiles it is possible to estimate the shear wall stresses (their ‘tangential elastic rigidities’) of the blood vessels, and anomalies in these stresses are commonly good indicators of the presence of specific diseases. A fortunate encounter between mathematics and mechanics led to the observation that the problem of finding the path that the propagation of a crack will follow inside a structure upon loading could be solved with the mathematical theory (the analysis of free-discontinuity problems) developed for the apparently unrelated image segmentation Mumford-Shah model. The variational fracture theory initiated by Francfort and Marigo is by now (20 years after) very well established. The second goal of this proposal is to further develop the ongoing collaboration between Song (Pharmaceutics), Siegel (Pharmaceutics), Sánchez (Numerical analysis), Calderer (Applied mathematics), and the PI on the study of the debonding of polymer gels from rigid substrates (relevant in the design of the synthetic polymers coating the metallic parts of pacemakers and other medical prostheses) from this variational fracture theory perspective. The third main goal is to apply the mathematical analysis of free-discontinuity problems to the modelling of the evolution of the cavity in the block caving technique in underground rock mining. This has been pursued by Ortega, Lecaros, and coworkers from the side of applied mathematics in academia, in collaboration with Gaete from the Geomechanics Research Department at El Teniente, research group to which Gutiérrez and the PI have joined in the last months. We propose to study the seismic activity induced by the fracture of the rock mass due to gravity, following the works in the last decade within the variational fracture theory that incorporate the inertia effects. The final aim is to optimize the injection of water jets for the aminoration of the seismic events near the operation sites. The three research lines are applications of the phase-field regularization by Ambrosio and Tortorelli of the Mumford-Shah free-discontinuity model, a different variant being required in each of the three contexts. The first stage of the implementation is of mathematical modelling and high-level numerical simulation abilities, in which the intuition and first-hand knowledge from the members of the research team that are experts in vascular function, ultrasound imaging, polymer chemistry, and mining geomechanics is translated into particular mathematical concepts and concrete computational methods. This is followed by a stage of calibration and validation, where the full interplay with experiments is required. The product of a robust and validated computational method will constitute then an advancement in the capabilities, available resources, and understanding in each of the applied disciplines.

Retinal vascular diseases are major causes of vision loss in the United States and around the world. To better treat these disorders, we need to understand the signaling pathways that control the growth and integrity of retinal blood vessels. Our recent publications and preliminary data detail a novel angiogenic signaling system centered around heme, a co-factor critical for oxygen transport, metabolism, and gene transcription. We found that heme promotes angiogenic growth in the retina by regulating tip/stalk selection, and that reduced heme production or import leads to reduced retinal vascularization and tissue hypoxia, similar to other retinal vasculopathies including retinopathy of prematurity, choroidal neovascularization, and the rare but important exudative vitreoretinopathies. Furthermore, we found that VEGF suppresses, while Norrin-bCatenin promotes, the expression of the obligate endothelial heme importer, Flvcr2. Based on these data, we hypothesize that heme, is involved in retinal angiogenesis and retinal vasculopathies. The Specific Aims of this proposal are to (1) determine how heme intersects with Notch signaling to control angiogenic tip/stalk selection, (2) characterize the role for Flvcr2/heme in VEGF-induced angiogenic proliferation and neo-vascularization, and (3) determine whether induction of Flvcr2/heme signaling is sufficient and necessary to reverse the vascular defects and downstream vision changes observed in mouse models of exudative vitreoretinopathy. To accomplish these aims, we developed new tools to directly manipulate heme in cultured retinal endothelial cells and assess heme transport and intracellular trafficking in vitro. We also generated new conditional knock-in and knock-out alleles to manipulate endothelial heme transport in vivo. Our studies will fundamentally impact our understanding of how endothelial heme levels are controlled, and the role of heme in retinal angiogenesis and vascular disease.

La respuesta inflamatoria al daño muscular puede comprometer la fuerza/masa al inducir la formación de tejido adiposo intermuscular (IMAT). IMAT se origina de la diferenciación adipogénica de células mesenquimales progenitoras fibro-adipogénicas (FAPs). Este proceso podría revertirse modulando la respuesta inflamatoria aguda. Sin embargo, el uso de antiinflamatorios inhibe la síntesis proteica y reduce la capacidad regenerativa muscular. Alternativamente, medidas físicas como el reposo funcional o la reincorporación temprana a la actividad han reportado efectos contradictorios sobre el proceso inflamatorio, lo que dificulta establecer indicaciones en el manejo de la lesión muscular. Por otro lado, se ha descrito un potente papel antinflamatorio local o sistémico del cuerpo cetónico β-hydroxybutirato (βHB); efecto mediado por la inhibición del inflamasoma NLRP3 y la secreción de citoquinas proinflamatorias. Importantemente, la activación del inflamasoma NLRP3 favorecería la adipogénesis de células mesenquimales, lo que sugiere un rol en la formación de IMAT. Se hipotetiza que la suplementación con βHB durante la recuperación de una lesión muscular aguda inhibe la diferenciación adipogénica de FAPs reduciendo la formación de IMAT lo que acelera la reparación y recuperación funcional del tejido muscular. Este efecto estaría mediado por la inhibición del inflamasoma NLRP3. Se inyectará una solución hiperosmótica al 25% de glicerol o salino en el músculo tibial anterior en ratones con o sin suplementación de 3 mg/g βHB durante 2 semanas post injuria. Se recolectará tejido muscular al 14dpi para análisis histológico de IMAT. Paralelamente, se aislarán FAPs del estroma vascular muscular al 3dpi. En FAPs aisladas se evaluarán proteínas de la vía NLPR3 inflamasoma y su capacidad adipogénica en respuesta al tratamiento in-vitro con 3mM βHB. Los resultados de esta propuesta nos permitirán mostrar los efectos terapéuticos de la suplementación dietaría con cuerpos cetónicos en la función y recuperación muscular post daño.

La respuesta inflamatoria al daño muscular puede comprometer la fuerza/masa al inducir la formación de tejido adiposo intermuscular (IMAT). IMAT se origina de la diferenciación adipogénica de células mesenquimales progenitoras fibro-adipogénicas (FAPs). Este proceso podría revertirse modulando la respuesta inflamatoria aguda. Sin embargo, el uso de antiinflamatorios inhibe la síntesis proteica y reduce la capacidad regenerativa muscular. Alternativamente, medidas físicas como el reposo funcional o la reincorporación temprana a la actividad han reportado efectos contradictorios sobre el proceso inflamatorio, lo que dificulta establecer indicaciones en el manejo de la lesión muscular. Por otro lado, se ha descrito un potente papel antinflamatorio local o sistémico del cuerpo cetónico β-hydroxybutirato (βHB); efecto mediado por la inhibición del inflamasoma NLRP3 y la secreción de citoquinas proinflamatorias. Importantemente, la activación del inflamasoma NLRP3 favorecería la adipogénesis de células mesenquimales, lo que sugiere un rol en la formación de IMAT. Se hipotetiza que la suplementación con βHB durante la recuperación de una lesión muscular aguda inhibe la diferenciación adipogénica de FAPs reduciendo la formación de IMAT lo que acelera la reparación y recuperación funcional del tejido muscular. Este efecto estaría mediado por la inhibición del inflamasoma NLRP3. Se inyectará una solución hiperosmótica al 25% de glicerol o salino en el músculo tibial anterior en ratones con o sin suplementación de 3 mg/g βHB durante 2 semanas post injuria. Se recolectará tejido muscular al 14dpi para análisis histológico de IMAT. Paralelamente, se aislarán FAPs del estroma vascular muscular al 3dpi. En FAPs aisladas se evaluarán proteínas de la vía NLPR3 inflamasoma y su capacidad adipogénica en respuesta al tratamiento in-vitro con 3mM βHB. Los resultados de esta propuesta nos permitirán mostrar los efectos terapéuticos de la suplementación dietaría con cuerpos cetónicos en la función y recuperación muscular post daño.

La respuesta inflamatoria al daño muscular puede comprometer la fuerza/masa al inducir la formación de tejido adiposo intermuscular (IMAT). IMAT se origina de la diferenciación adipogénica de células mesenquimales progenitoras fibro-adipogénicas (FAPs). Este proceso podría revertirse modulando la respuesta inflamatoria aguda. Sin embargo, el uso de antiinflamatorios inhibe la síntesis proteica y reduce la capacidad regenerativa muscular. Alternativamente, medidas físicas como el reposo funcional o la reincorporación temprana a la actividad han reportado efectos contradictorios sobre el proceso inflamatorio, lo que dificulta establecer indicaciones en el manejo de la lesión muscular. Por otro lado, se ha descrito un potente papel antinflamatorio local o sistémico del cuerpo cetónico β-hydroxybutirato (βHB); efecto mediado por la inhibición del inflamasoma NLRP3 y la secreción de citoquinas proinflamatorias. Importantemente, la activación del inflamasoma NLRP3 favorecería la adipogénesis de células mesenquimales, lo que sugiere un rol en la formación de IMAT. Se hipotetiza que la suplementación con βHB durante la recuperación de una lesión muscular aguda inhibe la diferenciación adipogénica de FAPs reduciendo la formación de IMAT lo que acelera la reparación y recuperación funcional del tejido muscular. Este efecto estaría mediado por la inhibición del inflamasoma NLRP3. Se inyectará una solución hiperosmótica al 25% de glicerol o salino en el músculo tibial anterior en ratones con o sin suplementación de 3 mg/g βHB durante 2 semanas post injuria. Se recolectará tejido muscular al 14dpi para análisis histológico de IMAT. Paralelamente, se aislarán FAPs del estroma vascular muscular al 3dpi. En FAPs aisladas se evaluarán proteínas de la vía NLPR3 inflamasoma y su capacidad adipogénica en respuesta al tratamiento in-vitro con 3mM βHB. Los resultados de esta propuesta nos permitirán mostrar los efectos terapéuticos de la suplementación dietaría con cuerpos cetónicos en la función y recuperación muscular post daño.

La suplementación con proteínas es una de las principales recomendaciones ante la practica regular de ejercicio físico de resistencia (RT). En personas mayores, la necesidad de proteína se incrementa particularmente ante cambios fisiológicos y fisiopatológicos los que se asocian con la pérdida de la función y tejido muscular, por lo que su ingesta se hace de mayor relevancia en esta población. Los lácteos fermentados como el yogur, y en especial los con un contenido extra de proteína, han aumentado su popularidad y consumo en el mercado nacional. Su composición nutricional resulta de particular interés, dado su perfil de aminoácidos y en particular su alto contenido de Leucina, el que podría compararse con los clásico suplementos de proteína recomendados para la ganancia y recuperación muscular. Objetivo: Analizar el efecto en la composición corporal, perfil lipídico, condición fisica y funcionalidad muscular inducidas por ingesta de yogures altos en proteína versus proteína Whey junto un programa de resistencia muscular en personas mayores Hipótesis: La ingesta de yogures altos en proteína conllevará a iguales o mayores ganancias de masa muscular, condición fisica y funcionalidad que las obtenidas con la ingesta de proteínas Whey en conjunto a un entrenamiento de resistencia en personas mayores. Metodología: Se reclutarán 16 personas mayores (60-75 años), sanas y sin intolerancia a la lactosa para llevar a cabo 8 semanas de entrenamiento de resistencia (RT) muscular 3 veces por semana, los que de forma aleatoria serán suplementados con yogurt alto en proteínas (YPRT) o proteína Whey (WPRT). Al inicio y al término de la intervención se evaluará la composición corporal mediante DEXA, fuerza muscular, consumo máximo de oxígeno y perfil lipídico. Resultados Esperados: Se espera que el grupo YPRT logre incrementos similares o superiores en la fuerza muscular, masa libre de grasa, perfil lipídico y disminución de la masa grasa y que el grupo WPRT.

Antimicrobial resistance is a global phenomenon aggravated in recent decades by the inappropriate use of antimicrobials in human and veterinary medicine, the lack of prevention and control measures for infections associated with health care, and the limited development of new antimicrobials. It causes an increase in mortality, morbidity, and health spending. In this sense, the irrational use of antimicrobials in food-producing animals can reduce the effectiveness of those antibiotics in treating animal and human diseases. It also represents an additional risk for antimicrobial resistance by transferring antibiotics to food for human consumption and generating a new source of exposure. The residual antibiotics in food have been related to some adverse effects on human health, including allergic reactions, disruption of digestive system function, and chronic toxic effects from prolonged low-level exposure. It also represents a risk for the animals by jeopardizing the effectiveness of the necessary treatments. Considering that, the project seeks to generate evidence regarding progress at the local level in regulatory issues and regarding the presence of antibiotics in food to raise awareness about the proper use of antibiotics in animals and humans and promote good practices

Water is an irreplaceable resource for developing socioeconomic activities and maintaining life on the planet. According to projections, water scarcity will increase, especially in those countries vulnerable to the effects of climate change and accelerated population growth. The negative impacts of the water deficit are already visible in some regions of the planet. Through the ECOH-WATER project, we will develop capacities for the access and use of rainwater in educational centers in Guatemala and Bolivia for sustainable consumption, adapting to the impacts generated by climate change through strategies based on local needs. To do this, we will first diagnose the areas at risk of drought using Geographic Information Systems (GIS) to prioritize interventions. In the selected areas, we will develop an Action Research study with a strong participatory component to involve communities in implementing a rainwater harvesting system. Additionally, we will implement educational strategies for developing skills in seeking rational and sustainable water use. The project will establish alliances with local actors for the project's sustainability. The search for strategies to access quality water for human, animal, and environmental consumption is a worldwide priority. It must involve the communities, raise awareness about natural resources and risk behaviors, and work collaboratively with decision-makers. On the other hand, the transdisciplinary work proposed in this project will allow the search for solutions with an integral vision. On the other hand, this project highlights the south-south collaboration to generate learning, enhance local resources, and move toward our region's sustainable development.

La suplementación con proteínas es una de las principales recomendaciones ante la practica regular de ejercicio físico de resistencia (RT). En personas mayores, la necesidad de proteína se incrementa particularmente ante cambios fisiológicos y fisiopatológicos los que se asocian con la pérdida de la función y tejido muscular, por lo que su ingesta se hace de mayor relevancia en esta población. Los lácteos fermentados como el yogur, y en especial los con un contenido extra de proteína, han aumentado su popularidad y consumo en el mercado nacional. Su composición nutricional resulta de particular interés, dado su perfil de aminoácidos y en particular su alto contenido de Leucina, el que podría compararse con los clásico suplementos de proteína recomendados para la ganancia y recuperación muscular. Objetivo: Analizar el efecto en la composición corporal, perfil lipídico, condición fisica y funcionalidad muscular inducidas por ingesta de yogures altos en proteína versus proteína Whey junto un programa de resistencia muscular en personas mayores Hipótesis: La ingesta de yogures altos en proteína conllevará a iguales o mayores ganancias de masa muscular, condición fisica y funcionalidad que las obtenidas con la ingesta de proteínas Whey en conjunto a un entrenamiento de resistencia en personas mayores. Metodología: Se reclutarán 16 personas mayores (60-75 años), sanas y sin intolerancia a la lactosa para llevar a cabo 8 semanas de entrenamiento de resistencia (RT) muscular 3 veces por semana, los que de forma aleatoria serán suplementados con yogurt alto en proteínas (YPRT) o proteína Whey (WPRT). Al inicio y al término de la intervención se evaluará la composición corporal mediante DEXA, fuerza muscular, consumo máximo de oxígeno y perfil lipídico. Resultados Esperados: Se espera que el grupo YPRT logre incrementos similares o superiores en la fuerza muscular, masa libre de grasa, perfil lipídico y disminución de la masa grasa y que el grupo WPRT.