Proyectos

Materia investigada: Regulación transcripcional, microbiología, metilaciones, cobre.

Materia investigada: Biomedicina, enfermedades cardiovasculares, regulación transcripcional.

Materia investigada: Regulación transcripcional, microbiología, metilaciones, cobre.

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.

Our interest in this project is to obtain two-dimensional models for a three-dimensional thin structures involving situations: • Magnetoelastic plates which are heterogeneous and whose heterogeneity occur at a small scale which depends of the thickness of the plate. Depending on energy scaling and the ratio between these two small parameters, different theories can be obtained. • Poroelastic shell containing a viscous fluid. • Quasistatic evolution problems for linearly elastoplastic shell with hardening.

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.

It is proposed to assess the feasibility of using ultrasound as a nonintrusive, in-situ, probe of plastic behavior in high-entropy alloys (HEAs). More specifically, whether it is possible to use ultrasound to reliably characterize the plasticity deformation mechanism---slip, TWIP, TRIP---of Fe80-xCo10Cr10Mnx. To this end, the speed of sound will be measured, continuously, as a function of applied stress in uniaxial tensile tests. In previous work, proposers have shown that the speed of sound as a function of stress provides a reliable tool to measure dislocation density in aluminum, copper, and stainless steel. In the latter case, it has also been shown to reliably discriminate between slip and twinning as a deformation mechanism. It is now proposed to study the possibility of extending this capability not only to new materials, HEAs, but also to a new mechanism, phase transformation. We will start with the materials whose plastic deformation is slip-dominated, since we have robust experience in this case. We shall then move to the TWIP material, where our more recent experience will be brought to bear, to end up with the unexplored, from the point of view of ultrasound, TRIP material. Samples for tensile loading will be prepared. They will be tested using a universal testing machine and ultrasound measurements of longitudinal wave velocity will be carried out in-situ. A decrease in the wave velocity as a function of applied stress will indicate a proliferation of dislocations; the dislocation density will be determined as a function of stress as will the parameters of Taylor's rule. An increase in wave velocity as a function of stress will indicate a decrease in average grain size. Modeling will be applied to determine whether this is due to twinning or phase transformation. These results will also be validated with post-mortem XRD, TEM, and metallography measurements, as well as ex-situ acoustic measurements. The success of the proposed research would have short-term and long-term benefits: In the short term it would provide a non-intrusive tool---ultrasound---to assist in the search for HEAs with pre-determined properties, as needed for specific applications. In the long-term, it would pave the way for the development of a practical, non-intrusive, tool for the evaluation of HEA pieces in service.

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.

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.

Conservation paleobiology deals with the use and application of paleontological data to the conservation of biodiversity. It implies the study of the circumstances driving species to the brink of extinction, to go extinct, or survive through the changes. In the present scenario of Global Change, this discipline seems useful as it can inform about the paths that species can undergo at present and in the near future. Particularly important to inform the state and faith of present-day ecosystems are those studies dealing with the last glacial-interglacial transition, since they show the changes faced by many still extant species under a scenario of global warming and an increasing human population. A close parallel to today’s threats to biodiversity. The present proposal will use the rich vertebrate fossil record from the site of Tagua Tagua 3 (TT3) in the Antiguo Lago de Tagua Tagua (ALTT), Region de O’Higgins, to investigate changes in biological communities through time. This record spans from the late Pleistocene (~13 kyr BP) to the mid Holocene (~6 kyr BP), presenting a continuous faunal sequence with extinct megafauna in its older component and extant vertebrates towards the Holocene. The record also attests the arrival and establishment of humans, as well as the occurrence of important changes in vegetation and climate. All this together makes of TT3 a unique record for central Chile, that offers the opportunity to make an adequate reconstruction of the recent past of a greatly endangered natural system. The ecosystem-through-time reconstruction and analysis includes the following objectives: (1) a comprehensive study of the fossil record to identify what, how many, and how abundant were the different species at different moments through time in the ALTT, with a particular emphasis on vertebrates; (2) to see how the communities reconstructed from the fossil record behave in moments of major environmental changes, including anthropogenic drivers of change, extinction of megafauna, and vegetation changes; (3) use food web modeling for analyzing the causes and consequences of the changes in these communities. This aims to pursue models that can integrate the fossil record and proxies of environmental change to understand the vulnerabilities to which these communities were exposed at different moments through time; (4) work in characterizing the present-day state of the vertebrate community in the area near the ALTT, aiming to build a modern picture in terms of community composition as well as in food web structure, to compare with what is revealed, and predicted, by the fossil record and associated models. The methodology to accomplishing these objectives includes: (1) fossil preparation, taxonomic identification, and quantification (MNI, NISP) for each level excavated in TT3; (2) to compare the faunal communities inferred from the fossil record to the available record of environmental changes through time (vegetation, climate, human arrival); (3) to stablish trophic relationships among the different species identified in the fossil record (using literature, stable isotope analyses results and zooarchaeological studies); this information will be used to implement food web models that explore the stability and complexity of different vertebrate communities through time and during times of particular important changes such as megafaunal extinctions, human arrival a changes in vegetation; (4) current species occurrences in the area will be inferred from the literature, open databases (GBIF) and complemented using species distributions models along with field species surveys; this information will be used to understand the current species composition of the area and to model current trophic interactions to compare with the ones inferred from the fossil record. Some expected results are a thorough characterization of community composition and food web topology through time, particularly at moments of important environmental changes. The arrival of humans during the late Pleistocene and the trophic connections generated with the fauna present should have an effect in the topology and stability of the food web. At the same time, the inclusion of a dynamic bottom-up controlled change (forested vs. shrubland) will provide important insights on how the food web and the vertebrate communities changed in moments of major vegetation changes. It is expected that some moments in the past will parallel the present-day conditions of biological systems from central Chile, providing clues on how to face the current environmental changes that endanger these ecosystems.