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Identifying interventions, such as drugs, that can counteract the effects of aging is crucial due to the complex nature of the aging process, which involves multiple biological processes. By targeting these processes, interventions have the potential to promote healthy aging. Utilizing pairs of drugs that exhibit synergistic effects becomes particularly effective as they can simultaneously impact multiple pathways associated with aging and reprogramming, enhancing their anti-aging potential. The Panacea (predicting anti-aging combinations from expression analysis) framework was developed to facilitate the discovery of such drug combinations. Deep generative models were incorporated into the Panacea framework to effectively capture complex patterns in gene expression data, leveraging their non-linear nature for an accurate representation of relationships and interactions. This makes them ideal for predicting drug combinations. The trained models, using the CMap dataset, demonstrated an improved performance to predict the effect of drugs. The age effect of these drug combinations was evaluated using an age-predictive model, revealing that synergistic anti-aging combinations mainly comprised reprogramming (the process of transforming one type of cell into another by altering its gene expression and properties), apoptosis (programmed cell death mechanism), and chemotherapy drugs, while pro-aging combinations involved cellular growth-limiting, longevity-extending, and chemotherapy drugs. These results emphasize the capability of deep generative models in predicting potent drug combinations for anti-aging and anti-cancer interventions.

The Wah Wah Springs Tuff (30.0 Ma) is one of several very large volume ash-flow tuffs (>3200 km³ of erupted magma) that were emplaced near the peak of the flare-up of activity in the Great Basin ignimbrite province of western North America. It can be characterized as a "monotonous intermediate" ignimbrite because of its intermediate concentrations of silica (~63 to ~70 wt. %), apparent uniform chemical and mineralogical characteristics, and crystal-rich nature (32 ± 10 % phenocrysts on a dense rock basis). The major phase assemblage found throughout deposit is similar to other monotonous intermediates with a few exceptions (pl > hnbl > bio, qtz >> cpx, opx > mt, ilm, ap, zcn, and po). Based on experiments on the monotonous intermediate Fish Canyon Tuff (Johnson & Rutherford, 1989a) and this phase assemblage, the Wah Wah Springs magma equilibrated between 775°C – 800°C. One hornblende-plagioclase thermometer with or without quartz (Holland & Blundy, 1994) and one Fe-Ti oxides thermometer (Anderson et al., 1993) most consistently yield temperatures within this range. The Fe-Ti oxides oxy barometer (Anderson et al., 1993) yield fO2 estimates 2 – 3 log units above the quartz-fayalite-magnetite buffer. The Al-in-hornblende geobarometer (Johnson & Rutherford 1989b) indicates pressures between 2.0 and 2.5 kb. Detailed compositional profiles across hornblende and plagioclase grains help constrain how intensive parameters changed during the evolution of the magma shortly before eruption. Plagioclase in the Wah Wah Springs displays oscillatory zonation with overall normal zonation (a maximum change of about An5 from core to rim). Hornblende is also zoned in Al2O3 and TiO2 which typically decrease as much as 2.5 wt. % and 1 wt. % respectively from core to rim. These zoning patterns are consistent with a decrease of temperature from core to rim that accompanied progressive crystallization of a large body of magma that closely approached equilibrium. These conditions in the parent magma for the Wah Wah Springs differ from interpretations of mineral compositions in the Fish Canyon Tuff which led Bachman et al., (2002) to propose that the near solidus magma body was "rejuvenated" or reheated immediately prior to eruption. This model cannot be applied to the Wah Wah Springs. Rather, the Wah Wah Springs magma appears to have been cooling and crystallizing prior to eruption.

Neste trabalho foram abordados dois temas geofísicos visando o avanço no conhecimento da litosfera do sul do cráton São Francisco. O primeiro tema teve como objetivo a proposição de um método alternativo para a definição de bordas de placas litosféricas, utilizando dados gravimétricos. Utilizou-se o mapa da primeira derivada vertical da anomalia gravimétrica Bouguer continuada para cima à altura de 100 km. Resultados crustais, ao longo de um perfil de sísmica de refração profunda, localizado no estado de Goiás e a modelagem gravimétrica 2-D de um perfil localizado entre os estados de São Paulo e Minas Gerais foram utilizados para calibrar os resultados da derivada vertical. Recentes dados geoquímicos, petrológicos e de tomografia sísmica reforçam o resultado de que, nas bordas sul e oeste, a placa São Franciscana estende-se sob a Faixa Brasília e parte da bacia do Paraná. O segundo tema foi a interpretação de uma anomalia gravimétrica Bouguer positiva, aproximadamente circular com amplitude da ordem de 25 mGal. Nesta mesma região existe uma anomalia positiva do geóide, também circular, com raio de aproximadamente 250 km e uma amplitude de +7 m. O método sísmico da função do receptor não mostra a existência de afinamento crustal, eliminando assim, uma das possíveis causas da anomalia gravimétrica. Perfis magnetotelúricos radiais à anomalia gravimétrica indicam a presença de uma região no manto com resistividade elétrica mais baixa (< 100 .m), com origem a 200 km de profundidade e estendendo até a crosta inferior. Os resultados da inversão gravimétrica 3-D do alto gravimétrico indicam que a crosta inferior mais densa atinge uma espessura de 12 km, se assumirmos um contraste de densidade de +50 kg/m3. Coincidentemente com a região de crosta inferior mais densa, as sondagens magnetotelúricas indicam uma crosta eletricamente mais condutora, reforçando a existência de um underplating magmático. A impregnação de material derivado do manto, na base da crosta, é evidenciado em superfície, pela presença de diversos diques de basaltos toleíticos de composição similar aos basaltos da parte norte da Bacia do Paraná (alto TiO2) de idades do Cretáceo Inferior. Os diques toleíticos estão distribuídos por toda região sul do cráton. O manto litosférico com menor resistividade elétrica estende-se até profundidade de 200 km, sugerindo que o manto litosférico do sul do cráton São Francisco sofreu um rejuvenescimento composicional e leve aumento de densidade (50 a 70 kg/m3), responsável pelo alto do geóide. A diminuição de resistividade elétrica no manto, abaixo de profundidade de 100 km, é mais facilmente explicada pela presença de fundidos carbonatíticos no manto superior, provenientes de partes mais profundas do manto e resultantes de um menor grau de fusão. O magmatismo carbonatítico foi anterior ao magmatismo toleítico, uma vez que dados petrológicos e geoquímicos mostram que os diques toleíticos do Cretáceo Inferior na região do Espinhaço apresentam de 5% a 10% de carbonatitos em sua composição. A forma semi-circular do limite sul erosional do Grupo Bambuí deve ser resultado da erosão dos sedimentos mais antigos, devido ao soerguimento da litosfera, durante o magmatismo carbonatítico. / This thesis comprises of two parts in which two geophysical studies are described improving the knowledge of the lithosphere of the south São Francisco craton. In the first part, we propose an alternative method for defining the limits of lithosphere plate using gravity data. We used the first vertical derivative of Bouguer anomaly upwarded to 100 km height. Crustal results along a deep refraction seismic profile in the Goiás state together with a 2-D gravity model along a profile between Minas Gerais and São Paulo states were used to calibrate the vertical derivative results. Recent geochemical, petrological data and seismic topography data reinforce the gravity results that the southern and western parts of the São Francisco plate extends under parts the Brasília Belt and parts of the Paraná basin. In the second part, the interpretation of a positive Bouguer gravity anomaly, circular shaped and + 25 mGal amplitude gravity anomaly is presented. This gravity anomaly coincides with a positive, circular shaped, 7 m amplitude geoid anomaly with 250 km of radius. Receiver function results do not show a crustal thinning, excluding this possibility as the cause of gravity high. Deep magnetotelluric soundings along two profiles radial to gravity anomaly indicate a region in the mantle with lower electrical resistivity (< 100 .m) from the depth of 200 km and extending upward and reaching the lower crust. The residual Bouguer anomalies are inverted using a 3-D algorithm and indicate that the denser lower crust reaches 12 km of thickness for + 50 kg/m3 of density contrast. Coincident with a denser lower crust, magnetotelluric soundings reveal a low electrical resistivity crust, reinforcing the presence of magmatic underplating. At the surface, the contamination of magmatic material in the lower crust is supported by the presence of basaltic tholeiitic dike swarms similar, in composition, to the basalts of northern Paraná basin (high TiO2) of Early Cretaceous age. Tholeiitic dikes swarms are distributed throughout the southern region of the craton. Lithospheric mantle with lower electrical resistivity reaches 200 km of depth, indicating that the lithospheric mantle in the southern São Francisco craton underwent compositional rejuvenation accompanied by a mild increase in density (+ 50 to + 70 kg/m3) responsible for the positive geoid anomaly. The decrease of electrical resistivity in the mantle at depths beyond 100 km is easier explained by the presence of carbonatitic melts in the upper mantle, derived from a low degree of partial melt of a metasomatized deeper mantle. The carbonatitic magmatism was prior to tholeiitic magmatism since petrological and geochemical data show that the Early Cretaceous Espinhaço tholeiitic dikes contain 5 to 10% of carbonatites in their composition. The circular shaped erosional limit of the Bambui Group may have been produced by lithosphere uplift at the time of carbonatitic magmatism.

Neste trabalho foram abordados dois temas geofísicos visando o avanço no conhecimento da litosfera do sul do cráton São Francisco. O primeiro tema teve como objetivo a proposição de um método alternativo para a definição de bordas de placas litosféricas, utilizando dados gravimétricos. Utilizou-se o mapa da primeira derivada vertical da anomalia gravimétrica Bouguer continuada para cima à altura de 100 km. Resultados crustais, ao longo de um perfil de sísmica de refração profunda, localizado no estado de Goiás e a modelagem gravimétrica 2-D de um perfil localizado entre os estados de São Paulo e Minas Gerais foram utilizados para calibrar os resultados da derivada vertical. Recentes dados geoquímicos, petrológicos e de tomografia sísmica reforçam o resultado de que, nas bordas sul e oeste, a placa São Franciscana estende-se sob a Faixa Brasília e parte da bacia do Paraná. O segundo tema foi a interpretação de uma anomalia gravimétrica Bouguer positiva, aproximadamente circular com amplitude da ordem de 25 mGal. Nesta mesma região existe uma anomalia positiva do geóide, também circular, com raio de aproximadamente 250 km e uma amplitude de +7 m. O método sísmico da função do receptor não mostra a existência de afinamento crustal, eliminando assim, uma das possíveis causas da anomalia gravimétrica. Perfis magnetotelúricos radiais à anomalia gravimétrica indicam a presença de uma região no manto com resistividade elétrica mais baixa (< 100 .m), com origem a 200 km de profundidade e estendendo até a crosta inferior. Os resultados da inversão gravimétrica 3-D do alto gravimétrico indicam que a crosta inferior mais densa atinge uma espessura de 12 km, se assumirmos um contraste de densidade de +50 kg/m3. Coincidentemente com a região de crosta inferior mais densa, as sondagens magnetotelúricas indicam uma crosta eletricamente mais condutora, reforçando a existência de um underplating magmático. A impregnação de material derivado do manto, na base da crosta, é evidenciado em superfície, pela presença de diversos diques de basaltos toleíticos de composição similar aos basaltos da parte norte da Bacia do Paraná (alto TiO2) de idades do Cretáceo Inferior. Os diques toleíticos estão distribuídos por toda região sul do cráton. O manto litosférico com menor resistividade elétrica estende-se até profundidade de 200 km, sugerindo que o manto litosférico do sul do cráton São Francisco sofreu um rejuvenescimento composicional e leve aumento de densidade (50 a 70 kg/m3), responsável pelo alto do geóide. A diminuição de resistividade elétrica no manto, abaixo de profundidade de 100 km, é mais facilmente explicada pela presença de fundidos carbonatíticos no manto superior, provenientes de partes mais profundas do manto e resultantes de um menor grau de fusão. O magmatismo carbonatítico foi anterior ao magmatismo toleítico, uma vez que dados petrológicos e geoquímicos mostram que os diques toleíticos do Cretáceo Inferior na região do Espinhaço apresentam de 5% a 10% de carbonatitos em sua composição. A forma semi-circular do limite sul erosional do Grupo Bambuí deve ser resultado da erosão dos sedimentos mais antigos, devido ao soerguimento da litosfera, durante o magmatismo carbonatítico. / This thesis comprises of two parts in which two geophysical studies are described improving the knowledge of the lithosphere of the south São Francisco craton. In the first part, we propose an alternative method for defining the limits of lithosphere plate using gravity data. We used the first vertical derivative of Bouguer anomaly upwarded to 100 km height. Crustal results along a deep refraction seismic profile in the Goiás state together with a 2-D gravity model along a profile between Minas Gerais and São Paulo states were used to calibrate the vertical derivative results. Recent geochemical, petrological data and seismic topography data reinforce the gravity results that the southern and western parts of the São Francisco plate extends under parts the Brasília Belt and parts of the Paraná basin. In the second part, the interpretation of a positive Bouguer gravity anomaly, circular shaped and + 25 mGal amplitude gravity anomaly is presented. This gravity anomaly coincides with a positive, circular shaped, 7 m amplitude geoid anomaly with 250 km of radius. Receiver function results do not show a crustal thinning, excluding this possibility as the cause of gravity high. Deep magnetotelluric soundings along two profiles radial to gravity anomaly indicate a region in the mantle with lower electrical resistivity (< 100 .m) from the depth of 200 km and extending upward and reaching the lower crust. The residual Bouguer anomalies are inverted using a 3-D algorithm and indicate that the denser lower crust reaches 12 km of thickness for + 50 kg/m3 of density contrast. Coincident with a denser lower crust, magnetotelluric soundings reveal a low electrical resistivity crust, reinforcing the presence of magmatic underplating. At the surface, the contamination of magmatic material in the lower crust is supported by the presence of basaltic tholeiitic dike swarms similar, in composition, to the basalts of northern Paraná basin (high TiO2) of Early Cretaceous age. Tholeiitic dikes swarms are distributed throughout the southern region of the craton. Lithospheric mantle with lower electrical resistivity reaches 200 km of depth, indicating that the lithospheric mantle in the southern São Francisco craton underwent compositional rejuvenation accompanied by a mild increase in density (+ 50 to + 70 kg/m3) responsible for the positive geoid anomaly. The decrease of electrical resistivity in the mantle at depths beyond 100 km is easier explained by the presence of carbonatitic melts in the upper mantle, derived from a low degree of partial melt of a metasomatized deeper mantle. The carbonatitic magmatism was prior to tholeiitic magmatism since petrological and geochemical data show that the Early Cretaceous Espinhaço tholeiitic dikes contain 5 to 10% of carbonatites in their composition. The circular shaped erosional limit of the Bambui Group may have been produced by lithosphere uplift at the time of carbonatitic magmatism.

In autologous stem cell therapy, cell characteristics determine the potency of stem cells for regeneration. Aging and ischemia are two factors that are often neglected in pre-clinical tests for stem cell therapy. Here, we characterized cardiac explant-derived cells (EDCs) with a focus on distinguishing the effect of age and ischemia and then we looked for the effects of the combination of the two factors. We observed that ischemia worsens the age effect on EDCs. EDCs that were derived from aged mice with a history of myocardial infarction showed the highest number of senescent cells with dysregulation of the DNA repair system resulting in activation of cell cycle checkpoints. We over-expressed the anti-senescence Mybl2 transcription factor in EDCs from ischemic aged mice. The senescent state, paracrine profile and superoxide dismutase antioxidant enzyme activity improved in these cells. In vivo, we observed a boost in the potency of the Mybl2-modified EDCs, with an increase in short-term engraftment leading to improved heart function in infarcted mice. In general, Mybl2 over-expression rejuvenates senescent EDCs.

The central concern of this thesis is the study of non-equilibrium behaviour in magnetic materials and its interpretation within the framework of the Preisach model of hysteresis. Comprehensive experimental characterizations of the field and temperature and time dependence of a suite of standard magnetic response functions have been performed on a variety of magnetic materials, including a naturally occurring mineral of nanodimensional titanomagnetite particles embedded in volcanic glass, a compressed powder of nanodimensional magnetite particles immobilized in an organic binder, a thin film of nanodimensional Fe particles embedded in alumina, and a series of sintered, bond-disordered CaxSr1-xRuO3 ferromagnets. The measurements were compared with numerical simulations based on a model Preisach ensemble of thermally activated two-level subsystems, characterized individually by a double well free energy profile in a two-dimensional configuration space, an elementary moment reversal, a dissipation field and a bias field, and characterized collectively by a distribution of these characteristic fields. Our efforts were concentrated on two principal spheres of investigation. (1) By performing detailed numerical simulations of the relaxation response of model Preisach collections of two-level subsystems under the same field and temperature protocols used to probe experimentally the relaxation dynamics of spin glasses, we have been able to show that aging, memory and rejuvenation effects are ubiquitous features of all materials which possess a broad distribution of free energy barriers which block the approach to thermal equilibrium. (2) We propose a general strategy for isolating and quantifying the two principal mechanisms, thermal fluctuations and barrier growth, which are jointly responsible for shaping the measured temperature dependence of the magnetic properties of all magnetic materials which exhibit a history dependent response to an external field excitation, and is based on the analysis of viscosity isotherms and, in particular, on a plot of T ln(tr/0) versus Ha , where tr is the time at which a viscosity isotherm measured in a field Ha at temperature T reverses sign. When thermal activation dominates barrier growth, this plot will yield a universal curve while, in the opposite limit the plot fractures into a family of isothermal curves. The strategy is applied to the analysis of each magnetic material listed above. / February 2009

In the late twentieth century, global economic forces changed the face of many North American cities. Cities which were built upon industry, that had provided both job certainty and economic vitality, faced questions of survival in response to shrinking population and urban blight. Unprepared for these drastic changes and unable to address them survival gave way to resignation. Buffalo, New York is an example of a once successful and vital city that continues to experience de-population due to the collapse of its industries. The collapse not only created economic repercussions but also effected the city’s built environment. Many of the Buffalo’s urban monuments, testaments to the ambition of the city, now sit empty; as do the working class neighbourhoods that surround them. The Thesis examines the role which architecture can play in understanding, strategizing and re-envisioning the life of deteriorating cities. Focusing on the City of Buffalo, the design centers on the New York Central Terminal. It proposes a radical repurposing of the Terminal to create a new urban hub which will spur the re-building of the city’s urban fabric. The design outlines a staged 25 year strategy for the de-construction of sparse areas and the strengthening of critical urban networks, thus creating a strong framework upon which a new physical fabric for the city can build and develop overtime. The Terminal, once a significant rail hub is re-envisioned as a revitalized hub for the new city. A key connective point within this urban framework, it encapsulates a variety of program moved from the surrounding neighbourhood to the site. The Terminal will act as an architectural catalyst for change, working within the larger urban strategy to spur a natural re-growth and densification of the city. The thesis presents the radical re-thinking of the architect’s role in the twenty-first century. As current economies and industries face change the urban climate is adapting from one of constant growth to one of strategic re-use. Skeletons of once successful cities lay across the North American landscape. Their urban artifacts: the grain mill, steel manufacturing plant and rail yards, which once supported whole cities as both providers of employment and definers of cultural identity, now stand as empty reminders of a prosperous past. The Thesis shows how these buildings , like the New York Central Terminal can be given a renewed cultural significance and powerful roles within the revived urban life of their cities.

The central concern of this thesis is the study of non-equilibrium behaviour in magnetic materials and its interpretation within the framework of the Preisach model of hysteresis. Comprehensive experimental characterizations of the field and temperature and time dependence of a suite of standard magnetic response functions have been performed on a variety of magnetic materials, including a naturally occurring mineral of nanodimensional titanomagnetite particles embedded in volcanic glass, a compressed powder of nanodimensional magnetite particles immobilized in an organic binder, a thin film of nanodimensional Fe particles embedded in alumina, and a series of sintered, bond-disordered CaxSr1-xRuO3 ferromagnets. The measurements were compared with numerical simulations based on a model Preisach ensemble of thermally activated two-level subsystems, characterized individually by a double well free energy profile in a two-dimensional configuration space, an elementary moment reversal, a dissipation field and a bias field, and characterized collectively by a distribution of these characteristic fields. Our efforts were concentrated on two principal spheres of investigation. (1) By performing detailed numerical simulations of the relaxation response of model Preisach collections of two-level subsystems under the same field and temperature protocols used to probe experimentally the relaxation dynamics of spin glasses, we have been able to show that aging, memory and rejuvenation effects are ubiquitous features of all materials which possess a broad distribution of free energy barriers which block the approach to thermal equilibrium. (2) We propose a general strategy for isolating and quantifying the two principal mechanisms, thermal fluctuations and barrier growth, which are jointly responsible for shaping the measured temperature dependence of the magnetic properties of all magnetic materials which exhibit a history dependent response to an external field excitation, and is based on the analysis of viscosity isotherms and, in particular, on a plot of T ln(tr/0) versus Ha , where tr is the time at which a viscosity isotherm measured in a field Ha at temperature T reverses sign. When thermal activation dominates barrier growth, this plot will yield a universal curve while, in the opposite limit the plot fractures into a family of isothermal curves. The strategy is applied to the analysis of each magnetic material listed above.

The central concern of this thesis is the study of non-equilibrium behaviour in magnetic materials and its interpretation within the framework of the Preisach model of hysteresis. Comprehensive experimental characterizations of the field and temperature and time dependence of a suite of standard magnetic response functions have been performed on a variety of magnetic materials, including a naturally occurring mineral of nanodimensional titanomagnetite particles embedded in volcanic glass, a compressed powder of nanodimensional magnetite particles immobilized in an organic binder, a thin film of nanodimensional Fe particles embedded in alumina, and a series of sintered, bond-disordered CaxSr1-xRuO3 ferromagnets. The measurements were compared with numerical simulations based on a model Preisach ensemble of thermally activated two-level subsystems, characterized individually by a double well free energy profile in a two-dimensional configuration space, an elementary moment reversal, a dissipation field and a bias field, and characterized collectively by a distribution of these characteristic fields. Our efforts were concentrated on two principal spheres of investigation. (1) By performing detailed numerical simulations of the relaxation response of model Preisach collections of two-level subsystems under the same field and temperature protocols used to probe experimentally the relaxation dynamics of spin glasses, we have been able to show that aging, memory and rejuvenation effects are ubiquitous features of all materials which possess a broad distribution of free energy barriers which block the approach to thermal equilibrium. (2) We propose a general strategy for isolating and quantifying the two principal mechanisms, thermal fluctuations and barrier growth, which are jointly responsible for shaping the measured temperature dependence of the magnetic properties of all magnetic materials which exhibit a history dependent response to an external field excitation, and is based on the analysis of viscosity isotherms and, in particular, on a plot of T ln(tr/0) versus Ha , where tr is the time at which a viscosity isotherm measured in a field Ha at temperature T reverses sign. When thermal activation dominates barrier growth, this plot will yield a universal curve while, in the opposite limit the plot fractures into a family of isothermal curves. The strategy is applied to the analysis of each magnetic material listed above.