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Mutations in valosin-containing protein (VCP) cause a rare, autosomal dominant disease called inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). One-third of patients with IBMPFD develop frontotemporal dementia, characterized by an extensive neurodegeneration in the frontal and temporal lobes. Neuropathologic hallmarks include nuclear and cytosolic inclusions positive to ubiquitin and transactive response DNA-binding protein 43 (TDP-43) in neurons and glial activation in affected regions. However, the pathogenic mechanisms by which mutant VCP triggers neurodegeneration remain unknown. Herein, we generated a mouse model selectively overexpressing a human mutant VCP in neurons to study pathogenic mechanisms of mutant VCP-mediated neurodegeneration and cognitive impairment. The overexpression of VCPA232E mutation in forebrain regions produced significant progressive impairments of cognitive function, including deficits in spatial memory, object recognition, and fear conditioning. Although overexpressed or endogenous VCP did not seem to focally aggregate inside neurons, TDP-43 and ubiquitin accumulated with age in transgenic mouse brains. TDP-43 was also found to co-localize with stress granules in the cytosolic compartment. Together with the appearance of high-molecular-weight TDP-43 in cytosolic fractions, these findings demonstrate the mislocalization and accumulation of abnormal TDP-43 in the cytosol of transgenic mice, which likely lead to an increase in cellular stress and cognitive impairment. Taken together, these results highlight an important pathologic link between VCP and cognition.

Mutations in valosin-containing protein (VCP) cause a rare, autosomal dominant disease called inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). One-third of patients with IBMPFD develop frontotemporal dementia, characterized by an extensive neurodegeneration in the frontal and temporal lobes. Neuropathologic hallmarks include nuclear and cytosolic inclusions positive to ubiquitin and transactive response DNA-binding protein 43 (TDP-43) in neurons and glial activation in affected regions. However, the pathogenic mechanisms by which mutant VCP triggers neurodegeneration remain unknown. Herein, we generated a mouse model selectively overexpressing a human mutant VCP in neurons to study pathogenic mechanisms of mutant VCP-mediated neurodegeneration and cognitive impairment. The overexpression of VCPA232E mutation in forebrain regions produced significant progressive impairments of cognitive function, including deficits in spatial memory, object recognition, and fear conditioning. Although overexpressed or endogenous VCP did not seem to focally aggregate inside neurons, TDP-43 and ubiquitin accumulated with age in transgenic mouse brains. TDP-43 was also found to co-localize with stress granules in the cytosolic compartment. Together with the appearance of high-molecular-weight TDP-43 in cytosolic fractions, these findings demonstrate the mislocalization and accumulation of abnormal TDP-43 in the cytosol of transgenic mice, which likely lead to an increase in cellular stress and cognitive impairment. Taken together, these results highlight an important pathologic link between VCP and cognition.

Little is known about the relationship between spirituality healing and perceptions about the medical encounter among Latinos. To examine the association between spirituality healing and attitudes of self-reported perceptions about the medical encounter. A cross-sectional telephone survey. 3,728 Latinos aged ≥18 years residing in the United States from Wave 1 of the Pew Hispanic Center/Robert Wood Johnson Foundation Latino Health Survey. Dependent variables were ever prayed for healing (yes/no), ever asked others to pray for healing (yes/no), considered important spiritual healing (very vs. somewhat or not important), and ever consulted a ‘curandero’ (folk healer in Latin America) (yes/no). The primary independent variables were feelings about the last time seeing a Doctor (confused by information given, or frustrated by lack of information) and perception of quality of medical care (excellent, good, fair or poor) within the past 12 months. Six percent of individuals reported that they had ever consulted a curandero, 60% prayed for healing, 49% asked others to pray for healing, and 69% considered spiritual healing as very important. In multivariable analyses, feeling confused was associated with increased odds of consulting a curandero (OR = 1.58; 95% CI, 1.02–2.45), praying for healing (OR = 1.30; 95% CI, 1.03–1.64), asking others to pray for healing (OR = 1.29; 95% CI, 1.03–1.62), and considering spiritual healing as very important (OR = 1.30; 95% CI, 1.01–1.66). Feeling frustrated by a lack of information was associated with asking others to pray for healing (OR = 1.29; 95% CI, 1.04–1.60). A better perception of quality of medical care was associated with lower odds of consulting a curandero (OR = 0.83; 95% CI, 0.70–0.98). Feelings about the medical encounter were associated with spirituality healing, praying for healing, and asking others to pray for healing. Feeling confused and perception of poor quality of medical care were associated with consulting a curand

Little is known about the relationship between spirituality healing and perceptions about the medical encounter among Latinos. To examine the association between spirituality healing and attitudes of self-reported perceptions about the medical encounter. A cross-sectional telephone survey. 3,728 Latinos aged ≥18 years residing in the United States from Wave 1 of the Pew Hispanic Center/Robert Wood Johnson Foundation Latino Health Survey. Dependent variables were ever prayed for healing (yes/no), ever asked others to pray for healing (yes/no), considered important spiritual healing (very vs. somewhat or not important), and ever consulted a ‘curandero’ (folk healer in Latin America) (yes/no). The primary independent variables were feelings about the last time seeing a Doctor (confused by information given, or frustrated by lack of information) and perception of quality of medical care (excellent, good, fair or poor) within the past 12 months. Six percent of individuals reported that they had ever consulted a curandero, 60% prayed for healing, 49% asked others to pray for healing, and 69% considered spiritual healing as very important. In multivariable analyses, feeling confused was associated with increased odds of consulting a curandero (OR = 1.58; 95% CI, 1.02–2.45), praying for healing (OR = 1.30; 95% CI, 1.03–1.64), asking others to pray for healing (OR = 1.29; 95% CI, 1.03–1.62), and considering spiritual healing as very important (OR = 1.30; 95% CI, 1.01–1.66). Feeling frustrated by a lack of information was associated with asking others to pray for healing (OR = 1.29; 95% CI, 1.04–1.60). A better perception of quality of medical care was associated with lower odds of consulting a curandero (OR = 0.83; 95% CI, 0.70–0.98). Feelings about the medical encounter were associated with spirituality healing, praying for healing, and asking others to pray for healing. Feeling confused and perception of poor quality of medical care were associated with consulting a curand

La memoria de tesis doctoral proporciona bases de los espacios de homología racional del esquema de Hilbert de puntos en superficies algebraicas arbitrarias, permitiendo realizar cálculo explícitos en superficies con la técnica de geometría enumerativa del esquema de Hilbert de puntos. Se realiza una construcción explicíta de dos tipos de bases; una descrita por subesquemas reducidos y otra descrita por subesquemas no reducidos. Para demostrar que los candidatos que se proponen constituyentes bases, se emplea la misma técnica que utiliza Mallavibarrena para el cálculo de bases de la homología del esquema de Hilbert de 4 puntos: se demuestra que los candidatos a base intersecan con una matriz triangular de entradas no nulas en la diagonal y se comprueba que dichos candidatos verifican la cardinalidad requirida para las bases en los trabajos de Göttsche. La segunda parte de la memoria establece una geometría de triángulos de Schubert en superficies algebraicas arbitrarias, trasladando a superficies la técnica de geometría enumerativa de los triángulos de Schubert. Para ello se define una variedad de triángulos de Schubert como la explosión sobre la diagonal de la segunda potencia cartesiana de la proyectivización del fibrado tangentes, y se calcula la cohomología racional de esta variedad. La técnica para el cálculo de bases es distinta del teorema de Bialynichi-Birula y se basa en los generadores y relaciones del anillo y en las matrices de intersección de los elementos de dimensión complementaria. Se comprueba la validez de la geometría construida aplicándola a la enumeración de dobles contactos: se generalizan y se demuestran en superficies arbitrarias la fórmula de Zeuthen-Schubert y las dos conjeturas de Schubert sobre dobles contactos. Para el cálculo de los dobles contactos se expresan las clases de las curvas y las de la familias de curvas como combinaciones lineales de las clases básicas de sus espacios de cohomología con coeficientes que dependen de los inva

La memoria de tesis doctoral proporciona bases de los espacios de homología racional del esquema de Hilbert de puntos en superficies algebraicas arbitrarias, permitiendo realizar cálculo explícitos en superficies con la técnica de geometría enumerativa del esquema de Hilbert de puntos. Se realiza una construcción explicíta de dos tipos de bases; una descrita por subesquemas reducidos y otra descrita por subesquemas no reducidos. Para demostrar que los candidatos que se proponen constituyentes bases, se emplea la misma técnica que utiliza Mallavibarrena para el cálculo de bases de la homología del esquema de Hilbert de 4 puntos: se demuestra que los candidatos a base intersecan con una matriz triangular de entradas no nulas en la diagonal y se comprueba que dichos candidatos verifican la cardinalidad requirida para las bases en los trabajos de Göttsche. La segunda parte de la memoria establece una geometría de triángulos de Schubert en superficies algebraicas arbitrarias, trasladando a superficies la técnica de geometría enumerativa de los triángulos de Schubert. Para ello se define una variedad de triángulos de Schubert como la explosión sobre la diagonal de la segunda potencia cartesiana de la proyectivización del fibrado tangentes, y se calcula la cohomología racional de esta variedad. La técnica para el cálculo de bases es distinta del teorema de Bialynichi-Birula y se basa en los generadores y relaciones del anillo y en las matrices de intersección de los elementos de dimensión complementaria. Se comprueba la validez de la geometría construida aplicándola a la enumeración de dobles contactos: se generalizan y se demuestran en superficies arbitrarias la fórmula de Zeuthen-Schubert y las dos conjeturas de Schubert sobre dobles contactos. Para el cálculo de los dobles contactos se expresan las clases de las curvas y las de la familias de curvas como combinaciones lineales de las clases básicas de sus espacios de cohomología con coeficientes que dependen de los inva