Integration of ATM, ATR, and DNA-PKcs Signaling Maintains Genome Integrity During Neurogenesis

The DNA damage response (DDR) orchestrates a network of cellular processes such as cell cycle progression, DNA repair, and apoptosis when complex DNA lesions arise to maintain genomic integrity. ATM, ATR, and DNA-PKcs (encoded by PRKDC) are related phosphatidylinositol-3-kinase like serine/threonine kinases (PIKK) that collectively regulate the DDR network. Studies have demonstrated these kinases can phosphorylate many of the same substrates, suggesting a significant potential for functional redundancy. However, deficiencies in these kinases have been linked to distinct neural degenerative and developmental disorders, underscoring their unique functions for maintain genomic integrity during nervous system development. Here we utilized mouse genetic analyses to identify the functional interplay between these kinases during neurogenesis. DNA-PKcs function is directly involved in and most associated with the non-homologous end-joining (NHEJ) pathway. The function of DNA-PKcs during neurogenesis remains unclear despite evidence linking mutations in related NHEJ factor genes to neurological diseases. For example, deficiency in Ku70, Ku80, XRCC4, or DNA ligase IV (Lig4), but not DNA-PKcs results in defective embryonic neurogenesis in mice. This discrepancy may arise from the fact that ATM and ATR can compensate for the loss of DNAPKcs. For instance, if ATM and DNA-PKcs were capable of functioning redundantly in neural tissue, then DNA-PKcs-null mice would not necessarily have a noticeable phenotype. Determining functional redundancy is difficult since Atr germ line and [Atm;Prkdc] double-null mice are embryonic lethal. To overcome these challenges, we used mice with germ line Prkdc inactivated in combination with conditional alleles for Atm and Atr to assess if these kinases function cooperatively in the DDR during neural development, consequently defining the role(s) of DNA-PKcs during neurogenesis. We found DNA-PKcs loss sensitized DNA damage induced p53-dependent apoptosis, and exacerbated checkpoint activation after ionizing radiation (IR) in a developmental stage and neural cell type-specific manner, independent of ATM and ATR. Our data suggests, during neurogenesis DNA-PKcs functions as a component of the DNA-PK holoenzyme to maintain genomic integrity in proliferating and non-proliferating neurons. We propose DNA-PK specifically enhances NHEJ DNA double-strand break repair kinetics during murine neurogenesis by acting as a scaffold protein, which is critical to maintain normal nervous development when high levels of genotoxic stress occur. In contrast, we found that ATM and ATR coordinated the DDR during neurogenesis to direct DNA damage induced apoptosis in proliferating and non-proliferating cortical neural progenitors. Furthermore, we found ATR controlled the IR-induced G2/M checkpoint, independent of ATM and DNA-PKcs. In summary, this work established a basic understanding of DNA-PKcs function during nervous system development with respect to ATM and ATR. Importantly, our data implicates DNA damage induced p53-dependent apoptosis can be activated in the absence of all three PIKK DNA damage-signaling kinases during murine neurogenesis. The human neurodegenerative disease ataxia telangiectasia (A-T) is thought to arise from mutations in ATM preventing the elimination of DNA damaged neurons during neurogenesis, which then fail to function appropriately, resulting in neural degeneration. It is thought murine models fail to recapitulate the neurodegenerative disease observed in humans because mice are more resistant to DNA damage. The observation of a PIKK-independent DNA damage induced apoptotic process occurring during murine neurogenesis suggests murine embryonic neurons posses a pathway to eliminate DNA damaged cells even in the absence of ATM, ATR, and DNA-PKcs. Therefore, murine models may fail to recapitulate A-T, not because mice are more resistant to DNA damage, but because they have an alternative mechanism to eliminate DNA damaged neurons during neural development. The emphasis on mouse genetics to dissect the important processes of these kinases during neurogenesis was an important step to ensure the data collected illustrated the DDR within a biological context. Overall, our work illustrates the divergent functions of these kinases, despite substrate overlap, to show how they play unique and essential cooperative roles during the DDR, underscoring the distinct neuropathology that develops when each is defective

Relación entre la exposición a narraciones orales por los padres de familia y el vocabulario comprensivo en niños de 3 años a 3 años 11 meses de diferentes niveles socioeconómicos de Lima Metropolitana

La presente tesis tiene como objetivo determinar la relación entre la exposición a narraciones orales por los padres de familia y el vocabulario comprensivo en niños de 3 años a 3 años 11 meses de diferentes niveles socioeconómicos de Lima Metropolitana. El tipo del estudio es el cuantitativo, con diseño descriptivo correlacional y descriptivo comparativo. La muestra está compuesta por 83 niños, de ambos sexos y por los respectivos padres de familia de los niños que conformaron la muestra. Para medir las variables, se elaboró y validó el Cuestionario de Exposición a Narraciones Orales por los Padres de Familia, el cual se aplicó a los padres de los niños de la muestra seleccionada. Por otro lado, a los niños se les administró el Test de Vocabulario en imágenes de Peabody (PPVTIII) para determinar el nivel de su vocabulario comprensivo. Los resultados indican un valor de chi cuadrado (X2 = 26,496) significativo al nivel de p<0,01 entre la exposición a narraciones orales por los padres familia y el vocabulario comprensivo de los niños de la muestra investigada. Se concluye que existe relación positiva entre la exposición a narraciones orales por los padres de familia y el vocabulario compresivo de los niños evaluados. Asimismo, se estableció diferencia significativa en la exposición a narraciones orales por los padres de familia en los niños del estudio, según el nivel socioeconómico

Estimular la capacidad creativa : propuesta para mejorar la convivencia escolar de los ni?os y ni?as del colegio CAFAM Santa Luc?a a partir de las artes pl?sticas

131 p. Recurso Electr?nicoEl siguiente trabajo es el resultado de un proceso de investigaci?n formativa desarrollado en el marco de la investigaci?n social, escolar, cultural y familiar, el cual busca mostrar la manera en que se abord? una problem?tica presente en las pr?cticas de observaci?n de la instituci?n educativa ?CAFAM SANTA LUCIA?, la cual fue intervenida con un Proyecto Pedag?gico de Aula, buscado aportar una estrategia para la estimulaci?n de la capacidad creativa con el fin de fortalecer y potenciar las relaciones interpersonales con los estudiantes de ciclo dos de grado cuarto. De all? emerge la propuesta de utilizar elementos de la expresi?n pl?stica para fortalecer el respeto por el otro y la creatividad como uno de los pilares del desarrollo integral de los ni?os de grado cuarto de dicha instituci?n. Palabras claves: capacidad creativa, expresi?n pl?stica, etapas del desarrollo, imaginaci?n, estimulaci?n, artes espaciales, relaciones interpersonales.The following work is the result of a process of formative research developed within the framework of social, school, cultural and family research, which seeks to show the way in which a problem was addressed in the observational practices of the educational institution " CAFAM SANTA LUCIA ", which was intervened with a Classroom Pedagogical Project, sought to provide a strategy for the stimulation of creative capacity in order to strengthen and strengthen interpersonal relationships with the students of cycle two of fourth grade. From there emerges the proposal to use elements of plastic expression to strengthen respect for the other and creativity as one of the pillars of the integral development of the fourth grade children of said institution. Keywords: creative ability, plastic expression, stages of development, imagination, stimulation, space arts, interpersonal relations

Plan estratégico para el hotel boutique Le Bonheur para el periodo del 2023 al 2027

El presente plan estratégico del hotel Le Bonheur tiene por objetivo alcanzar, en los próximos cinco años, un posicionamiento destacado en el sector de hoteles boutiques, en Fort Lauderdale, estado de Florida, Estados Unidos, logrando una ocupación anual promedio que sea superior al 60%, lo que permitirá superar los objetivos planteados para el crecimiento del negocio, generando la rentabilidad esperada por los accionistas del hotel y el correcto cumplimiento de las obligaciones financieras. Los objetivos específicos son brindar una experiencia de servicio reconocida y diferenciada; lograr un nivel de ocupabilidad anual mayor al 60%, lo que permitirá superar las metas trazadas; ser un hotel con altos estándares de calidad en el mantenimiento de la infraestructura, las habitaciones y los espacios comunes; contar con colaboradores motivados y comprometidos a través de la capacitación constante; implementar y repotenciar los canales digitales y desarrollar sistemas automatizados para optimizar los procesos de atención de los clientes y su experiencia

Economic evaluation of a novel community-based diabetes care model in rural Mexico: a cost and cost-effectiveness study.

OBJECTIVES: Diabetes is the leading cause of disability-adjusted life years in Mexico, and cost-effective care models are needed to address the epidemic. We sought to evaluate the cost and cost-effectiveness of a novel community-based model of diabetes care in rural Mexico, compared with usual care. DESIGN: We performed time-driven activity-based costing to estimate annualised costs associated with typical diabetes care in Chiapas, Mexico, as well as a novel diabetes care model known as Compañeros En Salud Programa de Enfermedades Crónicas (CESPEC). We conducted Markov chain analysis to estimate the cost-effectiveness of CESPEC compared with usual care from a societal perspective. We used patient outcomes from CESPEC in 2016, as well as secondary data from existing literature. SETTING: Rural primary care clinics in Chiapas, Mexico. PARTICIPANTS: Adults with diabetes. INTERVENTIONS: CESPEC is a novel, comprehensive, diabetes care model that integrates community health workers, provider education, supply chain management and active case finding. OUTCOME MEASURE: The primary outcome was the incremental cost-effectiveness of CESPEC compared with care as usual, per quality-adjusted life year (QALY) gained, expressed in 2016 US dollars. RESULTS: The economic cost of the CESPEC diabetes model was US$144 per patient per year, compared with US$125 for diabetes care as usual. However, CESPEC care was associated with 0.13 additional years of health-adjusted life expectancy compared with usual care and 0.02 additional years in the first 5 years of treatment. This translated to an incremental cost-effectiveness ratio (ICER) of US$2981 per QALY gained over a patient's lifetime and an ICER of US$10 444 over the first 5 years. Findings were robust to multiple sensitivity analyses. CONCLUSIONS: CESPEC is a cost-effective, community-based model of diabetes care for patients in rural Mexico. Given the high prevalence and significant morbidity associated with diabetes in Mexico and other countries in Central America, this model should be considered for broader scale up and evaluation

Thermodynamical limit of general gl(N) spin chains II: Excited states and energies

We consider the thermodynamical limit of a gl(N) spin chain with arbitrary representation at each site of the chain. We consider excitations (with holes and new strings) above the vacuum and compute their corrections in 1/L to the densities and the energy.Comment: 29 pages misprints in the example of sect 5.1 amended and a mistake in theorem 5.4 correcte