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

Alcoholic beverage consumption in adolescents of Area IV of the Cienfuegos municipality

Foundation: There is currently an increase in the consumption of alcoholic beverages in adolescents, which can become an important health problem. Objective: To describe alcoholic beverages consumption in adolescents. Method: A descriptive study conducted from January 2014 to January 2015, in Area of health IVof the Cienfuegos Municipality, which included 315 adolescents selected through simple random sampling. The following variables were analyzed: age, sex, alcohol consumption, age of onset of alcohol consumption, first alcoholic beverage consumed, frequency of consumption, place of consumption, if experienced drunkenness and experienced sensation, alcohol consumption by relatives with whom he lives and by friends or schoolmates, information on the undesirable effects of alcohol and who provided the information. Results: All adolescents reported consuming alcoholic beverages; 58, 4% started it with the ingestion of beer; 22% consume once a week; 88, 9% do it in bars, discos and public places; 50, 5% of consumers are smokers and 73, 6% referred to the family as a source for information on alcohol consumption. The age of onset of consumption in general is between 14 and 16 years, with an earlier onset in the female sex. Almost all referred alcohol consumption by relatives, showed a near similar relationship by friends or school friends and the whole know the undesirable effects of alcohol. Conclusion: Alcoholic beverage consumption is a health problem in the Territory

Role of students of medicine in the progress of public health in Latin America.

Sr. Editor Según la OPS, la Salud Pública es el esfuerzo organizado de la sociedad, principalmente a través de sus instituciones de carácter público, para mejorar, promover, proteger y restaurar la salud de las poblaciones por medio de actuaciones de alcance colectivo (1). Siguiendo esta definición la educación y práctica médica necesitan salir de las aulas y los hospitales y llegar a donde la realidad social, cultural y económica no lo permite. En Latinoamérica el desarrollo de estas actuaciones colectivas se han convertido en iniciativas netamente estudiantiles sin quitarle valor a los estamentos gubernamentales, pero entendiendo que cada día toman más fuerza y credibilidad (2).  Estudiantes que se ven reflejados en un órgano creado en 1986 en Valparaíso, Chile denominado Federación Latinoamericana de Sociedades Científicas de Estudiantes de Medicina FELSOCEM, organización no gubernamental, de carácter científico, no partidista y sin fines de lucro cuyo objetivo general es elevar el nivel científico de los estudiantes de pregrado, promoviendo la investigación cientifica y la educación médica continuada, con proyección a la comunidad (3). Los objetivos de salud pública y la misión de esta organización son similares, y son aún más las actividades que la respaldan como las intervenciones comunitarias denominadas Intervención Rural de Investigación y Saneamiento (IRIS), Campamento Interdisciplinar Regional de Investigación y Servicio (CIRIS) y el Campamento Universitario Multidisciplinar de Investigacion y Servicio (CUMIS), entre otras (4). En Colombia se realizan alrededor de 5 a 10 intervenciones a comunidades vulnerables tanto regionales como nacionales las cuales son administradas por medio de la Asociacion de Sociedades Científicas de Estudiantes de Medicina de Colombia ASCEMCOL que hace parte de FELSOCEM, la cual  con ayuda de organizaciones oficiales como el ejército nacional y el ministerio de Salud le dan importancia a los estudiantes que se ven beneficiados de los conocimientos y prácticas que realizan en dichos eventos.   El impacto es inconmensurable y los beneficios  tanto para los estudiantes como para las organizaciones que los patrocinan son ineludibles. Involucrados en estos procesos, podemos también nombrar el trabajo de investigación cientifica que se desarrolla con la población vulnerable encontrando información muy valiosa para generar política públicas futuras que mejoren la calidad de vida de la población y la salud a largo plazo.   </p

High infestation of invasive Aedes mosquitoes in used tires along the local transport network of Panama

Background: The long‑distance dispersal of the invasive disease vectors Aedes aegypti and Aedes albopictus has intro‑ duced arthropod‑borne viruses into new geographical regions, causing a significant medical and economic burden. The used‑tire industry is an effective means of Aedes dispersal, yet studies to determine Aedes occurrence and the factors influencing their distribution along local transport networks are lacking. To assess infestation along the primary transport network of Panama we documented all existing garages that trade used tires on the highway and surveyed a subset for Ae. aegypti and Ae. albopictus. We also assess the ability of a mass spectrometry approach to classify mos‑ quito eggs by comparing our findings to those based on traditional larval surveillance. Results: Both Aedes species had a high infestation rate in garages trading used tires along the highways, providing a conduit for rapid dispersal across Panama. However, generalized linear models revealed that the presence of Ae. aegypti is associated with an increase in road density by a log‑odds of 0.44 (0.73 ± 0.16; P = 0.002), while the presence of Ae. albopictus is associated with a decrease in road density by a log‑odds of 0.36 (0.09 ± 0.63; P = 0.008). Identifica‑ tion of mosquito eggs by mass spectrometry depicted similar occurrence patterns for both Aedes species as that obtained with traditional rearing methods. Conclusions: Garages trading used tires along highways should be targeted for the surveillance and control of Aedes‑mosquitoes and the diseases they transmit. The identification of mosquito eggs using mass spectrometry allows for the rapid evaluation of Aedes presence, affording time and cost advantages over traditional vector surveil‑ lance; this is of importance for disease risk assessment.Background: The long‑distance dispersal of the invasive disease vectors Aedes aegypti and Aedes albopictus has intro‑ duced arthropod‑borne viruses into new geographical regions, causing a significant medical and economic burden. The used‑tire industry is an effective means of Aedes dispersal, yet studies to determine Aedes occurrence and the factors influencing their distribution along local transport networks are lacking. To assess infestation along the primary transport network of Panama we documented all existing garages that trade used tires on the highway and surveyed a subset for Ae. aegypti and Ae. albopictus. We also assess the ability of a mass spectrometry approach to classify mos‑ quito eggs by comparing our findings to those based on traditional larval surveillance. Results: Both Aedes species had a high infestation rate in garages trading used tires along the highways, providing a conduit for rapid dispersal across Panama. However, generalized linear models revealed that the presence of Ae. aegypti is associated with an increase in road density by a log‑odds of 0.44 (0.73 ± 0.16; P = 0.002), while the presence of Ae. albopictus is associated with a decrease in road density by a log‑odds of 0.36 (0.09 ± 0.63; P = 0.008). Identifica‑ tion of mosquito eggs by mass spectrometry depicted similar occurrence patterns for both Aedes species as that obtained with traditional rearing methods. Conclusions: Garages trading used tires along highways should be targeted for the surveillance and control of Aedes‑mosquitoes and the diseases they transmit. The identification of mosquito eggs using mass spectrometry allows for the rapid evaluation of Aedes presence, affording time and cost advantages over traditional vector surveil‑ lance; this is of importance for disease risk assessment

Una oportunidad para Pillsens

Pillsens es una compañía farmacéutica de origen finlandés con presencia en Estados Unidos y Francia, dedicada a la fabricación y distribución de medicamentos, principalmente, analgésicos y antioxidantes, denominados Rubbana y AndyOx, respectivamente. El presente trabajo consiste en analizar y desarrollar el plan estratégico de Pillsens para el periodo comprendido entre el año 2022 y el año 2025, con la finalidad de obtener mayores ingresos, disminuir costos y gastos, e incrementar significativamente la presencia de Pillsens en el mercado estadounidense. Luego del análisis realizado, se determinó la necesidad de proponer como alternativa para lograr los objetivos planteados la suscripción de una alianza comercial con CVS, compañía farmacéutica estadounidense, que permitirá a Pillsens la fácil distribución de sus productos en el territorio estadounidense, así como el ahorro en costos de almacenamiento y distribución. El objetivo de la alianza es que la compañía obtenga mejores resultados financieros, debido principalmente al incremento en el volumen de ventas y a las eficiencias que se generan por el acuerdo comercial suscrito, primordialmente ahorro en publicidad y marketing. Asimismo, se determinó que la manera más eficiente de llevar a cabo el negocio es a través de la venta de productos producidos y embalados especialmente para CVS, es decir, el desarrollo de una marca blanca. Por otro lado, se debe mencionar que la ventaja competitiva de la alianza comercial es la diferenciación, pues el proceso de producción mantiene altos estándares de calidad; del mismo modo, se buscó mantener liderazgo en costos, estableciendo el foco principalmente en los canales de distribución, tecnología y servicio de cliente. Según las proyecciones realizadas al 2025, se espera que al término de la alianza, Pillsens haya generado mejoras en su EBITDA hasta en un 25 % y principalmente en ingresos hasta en un 21 %.Pillsens is a pharmaceutical company incorporated in Finland, with business in the United States and France, dedicated to the manufacture and distribute medicines, mainly analgesics and antioxidants, called Rubbana and AndyOx, respectively. This work consists in analyzing and developing Pillsens strategic plan for the period 2022-2025, with the purpose of obtaining a higher income, reduce costs and expenses, and significantly increase the presence of Pillsens in the US market. After the analysis carried out, we determined the need to propose as an alternative to achieve the stated objectives the negotiation and execution of a commercial alliance with CVS, an American pharmaceutical company, which will allow Pillsens to easily distribute its products in the United States, as well as saving costs of storage and distribution. The purpose of the alliance is for the company to obtain the better financial results possible, principally due to the increase in sales volume and the efficiencies generated by the comercial alliance signed, mainly because of the savings in advertising and marketing. Likewise, it was determined that the most efficient way to carry out business is through the sale of products produced and packaged especially for CVS, that is, the development of a white label. We must mention that the competitive advantage of the commercial alliance is differentiation, since the production process maintains high quality standards, in the same way, it sought to maintain leadership in costs, establishing the focus mainly on the distribution channel, technology and customer service. According to the projections made to 2025, it is expected that at the end of the alliance, Pillsens will have generated improvements in its EBITDA of up to 25 % and mainly in revenues of up to 21 %

Plan de negocios para el dise?o e implementaci?n de un centro integral de desarrollo para el adulto mayor dirigido al nivel socioecon?mico A-B en la ciudad de Arequipa

Enmarcados en el contexto del crecimiento econ?mico del pa?s, incluyendo el departamento de Arequipa, y del incremento global de la poblaci?n adulta mayor y su proyecci?n. Lejos de representar una alternativa m?s de algunos centros de reposo o descanso para el adulto mayor, la opci?n dise?ada es la de apreciar y rescatar el valor que tiene en potencia el adulto mayor, para poder compartir el conocimiento y expertiz desarrollado en su vida profesional a manera de talleres y charlas a j?venes de manera gratuita. Teniendo en cuenta que los factores determinantes para hacer sostenible el negocio, son: (i) la buena reputaci?n, (ii) el servicio adecuado y (iii) la confianza que se genere en el p?blico objetivo. Se determina viable la implementaci?n de un centro de atenci?n integral de desarrollo para el adulto mayor, dirigido al nivel socio econ?mico AB, en la ciudad de Arequipa

Plan de negocio para la implementaci?n de una tienda de venta de productos y servicios para el cuidado del adulto mayor

El plan de negocio denominado A?os M?gicos, es una tienda f?sica y virtual de venta de productos y servicios especializados al cuidado del adulto mayor. A?os M?gicos est? enfocado en contribuir y apoyar al Adulto Mayor durante el proceso de envejecimiento de manera m?s activa y segura; as? como tambi?n en la prevenci?n y tratamiento de enfermedades o incapacidades f?sicas propias de la edad. El negocio f?sico operar? dentro de un centro comercial de la zona 7 de Lima Metropolitana, ofreciendo al p?blico lime?o tres l?neas de productos: l?nea preventiva, de asistencia y movilidad; y de cuidado. El amplio portafolio de productos, ambientes de alegr?a y vitalidad har?n de esta una experiencia de compra ?nica para nuestros adultos mayores, tutores y familiares; reconociendo de esta manera a A?os M?gicos como una tienda pensada en ellos. El principal inter?s es la plena satisfacci?n y el mejoramiento de la calidad de vida de nuestros adultos mayores en temas de cuidado y prevenci?n a trav?s de un envejecimiento saludable