Novel mechanisms of neurogenesis: the role of the new centrosomal protein Akna

Understanding the basic cell biology of neural stem and progenitor cells is fundamental, on the one hand, to know how the large and complex brain of humans has evolved and in the other hand, for their successful application in regenerative medicine. While many central features are shared between different types of neural progenitors from diverse sources, there may be possibly an equal number of differences, and therefore it is of paramount importance to compare them. Towards that end, our laboratory identifies and investigates novel genes and molecular mechanisms regulating homeostasis and fate commitment of neural progenitors common to the developing and the adult brain, in mouse and recently, in humans. This line of experimentation has led to the discovery of new factors and biological phenomena essential for both embryonic and adult neurogenesis, and has been critical in pioneering and further developing direct neuronal reprogramming i.e. forced neurogenesis. My PhD work is the functional characterization of one such common candidate genes called Akna, and the investigation of its molecular regulation. I have discovered that this gene, erroneously annotated as an AT-hook transcription factor, is in fact an integral component of interphase centrosomes in the differentiating subtype of neural stem cells - radial glia - and in basal progenitors of the developing forebrain and in neuronal precursors of the adult brain. It localizes predominantly at subdistal appendages of mother centrioles where it regulates the organization and polymerization of microtubules. Gain- and loss-of-function experiments in the murine developing cerebral cortex show that Akna is necessary and sufficient for the delamination of differentiating neural stem cells in the (apical) ventricular zone towards the adjacent (basal) subventricular zone, where it is highest expressed. There, it is required for the retention of basal progenitors. Its subsequent downregulation allows repolarization and migration of young neurons to the cortical plate, where Akna is not detectable. Notably, cells that express Akna have mostly centrosome-based microtubule nucleation, while those without Akna, i.e. neurons, largely nucleate microtubules from noncentrosomal sources. This is indeed also the case for other cell types including adult brain neural precursors (neuroblasts) and immune cells; both of which have high levels of Akna. Furthermore, Akna’s enrichment in the outer subventricular zone of the folded ferret and macaque brains together with manipulation in human induced pluripotent stem cell-derived cerebral organoids suggest a conserved role in brain ontogeny and phylogeny. The delamination process of epithelial-like neural stem cells is reminiscent of the mesenchymal transition that can occur in true epithelial cells. In fact, many factors and molecular pathways are common to both processes, and so is Akna. We have found that it is upregulated early in mammary gland epithelial cells undergoing epithelial to mesenchymal transition. In its absence, disassembly of cell-cell junctions is impaired because degradation of epithelial adhesion molecules is delayed and hence, the resulting mesenchymal cell scattering is impaired. This, together with the above-mentioned results, supports a mechanistic model in which Akna’s role as microtubule organizer at centrosomes facilitates disassembly of cell-cell contacts and cell polarization in epithelial cells in general. Altogether, the results of my work uncover previously unconsidered, and therefore not observed, roles of centrosomal microtubule nucleation and highlights the key relevance of centrosome composition

Novel mechanisms of neurogenesis: the role of the new centrosomal protein Akna

Understanding the basic cell biology of neural stem and progenitor cells is fundamental, on the one hand, to know how the large and complex brain of humans has evolved and in the other hand, for their successful application in regenerative medicine. While many central features are shared between different types of neural progenitors from diverse sources, there may be possibly an equal number of differences, and therefore it is of paramount importance to compare them. Towards that end, our laboratory identifies and investigates novel genes and molecular mechanisms regulating homeostasis and fate commitment of neural progenitors common to the developing and the adult brain, in mouse and recently, in humans. This line of experimentation has led to the discovery of new factors and biological phenomena essential for both embryonic and adult neurogenesis, and has been critical in pioneering and further developing direct neuronal reprogramming i.e. forced neurogenesis. My PhD work is the functional characterization of one such common candidate genes called Akna, and the investigation of its molecular regulation. I have discovered that this gene, erroneously annotated as an AT-hook transcription factor, is in fact an integral component of interphase centrosomes in the differentiating subtype of neural stem cells - radial glia - and in basal progenitors of the developing forebrain and in neuronal precursors of the adult brain. It localizes predominantly at subdistal appendages of mother centrioles where it regulates the organization and polymerization of microtubules. Gain- and loss-of-function experiments in the murine developing cerebral cortex show that Akna is necessary and sufficient for the delamination of differentiating neural stem cells in the (apical) ventricular zone towards the adjacent (basal) subventricular zone, where it is highest expressed. There, it is required for the retention of basal progenitors. Its subsequent downregulation allows repolarization and migration of young neurons to the cortical plate, where Akna is not detectable. Notably, cells that express Akna have mostly centrosome-based microtubule nucleation, while those without Akna, i.e. neurons, largely nucleate microtubules from noncentrosomal sources. This is indeed also the case for other cell types including adult brain neural precursors (neuroblasts) and immune cells; both of which have high levels of Akna. Furthermore, Akna’s enrichment in the outer subventricular zone of the folded ferret and macaque brains together with manipulation in human induced pluripotent stem cell-derived cerebral organoids suggest a conserved role in brain ontogeny and phylogeny. The delamination process of epithelial-like neural stem cells is reminiscent of the mesenchymal transition that can occur in true epithelial cells. In fact, many factors and molecular pathways are common to both processes, and so is Akna. We have found that it is upregulated early in mammary gland epithelial cells undergoing epithelial to mesenchymal transition. In its absence, disassembly of cell-cell junctions is impaired because degradation of epithelial adhesion molecules is delayed and hence, the resulting mesenchymal cell scattering is impaired. This, together with the above-mentioned results, supports a mechanistic model in which Akna’s role as microtubule organizer at centrosomes facilitates disassembly of cell-cell contacts and cell polarization in epithelial cells in general. Altogether, the results of my work uncover previously unconsidered, and therefore not observed, roles of centrosomal microtubule nucleation and highlights the key relevance of centrosome composition

Modern epidemiology and its discontents

O objetivo deste artigo é apresentar o debate em curso na epidemiologia, evidenciando lados opostos na luta para definir o caminho nos próximos anos. Discussão entre epidemiólogos em meados dos anos 1990, que defendem que a epidemiologia deve necessariamente tratar de contexto amplo contra aqueles que acreditam que a ciência e a saúde pública são mais bem servidas focalizando o nível individual. O conceito de estilos de raciocínio de Ian Hacking foi usado como ferramenta teórica. A literatura foi revisada usando um conjunto nuclear de artigos como ponto de entrada, buscando os artigos que os citaram, e então seguindo as citações do conjunto resultante na base Scopus. Os argumentos principais, de acordo com níveis (ontológico, epistemológico, axiológico e pragmático), foram apresentados a fim de mostrar uma discordância ainda mais profunda, na própria concepção de ciência e da sua relação com questões sociais e políticas públicas.El objetivo de este artículo es presentar el debate actual en epidemiología, evidenciando lados opuestos en la lucha para definir el camino en los próximos años. La discusión de los epidemiólogos en la mitad de los años 90, se dio entre quienes defienden que la epidemiología debe necesariamente tratar del contexto amplio contra aquellos que piensan que la ciencia y la salud pública son mejor atendidas enfocando el nivel individual. El concepto de estilos de raciocinio de Ian Hacking fue usado como herramienta teórica. La literatura fue revisada usando un conjunto nuclear de artículos como punto de entrada, buscando los artículos que los citaron, y posteriormente siguiendo las citaciones del conjunto resultante en la base Scopus. Los argumentos principales, de acuerdo con los niveles (ontológico, epistemológico, axiológico y pragmático), fueron presentados a fin de mostrar una discordancia mucho más profunda, en la propia concepción de ciencia y de su relación con aspectos sociales y políticas públicas.The goal of this article is to present a snapshot of an ongoing debate within epidemiology, pitching opposing sides in the struggle to define the path it should follow in the years to come. The debate among epidemiologists in the mid-90s pitted those who defended the idea that epidemiology should necessarily deal with a wide context against those who believed that science and public health are better served by focusing on the individual level. Ian Hacking’s concept of styles of reasoning was used as a theoretical tool. The literature was reviewed using a core set of articles as an entry point, seeking articles that cited them, and then back-tracking the citations of the resulting set in the Scopus database. The main arguments are presented according to levels (ontological, epistemological, axiological and pragmatic), in order to show an even deeper disagreement, in the very conception of science and its relation to social issues and public policy

Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA

The serotonin neurotransmitter system is widespread in the brain and implicated in modulation of neuronal responses to other neurotransmitters. Among 14 serotonin receptor subtypes, 5-HT2cR plays a pivotal role in controlling neuronal network excitability. Serotonergic activity conveyed through receptor 5-HT2cR is regulated post-transcriptionally via two mechanisms, alternative splicing and A-to-I RNA editing. Brain-specific small nucleolar RNA SNORD115 harbours a phylogenetically conserved 18-nucleotide antisense element with perfect complementarity to the region of 5ht2c primary transcript that undergoes post-transcriptional changes. Previous 5ht2c minigene studies have implicated SNORD115 in fine-tuning of both post-transcriptional events. We monitored post-transcriptional changes of endogenous 5ht2c transcripts during neuronal differentiation. Both SNORD115 and 5ht2c were upregulated upon neuronal commitment. We detected increased 5ht2c alternative exon Vb inclusion already at the stage of neuronal progenitors, and more extensive A-to-I editing of non-targeted sites A and B compared to adjacent adenosines at sites E, C and D throughout differentiation. As the extent of editing is known to positively correlate with exon Vb usage while it reduces receptor functionality, our data support the model where SNORD115 directly promotes alternative exon inclusion without the requirement for conversion of key adenosines to inosines, thereby favouring production of full-length receptor isoforms with higher potency

Justice and Fairness in Tourism: A Grounded Theory Study of Cultural Justice in Quintana Roo, Mexico

Equity and fairness in the distribution of tourism benefits and participation in tourism decision-making are key tenets of sustainable tourism. However, little attention has been paid to the study and conceptualization of justice in tourism and robust theoretical or methodological foundations to examine fairness and justice; in particular, in regards to the well-being of ethnic, minority and/or disadvantaged groups are especially lacking in tourism studies. This dissertation reports the results of a grounded theory study of justice and equity in relation to tourism and the Yucatecan Maya in Quintana Roo, Mexico. A robust framework is offered to guide the study of cultural justice in tourism, which was developed based on theoretical contributions from environmental justice, social justice, and political philosophy, among others, and empirical data from multiple sources. Data were collected through in-depth interviews with 47 tourism stakeholders, participant observation, and examination of tourism-related government reports, statistics and other data related to legislation, planning and development. Issues of justice were found to be complex and multifaceted, rooted in post-colonial and contemporary power dynamics that affect the economic, social, and cultural status of the Yucatecan Maya in society. The study identified four major issues directly related to tourism that affected the economic and cultural well-being of this ethnic group: cultural exploitation, cultural marginalization, cultural racism, and cultural domination. The extensive research also identified the positive role of tourism in providing for cultural justice, in particular, recognition and respect for cultural, ethnic and minority groups and the cultural sustainability of their cultural manifestations. Based on the above findings and drawing upon theoretical contributions in the extensive literature on justice and fairness, it is argued that discourses of justice and equity in tourism should look beyond the distribution of tourism benefits and access to political power and address intangible matters of respect, recognition, and cultural valuation. A number of key principles to help address cultural injustices are suggested and implications for tourism policy and practice discussed

Autologous fat grafting as a novel technique for primary essential cutis verticis gyrata

Antecedentes: La cutis verticis gyrata (CVG) es una afección de crecimiento excesivo de la piel y laxitud excesiva del cuero cabelludo, que da lugar a surcos y pliegues profundos que se asemejan a las circunvoluciones y la superficie externa del cerebro. Los abordajes para el tratamiento de la CVG van desde el conservador hasta el quirúrgico, siendo este último el predominante, sin embargo, la cirugía propuesta en la literatura reciente puede no ser adecuada para pacientes que desean un abordaje menos invasivo. Objetivo: Reportar el primer caso de inyección de grasa autóloga como una nueva opción de tratamiento para la CVG esencial primaria. Método: Un hombre colombiano de 51 años de edad, sin antecedentes médicos fue tratado con una inyección de grasa autóloga en el cuero cabelludo, con tratamiento previo fallido con presoterapia aplicada directamente sobre la piel se describe. Resultados: Se logró una mejoría cosmética exitosa y un abordaje menos invasivo después de dos sesiones de injerto de grasa autóloga. Conclusiones: Este método permitió excelentes resultados cosméticos preservando la opción de reparación quirúrgica posterior en casos refractarios. © 2023 El autor(es)Background: Cutis verticis gyrata (CVG) is a condition of excessive skin growth and excessive laxity of the scalp, leading to deep furrows and folds that resemble the gyri and outer surface of the brain. Approaches for the treatment of CVG range from conservative to surgical, the last one being the predominant way of treating the condition, however, the surgery proposed in the recent literature may not be suitable for patients who desire a less invasive approach. Aim: To report the first case of autologous fat injection as a novel treatment option for primary essential CVG. Methods: A 51 -year-old Colombian man, with no medical records was treated with a scalp injection of autologous fat, with previous failed treatment with pressure therapy apply directly on skin is described. Results: A successful cosmetic improvement and a less invasive approach was reached after two sessions of autologous fat grafting. Conclusion: This method allowed excellent cosmetic outcomes while preserving the option of subsequent surgical repair in refractory cases. © 2023 The Author(s

Arquitectura Tecnológica Para Big Data

The term Big Data with each passing day, it becomes more important, which is why in this research is studied, analyzed and disclosed in a comprehensive manner the different architectures of Big Data, withits features, tools, technologies and standards related to that end, for the sole purpose of providing assistance to the business sector for possible implementation of Big Data.El termino Big Data cada día que pasa, se torna más importante, es por esto que en la presente investigación se estudia, analiza y da a conocer de manera exhaustiva las diferentes arquitecturas de Big Data, con sus características, herramientas, tecnologías y estándares relacionadas con dicho termino, con el único objetivo de brindar una ayuda al sector empresarial para una posible implementación de Big Data

Análisis de la importancia de los videojuegos aplicados a la metacognición y aprendizaje significativo

El presente artículo es un planteamiento basado en la exploración de documentos y la experiencia obtenida en la misma, como fuente para corroborar o no, si el videojuego aplicado a la metacognición es contraproducente en el aprendizaje significativo, en él se indica que la metacognición se concibe como la capacidad de autorregular los procesos de aprendizaje, además vincula operaciones mentales que implican conocimiento y aprendizaje y que el videojuego, por su parte, es cualquier forma de software de entretenimiento, ejecutado en cualquier dispositivo digital con pantalla y por supuesto, la participación de uno o varios jugadores, esto revela que jugar un videojuego, por sencillo que este parezca, envuelve capacidades metacognitivas que conllevan a un aprendizaje significativo, contextualizamos que lo que genera esta gran posibilidad de aprendizaje es que los videojuegos ofrecen la ventaja de poder equivocarse y de poderse volver a intentar, esta es la premisa de confirmación que persigue esta investigación por lo que enuncia “al jugar videojuegos se utiliza la metacognición y se aprende y, al ser este aprendizaje imperecedero, se considera aprendizaje significativo”

Propuesta metodológica para el mejoramiento de procesos utilizando el enfoque Harrington y la Norma ISO 9004

The following article shows the elaboration of a methodological proposition for processes improvement, following the Harrington approach for processes improvement and the ISO 9004 norm version2000, in a Services company. Based in these two methodologies an improvement sketch is built for the work orders process.The last part of the report shows the conclusions on the development improvement process and it states some recommendations to transform improvement into a tool that generates new progress opportunities.El siguiente artículo presenta la elaboración de una propuesta metodológica para el mejoramiento de procesos, siguiendo el Enfoque Harrington para el mejoramiento de procesos y la Norma ISO 9004 versión 2000, en una compañía de Servicios. Basados en estas dos metodologías se construye un esquema de mejoramiento para el proceso de las Órdenes de Trabajo. En la parte final del informe se presentan las conclusiones acerca del proceso de mejoramiento desarrollado y se plantean algunas recomendaciones para hacer del mejoramiento una herramienta generadora de nuevas oportunidades de progreso

Propuesta metodológica para el mejoramiento de procesos utilizando el enfoque Harrington y la Norma ISO 9004

El siguiente artículo presenta la elaboración de una propuesta metodológica para el mejoramiento de procesos, siguiendo el Enfoque Harrington para el mejoramiento de procesos y la Norma ISO 9004 versión 2000, en una compañía de Servicios. Basados en estas dos metodologías se construye un esquema de mejoramiento para el proceso de las Órdenes de Trabajo. En la parte final del informe se presentan las conclusiones acerca del proceso de mejoramiento desarrollado y se plantean algunas recomendaciones para hacer del mejoramiento una herramienta generadora de nuevas oportunidades de progreso