Lysosomal signaling is required for embryonic stem cell differentiation and human development

Self-renewal and differentiation are the two key properties that characterize stem cells. To initiate differentiation, pluripotent embryonic stem cells (ESC) must be forced out of self-renewal, the transcriptional networks conferring stem cell identity need to be dissolved and lineages must be chosen. Compared to acquisition and maintenance of ESCs pluripotency, the mechanisms driving exit from this cell state are ill defined. Previous work has identified the tumor suppressor Folliculin (Flcn) as a novel gene required for exit from the ESC state during differentiation (Betschinger et al., 2013a). Flcn loss of function in mice is early embryonic lethal consistent with being required for exit from pluripotency in vivo. It has been shown in ESCs that Flcn and two associated proteins, Fnip1 and Fnip2, regulate the subcellular localization of the basic helix-loop-helix transcription factor Tfe3. In wildtype ESCs, Tfe3 is ubiquitously detected in the nucleus and cytoplasm. Upon ESC differentiation, Tfe3 is excluded from the nucleus whereas Flcn loss of function ESCs harbor constitutive nuclear Tfe3 localization and are, consequentially, impaired in differentiation. Consistently, ectopic nuclear Tfe3 similarly inhibits ESC differentiation. Recently, Flcn has been identified in a metabolic pathway leading to the activation of the mTORC1 complex in an amino-acid sensing dependent manner after nutrient starvation (Tsun et al., 2013). However, mTORC1 activity is not required for ESC differentiation. To gain insights into the regulation of this process, we conducted a genome-wide CRISPR/Cas9 screen in ESCs that aimed to identify genes that, similar to Flcn, are required for the maintenance of stem cell identity upon long term exposure to differentiation stimuli. Although molecularly related to amino-acid sensing dependent mTORC1 regulation, our findings suggest an alternate mode of action that may be founded in the non-starving nature of ESC differentiation. In addition, we show in ESC that the lysosome regulates the assembly of a Flcn-Tfe3 axis, whose impairment induces an embryonic developmental arrest. Additionally, in a collaborative work with human geneticists, we identified five Tfe3 point mutations in a human syndrome called hypomelanosis of Ito. Symptoms associated with this developmental disorder include severe intellectual disability, coarse facial features, frontonasal dysplasia, obesity, epilepsy and growth retardation, suggesting a pleiotropic developmental disorder. To understand the developmental nature of the disease, we tested these mutations in ESCs and we found them causing defects in exit from self-renewal and nuclear Tfe3 accumulation. Taken together, the work presented in this thesis has allowed the identification of the lysosome as a critical organelle required for the control of the exit from pluripotency and indicates that lysosomal recruitment of Tfe3 is required for its inactivation, which is a crucial step to enable normal developmental progression

Problem-based learning and the Inverted Classroom as a learning strategy for the development of maths

Todo cambio en el ámbito educativo debe originarse con la identificación y planteamiento de problemas pedagógicos para lograr mejorar la calidad académica de los docentes y de los demás actores involucrados. El objetivo del proyecto fue realizar un diagnóstico de las competencias matemáticas por medio de las Pruebas Saber de 3° para diseñar estrategias basadas en el ABP y el aula invertida como herramientas que faciliten el aprendizaje y favorezcan la motivación y concentración en esta asignatura específica. El estudio fue de tipo descriptivo. La población estuvo conformada por los estudiantes de grado tercero de la Institución Educativa Departamental (IED) Rural San Pedro Apóstol, donde se realizó un análisis de los resultados de sus pruebas, evidenciando debilidad en los planteamientos e interpretaciones de problemas matemáticos. Por tal motivo, se hizo necesaria la implementación de estas dos herramientas metodológicas para mejorar la capacidad de razonamiento y acentuar un sólido pensamiento crítico en los estudiantes.Any change in the educational field must originate with the identification and approach of pedagogical problems to achieve the academic quality of the teachers and the other actors involved. The objective of the project was to make a diagnosis of the mathematical competences through the Knowledge Saber of 3 ° to design strategies based on the PBL and the Inverted Classroom as tools that facilitate learning and encourage motivation and concentration in this specific subject. The study was descriptive. The population was conformed by the students of third degree of the IED Rural San Pedro Apóstol, where an analysis of the results of their tests was made, evidencing weakness in the approaches and interpretations of mathematical problems. For this reason, it became necessary to implement these two methodological tools to improve the reasoning capacity and accentuate a solid critical thinking in student

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Experiencias de aprendizaje

Libro de experiencias de aprendizaje del grupo de investigación Giteca y de los semilleros de investigación en la que se visualizan las diferentes experiencias lideradas por instructores y aprendices en las diferentes áreas y líneas de formación.Book of learning experiences of the Giteca research group and the research hotbeds in which the different experiences led by instructors and apprentices in the different areas and lines of training are visualized.Propagación in vitro como un camino de aprendizaje para la formación profesional integral -- Experiencias significativas de aprendizaje, laboratorio de hematología y parasitología animal del Complejo Tecnológico para la Gestión Agroempresarial CTPGA-SENA -- Experiencias significativas adquiridas por aprendices en el área de SENNOVA, Complejo Tecnológico para la Gestión Agroempresarial. Regional – Antioquia -- El papel de la prensa escrita en el desarrollo de la competencia textual -- Aprendiendo a Emprender con un emprendedor -- Ven y te cuento sobre ADSI -- Observaciones fenológicas del cultivo de cacao (Theobroma cacao) en los municipios de Tarazá, El Bagre y Caucasia dentro de la formación del programa SENA emprende rural -- Tejiendo sueños desde la formación -- Forraje verde hidropónico como alternativa para disminuir la expansión de la frontera agrícola en el Putumayo -- La importancia del saber hacer para ser competente en el sector agrícola -- Experiencia significativa de aprendizaje semilleros de investigación -- La investigación como ente transformador de pensamientos -- Piscícola Paraguay; Mi Sueño, Mi Proyecto de Vida! -- Estrategia de aprendizaje a través de la investigación y la empresa aplicando un programa de Responsabilidad Social Empresarial –RSE -- Matemática aplicada para procesos agroindustriales de panificaciónna85 página

Visualizing ultrastructural details of placental tissue with super-resolution structured illumination microscopy

Super-resolution fluorescence microscopy is a widely employed technique in cell biology research, yet remains relatively unexplored in the field of histopathology. Here, we describe the sample preparation steps and acquisition parameters necessary to obtain fluorescent multicolor super-resolution structured illumination microscopy (SIM) images of both formalin-fixed paraffin-embedded and cryo-preserved placental tissue sections. We compare super-resolved images of chorionic villi against diffraction-limited deconvolution microscopy and show the significant contrast and resolution enhancement attainable with SIM, demonstrating the applicability of this imaging technique for both clinical diagnosis and biological research