La protección frente al ruido de los forjados proyectados por Eduardo Torroja en la E.T.S. de Arquitectura de la Ciudad Universitaria de Madrid.

En este trabajo se exponen y se analizan los resultados de las mediciones acústicas del aislamiento acústico a ruido aéreo y a ruido de impactos de los forjados de hormigón armado macizo, proyectados por D. Eduardo Torroja Miret y fabricados en la primera mitad de los años 1930 en la Escuela Técnica Superior de Arquitectura de la UPM, situada en la Ciudad Universitaria de Madrid. Los valores experimentales obtenidos de los parámetros acústicos: índice ponderado de reducción acústica aparente R’w y nivel de presión acústica ponderado de impactos normalizado L’n,w están bien relacionados con los previstos por las estimaciones en los modelos de cálculo de las normas europeas EN 12354 partes 1, 2:2000. Se ha obtenido una relación experimental de reciprocidad para la suma de los valores del índice de reducción acústica aparente y el nivel de presión sonora de impactos normalizado

Wt1 transcription factor impairs cardiomyocyte specification and drives a phenotypic switch from myocardium to epicardium.

During development, the heart grows by addition of progenitor cells to the poles of the primordial heart tube. In the zebrafish, Wilms tumor 1 transcription factor a (wt1a) and b (wt1b) genes are expressed in the pericardium, at the venous pole of the heart. From this pericardial layer, the proepicardium emerges. Proepicardial cells are subsequently transferred to the myocardial surface and form the epicardium, covering the myocardium. We found that while wt1a and wt1b expression is maintained in proepicardial cells, it is downregulated in pericardial cells that contributes cardiomyocytes to the developing heart. Sustained wt1b expression in cardiomyocytes reduced chromatin accessibility of specific genomic loci. Strikingly, a subset of wt1a- and wt1b-expressing cardiomyocytes changed their cell-adhesion properties, delaminated from the myocardium and upregulated epicardial gene expression. Thus, wt1a and wt1b act as a break for cardiomyocyte differentiation, and ectopic wt1a and wt1b expression in cardiomyocytes can lead to their transdifferentiation into epicardial-like cells.NM has been funded by SNF grant 320030E-164245 and ERC Consolidator grant 2018 819717. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Benoît Zuber is supported by SNF grant 179520 and ERA-NET NEURON grant 185536. M.O. was supported by SNF grant PCEFP3_186993.S

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Evaluación cualitativa de un proceso participativo de adaptación de una guía de promoción de la salud

Fundamentos: En las últimas décadas, en España, el interés mostrado hacia la participación comunitaria en salud ha ido creciendo. Sin embargo, no existen guías basadas en la evidencia para promover la participación comunitaria en salud. Por eso, entre 2017 y 2018 se llevó a cabo el proyecto AdaptA GPS a través de 10 nodos de trabajo en 10 comunidades autónomas, para adaptar al contexto español la guía de participación comunitaria en salud NG44 del instituto NICE de Reino Unido. El objetivo de este artículo fue evaluar el proceso de adaptación (los aspectos a mejorar y los aprendizajes resultantes) del proyecto AdaptA GPS a través de la valoración de sus participantes. Métodos: Se realizó una evaluación cualitativa a través de dos cuestionarios con respuestas abiertas, autoadministrados en cada nodo de trabajo, uno por la persona coordinadora y uno por las personas del nodo (entre 6 y 10 personas por nodo), y se realizó un análisis temático. Resultados: Se identificaron tres temas principales que reflejan las perspectivas de las personas participantes sobre el proceso de adaptación: factores positivos (metodología participativa, trabajo multicéntrico y diversidad de participantes), aspectos mejorables (escasa participación ciudadana y falta de financiación) y aprendizajes adquiridos (trabajo en red y la importancia de impulsar investigaciones en este campo). Conclusiones: El proyecto AdaptA GPS fue un proyecto innovador que favoreció la creación de vínculos y sinergias, fomentando la coproducción gracias a su enfoque participativo, que ha sentado las bases para futuros procesos colaborativos de participación comunitaria. Background: In the last decades, in Spain, the interest shown towards community participation in health has been growing. However, there are no evidence-based guidelines to promote community participation in health. For this reason, between 2017 and 2018 the AdaptA GPS project was carried out through 10 working groups from 10 autonomous communities, to adapt the NG44 community participation guide in health from the NICE institute in the United Kingdom to the Spanish context. The objective of this article was to evaluate the adaptation process (the aspects to be improved and the resulting learning) of the AdaptA GPS project through the evaluation of its participants. Methods: A qualitative evaluation was carried out through two questionnaires with open-ended questions, self-administered in each working group, one by the group coordinator and one by the whole working group (between 6 and 10 people per group), and the answers were analysed thematically. Results: Three main themes were identified that reflect the perspectives of the participants about the adaptation process: positive factors (participatory methodology, collaborative work and diversity of participants), aspects that could be improved (scarce people''s participation and lack of funding) and acquired learning (working in network and the importance of promoting research in this field). Conclusions: The AdaptA GPS project was an innovative project that favored the creation of networks and synergies, fostering co-production thanks to its participatory approach, which has laid the foundations for future collaborative processes of community engagement

Monitorización del consumo de sustancias de abuso legales e ilegales en España a través de las aguas residuales en el marco de la red ESAR-Net

Trabajo presentado en el 4th Congreso Internacional y XLIX Jornadas Nacionales de Socidrogalcohol - VIII Congreso Nacional Patología Bio-Psicosocial, celebrado en Tenerife del 06 al 08 de octubre de 2022

A Genome-Wide RNAi Screen Identifies Regulators of Cholesterol-Modified Hedgehog Secretion in Drosophila

Hedgehog (Hh) proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI) but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg) morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion

Cytoneme-Mediated Delivery of Hedgehog Regulates the Expression of Bone Morphogenetic Proteins to Maintain Germline Stem Cells in Drosophila

Genetic manipulation of the germline stem cell niche in Drosophila ovaries reveals that support cells ensure the maintenance of stem cells by modulating the spread of Hedgehog within the niche

The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling

Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding “EGF-like” domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the “WIF” domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling

Intracellular Trafficking and Synaptic Function of APL-1 in Caenorhabditis elegans

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of b-amyloid plaques in the brain. Plaques are composed of the amyloid-b peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer’s Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality. Methodology/Principal Findings: We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads t