The life cycle of the Mu-Opioid Receptor

Opioid receptors are undisputed targets for the treatment of pain. Unfortunately, targeting these receptors therapeutically poses significant challenges including addiction, dependence, tolerance and the appearance of side-effects such as respiratory depression and constipation. Moreover, misuse of prescription and illicit narcotics has resulted in the current opioid crisis. The mu-opioid receptor is the cellular mediator of the effects of most commonly used opioids and is a prototypical G protein-coupled receptor (GPCR) where new pharmacological, signalling and cell biology concepts have been coined. This review summarises our knowledge of the life cycle of this therapeutic target including its biogenesis, trafficking to and from the plasma membrane, and how the regulation of these processes impacts its function and is related to pathophysiological conditions

Las escuelas infantiles 0-3 en Navarra : características, estrategias y retos para promover la equidad

La extensión del 0-3 en España es ya un reto presente en las agendas políticas estatales, autonómicas y locales. Contemplado en las normativas estatales desde hace décadas, su desarrollo por parte de ayuntamientos y gobiernos regionales ha sido especialmente intenso en los últimos años. Sin embargo, analizar este aspecto no es tarea sencilla. La diversidad de modelos y la ausencia de datos comparables entre territorios no hacen fácil avanzar en la generación de conocimiento. Tan solo los estudios de caso, con sus especificidades, permiten profundizar en los modelos de gestión y su impacto. El objetivo de este artículo es presentar cómo el paradigma de atención 0-3 de Navarra ha respondido al reto de promover un modelo más equitativo y universal. Desde un análisis específico de su evolución y sus distintas medidas de extensión, se pretende identificar las estrategias orientadas a la extensión universal y la equidad en el acceso a la infancia más vulnerable al sistema 0-3. Para ello, se realiza un análisis normativo y estadístico de fuentes secundarias, así como distintas entrevistas en profundidad a personal técnico y de gestión. Los resultados aspiran a presentar las medidas desarrolladas y a compartir sus avances y retos con otros territorios, de tal forma que contribuyan a generar conocimiento sobre el desarrollo de esta política de promoción de la infancia.L'extensió del 0-3 a Espanya és ja un repte present en les agendes polítiques estatals, autonòmiques i locals. Contemplat en les normatives estatals des de fa dècades, el seu desenvolupament per part d'ajuntaments i governs regionals ha estat especialment intens en els últims anys. No obstant això, analitzar aquest aspecte no és tasca senzilla. La diversitat de models i l'absència de dades comparables entre territoris no fan fàcil avançar en la generació de coneixement. Tan sols els estudis de cas, amb les seves especificitats, permeten aprofundir en els models de gestió i el seu impacte. L'objectiu d'aquest article és presentar com el paradigma d'atenció 0-3 de Navarra ha respost al repte de promoure un model més equitatiu i universal. Des d'una anàlisi específica de la seva evolució i les seves diferents mesures d'extensió, es pretén identificar les estratègies orientades a l'extensió universal i l'equitat en l'accés a la infància més vulnerable al sistema 0-3. Per a això, es realitza una anàlisi normativa i estadístic de fonts secundàries, així com diferents entrevistes en profunditat a personal tècnic i de gestió. Els resultats aspiren a presentar les mesures desenvolupades i a compartir els seus avanços i reptes amb altres territoris, de tal forma que contribueixin a generar coneixement sobre el desenvolupament d'aquesta política de promoció de la infància.The provision of early childhood education for 0 to 3-year-olds in Spain is a challenge for state, regional and local policy agendas. Regulated by state legislation for many decades, the evolution of educational policy for 0 to 3-year-olds by city councils and regional governments has been especially intense in recent years. However, analysing this evolution is not an easy task. The diversity of models and the absence of comparable data between regions makes analysis difficult. Only case studies, which are necessarily specific, enable us to look into mod- els of delivery and impact in more depth. The aim of this paper is to show how the provision of early childhood education in Navarra has responded to the challenge of promoting a more equitable and universal model. Through a specific analysis of the development and various models of educational provision, the paper aims to identify strategies aimed at providing universal and equitable access to early childhood education for the most vulnerable children. A review of secondary regulatory and statistical sources is carried out, as well as in-depth interviews with technical and management personnel. The results aim to show the measures taken, and to share progress and challenges with other regions, to ultimately cont ibute to the understanding of the evolution of this policy for early childhood development

How building and district algorithms enhance renewable energy integration in energy markets

© 2019 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting /republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other worksThis study shows the results of the SABINA H2020 project, which analyzes the effect of two level optimization algorithms to increase the consumption of renewable power sources and reduce greenhouse gas emissions. First, at building level, a building algorithm maximizes the self-consumption of generated energy by its own renewable power sources. Second, at district level, a market integrated district algorithm takes into account aspects related to the electricity grid, such as the electricity generation mix and the prices of electricity and ancillary services, and aggregates the energy flexibility forecast of buildings to minimize the overall CO 2 emissions while ensuring a cost reduction to prosumersPeer ReviewedPostprint (published version

Transcriptional response to metal starvation in the emerging pathogen Mycoplasma genitalium is mediated by Fur-dependent and -independent regulatory pathways

Transition metals participate in numerous enzymatic reactions and they are essential for survival in all living organisms. For this reason, bacterial pathogens have evolved dedicated machineries to effectively compete with their hosts and scavenge metals at the site of infection. In this study, we investigated the mechanisms controlling metal acquisition in the emerging human pathogen Mycoplasma genitalium. We observed a robust transcriptional response to metal starvation, and many genes coding for predicted lipoproteins and ABC-transporters were significantly up-regulated. Transcriptional analysis of a mutant strain lacking a metalloregulator of the Fur family revealed the activation of a full operon encoding a putative metal transporter system and a gene coding for a Histidine-rich lipoprotein (Hrl). We recognized a conserved sequence with dyad symmetry within the promoter region of the Fur-regulated genes. Mutagenesis of the predicted Fur operator within the hrl promoter abrogated Fur- and metal-dependent expression of a reporter gene. Metal starvation still impelled a strong transcriptional response in the fur mutant, demonstrating the existence of Fur-independent regulatory pathways controlling metal homeostasis. Finally, analysis of metal accumulation in the wild-type strain and the fur mutant by ICP-MS revealed an important role of Fur in nickel acquisition

Transcriptional response to metal starvation in the emerging pathogen Mycoplasma genitalium is mediated by Fur-dependent and -independent regulatory pathways

Transition metals participate in numerous enzymatic reactions and they are essential for survival in all living organisms. For this reason, bacterial pathogens have evolved dedicated machineries to effectively compete with their hosts and scavenge metals at the site of infection. In this study, we investigated the mechanisms controlling metal acquisition in the emerging human pathogen Mycoplasma genitalium. We observed a robust transcriptional response to metal starvation, and many genes coding for predicted lipoproteins and ABC-transporters were significantly up-regulated. Transcriptional analysis of a mutant strain lacking a metalloregulator of the Fur family revealed the activation of a full operon encoding a putative metal transporter system and a gene coding for a Histidine-rich lipoprotein (Hrl). We recognized a conserved sequence with dyad symmetry within the promoter region of the Fur-regulated genes. Mutagenesis of the predicted Fur operator within the hrl promoter abrogated Fur- and metal-dependent expression of a reporter gene. Metal starvation still impelled a strong transcriptional response in the fur mutant, demonstrating the existence of Fur-independent regulatory pathways controlling metal homeostasis. Finally, analysis of metal accumulation in the wild-type strain and the fur mutant by ICP-MS revealed an important role of Fur in nickel acquisition. Keywords: Ferric uptake regulator; Histidine-rich proteins; Mycoplasma genitalium; emerging STI pathogen; metal acquisition systems; metallome; novel therapeutic targets

Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine

Altres ajuts: La Marató TV3 (201502 i 201516). This work has been developed in the context of AdvanceCat with the support of ACCIÓ (Catalonia Trade & Investment; Generalitat de Catalunya) under the Catalonian ERDF operational program (European Regional Development Fund) 2014-2020. FEB is sponsored by the "Researchers Stabilization Program" from the Spanish "Sistema Nacional de Salud" (SNS-ISCIII) and "Direcció d'Estratègia i Coordinació" Catalan Health Department (CES07/015).Undesired immune responses have drastically hampered outcomes after allogeneic organ transplantation and cell therapy, and also lead to inflammatory diseases and autoimmunity. Umbilical cord mesenchymal stem cells (UCMSCs) have powerful regenerative and immunomodulatory potential, and their secreted extracellular vesicles (EVs) are envisaged as a promising natural source of nanoparticles to increase outcomes in organ transplantation and control inflammatory diseases. However, poor EV preparations containing highly-abundant soluble proteins may mask genuine vesicular-associated functions and provide misleading data. Here, we used Size-Exclusion Chromatography (SEC) to successfully isolate EVs from UCMSCs-conditioned medium. These vesicles were defined as positive for CD9, CD63, CD73 and CD90, and their size and morphology characterized by NTA and cryo-EM. Their immunomodulatory potential was determined in polyclonal T cell proliferation assays, analysis of cytokine profiles and in the skewing of monocyte polarization. In sharp contrast to the non-EV containing fractions, to the complete conditioned medium and to ultracentrifuged pellet, SEC-purified EVs from UCMSCs inhibited T cell proliferation, resembling the effect of parental UCMSCs. Moreover, while SEC-EVs did not induce cytokine response, the non-EV fractions, conditioned medium and ultracentrifuged pellet promoted the secretion of pro-inflammatory cytokines by polyclonally stimulated T cells and supported Th17 polarization. In contrast, EVs did not induce monocyte polarization, but the non-EV fraction induced CD163 and CD206 expression and TNF-α production in monocytes. These findings increase the growing evidence confirming that EVs are an active component of MSC's paracrine immunosuppressive function and affirm their potential for therapeutics in nanomedicine. In addition, our results highlight the importance of well-purified and defined preparations of MSC-derived EVs to achieve the immunosuppressive effect

Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

There is a subtype of breast cancer characterized by the overexpression of the oncogene HER2. Although most patients with this diagnosis benefit from HER2-targeted treatments, some do not respond to these therapies and others develop resistance with time. New tools are therefore warranted for the treatment of this patient population, and for early identification of those individuals at a higher risk of developing innate or acquired resistance to current treatments. Here, we show that HER2 forms heteromer complexes with the cannabinoid receptor CB2R, the expression of these structures correlates with poor patient prognosis, and their disruption promotes antitumor responses. Collectively, our results support HER2–CB2R heteromers as new therapeutic targets and prognostic tools in HER2+ breast cancer

A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

Cancer cells possess aberrant proteomes that can arise by the disruption of genes involved in physiological protein degradation. Here we demonstrate the presence of promoter CpG island hypermethylation-linked inactivation of DERL3 (Derlin-3), a key gene in the endoplasmic reticulum-associated protein degradation pathway, in human tumours. The restoration of in vitro and in vivo DERL3 activity highlights the tumour suppressor features of the gene. Using the stable isotopic labelling of amino acids in cell culture workflow for differential proteome analysis, we identify SLC2A1 (glucose transporter 1, GLUT1) as a downstream target of DERL3. Most importantly, SLC2A1 overexpression mediated by DERL3 epigenetic loss contributes to the Warburg effect in the studied cells and pinpoints a subset of human tumours with greater vulnerability to drugs targeting glycolysis

Apuntes sobre la transparencia

Trece contribuciones de expertos españoles y extranjeros sobre transparencia

The effect of building energy management systems on battery aging

Smart buildings are a key element to walk towards smart cities and grids. Nonetheless, there are several degrees of intelligence. A first step is to incorporate commercial self-consumption solutions in buildings so they can manage the energy from local renewable power generators. A second step is to substitute this commercial solutions with an optimized Energy Management System (EMS) to reduce the electricity bill at the end of the month. Further. This EMS may contribute to stabilize and improve the quality and emissions of the electricity grid by offering some energy flexibility to the electricity system in favour of decentralization. This study compares the battery aging between buildings that count with an EMS to optimize the electricity bill under three scenarios in contrast to those that have a simple self-consumption kit. Lithium ion battery lifespan is estimated by means of an electric equivalent battery circuit model that runs on Matlab and simulates its behaviour through time. Moreover, this study evaluates the distribution of the battery costs regarding its use, observing that batteries controlled by simple self-consumption kits have longer lifespan because they are underused, ending up in higher calendar aging costs than the ones that are controlled by EMS