Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons

Axonal growth is essential for establishing neuronal circuits during brain development and for regenerative processes in the adult brain. Unfortunately, the extracellular signals controlling axonal growth are poorly understood. Here we report that a reduction in extracellular ATP levels by tissue-nonspecific alkaline phosphatase (TNAP) is essential for the development of neuritic processes by cultured hippocampal neurons. Selective blockade of TNAP activity with levamisole or specific TNAP knockdown with short hairpin RNA interference inhibited the growth and branching of principal axons, whereas addition of alkaline phosphatase (ALP) promoted axonal growth. Neither activation nor inhibition of adenosine receptors affected the axonal growth, excluding the contribution of extracellular adenosine as a potential hydrolysis product of extracellular ATP to the TNAP-mediated effects. TNAP was colocalized at axonal growth cones with ionotropic ATP receptors (P2X7 receptor), whose activation inhibited axonal growth. Additional analyses suggested a close functional interrelation of TNAP and P2X7 receptors whereby TNAP prevents P2X7 receptor activation by hydrolyzing ATP in the immediate environment of the receptor. Furthermore inhibition of P2X7 receptor reduced TNAP expression, whereas addition of ALP enhanced P2X7 receptor expression. Our results demonstrate that TNAP, regulating both ligand availability and protein expression of P2X7 receptor, is essential for axonal development

Increased levels of extracellular ATP in glaucomatous retinas: Possible role of the vesicular nucleotide transporter during the development of the pathology

Purpose: To study retinal extracellular ATP levels and to assess the changes in the vesicular nucleotide transporter (VNUT) expression in a murine model of glaucoma during the development of the disease. Methods: Retinas were obtained from glaucomatous DBA/2J mice at 3, 9, 15, and 22 months together with C57BL/6J mice used as age-matched controls. To study retinal nucleotide release, the retinas were dissected and prepared as flattened whole mounts and stimulated in Ringer buffer with or without 59 mM KCl. To investigate VNUT expression, sections of the mouse retinas were evaluated with immunohistochemistry and western blot analysis using newly developed antibodies against VNUT. All images were examined and photographed under confocal microscopy. Electroretinogram (ERG) recordings were performed on the C57BL/6J and DBA/2J mice to analyze the changes in the electrophysiological response; a decrease in the scotopic threshold response was observed in the 15-month-old DBA/2J mice. Results: In the 15-month-old control and glaucomatous mice, electrophysiological changes of 42% were observed. In addition, 50% increases in the intraocular pressure (IOP) were observed when the pathology was fully established. The responses in the retinal ATP net release as the pathology progressed varied from 0.32±0.04 pmol/retina (3 months) to 1.10±0.06 pmol/retina (15 months; threefold increase). Concomitantly, VNUT expression was significantly increased during glaucoma progression in the DBA/2J mice (58%) according to the immunohistochemical and western blot analysis. Conclusions: These results may indicate a possible correlation between retinal dysfunction and increased levels of extracellular ATP and nucleotide transporter. These data support an excitotoxicity role for ATP via P2X7R in glaucoma. This modified cellular environment could contribute to explaining the functional and biochemical alterations observed during the development of the pathology

Nuevos datos sobre la estratigrafía de subsuelo del acuífero de Torrevieja (Alicante): implicaciones en el modelo conceptual de funcionamiento.

El análisis estratigráfico de sondeos de investigación realizados en el acuifera de Torrevieja pone de manifiesto la coincidencia de las unidades hidrogeológicas con las estratigráficas y permite una mayor precisión en la definición de las primeras al poder constatar que las variaciones internas dentro de las unidades estratigráficas tienen reflejo en la geometria de los acuiferos y los parámetros hidrogeológicos. Asi mismo, la interpretación genética de los sedimentos y la caracterización de las discontinuidades que los limitan permiten realizar una extrapolación predictiva de las caracteristicas geológicas de subsuelo que pueden ser aplicadas a la modelización de las unidades hidrogeológicas

Dinosaur swim tracks from the Lower Cretaceous of La Rioja, Spain: An ichnological approach to non-common behaviours

The reconstruction of behavioural patterns performed by non-avian dinosaurs is an important task of palaeontology in order to globally understand how these animals interacted with their environment. Their relation with aquatic lifestyles has always been an intriguing question that has been extensively studied during the last decades, especially focused on some specific groups. The present work describes a new tracksite with 27 swimming tracks located in a fluvial setting from the Lower Cretaceous Urbion Group of La Rioja (Spain). They are preserved as natural casts with sizes between 8.5 and 29.2 cm and a predominant orientation. The tracks have been classified into 6 different morphotypes according to their morphology, and grouped into 5 different categories depending on the different pes-substrate interactions, following the proposal of Romilio et al. (2013). Some tracks were produced while the animal was moving in partial or complete buoyancy, and displacement was conducted by water and sediment impulsion, not just a mere paddling. Other tracks could be impressed in a bottom-walked, when the trackmaker touched the digit tips on the ground vertically or sub-vertically. This new tracksite confirms the capabilities of some groups of non-avian dinosaurs to interact with shallow water environments where they could print their pedes as they moved, either in complete buoyancy or during a displacement with some vertical component in the water column. It also contributes to the better understanding of swimming track morphologies as especially dependent on pes-sediment interaction and environment more than differences in pes configuration itself, causing the high variability of swimming footprints even when they belong to the same trackway. The classification of swimming tracks and footprints into categories dependent on the pes-substrate interaction could be a good guiding principle to avoid problematics about ichnotaxonomical definition.Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEUniversidad de La RiojaConsejeria de Educacion y Cultura (Gobierno de La Rioja)Instituto de Estudios RiojanosMinisterio de Ciencia, Innovación y UniversidadesEuropean Regional Development FundUniversidad del País VascoMinisterio de Ciencia e Innovaciónpu

Comparison of the WRF and HARMONIE models ability for mountain wave warnings

Mountain lee waves usually involve aircraft icing and turbulence events. These weather phenomena, in turn, are a threat to aviation safety. For this reason, mountain lee waves are an interesting subject of study for the scientific community. This paper analyses several mountain lee waves events in the south-east of the Guadarrama mountain range, near the Adolfo Suarez Madrid-Barajas airport (Spain), using the Weather Research and Forecasting (WRF) and the HARMONIE-AROME high-resolution numerical models. For this work, simulated brightness temperature from the optimum WRF parametrization schemes and from the HARMONIE are validated using satellite observations to evaluate the performance of the models in reproducing the lenticular clouds associated to mountain lee waves. The brightness temperature probability density shows interesting differences between both models. Following, a mountain wave characterization is performed simulating some atmospheric variables (wind direction, wind speed, atmospheric stability, liquid water content and temperature) in several grid points located in the leeward, windward and over the summit of the mountains. The characterization results are compared for both numerical models and a decision tree is developed for each to forecast and warn the mountain lee waves, lenticular clouds and icing events with a 24 to 48 h lead time. These warnings are validated using several skill scores, revealing similar results for both models.This work was partially supported by research projects: PID2019- 105306RB-I00, CGL2016-78702-C2-1-R and CGL2016-78702-C2-2-R (SAFEFLIGHT project), FEI-EU-17-16 and SPESMART AND SPESVALE (ECMWF Special Projects). J. Díaz-Fernández acknowledges the grant supported from the MINECO-FPI program (BES-2017)

Analysis of the October 2014 subtropical cyclone using the WRF and the HARMONIE-AROME numerical models: Assessment against observations

Subtropical cyclones (STCs) are low-pressure systems characterized by having a thermal hybrid structure and sharing tropical and extratropical characteristics. These cyclones are widely studied due to their harmful impacts, in some cases, similar to those caused by hurricanes or tropical storms. From a numerical modeling point of view, they are considered a challenge on account of their rapid intensification. That is the reason why this paper analyzes the simulations of the STC that occurred in October 2014 near the Canary Islands through two highresolution numerical models: Weather Research and Forecasting (WRF) and HARMONIE-AROME. In this study, the simulations obtained with both models of this STC are analyzed versus different observational data. METAR data are used to validate some surface simulated variables throughout the STC life while soundings are chosen to study the tropospheric behavior. Finally, MSG-SEVIRI satellite brightness temperature is used to be compared to those brightness temperatures simulated by both models to give information of the cloud top spatial structure of this atmospheric system. The 2 m temperature, 2 m dew-point temperature, and 10 m wind speed variables do not show significant deviations when carrying out the validation of both models against the available METAR data. It is outstanding the good results found for the HARMONIE-AROME model when analyzing the temperature sounding for both analyzed dates. Additionally, regarding the wind speed sounding, better results are presented in general by the HARMONIE-AROME model, being the WRF model slightly better during the pre-STC stage. Moreover, the skillfulness of the HARMONIE-AROME model is highlighted when simulating the infrared brightness temperature and cloud distribution compared to the WRF model.This work was partially supported by research projects: PID2019- 105306RB-I00, PCIN-2014-013-C07-04, and PCIN2016-080 (UE ERANET Plus NEWA Project), CGL2016-78702-C2-1-R and CGL2016- 78702-C2-2-R (SAFEFLIGHT project), FEI-EU-17-16 and the two ECMWF Special Projects (SPESMART and SPESVALE). JJGA is supported by the FJC2018-035821 grant and JDF acknowledges the grant supported from the MINECO-FPI program (BES-2017)

Non-IgE-mediated cow’s milk allergy: Consensus document of the Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP), the Spanish Association of Paediatric Primary Care (AEPAP), the Spanish Society of Extra-hospital Paediatrics and Primary Health Care (SEPEAP), and the Spanish Society of Paediatric ClinicaL Immunology, Allergy, and Asthma (SEICAP)

Non-IgE-mediated cow's milk allergy is a frequent disorder in paediatrics. As patients might be seen by professionals from different specialties and levels of expertise, a great variability in diagnostic procedures and disease monitoring is commonly observed. Therefore, four scientific societies involved in its management have developed a consensus document providing specific recommendations related to its prevention, diagnosis, treatment and follow up.La alergia a las proteínas de leche de vaca no mediada por IgE es una patología frecuente, en cuyo manejo están implicados profesionales de diferentes áreas existiendo a día de hoy una gran variabilidad en la forma de abordar su diagnóstico, tratamiento, seguimiento y prevención. Con el objetivo de unificar pautas de actuación se ha elaborado un documento de consenso entre cuatro de las sociedades científicas implicadas en el abordaje de niños con dicha patologí

Effect of the β-amyloid peptide on microglia activation: ATP release

Previous studies have shown a key role of microglial cells in the neuroinflammatory processes associated with some neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglia sense several types of diffusible molecules that regulate the multiple repertoire of microglial functions. Among them, extracellular nucleotides, acting on microglial P2 receptors, have central roles. In this sense, the ionotropic P2X7 receptor has gained recognition as a key regulator of microglial-mediated inflammatory responses.It is known that microglia releases ATP and other nucleotides to the extracellular medium. Although several mechanisms, such as release trough conexins or panexins, has been proposed, a vesicular origin for this released nucleotides, relying on the activity of the vesicular nucleotide transporter (VNUT), cannot be ruled out.In this work we evaluated whether the expression of VNUT and the P2X7 receptor, as well as the ATP release, could be modified in the reactive microglia. To achieve microglia activation we stimulated the cells with the lipopolysaccharide (LPS). Moreover, we analyzed the effect of the b-amyloid peptide b1-42, which is also able to activate the microglial cells, on the expression of VNUT and the ATP release in the microglia.Previous studies have shown a key role of microglial cells in the neuroinflammatory processes associated with some neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglia sense several types of diffusible molecules that regulate the multiple repertoire of microglial functions. Among them, extracellular nucleotides, acting on microglial P2 receptors, have central roles. In this sense, the ionotropic P2X7 receptor has gained recognition as a key regulator of microglial-mediated inflammatory responses.It is known that microglia releases ATP and other nucleotides to the extracellular medium. Although several mechanisms, such as release trough conexins or panexins, has been proposed, a vesicular origin for this released nucleotides, relying on the activity of the vesicular nucleotide transporter (VNUT), cannot be ruled out.In this work we evaluated whether the expression of VNUT and the P2X7 receptor, as well as the ATP release, could be modified in the reactive microglia. To achieve microglia activation we stimulated the cells with the lipopolysaccharide (LPS). Moreover, we analyzed the effect of the b-amyloid peptide b1-42, which is also able to activate the microglial cells, on the expression of VNUT and the ATP release in the microgli

El transportador vesicular de nucleótidos (VNUT). Relevancia en tejidos neurales y neuroendocrinos. Nuevas perspectivas farmacológicas

Vesicular storage of neurotransmitters, which allows their subsequent exocytotic release, is essential for chemical transmission in neurons and endocrine cells. Neurotransmitter uptake to secretory vesicles is carried out by vesicular transporters, which use the electrochemical gradient of protons generated by a vacuolar proton-ATPase as transport driving force. ATP and other nucleotides and dinucleotides are relevant signaling molecules that participate in a variety of biological process. Although the active transport of nucleotides has been pharmacologically and biochemically characterized in a diversity of secretory vesicles, the protein responsible for such vesicular accumulation remained unidentified for some time. In 2008, SLC17A9, the last identified member of the SLC17 transporter family, was found to encode the vesicular nucleotide transporter (VNUT). VNUT is expressed in various ATP-secreting cells and is able to transport several nucleotides in a vesicular membrane potential- dependent fashion. VNUT knockout mice lack vesicular storage and release of ATP from neurons and neuroendocrine cells, resulting in blockage of the purinergic chemical transmission. This review summarizes the current studies on VNUT and analyzes the relevance of vesicular nucleotide transport in different cells types and tissues. The possible use of VNUT inhibitors and interference RNA to reduce VNUT gene expression for therapeutic purposes is also discussed.El almacenamiento vesicular de los neurotransmisores, que permite su subsecuente liberación exocitótica, es un proceso esencial para la transmisión química en neuronas y células endocrinas. La acumulación de los neurotransmisores en vesículas de secreción se lleva a cabo por medio de transportadores vesiculares, que utilizan el gradiente electroquímico de protones generado por una ATPasa vacuolar como fuerza impulsora del transporte. El ATP, así como otros nucleótidos y dinucleótidos, son importantes moléculas señalizadoras que intervienen en una gran variedad de procesos biológicos. Aunque el transporte activo de nucleótidos se ha caracterizado desde el punto de vista bioquímico y farmacológico en una variedad de vesículas de secreción, la proteína responsable de esta acumulación vesicular permaneció durante mucho tiempo desconocida. En 2008, se demostró que SLC17A9, el último miembro identificado de la familia de transportadores SLC17, codifica el transportador vesicular de nucleótidos (VNUT). VNUT se expresa en una variedad de células que liberan ATP y ha mostrado ser capaz de transportar varios nucleótidos de manera dependiente del potencial de membrana vesicular. Ratones deficientes en VNUT pierden la capacidad de almacenar y liberar ATP de neuronas y células neuroendocrinas, lo que resulta en un bloqueo de la transmisión química purinérgica. En esta revisión se pretende resumir los estudios llevados a cabo hasta la fecha sobre VNUT y analizar la relevancia del transporte vesicular de nucleótidos en distintos tipos celulares y tejidos. Asimismo, se discute el posible uso de inhibidores de VNUT, así como de ARNs de interferencia que reduzcan su expresión, con fines terapéuticos

Wind kinetic energy climatology and effective resolution for the ERA5 reanalysis

Producción CientíficaERA5 represents the state of the art for atmospheric reanalyses and is widely used in meteorological and climatological research. In this work, this dataset is evaluated using the wind kinetic energy spectrum. Seasonal climatologies are generated for 30° latitudinal bands in the Northern Hemisphere (periodic domain) and over the North Atlantic area (limited-area domain). The spectra are also assessed to determine the effective resolution of the reanalysis. The results present notable differences between the latitudinal domains, indicating that ERA5 is properly capturing the synoptic conditions. The seasonal variability is adequate too, being winter the most energetic, and summer the least energetic season. The limited area domain results introduce a larger energy density and range. Despite the good results for the synoptic scales, the reanalysis’ spectra are not able to properly reproduce the dissipation rates at mesoscale. This is a source of uncertainties which needs to be taken into account when using the dataset. Finally, a cyclone tropical transition is presented as a case study. The spectrum generated shows a clear difference in energy density at every wavelength, as expected for a highly-energetic status of the atmosphere.Ministerio de Asuntos Económicos y Transformación Digital y Universidad Complutense de Madrid (projects: (PID2019-105306RB-I00 (IBER - CANES), CGL2016-78702 (SAFEFLIGHT), PCIN-2016-080 and FEI-EU-17-16)Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL