Dynamic L-type CaV1.2 channel trafficking facilitates CaV1.2 clustering and cooperative gating.

L-type CaV1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. CaV1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent CaV1.2 channels (e.g. cooperative gating). Here, we tested the hypothesis that dynamic intracellular and perimembrane trafficking of CaV1.2 channels is critical for formation and dissolution of functional channel clusters mediating cooperative gating. We found that CaV1.2 moves in vesicular structures of circular and tubular shape with diverse intracellular and submembrane trafficking patterns. Both microtubules and actin filaments are required for dynamic movement of CaV1.2 vesicles. These vesicles undergo constitutive homotypic fusion and fission events that sustain CaV1.2 clustering, channel activity and cooperative gating. Our study suggests that CaV1.2 clusters and activity can be modulated by diverse and unique intracellular and perimembrane vesicular dynamics to fine-tune Ca2+ signals

β-adrenergic-mediated dynamic augmentation of sarcolemmal CaV 1.2 clustering and co-operativity in ventricular myocytes.

Key pointsPrevailing dogma holds that activation of the β-adrenergic receptor/cAMP/protein kinase A signalling pathway leads to enhanced L-type CaV 1.2 channel activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. However, the full mechanistic and molecular details underlying this phenomenon are incompletely understood. CaV 1.2 channel clusters decorate T-tubule sarcolemmas of ventricular myocytes. Within clusters, nanometer proximity between channels permits Ca2+ -dependent co-operative gating behaviour mediated by physical interactions between adjacent channel C-terminal tails. We report that stimulation of cardiomyocytes with isoproterenol, evokes dynamic, protein kinase A-dependent augmentation of CaV 1.2 channel abundance along cardiomyocyte T-tubules, resulting in the appearance of channel 'super-clusters', and enhanced channel co-operativity that amplifies Ca2+ influx. On the basis of these data, we suggest a new model in which a sub-sarcolemmal pool of pre-synthesized CaV 1.2 channels resides in cardiomyocytes and can be mobilized to the membrane in times of high haemodynamic or metabolic demand, to tune excitation-contraction coupling.AbstractVoltage-dependent L-type CaV 1.2 channels play an indispensable role in cardiac excitation-contraction coupling. Activation of the β-adrenergic receptor (βAR)/cAMP/protein kinase A (PKA) signalling pathway leads to enhanced CaV 1.2 activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. CaV 1.2 channels exhibit a clustered distribution along the T-tubule sarcolemma of ventricular myocytes where nanometer proximity between channels permits Ca2+ -dependent co-operative gating behaviour mediated by dynamic, physical, allosteric interactions between adjacent channel C-terminal tails. This amplifies Ca2+ influx and augments myocyte Ca2+ transient and contraction amplitudes. We investigated whether βAR signalling could alter CaV 1.2 channel clustering to facilitate co-operative channel interactions and elevate Ca2+ influx in ventricular myocytes. Bimolecular fluorescence complementation experiments reveal that the βAR agonist, isoproterenol (ISO), promotes enhanced CaV 1.2-CaV 1.2 physical interactions. Super-resolution nanoscopy and dynamic channel tracking indicate that these interactions are expedited by enhanced spatial proximity between channels, resulting in the appearance of CaV 1.2 'super-clusters' along the z-lines of ISO-stimulated cardiomyocytes. The mechanism that leads to super-cluster formation involves rapid, dynamic augmentation of sarcolemmal CaV 1.2 channel abundance after ISO application. Optical and electrophysiological single channel recordings confirm that these newly inserted channels are functional and contribute to overt co-operative gating behaviour of CaV 1.2 channels in ISO stimulated myocytes. The results of the present study reveal a new facet of βAR-mediated regulation of CaV 1.2 channels in the heart and support the novel concept that a pre-synthesized pool of sub-sarcolemmal CaV 1.2 channel-containing vesicles/endosomes resides in cardiomyocytes and can be mobilized to the sarcolemma to tune excitation-contraction coupling to meet metabolic and/or haemodynamic demands

Modelamiento hidráulico del sistema de drenaje pluvial en la zona urbana del Distrito de Chocope – Ascope – La Libertad – 2021

La presente investigación tuvo como objetivo principal realizar el Modelamiento hidráulico del sistema de drenaje pluvial en la zona urbana del Distrito de Chocope, Ascope, La Libertad. Se aplicó la investigación descriptiva, diseño de investigación fue el no experimental – transversal, descriptivo simple. La población del estudio es la localidad de Chocope, se utilizó el muestreo no probabilístico. Con el estudio topográfico de la zona de estudio se determinó que la localidad de Chocope presenta orografía plana, área de 623,668.99 m . En el estudio de mecánica de suelos se encontraron arcillas-limosas. Se elaboró el estudio hidrológico, se calculó que las precipitaciones máximas en 24 horas Subcuenca Bajo Chicama para el periodo de retorno de 10 años varía entre 0.0 a 77.1 mm. Se desarrolló el diseño hidráulico pluvial utilizando el método racional, se efectuó el modelamiento hidráulico de cunetas convencionales, 214 sumideros, se cuenta con 7326.3m de tuberías, el caudal máximo que se conducirá en las tuberías de PVC es de 1868.65 L/s en el tramo-57, diámetro máximo de tubería de 39 pulgadas, velocidad máxima registrada de 3.43 m/s. Concluyendo que este sistema de drenaje es apto e importante para la localidad de Chocope porque permitirá la evacuación de las aguas pluviales

Fermion Generations, Masses and Mixing Angles from Extra Dimensions

We discuss a toy model in six dimensions that predicts two fermion generations, natural mass hierarchy and intergenerational mixing. Matter is described by vector-like six dimensional fermions, one per each irreducible standard model representation. Two fermion generations arise from the compactification mechanism, through orbifold projection. They are localized in different regions of the compact space by a six dimensional mass term. Flavour symmetry is broken via Yukawa couplings, with a Higgs vacuum expectation value not constant in the extra space. A hierarchical spectrum is obtained from order one dimensionless parameters of the six dimensional theory. The Cabibbo angle arises from the soft breaking of six dimensional parity symmetry. We also briefly discuss how the present model could be extended to cover the realistic case.Comment: 22 pages, 2 figures. References added, modified comment on neutrino masses, published versio

Microplasma Processed Ultrathin Boron Nitride Nanosheets for Polymer Nanocomposites with Enhanced Thermal Transport Performance

This Research Article reports on the enhancement of the thermal transport properties of nanocomposite materials containing hexagonal boron nitride in poly(vinyl alcohol) through room-temperature atmospheric pressure direct-current microplasma processing. Results show that the microplasma treatment leads to exfoliation of the hexagonal boron nitride in isopropyl alcohol, reducing the number of stacks from amp;gt;30 to a few or single layers. The thermal diffusivity of the resulting nanocomposites reaches 8.5 mm(2) s(-1) times greater than blank poly(vinyl alcohol) and twice that of nanocomposites containing nonplasma treated boron nitride nanosheets. From TEM analysis, we observe much less aggregation Of the nanosheets after plasma processing along with indications of an amorphous carbon interfacial layer, which may contribute to stable dispersion of boron nitride nanosheets in the resulting plasma treated colloids.Funding Agencies|National Natural Science Foundation of China [51203135, 51173174]; Invest NI PoC award [325]; COST Action [TD1208]; Engineering &amp; Physical Sciences Research Council (EPSRC) [EP/M024938/1, EP/K022237/1]</p

Smart System for Monitoring Electric Generators Based on Open-Source Platforms

Este articulo presenta el diseño y prototipado de un sistema inteligente, que sirve para la gestión automática de un generador eléctrico, basado en la arquitectura del IoT, a través del protocolo de comunicación MQTT.El prototipo, permite automatizar diversas funciones de un generador eléctrico ante la interrupción del fluido eléctrico; tales como: encendido y apagado de forma automática, teniendo en cuenta las condiciones eléctricas. También, controlar variables como el nivel de combustible, temperatura, horas de uso del equipo; que facilita cambios de aceite, y mantenimientos preventivos. Adicionalmente, cuenta con un gestor automático de carga de potencia, que evita que el generador inicie con una potencia máxima desde el arranque; logrando de esta forma ampliar el margen de vida útil de los circuitos electrónico de potencia. Finalmente, para controlar de manera remota las funciones mencionadas, se presenta una aplicación móvil para que el usuario final pueda monitorear en tiempo real el funcionamiento del generador, mediante la implementación del protocolo de comunicación de Message Queue Telemetry Transport (MQTT)

ICTV Virus Taxonomy Profile: Asfarviridae

The family Asfarviridae includes the single species African swine fever virus, isolates of which have linear dsDNA genomes of 170–194 kbp. Virions have an internal core, an internal lipid membrane, an icosahedral capsid and an outer lipid envelope. Infection of domestic pigs and wild boar results in an acute haemorrhagic fever with transmission by contact or ingestion, or by ticks of the genus Ornithodoros. Indigenous pigs act as reservoirs in Africa, where infection is endemic, and from where introductions occur periodically to Europe. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Asfarviridae, which is available at www.ictv.global/report/asfarviridae.info:eu-repo/semantics/publishedVersio