Functional LTCC-ß2AR Complex Needs Caveolin-3 and Is Disrupted in Heart Failure.

BACKGROUND: Beta-2 adrenergic receptors (ß2ARs) but not beta-2 adrenergic receptors (ß1ARs) form a functional complex with L-type Ca2+ channels (LTCCs) on the cardiomyocyte membrane. However, how microdomain localization in the plasma membrane affects the function of these complexes is unknown. We aim to study the coupling between LTCC and ß adrenergic receptors in different cardiomyocyte microdomains, the distinct involvement of PKA and CAMKII (Ca2+/calmodulin-dependent protein kinase II) and explore how this functional complex is disrupted in heart failure. METHODS: Global signaling between LTCCs and ß adrenergic receptors was assessed with whole-cell current recordings and western blot analysis. Super-resolution scanning patch-clamp was used to explore the local coupling between single LTCCs and ß1AR or ß2AR in different membrane microdomains in control and failing cardiomyocytes. RESULTS: LTCC open probability (Po) showed an increase from 0.054±0.003 to 0.092±0.008 when ß2AR was locally stimulated in the proximity of the channel (<350 nm) in the transverse tubule microdomain. In failing cardiomyocytes, from both rodents and humans, this transverse tubule coupling between LTCC and ß2AR was lost. Interestingly, local stimulation of ß1AR did not elicit any change in the Po of LTCCs, indicating a lack of proximal functional interaction between the two, but we confirmed a general activation of LTCC via ß1AR. By using blockers of PKA and CaMKII and a Caveolin-3-knockout mouse model, we conclude that the ß2AR-LTCC regulation requires the presence of caveolin-3 and the activation of the CaMKII pathway. By contrast, at a cellular "global" level PKA plays a major role downstream ß1AR and results in an increase in LTCC current. CONCLUSIONS: Regulation of the LTCC activity by proximity coupling mechanisms occurs only via ß2AR, but not ß1AR. This may explain how ß2ARs tune the response of LTCCs to adrenergic stimulation in healthy conditions. This coupling is lost in heart failure; restoring it could improve the adrenergic response of failing cardiomyocytes.

Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity.

Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cyclic 3',5'-cyclic adenosine monophosphate (cAMP)-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of Popeye domain-containing protein 1 (POPDC1) (or blood vessel epicardial substance (BVES)), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as protein kinase A (PKA) and exchange factor directly activated by cAMP, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have an unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including the hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wild-type mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP-PKA-PDE signaling.

The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction.

The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac nervous system (ICNS) includes the network of the intracardiac ganglia and interconnecting neurons. The cardiac ganglia contribute to the tight modulation of cardiac electrophysiology, working as a local hub integrating the inputs of the extrinsic innervation and the ICNS. A better understanding of the role of the ICNS for the modulation of the cardiac conduction system will be crucial for targeted therapies of various arrhythmias. We describe the embryonic development, anatomy, and physiology of the ICNS. By correlating the topography of the intracardiac neurons with what is known regarding their biophysical and neurochemical properties, we outline their physiological role in the control of pacemaker activity of the sinoatrial and atrioventricular nodes. We conclude by highlighting cardiac disorders with a putative involvement of the ICNS and outline open questions that need to be addressed in order to better understand the physiology and pathophysiology of the ICNS.

NePCM Based on Silver Dispersions in Poly(Ethylene Glycol) as a Stable Solution for Thermal Storage.

The main objective of this study is to design and characterize silver suspensions based on poly(ethylene glycol) PEG400, Ag/PEG400, as energy storage media for low-temperature applications. A polyvinylpyrrolidone (PVP) treatment was applied to ~22 nm silver nanoparticles to ensure good stability in poly(ethylene glycol). An array of different experimental techniques was utilized to analyze the molecular mass and purity of base poly(ethylene glycol), morphology of dry PVP-capped Ag nanoparticles, hydrodynamic average size of dispersed Ag particles, as well as thermal stability of PEG400 and Ag/PEG400 dispersions. Samples exhibited good temporal stabilities with average hydrodynamic diameter around 50 nm according to dynamic light scattering analyses. Melting and solidification transitions were investigated in terms of temperature and enthalpy from differential scanning calorimeter (DSC) thermograms. The thermophysical characterization was completed with thermal conductivity (k), dynamic viscosity (η), isobaric heat capacity (Cp), density (ρ), and surface tension (σ) measurements of designed materials using a Hot Disk thermal conductivimeter, a rotational rheometer, a DSC calorimeter working with a quasi-isothermal modulated method, a U-tube densimeter and a drop shape analyzer, respectively. For a nanoparticle loading of only 1.1% in mass, sub-cooling reduced by 7.1% and thermal conductive improved by 3.9%, with almost no penalization in dynamic viscosity (less than 5.4% of increase). Maximum modifications in Cp, ρ, and σ were 0.9%, 2.2%, and 2.2%, respectively. Experimental results were compared with the values provided by using different theoretical or semi-empirical equations. In particular, good descriptions of dynamic viscosity as functions of temperature and nanoparticle volume concentration were obtained by using the Vogel-Fulcher-Tammann equation and a first-order polynomial η( ϕ v , n p ) correlation, with absolute average deviations of 2.2% and 0.55%, respectively.

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2BV618G unusually allowed Mg2+ permeation, whereas nearby N615I reduced Ca2+ permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations.

Surface oxidation of single wall carbon nanohorns for the production of surfactant free water-based colloids.

In this work, powders of Single Wall Carbon Nanohorns (SWCNHs), a typical hydrophobic material, were oxidized with concentrated HNO3 with the aim of surface carboxylation and consequent improved hydrophilicity and dispersibility in polar solvents. Dynamic Light Scattering and ζ-potential measurements demonstrated that very stable colloidal suspensions of SWCNH in water were obtained in total absence of stabilizers. By properly optimizing the reaction parameters, the suspensions achieved stability even higher than colloids with similar composition but prepared with the use of surfactants. Surface damage and oxidation degree of SWCNHs were evaluated by SEM microscopy, Thermogravimetric Analysis, Residual Gas Analysis, XPS and UV-visible spectroscopy.

PEG 400-Based Phase Change Materials Nano-Enhanced with Functionalized Graphene Nanoplatelets.

This study presents new Nano-enhanced Phase Change Materials, NePCMs, formulated as dispersions of functionalized graphene nanoplatelets in a poly(ethylene glycol) with a mass-average molecular mass of 400 g·mol-1 for possible use in Thermal Energy Storage. Morphology, functionalization, purity, molecular mass and thermal stability of the graphene nanomaterial and/or the poly(ethylene glycol) were characterized. Design parameters of NePCMs were defined on the basis of a temporal stability study of nanoplatelet dispersions using dynamic light scattering. Influence of graphene loading on solid-liquid phase change transition temperature, latent heat of fusion, isobaric heat capacity, thermal conductivity, density, isobaric thermal expansivity, thermal diffusivity and dynamic viscosity were also investigated for designed dispersions. Graphene nanoplatelet loading leads to thermal conductivity enhancements up to 23% while the crystallization temperature reduces up to in 4 K. Finally, the heat storage capacities of base fluid and new designed NePCMs were examined by means of the thermophysical properties through Stefan and Rayleigh numbers. Functionalized graphene nanoplatelets leads to a slight increase in the Stefan number.

Characterization and Simulation of the Heat Transfer Behaviour of Water-Based ZnO Nanofluids.

This paper deals with the characterization and modelling of water-based nanofluids containing zinc oxide (ZnO) nanoparticles in concentrations ranging between 1 and 10 wt%. Low concentrations were chosen to reduce fouling and excessive pressure drops. First of all, the stability was verified by means of an instrument, based on the dynamic light scattering (DLS) technique, measuring mean nanoparticle diameters and Zeta potential. Moreover, nanofluids pH was measured. Then, thermal conductivities and dynamic viscosities were measured, analysing their dependence on temperature and nanoparticle concentration. Thermal conductivity was measured by means of a hot disk apparatus in the temperature range between 10 and 70 degrees C, while viscosity was measured by a magnetic suspension rheometer in the same range of temperatures. Finally, the heat transfer capability of these fluids was studied measuring their heat transfer coefficients in a dedicated apparatus between 18 and 40 degrees C. Heat transfer coefficient was evaluated at different Reynolds number, in turbulent flow regime. Reynolds and Nusselt numbers were deduced by using previously measured thermal conductivity and viscosity values. Moreover, numerical simulations in two-dimensional turbulent and steady state flow were carried out. No increase in heat transfer coefficient in the temperature range between 18 and 40 degrees C was found. Comparison between experimental and numerical simulation data, in terms of wall temperature profiles, showed a good agreement.

Tuning the thermal diffusivity of silver based nanofluids by controlling nanoparticle aggregation.

With the aim of preparing stable nanofluids for heat exchange applications and to study the effect of surfactant on the aggregation of nanoparticles and thermal diffusivity, stable silver colloids were synthesized in water by a green method, reducing AgNO3 with fructose in the presence of poly-vinylpyrollidone (PVP) of various molecular weights. A silver nanopowder was precipitated from the colloids and re-dispersed at 4 vol% in deionized water. The Ag colloids were characterized by UV-visible spectroscopy, combined dynamic light scattering and ζ-potential measurements, and laser flash thermal diffusivity. The Ag nanopowders were characterized by scanning electron microscopy and thermal gravimetric analysis. It was found that the molecular weight of PVP strongly affects the ζ-potential and the aggregation of nanoparticles, thereby affecting the thermal diffusivity of the obtained colloids. In particular, it was observed that on increasing the molecular weight of PVP the absolute value of the ζ-potential is reduced, leading to increased aggregation of nanoparticles. A clear relation was identified between thermal diffusivity and aggregation, showing higher thermal diffusivity for nanofluids having higher aggregation. A maximum improvement of thermal diffusivity by about 12% was found for nanofluids prepared with PVP having higher molecular weight.

Experimental stability analysis of different water-based nanofluids.

In the recent years, great interest has been devoted to the unique properties of nanofluids. The dispersion process and the nanoparticle suspension stability have been found to be critical points in the development of these new fluids. For this reason, an experimental study on the stability of water-based dispersions containing different nanoparticles, i.e. single wall carbon nanohorns (SWCNHs), titanium dioxide (TiO2) and copper oxide (CuO), has been developed in this study. The aim of this study is to provide stable nanofluids for selecting suitable fluids with enhanced thermal characteristics. Different dispersion techniques were considered in this study, including sonication, ball milling and high-pressure homogenization. Both the dispersion process and the use of some dispersants were investigated as a function of the nanoparticle concentration. The high-pressure homogenization was found to be the best method, and the addition of n-dodecyl sulphate and polyethylene glycol as dispersants, respectively in SWCNHs-water and TiO2-water nanofluids, improved the nanofluid stability.