Role of nano-capacitor on dielectric constant enhancement in PEO:NH4SCN:xCeO2 polymer nano-composites: Electrical and electrochemical properties

Solution casting technique has been successfully employed to prepare nano-composite films. Various weight ratios of cerium oxide (CeO2) nanoparticle were added to a PEO:NH4SCN:xCeO2 polymer matrix to enhance the ionic conductivity at ambient temperature. The electrical and electrochemical properties of the composite electrolyte systems have been investigated using impedance, dielectric properties (ɛ*, tanδ, and M*), transfer number measurement (TNM), linear sweep voltammetry (LSV), and cyclic voltammetry (CV) techniques. The highest ionic conductivity of ∼8.57 × 10−4 S/cm is obtained for the system incorporated with 3 wt.% of CeO2 filler. This study presented a new approach and the complex permittivity confirmed that the real part value of dielectric constant (ɛ′) for all samples has found to be much higher than the imaginary part (ɛ″) value. The appearance of the peaks at a characteristic frequency in the loss tangent indicates the existence of relaxation. Low dielectric modulus is observed for 3 wt.% of CeO2 incorporated. The TNM measurements confirmed the ionic conductivity of NCSPEs and ion transport tion of films have been found to be 0.84, 0.96 and 0.92 for 1 wt.%, 3 wt.%, and 5 wt.% of CeO2, respectively. The system incorporated with 3 wt.% of CeO2 has discovered to be electrochemically stable up to 1.4 V. From the CV analysis it is noticeable that the energy storage mechanism of the EDLC is a combination of double-layer capacitance and pseudo capacitance. A value of 88.9 F/g is achieved at 20 mV/s

Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism

AP2? Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity.

Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 ? subunit (AP2?) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2? mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2? mutations reduced CaSR signaling via G?q/11 and G?i/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by G?q/11. Thus, compartmental bias for CaSR-mediated G?q/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling

AP2σ mutations impair calcium-sensing receptor trafficking and signaling, and reveal an endosomal pathway that spatially-directs G-protein selectivity

Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2σ mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2σ mutations reduced CaSR signaling via Gαq/11 and Gαi/o pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Gαq/11. Thus, compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling