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Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects cholesterol homeostasis by targeting hepatic LDL receptor (LDLR) for lysosomal degradation. Clinically, PCSK9 inhibitors effectively reduce LDL-cholesterol (LDL-C) levels and the incidence of cardiovascular events. Because microRNAs (miRs) are integral regulators of cholesterol homeostasis, we investigated the involvement of miR-483 in regulating LDL-C metabolism. Using in silico analysis, we predicted that miR-483-5p targets the 3'-UTR of PCSK9 mRNA. In HepG2 cells, miR-483-5p targeted the PCSK9 3'-UTR, leading to decreased PCSK9 protein and mRNA expression, increased LDLR expression, and enhanced LDL-C uptake. In hyperlipidemic mice and humans, serum levels of total cholesterol and LDL-C were inversely correlated with miR-483-5p levels. In mice, hepatic miR-483 overexpression increased LDLR levels by targeting Pcsk9, with a significant reduction in plasma total cholesterol and LDL-C levels. Mechanistically, the cholesterol-lowering effect of miR-483-5p was significant in mice receiving AAV8 PCSK9-3'-UTR but not Ldlr-knockout mice or mice receiving AAV8 PCSK9-3'-UTR (ΔBS) with the miR-483-5p targeting site deleted. Thus, exogenously administered miR-483 or similarly optimized compounds have potential to ameliorate hypercholesterolemia.

RationaleEndothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive.ObjectivesWe investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH.MethodsBioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE2-/-) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension.Measurements and main resultsPhosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPKα2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension.ConclusionsImpaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.

Abstract: Inverse polarization transmission of light, with the TE transmittance η TE largely exceeding the TM transmittance η TM, through subwavelength metallic gratings at certain wavelength in deep ultraviolet band is theoretically investigated. By using the Fourier modal method and the planar waveguide theory, we show that the light transmission involves both the surface plasmon and the low-loss waveguide modes. Strong coupling of the incident wave to surface plasmon polariton results in the minimum in TM transmittance, whereas the coupling to the low-loss mode leads to the TE transmittance maximum. The established physical mechanism is sufficient to explain the inverse polarizing phenomenon observed in aluminum grating at the wavelength of 193nm, which may lead to important applications such as effective and compact polarizer used in DUV lithography. [Copyright &y& Elsevier]

Achieving a large enhancement of local electromagnetic fields in the ultraviolet waveband is desirable for some applications such as surface-enhanced Raman scattering and surface-enhanced fluorescence. In addition, it is more significant for some applications such as plasmon-enhanced harmonic generation to enhance the intensity of local electromagnetic fields and increase their decay time at the same time. In this paper, using the finite-difference time-domain method, we numerically demonstrate that using the linearly polarized light with a wavelength of 325 nm as the illumination light, an isolated triangular Al-SiO 2 -Al hybrid nanoplate with optimized geometric parameters can produce a local electric field enhanced by a factor of about 108 at one of its top apexes, and produce two local electric fields enhanced by a factor of about 150 at two transverse dielectric/metal interfaces of one of its longitudinal side edges. Moreover, we also numerically demonstrate that the decay time of enhanced local electric fields produced by the isolated triangular Al-SiO 2 -Al hybrid nanoplate is about 1.6 times as large as that of enhanced local electric fields produced by an isolated triangular Al nanoplate. These unique properties of the isolated triangular Al-SiO 2 -Al hybrid nanoplate arise because of both the transverse coupling and the longitudinal coupling of localized surface plasmon polaritons in this structure. Our findings make triangular Al-SiO 2 -Al hybrid nanoplates very promising for application in many fields such as surface-enhanced Raman scattering and plasmon-enhanced harmonic generation., (© 2021 IOP Publishing Ltd.)