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Background and Purpose: As a calcium channel blocker, diltiazem acts mainly on the voltage-gated calcium channels, Ca(v)1.2, for its beneficial effects in cardiovascular diseases such as hypertension, angina and/or supraventricular arrhythmias. However, the effects of diltiazem on different isoforms of Ca(v)1.2 channels expressed in heart and vascular smooth muscles remain to be investigated. Here, we characterized the effects of diltiazem on the splice variants of Ca(v)1.2 channels, predominant in cardiac and vascular smooth muscles.Experimental Approach: Cardiac and smooth muscle isoforms of Ca(v)1.2 channels were expressed in human embryonic kidney cells and their electrophysiological properties were characterized using whole-cell patch-clamp techniques.Key Results: Under closed-channel and use-dependent block (0.03 Hz), cardiac splice variant Ca(v)1.2CM was less sensitive to diltiazem than two major smooth muscle splice variants, Ca(v)1.2SM and Ca(v)1.2b. Ca(v)1.2CM has a more positive half-inactivation potential than the smooth muscle channels, and diltiazem shifted it less to negative potential. Additionally, the current decay was slower in Ca(v)1.2CM channels. When we modified alternatively spliced exons of cardiac Ca(v)1.2CM channels into smooth muscle exons, we found that all three loci contribute to the different diltiazem sensitivity between cardiac and smooth muscle splice isoforms.Conclusions and Implications: Alternative splicing of Ca(v)1.2 channels modifies diltiazem sensitivity in the heart and blood vessels. Gating properties altered by diltiazem are different in the three channels. [ABSTRACT FROM AUTHOR]

The paper proposes a method to effectively fuse multi-exposure inputs and generate high-quality high dynamic range (HDR) images with unpaired datasets. Deep learning-based HDR image generation methods rely heavily on paired datasets. The ground truth images play a leading role in generating reasonable HDR images. Datasets without ground truth are hard to be applied to train deep neural networks. Recently, Generative Adversarial Networks (GAN) have demonstrated their potentials of translating images from source domain $X$ to target domain $Y$ in the absence of paired examples. In this paper, we propose a GAN-based network for solving such problems while generating enjoyable HDR results, named UPHDR-GAN. The proposed method relaxes the constraint of the paired dataset and learns the mapping from the LDR domain to the HDR domain. Although the pair data are missing, UPHDR-GAN can properly handle the ghosting artifacts caused by moving objects or misalignments with the help of the modified GAN loss, the improved discriminator network and the useful initialization phase. The proposed method preserves the details of important regions and improves the total image perceptual quality. Qualitative and quantitative comparisons against the representative methods demonstrate the superiority of the proposed UPHDR-GAN. [ABSTRACT FROM AUTHOR]

The complex sea ice conditions in Arctic waters has different impacts on the legs of the Arctic passage, and ships of specific ice classes face different navigation risks. Therefore, the quantitative analysis of the navigation risks faced in different legs has important practical significance. Based on the POLARIS introduced by IMO, the sea ice condition data from 2011 to 2020 was used to quantify the navigation risk of the Arctic Northeast passage. The risk index outcome (RIO) of the Arctic Northeast Passage were calculated. The navigable windows of the route for ice class 1A ships sailing independently under different sea ice conditions in the last decade were determined, with a navigable period of 91 days under normal sea ice conditions, approximately 175 days under light sea ice conditions and only week 40 close to navigation under severe sea ice conditions. The three critical waters affecting the safety of ships were identified. Combined with the navigable windows and critical waters, recommendations on ship's navigation and manipulation and recommendations for stakeholders were given. The method and results provided reference and support for the assessment of the navigation risk of ships in the Northeast Passage and safety navigation and operations of ships, and satisfied the needs of relevant countries and enterprises to rationally arrange shipment dates and sailing plans based on different ice classes of ships. [ABSTRACT FROM AUTHOR]

The channel redundancy of convolutional neural networks (CNNs) results in the large consumption of memories and computational resources. In this work, we design a novel Slim Convolution (SlimConv) module to boost the performance of CNNs by reducing channel redundancies. Our SlimConv consists of three main steps: Reconstruct, Transform, and Fuse. It aims to reorganize and fuse the learned features more efficiently, such that the method can compress the model effectively. Our SlimConv is a plug-and-play architectural unit that can be used to replace convolutional layers in CNNs directly. We validate the effectiveness of SlimConv by conducting comprehensive experiments on various leading benchmarks, such as ImageNet, MS COCO2014, Pascal VOC2012 segmentation, and Pascal VOC2007 detection datasets. The experiments show that SlimConv-equipped models can achieve better performances consistently, less consumption of memory and computation resources than non-equipped counterparts. For example, the ResNet-101 fitted with SlimConv achieves 77.84% top-1 classification accuracy with 4.87 GFLOPs and 27.96M parameters on ImageNet, which shows almost 0.5% better performance with about 3 GFLOPs and 38% parameters reduced. [ABSTRACT FROM AUTHOR]

Abnormalities of the L-arginine-nitric oxide pathway induce hypertension. 5-Lipoxygenase (5-LO) is the key enzyme involved in synthesis of leukotrienes (LTs). However, whether nitricoxide synthase dysfunction induces hypertensive vascular remodeling by regulating 5-LO activity and its downstream inflammatory metabolites remains unknown. Six-week L-NAME treatment significantly induced hypertension and vascular remodeling in both wild-type (WT) and 5-LO–knockout (5-LO–KO) mice, and blood pressure in caudal and carotid arteries was lower in 5-LO–KO than WT mice with L-NAME exposure. On histology, L-NAME induced less media thickness, media-to-lumen ratio, and collagen deposition and fewer Ki-67–positive vascular smooth muscle cells (VSMCs) but more elastin expression in thoracic and mesenteric aortas of 5-LO–KO than L-NAME–treated WT mice. L-NAME significantly increased LT content, including LTB4 and cysteinyl LT (CysLTs), in plasma and neutrophil culture supernatants from WT mice. On immunohistochemistry, L-NAME promoted the colocalization of 5-LO and 5-LO–activating protein on the nuclear envelope of cultured neutrophils, which was accompanied by elevated LT content in culture supernatants. In addition, LTs significantly promoted BrdU incorporation, migration and phenotypic modulation in VSMCs. L-NAME may activate the 5-LO/LT pathway in immune cells, such as neutrophils, and promote the products of 5-LO metabolites, including LTB4 and CysLTs, which aggravate vascular remodeling in hypertension. 5-LO deficiency may protect against hypertension and vascular remodeling by reducing levels of 5-LO downstream inflammatory metabolites. Unlabelled Image • L-NAME activated 5-LO and boosted 5-LO metabolits, including LTB4 and CysLTs, in neutrophils. • L-NAME induced circulating LTB4 and CysLTs significantly increased in WT mice but not in 5-LO deficient mice. • LTB4 and CysLTs induced remodeling phenotypes, including proliferation, migration, and phenotypic modulation, in VSMCs • 5-LO deficiency protected against L-NAME-induced hypertensive vascular remodeling by reducing 5-LO inflammatory metabolits. [ABSTRACT FROM AUTHOR]

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse- FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling. [ABSTRACT FROM AUTHOR]