NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction.

Background: The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload-induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential.

FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models.

Background: We developed the FORCE platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression.

Differences in Ancestry and Presence of Gastric Precursor Lesions in Individuals With Young- and Average-Onset Gastric Cancer.

Background: There has been a paradoxical rise in young-onset gastric cancer (YOGC), defined as gastric cancer (GC) diagnosed before age 50. Precursor lesions may contribute to pathogenesis, though their role in progression to different histologic subtypes is unclear. The impact of self-reported race is also poorly characterized and may be unreliable as a proxy for genetic differences.

Belimumab safety in adult and paediatric Chinese patients with systemic lupus erythematosus: A Phase 4, multicentre, observational study.

Objective: Although belimumab has been widely used in patients with systemic lupus erythematosus (SLE) globally, real-world safety data among Chinese patients are limited, particularly for children. This study assessed the safety and tolerability of belimumab in adult and paediatric patients with SLE in China in real-world clinical practice.

Methods: This Phase 4, multicentre, prospective, observational study enrolled patients prescribed intravenous belimumab by their physicians in tertiary hospitals, independent of a clinical study, during routine clinical visits between May 2021 and May 2022.

Simultaneous multislice echo-planar diffusion-weighted imaging (DWI) in patients with focal liver lesions: a comparative study with conventional DWI.

Background: Simultaneous multislice (SMS) technology improves acquisition efficiency of diffusion-weighted imaging (DWI). This study aimed to evaluate the performance of SMS-DWI in image quality and apparent diffusion coefficient (ADC) measurements for focal liver lesions (FLLs) as compared with that of conventional DWI (CON-DWI).

Methods: The institutional ethics committee of West China Hospital, Sichuan University approved this single-center, prospective study conducted from February 2021 to March 2022.

Vision Improvement in Keratoconus Patients Trained With Perceptual Learning: A Randomized Controlled Trial.

Purpose: To investigate the effectiveness and maintenance of perceptional learning (PL) on vision improvement in keratoconus (KC) patients corrected with spectacles.

Design: Randomized, double-blind clinical trial.

Methods: Non-progressive KC patients 9 years of age or older who had best spectacle-corrected distance visual acuity (CDVA) of 0 to 1.

Dissecting diazirine photo-reaction mechanism for protein residue-specific cross-linking and distance mapping.

While photo-cross-linking (PXL) with alkyl diazirines can provide stringent distance restraints and offer insights into protein structures, unambiguous identification of cross-linked residues hinders data interpretation to the same level that has been achieved with chemical cross-linking (CXL). We address this challenge by developing an in-line system with systematic modulation of light intensity and irradiation time, which allows for a quantitative evaluation of diazirine photolysis and photo-reaction mechanism. Our results reveal a two-step pathway with mainly sequential generation of diazo and carbene intermediates.

Investigation on the Deformation and Surface Quality of a Bearing Outer Ring during Grinding Processing.

Thin-walled bearings are widely used owing to the advantages of their light structure, high hardness, and strong load-carrying capacity. However, thin-walled bearings are often prone to deformation during the machining process, which can seriously affect the performance of the bearings. In addition, the machining deformation and quality of bearings are difficult to balance.

Estimating Flow Direction of Circle of Willis Using Dynamic Arterial Spin-Labeling MR Angiography.

Background And Purpose: The circle of Willis (COW) is a crucial mechanism for cerebral collateral circulation. This proof-of-concept study aims to develop and assess an analysis method to characterize the hemodynamics of the arterial segments in the COW by using arterial spin-labeling (ASL) based non-contrast-enhanced dynamic MR angiography (dMRA).

Materials And Methods: The developed analysis method uses a graph model, bootstrap strategy, and ensemble learning methodologies to determine the time curve shift from ASL dMRA to estimate the flow direction within the COW.

Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells.

Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome.

S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.

Background: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection.

Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.

Background: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF.

Refined preferences of prioritizers improve intelligent diagnosis for Mendelian diseases.

Phenotype-guided gene prioritizers have proved a highly efficient approach to identifying causal genes for Mendelian diseases. In our previous study, we preliminarily evaluated the performance of ten prioritizers. However, all the selected software was run based on default settings and singleton mode.

Clinical Outcomes of Deferred Lesions by IVUS Versus FFR-Guided Treatment Decision.

Background: There are limited data regarding the safety of deferral of percutaneous coronary intervention based on intravascular ultrasound (IVUS) findings. The current study sought to compare the prognosis between deferred lesions based on IVUS and fractional flow reserve (FFR)-guided treatment decision.

Methods: This study is a post hoc analysis of the FLAVOUR randomized trial (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients With Intermediate Stenosis) that compared 2-year clinical outcomes between IVUS- and FFR-guided treatment decision on intermediate coronary artery lesions using predefined criteria.

Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer.

Background: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer .

Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation.

Background: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF).

Methods: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining.

Fgfr1 deficiency in osteocytes leads to increased bone mass by enhancing Wnt/β-catenin signaling.

Osteoporosis (OP) is the most common skeletal disease in middle-aged and elderly people. A comprehensive understanding of the pathogenesis of osteoporosis is important. Fibroblast growth factor receptor 1 (FGFR1) is an important molecule for skeletal development and bone remodeling.

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.

Background: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.

Endothelial HDAC1-ZEB2-NuRD Complex Drives Aortic Aneurysm and Dissection Through Regulation of Protein S-Sulfhydration.

Background: Aortic aneurysm and aortic dissection (AAD) are life-threatening vascular diseases, with endothelium being the primary target for AAD treatment. Protein S-sulfhydration is a newly discovered posttranslational modification whose role in AAD has not yet been defined. This study aims to investigate whether protein S-sulfhydration in the endothelium regulates AAD and its underlying mechanism.

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro.