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Ubiquitin C‐terminal hydrolase L1 (UCHL1) plays vital roles in cell proliferation, angiogenesis, inflammation and oxidative stress. Nevertheless, it is unclear whether UCHL1 could regulate the biologic behaviour of cells and ultimately influences wound healing. We aim to illustrate the roles and the underlying mechanism of UCHL1 in cutaneous wound healing. Murine full‐thickness excisional wound model was utilised to study the effects of UCHL1 on wound healing through topical administration of the UCHL1 inhibitor LDN57444, followed by assessment of wound areas and histological alterations. Subsequently, ethynyldeoxyuridine, scratch and transwell assays were performed to examine fibroblast migration and proliferation. The extracellular matrix (ECM)‐related genes expression and transforming growth factor‐β (TGF‐β)/Smad signalling pathways activation were investigated by immuno‐fluorescent staining, Western blots and quantitative reverse transcription polymerase chain reaction. We identified elevated UCHL1 expression in non‐healing wound tissues. The UCHL1 expression displayed a dynamic change and reached a peak on Day‐7 post‐wounding during the healing process in mice. Cutaneous administration of LDN57444 promoted wound healing by facilitating collagen deposition, myofibroblast activation and angiogenesis. In vitro experiments demonstrated that UCHL1 concentration dependently inhibited migration, ECM synthesis and activation of human dermal fibroblasts, which was mechanistically related to downregulation of TGF‐β/Smad signalling. Furthermore, these effects could be reversed by TGF‐β inhibitor SB431542. Our findings reveal that UCHL1 is a negative regulator of cutaneous wound healing and considered as a novel prospective therapeutic target for effective wound healing. [ABSTRACT FROM AUTHOR]

X80 steel plays a pivotal role in the development of oil and gas pipelines; however, its welded joints, particularly the heat-affected zone (HAZ), are susceptible to stress corrosion cracking (SCC) due to their complex microstructures. This study investigates the SCC initiation mechanisms of X80 steel welded joints under practical pipeline conditions with varying levels of cathodic protection. The SCC behaviors were analyzed through electrochemical measurements, hydrogen permeation tests, and interrupted slow strain rate tensile tests (SSRTs) conducted in a near-neutral pH environment under different potential conditions (OCP, −1.1 VSCE, −1.2 VSCE). These behaviors were influenced by microstructure type, grain size, martensite/austenite (M/A) constituents, and dislocation density. The sub-zones of the weld exhibited differing SCC resistance, with the fine-grain (FG) HAZ, base metal (zone), welded metal (WM) zone, and coarse-grain (CG) HAZ in descending order. In particular, the presence of coarse grains, low dislocation density, and extensive M/A islands collectively increased corrosion susceptibility and SCC sensitivity in the CGHAZ compared to other sub-zones. The SCC initiation mechanisms of the sub-zones within the X80-steel welded joint were primarily anodic dissolution (AD) under open-circuit potential (OCP) condition, shifting to either hydrogen-enhanced local plasticity (HELP) or hydrogen embrittlement (HE) mechanisms at −1.1 VSCE or −1.2 VSCE, respectively. [ABSTRACT FROM AUTHOR]

Podocytes are key to the glomerular filtration barrier by forming a slit diaphragm between interdigitating foot processes; however, the molecular details and functional importance of protein folding and degradation in the ER remain unknown. Here, we show that the SEL1L-HRD1 protein complex of ER-associated degradation (ERAD) is required for slit diaphragm formation and glomerular filtration function. SEL1L-HRD1 ERAD is highly expressed in podocytes of both mouse and human kidneys. Mice with podocyte-specific Sel1L deficiency develop podocytopathy and severe congenital nephrotic syndrome with an impaired slit diaphragm shortly after weaning and die prematurely, with a median lifespan of approximately 3 months. We show mechanistically that nephrin, a type 1 membrane protein causally linked to congenital nephrotic syndrome, is an endogenous ERAD substrate. ERAD deficiency attenuated the maturation of nascent nephrin, leading to its retention in the ER. We also show that various autosomal-recessive nephrin disease mutants were highly unstable and broken down by SEL1L-HRD1 ERAD, which attenuated the pathogenicity of the mutants toward the WT allele. This study uncovers a critical role of SEL1L-HRD1 ERAD in glomerular filtration barrier function and provides insights into the pathogenesis associated with autosomal-recessive disease mutants., Introduction The key function of the kidneys is the ultrafiltration of blood in the glomerulus, where podocytes, specialized differentiated epithelial cells, wrap around capillaries of the glomerulus via a unique [...]