Highlights d RNA granules ''hitchhike'' on motile lysosomes during longdistance transport d ANXA11 binds to RNA and lysosomes via phase separating and membrane binding domains d ANXA11 tethers RNA granules to lysosomes and is required for axonal RNA transport d ALS-associated ANXA11 mutations impair its tethering function and RNA transport
Constraint can be divided into two conditions of in‐plane and out‐of‐plane, and each of them has its own parameter to characterize. However, in most cases, there exists a compound change of both in‐plane and out‐of‐plane constraint in structures, a unified measure that can reflect both of them is needed. In this paper, the finite element method (FEM) was used to calculate the equivalent plastic strain (ɛp) distribution ahead of crack tips for specimens with different in‐plane and out‐of‐plane constraints, and the FEM simulations based on Gurson–Tvergaard–Needleman (GTN) damage model and a small number of tests were used to obtain fracture toughness for the specimens with different constraints. Unified measure and characterisation parameter of in‐plane and out‐of‐plane constraints based on crack‐tip equivalent plastic strain has been investigated. The results show that the area APEEQ surrounded by the ɛp isoline ahead of crack tips can characterize both in‐plane and out‐of‐plane constraints. Based on the area APEEQ, a unified constraint characterisation parameter Ap was defined. It was found that there exists a sole linear relation between the normalised fracture toughness JIC/Jref and regardless of the in‐plane constraint, out‐of‐plane constraint and the selection of the ɛp isolines. The unified JIC/Jref−reference line can be used to determine constraint‐dependent fracture toughness of materials. The FEM simulations with the GTN damage model (local approach) can be used in obtaining the unified JIC/Jref−reference line for materials with ductile fracture.
Aims: Angiotensin II (AngII), a vasoconstrictive peptide of the renin–angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1–7) [Ang-(1–7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1β axis in liver fibrosis.Results:
In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1–7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-κB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1–7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects.Innovation and Conclusions:
Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1–7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1–20.
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