ABSTRACT
Cathepsin L (CTSL) has been implicated in aging and age-related diseases, such as cardiovascular diseases, specifically atherosclerosis. However, the underlying mechanism(s) is not well documented. Recently, we demonstrated a role of CUT-like homeobox 1 (CUX1) in regulating the p16INK4a-dependent cellular senescence in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) via its binding to an atherosclerosis-associated functional SNP (fSNP) rs1537371 on the CDKN2A/B locus. In this study, to determine if CTSL, which was reported to proteolytically activate CUX1, regulates cellular senescence via CUX1, we measured the expression of CTSL, together with CUX1 and p16INK4a, in human ECs and VSMCs undergoing senescence. We discovered that CUX1 is not a substrate that is cleaved by CTSL. Instead, CTSL is an upstream regulator that activates CUX1 transcription indirectly in a process that requires the proteolytic activity of CTSL. Our findings suggest that there is a transcription factor in between CTSL and CUX1, and cleavage of this factor by CTSL can activate CUX1 transcription, inducing endothelial senescence. Thus, our findings provide new insights into the signal transduction pathway that leads to atherosclerosis-associated cellular senescence.
ABSTRACT
High-pressure air blasting (HPAB) is one of the main feasible technologies to improve the extraction efficiency of unconventional gases. At present, there are few visual studies on the evolution characteristics of pore structure in coal under HPAB, resulting in an unclear understanding of the mesoscopic damage evolution mechanism of coal under HPAB. To study the dynamic response and mesoporous structure evolution characteristics of coal under HPAB, simulated coal specimens were used in HPAB experiments. The pore structure characteristics of coal at different locations away from the blasthole after HPAB were analyzed by using computed tomography scanning and 3D reconstruction technology. The maximum sphere algorithm was used to study the law of pore connectivity and reveal the mesoscopic damage evolution mechanism of coal under HPAB. The results indicate that the stress wave and attenuation and the crack propagation direction are greatly affected by the confining pressure. Compared without confining stress, the radial strain attenuation index decreases by 11.97% and the lateral strain attenuation index increases by 15.36% under confining pressure. Without confining pressure, the crack direction is disordered. On the contrary, the crack expands along the σ1 and σ2 directions with confining pressure, while the expansion along other directions is inhibited. The stress wave has a great influence on the pore structure in the nearby zone. Compared with before HPAB, at 25 mm distance from the blasthole, the number of pores increased by 24.80%, the number of throats increased by 12.96 times, the maximum equivalent radius of throats increased by 52.15%, and the maximum channel length of the throat increased by 56.06%. With the increase of the distance, the stress wave has little influence on the pore structure in the middle and far zones. The porosity of representative elementary volume and the distance from the blasthole decay in a power function trend. The maximum disturbance distance under HPAB can reach nearly 110 times of the blasthole radius. The study results provide a theoretical basis for enhancing the coal seam permeability and gas drainage of low-permeability coal seam by HPAB.
