Research on the multi-field coupling effects in rocks has been ongoing for several decades, encompassing studies on single physical fields as well as two-field (TH, TM, HM) and three-field (THM) couplings. However, the environmental conditions of rock masses in deep resource extraction and underground space development are highly complex. In such settings, rocks are put through thermal-hydrological-mechanical-chemical (THMC) coupling effects under peak temperatures, strong osmotic pressures, extreme stress, and chemically reactive environments. The interaction between these fields is not a simple additive process but rather a dynamic interplay where each field influences the others. This paper provides a comprehensive analysis of fragmentation evolution, deformation mechanics, mechanical constitutive models, and the construction of coupling models under multi-field interactions. Based on rock strength theory, the constitutive models for both multi-field coupling and creep behavior in rocks are developed. The research focus on multi-field coupling varies across industries, reflecting the diverse needs of sectors such as mineral resource extraction, oil and gas production, geothermal energy, water conservancy, hydropower engineering, permafrost engineering, subsurface construction, nuclear waste disposal, and deep energy storage. The coupling of intense stress, fluid flow, temperature, and chemical factors not only triggers interactions between these fields but also alters the physical and mechanical properties of the rocks themselves. Investigating the mechanical behavior of rocks under these conditions is essential for averting accidents and assuring the soundness of engineering projects. Eventually, we discuss vital challenges and future directions in multi-field coupling research, providing valuable insights for engineering applications and addressing allied issues.
Introduction Lung adenocarcinoma, a disease with complex pathogenesis, high mortality and poor prognosis, is one of the subtypes of lung cancer. Hence, it is very crucial to find novel biomarkers as diagnostic and therapeutic targets for LUAD. Methods GSE10072 was used for DEGs and WGCNA, and the intersection genes were subjected to enrichment analysis through Metascape and GSEA. Key genes were screened by three machine learning methods. Further, the reliability of key genes was identified by ROC, COX regression analysis and qRT-PCR. CIBERSORT and Spearman analysis were used for understanding the relationships of LUAD, immunity and key genes. In addition, ceRNA networks and potential drugs of key genes were constructed and predicted. Results After overlapping 631 DEGs and key module genes, 623 intersection genes were obtained. Subsequently, DUOX1, CD36, AGTR1, FHL5 and SSR4 were further selected using three machine learning methods. Reliability analysis demonstrated that AGTR1 possesses important predictive value for the occurrence and prognosis of LUAD. The enrichment analysis showed that AGTR1 was significantly enriched in the GPCR-related pathways. Immune infiltration analysis showed that the development of LUAD was related to the changes of immune cells such as M2 macrophages and neutrophils, which were regulated by AGTR1. Further, AGTR1 is also involved in regulating immune chemokines, checkpoints and immune regulatory factors such as PECAM1, ADARB1, SPP1 and ENO1, all of them playing important roles in immune cell regulation, tumor cell proliferation and migration. Further, the drug-gene interaction network screened out 13 potential drugs such as Benazepril, Valsartan, Eprosartan, and so on. Discussion AGTR1 is a potential biomarker for the occurrence and progression of LUAD, closely related to tumor immunity, proliferation and migration. It can serve as a new target for the diagnosis and treatment of LUAD.
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a critical pathological feature in the pathogenesis of pulmonary arterial hypertension (PAH), but the regulatory mechanisms remain largely unknown. Herein, we demonstrated that interferon regulatory factor 9 (IRF9) accelerated PASMCs proliferation by regulating Prohibitin 1 (PHB1) expression and the AKT-GSK3β signaling pathway. Compared with control groups, the rats treated with chronic hypoxia (CH), monocrotaline (MCT) or sugen5416 combined with chronic hypoxia (SuHx), and mice challenged with CH had significantly thickened pulmonary arterioles and hyperproliferative PASMCs. More importantly, the protein level of IRF9 was found to be elevated in the thickened medial wall of the pulmonary arterioles in all of these PAH models. Notably, overexpression of IRF9 significantly promoted the proliferation of rat and human PASMCs, as evidenced by increased cell counts, EdU-positive cells and upregulated biomarkers of cell proliferation. In contrast, knockdown of IRF9 suppressed the proliferation of rat and human PASMCs. Mechanistically, IRF9 directly restrained PHB1 expression and interacted with AKT to inhibit the phosphorylation of AKT at thr308 site, which finally led to mitochondrial dysfunction and PASMC proliferation. Unsurprisingly, MK2206, a specific inhibitor of AKT, partially reversed the PASMC proliferation inhibited by IRF9 knockdown. Thus, our results suggested that elevation of IRF9 facilitates PASMC proliferation by regulating PHB1 expression and AKT signaling pathway to affect mitochondrial function during the development of PAH, which indicated that targeting IRF9 may serve as a novel strategy to delay the pathological progression of PAH.
This study aimed to quantify the global impact of pneumoconiosis resulting from occupational exposure to particulate matter, gasses, and fumes from 1990 to 2021, utilizing data from the Global Burden of Disease Study 2021. The analysis evaluated the global, regional, and national burden of pneumoconiosis attributable to workplace exposure to particulate matter, gasses, and fumes. It explored variations in disease impact across different demographics, including age and gender, and analyzed the relationship between disease burden and the Socio-Demographic Index (SDI). Furthermore, an ARIMA model was employed to forecast future trends of pneumoconiosis up to 2050. The year 2021 saw pneumoconiosis from occupational particulate matter, gasses, and fumes account for roughly 4,775 deaths and 117.80 thousand disability-adjusted life years (DALYs). Over the past three decades, there was a notable decline in the disease's burden. The condition predominantly affected males and those aged above 60. Future projections suggest a decrease in mortality rates in low to middle SDI regions, while high SDI regions may experience an increase in ASMR. Additionally, both ASMR and ASDR are anticipated to rise globally. Nationally, the Czech Republic, France, and the United States are expected to show relatively higher mortality rates in 2030 and 2050. Countries like Kazakhstan, Egypt, Mongolia, and Peru are projected to experience elevated levels of ASMR, DALY rates, and ASDR. The findings underscore the urgent need for policymakers to create and improve targeted preventive strategies to reduce the incidence of pneumoconiosis among specific populations.
Activation of the CaSR (extracellular calcium-sensing receptor) has been recognized as a critical mediator of hypoxia-induced pulmonary hypertension. Preventive targeting of the early initiating phase as well as downstream events after CaSR activation remains unexplored. As a representative of the G protein-coupled receptor family, CaSR polymerizes on cell surface upon stimulation. Immunoblotting together with MAL-PEG technique identified a reactive oxygen species-sensitive CaSR polymerization through its extracellular domain in pulmonary artery smooth muscle cells upon exposure to acute hypoxia. Fluorescence resonance energy transfer screening employing blocking peptides determined that cycteine129/131 residues in the extracellular domain of CaSR formed intermolecular disulfide bonds to promote CaSR polymerization. The monitoring of intracellular Ca 2+ signal highlighted the pivotal role of CaSR polymerization in its activation. In contrast, the blockade of disulfide bonds formation using a peptide decreased both CaSR and hypoxia-induced mitogenic factor expression as well as other hypoxic-related genes in vitro and in vivo and attenuated pulmonary hypertension development in rats. The blocking peptide did not affect systemic arterial oxygenation in vivo but inhibited acute hypoxia-induced pulmonary vasoconstriction. Pharmacokinetic analyses revealed a more efficient lung delivery of peptide by inhaled nebulizer compared to intravenous injection. In addition, the blocking peptide did not affect systemic arterial pressure, body weight, left ventricular function, liver, or kidney function or plasma Ca 2+ level. In conclusion, a peptide blocking CaSR polymerization reduces its hypoxia-induced activation and downstream events leading to pulmonary hypertension and represents an attractive inhaled preventive alternative worthy of further development.
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