Understanding the hydromechanical behavior and permeability stress sensitivity of hydraulic fractures is fundamental for geotechnical applications associated with fluid injection.This paper presents a three-dimensiona...Understanding the hydromechanical behavior and permeability stress sensitivity of hydraulic fractures is fundamental for geotechnical applications associated with fluid injection.This paper presents a three-dimensional(3D)benchmark model of a laboratory experiment on graywacke to examine the dynamic hydraulic fracturing process under a polyaxial stress state.In the numerical model,injection pressures after breakdown(postbreakdown)are varied to study the impact on fracture growth.The fluid pressure front and crack front are identified in the numerical model to analyze the dynamic relationship between fluid diffusion and fracture propagation.Following the hydraulic fracturing test,the polyaxial stresses are rotated to investigate the influence of the stress field rotation on the fracture slip behavior and permeability.The results show that fracture propagation guides fluid diffusion under a high postbreakdown injection pressure.The crack front runs ahead of the fluid pressure front.Under a low postbreakdown injection pressure,the fluid pressure front gradually reaches the crack front,and fluid diffusion is the main driving factor of fracture propagation.Under polyaxial stress conditions,fluid injection not only opens tensile fractures but also induces hydroshearing.When the polyaxial stress is rotated,the fracture slip direction of a fully extended fracture is consistent with the shear stress direction.The fracture slip direction of a partly extended fracture is influenced by the increase in shear stress.Normal stress affects the permeability evolution by changing the average mechanical aperture.Shear stress can induce shearing and sliding on the fracture plane,thereby increasing permeability.展开更多
Radiation-induced thrombocytopenia(RIT)faces a perplexing challenge in the clinical treatment of cancer patients,and current therapeutic approaches are inadequate in the clinical settings.In this research,oxymatrine,a...Radiation-induced thrombocytopenia(RIT)faces a perplexing challenge in the clinical treatment of cancer patients,and current therapeutic approaches are inadequate in the clinical settings.In this research,oxymatrine,a new molecule capable of healing RIT was screened out,and the underlying regulatory mechanism associated with magakaryocyte(MK)differentiation and thrombopoiesis was demonstrated.The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro.The ability to induce thrombopoiesis was subsequently demonstrated in Tg(cd41:enhanced green fluorescent protein(eGFP))zebrafish and RIT model mice.In addition,we carried out network pharmacological prediction,drug affinity responsive target stability assay(DARTS)and cellular thermal shift assay(CETSA)analyses to explore the potential targets of oxymatrine.Moreover,the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,Western blot(WB),and immunofluorescence.Oxymatrine markedly promoted MK differentiation and maturation in vitro.Moreover,oxymatrine induced thrombopoiesis in Tg(cd41:eGFP)zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice.Mechanistically,oxymatrine directly binds to toll-like receptor 2(TLR2)and further regulates the downstream pathway stimulator of interferon genes(STING)/nuclear factor-kappaB(NF-kB),which can be blocked by C29 and C-176,which are specific inhibitors of TLR2 and STING,respectively.Taken together,we demonstrated that oxymatrine,a novel TLR2 agonist,plays a critical role in acceleratingMKdifferentiation and thrombopoiesis via the STING/NF-kB axis,suggesting that oxymatrine is a promising candidate for RIT therapy.展开更多
基金supported by the Knowledge Innovation Program of Wuhan-Basic Research (Grant No.2022010801010159)support from the Helmholtz Association's Initiative and Networking Fund for the Helmholtz Young Investigator Group ARES (Contract number VH-NG-1516)supported by the Swedish Radiation Safety Authority (Project SSM2020-2758).
文摘Understanding the hydromechanical behavior and permeability stress sensitivity of hydraulic fractures is fundamental for geotechnical applications associated with fluid injection.This paper presents a three-dimensional(3D)benchmark model of a laboratory experiment on graywacke to examine the dynamic hydraulic fracturing process under a polyaxial stress state.In the numerical model,injection pressures after breakdown(postbreakdown)are varied to study the impact on fracture growth.The fluid pressure front and crack front are identified in the numerical model to analyze the dynamic relationship between fluid diffusion and fracture propagation.Following the hydraulic fracturing test,the polyaxial stresses are rotated to investigate the influence of the stress field rotation on the fracture slip behavior and permeability.The results show that fracture propagation guides fluid diffusion under a high postbreakdown injection pressure.The crack front runs ahead of the fluid pressure front.Under a low postbreakdown injection pressure,the fluid pressure front gradually reaches the crack front,and fluid diffusion is the main driving factor of fracture propagation.Under polyaxial stress conditions,fluid injection not only opens tensile fractures but also induces hydroshearing.When the polyaxial stress is rotated,the fracture slip direction of a fully extended fracture is consistent with the shear stress direction.The fracture slip direction of a partly extended fracture is influenced by the increase in shear stress.Normal stress affects the permeability evolution by changing the average mechanical aperture.Shear stress can induce shearing and sliding on the fracture plane,thereby increasing permeability.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82074129,82004073,82204666,and 82374073)the Science and Technology Planning Project of Sichuan Province,China(Grant Nos.:2022JDJQ0061,2022ZYD0087,2022YFS0607,2022YFS0635,and 2022YFS0635-B1)+1 种基金the Joint Project of Xuzhou District People's Government and Southwest Medical University,China(Grant No.:2021XZXNYD01)Science and Technology Planning Project of Yibin City,China(Grant Nos.:2022NY020,2021ZYY009,and 2021ZYY005).
文摘Radiation-induced thrombocytopenia(RIT)faces a perplexing challenge in the clinical treatment of cancer patients,and current therapeutic approaches are inadequate in the clinical settings.In this research,oxymatrine,a new molecule capable of healing RIT was screened out,and the underlying regulatory mechanism associated with magakaryocyte(MK)differentiation and thrombopoiesis was demonstrated.The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro.The ability to induce thrombopoiesis was subsequently demonstrated in Tg(cd41:enhanced green fluorescent protein(eGFP))zebrafish and RIT model mice.In addition,we carried out network pharmacological prediction,drug affinity responsive target stability assay(DARTS)and cellular thermal shift assay(CETSA)analyses to explore the potential targets of oxymatrine.Moreover,the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses,Western blot(WB),and immunofluorescence.Oxymatrine markedly promoted MK differentiation and maturation in vitro.Moreover,oxymatrine induced thrombopoiesis in Tg(cd41:eGFP)zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice.Mechanistically,oxymatrine directly binds to toll-like receptor 2(TLR2)and further regulates the downstream pathway stimulator of interferon genes(STING)/nuclear factor-kappaB(NF-kB),which can be blocked by C29 and C-176,which are specific inhibitors of TLR2 and STING,respectively.Taken together,we demonstrated that oxymatrine,a novel TLR2 agonist,plays a critical role in acceleratingMKdifferentiation and thrombopoiesis via the STING/NF-kB axis,suggesting that oxymatrine is a promising candidate for RIT therapy.
