Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper th...Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.展开更多
Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their h...Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their high technological maturity.Since the Fukushima accident,research on accident-tolerant fuels(ATFs),which are more resistant to serious accidents than conventional fuels,has gradually increased.This study analyzes the neutronics and thermal hydraulics of an SPWR(ACPR50S)for different ATFs,BeO+UO_(2)−SiC,BeO+UO_(2)−FeCrAl,U_(3)Si_(2)−SiC,and U_(3)Si_(2)−FeCrAl,based on a PWR fuel management code,the Bamboo-C deterministic code.In the steady state,the burnup calculations,reactivity coefficients,power and temperature distributions,and control rod reactivity worth were studied.The transients of the control rod ejection accident for the two control rods with the maximum and minimum reactivity worth were analyzed.The results showed that 5%B-10 enrichment in the wet annular burnable absorbers assembly can effectively reduce the initial reactivity and end-of-life reactivity penalty.The BeO+UO2−SiC core exhibited superior neutronic characteristics in terms of burnup and negative temperature reactivity compared with the other three cases owing to the strong moderation ability of BeO+UO_(2)and low neutron absorption of SiC.However,the U_(3)Si_(2)core had a marginally better power-flattening effect than BeO+UO_(2),and the differential worth of each control rod group was similar between different ATFs.During the transient of a control rod ejection,the changes in the fuel temperature,coolant temperature,and coolant density were similar.The maximum difference was less than 10℃ for the fuel temperature and 2℃ for the coolant temperature.展开更多
Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tu...Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.展开更多
Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and m...Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.展开更多
It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research...It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research hot topic.However,there remains an urgent need to elucidate its specific mechanisms.This study aimed to explore the impact of a high-fat diet(HFD)on liver health and cognitive function,and to further uncover the regulatory effect of aerobic exercise by liver-specific activating transcription factor 3(Atf3)knockout(ATF3cKO)mice in a“liver-brain”axis mode.The 5-week-old C57BL/6 and ATF3cKO mice were fed with HFD for 32 weeks,and sequentially subjected to aerobic exercise intervention at the 20th week for another 12 consecutive weeks.Meanwhile,C57BL/6 mice were provided with a normal diet as the control group.The functional parameters of liver and brain of all mice were assessed.Cognitive capacity of all mice was assessed by the Morris water maze(MWM).Inflammatory factors in the serum and brain of mice were quantified using enzyme-linked immunosorbent assay(ELISA),and the expression of inflammasomes was detected by immunohistochemistry(IHC).Additionally,the activation of nuclear factor-κB(NF-κB)and phosphoinositide 3-kinase(PI3K)signal pathways was analyzed by Western blotting.In this study,HFD impaired hepatic and brain functions,while aerobic exercise and liver-specific Atf3 knockout suppressed inflammatory factors in the peripheral circulation through hepatoprotective mechanisms,thereby attenuating cerebral inflammation and preserving neurological integrity,as well as mitigating HFD-induced cognitive decline.展开更多
基金supported by the National Natural Science Foundation of China(82071143,82371000,82270361)Key Research and Development Program of Jiangsu Province(BE2022795)+2 种基金the Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22_1801)the Jiangsu Province Capability Improvement Project through the Science,Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit(YJXYYJSDW4)Jiangsu Provincial Medical Innovation Center(CXZX202227).
文摘Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon(RAP).Despite its therapeutic effects,the surgical risk and unclear mechanism hamper the clinical application.Numerous evidences support macrophages as the key immune cells during bone remodeling.Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1CreERT2;R26GFP lineage tracing system.Fluorescence staining,flow cytometry analysis,and western blot determined the significantly enhanced expression of binding immunoglobulin protein(BiP)and emphasized the activation of sensor activating transcription factor 6(ATF6)in macrophages.Then,we verified that macrophage specific ATF6 deletion(ATF6f/f;CX3CR1CreERT2 mice)decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy.In contrast,macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement.In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6.At the mechanism level,RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfαpromotor and augmenting its transcription.Additionally,molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element(ERSE).Taken together,ATF6 may aggravate orthodontic bone remodeling by promoting Tnfαtranscription in macrophages,suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
基金supported by the National Natural Science Foundation of China (No. 12205150)Natural Science Foundation of Jiangsu Province (No. BK20210304)+1 种基金China Postdoctoral Science Foundation (Nos. 2020M681594 and 2019TQ0148)Jiangsu Province Postdoctoral Science Foundation (Nos. 2020Z231)
文摘Small modular reactors have received widespread attention owing to their inherent safety,low investment,and flexibility.Small pressurized water reactors(SPWRs)have become important candidates for SMRs owing to their high technological maturity.Since the Fukushima accident,research on accident-tolerant fuels(ATFs),which are more resistant to serious accidents than conventional fuels,has gradually increased.This study analyzes the neutronics and thermal hydraulics of an SPWR(ACPR50S)for different ATFs,BeO+UO_(2)−SiC,BeO+UO_(2)−FeCrAl,U_(3)Si_(2)−SiC,and U_(3)Si_(2)−FeCrAl,based on a PWR fuel management code,the Bamboo-C deterministic code.In the steady state,the burnup calculations,reactivity coefficients,power and temperature distributions,and control rod reactivity worth were studied.The transients of the control rod ejection accident for the two control rods with the maximum and minimum reactivity worth were analyzed.The results showed that 5%B-10 enrichment in the wet annular burnable absorbers assembly can effectively reduce the initial reactivity and end-of-life reactivity penalty.The BeO+UO2−SiC core exhibited superior neutronic characteristics in terms of burnup and negative temperature reactivity compared with the other three cases owing to the strong moderation ability of BeO+UO_(2)and low neutron absorption of SiC.However,the U_(3)Si_(2)core had a marginally better power-flattening effect than BeO+UO_(2),and the differential worth of each control rod group was similar between different ATFs.During the transient of a control rod ejection,the changes in the fuel temperature,coolant temperature,and coolant density were similar.The maximum difference was less than 10℃ for the fuel temperature and 2℃ for the coolant temperature.
基金supported by State Key Program of National Natural Science Foundation of China(Grant No.82130092)the General Program of National Natural Science Foundation of China(Grant No.82373522)the National Natural Science Foundation of China(Grant No.82404196).
文摘Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.
基金supported by the National Natural Science Foundation of China(Grant No.81702884)Natural Science Foundation of Shandong Province(Grant Nos.ZR2022MH272,ZR2020QH216,and ZR2023QH115)Medicine and Health Science and Technology Foundation of Shandong Province(Grant Nos.202402060623 and 202202080721).
文摘Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.
基金supported by the National Natural Science Foundation of China(32471186 and 31771318)the 14th Five-Year-Plan Advantageous and Characteristic Disciplines(Groups)of Colleges and Universities in Hubei Province for Exercise and Brain Science+1 种基金as well as the Leading Talent Program and Innovative Start-up Foundation from Wuhan Sports University to Ning Chensupported by the Hubei Natural Science Foundation(2022CFB929)and China Postdoctoral Science Foundation(2023M732727)to Tong Wu.
文摘It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function.The concept of multi-organ crosstalk coordinating disease progression has become the current research hot topic.However,there remains an urgent need to elucidate its specific mechanisms.This study aimed to explore the impact of a high-fat diet(HFD)on liver health and cognitive function,and to further uncover the regulatory effect of aerobic exercise by liver-specific activating transcription factor 3(Atf3)knockout(ATF3cKO)mice in a“liver-brain”axis mode.The 5-week-old C57BL/6 and ATF3cKO mice were fed with HFD for 32 weeks,and sequentially subjected to aerobic exercise intervention at the 20th week for another 12 consecutive weeks.Meanwhile,C57BL/6 mice were provided with a normal diet as the control group.The functional parameters of liver and brain of all mice were assessed.Cognitive capacity of all mice was assessed by the Morris water maze(MWM).Inflammatory factors in the serum and brain of mice were quantified using enzyme-linked immunosorbent assay(ELISA),and the expression of inflammasomes was detected by immunohistochemistry(IHC).Additionally,the activation of nuclear factor-κB(NF-κB)and phosphoinositide 3-kinase(PI3K)signal pathways was analyzed by Western blotting.In this study,HFD impaired hepatic and brain functions,while aerobic exercise and liver-specific Atf3 knockout suppressed inflammatory factors in the peripheral circulation through hepatoprotective mechanisms,thereby attenuating cerebral inflammation and preserving neurological integrity,as well as mitigating HFD-induced cognitive decline.
