Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)...Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.展开更多
We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repet...We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.展开更多
Cementation is produced by mixing a certain amount of cement with the saturated clay. The purpose of this paper is to model the cementation effect on the mechanical behavior of cement-treated clay. A micromechanical s...Cementation is produced by mixing a certain amount of cement with the saturated clay. The purpose of this paper is to model the cementation effect on the mechanical behavior of cement-treated clay. A micromechanical stress-strain model is developed considering explicitly the cementation at inter-cluster contacts. The inter-cluster bonding and debonding during mechanical loading are introduced in two ways： an additional cohesion in the shear sliding and a higher yield stress in normal compression. The model is used to simulate isotropic compression and undrained triaxial tests under various confining stresses on cement-treated Singapore clay with various cement contents. The applicability of the present model is evaluated through comparisons between numerical and experimental results. The evolution of local stresses and local strains in inter-cluster planes is dis- cussed in order to explain the induced anisotropy due to debonding at contact level under the applied loads.展开更多
Previous studies on the hollow cylinder torsional shear test(HCTST)have mainly focused on the macroscopic behavior,while the micromechanical responses in soil specimens with shaped particles have rarely been investiga...Previous studies on the hollow cylinder torsional shear test(HCTST)have mainly focused on the macroscopic behavior,while the micromechanical responses in soil specimens with shaped particles have rarely been investigated.This paper develops a numerical model of the HCTST using the discrete element method(DEM).The method of bonded spheres in a hexagonal arrangement is proposed to generate flexible boundaries that can achieve real-time adjustment of the internal and external cell pressures and capture the inhomogeneous deformation in the radial direction during shearing.Representative angular particles are selected from Toyoura sand and reproduced in this model to approximate real sand particles.The model is then validated by comparing numerical and experimental results of HCTSTs on Toyoura sand with different major principal stress directions.Next,a series of HCTSTs with different combinations of major principal stress direction(a)and intermediate principal stress ratio(b)is simulated to quantitatively characterize the sand behavior under different shear conditions.The results show that the shaped particles are horizontally distributed before shearing,and the initial anisotropic packing structure further results in different stressestrain curves in cases with different a and b values.The distribution of force chains is affected by both a and b during the shear process,together with the formation of the shear bands in different patterns.The contact normal anisotropy and contact force anisotropy show different evolution patterns when either a or b varies,resulting in the differences in the non-coaxiality and other macroscopic responses.This study improves the understanding of the macroscopic response of sand from a microscopic perspective and provides valuable insights for the constitutive modeling of sand.展开更多
Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected pa...Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.展开更多
In this study, we aim to investigate a unified modeling method for the monotonic and cyclic behaviors of sand and clay. A simple double-yield-surface model, with plastic hardening modulus and dilatancy relation being ...In this study, we aim to investigate a unified modeling method for the monotonic and cyclic behaviors of sand and clay. A simple double-yield-surface model, with plastic hardening modulus and dilatancy relation being dependent on density state unlike in existing approaches, is developed by considering the location of the critical state line. The model is used to simulate the drained and undrained tests of various sands and clays under monotonic and cyclic loadings. Prediction results are compared with experimental results, which show that the proposed approach is capable of modeling the monotonic and cyclic behaviors of sand and clay.展开更多
Coronavirus disease 2019(COVID-19)is a highly contagious disease and a serious threat to human health.COVID-19 can cause multiple organ dysfunction,such as respiratory and circulatory failure,liver and kidney injury,d...Coronavirus disease 2019(COVID-19)is a highly contagious disease and a serious threat to human health.COVID-19 can cause multiple organ dysfunction,such as respiratory and circulatory failure,liver and kidney injury,disseminated intravascular coagulation,and thromboembolism,and even death.The World Health Organization reports that the mortality rate of severe-type COVID-19 is over 50%.Currently,the number of severe cases worldwide has increased rapidly,but the experience in the treatment of infected patients is still limited.Given the lack of specific antiviral drugs,multi-organ function support treatment is important for patients with COVID-19.To improve the cure rate and reduce the mortality of patients with severe-and critical-type COVID-19,this paper summarizes the experience of organ function support in patients with severe-and criticaltype COVID-19 in Optical Valley Branch of Tongji Hospital,Wuhan,China.This paper systematically summarizes the procedures of functional support therapies for multiple organs and systems,including respiratory,circulatory,renal,hepatic,and hematological systems,among patients with severe-and critical-type COVID-19.This paper provides a clinical reference and a new strategy for the optimal treatment of COVID-19 worldwide.展开更多
Experiments show that silts and silty soils exhibit contraction followed by dilation during shearing and the slope of failure line decreases at large strains, termed as phase transformation behaviour. This paper is to...Experiments show that silts and silty soils exhibit contraction followed by dilation during shearing and the slope of failure line decreases at large strains, termed as phase transformation behaviour. This paper is to develop a new micromechanical stress-strain model that accounts for the phase transformation behaviour by explicitly employing the phase transformation line and its related friction angles. The overall strain includes plastic sliding and plastic compression among grains. The internal-friction angle at the phase transformation state and the void state variable are employed to describe the phase transformation behaviour. The model is examined by simulating undrained and drained triaxial compression tests performed on Pitea silts. The local stress-strain behaviour for contact planes is also investigated.展开更多
1 Introduction For geotechnical engineering,numerous applications involve multiscale and multiphysics processes,such as internal erosion,hydraulic fracturing,energy piles,municipal waste disposal,production from uncon...1 Introduction For geotechnical engineering,numerous applications involve multiscale and multiphysics processes,such as internal erosion,hydraulic fracturing,energy piles,municipal waste disposal,production from unconventional oil and gas reservoirs,heat stimulation and depressurization of natural gas hydrate formation,pavement subjected to heating-cooling cycles.展开更多
1Introduction Geomaterials,such as soil,rock,and concrete,have a clearly defined microstructure at the level of individual grains(Sprunt and Brace,1974;Ichikawa et al.,2001).While difficult to observe directly,these m...1Introduction Geomaterials,such as soil,rock,and concrete,have a clearly defined microstructure at the level of individual grains(Sprunt and Brace,1974;Ichikawa et al.,2001).While difficult to observe directly,these microstructures,including their particle size distribution,particle shape,mineralogy,interaction,and bonding behavior,have a strong influence on both microand macroscopic behaviors of geomaterials(Gao and Zhao,2013);He et al.,2018;Alqam et al.,2019;Sun et al.,2020;Yin et al.,2020;Wang et al.,2022 .In recent years,various kinds of engineered geomaterials,such as fiber-reinforced and bio-reinforced soils,have been shown to have even more sophisticated microstructures(Uygunoglu,2008;Mujah et al.,2019).展开更多
基金supported by the National Natural Science Foundation of China,No.8227050826(to PL)Tianjin Science and Technology Bureau Foundation,No.20201194(to PL)Tianjin Graduate Research and Innovation Project,No.2022BKY174(to CW).
文摘Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
基金supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBSS00047(to PL)the National Natural Science Foundation of China,Nos.82072166(to PL),82071394(to XG)+4 种基金Science and Technology Planning Project of Tianjin,No.20YFZCSY00030(to PL)Science and Technology Project of Tianjin Municipal Health Commission,No.TJWJ2021QN005(to XG)Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-006ATianjin Municipal Education Commission Scientific Research Program Project,No.2020KJ164(to JZ)China Postdoctoral Science Foundation,No.2022M712392(to ZY).
文摘We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.
基金supported by Research Fund for the Doctoral Program of Higher Education of China(20110073120012)Shanghai Pujiang Talent plan(11PJ1405700)
文摘Cementation is produced by mixing a certain amount of cement with the saturated clay. The purpose of this paper is to model the cementation effect on the mechanical behavior of cement-treated clay. A micromechanical stress-strain model is developed considering explicitly the cementation at inter-cluster contacts. The inter-cluster bonding and debonding during mechanical loading are introduced in two ways： an additional cohesion in the shear sliding and a higher yield stress in normal compression. The model is used to simulate isotropic compression and undrained triaxial tests under various confining stresses on cement-treated Singapore clay with various cement contents. The applicability of the present model is evaluated through comparisons between numerical and experimental results. The evolution of local stresses and local strains in inter-cluster planes is dis- cussed in order to explain the induced anisotropy due to debonding at contact level under the applied loads.
基金supports from the National Key R&D Program of China(Grant No.2023YFC3009400)Research Grants Council of Hong Kong(Grant Nos.15220221 and 15229223).
文摘Previous studies on the hollow cylinder torsional shear test(HCTST)have mainly focused on the macroscopic behavior,while the micromechanical responses in soil specimens with shaped particles have rarely been investigated.This paper develops a numerical model of the HCTST using the discrete element method(DEM).The method of bonded spheres in a hexagonal arrangement is proposed to generate flexible boundaries that can achieve real-time adjustment of the internal and external cell pressures and capture the inhomogeneous deformation in the radial direction during shearing.Representative angular particles are selected from Toyoura sand and reproduced in this model to approximate real sand particles.The model is then validated by comparing numerical and experimental results of HCTSTs on Toyoura sand with different major principal stress directions.Next,a series of HCTSTs with different combinations of major principal stress direction(a)and intermediate principal stress ratio(b)is simulated to quantitatively characterize the sand behavior under different shear conditions.The results show that the shaped particles are horizontally distributed before shearing,and the initial anisotropic packing structure further results in different stressestrain curves in cases with different a and b values.The distribution of force chains is affected by both a and b during the shear process,together with the formation of the shear bands in different patterns.The contact normal anisotropy and contact force anisotropy show different evolution patterns when either a or b varies,resulting in the differences in the non-coaxiality and other macroscopic responses.This study improves the understanding of the macroscopic response of sand from a microscopic perspective and provides valuable insights for the constitutive modeling of sand.
文摘Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.
基金supported by the National Natural Science Foundation of China(No.41372285)the Research Fund for the Doctoral Program of Higher Education of China(No.20110073120012)+1 种基金Shanghai Pujiang Talent Plan(No.11PJ1405700)the European Community through the program‘People’as part of the Industry-Academia Pathways and Partnerships project CREEP(PIAPP-GA-2011-286397)
文摘In this study, we aim to investigate a unified modeling method for the monotonic and cyclic behaviors of sand and clay. A simple double-yield-surface model, with plastic hardening modulus and dilatancy relation being dependent on density state unlike in existing approaches, is developed by considering the location of the critical state line. The model is used to simulate the drained and undrained tests of various sands and clays under monotonic and cyclic loadings. Prediction results are compared with experimental results, which show that the proposed approach is capable of modeling the monotonic and cyclic behaviors of sand and clay.
文摘Coronavirus disease 2019(COVID-19)is a highly contagious disease and a serious threat to human health.COVID-19 can cause multiple organ dysfunction,such as respiratory and circulatory failure,liver and kidney injury,disseminated intravascular coagulation,and thromboembolism,and even death.The World Health Organization reports that the mortality rate of severe-type COVID-19 is over 50%.Currently,the number of severe cases worldwide has increased rapidly,but the experience in the treatment of infected patients is still limited.Given the lack of specific antiviral drugs,multi-organ function support treatment is important for patients with COVID-19.To improve the cure rate and reduce the mortality of patients with severe-and critical-type COVID-19,this paper summarizes the experience of organ function support in patients with severe-and criticaltype COVID-19 in Optical Valley Branch of Tongji Hospital,Wuhan,China.This paper systematically summarizes the procedures of functional support therapies for multiple organs and systems,including respiratory,circulatory,renal,hepatic,and hematological systems,among patients with severe-and critical-type COVID-19.This paper provides a clinical reference and a new strategy for the optimal treatment of COVID-19 worldwide.
基金supported by the Research Fund for the Doctoral Program of Higher Education of China(No.20110073120012)the Shanghai Pujiang Talent Plan(No.11PJ1405700)+2 种基金the National Natural Science Foundation of China(Nos.41240024,41372285 and 41372264)the Zhejiang Provincial Natural Science Foundation of China(No.1LY13E080013)the NSFC/ANR Joint Research Scheme(Nos.51161130523 and RISMOGEO)
文摘Experiments show that silts and silty soils exhibit contraction followed by dilation during shearing and the slope of failure line decreases at large strains, termed as phase transformation behaviour. This paper is to develop a new micromechanical stress-strain model that accounts for the phase transformation behaviour by explicitly employing the phase transformation line and its related friction angles. The overall strain includes plastic sliding and plastic compression among grains. The internal-friction angle at the phase transformation state and the void state variable are employed to describe the phase transformation behaviour. The model is examined by simulating undrained and drained triaxial compression tests performed on Pitea silts. The local stress-strain behaviour for contact planes is also investigated.
基金This work is supported by the Research Grants Council(RGC)of the Hong Kong Special Administrative Region Government(HKSARG)of China(No.N_PolyU534/20).
文摘1 Introduction For geotechnical engineering,numerous applications involve multiscale and multiphysics processes,such as internal erosion,hydraulic fracturing,energy piles,municipal waste disposal,production from unconventional oil and gas reservoirs,heat stimulation and depressurization of natural gas hydrate formation,pavement subjected to heating-cooling cycles.
基金supported by the Research Grants Council(RGC)of Hong Kong,China(No.15226322)the National Natural Science Foundation of China(No.42207210)。
文摘1Introduction Geomaterials,such as soil,rock,and concrete,have a clearly defined microstructure at the level of individual grains(Sprunt and Brace,1974;Ichikawa et al.,2001).While difficult to observe directly,these microstructures,including their particle size distribution,particle shape,mineralogy,interaction,and bonding behavior,have a strong influence on both microand macroscopic behaviors of geomaterials(Gao and Zhao,2013);He et al.,2018;Alqam et al.,2019;Sun et al.,2020;Yin et al.,2020;Wang et al.,2022 .In recent years,various kinds of engineered geomaterials,such as fiber-reinforced and bio-reinforced soils,have been shown to have even more sophisticated microstructures(Uygunoglu,2008;Mujah et al.,2019).
