Two simple and sensitive high performance liquid chromatography–tandem mass spectrometry(HPLC–MS/MS) methods were developed and validated for the determination of fenticonazole in human plasma after percutaneous and...Two simple and sensitive high performance liquid chromatography–tandem mass spectrometry(HPLC–MS/MS) methods were developed and validated for the determination of fenticonazole in human plasma after percutaneous and intravaginal administration. Mifepristone was used as an internal standard(IS), and simple protein precipitation by acetonitrile containing 2% acetic acid was utilized for extracting the analytes from the plasma samples. Chromatographic separation was performed on a Kinetex XB-C_(18) column. The quantitation was performed by a mass spectrometer equipped with an electrospray ionization source in multiple reactions monitoring(MRM) positive ion mode using precursor-to-product ion transitions of m/z 455.2–199.1 for fenticonazole and m/z 430.2–372.3 for mifepristone. The validated linear ranges of fenticonazole were 5–1000 pg/m L and 0.1–20 ng/m L in plasma for the methods A and B, respectively. For the two methods, the accuracy data ranged from 85% to 115%, the intra- and inter-batch precision data were less than 15%, the recovery data were more than 90%, and no matrix interference was observed. The methods A and B were successfully validated and applied to the pharmacokinetic studies of fenticonazole gel in Chinese healthy volunteers after percutaneous and intravaginal administration, respectively.展开更多
Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on sti...Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on stiffened blood vessel wall or extracellular matrix(ECM)under shear flow[1-3].However,the mechanical dependence of calcium flux and trail formation in neutrophils remains unclear yet in these processes.First,the effect of substrate stiffness through ECs on neutrophil calcium spike was quantified when the individual neutrophils adhered to EC monolayer pre-placed onto stiffness-varied polyacrylamide(PA)substrate(5 or 34.88 kPa)or glass surface.Our data indicated that E-/P-selectins and ICAM-1s on HUVECs and b2-integrins,PSGL-1s,and CD44s on neutrophils were all involved in mediating neutrophil calcium spike in a stiffness-dependent manner,in which the increase of substrate stiffness enhanced the calcium intensity and spike number.Such stiffness-dependent calcium response is associated with selectin-induced b2-integrin activation through Syk/Src signaling pathway and the F-actin/myosin II function.Moreover,tension-activated calcium ion channels displayed critical roles in initiating stiffness-dependent calcium spike [4].Second,the trail formation of neutrophils to ECs monolayer pre-placed onto the same PA substrate were also tested under shear flow.Live fluorescence imaging showed that neutrophils are able to form long membrane tethers during migration and subsequently leave behind membranous long-lasting trails under shear,which are enriched in LFA-1,Mac-1,and CD44.Moreover,the formation of the trails was inhibited by blocking LFA-1s and Mac-1s,suggesting an important role forβ2-integrins in the trial formation.The recruitment of monocytes was inhibited when pre-blocking ICAM-1s on flowing monocytes,indicating that the neutrophil’s trails employβ2-integrin-ICAM-1 binding to recruit the monocytes.Intriguingly,both the length and the area of the trails increase with increasing substrate stiffness,resulting in the enhanced monocyte recruitment.Inhibition of actin binding protein Arp2/3 impairs the trail formation and dramatically decreases the neutrophil-dependent monocyte recruitment.These data provide an insight into understanding how stiffening of vascular wall could regulate the calcium flux of adhered neutrophils and thus the immune responses in atherosclerosis.They also imply that local mechanical microenvironment is remodeled with the migration of neutrophils,leaving the trails presented to induce and regulate monocyte recruitment.All the results are meaningful in elucidating the occurrence and development of atherosclerosis or fibrosis from the viewpoint of mechanotransduction and also for the potential intervention of cardiovascular disease progress.展开更多
Implant materials,as foreign objects to host,can cause various degrees of inflammation in most cases.The inflammation is triggered by a series of immune responses and directly impacts the tissue regeneration process,w...Implant materials,as foreign objects to host,can cause various degrees of inflammation in most cases.The inflammation is triggered by a series of immune responses and directly impacts the tissue regeneration process,which determines the outcome of tissue repair.The immune responses are complex process involving numerous immune cells and can be divide into innate immune and adaptive immune responses.Once materials are implanted,innate immune responses are activated under the mediation of several immune cells(e.g.neutrophils and macrophages),meanwhile immature dendritic cells(imDCs)are recruited to the implant sites to recognize,internalize and process antigens.Upon antigen uptake,imDCs gradually differentiate into mature dendritic cells(mDCs)and migrate to secondary lymph nodes.In the lymph nodes,mDCs present processed antigen peptides to naive T lymphocytes and activate their antigen specific proliferation,resulting in initiation of adaptive immune responses.Due to their key position in the immune system,serving to bridge innate and adaptive immunity,DCs are crucial to guiding and modulating the immune responses caused by implanted materials.Therefore,figuring out the response of DCs to implanted materials and the exact role of DCs in tissue healing processes will provide deeper insight for the rational design of biomaterials.Previous studies on the effects of implants on immune functions of DCs are mainly focused on physical and chemical properties of the materials(e.g.released chemical composition,surface chemistry,substrate stiffness and surface topography).All these factors will change the microenvironment of the tissue around implant materials,which affect the immune functions of DCs.However,the change of microenvironment not only directly derives from the physical and chemical properties of the material(intrinsic),but also indirectly results from the remodeled extracellular matrix(ECM)caused by implanted materials.When blood or tissue fluid contact with materials after implantation,proteins(e.g.fibrin and collagen)will absorb and deposit on the surface of implants,leading to a provisionally stable matrix with microporous fibrous-liked network structure.It means that the remodeled ECM can provide adhesion sites for recruited DCs and form spatial confinement.DCs,as a kind of cells that are extremely sensitive to mechanical stimuli,theoretically,can response to the mechanical stimuli coming from spatial confinement of remodeled ECM,which may lead to a series of modulations in their cell morphologies and immune functions.Then,the remodeled ECM is a non-negligible mechanical cue.However,to the best of our knowledge,there is a lack of a simple and effective model to establish the relationship between the immune functions of DCs and remodeled ECM.Most studies on the responses of DCs to implanted materials are still based on suspension culture model,which is the normal status of DCs in vitro culture systems.In addition,the processes by which DC exerts immune functions(both endocytosis and antigen presentation)are dynamically physical interaction.It means that the changes of DCs’immune functions are highly correlated with the changes of their biomechanical characteristics caused by remodeled ECM.In this work,we have found that the ECM was remodeled by a large amount of fibrin matrix deposited on the surface of implants in the early stage of the inflammations following implantation.Thus,we used non-toxic salmon fibrin hydrogels with microporous fibrous-liked network structure to mimic the deposited fibrin matrix.Then,human monocyte-derived DCs were cultured on the surface and inside of the fibrin hydrogels to mimic the different spatial confinement states of fibrin matrix.Our results indicated that cell morphologies and cytoskeleton structures of DCs were regulated by the spatial confinement of fibrin hydrogels,resulting in generating mechanical stimuli for DCs.Furthermore,we have found that the biomechanical characteristics and the immune functions of both imDCs and mDC were also modulated.Considering the changes in surface markers,secreted cytokines and biomechanical characteristics of DCs,it indicates that the tendency and magnitude of modulations were highly associated with the spatial confinement of fibrin hydrogels.This model demonstrated that mechanical stimuli deriving from spatial confinement of deposited fibrin matrix is an important factor for regulating the biomechanical characteristics and immune functions of DCs.展开更多
Multifaceted asymmetric radiation from the edge(MARFE) movement which can cause density limit disruption is often encountered during high density operation on many tokamaks. Therefore, identifying and predicting MARFE...Multifaceted asymmetric radiation from the edge(MARFE) movement which can cause density limit disruption is often encountered during high density operation on many tokamaks. Therefore, identifying and predicting MARFE movement is meaningful to mitigate or avoid density limit disruption for the steady-state high-density plasma operation. A machine learning method named random forest(RF) has been used to predict the MARFE movement based on the density ramp-up experiment in the 2022’s first campaign of Experimental Advanced Superconducting Tokamak(EAST). The RF model shows that besides Greenwald fraction which is the ratio of plasma density and Greenwald density limit, dβp/dt,H98and d Wmhd/dt are relatively important parameters for MARFE-movement prediction. Applying the RF model on test discharges, the test results show that the successful alarm rate for MARFE movement causing density limit disruption reaches ~ 85% with a minimum alarm time of ~ 40 ms and mean alarm time of ~ 700 ms. At the same time, the false alarm rate for non-disruptive and non-density-limit disruptive discharges can be kept below 5%. These results provide a reference to the prediction of MARFE movement in high density plasmas, which can help the avoidance or mitigation of density limit disruption in future fusion reactors.展开更多
[Objectives]The paper was to establish an evaluation method for the uncertainty of stevioside(including stevioside,rebaudioside A,rebaudioside B,rebaudioside C,rebaudioside F,Dulcoside A,rubusoside and steviolbioside)...[Objectives]The paper was to establish an evaluation method for the uncertainty of stevioside(including stevioside,rebaudioside A,rebaudioside B,rebaudioside C,rebaudioside F,Dulcoside A,rubusoside and steviolbioside)content determination in fermented milk based on HPLC.[Methods]The mathematical model of stevioside content and the propagation rate of uncertainty were established,and the sources of uncertainty were analyzed.[Results]The uncertainty mainly came from four main aspects,including standard uncertainty u(C)introduced by solution concentration C,standard uncertainty u(V)introduced by sample volume V,standard uncertainty u(m)introduced by sample mass m weighing and standard uncertainty u(f_(rep))introduced by measurement repeatability of stevioside content after sample dissolution and constant volume.The uncertainty estimation table and fishbone chart of stevioside content X determination were established.The relative synthetic standard uncertainty of stevioside content was obtained,and the standard uncertainty was extended to form the measurement result of stevioside content and its uncertainty report.[Conclusions]The evaluation results can be directly applied to the daily practical detection work.展开更多
In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,ath...In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,atherosclerosis,obesity,and menopause,are associated with osteoporotic phenotypes.It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass.Furthermore,similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models.Abnormal lipid metabolism(such as increased oxidized lipids and elevated plasma cholesterol)affects bone microenvironment ho-meostasis via cross-organ communication,promoting differentiation of mesenchymal stem cells to adipocytes,and inhibiting commitment towards osteoblasts.Moreover,disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cyto-kines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts.Conclusively,this review addresses the possible link be-tween lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism bal-ance.We also summarize the possible approaches and prospects of intervening lipid meta-bolismforosteoporosistreatment.展开更多
Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer.It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors ...Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer.It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors in vivo.However,the role of extracellular matrix(ECM)stiffness in colon cancer cell(CCCs)invasion and metastasis remains unclear.Here,bioinformatical analysis suggested that a high expression level of yes associated protein 1(YAP1)was significantly associated with metastasis and poor prognosis in colon cancer patients.We further investigated the effects of polyacrylamide hydrogels with different stiffnesses(3,20,and 38 kPa),which were simulated as ECM,on the mechanophenotype(F-actin cytoskeleton organization,electrophoretic rate,membrane fluidity,and Young's modulus)of CCCs.The results showed that a stiffer ECM could induce the maturation of focal adhesions and formation of stress fibers in CCCs,regulate their mechanophenotypes,and promote cell motility.We also demonstrated that the expression levels of YAP1 and paxillin were positively correlated in patients with colon cancer.YAP1 knockdown reduces paxillin clustering and cell motility and alters the cellular mechanophenotypes of CCCs.This is of great significance for an in-depth understanding of the invasion and metastatic mechanisms of colon cancer and for the optimization of clinical therapy from the perspective of mechanobiology.展开更多
Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated me...Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.展开更多
Neurotransmitter gamma-aminobutiric acid （GABA） through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibito...Neurotransmitter gamma-aminobutiric acid （GABA） through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells （NSCs/ NPCs）. The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na＋/K＋/2CF co-transporter NKCC1 driving CF influx and neuron-specific K＋/Cl co-transporter KCC2 driving Cl efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 （DISC1） and brain-derived neurotrophic factor （BDNF） signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and new-born neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance.展开更多
Lithium-rich layered oxides(LLOs)have been extensively studied as cathode materials for lithium-ion batteries(LIBs)by researchers all over the world in the past decades due to their high specific capacities and high c...Lithium-rich layered oxides(LLOs)have been extensively studied as cathode materials for lithium-ion batteries(LIBs)by researchers all over the world in the past decades due to their high specific capacities and high charge-discharge voltages.However,as cathode materials LLOs have disadvantages of significant voltage and capacity decays during the charge-discharge cycling.It was shown in the past that fine-tuning of structures and compositions was critical to the performances of this kind of materials.In this report,LLOs with target composition of Li1.17Mn0.50Ni0.24Co0.09O2 were prepared by carbonate co-precipitation method with different pH values.X-ray powder diffraction(XRD),scanning electron microscopy(SEM),transmission electron microscope(TEM),and electrochemical impedance spectroscopies(EIS)were used to investigate the structures and morphologies of the materials and to understand the improvements of their electrochemical performances.With the pH values increased from 7.5 to 8.5,the Li/Ni ratios in the compositions decreased from 5.17 to 4.64,and the initial Coulombic efficiency,cycling stability and average discharge voltages were gained impressively.Especially,the material synthesized at pH=8.5 delivered a reversible discharge capacity of 263 mAhg−1 during the first cycle,with 79.0%initial Coulombic efficiency,at the rate of 0.1 C and a superior capacity retention of 94%after 100 cycles at the rate of 1 C.Furthermore,this material exhibited an initial average discharge voltage of 3.65 V,with a voltage decay of only 0.09 V after 50 charge-discharge cycles.The improved electrochemical performances by varying the pH values in the synthesis process can be explained by the mitigation of layered-to-spinel phase transformation and the reduction of solid-electrolyte interface(SEI)resistance.We hope this work can shed some light on the alleviation of voltage and capacity decay issues of the LLOs cathode materials.展开更多
Increasing active metal sites is a valid approach to improve the catalytic activity of the catalyst. Co^(3+) is the main active metal site of Co-based catalysts. In this research work, through the partial transformati...Increasing active metal sites is a valid approach to improve the catalytic activity of the catalyst. Co^(3+) is the main active metal site of Co-based catalysts. In this research work, through the partial transformation of CoFePBA (CFP) via low-temperature heat treatment, the effective control of the Co^(3+)/Co^(2+) ratio has been achieved. The partial transformation strategy of low-temperature heat treatment can not only maintain the original framework structure of CFP, but also increase more active sites. The characterization results show that the CFP-200 sample obtained via heat treatment at 200 ℃ for 2 h under N2 atmosphere has the highest Co^(3+)/Co^(2+) ratio. As an oxygen evolution reaction electrocatalyst, CFP-200 shows the best electrocatalytic activity among all samples. In 1.0 mol/L KOH electrolyte, the overpotential is 312 mV at a current density of 10 mA/cm2. Therefore, low-temperature heat treatment provides an effective method for preparing low-cost and high-efficiency electrocatalysts.展开更多
Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of th...Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.展开更多
文摘Two simple and sensitive high performance liquid chromatography–tandem mass spectrometry(HPLC–MS/MS) methods were developed and validated for the determination of fenticonazole in human plasma after percutaneous and intravaginal administration. Mifepristone was used as an internal standard(IS), and simple protein precipitation by acetonitrile containing 2% acetic acid was utilized for extracting the analytes from the plasma samples. Chromatographic separation was performed on a Kinetex XB-C_(18) column. The quantitation was performed by a mass spectrometer equipped with an electrospray ionization source in multiple reactions monitoring(MRM) positive ion mode using precursor-to-product ion transitions of m/z 455.2–199.1 for fenticonazole and m/z 430.2–372.3 for mifepristone. The validated linear ranges of fenticonazole were 5–1000 pg/m L and 0.1–20 ng/m L in plasma for the methods A and B, respectively. For the two methods, the accuracy data ranged from 85% to 115%, the intra- and inter-batch precision data were less than 15%, the recovery data were more than 90%, and no matrix interference was observed. The methods A and B were successfully validated and applied to the pharmacokinetic studies of fenticonazole gel in Chinese healthy volunteers after percutaneous and intravaginal administration, respectively.
基金supported by National Natural Science Foundation of China Grant( 31627804,91642203, 11772345,91539119)Chinese Academy of Sciences Strategic Priority Research Program ( XDB22040101)Frontier Science Key Project( QYZDJ-SSWJSC018)
文摘Atherosclerosis or fibrosis and cirrhosis undergo chronic inflammation associated with the adhesion between neutrophils and endothelial cells(ECs)that is mediated by their respective cellular adhesive molecules on stiffened blood vessel wall or extracellular matrix(ECM)under shear flow[1-3].However,the mechanical dependence of calcium flux and trail formation in neutrophils remains unclear yet in these processes.First,the effect of substrate stiffness through ECs on neutrophil calcium spike was quantified when the individual neutrophils adhered to EC monolayer pre-placed onto stiffness-varied polyacrylamide(PA)substrate(5 or 34.88 kPa)or glass surface.Our data indicated that E-/P-selectins and ICAM-1s on HUVECs and b2-integrins,PSGL-1s,and CD44s on neutrophils were all involved in mediating neutrophil calcium spike in a stiffness-dependent manner,in which the increase of substrate stiffness enhanced the calcium intensity and spike number.Such stiffness-dependent calcium response is associated with selectin-induced b2-integrin activation through Syk/Src signaling pathway and the F-actin/myosin II function.Moreover,tension-activated calcium ion channels displayed critical roles in initiating stiffness-dependent calcium spike [4].Second,the trail formation of neutrophils to ECs monolayer pre-placed onto the same PA substrate were also tested under shear flow.Live fluorescence imaging showed that neutrophils are able to form long membrane tethers during migration and subsequently leave behind membranous long-lasting trails under shear,which are enriched in LFA-1,Mac-1,and CD44.Moreover,the formation of the trails was inhibited by blocking LFA-1s and Mac-1s,suggesting an important role forβ2-integrins in the trial formation.The recruitment of monocytes was inhibited when pre-blocking ICAM-1s on flowing monocytes,indicating that the neutrophil’s trails employβ2-integrin-ICAM-1 binding to recruit the monocytes.Intriguingly,both the length and the area of the trails increase with increasing substrate stiffness,resulting in the enhanced monocyte recruitment.Inhibition of actin binding protein Arp2/3 impairs the trail formation and dramatically decreases the neutrophil-dependent monocyte recruitment.These data provide an insight into understanding how stiffening of vascular wall could regulate the calcium flux of adhered neutrophils and thus the immune responses in atherosclerosis.They also imply that local mechanical microenvironment is remodeled with the migration of neutrophils,leaving the trails presented to induce and regulate monocyte recruitment.All the results are meaningful in elucidating the occurrence and development of atherosclerosis or fibrosis from the viewpoint of mechanotransduction and also for the potential intervention of cardiovascular disease progress.
基金funded by grants from the National Natural Science Foundation of China ( 31771014, 11762006,31660258,31860262,11762006,81460254 )the 2011 Collaborative Innovation Program of Guizhou Province ( 2015-04)+1 种基金the Science and Technology Innovative Talent Team of Guizhou Province ( 2015-4021)the Science and Technology Foundation of Guizhou Province ( 2018-1412,2016-5676,2017-5718)
文摘Implant materials,as foreign objects to host,can cause various degrees of inflammation in most cases.The inflammation is triggered by a series of immune responses and directly impacts the tissue regeneration process,which determines the outcome of tissue repair.The immune responses are complex process involving numerous immune cells and can be divide into innate immune and adaptive immune responses.Once materials are implanted,innate immune responses are activated under the mediation of several immune cells(e.g.neutrophils and macrophages),meanwhile immature dendritic cells(imDCs)are recruited to the implant sites to recognize,internalize and process antigens.Upon antigen uptake,imDCs gradually differentiate into mature dendritic cells(mDCs)and migrate to secondary lymph nodes.In the lymph nodes,mDCs present processed antigen peptides to naive T lymphocytes and activate their antigen specific proliferation,resulting in initiation of adaptive immune responses.Due to their key position in the immune system,serving to bridge innate and adaptive immunity,DCs are crucial to guiding and modulating the immune responses caused by implanted materials.Therefore,figuring out the response of DCs to implanted materials and the exact role of DCs in tissue healing processes will provide deeper insight for the rational design of biomaterials.Previous studies on the effects of implants on immune functions of DCs are mainly focused on physical and chemical properties of the materials(e.g.released chemical composition,surface chemistry,substrate stiffness and surface topography).All these factors will change the microenvironment of the tissue around implant materials,which affect the immune functions of DCs.However,the change of microenvironment not only directly derives from the physical and chemical properties of the material(intrinsic),but also indirectly results from the remodeled extracellular matrix(ECM)caused by implanted materials.When blood or tissue fluid contact with materials after implantation,proteins(e.g.fibrin and collagen)will absorb and deposit on the surface of implants,leading to a provisionally stable matrix with microporous fibrous-liked network structure.It means that the remodeled ECM can provide adhesion sites for recruited DCs and form spatial confinement.DCs,as a kind of cells that are extremely sensitive to mechanical stimuli,theoretically,can response to the mechanical stimuli coming from spatial confinement of remodeled ECM,which may lead to a series of modulations in their cell morphologies and immune functions.Then,the remodeled ECM is a non-negligible mechanical cue.However,to the best of our knowledge,there is a lack of a simple and effective model to establish the relationship between the immune functions of DCs and remodeled ECM.Most studies on the responses of DCs to implanted materials are still based on suspension culture model,which is the normal status of DCs in vitro culture systems.In addition,the processes by which DC exerts immune functions(both endocytosis and antigen presentation)are dynamically physical interaction.It means that the changes of DCs’immune functions are highly correlated with the changes of their biomechanical characteristics caused by remodeled ECM.In this work,we have found that the ECM was remodeled by a large amount of fibrin matrix deposited on the surface of implants in the early stage of the inflammations following implantation.Thus,we used non-toxic salmon fibrin hydrogels with microporous fibrous-liked network structure to mimic the deposited fibrin matrix.Then,human monocyte-derived DCs were cultured on the surface and inside of the fibrin hydrogels to mimic the different spatial confinement states of fibrin matrix.Our results indicated that cell morphologies and cytoskeleton structures of DCs were regulated by the spatial confinement of fibrin hydrogels,resulting in generating mechanical stimuli for DCs.Furthermore,we have found that the biomechanical characteristics and the immune functions of both imDCs and mDC were also modulated.Considering the changes in surface markers,secreted cytokines and biomechanical characteristics of DCs,it indicates that the tendency and magnitude of modulations were highly associated with the spatial confinement of fibrin hydrogels.This model demonstrated that mechanical stimuli deriving from spatial confinement of deposited fibrin matrix is an important factor for regulating the biomechanical characteristics and immune functions of DCs.
基金This work is supported by the National MCF Energy R&D Program of China(Grant Nos.2018YFE0302100 and 2019YFE03010003)the National Natural Science Foundation of China(Grant Nos.12005264,12105322,and 12075285)+3 种基金the National Magnetic Confinement Fusion Science Program of China(Grant No.2022YFE03100003)the Natural Science Foundation of Anhui Province of China(Grant No.2108085QA38)the Chinese Postdoctoral Science Found(Grant No.2021000278)the Presidential Foundation of Hefei institutes of Physical Science(Grant No.YZJJ2021QN12).
文摘Multifaceted asymmetric radiation from the edge(MARFE) movement which can cause density limit disruption is often encountered during high density operation on many tokamaks. Therefore, identifying and predicting MARFE movement is meaningful to mitigate or avoid density limit disruption for the steady-state high-density plasma operation. A machine learning method named random forest(RF) has been used to predict the MARFE movement based on the density ramp-up experiment in the 2022’s first campaign of Experimental Advanced Superconducting Tokamak(EAST). The RF model shows that besides Greenwald fraction which is the ratio of plasma density and Greenwald density limit, dβp/dt,H98and d Wmhd/dt are relatively important parameters for MARFE-movement prediction. Applying the RF model on test discharges, the test results show that the successful alarm rate for MARFE movement causing density limit disruption reaches ~ 85% with a minimum alarm time of ~ 40 ms and mean alarm time of ~ 700 ms. At the same time, the false alarm rate for non-disruptive and non-density-limit disruptive discharges can be kept below 5%. These results provide a reference to the prediction of MARFE movement in high density plasmas, which can help the avoidance or mitigation of density limit disruption in future fusion reactors.
文摘[Objectives]The paper was to establish an evaluation method for the uncertainty of stevioside(including stevioside,rebaudioside A,rebaudioside B,rebaudioside C,rebaudioside F,Dulcoside A,rubusoside and steviolbioside)content determination in fermented milk based on HPLC.[Methods]The mathematical model of stevioside content and the propagation rate of uncertainty were established,and the sources of uncertainty were analyzed.[Results]The uncertainty mainly came from four main aspects,including standard uncertainty u(C)introduced by solution concentration C,standard uncertainty u(V)introduced by sample volume V,standard uncertainty u(m)introduced by sample mass m weighing and standard uncertainty u(f_(rep))introduced by measurement repeatability of stevioside content after sample dissolution and constant volume.The uncertainty estimation table and fishbone chart of stevioside content X determination were established.The relative synthetic standard uncertainty of stevioside content was obtained,and the standard uncertainty was extended to form the measurement result of stevioside content and its uncertainty report.[Conclusions]The evaluation results can be directly applied to the daily practical detection work.
基金sponsored by the Key Program of the National Natural Science Foundation of China(No.81930067)the Natural Science Foundation of China(No.82002316)the Youth Cultivation Project of Army Medical University(China)(No.2020XQN08).
文摘In recent years,researchers have become focused on the relationship between lipids and bone metabolism balance.Moreover,many diseases related to lipid metabolism dis-orders,such as nonalcoholic fatty liver disease,atherosclerosis,obesity,and menopause,are associated with osteoporotic phenotypes.It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass.Furthermore,similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models.Abnormal lipid metabolism(such as increased oxidized lipids and elevated plasma cholesterol)affects bone microenvironment ho-meostasis via cross-organ communication,promoting differentiation of mesenchymal stem cells to adipocytes,and inhibiting commitment towards osteoblasts.Moreover,disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cyto-kines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts.Conclusively,this review addresses the possible link be-tween lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism bal-ance.We also summarize the possible approaches and prospects of intervening lipid meta-bolismforosteoporosistreatment.
基金supported by the National Natural Science Foundation of China(grant numbers 12132006,32371373,31771014,and 82060555).
文摘Distal metastasis is the main cause of clinical treatment failure in patients with colon cancer.It is now known that the invasion and metastasis of cancer cells is precisely regulated by chemical and physical factors in vivo.However,the role of extracellular matrix(ECM)stiffness in colon cancer cell(CCCs)invasion and metastasis remains unclear.Here,bioinformatical analysis suggested that a high expression level of yes associated protein 1(YAP1)was significantly associated with metastasis and poor prognosis in colon cancer patients.We further investigated the effects of polyacrylamide hydrogels with different stiffnesses(3,20,and 38 kPa),which were simulated as ECM,on the mechanophenotype(F-actin cytoskeleton organization,electrophoretic rate,membrane fluidity,and Young's modulus)of CCCs.The results showed that a stiffer ECM could induce the maturation of focal adhesions and formation of stress fibers in CCCs,regulate their mechanophenotypes,and promote cell motility.We also demonstrated that the expression levels of YAP1 and paxillin were positively correlated in patients with colon cancer.YAP1 knockdown reduces paxillin clustering and cell motility and alters the cellular mechanophenotypes of CCCs.This is of great significance for an in-depth understanding of the invasion and metastatic mechanisms of colon cancer and for the optimization of clinical therapy from the perspective of mechanobiology.
基金supported by the Integration Project of NSFC Joint Fund for Regional Innovation and Development(U23A6008)the Key Programme of National Natural Science Foundation of China(81930067)+2 种基金the Youth Program of National Natural Science Foundation of China(82002316)the General Program of Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0176)the China Postdoctoral Science Foundation(2021MD703946).
文摘Osteoarthritis(OA)is a progressive degenerative joint sickness related with mechanics,obesity,ageing,etc.,mainly characterized by cartilage degeneration,subchondral bone damage and synovium inflammation.Coordinated mechanical absorption and conduction of the joint play significant roles in the prevalence and development of OA.Subchondral bone is generally considered a load-burdening tissue where mechanosensitive cells are resident,including osteocytes,osteoblast lineage cells,and osteoclast lineage cells(especially less concerned in mechanical studies).Mechano-signaling imbalances affect complicated cellular events and disorders of subchondral bone homeostasis.This paper will focus on the significance of mechanical force as the pathogenesis,involvement of various mechanical force patterns in mechanosensitive cells,and mechanobiology research of loading devices in vitro and in vivo,which are further discussed.Additionally,various mechanosensing structures(e.g.,transient receptor potential channels,gap junctions,primary cilia,podosome-associated complexes,extracellular vesicles)and mechanotransduction signaling pathways(e.g.,Ca^(2+) signaling,Wnt/β-catenin,RhoA GTPase,focal adhesion kinase,cotranscriptional activators YAP/TAZ)in mechanosensitive bone cells.Finally,we highlight potential targets for improving mechanoprotection in the treatment of OA.These advances furnish an integration of mechanical regulation of subchondral bone homeostasis,as well as OA therapeutic approaches by modulating mechanical homeostasis.
文摘Neurotransmitter gamma-aminobutiric acid （GABA） through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells （NSCs/ NPCs）. The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na＋/K＋/2CF co-transporter NKCC1 driving CF influx and neuron-specific K＋/Cl co-transporter KCC2 driving Cl efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 （DISC1） and brain-derived neurotrophic factor （BDNF） signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and new-born neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance.
基金the National Natural Science Foundation of China(No.21271145)the National Science Foundation of Hubei Province(No.2015CFB537)+1 种基金the Science and Technology Innovation Committee of Shenzhen Municipality(No.JCYJ20170306171321438)the financial support for this investigation.
文摘Lithium-rich layered oxides(LLOs)have been extensively studied as cathode materials for lithium-ion batteries(LIBs)by researchers all over the world in the past decades due to their high specific capacities and high charge-discharge voltages.However,as cathode materials LLOs have disadvantages of significant voltage and capacity decays during the charge-discharge cycling.It was shown in the past that fine-tuning of structures and compositions was critical to the performances of this kind of materials.In this report,LLOs with target composition of Li1.17Mn0.50Ni0.24Co0.09O2 were prepared by carbonate co-precipitation method with different pH values.X-ray powder diffraction(XRD),scanning electron microscopy(SEM),transmission electron microscope(TEM),and electrochemical impedance spectroscopies(EIS)were used to investigate the structures and morphologies of the materials and to understand the improvements of their electrochemical performances.With the pH values increased from 7.5 to 8.5,the Li/Ni ratios in the compositions decreased from 5.17 to 4.64,and the initial Coulombic efficiency,cycling stability and average discharge voltages were gained impressively.Especially,the material synthesized at pH=8.5 delivered a reversible discharge capacity of 263 mAhg−1 during the first cycle,with 79.0%initial Coulombic efficiency,at the rate of 0.1 C and a superior capacity retention of 94%after 100 cycles at the rate of 1 C.Furthermore,this material exhibited an initial average discharge voltage of 3.65 V,with a voltage decay of only 0.09 V after 50 charge-discharge cycles.The improved electrochemical performances by varying the pH values in the synthesis process can be explained by the mitigation of layered-to-spinel phase transformation and the reduction of solid-electrolyte interface(SEI)resistance.We hope this work can shed some light on the alleviation of voltage and capacity decay issues of the LLOs cathode materials.
基金supported by the National Natural Science Foundation of China (NSFC, No. U1904215)the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (TAPP)+3 种基金Natural Science Foundation of Jiangsu Province (No. BK20200044)Program for Young Changjiang Scholars of the Ministry of Education (No. Q2018270)Open Fund of National Joint Engineering Research Center for abrasion control and molding of metal materials (No. HKDNM2019010)Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Increasing active metal sites is a valid approach to improve the catalytic activity of the catalyst. Co^(3+) is the main active metal site of Co-based catalysts. In this research work, through the partial transformation of CoFePBA (CFP) via low-temperature heat treatment, the effective control of the Co^(3+)/Co^(2+) ratio has been achieved. The partial transformation strategy of low-temperature heat treatment can not only maintain the original framework structure of CFP, but also increase more active sites. The characterization results show that the CFP-200 sample obtained via heat treatment at 200 ℃ for 2 h under N2 atmosphere has the highest Co^(3+)/Co^(2+) ratio. As an oxygen evolution reaction electrocatalyst, CFP-200 shows the best electrocatalytic activity among all samples. In 1.0 mol/L KOH electrolyte, the overpotential is 312 mV at a current density of 10 mA/cm2. Therefore, low-temperature heat treatment provides an effective method for preparing low-cost and high-efficiency electrocatalysts.
基金supported by the National Natural Science Foundation of China(Grant Nos.31627804,11772345,and 91539119)the Scientific Instrument Developing Project of the Chinese Academy of Sciences(Grant No.GJJSTU20220002)Frontier Science Key Project of Chinese Science Academy(Grant No.QYZDJ-SSWJSC018).
基金This work was supported by the Canadian Institutes of Health Research(CIHR PJT-153155)ZPF and a Natural Sciences and Engineering Research Council of Canada Discovery Grant(NSERC RGPIN-2016-04574)to HSS.
文摘Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal brain.AD-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators.In this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in vivo.We demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell injury.Single dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 h.Chronic administration reduced the mortality rate and preserved whole-brain morphology following neonatal HI.The in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.
