The calculation of Ecological Footprint （EF） on the basis of Input-Output model （I-O model） was advanced by Bicknell, and modified and improved hy Ferng who corrected the footprint＇s aggregation to each sectors. ...The calculation of Ecological Footprint （EF） on the basis of Input-Output model （I-O model） was advanced by Bicknell, and modified and improved hy Ferng who corrected the footprint＇s aggregation to each sectors. For the lack of sufficient teehnique to deal with the trade between the research areas and the rest of the world, it it necessary to improve this method. And a dynamic analysis of the change of footprint based on I-O model, which could explore the factor impacting the footprint using the ,special advantage of I-O model, ought to be put into practice. After introducing the new method in detail, we calculate and compare the EF and the change of Gansu Province in the northwest of China in 1997 and 2002. The result shows that there was an increase of EF in 2002 caused by final domestic demand. Further; the inerement in EF export was 2.0 × 10^5 ha and 1.6 × 10^6 ha in import. The out-of- region support dropped from 22.6% to 18. 6%. We introduce three factors causing the EF change based on the character of I-O model： the productivity of the resourve which is explained by the change of resource used to obtain one unit output in a sector, the improvement of the economics and the final demand. Finally, we find that the effects of the three factors on the EF change are not identical except the industry sectors and the change of factors in the agriculture and the industry sectors works notably.展开更多
The bicoordination chiral inducement catalysis of (R)-4-thiazolidinecarboxylic acid inthe enantioselective borane reduction of prochiral ketones has been studied. The fact that theabsolute configuration of the main pr...The bicoordination chiral inducement catalysis of (R)-4-thiazolidinecarboxylic acid inthe enantioselective borane reduction of prochiral ketones has been studied. The fact that theabsolute configuration of the main product can be changed by simply using different operationmethods was firstly verified. And the reason of bicoordination chiral inducement was discussed.展开更多
Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells en...Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.展开更多
Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various ne...Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.展开更多
Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells ...Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.展开更多
0 INTRODUCTION.According to the China Earthquake Networks Center,an M6.8 earthquake struck Dingri County,Xizang Autonomous Region,China,on 7 January 2025 at 9:05 a.m.local time.The epicenter is located at 28.5°N,...0 INTRODUCTION.According to the China Earthquake Networks Center,an M6.8 earthquake struck Dingri County,Xizang Autonomous Region,China,on 7 January 2025 at 9:05 a.m.local time.The epicenter is located at 28.5°N,87.45°E,with a depth of~10 km.展开更多
To investigate the wind⁃induced vibration re⁃sponse characteristics of multispan double⁃layer cable photo⁃voltaic(PV)support structures,wind tunnel tests using an aeroelastic model were carried out to obtain the wind⁃...To investigate the wind⁃induced vibration re⁃sponse characteristics of multispan double⁃layer cable photo⁃voltaic(PV)support structures,wind tunnel tests using an aeroelastic model were carried out to obtain the wind⁃induced vibration response data of a three⁃span four⁃row double⁃layer cable PV support system.The wind⁃induced vibration characteristics with different PV module tilt angles,wind speeds,and wind direction angles were analyzed.The results showed that the double⁃layer cable large⁃span flexible PV support can effectively control the wind⁃induced vibration response and prevent the occur⁃rence of flutter under strong wind conditions.The maxi⁃mum value of the wind⁃induced vibration displacement of the flexible PV support system occurs in the windward first row.The upstream module has a significant shading effect on the downstream module,with a maximum effect of 23%.The most unfavorable wind direction angles of the structure are 0°and 180°.The change of the wind direction angle in the range of 0°to 30°has little effect on the wind vi⁃bration response.The change in the tilt angle of the PV modules has a greater impact on the wind vibration in the downwind direction and a smaller impact in the upwind di⁃rection.Special attention should be paid to the structural wind⁃resistant design of such systems in the upwind side span.展开更多
The trade-offbetween strength and ductility remains a persistent obstacle in the development of advanced structural materials.In the present study,a novel dual-heterogeneous structure with a bimodal grain distribution...The trade-offbetween strength and ductility remains a persistent obstacle in the development of advanced structural materials.In the present study,a novel dual-heterogeneous structure with a bimodal grain distribution in both ferrite and austenite phases was fabricated via cold rolling and partial recrystallization annealing on solution-treated 2205 duplex stainless steel(DSS).The processed steel exhibited superior mechanical properties,with the yield strength increasing from 586 MPa to 903 MPa,and the ultimate tensile strength from 796 MPa to 1082 MPa,while maintaining a high total elongation of 35.3%.Based on in-situ electron backscatter diffraction(EBSD)and scanning electron microscope(SEM)analyses,the microstructural deformation behavior and strengthening mechanisms of the dual-heterostructured 2205 DSS were elucidated.The outstanding combination of strength and ductility was ascribed to the synergistic effects of grain refinement,dislocation strengthening,and hetero-deformation induced(HDI)strengthening.Moreover,the high ductility in DSS was attributed to the coactivation of cross-slip systems in ferrite{110}and{112}along with the single-slip systems in austenite{111}.These findings provide a new strategy for the design and development of high-strength and ultra-high-strength DSSs.展开更多
Discrete fracture network(DFN)commonly existing in natural rock masses plays an important role in geological complexity which can influence rock fracturing behaviour during fluid injection.This paper simulated the hyd...Discrete fracture network(DFN)commonly existing in natural rock masses plays an important role in geological complexity which can influence rock fracturing behaviour during fluid injection.This paper simulated the hydraulic fracturing process in lab-scale coal samples with DFNs and the induced seismic activities by the discrete element method(DEM).The effects of DFNs on hydraulic fracturing,induced seismicity and elastic property changes have been concluded.Denser DFNs can comprehensively decrease the peak injection pressure and injection duration.The proportion of strong seismic events increases first and then decreases with increasing DFN density.In addition,the relative modulus of the rock mass is derived innovatively from breakdown pressure,breakdown fracture length and the related initiation time.Increasing DFN densities among large(35–60 degrees)and small(0–30 degrees)fracture dip angles show opposite evolution trends in relative modulus.The transitional point(dip angle)for the opposite trends is also proportionally affected by the friction angle of the rock mass.The modelling results have much practical meaning to infer the density and geometry of pre-existing fractures and the elastic property of rock mass in the field,simply based on the hydraulic fracturing and induced seismicity monitoring data.展开更多
Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic m...Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic membrane(d AM)make it a subject of exploration for its potential impact on the anti-inflammatory response of macrophages.Experimental findings unequivocally demonstrate that d AM promotes anti-inflammatory M2 polarization of macrophage,with its cytokine-rich content posited as a potential mediator.The application of RNA sequencing unveils differential gene expression,implicating the hypoxia inducible factor-1α(HIF-1α)signaling pathway in this intricate interplay.Subsequent investigation further demonstrates that d AM facilitates anti-inflammatory M2 polarization of macrophage through the upregulation of epidermal growth factor(EGF),which,in turn,activates the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway and stabilizes HIF-1α.This cascade results in a noteworthy augmentation of anti-inflammatory gene expression.This study significantly contributes to advancing our comprehension of d AM's immunomodulatory role in tissue repair,thereby suggesting promising therapeutic potential.展开更多
Advanced geological prediction is a crucial means to ensure safety and efficiency in tunnel construction.However,diff erent advanced geological forecasting methods have their own limitations,resulting in poor detectio...Advanced geological prediction is a crucial means to ensure safety and efficiency in tunnel construction.However,diff erent advanced geological forecasting methods have their own limitations,resulting in poor detection accuracy.Using multiple methods to carry out a comprehensive evaluation can eff ectively improve the accuracy of advanced geological prediction results.In this study,geological information is combined with the detection results of geophysical methods,including transient electromagnetic,induced polarization,and tunnel seismic prediction,to establish a comprehensive analysis method of adverse geology.First,the possible main adverse geological problems are determined according to the geological information.Subsequently,various physical parameters of the rock mass in front of the tunnel face can then be derived on the basis of multisource geophysical data.Finally,based on the analysis results of geological information,the multisource data fusion algorithm is used to determine the type,location,and scale of adverse geology.The advanced geological prediction results that can provide eff ective guidance for tunnel construction can then be obtained.展开更多
The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response t...The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response to airborne irritants,this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea,cough,wheezing,and chest tightness.Conventional asthma therapies,such as corticosteroids,long-actingβ-agonists,and antiinflammatory agents,often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively.These limitations have prompted researchers to explore innovative therapeutic strategies,including stem cell-related interventions,offering hope to those afflicted with this incurable disease.In this review,we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
In recent years,train-tail swaying of 160 km/h electric multiple units(EMUs)inside single-line tunnels has been heavily researched,because the issue needs to be solved urgently.In this paper,a co-simulation model of v...In recent years,train-tail swaying of 160 km/h electric multiple units(EMUs)inside single-line tunnels has been heavily researched,because the issue needs to be solved urgently.In this paper,a co-simulation model of vortex-induced vibration(VIV)of the tail car body is established,and the aerodynamics of train-tail swaying is studied.The simulation results were confirmed through a field test of operating EMUs.Furthermore,the influence mechanism of train-tail swaying on the wake flow field is studied in detail through a wind-tunnel experiment and a simulation of a reduced-scaled train model.The results demonstrate that the aerodynamic force frequency(i.e.,vortex-induced frequency)of the train tail increases linearly with train speed.When the train runs at 130 km/h,with a small amplitude of train-tail swaying(within 10 mm),the vortex-induced frequency is 1.7 Hz,which primarily depends on the nose shape of the train tail.After the tail car body nose is extended,the vortex-induced frequency is decreased.As the swaying amplitude of the train tail increases(exceeding 25 mm),the separation point of the high-intensity vortex in the train wake shifts downstream to the nose tip,and the vortex-induced frequency shifts from 1.7 Hz to the nearby car body hunting(i.e.,the primary hunting)frequency of 1.3 Hz,which leads to the frequency-locking phenomenon of VIV,and the resonance intensifies train-tail swaying.For the motor vehicle of the train tail,optimization of the yaw damper to improve its primary hunting stability can effectively alleviate train-tail swaying inside single-line tunnels.Optimization of the tail car body nose shape reduces the amplitude of the vortex-induced force,thereby weakening the aerodynamic effect and solving the problem of train-tail swaying inside the single-line tunnels.展开更多
Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease.The accumulation of amyloid-βpeptides,a key hallmark of Alzheimer's disease,is be...Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease.The accumulation of amyloid-βpeptides,a key hallmark of Alzheimer's disease,is believed to induce neuritic abnormalities,including reduced growth,extension,and abnormal growth cone morphology,all of which contribute to decreased connectivity.However,the precise cellular and molecular mechanisms governing this response remain unknown.In this study,we used an innovative approach to demonstrate the effect of amyloid-βon neurite dynamics in both two-dimensional and three-dimensional cultu re systems,in order to provide more physiologically relevant culture geometry.We utilized various methodologies,including the addition of exogenous amyloid-βpeptides to the culture medium,growth substrate coating,and the utilization of human-induced pluripotent stem cell technology,to investigate the effect of endogenous amyloid-βsecretion on neurite outgrowth,thus paving the way for potential future applications in personalized medicine.Additionally,we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition.We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway,achieved through modulation with Y-27632(a ROCK inhibitor)and Ibuprofen(a Rho A inhibitor),respectively,can restore and even enhance neuronal connectivity in the presence of amyloid-β.In summary,this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition,but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-βpeptides,along with potential intervention points to restore neurite growth.Thereby,we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical,predictive outcomes of drugs and their ability to promote neurite outgrowth,both generally and in a patient-specific manner.展开更多
Photobiomodulation,originally used red and near-infrared lasers,can alter cellular metabolism.It has been demonstrated that the visible spectrum at 451-540 nm does not necessarily increase cell proliferation,near-infr...Photobiomodulation,originally used red and near-infrared lasers,can alter cellular metabolism.It has been demonstrated that the visible spectrum at 451-540 nm does not necessarily increase cell proliferation,near-infrared light promotes adipose stem cell proliferation and affects adipose stem cell migration,which is necessary for the cells homing to the site of injury.In this in vitro study,we explored the potential of adipose-derived stem cells to differentiate into neurons for future translational regenerative treatments in neurodegenerative disorders and brain injuries.We investigated the effects of various biological and chemical inducers on trans-differentiation and evaluated the impact of photobiomodulation using 825 nm near-infrared and 525 nm green laser light at 5 J/cm2.As adipose-derived stem cells can be used in autologous grafting and photobiomodulation has been shown to have biostimulatory effects.Our findings reveal that adipose-derived stem cells can indeed trans-differentiate into neuronal cells when exposed to inducers,with pre-induced cells exhibiting higher rates of proliferation and trans-differentiation compared with the control group.Interestingly,green laser light stimulation led to notable morphological changes indicative of enhanced trans-differentiation,while near-infrared photobiomodulation notably increased the expression of neuronal markers.Through biochemical analysis and enzyme-linked immunosorbent assays,we observed marked improvements in viability,proliferation,membrane permeability,and mitochondrial membrane potential,as well as increased protein levels of neuron-specific enolase and ciliary neurotrophic factor.Overall,our results demonstrate the efficacy of photobiomodulation in enhancing the trans-differentiation ability of adipose-derived stem cells,offering promising prospects for their use in regenerative medicine for neurodegenerative disorders and brain injuries.展开更多
Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patient...Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients.The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain.Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024.After screening,76 articles were included in the analysis from which 178 separate transplant studies were identified.From these,graft survival could be assessed in 52 studies and differentiation in 129 studies.Overall,we found that graft survival ranged from<1% to 500% of cells transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.展开更多
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal...TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.展开更多
The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed patho...The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.展开更多
基金supported by National Natural Science Foundation of China (Grant No.40671076)CAS (Chinese Academy of Sciences) Action Plan for West Development Project (Grant No.KZCX2-XB2-04-04)
文摘The calculation of Ecological Footprint （EF） on the basis of Input-Output model （I-O model） was advanced by Bicknell, and modified and improved hy Ferng who corrected the footprint＇s aggregation to each sectors. For the lack of sufficient teehnique to deal with the trade between the research areas and the rest of the world, it it necessary to improve this method. And a dynamic analysis of the change of footprint based on I-O model, which could explore the factor impacting the footprint using the ,special advantage of I-O model, ought to be put into practice. After introducing the new method in detail, we calculate and compare the EF and the change of Gansu Province in the northwest of China in 1997 and 2002. The result shows that there was an increase of EF in 2002 caused by final domestic demand. Further; the inerement in EF export was 2.0 × 10^5 ha and 1.6 × 10^6 ha in import. The out-of- region support dropped from 22.6% to 18. 6%. We introduce three factors causing the EF change based on the character of I-O model： the productivity of the resourve which is explained by the change of resource used to obtain one unit output in a sector, the improvement of the economics and the final demand. Finally, we find that the effects of the three factors on the EF change are not identical except the industry sectors and the change of factors in the agriculture and the industry sectors works notably.
文摘The bicoordination chiral inducement catalysis of (R)-4-thiazolidinecarboxylic acid inthe enantioselective borane reduction of prochiral ketones has been studied. The fact that theabsolute configuration of the main product can be changed by simply using different operationmethods was firstly verified. And the reason of bicoordination chiral inducement was discussed.
基金supported by the National Natural Science Foundation of China,No.32171356(to YW)Self-Support Research Projects of Shihezi University,No.ZZZC2021105(to WJ)+1 种基金Capital Medical University Natural Science Cultivation Fund,No.PYZ23044(to FQM)Beijing Municipal Natural Science Foundation,No.7244410(to JHD)。
文摘Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells.However,adult tissue–derived mesenchymal stem cells encounter various obstacles,including limited tissue sources,invasive acquisition methods,cellular heterogeneity,purification challenges,cellular senescence,and diminished pluripotency and proliferation over successive passages.In this study,we used induced pluripotent stem cell-derived mesenchymal stem cells,known for their self-renewal capacity,multilineage differentiation potential,and immunomodulatory characteristics.We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury.Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation.Furthermore,the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats.Additionally,our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization.Collectively,our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats,offering promising therapeutic strategies for clinical translation.
基金supported by the National Natural Science Foundation of China,Nos.82471471(to WJ),82471485(to FY)Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation,No.tzjhjw(to WJ)+1 种基金Shaanxi Key Research and Development Plan Project,No.2023-YBSF-353(to XW)the Joint Fund Project of Innovation Research Institute of Xijing Hospital,No.LHJJ24JH13(to ZS)。
文摘Epilepsy is a serious neurological disorder;however,the effectiveness of current medications is often suboptimal.Recently,stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases,igniting interest in its applicability for epilepsy treatment.This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells.Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells,including genetically modified variants.Clinical trials involving patientderived mesenchymal stem cells have shown promising results,with reductions in the frequency of epileptic seizures and improvements in neurological,cognitive,and motor functions reported.Another promising therapeutic strategy involves neural stem cells.These cells can be cultured outside the body and directed to differentiate into specific cell types.The transplant of neural stem cells has the potential to replace lost inhibitory interneurons,providing a novel treatment avenue for epilepsy.Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell.In epilepsy treatment,embryonic stem cells can serve three primary functions:neuron regeneration,the maintenance of cellular homeostasis,and restorative activity.One notable strategy involves differentiating embryonic stem cells intoγ-aminobutyric acidergic neurons for transplantation into lesion sites.This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy.Induced pluripotent stem cells share the same genetic background as the donor,thereby reducing the risk of immune rejection and addressing ethical concerns.However,research on induced pluripotent stem cell therapy remains in the preclinical stage.Despite the promise of stem cell therapies for epilepsy,several limitations must be addressed.Safety concerns persist,including issues such as tumor formation,and the low survival rate of transplanted cells remains a significant challenge.Additionally,the high cost of these treatments may be prohibitive for some patients.In summary,stem cell therapy shows considerable promise in managing epilepsy,but further research is needed to overcome its existing limitations and enhance its clinical applicability.
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX),and 81671189(to RX)。
文摘Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.
基金funded by the National Key R&D Program of China(No.2020YFC150071)partly supported by the Shaanxi Province Geoscience Big Data and Geohazard Prevention Innovation Team(2022)and the Research Funds for the Interdisciplinary Projects,CHU(No.300104240914)。
文摘0 INTRODUCTION.According to the China Earthquake Networks Center,an M6.8 earthquake struck Dingri County,Xizang Autonomous Region,China,on 7 January 2025 at 9:05 a.m.local time.The epicenter is located at 28.5°N,87.45°E,with a depth of~10 km.
基金The National Natural Science Foundation of China(No.52338011).
文摘To investigate the wind⁃induced vibration re⁃sponse characteristics of multispan double⁃layer cable photo⁃voltaic(PV)support structures,wind tunnel tests using an aeroelastic model were carried out to obtain the wind⁃induced vibration response data of a three⁃span four⁃row double⁃layer cable PV support system.The wind⁃induced vibration characteristics with different PV module tilt angles,wind speeds,and wind direction angles were analyzed.The results showed that the double⁃layer cable large⁃span flexible PV support can effectively control the wind⁃induced vibration response and prevent the occur⁃rence of flutter under strong wind conditions.The maxi⁃mum value of the wind⁃induced vibration displacement of the flexible PV support system occurs in the windward first row.The upstream module has a significant shading effect on the downstream module,with a maximum effect of 23%.The most unfavorable wind direction angles of the structure are 0°and 180°.The change of the wind direction angle in the range of 0°to 30°has little effect on the wind vi⁃bration response.The change in the tilt angle of the PV modules has a greater impact on the wind vibration in the downwind direction and a smaller impact in the upwind di⁃rection.Special attention should be paid to the structural wind⁃resistant design of such systems in the upwind side span.
基金supported by the National Natural Science Foundation of China(Nos.U1960115 and U21A20116)the Fundamental Research Funds for the Central Universities(No.N232405-10)Special thanks are due to the instrumental and data analysis from Analytical and Testing Center,Northeastern University.
文摘The trade-offbetween strength and ductility remains a persistent obstacle in the development of advanced structural materials.In the present study,a novel dual-heterogeneous structure with a bimodal grain distribution in both ferrite and austenite phases was fabricated via cold rolling and partial recrystallization annealing on solution-treated 2205 duplex stainless steel(DSS).The processed steel exhibited superior mechanical properties,with the yield strength increasing from 586 MPa to 903 MPa,and the ultimate tensile strength from 796 MPa to 1082 MPa,while maintaining a high total elongation of 35.3%.Based on in-situ electron backscatter diffraction(EBSD)and scanning electron microscope(SEM)analyses,the microstructural deformation behavior and strengthening mechanisms of the dual-heterostructured 2205 DSS were elucidated.The outstanding combination of strength and ductility was ascribed to the synergistic effects of grain refinement,dislocation strengthening,and hetero-deformation induced(HDI)strengthening.Moreover,the high ductility in DSS was attributed to the coactivation of cross-slip systems in ferrite{110}and{112}along with the single-slip systems in austenite{111}.These findings provide a new strategy for the design and development of high-strength and ultra-high-strength DSSs.
基金Australian Research Council Linkage Program(LP200301404)for sponsoring this researchthe financial support provided by the State Key Laboratory of Geohazard Prevention and Geoenvironment Protection(Chengdu University of Technology,SKLGP2021K002)National Natural Science Foundation of China(52374101,32111530138).
文摘Discrete fracture network(DFN)commonly existing in natural rock masses plays an important role in geological complexity which can influence rock fracturing behaviour during fluid injection.This paper simulated the hydraulic fracturing process in lab-scale coal samples with DFNs and the induced seismic activities by the discrete element method(DEM).The effects of DFNs on hydraulic fracturing,induced seismicity and elastic property changes have been concluded.Denser DFNs can comprehensively decrease the peak injection pressure and injection duration.The proportion of strong seismic events increases first and then decreases with increasing DFN density.In addition,the relative modulus of the rock mass is derived innovatively from breakdown pressure,breakdown fracture length and the related initiation time.Increasing DFN densities among large(35–60 degrees)and small(0–30 degrees)fracture dip angles show opposite evolution trends in relative modulus.The transitional point(dip angle)for the opposite trends is also proportionally affected by the friction angle of the rock mass.The modelling results have much practical meaning to infer the density and geometry of pre-existing fractures and the elastic property of rock mass in the field,simply based on the hydraulic fracturing and induced seismicity monitoring data.
基金supported by the National Natural Science Foundation of China(No.82302772)Guizhou Basic Research Project(No.ZK[2023]General 201)partially supported by Wuhan Kangchuang Biotechnology Co.,Ltd。
文摘Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic membrane(d AM)make it a subject of exploration for its potential impact on the anti-inflammatory response of macrophages.Experimental findings unequivocally demonstrate that d AM promotes anti-inflammatory M2 polarization of macrophage,with its cytokine-rich content posited as a potential mediator.The application of RNA sequencing unveils differential gene expression,implicating the hypoxia inducible factor-1α(HIF-1α)signaling pathway in this intricate interplay.Subsequent investigation further demonstrates that d AM facilitates anti-inflammatory M2 polarization of macrophage through the upregulation of epidermal growth factor(EGF),which,in turn,activates the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway and stabilizes HIF-1α.This cascade results in a noteworthy augmentation of anti-inflammatory gene expression.This study significantly contributes to advancing our comprehension of d AM's immunomodulatory role in tissue repair,thereby suggesting promising therapeutic potential.
基金National Natural Science Foundation of China(grant numbers 42293351,41877239,51422904 and 51379112).
文摘Advanced geological prediction is a crucial means to ensure safety and efficiency in tunnel construction.However,diff erent advanced geological forecasting methods have their own limitations,resulting in poor detection accuracy.Using multiple methods to carry out a comprehensive evaluation can eff ectively improve the accuracy of advanced geological prediction results.In this study,geological information is combined with the detection results of geophysical methods,including transient electromagnetic,induced polarization,and tunnel seismic prediction,to establish a comprehensive analysis method of adverse geology.First,the possible main adverse geological problems are determined according to the geological information.Subsequently,various physical parameters of the rock mass in front of the tunnel face can then be derived on the basis of multisource geophysical data.Finally,based on the analysis results of geological information,the multisource data fusion algorithm is used to determine the type,location,and scale of adverse geology.The advanced geological prediction results that can provide eff ective guidance for tunnel construction can then be obtained.
基金the Joint Innovation Project Funds of Huaqiao University,No.2022YX001.
文摘The global incidence of asthma,a leading respiratory disorder affecting more than 235 million people,has dramatically increased in recent years.Characterized by chronic airway inflammation and an imbalanced response to airborne irritants,this chronic condition is associated with elevated levels of inflammatory factors and symptoms such as dyspnea,cough,wheezing,and chest tightness.Conventional asthma therapies,such as corticosteroids,long-actingβ-agonists,and antiinflammatory agents,often evoke diverse adverse reactions and fail to reduce symptoms and hospitalization rates over the long term effectively.These limitations have prompted researchers to explore innovative therapeutic strategies,including stem cell-related interventions,offering hope to those afflicted with this incurable disease.In this review,we describe the characteristics of stem cells and critically assess the potential and challenges of stem cell-based therapies to improve disease management and treatment outcomes for asthma and other diseases.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金supported by the National Natural Science Foundation of China(Nos.52372403 and U2268211)the Natural Science Foundation of Sichuan Province(No.2022NSFSC0034),China+1 种基金the National Railway Group Science and Technology Program(No.2023J071)the Traction Power State Key Laboratory of the Independent Research and Development Projects(No.2022TPL-T02),China.
文摘In recent years,train-tail swaying of 160 km/h electric multiple units(EMUs)inside single-line tunnels has been heavily researched,because the issue needs to be solved urgently.In this paper,a co-simulation model of vortex-induced vibration(VIV)of the tail car body is established,and the aerodynamics of train-tail swaying is studied.The simulation results were confirmed through a field test of operating EMUs.Furthermore,the influence mechanism of train-tail swaying on the wake flow field is studied in detail through a wind-tunnel experiment and a simulation of a reduced-scaled train model.The results demonstrate that the aerodynamic force frequency(i.e.,vortex-induced frequency)of the train tail increases linearly with train speed.When the train runs at 130 km/h,with a small amplitude of train-tail swaying(within 10 mm),the vortex-induced frequency is 1.7 Hz,which primarily depends on the nose shape of the train tail.After the tail car body nose is extended,the vortex-induced frequency is decreased.As the swaying amplitude of the train tail increases(exceeding 25 mm),the separation point of the high-intensity vortex in the train wake shifts downstream to the nose tip,and the vortex-induced frequency shifts from 1.7 Hz to the nearby car body hunting(i.e.,the primary hunting)frequency of 1.3 Hz,which leads to the frequency-locking phenomenon of VIV,and the resonance intensifies train-tail swaying.For the motor vehicle of the train tail,optimization of the yaw damper to improve its primary hunting stability can effectively alleviate train-tail swaying inside single-line tunnels.Optimization of the tail car body nose shape reduces the amplitude of the vortex-induced force,thereby weakening the aerodynamic effect and solving the problem of train-tail swaying inside the single-line tunnels.
基金supported by a BBSRC CASE training studentship,No.BB/K011413/1(to KG)。
文摘Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease.The accumulation of amyloid-βpeptides,a key hallmark of Alzheimer's disease,is believed to induce neuritic abnormalities,including reduced growth,extension,and abnormal growth cone morphology,all of which contribute to decreased connectivity.However,the precise cellular and molecular mechanisms governing this response remain unknown.In this study,we used an innovative approach to demonstrate the effect of amyloid-βon neurite dynamics in both two-dimensional and three-dimensional cultu re systems,in order to provide more physiologically relevant culture geometry.We utilized various methodologies,including the addition of exogenous amyloid-βpeptides to the culture medium,growth substrate coating,and the utilization of human-induced pluripotent stem cell technology,to investigate the effect of endogenous amyloid-βsecretion on neurite outgrowth,thus paving the way for potential future applications in personalized medicine.Additionally,we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition.We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway,achieved through modulation with Y-27632(a ROCK inhibitor)and Ibuprofen(a Rho A inhibitor),respectively,can restore and even enhance neuronal connectivity in the presence of amyloid-β.In summary,this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition,but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-βpeptides,along with potential intervention points to restore neurite growth.Thereby,we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical,predictive outcomes of drugs and their ability to promote neurite outgrowth,both generally and in a patient-specific manner.
基金supported by the National Research Foundation(NRF)S&F-Scarce Skills Postdoctoral Fellowship,No.120752(to AC)the Global Excellence and Stature,Fourth Industrial Revolution(GES 4.0)Postgraduate Scholarship(to MJR)the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa(SARChI/NRF-DST),No.146290(to DDS and HA).
文摘Photobiomodulation,originally used red and near-infrared lasers,can alter cellular metabolism.It has been demonstrated that the visible spectrum at 451-540 nm does not necessarily increase cell proliferation,near-infrared light promotes adipose stem cell proliferation and affects adipose stem cell migration,which is necessary for the cells homing to the site of injury.In this in vitro study,we explored the potential of adipose-derived stem cells to differentiate into neurons for future translational regenerative treatments in neurodegenerative disorders and brain injuries.We investigated the effects of various biological and chemical inducers on trans-differentiation and evaluated the impact of photobiomodulation using 825 nm near-infrared and 525 nm green laser light at 5 J/cm2.As adipose-derived stem cells can be used in autologous grafting and photobiomodulation has been shown to have biostimulatory effects.Our findings reveal that adipose-derived stem cells can indeed trans-differentiate into neuronal cells when exposed to inducers,with pre-induced cells exhibiting higher rates of proliferation and trans-differentiation compared with the control group.Interestingly,green laser light stimulation led to notable morphological changes indicative of enhanced trans-differentiation,while near-infrared photobiomodulation notably increased the expression of neuronal markers.Through biochemical analysis and enzyme-linked immunosorbent assays,we observed marked improvements in viability,proliferation,membrane permeability,and mitochondrial membrane potential,as well as increased protein levels of neuron-specific enolase and ciliary neurotrophic factor.Overall,our results demonstrate the efficacy of photobiomodulation in enhancing the trans-differentiation ability of adipose-derived stem cells,offering promising prospects for their use in regenerative medicine for neurodegenerative disorders and brain injuries.
基金supported by research grants from the Michael J Fox Foundation for Parkinson’s Research(grant numbers:17244 and 023410)Science Foundation Ireland(Grant Numbers:19/FFP/6554)(to ED)。
文摘Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source.Unlike current therapeutic options for patients,this approach has the potential to provide longterm stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients.The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain.Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies,the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease.A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024.After screening,76 articles were included in the analysis from which 178 separate transplant studies were identified.From these,graft survival could be assessed in 52 studies and differentiation in 129 studies.Overall,we found that graft survival ranged from<1% to 500% of cells transplanted,with a median of 51%of transplanted cells surviving in the brain;while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%.This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.
基金supported by the Koeln Fortune Program/Faculty of Medicine,University of Cologne,the Alzheimer Forschung Initiative e.V.(grant#22039,to HZ)open-access funding from the DFG/GRC issued to the University of CologneAlzheimer Forschung Initiative e.V.for Open Access Publishing(a publication grant#P2401,to MAAK)。
文摘TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon.TAU is missorted and aggregated in an array of diseases known as tauopathies.Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications,changes of which affect microtubule stability and dynamics,microtubule interaction with other proteins and cellular structures,and mediate recruitment of microtubule-severing enzymes.As impairment of microtubule dynamics causes neuronal dysfunction,we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics.We therefore aimed to study the effects of a disease-causing mutation of TAU(P301L)on the levels and localization of microtubule post-translational modifications indicative of microtubule stability and dynamics,to assess whether P301L-TAU causes stability-changing modifications to microtubules.To investigate TAU localization,phosphorylation,and effects on tubulin post-translational modifications,we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons(i Neurons)and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU(p R5 mice).Human neurons expressing the longest TAU isoform(2N4R)with the P301L mutation showed increased TAU phosphorylation at the AT8,but not the p-Ser-262 epitope,and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons.P301L-TAU showed pronounced somatodendritic presence,but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU.P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation,but reduced acetylation,of microtubules compared with non-transgenic littermates.In sum,P301L-TAU results in changes in microtubule PTMs,suggestive of impairment of microtubule stability.This is accompanied by missorting and aggregation of TAU in mice but not in i Neurons.Microtubule PTMs/impairment may be of key importance in tauopathies.
基金supported by Singapore National Medical Research Council(NMRC)grants,including CS-IRG,HLCA2022(to ZDZ),STaR,OF LCG 000207(to EKT)a Clinical Translational Research Programme in Parkinson's DiseaseDuke-Duke-NUS collaboration pilot grant(to ZDZ)。
文摘The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.
