This paper describes procedure for estimation of travel time on signalized arterial roads based on multiple data sources with application of dimensionality reduction. Travel time estimation approach incorporates forec...This paper describes procedure for estimation of travel time on signalized arterial roads based on multiple data sources with application of dimensionality reduction. Travel time estimation approach incorporates forecast of transportation nodes impendence and travel time on network links. Forecasting period is two hours and the estimation is based on historical data and real time data on traffic conditions. Travel time estimation combines multivariate regression, principal component analysis, KNN （k-nearest neighbours）, cross validation and EWMA （exponentially weighted moving average） methods. When comparing estimation methodologies, relevantly better results were achieved by KNN method than with EWMA method. This is true for every time interval considered except for evening time interval when signalized arterial roads were uncongested.展开更多
This study aims to divide traffic into meaningful clusters （regimes） and to investigate their impact on accident likelihood and accident severity. Furthermore, the likelihood of pow- ered-two-wheelers （PTWs） invol...This study aims to divide traffic into meaningful clusters （regimes） and to investigate their impact on accident likelihood and accident severity. Furthermore, the likelihood of pow- ered-two-wheelers （PTWs） involvement in an accident is examined. To achieve the aims of the study, traffic and accident data during the period 2006-2011 from two major arterials in Athens were collected and processed. Firstly, a finite mixture cluster analysis was imple- mented to classify traffic into clusters. Afterwards, discriminant analysis was carried out in order to correctly assign new cases to the existing regimes by using a training and a testing set. Lastly, Bayesian logistic regression models were developed to investigate the impact of traffic regimes on accident likelihood and severity. The findings of this study suggest that urban traffic can be divided into different regimes by using average traffic occupancy and its standard deviation, measured by nearby upstream and downstream loop detectors. The results revealed potential hazardous traffic conditions, which are discussed in the paper. In general, high occupancy values increase accident likelihood, but tend to lead slight acci- dents, while PTWs are more likely to be involved in an accident, when traffic occupancy is high. Transitions from high to low occupancy also increase accident likelihood.展开更多
平均动脉压(mean arterial pressure,MAP)和脉压是反映脑灌注的两项指标,其在急性缺血性脑卒中后能否指导降压治疗策略的选择尚不明确。本研究基于中国急性缺血性脑卒中降压试验(the China antihypertensive trial in acute ischemic st...平均动脉压(mean arterial pressure,MAP)和脉压是反映脑灌注的两项指标,其在急性缺血性脑卒中后能否指导降压治疗策略的选择尚不明确。本研究基于中国急性缺血性脑卒中降压试验(the China antihypertensive trial in acute ischemic stroke,CATIS),根据MAP和脉压水平进行分层,探讨早期降压干预对缺血性脑卒中后不良临床结局的影响。方法:该试验将4 071例收缩压升高的急性缺血性脑卒中患者随机分配至降压治疗组(目标是在随机化后24h内收缩压降低10%~25%,7 d内血压将至<140/90 mm Hg,并在住院期间维持该水平,1 mm Hg=0.133 k Pa)或住院期间停止降压治疗的对照组。展开更多
Background There is still limited data on predictive value of coronary computed tomography angiography(CCTA)–derived fractional flow reserve(CT-FFR) for long term outcomes. We examined the long-term prognostic value ...Background There is still limited data on predictive value of coronary computed tomography angiography(CCTA)–derived fractional flow reserve(CT-FFR) for long term outcomes. We examined the long-term prognostic value of CT-FFR combined with CCTA–defined atherosclerotic extent in diabetic patients with coronary artery disease(CAD).Methods A retrospective pooled analysis of individual patient data was performed. Deep-learning-based vessel-specific CTFFR was calculated. All patients enrolled were followed-up for at least 5 years. Predictive abilities for major adverse cardiac events(MACE) were compared among three models(model 1), constructed using clinical variables;model 2, model 1+CCTA–derived atherosclerotic extent(Leiden risk score);and model 3, model 2+CT-FFR.Results A total of 480 diabetic patients [median age, 61(55–66) years;52.9% men] were included. During a median follow-up time of 2197(2126–2355) days, 55 patients(11.5%) experienced MACE. In multivariate-adjusted Cox models, Leiden risk score(HR: 1.06;95% CI: 1.01–1.11;P = 0.013) and CT-FFR ≤ 0.80(HR: 6.54;95% CI: 3.18–13.45;P < 0.001) were the independent predictors. The discriminant ability was higher in model 2 than in model 1(C-index, 0.75 vs. 0.63;P < 0.001) and was further promoted by adding CT-FFR to model 3(C-index, 0.81 vs. 0.75;P = 0.002). Net reclassification improvement(NRI) was 0.19(P = 0.009) for model 2 beyond model 1. Of note, adding CT-FFR to model 3 also exhibited significantly improved reclassification compared with model 2(NRI = 0.14;P = 0.011).Conclusion In diabetic patients with CAD, CT-FFR provides robust and incremental prognostic information for predicting longterm outcomes. The combined model exhibits improved prediction abilities, which is beneficial for risk stratification.展开更多
Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms...Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.展开更多
Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms o...Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.展开更多
Background:Baicalin(BC)and geniposide(GD)are effective components of natural remedies,and studies have shown that they protect against cerebral ischemic stroke(CIS).Transient receptor potential vanilloid 4(TRPV4)is a ...Background:Baicalin(BC)and geniposide(GD)are effective components of natural remedies,and studies have shown that they protect against cerebral ischemic stroke(CIS).Transient receptor potential vanilloid 4(TRPV4)is a calcium-permeable channel that plays important roles in vascular function and vasodilation.However,no studies are available on the effect of BC/GD on the TRPV4 channel and rat cerebral basilar artery(CBA).This study examined the effect of the combination of BC/GD(7:3)on cerebral vascular function after CIS.Methods:We used western blotting to determine TRPV4 protein levels and live cell fluorescence Ca 2+imaging and patch clamp to determine how BC/GD activates TRPV4 channels.Isolated vessel experiments were used to observe the dilatory effects of BC/GD on CBA under different conditions.Laser Doppler imaging was used to measure cerebral blood flow in rats.Triphenyl tetrazolium chloride and Nissl stainings were used to determine the infarct area in the rat brain and neuronal damage,respectively.Results:BC/GD significantly boosted TRPV4 protein levels in vascular smooth muscle cells(VSMCs)during oxygen-glucose deprivation and increased[Ca 2+]i in TRPV4-HEK 293 cells and VSMCs.This effect was not observed in vector-HEK 293 cells.In patch clamp experiments,BC/GD increased Ca 2+currents in TRPV4-HEK 293 cells,whereas no significant changes were observed in vector-HEK 293 cells.BC/GD dilated CBA contractions induced by U46619 and KCl,with a concentration-dependent increase of the dilatory effect.In the middle cerebral artery occlusion model,cerebral blood flow in the ischemic side significantly decreased,whereas BC/GD intervention significantly increased cerebral blood perfusion in the ischemic side,reduced the infarct area,and improved neurological function scores and neuronal damage.Conclusion:BC/GD activates the TRPV4 channel,leading to Ca ^(2+) influx,which in turn activates the intermediate conductance calcium-activated potassium channels channel to regulate vasodilation in vascular smooth muscle.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is a major type of liver cancer worldwide.In advanced stages,portal vein tumor thrombosis(PVTT)and jaundice are common,whereas obstructive jaundice(OJ)is relatively rare.Both co...BACKGROUND Hepatocellular carcinoma(HCC)is a major type of liver cancer worldwide.In advanced stages,portal vein tumor thrombosis(PVTT)and jaundice are common,whereas obstructive jaundice(OJ)is relatively rare.Both conditions markedly reduce survival and increase therapeutic complexity.Recently,hepatic artery infusion chemotherapy(HAIC)in combination with targeted immunotherapy has shown promise for advanced HCC.CASE SUMMARY We report a 47-year-old male with advanced HCC complicated by PVTT and OJ,who was admitted with marked jaundice of the skin and sclera.Imaging revealed a large hepatic mass(14.5 cm×11.3 cm)in the right lobe with associated portal vein tumor thrombus.The tertiary bile duct was only mildly dilated,making percutaneous transhepatic cholangiography drainage infeasible.The patient underwent reduced-dose HAIC,which resulted in significant tumor shrinkage and marked reduction in serum bilirubin.This improvement enabled sequential treatment with lenvatinib and camrelizumab.After six cycles,both liver function and alphafetoprotein levels improved.The patient achieved a progression-free survival of 20 months and an overall survival of 29 months.CONCLUSION HAIC can treat high-bilirubin HCC with PVTT and OJ,allowing for subsequent targeted immunotherapy.展开更多
White matter injury is a key factor impacting stroke recovery.Physical exercise can promote white matter repair.Immune cells,especially regulatory T(Treg)cells,contribute to strengthening white matter integrity,yet li...White matter injury is a key factor impacting stroke recovery.Physical exercise can promote white matter repair.Immune cells,especially regulatory T(Treg)cells,contribute to strengthening white matter integrity,yet little is known about the underlying mechanism.To examine this,we established a transient middle cerebral artery occlusion male mouse model.We found that physical exercise elevated brain Treg cells,thereby enhancing neurological recovery,reducing neuroinflammation,promoting myelin debris clearance,and accelerating white matter repair.Depletion of Treg cells caused a decrease in these positive effects of physical exercise.Mechanistically,the rise in osteopontin triggered by physical exercise is dampened when Treg cells are depleted.In addition,Treg-conditioned medium reduced oxygen-glucose deprivation/re-oxygenation-induced microglial inflammation and enhanced phagocytosis,which could be blocked by osteopontin antibodies.Importantly,although Treg infusion could mimic the protective effects of physical exercise,osteopontin blockade partially countered the effects of physical exercise and Treg cells.Finally,our sequencing data revealed a marked upregulation of C-X-C motif chemokine ligand 12(CXCL12)mRNA expression subsequent to physical exercise,which was confirmed at the protein level.Stimulation of Treg cells with stroke brain lysates increased C-X-C motif chemokine receptor 4(CXCR4)expression,indicating a potential role for the CXCL12-CXCR4 axis in recruiting Treg cells.These findings suggest that physical exercise promotes white matter repair after ischemic stroke by Treg cells.展开更多
Background In patients with coronary artery disease,age is of known significance in predicting outcomes.Data on clinical outcomes in patients≥85 years undergoing percutaneous coronary intervention(PCI)remain scarce.T...Background In patients with coronary artery disease,age is of known significance in predicting outcomes.Data on clinical outcomes in patients≥85 years undergoing percutaneous coronary intervention(PCI)remain scarce.The study aim was to determine clinical characteristics,risk of adverse cardiovascular events,and mortality in patients aged≥85 years compared to those aged<85 undergoing PCI.Methods In this retrospective study,data were obtained from the nationwide Netherlands Heart Registration on patients undergoing PCI between January 1st,2017 and January 1st,2021.The primary endpoint was all-cause mortality at long-term followup.Results A total of 155,683 patients underwent PCI,of which 100,209(64.4%)acute coronary syndrome cases.Compared to patients aged<85 years,patients aged≥85 were more often female and showed a higher number of cardiovascular comorbidities,including impaired left ventricle ejection fraction and reduced kidney function.Mortality at short-term and long-term follow-up were significantly higher in those aged≥85(P<0.001).Patients aged≥85 were more likely to have a myocardial infarction within 30 days following the index intervention(0.9%vs.0.7%;P=0.024),though they less often underwent revascularization at longterm follow-up compared to patients aged<85(P<0.001).Conclusions The elderly(≥85 years)patient requiring PCI carries an extensive cardiovascular risk profile,translating in significant risk of recurrent cardiovascular events and increased mortality rate.Clinicians should carefully weigh perceived risks and potential benefits in the individual patient,considering the patients’age,cardiovascular risk profile,and associated risk of morbidity and mortality.展开更多
BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such a...BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such as factor V Leiden(FVL)mutation.CASE SUMMARY A kidney transplant recipient with FVL mutation developed an acute transplant renal artery thrombosis.The immediate post-operative Doppler ultrasonography revealed thrombosis of the main and inferior polar renal arteries.Emergent thrombectomy and separate arterial re-anastomoses were performed after cold perfusion with heparinized saline and vasodilator solution.Reperfusion was successful with immediate urine output and gradual improvement in renal function.The patient was discharged on direct oral anticoagulation therapy.CONCLUSION Early detection and surgical intervention can preserve graft function in posttransplant renal artery thrombosis even in patients at high risk.展开更多
Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after...Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.展开更多
AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in vario...AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.展开更多
Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Isc...Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).展开更多
Vascular cognitive impairment and dementia is a debilitating neurological disorder caused by chronic cerebral hypoperfusion,for which no effective causative treatments are currently available.Intermittent hypoxia has ...Vascular cognitive impairment and dementia is a debilitating neurological disorder caused by chronic cerebral hypoperfusion,for which no effective causative treatments are currently available.Intermittent hypoxia has been shown to enhance cerebral blood flow in mice,but its efficacy in a model of vascular cognitive impairment and dementia remains unclear.In this study,we established a mouse model of vascular cognitive impairment and dementia by bilateral carotid artery stenosis.Intermittent hypoxia was induced before and after this stenosis.We found that intermittent hypoxia increased cerebral blood flow,oxygen saturation,and microcirculation in the prefrontal cortex and hippocampus in the model mice,without causing neurovascular damage.Additionally,intermittent hypoxia significantly improved cognitive function in the mouse model of vascular cognitive impairment and dementia,with perconditioning showing greater efficacy than preconditioning.Improvements in cerebral microcirculation and blood flow were positively correlated with cognitive recovery.Even in a mouse model of vascular cognitive impairment and dementia with comorbidities induced by a high-fat,high-fructose diet,intermittent hypoxic perconditioning demonstrated protective effects on cognitive function.Proteomic analysis indicated that mitochondrial protection is a key mechanism,particularly through upregulating NDUFB8 expression and increasing the activity of mitochondrial complex I.These findings suggest that intermittent hypoxia is a potential non-invasive strategy for the prevention and treatment of vascular cognitive impairment and dementia.展开更多
Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesio...Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.展开更多
Purpose–This study aims to make full use of the advantages of connected and autonomous vehicles(CAVs)and dedicated CAV lanes to ensure all CAVs can pass intersections without stopping.Design/methodology/approach–The...Purpose–This study aims to make full use of the advantages of connected and autonomous vehicles(CAVs)and dedicated CAV lanes to ensure all CAVs can pass intersections without stopping.Design/methodology/approach–The authors developed a signal coordination model for arteries with dedicated CAV lanes by using mixed integer linear programming.CAV non-stop constraints are proposed to adapt to the characteristics of CAVs.As it is a continuous problem,various situations that CAVs arrive at intersections are analyzed.The rules are discovered to simplify the problem by discretization method.Findings–A case study is conducted via SUMO traffic simulation program.The results show that the efficiency of CAVs can be improved significantly both in high-volume scenario and medium-volume scenario with the plan optimized by the model proposed in this paper.At the same time,the progression efficiency of regular vehicles is not affected significantly.It is indicated that full-scale benefits of dedicated CAV lanes can only be achieved with signal coordination plans considering CAV characteristics.Originality/value–To the best of the authors’knowledge,this is the first research that develops a signal coordination model for arteries with dedicated CAV lanes.展开更多
Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem ce...Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.展开更多
In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause o...In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause of life-threating hemorrhage and the different causes of uterine pseudoaneurysms.Uterine artery pseudoaneurysm is a complication of both surgical gynecological and nontraumatic procedures.Massive hemorrhage is the consequence of the rupture of the pseudoaneurysm.Uterine artery pseudoaneurysm can develop after obstetric or gynecological procedures,being the most frequent after cesarean or vaginal deliveries,curettage and even during pregnancy.However,there are several cases described unrelated to pregnancy,such as after conization,hysteroscopic surgery or laparoscopic myomectomy.Hemorrhage is the clinical manifestation and it can be life-threatening so suspicion of this vascular lesion is essential for early diagnosis and treatment.However,there are other uterine vascular anomalies that may be the cause of severe hemorrhage,which must be taken into account in the differential diagnosis.Computed tomography angiography and embolization is supposed to be the first therapeutic option in most of them.展开更多
文摘This paper describes procedure for estimation of travel time on signalized arterial roads based on multiple data sources with application of dimensionality reduction. Travel time estimation approach incorporates forecast of transportation nodes impendence and travel time on network links. Forecasting period is two hours and the estimation is based on historical data and real time data on traffic conditions. Travel time estimation combines multivariate regression, principal component analysis, KNN （k-nearest neighbours）, cross validation and EWMA （exponentially weighted moving average） methods. When comparing estimation methodologies, relevantly better results were achieved by KNN method than with EWMA method. This is true for every time interval considered except for evening time interval when signalized arterial roads were uncongested.
基金supported by the special fund for research grants of NTUA for PhD studies
文摘This study aims to divide traffic into meaningful clusters （regimes） and to investigate their impact on accident likelihood and accident severity. Furthermore, the likelihood of pow- ered-two-wheelers （PTWs） involvement in an accident is examined. To achieve the aims of the study, traffic and accident data during the period 2006-2011 from two major arterials in Athens were collected and processed. Firstly, a finite mixture cluster analysis was imple- mented to classify traffic into clusters. Afterwards, discriminant analysis was carried out in order to correctly assign new cases to the existing regimes by using a training and a testing set. Lastly, Bayesian logistic regression models were developed to investigate the impact of traffic regimes on accident likelihood and severity. The findings of this study suggest that urban traffic can be divided into different regimes by using average traffic occupancy and its standard deviation, measured by nearby upstream and downstream loop detectors. The results revealed potential hazardous traffic conditions, which are discussed in the paper. In general, high occupancy values increase accident likelihood, but tend to lead slight acci- dents, while PTWs are more likely to be involved in an accident, when traffic occupancy is high. Transitions from high to low occupancy also increase accident likelihood.
文摘平均动脉压(mean arterial pressure,MAP)和脉压是反映脑灌注的两项指标,其在急性缺血性脑卒中后能否指导降压治疗策略的选择尚不明确。本研究基于中国急性缺血性脑卒中降压试验(the China antihypertensive trial in acute ischemic stroke,CATIS),根据MAP和脉压水平进行分层,探讨早期降压干预对缺血性脑卒中后不良临床结局的影响。方法:该试验将4 071例收缩压升高的急性缺血性脑卒中患者随机分配至降压治疗组(目标是在随机化后24h内收缩压降低10%~25%,7 d内血压将至<140/90 mm Hg,并在住院期间维持该水平,1 mm Hg=0.133 k Pa)或住院期间停止降压治疗的对照组。
文摘Background There is still limited data on predictive value of coronary computed tomography angiography(CCTA)–derived fractional flow reserve(CT-FFR) for long term outcomes. We examined the long-term prognostic value of CT-FFR combined with CCTA–defined atherosclerotic extent in diabetic patients with coronary artery disease(CAD).Methods A retrospective pooled analysis of individual patient data was performed. Deep-learning-based vessel-specific CTFFR was calculated. All patients enrolled were followed-up for at least 5 years. Predictive abilities for major adverse cardiac events(MACE) were compared among three models(model 1), constructed using clinical variables;model 2, model 1+CCTA–derived atherosclerotic extent(Leiden risk score);and model 3, model 2+CT-FFR.Results A total of 480 diabetic patients [median age, 61(55–66) years;52.9% men] were included. During a median follow-up time of 2197(2126–2355) days, 55 patients(11.5%) experienced MACE. In multivariate-adjusted Cox models, Leiden risk score(HR: 1.06;95% CI: 1.01–1.11;P = 0.013) and CT-FFR ≤ 0.80(HR: 6.54;95% CI: 3.18–13.45;P < 0.001) were the independent predictors. The discriminant ability was higher in model 2 than in model 1(C-index, 0.75 vs. 0.63;P < 0.001) and was further promoted by adding CT-FFR to model 3(C-index, 0.81 vs. 0.75;P = 0.002). Net reclassification improvement(NRI) was 0.19(P = 0.009) for model 2 beyond model 1. Of note, adding CT-FFR to model 3 also exhibited significantly improved reclassification compared with model 2(NRI = 0.14;P = 0.011).Conclusion In diabetic patients with CAD, CT-FFR provides robust and incremental prognostic information for predicting longterm outcomes. The combined model exhibits improved prediction abilities, which is beneficial for risk stratification.
文摘Peripheral artery disease(PAD)remains a significant global health issue,with current treatments primarily focused on relieving symptoms and addressingmacrovascular issues.However,critical immunoinflammatory mechanisms are often overlooked.Recent evidence suggests that monocyte phenotypic plasticity plays a central role in PAD development,affecting atherogenesis,plaque progression,ischemia-reperfusion injury,and chronic ischemic remodeling.This narrative review aims to summarize the latest advances(2023-2025)in understanding monocyte diversity,functional states,and their changes throughout different stages of PAD.We discuss both established and emerging biomarkers,such as circulating monocyte subset proportions,functional assays,immune checkpoint expression,and multi-omics signatures,highlighting their potential for prognosis and the challenges in translating them to clinical practice.We also present a stage-specific approach to mapping out potential therapies,linking monocyte phenotypes to molecular targets and possible interventions.Additionally,we address regulatory,economic,and implementation considerations for applying these findings in a clinical setting.The goal of this review is to facilitate the development of targeted immunomodulatory strategies to improve limb and cardiovascular outcomes in PAD by combining mechanistic understanding with therapeutic innovation.
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
基金supported by the National Key R&D Program of China,Nos.2021YFA1101703/2021YFA1101700(to YD).
文摘Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.
基金supported by the Chinese Medicine"Dual Chain Integration"Young and Middle-aged Scientific Research and Innovation Teams(No.2022-SLRH-YQ-006)the Key R&D Programme Projects of Xianyang Municipality(No.L2023-ZDYF-SF-014)+1 种基金the Shaanxi University of Traditional Chinese Medicine Science,Education and Research Collaborative Educational Achievement Transformation Project(No.2024KC03)the open research topic from the Key Laboratory of Neurological Diseases in Traditional Chinese Medicine,Shaanxi Province(No.KF202315).
文摘Background:Baicalin(BC)and geniposide(GD)are effective components of natural remedies,and studies have shown that they protect against cerebral ischemic stroke(CIS).Transient receptor potential vanilloid 4(TRPV4)is a calcium-permeable channel that plays important roles in vascular function and vasodilation.However,no studies are available on the effect of BC/GD on the TRPV4 channel and rat cerebral basilar artery(CBA).This study examined the effect of the combination of BC/GD(7:3)on cerebral vascular function after CIS.Methods:We used western blotting to determine TRPV4 protein levels and live cell fluorescence Ca 2+imaging and patch clamp to determine how BC/GD activates TRPV4 channels.Isolated vessel experiments were used to observe the dilatory effects of BC/GD on CBA under different conditions.Laser Doppler imaging was used to measure cerebral blood flow in rats.Triphenyl tetrazolium chloride and Nissl stainings were used to determine the infarct area in the rat brain and neuronal damage,respectively.Results:BC/GD significantly boosted TRPV4 protein levels in vascular smooth muscle cells(VSMCs)during oxygen-glucose deprivation and increased[Ca 2+]i in TRPV4-HEK 293 cells and VSMCs.This effect was not observed in vector-HEK 293 cells.In patch clamp experiments,BC/GD increased Ca 2+currents in TRPV4-HEK 293 cells,whereas no significant changes were observed in vector-HEK 293 cells.BC/GD dilated CBA contractions induced by U46619 and KCl,with a concentration-dependent increase of the dilatory effect.In the middle cerebral artery occlusion model,cerebral blood flow in the ischemic side significantly decreased,whereas BC/GD intervention significantly increased cerebral blood perfusion in the ischemic side,reduced the infarct area,and improved neurological function scores and neuronal damage.Conclusion:BC/GD activates the TRPV4 channel,leading to Ca ^(2+) influx,which in turn activates the intermediate conductance calcium-activated potassium channels channel to regulate vasodilation in vascular smooth muscle.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is a major type of liver cancer worldwide.In advanced stages,portal vein tumor thrombosis(PVTT)and jaundice are common,whereas obstructive jaundice(OJ)is relatively rare.Both conditions markedly reduce survival and increase therapeutic complexity.Recently,hepatic artery infusion chemotherapy(HAIC)in combination with targeted immunotherapy has shown promise for advanced HCC.CASE SUMMARY We report a 47-year-old male with advanced HCC complicated by PVTT and OJ,who was admitted with marked jaundice of the skin and sclera.Imaging revealed a large hepatic mass(14.5 cm×11.3 cm)in the right lobe with associated portal vein tumor thrombus.The tertiary bile duct was only mildly dilated,making percutaneous transhepatic cholangiography drainage infeasible.The patient underwent reduced-dose HAIC,which resulted in significant tumor shrinkage and marked reduction in serum bilirubin.This improvement enabled sequential treatment with lenvatinib and camrelizumab.After six cycles,both liver function and alphafetoprotein levels improved.The patient achieved a progression-free survival of 20 months and an overall survival of 29 months.CONCLUSION HAIC can treat high-bilirubin HCC with PVTT and OJ,allowing for subsequent targeted immunotherapy.
基金supported by the National Natural Science Foundation of China,Nos.82172546(to XH),82172547(to ZZ)the Natural ScienceFoundation of Guangdong Province,Nos.2023A1515012695(to XH),2024A1515010419(to ZZ)the Science and Technology Plan Project of Guangzhou,Nos.202201020413(to ZZ),2023A04J1099(to ZZ).
文摘White matter injury is a key factor impacting stroke recovery.Physical exercise can promote white matter repair.Immune cells,especially regulatory T(Treg)cells,contribute to strengthening white matter integrity,yet little is known about the underlying mechanism.To examine this,we established a transient middle cerebral artery occlusion male mouse model.We found that physical exercise elevated brain Treg cells,thereby enhancing neurological recovery,reducing neuroinflammation,promoting myelin debris clearance,and accelerating white matter repair.Depletion of Treg cells caused a decrease in these positive effects of physical exercise.Mechanistically,the rise in osteopontin triggered by physical exercise is dampened when Treg cells are depleted.In addition,Treg-conditioned medium reduced oxygen-glucose deprivation/re-oxygenation-induced microglial inflammation and enhanced phagocytosis,which could be blocked by osteopontin antibodies.Importantly,although Treg infusion could mimic the protective effects of physical exercise,osteopontin blockade partially countered the effects of physical exercise and Treg cells.Finally,our sequencing data revealed a marked upregulation of C-X-C motif chemokine ligand 12(CXCL12)mRNA expression subsequent to physical exercise,which was confirmed at the protein level.Stimulation of Treg cells with stroke brain lysates increased C-X-C motif chemokine receptor 4(CXCR4)expression,indicating a potential role for the CXCL12-CXCR4 axis in recruiting Treg cells.These findings suggest that physical exercise promotes white matter repair after ischemic stroke by Treg cells.
文摘Background In patients with coronary artery disease,age is of known significance in predicting outcomes.Data on clinical outcomes in patients≥85 years undergoing percutaneous coronary intervention(PCI)remain scarce.The study aim was to determine clinical characteristics,risk of adverse cardiovascular events,and mortality in patients aged≥85 years compared to those aged<85 undergoing PCI.Methods In this retrospective study,data were obtained from the nationwide Netherlands Heart Registration on patients undergoing PCI between January 1st,2017 and January 1st,2021.The primary endpoint was all-cause mortality at long-term followup.Results A total of 155,683 patients underwent PCI,of which 100,209(64.4%)acute coronary syndrome cases.Compared to patients aged<85 years,patients aged≥85 were more often female and showed a higher number of cardiovascular comorbidities,including impaired left ventricle ejection fraction and reduced kidney function.Mortality at short-term and long-term follow-up were significantly higher in those aged≥85(P<0.001).Patients aged≥85 were more likely to have a myocardial infarction within 30 days following the index intervention(0.9%vs.0.7%;P=0.024),though they less often underwent revascularization at longterm follow-up compared to patients aged<85(P<0.001).Conclusions The elderly(≥85 years)patient requiring PCI carries an extensive cardiovascular risk profile,translating in significant risk of recurrent cardiovascular events and increased mortality rate.Clinicians should carefully weigh perceived risks and potential benefits in the individual patient,considering the patients’age,cardiovascular risk profile,and associated risk of morbidity and mortality.
文摘BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such as factor V Leiden(FVL)mutation.CASE SUMMARY A kidney transplant recipient with FVL mutation developed an acute transplant renal artery thrombosis.The immediate post-operative Doppler ultrasonography revealed thrombosis of the main and inferior polar renal arteries.Emergent thrombectomy and separate arterial re-anastomoses were performed after cold perfusion with heparinized saline and vasodilator solution.Reperfusion was successful with immediate urine output and gradual improvement in renal function.The patient was discharged on direct oral anticoagulation therapy.CONCLUSION Early detection and surgical intervention can preserve graft function in posttransplant renal artery thrombosis even in patients at high risk.
基金supported by the National Natural Science Foundation of China,Nos.82171456(to QY)and 81971229(to QY)the Natural Science Foundation of Chongqing,Nos.CSTC2021JCYJ-MSXMX0263(to QY)and CSTB2023NSCQ-MSX1015(to XL)Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).
文摘Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.
基金supported by the National Natural Science Foundation of China,Nos.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT)National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT)+1 种基金Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).
文摘AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.
基金supported by the National Institute of Health/National Eye Institute(NIH/NEI)grants(R00 EY029373,R01 EY035658)to AYFKnights Templar Eye Foundation Research Grant to ESIntramural UAMS Hornick and Sturgis grants to AYF and ES respectively。
文摘Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).
基金supported by the Beijing Nova Program,Nos.20230484436,Z211100002121038the Chinese Institutes for Medical Research,No.CX23YQ01+1 种基金the NationalNatural Science Foundation of China,Nos.32100925,82027802Beijing-Tianjin-Hebei Basic Research Cooperation Project,No.22JCZXJC00190(all to XJand JL).
文摘Vascular cognitive impairment and dementia is a debilitating neurological disorder caused by chronic cerebral hypoperfusion,for which no effective causative treatments are currently available.Intermittent hypoxia has been shown to enhance cerebral blood flow in mice,but its efficacy in a model of vascular cognitive impairment and dementia remains unclear.In this study,we established a mouse model of vascular cognitive impairment and dementia by bilateral carotid artery stenosis.Intermittent hypoxia was induced before and after this stenosis.We found that intermittent hypoxia increased cerebral blood flow,oxygen saturation,and microcirculation in the prefrontal cortex and hippocampus in the model mice,without causing neurovascular damage.Additionally,intermittent hypoxia significantly improved cognitive function in the mouse model of vascular cognitive impairment and dementia,with perconditioning showing greater efficacy than preconditioning.Improvements in cerebral microcirculation and blood flow were positively correlated with cognitive recovery.Even in a mouse model of vascular cognitive impairment and dementia with comorbidities induced by a high-fat,high-fructose diet,intermittent hypoxic perconditioning demonstrated protective effects on cognitive function.Proteomic analysis indicated that mitochondrial protection is a key mechanism,particularly through upregulating NDUFB8 expression and increasing the activity of mitochondrial complex I.These findings suggest that intermittent hypoxia is a potential non-invasive strategy for the prevention and treatment of vascular cognitive impairment and dementia.
基金supported by the Qingdao Medical Health Research Project,No.2023-WJZD212(to XX)。
文摘Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.
基金supported by“Pioneer”and“Leading Goose”R&D Program of Zhejiang(2022C01042),and Alibaba-Zhejiang University Joint Research Institute of Frontier Technologies.
文摘Purpose–This study aims to make full use of the advantages of connected and autonomous vehicles(CAVs)and dedicated CAV lanes to ensure all CAVs can pass intersections without stopping.Design/methodology/approach–The authors developed a signal coordination model for arteries with dedicated CAV lanes by using mixed integer linear programming.CAV non-stop constraints are proposed to adapt to the characteristics of CAVs.As it is a continuous problem,various situations that CAVs arrive at intersections are analyzed.The rules are discovered to simplify the problem by discretization method.Findings–A case study is conducted via SUMO traffic simulation program.The results show that the efficiency of CAVs can be improved significantly both in high-volume scenario and medium-volume scenario with the plan optimized by the model proposed in this paper.At the same time,the progression efficiency of regular vehicles is not affected significantly.It is indicated that full-scale benefits of dedicated CAV lanes can only be achieved with signal coordination plans considering CAV characteristics.Originality/value–To the best of the authors’knowledge,this is the first research that develops a signal coordination model for arteries with dedicated CAV lanes.
基金supported by the National Nature Science Foundation of China,No.81471308(to JL)the Innovative Leading Talents of Liaoning Province,No.XLYC1902031(to JL)+2 种基金Science and Technology Projects in Liaoning Province,No.2022-BS-238(to CH)Young Top Talents of Liaoning Province,No.XLYC1907009(to LW)Dalian Science and Technology Innovation Fund,No.2018J11CY025(to JL)。
文摘Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.
文摘In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause of life-threating hemorrhage and the different causes of uterine pseudoaneurysms.Uterine artery pseudoaneurysm is a complication of both surgical gynecological and nontraumatic procedures.Massive hemorrhage is the consequence of the rupture of the pseudoaneurysm.Uterine artery pseudoaneurysm can develop after obstetric or gynecological procedures,being the most frequent after cesarean or vaginal deliveries,curettage and even during pregnancy.However,there are several cases described unrelated to pregnancy,such as after conization,hysteroscopic surgery or laparoscopic myomectomy.Hemorrhage is the clinical manifestation and it can be life-threatening so suspicion of this vascular lesion is essential for early diagnosis and treatment.However,there are other uterine vascular anomalies that may be the cause of severe hemorrhage,which must be taken into account in the differential diagnosis.Computed tomography angiography and embolization is supposed to be the first therapeutic option in most of them.
