OBJECTIVE:Postmenopausal women are vulnerable to insufficient physical activity and prolonged sitting. While both behaviors have been individually associated with mortality, their joint effects remain unclear. METHODS:We analyzed 5355 postmenopausal women (median age 63 years [interquartile range 56-71]) from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. Leisure-time physical activity was categorized as insufficient (<600 metabolic equivalent of task minutes per week) or sufficient (≥600 metabolic equivalent of task minutes per week). Sitting time was classified as <6 h/day, 6-8 h/day, or ≥ 8 h/day. Survey-weighted Cox proportional hazards models examined the independent and joint associations of physical activity and sitting time with all-cause, cardiovascular disease, cancer and other-cause mortality. RESULTS:During a median follow-up of 78 months, 673 (13.8%) deaths occurred, including 201 from cardiovascular disease, 162 from cancer, and 310 from other causes. Both sufficient leisure-time physical activity and shorter sitting time were independently associated with lower risks of all-cause, cardiovascular disease, and other-cause mortality, but not cancer mortality. In joint analyses, participants with sufficient physical activity and < 6 h/day sitting had the lowest all-cause (adjusted hazard ratio 0.25, 95% confidence interval 0.16-0.39), cardiovascular disease (adjusted hazard ratio 0.15, 95% confidence interval 0.08-0.30) and other-cause (adjusted hazard ratio 0.17, 95% confidence interval 0.08-0.37) mortality, compared with those with insufficient physical activity and ≥ 8 h/day sitting. CONCLUSION:In this prospective cohort study of US postmenopausal women, the combination of sufficient physical activity and lower sitting time was associated with lower risks of all-cause and cardiovascular disease mortality.

Introduction:Adipose-derived stem cells (ADSCs) demonstrate therapeutic potential for ischemic stroke, primarily through paracrine actions. However, the specific intracellular signaling pathways underlying these benefits remain unclear. This study investigates the critical role of JAK1/STAT3 signaling in neuroprotection mediated by ADSC-conditioned medium (ADSC-CM). Methods:We employed a dual-model approach. In vivo, rats subjected to transient middle cerebral artery occlusion (tMCAO) received intravenous ADSC-CM or vehicle at 2, 24, and 48 h post-ischemia, with or without the JAK1 inhibitor GLPG0634. Neurological function was evaluated over a period of 7 days. Subsequently, infarct volume, brain edema, neuronal survival, neurovascular regeneration, synaptic ultrastructure, mitochondrial function, and energy metabolism were analyzed. In vitro, primary cortical neurons subjected to oxygen-glucose deprivation (OGD) were treated with ADSC-CM with or without GLPG0634 to assess neurite outgrowth. Activation of the JAK1/STAT3 pathway was confirmed by Western blot in both models. Results:In vivo, ADSC-CM significantly improved neurological function, reduced infarct volume and brain edema, and enhanced neuronal survival, nerve fiber regeneration, angiogenesis, synaptic plasticity, and mitochondrial function in tMCAO rats. In vitro, ADSC-CM promoted neurite outgrowth in OGD-injured neurons. Crucially, all these multifaceted neuroprotective effects were completely abolished by co-treatment with GLPG0634. Mechanistically, ADSC-CM robustly activated JAK1 and STAT3 phosphorylation in both models, an effect effectively inhibited by GLPG0634. Discussion:The neuroprotective effects of ADSC-CM are mechanistically linked to the activation of the JAK1/STAT3 pathway, which mitigates ischemic damage by promoting neuronal salvage, neurovascular regeneration, synaptic plasticity, and metabolic recovery, thereby enhancing neurological functional recovery after stroke.

Whether physical activity (PA) levels relate to mortality in postmenopausal women remains not well understood. We analyzed 5,880 postmenopausal women from NHANES 2007–2018 (median follow-up:77 months). PA—including total PA (TPA), leisure-time PA (LTPA), and occupational PA (OPA)—was assessed using the Global Physical Activity Questionnaire and expressed as metabolic equivalent of task (MET)-minutes/week. TPA was classified as no, insufficiently active (< 600), or sufficiently active (≥ 600), while LTPA and OPA were classified as no, low (< 600), or high (≥ 600). Weighted proportional hazards Cox models and restricted cubic spline (RCS) analyses examined associations with all-cause, cardiovascular disease (CVD), and non-CVD mortality. During follow-up, 718 deaths occurred (215 CVD, 503 non-CVD). Compared with no PA, insufficiently and sufficiently active TPA were associated with reduced risks of all-cause, CVD, and non-CVD mortality; both low and high LTPA with reduced risks of all-cause and non-CVD mortality; and low OPA with reduced risks of all-cause and non-CVD mortality. RCS analyses showed linear inverse associations for TPA and non-linear inverse associations for LTPA with all-cause and non-CVD mortality, while OPA showed no significant associations. Tests for trend were significant for TPA in relation to all-cause and non-CVD mortality, and for LTPA across all three outcomes. Sensitivity analyses excluding early deaths yielded similar results. Higher TPA and LTPA were associated with reduced risks of all-cause and non-CVD mortality among postmenopausal women. Promoting adequate PA, particularly moving from inactivity to modest levels, may be an effective strategy to support healthy aging in this population.

BACKGROUND:Mood disorders are important clinical manifestations of vascular depression (VaDep). We explored the efficacy of escitalopram plus tandospirone citrate in treating VaDep and the involvement of blood neurotransmitters during the treatment. METHODS:This single-center, double blind, randomized controlled study randomly divided patients with VaDep into Monotherapy group (escitalopram + placebo) or Combined group (escitalopram + tandospirone citrate). The primary outcome measures were the changes in psychological assessment scales from baseline to week 12, including the Hamilton Anxiety Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Patient Health Questionnaire-15 (PHQ-15), Somatic Symptom Scale (SSS). RESULTS:Compared with the Monotherapy group, the Combined group reported a significant decrease in the HAMD score at post-treatment week 2 (95 % CI 3.97 to 5.85, p < 0.001), in the PHQ-15 score at post-treatment weeks12 (95 % CI 0.54 to 1.37, p < 0.001), and increased in platelet 5-HT1AR at post-treatment weeks 12 (95 % CI 0.08 to 0.29, p < 0.0001). In both groups, the level of platelet 5-HT1BR was significantly lower at post-treatment week 12 than before the treatment (p < 0.001). The mediation analysis showed that tandospirone ameliorated somatization symptoms by alleviating depression, with platelet 5-HT1BR playing a regulatory role by alleviating depression (β = 0.28; 95 % CI: 0.25 to 0.31). CONCLUSION:Combination treatment significantly improves anxiety, depression, and somatization symptoms in patients with VaDep in which platelet 5-HT1AR and platelet 5-HT1BR are potential objective indicators. These findings may provide clinical insights for the treatment of VaDep.

BackgroundTo investigate the efficacy and underlying mechanisms of a combined therapy of estradiol/dydrogesterone and escitalopram in treating perimenopausal anxiety and depression.MethodsA total of 195 patients were randomized to receive escitalopram, estradiol/dydrogesterone, or combination therapy for 12 weeks. The primary efficacy endpoints were the changes in scores of the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) at week 12 compared with the baseline.ResultsCompared with the baseline, all groups reported a gradual decrease in Patient Health Questionnaire Somatic Symptom Scale (PHQ-15), the Patient Health Questionnaire Depression Scale (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7), HAMD, and HAMA scores (P<0.001 for all), and a gradual increase in serum estradiol (E2) and 5-Hydroxytryptamine (5-HT) (P<0.001 for both), with the most pronounced changes in the Combined group (Comb group). In intergroup comparison, at weeks 4, 8, 12, the scores of PHQ-15, GAD-7, PHQ-9, HAMA, and HAMD were most reduced in the Comb group; At weeks 2, 4, 8, 12, E2 level was significantly higher in the Comb group and estradiol/dydrogesterone group (E/D group) than in the escitalopram group (ESC group); at weeks 4, 8, and 12, 5-HT level was significantly higher in the Comb group than in the E/D group; and at week 4 and 12, 5-HT level was significantly higher in the Comb group than in the ESC group.ConclusionsEstradiol/dydrogesterone plus escitalopram significantly improves anxiety, depression, and somatic symptoms in perimenopausal women. These findings provide clinical evidence of estradiol/dydrogesterone plus escitalopram regimen for the treatment of patients with perimenopausal anxiety and depression.

The primary objective of this study is to develop a specialized deep learning framework specifically adapted for the unique physical characteristics of neurovascular Optical Coherence Tomography (OCT) imaging. Although Polyp-PVT, originally designed for polyp segmentation, shows promise for OCT analysis, it faces limitations in neurovascular applications. The default RGB input wastes resources on duplicated grayscale data, while its fixed-scale fusion struggles with vascular curvature variations. Furthermore, the attention mechanism fails to capture radial vessel patterns, and geometric constraints limit thin boundary detection. To address these challenges, we propose Brain-OCT-PVT with key innovations: a single-channel input stem reducing parameters by two-thirds; a Radial Intensity Module (RIM) using polar transforms and angular convolution to model annular structures; and a Deformable Cross-scale Fusion Module (D-CFM) with learnable offsets. The Boundary-aware Attention Module (BAM) combines Laplace edge detection with Swin-Transformer for sub-pixel consistency. A specialized loss function combines Dice Similarity Coefficient (Dice), BoundaryIoU on 2-pixel dilated edges, and Focal Tversky to handle extreme class imbalance. Evaluation on 13 clinical cases achieves a Dice score of 95.06% and an 95% Hausdorff Distance (HD95) of 0.269 mm, demonstrating superior performance compared to existing approaches.

Little is known about the combined association of physical activity (PA) and dietary quality (DQ) with stroke and its mortality outcomes. This study aims to investigate the individual and combined association of PA and DQ on odds of prevalent stroke and mortality among stroke survivors. We analysed data from 20 225 adults participating in the 2007-2018 National Health and Nutrition Examination Survey, including 838 stroke survivors. PA was measured by the self-reported metabolic equivalent to task (MET) minutes per week and DQ by Healthy Eating Index 2020 (HEI-2020). Logistic regression models evaluated associations with the odds of prevalent stroke, and Cox proportional hazards regression models assessed mortality risks among stroke survivors. Compared with no PA-lower DQ (reference), low PA-lower DQ (adjusted OR 0·49, 95 % CI 0·32-0·75), low PA-higher DQ (adjusted OR 0·56, 95 % CI 0·34-0·92), high PA-lower DQ (adjusted OR 0·66, 95 % CI 0·44-0·99) and high PA-higher DQ (adjusted OR 0·50, 95 % CI 0·34-0·73) were significantly associated with lower odds of stroke. Among stroke survivors, reduced mortality was observed for low PA-higher DQ (adjusted hazard ratio (HR) 0·43; 95 % CI 0·19-0·95), high PA-lower DQ (HR 0·36; 95 % CI 0·17-0·75) and high PA-higher DQ (HR 0·47; 95 % CI 0·27-0·83). This large observational study showed that a combination of appropriate PA and higher DQ is associated with reduced odds of stroke and mortality among stroke survivors. These findings support lifestyle modification as a strategy for stroke prevention and survivor care.

Background Symptomatic intracerebral hemorrhage (sICH) after intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke (AIS) remains a feared yet unpredictable complication. We aimed to develop and validate a new predictive model incorporating clinical variables and noncontrast head computed tomography imaging features to predict sICH in patients with AIS receiving intravenous recombinant tissue plasminogen activator. Methods and Results The predictive model was derived from 808 patients with AIS in the derivation cohort in Southeast China, based on multivariable logistic regression analysis. External validation was conducted in a validation cohort from Central China. Discrimination, calibration, and clinical usefulness of the predictive model were assessed. We observed 32 sICH events among 808 patients with AIS in the derivation cohort, and 21 sICH events out of 612 participants in the validation cohort. The variables in the predictive model included cerebral small vessel disease burden and early infarct signs on head computed tomography scan, atrial fibrillation, age, systolic blood pressure, and initial National Institutes of Health Stroke Scale score. The fitted model showed promising discrimination (optimism‐corrected C statistic of 0.80) and acceptable calibration (Hosmer and Lemeshow goodness of fit P=0.816) in the derivation cohort. External validation showed similar discrimination (C statistic 0.82 [95% CI, 0.72–0.91]) and calibration (Hosmer and Lemeshow goodness of fit P=0.866). Conclusions Our internally and externally validated prediction model for sICH in patients with AIS who received intravenous thrombolysis may facilitate individualized prediction for intracerebral bleeding risk after intravenous thrombolysis for acute ischemic stroke.

Background Perilladehyde, an extract of perillae in the Labiatae family, can produce significant anti-inflammatory and antioxidant effects. Although literature evidences the favorable effect of perillaldehyde on ischemic stroke, the exact mechanism remains blurred. Purpose This study attempted to explore the impact of perillaldehyde on cerebral ischemia-reperfusion injury and the related action mechanism. Methods The rat tMCAO and neuronal OGD/R models were established to simulate cerebral ischemia-reperfusion injury. Lentiviruses were used to interfere with the expression of Nrf2 and Trx2 in neurons. The effects and action mechanisms of perillaldehyde were explored by various experimental methods, including chromatin immunoprecipitation assay, Western Blot, flow cytometry, dual-luciferase reporter gene assay, transmission electron microscopy, MRI, RNA-seq, and immunofluorescence staining. Results Perillaldehyde pretreatment effectively mitigated the tMCAO-induced brain injury in rats by reducing cerebral infarction, improving neuromotor function, and attenuating cell apoptosis in the ischemic penumbra. In vitro, perillaldehyde pretreatment alleviated cell death and excessive oxidative stress, preserved the mitochondrial membrane integrity, enhanced mitochondrial energy metabolism, and facilitated the restoration of mitochondrial ultrastructure after OGD/R. The mechanism probe revealed that perillaldehyde activated the Nrf2/Keap1/Trx2 signaling axis, thus promoting the transcription of Trx2 and improving mitochondrial structure and function. The aforementioned impacts of perillaldehyde were somewhat counteracted by disrupting the expression of Nrf2 and Trx2, suggesting that the neuroprotection of perillaldehyde partially involves the activation of the Nrf2/Keap1/Trx2 axis. Conclusions This study firstly demonstrates the existence of the Nrf2/Keap1/Trx2 signaling axis in cerebral ischemia-reperfusion injury and evidences that perillaldehyde pretreatment can promote the restoration of neuronal mitochondrial structure and function by activating the Nrf2/Keap1/Trx2 axis after cerebral ischemia-reperfusion injury. These findings signify that perillaldehyde holds great promises for clinical management of ischemic stroke.

Ferroptosis, a recently identified form of regulated cell death, is characterized by lipid peroxidation and iron accumulation, plays a critical role in early brain injury after subarachnoid hemorrhage. Ginsenoside Rd, an active compound isolated from ginseng, is known for its neuroprotective properties. However, its influence on SAH-induced ferroptosis remains unclear. In this study, we constructed an SAH model using intravascular perforation in vivo and treated HT22 cells with oxyhemoglobin to simulate the condition in vitro. We observed significant changes in ferroptosis markers, including GPX4 and ACSL4, following SAH. Administration of ginsenoside Rd to both rats and HT22 cells effectively inhibited neuronal ferroptosis induced by SAH, alleviating neurological deficits and cognitive dysfunction in rats. Notably, the neuroprotective properties of ginsenoside Rd were countered by the STING pathway agonist 2’3’-cGAMP. Experiments conducted in vitro and in vivo illustrated that the impacts of ginsenoside Rd were counteracted by the BQR inhibitor. Our findings suggest that ginsenoside Rd mitigates EBI after SAH by suppressing neuronal ferroptosis through the cGAS/STING pathway while upregulating DHODH levels. These outcomes emphasize the potential of ginsenoside Rd as a therapeutic candidate for subarachnoid hemorrhage.

To investigate the causal relationship between oral infectious diseases and lacunar stroke (LS) and to identify the role of interleukin-1α (IL-1α), interleukin-6 (IL-6), tumor necrosis factor (TNF), and C-reaction protein (CRP) as potential mediators. The meta-analysis incorporating cross-sectional studies was carried out. Additionally, two-sample Mendelian randomization (MR) analysis was performed to explore the associations between genetically predicted oral infectious diseases (including dental caries, periodontitis, and pulp and periapical diseases) and lacunar stroke, utilizing summary-level data from genome-wide association studies (GWAS). This was followed by a mediation analysis to explore the role of IL-1α, IL-6, TNF, and CRP. Meta-analysis suggested that individuals with periodontitis have a 5.16 times higher risk of developing LS compared to those without periodontitis (95%CI 3.68-7.24). Genetically predicted pulp and periapical diseases (Odds ratios [OR]: 1.20, 95% CI 1.03-1.41) and periodontitis (OR: 1.24, 95%CI 1.03-1.49) showed a moderate association with LS. However, the mediation analysis yielded negative results. The evidence derived from both the MR study and the meta-analysis suggested a potential association between periodontitis and LS. These findings indicated that periodontitis might play a role in the development of LS. However, given the limitations inherent in our research, further studies are necessary to validate these conclusions.

Whether physical activity is associated with functional outcomes from ischemic stroke remains poorly understood. We aimed to explore the association of pre-stroke physical activity and functional outcomes in patients with acute ischemic stroke according to sex. Pre-stroke physical activity was assessed using a four-level questionnaire named Saltin-Grimby Physical Activity Level Scale (SGPALS). Our primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0-2 three months after stroke onset. The secondary outcome was the shift in the mRS score at 3 and 6 months. A prospective cohort study design was used to estimate the multivariable-adjusted odds of functional independence with pre-stroke physical activity. We analyzed 257 men and 142 women participants, including 230 physically inactive and 169 active ones in the final analysis. Physical active participants were at a higher odds of achieving functional independence at 3 months (adjusted OR 4.14, 95% CI 2.35-7.31; adjusted common odds ratio (cOR) 2.38, 95% CI 1.60-3.56). When stratified by sex adjusted point estimates from logistic regression models indicated that pre-stroke physical activity was significantly associated with 3-month functional independence in both men (adjusted OR 4.75, 95%CI 2.23-10.09; adjusted cOR 2.70, 95% CI 1.63-4.51) and women (adjusted OR 3.64, 95% CI 1.44-9.18; adjusted cOR 2.10, 95% CI 1.01-4.43). This study showed an association between physical activity and functional independence 3 months after ischemic stroke. Moreover, no indication of sex difference in this association were observed.

Background: Cerebrospinal fluid (CSF) analysis in patients with Coronavirus disease 2019 (COVID-19) and co-existing acute neurological involvement remains poorly understood. Objective: To investigate the CSF profile in patients with COVID-19 and co-existing acute neurological involvement. Methods: This prospective case series study included patients with confirmed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and co-existing acute neurological involvement who underwent lumbar puncture in two teaching hospitals between November 2022 and April 2023. Demographics, clinical characteristics, and CSF profile, including leukocyte count, total protein, and glucose levels, oligoclonal band (OCB) patterns, blood-CSF barrier function, SARS-CoV-2 mRNA, and SARS-CoV-2 antibodies were described. Results: A total of 26 participants were analyzed. The median age was 51 (interquartile range [IQR] 39-76) years, and 18 (69.2%) were male. The median open CSF pressure was 140mm (IQR 110-183) water column, and the median CSF total protein was slightly elevated (485 [IQR 350-611] mg/L). The most frequent pathological finding was elevated CSF total protein (12 [46.2%] samples) and blood-CSF barrier dysfunction (12 [46.2%] samples). SARS-CoV-2 was undetectable in all CSF samples using the reverse-transcriptase-polymerase-chain-reaction detection. SARS-CoV-2-IgG-antibody was positive in five CSF samples, while SARS-Cov-2 IgM antibodies were not detected in all participants. Conclusions: This study showed that some patients with COVID-19 and co-existing acute neurological involvement presented non-specific inflammatory CSF abnormalities despite no SARS-CoV-2 being detected in the CSF. Our findings suggest that neurological injury is related to disordered immune responses associated with systemic inflammation rather than direct virus invasion.

Exercise training can exert favorable effects on the remodeling of neural structures, functional reconstruction, and the recovery of neurovascular units after cerebral ischemia. It has also been documented to activate the JNK/c-jun pathway, which is involved in diverse cellular processes, including growth regulation, transformation, and programmed cell death. However, it remains obscure regarding the role of the JNK/c-jun pathway in the aforementioned exercise training-conferred neurological benefits. In this study, rats received exercise training after transient middle cerebral artery occlusion. The potential impact of exercise training on apoptosis, nerve remodeling, functional remodeling, and vascular regeneration was investigated by Western blotting, immunofluorescence staining, transmission electron microscopy, Golgi staining, Tunel staining, and neurological function assessment, etc. Exercise training activated the JNK/c-jun pathway, which was closely linked with cerebral ischemia-reperfusion (I/R) injury. The training mitigated cerebral I/R injury-induced cell apoptosis and promoted neural structural remodeling, neurological function recovery, and vascular regeneration in the ischemic penumbra. However, the protective benefits of exercise training were offset by the JNK inhibitor, SP600125. After cerebral ischemia, exercise training can promote neural structural remodeling, neurological functional recovery, and vascular regeneration. These processes may be achieved by activating the JNK/c-jun signaling pathway.

Ischemic stroke (IS) stands as a principal contributor to high rates of sickness and death. The condition's pathological development is complicated, featuring mechanisms like mitochondrial impairment and the activation of microglial cells. A thorough grasp of these intricate processes is vital for creating successful treatment strategies. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to find gene sets with a strong correlation to IS. Integrated machine learning approachs were used to identify key mitochondrial-related genes (MRGs). From this analysis, SPTLC2 was identified as a pivotal MRG and was subsequently analyzed in detail using single-cell RNA sequencing (scRNA-seq) datasets. We performed functional confirmation using experimental stroke simulations, which included transient middle cerebral artery occlusion (tMCAO) in mice and in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) on primary microglia. WGCNA revealed two critical modules (yellow and blue) comprising 5348 genes, which were predominantly enriched in immune response, nerve regeneration, and lipid metabolism. We exhibited the robust and superior performance of MRGs in stroke prediction, which contributed to an optimal combination of ridge regression and random forest fitted on 18 MRGs. Subsequently, elevated expression of the SPTLC2 gene was observed in microglia following stroke. Functional studies and experimental validation demonstrated that SPTLC2 promoted microglial pro-inflammatory phenotype, metabolic reprogramming towards glycolysis, and exacerbated cell–cell communication alterations. SPTLC2-specific knockdown in myeloid cells using an adeno-associated virus (AAV) in our tMCAO model alleviated neurobehavioral deficits, reduced infarct volume, and improved mitochondrial function by elevating oxidative stress and mitigating mitochondrial membrane potential depolarization. Additionally, SPTLC2 was regulated by the transcription factor FLI1, and molecular docking identified potential drugs targeting SPTLC2, including Nystatin A3, Moxidectin, and Lumacaftor. Our study highlights SPTLC2 as a critical mediator of microglial activation and metabolic reprogramming in ischemic stroke, providing a foundation for developing novel therapeutic strategies targeting SPTLC2 to improve stroke outcomes. Highlights 1. SPTLC2 is identified as a key driver of neuroinflammation after ischemic stroke. 2. SPTLC2 promotes pro-inflammatory microglial activation and a metabolic shift to glycolysis. 3. Targeting the FLI1-SPTLC2 regulatory axis alleviates ischemic brain injury in mice. 4. SPTLC2 represents a promising therapeutic target for improving stroke outcomes.

ObjectiveStroke is a leading cause of disability worldwide, imposing a significant burden on patients, families, and society. To create and verify a prediction model for activities of daily living (ADL) dysfunction in stroke survivors, pinpoint key predictors, and analyze the traits of those at risk.MethodsData from the China Health and Retirement Longitudinal Study wave 5 was used in this cross-sectional study. 1,131 stroke survivors were included and split into training and testing sets. The least absolute shrinkage and selection operator regression and multivariate logistic regression were applied for model development. Model performance was evaluated using the area under the receiver operating characteristic curve(AUC), calibration plots, and decision curve analysis. SHapley Additive exPlanations values were calculated to understand predictor importance.ResultsSix variables (age, the 10-item Center for Epidemiologic Studies Depression Scale score, memory disorder, self-rated health, pain count, and heavy physical activity) were identified as significant predictors. The model showed good discriminatory power (training set AUC = 0.804, testing set AUC = 0.779), accurate calibration, and clinical utility.ConclusionA prediction model for ADL dysfunction in stroke survivors was successfully developed and validated. It can help in formulating personalized medical plans, potentially enhancing stroke survivors' ADL ability and quality of life.

For decades, scientists have explored the patterns of neural network remodeling that occur after a stroke. Several studies have shown that both motor cortexes (MCs) undergo crucial remodeling after cerebral ischemia. However, the mechanism by which corticofugal fibers are remodeled is not well understood. Therefore, this study was aimed at investigating the changes in the bilateral red nucleus (RN) and MC-RN projections during recovery from a large-area stroke in a rat stroke model with or without constraint-induced movement therapy (CIMT). A large-area middle cerebral artery occlusion (MCAO) model was established in rats using the Longa method. CIMT was initiated 7 days after MCAO and continued for 1, 2, or 3 weeks. Rats in the control group underwent spontaneous recovery. Locomotor impairment was evaluated using the CatWalk automated gait analysis system, and overall neurological function was evaluated with the modified neurological severity score. Bilateral MC-RN projections were visualized by labeling fiber tracts with an anterograde tracer. Postsynaptic density 95 (PSD95), growth-associated protein 43 (GAP43), and synaptophysin expression levels in the RN were detected using western blotting and immunohistochemistry. The results showed that CIMT promoted motor recovery after a stroke, increased levels of GAP43 and PSD95 in the contralesional but not ipsilesional RN, and increased projections from the MC to the bilateral RN. Thus, CIMT promotes neuroplasticity after a large-area stroke by stimulating axon outgrowth, improving postsynaptic membrane function in the contralesional RN, and increasing bilateral projections of the MC-RN. These results provide evidence for the therapeutic efficacy of CIMT in restoring motor function and help with understanding RN plasticity after a large-area stroke.

Stroke is a leading cause of disability worldwide, imposing a significant burden on patients, families, and society. Despite advancements in acute phase stroke treatment, a large number of stroke survivors experience limitations in activities of daily living, which severely impacts their quality of life. Understanding the factors associated with ADL dysfunction in stroke survivors and predicting its occurrence at an early stage is crucial for developing targeted interventions. To create and verify a prediction model for activities of daily living (ADL) dysfunction in stroke survivors, pinpoint key predictors, and analyze the traits of those at risk. Data from the China Health and Retirement Longitudinal Study wave 5 was used in this cross-sectional study. 1,131 stroke survivors were included and split into training and testing sets. The least absolute shrinkage and selection operator regression and multivariate logistic regression were applied for model development. Model performance was evaluated using the area under the receiver operating characteristic curve(AUC), calibration plots, and decision curve analysis. SHapley Additive exPlanations values were calculated to understand predictor importance. Six variables (age, the 10-item Center for Epidemiologic Studies Depression Scale score, memory disorder, self-rated health, pain count, and heavy physical activity) were identified as significant predictors. The model showed good discriminatory power (training set AUC = 0.804, testing set AUC = 0.779), accurate calibration, and clinical utility. A prediction model for ADL dysfunction in stroke survivors was successfully developed and validated. It can help in formulating personalized medical plans, potentially enhancing stroke survivors' ADL ability and quality of life.

Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic mark involved in various pathological processes, yet its role in IS remains unclear. This study aimed to investigate the role of m5C modification in IS and its underlying mechanisms. In vitro, human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), while in vivo, a transient middle cerebral artery occlusion (tMCAO) mouse model was established. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of NSUN2 and heat shock protein family B member 1 (HSPB1). The contents of pro-inflammatory cytokines and ferroptosis-related indicators were measured using enzyme-linked immunosorbent assay and commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone dehydrogenase 1 (NQO-1) pathway proteins was detected by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were performed to assess the interaction between NSUN2 and HSPB1. Results showed that NSUN2 was downregulated in OGD/R-treated HBMECs and tMCAO mice. Furthermore, NSUN2 overexpression mitigated OGD/R-induced inflammation and ferroptosis. Mechanistically, NSUN2 mediated m5C methylation at site 621 in HSPB1 mRNA, enhancing its stability. Knockdown of HSPB1 abolished the protective effects of NSUN2, exacerbating inflammation and ferroptosis in OGD/R-treated HBMECs. Further investigations revealed that the NSUN2/HSPB1 axis exerted its protective role by activating the NRF2/HO-1/NQO-1 pathway. Inhibition of this pathway reversed the beneficial effects of HSPB1 overexpression. In tMCAO mice, NSUN2 overexpression reduced cerebral infarct volume, improved antioxidant capacity, and activated the NRF2/HO-1/NQO-1 pathway. In conclusion, NSUN2-mediated m⁵C methylation stabilized HSPB1 and activated the NRF2/HO-1/NQO-1 pathway, thereby mitigating inflammation and ferroptosis in IS. Targeting the NSUN2/HSPB1 axis may represent a novel therapeutic strategy for IS.