TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair.

BACKGROUND: The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ischemic stroke is neuroprotective and implicated in remyelination. However, the lack of effective therapies calls for the need to investigate the regenerative process of remyelination and the role of rehabilitation therapy. This study sought to investigate whether and how moderate physical exercise (PE) promotes oligodendrogenesis and remyelination in rats with transient middle cerebral artery occlusion (tMCAO). METHODS: Male Sprague-Dawley rats (weighing 250-280 g) were subjected to tMCAO. AAV-shRNA was injected into the lateral ventricle to silence the Trem2 gene before the operation. The rats in the physical exercise group started electric running cage training at 48 h after the operation. The Morris water maze and novel object recognition test were used to evaluate cognitive function. Luxol fast blue staining, diffusion tensor imaging, and electron microscopy were used to observe myelin injury and repair. Immunofluorescence staining was applied to observe the proliferation and differentiation of oligodendrocyte precursor cells (OPCs). Expression of key molecules were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, and Enzyme-linked immunosorbent assay, respectively. RESULTS: PE exerted neuroprotective efects by modulating microglial state, promoting remyelination and recovery of neurological function of rats over 35 d after stroke, while silencing Trem2 expression in rats suppressed the aforementioned effects promoted by PE. In addition, by leveraging the activin-A neutralizing antibody, we found a direct beneficial effect of PE on microglia-derived activin-A and its subsequent role on oligodendrocyte differentiation and remyelination mediated by the activin-A/Acvr axis. CONCLUSIONS: The present study reveals a novel regenerative role of PE in white matter injury after stroke, which is mediated by upregulation of TREM2 and microglia-derived factor for oligodendrocytes regeneration. PE is an effective therapeutic approach for improving white matter integrity and alleviating neurological function deficits after ischemic stroke.

Association of fresh vegetable and salt-preserved vegetable consumptions with estimated glomerular filtration rate.

OBJECTIVE: This study aimed to investigate the relationship between the consumption of fresh and salt-preserved vegetables and the estimated glomerular filtration rate (eGFR), which requires further research. METHODS: For this purpose, the data of those subjects who participated in the 2011-2012 and 2014 surveys of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and had biomarker data were selected. Fresh and salt-preserved vegetable consumptions were assessed at each wave. eGFR was assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation based on plasma creatinine. Furthermore, a linear mixed model was used to evaluate associations between fresh/salt-preserved vegetables and eGFR. RESULTS: The results indicated that the median baseline and follow-up eGFRs were 72.47 mL/min/1.73 m² and 70.26 mL/min/1.73 m², respectively. After applying adjusted linear mixed model analysis to the data, the results revealed that compared to almost daily intake, occasional consumption of fresh vegetables was associated with a lower eGFR (ß=-2.23, 95% CI: -4.23, -0.23). Moreover, rare or no consumption of salt-preserved vegetables was associated with a higher eGFR (ß = 1.87, 95% CI: 0.12, 3.63) compared to individuals who consumed salt-preserved vegetables daily. CONCLUSION: Fresh vegetable consumption was direct, whereas intake of salt-preserved vegetables was inversely associated with eGFR among the oldest subjects, supporting the potential benefits of diet-rich fresh vegetables for improving eGFR.

Hb New York, preliminary results concerning the hematologic characteristics and the effects on thalassemia.

BACKGROUND: The hematological phenotype and genotype analysis of hemoglobin New York (Hb New York) combined with α or ß thalassemia has been rarely reported, and whether there is any effect of Hb New York on thalassemia has not been well explored. METHODS AND RESULTS: In this study, peripheral blood samples from 346 Hb New York carriers were collected for blood cell parameter analysis. When comparing Hb New York heterozygotes, Hb New York combined with α0 thalassemia or α+ thalassemia, we found that the differences in hemoglobin (HGB), MCV and MCH values were statistically significant (P < 0.05). The HGB, MCV and MCH values of α thalassemia patients were not different from Hb New York combined with α thalassemia group (P > 0.05). When Hb New York heterozygotes were compared to Hb New York combined with ß0 thalassemia or ß+ thalassemia, the differences in MCV and MCH values were statistically significant (P < 0.05). However, the differences in MCV and MCH values were not statistically significant between Hb New York combined with ß thalassemia and ß thalassemia (P > 0.05). CONCLUSIONS: Our study shows that the hematological characteristics of Hb New York combined with thalassemia are similar to the corresponding thalassemia, and Hb New York does not aggravate the clinical manifestations of thalassemia.

Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain.

BACKGROUND: Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer's disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. METHODS: Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. RESULTS: Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. CONCLUSIONS: Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Bioinformatic Analysis of Exosomal MicroRNAs of Cerebrospinal Fluid in Ischemic Stroke Rats After Physical Exercise.

Physical exercise is beneficial to the structural and functional recovery of post-ischemic stroke, but its molecular mechanism remains obscure. Herein, we aimed to explore the underlying mechanism of exercise-induced neuroprotection from the perspective of microRNAs (miRNAs). Adult male Sprague-Dawley (SD) rats were randomly distributed into 4 groups, i.e., the physical exercise group with the transient middle cerebral artery occlusion (tMCAO) surgery (PE-IS, n = 28); the physical exercise group without tMCAO surgery (PE, n = 6); the sedentary group with tMCAO surgery (Sed-IS, n = 28); and the sedentary group without tMCAO surgery (Sed, n = 6). Notably, rats in the PE-IS and PE groups were subjected to a running exercise for 28 days while rats in the Sed-IS and Sed groups received no exercise training. After long-term exercise, exosomal miRNAs of cerebrospinal fluid (CSF) were analyzed using high-throughput sequencing. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed for the differentially expressed miRNAs. Physical exercise improved the neurological function and attenuated the lesion expansion after stroke. In total, 41 differentially expressed miRNAs were screened for the GO and KEGG analysis. GO enriched terms were associated with the central nervous system, including cellular response to retinoic acid, vagus nerve morphogenesis, cellular response to hypoxia, dendritic cell chemotaxis, cell differentiation, and regulation of neuron death. Besides, these differentially expressed miRNAs were linked to the pathophysiological process of stroke, including axon guidance, NF-kappa B signaling pathway, thiamine metabolism, and MAPK signaling pathway according to KEGG analysis. In summary, exercise training significantly alleviated the neurological damage at both functional and structural levels. Moreover, the differentially expressed miRNAs regulating multiple signal pathways were potentially involved in the neuroprotective effects of physical exercise. Therefore, these miRNAs altered by physical exercise might represent the therapeutic strategy for cerebral ischemia.

Ultrasonographic diagnosis in rare primary cervical cancer.

INTRODUCTION: Although ultrasonography has been reported to have similar diagnostic accuracy to magnetic resonance imaging, it is not a standard imaging modality for cervical cancer. We aimed to summarize the ultrasonographic features of rare primary cervical cancer. METHODS: This was a retrospective study of patients with cervical cancer who were diagnosed between June 2014 and October 2019. They were divided into common-type cervical cancer (ie, cervical squamous cell carcinoma) and rare-type cervical cancer groups including adenocarcinoma, adenosquamous carcinoma, and small cell carcinoma. All patients were staged according to the tumor, nodes, and metastases criteria. RESULTS: Of the 64 patients, the diagnosis was suspected on ultrasonography in 61 (95.3%) patients and missed on ultrasonography in three patients. The tumor size was smaller in the rare-type cervical cancer group (p<0.05). Hypoechoic lesions in common-type cervical cancer and isoechoic lesions accounted for 74.4% (32/43) and 61.9% (13/21) of patients in the rare-type cervical cancer group, respectively (p<0.001). Meanwhile, 67.4% (29/43) of tumors in common-type cervical cancer were exophytic, while 66.7% (14/21) in rare-type cervical cancer were endophytic (p=0.01). Color Doppler blood signals, as compared with normal cervical tissue, were found in all patients. There was good consistency between ultrasonographic and pathologic diagnosis of rare-type cervical cancer (weighted kappa=0.87). CONCLUSIONS: Most patients with rare-type cervical cancer present with isoechoic lesions. The coincidence rate between ultrasonographic and pathologic diagnosis of rare-type cervical cancer is 87%.

Predicting poor outcomes and the need for surgical treatment in neonates with meconium peritonitis.

OBJECTIVE: The objective of this study is to determine factors associated with poor outcomes and the need for surgical treatment in neonates with meconium peritonitis (MP). METHODS: We evaluated the association between prenatal ultrasound features, maternal characteristics, and the likelihood of surgery, mortality, and serious morbidity in 49 neonates with a prenatal diagnosis of MP, who were born in Guangzhou Women and Children's Medical Center between January 2011 and December 2016. RESULTS: Thirty of 49 neonates (61.2%) required surgical treatment, and 17 (34.7%) had a poor outcome. Independent predictors of need for surgical treatment were polyhydramnios, maternal intrahepatic cholestasis of pregnancy (associated with lower risk), and persistence of peritoneal fluid. The model correctly predicted 70.0% of the neonates who required surgery (at a 10% false-positive rate; area under the curve [AUC]: 0.86 [95% CI, 0.75-0.97]). For poor outcomes, independent predictors were low gestational age at birth, persistence of peritoneal fluid, and polyhydramnios. For the latter, the model only achieved a detection rate of 52.9% (10% false-positive rate, AUC: 0.82 [95% CI, 0.70-0.94]). CONCLUSIONS: A combination of prenatal ultrasound features and maternal characteristics correctly predicted 70.0% the need for neonatal surgery. Prediction of poor outcome-based prenatal ultrasound features and gestational age did not perform well.

Online compensation detecting for real-time reduction of compensatory motions during reaching: a pilot study with stroke survivors.

BACKGROUND: Compensations are commonly observed in patients with stroke when they engage in reaching without supervision; these behaviors may be detrimental to long-term functional improvement. Automatic detection and reduction of compensation cab help patients perform tasks correctly and promote better upper extremity recovery. OBJECTIVE: Our first objective is to verify the feasibility of detecting compensation online using machine learning methods and pressure distribution data. Second objective was to investigate whether compensations of stroke survivors can be reduced by audiovisual or force feedback. The third objective was to compare the effectiveness of audiovisual and force feedback in reducing compensation. METHODS: Eight patients with stroke performed reaching tasks while pressure distribution data were recorded. Both the offline and online recognition accuracy were investigated to assess the feasibility of applying a support vector machine (SVM) based compensation detection system. During reduction of compensation, audiovisual feedback was delivered using virtual reality technology, and force feedback was delivered through a rehabilitation robot. RESULTS: Good classification performance was obtained in online compensation recognition, with an average F1-score of over 0.95. Based on accurate online detection, real-time feedback significantly decreased compensations of patients with stroke in comparison with no-feedback condition (p < 0.001). Meanwhile, the difference between audiovisual and force feedback was also significant (p < 0.001) and force feedback was more effective in reducing compensation in patients with stroke. CONCLUSIONS: Accurate online recognition validated the feasibility of monitoring compensations using machine learning algorithms and pressure distribution data. Reliable online detection also paved the way for reducing compensations by providing feedback to patients with stroke. Our findings suggested that real-time feedback could be an effective approach to reducing compensatory patterns and force feedback demonstrated a more enviable potential compared with audiovisual feedback.

Parental Self-efficacy and Health-related Outcomes Among Children with Hirschsprung Disease: A Cross-sectional Study.

PURPOSE: Little attention has been put to parental self-efficacy (PSE) on the home care management and its impact on the health-related outcome in children with Hirschsprung disease (HD) after surgery. The purpose of this study was to investigate the association between PSE and post-operative outcome and quality of life (QoL) in children with HD. DESIGN AND METHODS: This study adopted a cross-sectional study design. Children diagnosed with HD who had surgery during 2015 and 2018, and their parents were included. Parental self-efficacy, children's post-operative fecal continence and QoL were evaluated with validated questionnaires; post-operative readmission and adverse events were extracted from electronic medical record system. RESULTS: Of the eligible families, 69.6% (96/138) responded to the follow-up. The median children's age at surgery and current age were 16 (interquartile range: 10-32) and 45 (interquartile range: 39.7-57) months, respectively. The mean PSE score is 8.78 points, with the lowest score in the bowel habit training dimension (7.88 ± 2.28), followed by getting social support dimension (8.07 ± 2.64). Multivariable linear regression showed that PSE was associated with fecal continence (ß = 0.043, 95% CI 0.013-0.072), pediatric QoL total score (ß = 0.210, 95% CI 0.011-0.409) and social score (ß = 0.273, 95% CI 0.022-0.525). No associations were observed between PSE and weight z-score, height z-score, readmission or adverse events. CONCLUSIONS: PSE is correlated with fecal continence and QoL of children with HD. PRACTICE IMPLICATIONS: PSE should be considered when designing a parental education program, with the focus on bowel habit training and getting social support.

Detecting compensatory movements of stroke survivors using pressure distribution data and machine learning algorithms.

BACKGROUND: Compensatory movements are commonly employed by stroke survivors during seated reaching and may have negative effects on their long-term recovery. Detecting compensation is useful for coaching the patient to reduce compensatory trunk movements and improving the motor function of the paretic arm. Sensor-based and camera-based systems have been developed to detect compensatory movements, but they still have some limitations, such as causing object obstructions, requiring complex setups and raising privacy concerns. To overcome these drawbacks, this paper proposes a compensatory movement detection system based on pressure distribution data and is unobtrusive, simple and practical. Machine learning algorithms were applied to classify compensatory movements automatically. Therefore, the purpose of this study was to develop and test a pressure distribution-based system for the automatic detection of compensation movements of stroke survivors using machine learning algorithms. METHODS: Eight stroke survivors performed three types of reaching tasks (back-and-forth, side-to-side, and up-and-down reaching tasks) with both the healthy side and the affected side. The pressure distribution data were recorded, and five features were extracted for classification. The k-nearest neighbor (k-NN) and support vector machine (SVM) algorithms were applied to detect and categorize the compensatory movements. The surface electromyography (sEMG) signals of nine trunk muscles were acquired to provide a detailed description and explanation of compensatory movements. RESULTS: Cross-validation yielded high classification accuracies (F1-score>0.95) for both the k-NN and SVM classifiers in detecting compensation movements during all the reaching tasks. In detail, an excellent performance was achieved in discriminating between compensation and noncompensation (NC) movements, with an average F1-score of 0.993. For the multiclass classification of compensatory movement patterns, an average F1-score of 0.981 was achieved in recognizing the NC, trunk lean-forward (TLF), trunk rotation (TR) and shoulder elevation (SE) movements. CONCLUSIONS: Good classification performance in detecting and categorizing compensatory movements validated the feasibility of the proposed pressure distribution-based system. Reliable classification accuracy achieved by the machine learning algorithms indicated the potential to monitor compensation movements automatically by using the pressure distribution-based system when stroke survivors perform seated reaching tasks.

High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats.

Repetitive transcranial magnetic stimulation (rTMS) has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS) on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO), following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX), NeuN and glial fibrillary acidic protein (GFAP), and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.

Low MDR1 and BAALC expression identifies a new subgroup of intermediate cytogenetic risk acute myeloid leukemia with a favorable outcome.

Treatment optimization in acute myeloid leukemia requires the accurate assignment of patients at diagnosis to specific risk groups to guide subsequent risk-adapted treatment stratification. In this study, we have evaluated the impact of expression of the gene BAALC in conjunction with MDR1 in AML with intermediate cytogenetic risk group to more precisely define risk assessment. Low MDR1/high BAALC, high MDR1/low BAALC, and high MDR1/high BAALC expressers demonstrated a similar clinical outcome with CR rate being 68.75-75% and relapse rate being 40-50% and therefore could be considered as a "combined group". In contrast, low expression of both BAALC and MDR1 identifies an intermediate cytogenetic risk group a distinctly favorable outcome, with higher CR rate being 93.3%, lower relapse rate being 7.1%, and longer OS being 50.3% than that of the "combined group". Moreover, low MDR1/low BAALC expressers in the intermediate cytogenetic risk group also demonstrated a comparable clinical outcome with patients in the favorable-risk group. Thus low MDR1/low BAALC expression identifies a subgroup of intermediate cytogenetic risk AML patients with a remarkably good long-term outcome achieved by chemotherapy alone.

Physical exercise promotes recovery of neurological function after ischemic stroke in rats.

Although physical exercise is an effective strategy for treatment of ischemic stroke, the underlying protective mechanisms are still not well understood. It has been recently demonstrated that neural progenitor cells play a vital role in the recovery of neurological function (NF) through differentiation into mature neurons. In the current study, we observed that physical exercise significantly reduced the infarct size and improved damaged neural functional recovery after an ischemic stroke. Furthermore, we found that the treatment not only exhibited a significant increase in the number of neural progenitor cells and neurons but also decreased the apoptotic cells in the peri-infarct region, compared to a control in the absence of exercise. Importantly, the insulin-like growth factor-1 (IGF-1)/Akt signaling pathway was dramatically activated in the peri-infarct region of rats after physical exercise training. Therefore, our findings suggest that physical exercise directly influences the NF recovery process by increasing neural progenitor cell count via activation of the IGF-1/Akt signaling pathway.

Compound heterozygosity for Southeast Asian hereditary persistence of fetal hemoglobin and ß0-thalassemia results in thalassemia intermedia: Pedigree analysis and genetic research in a family from South China. A case report.

RATIONALE: Compound heterozygotes for deletional ß-thalassemia can be difficult to diagnose due to its diverse clinical presentations and no routine screenings. This can lead to disease progression and delay in treatment. PATIENT CONCERNS: We reported pedigree analysis and genetic research in a family with rare ß-thalassemia. DIAGNOSIS: Pedigree analysis and genetic research demonstrated that the patient was a compound heterozygote for ß-thalassemia CD17/Southeast Asian hereditary persistence of fetal hemoglobin deletion, inherited from the parents. Magnetic resonance imaging T2* examination revealed severe iron deposition in the liver. Echocardiography revealed endocardial cushion defect. INTERVENTIONS: The patient was treated with Deferasirox after receiving the final molecular genetic diagnosis. The initial once-daily dose of Deferasirox was 20 mg/kg/d. OUTCOMES: The patient discontinued the medication three months after the first visit. Two years later, the patient visited the Department of Hepatobiliary and Pancreatic Diseases. He was recommended to undergo splenectomy after surgical repair of the congenital heart disease. However, the patient refused surgical treatment because of the economic burden. LESSONS: We report that fetal hemoglobin is a sensitive indicator for screening large deletions of the ß-globin gene, which can be effectively confirmed by the multiplex ligation-dependent probe amplification assay. In non-transfusion-dependent thalassemia patients, iron status assessment should be regularly performed, and iron chelation treatment should be initiated early. This case will provide insights for the diagnosis of rare genotypes of ß-thalassemia and has important implications for genetic counseling.

Correct Information Unit Analysis in Different Discourse Tasks Among Persons With Anomic Aphasia Based on Mandarin AphasiaBank.

PURPOSE: This study aimed to explore how well persons with anomic aphasia communicate information during discourse regarding quantity, quality, and efficiency compared to neurotypical controls, to investigate the influence of discourse tasks on informativeness and efficiency and to examine impact factors like aphasia severity and cognitive ability. METHOD: Language samples of four discourse tasks from 31 persons with anomic aphasia and 31 neurotypical controls were collected from Mandarin AphasiaBank. Correct information unit (CIU) analysis measures including the total number of CIUs, percentage of CIUs, CIUs per minute, and words per minute were calculated. Group differences and the effects of discourse tasks on informativeness and efficiency were investigated. Correlations of CIU analysis measures with aphasia severity and cognitive ability were examined. RESULTS: Persons with anomic aphasia showed lower efficiency in conveying information than controls. They underperformed controls on all CIU analysis measures when executing story narrative tasks. Discourse tasks influenced the informativeness and efficiency of both groups. Neurotypical controls delivered the greatest quantity of information most efficiently when narrating stories. Persons with anomic aphasia exhibited reduced quantity of information during procedural discourse and displayed superior information quality in sequential-picture descriptions. Discourse information may be impacted by aphasia severity and cognitive ability, with varying effects depending on the task. CONCLUSIONS: Persons with anomic aphasia are inefficient in communicating discourse messages and perform poorly on all measures in story narratives. When measuring discourse information, the effects of discourse tasks and factors like aphasia severity and cognitive ability should be considered.

High-frequency repetitive transcranial magnetic stimulation promotes neural stem cell proliferation after ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202408000-00031/figure1/v/2023-12-16T180322Z/r/image-tiff Proliferation of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage. Transcranial magnetic stimulation (TMS) has recently emerged as a tool for inducing endogenous neural stem cell regeneration, but its underlying mechanisms remain unclear. In this study, we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells. Additionally, repetitive TMS reduced the volume of cerebral infarction in a rat model of ischemic stroke caused by middle cerebral artery occlusion, improved rat cognitive function, and promoted the proliferation of neural stem cells in the ischemic penumbra. RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia. Furthermore, PCR analysis revealed that repetitive TMS promoted AKT phosphorylation, leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4. This effect was also associated with activation of the glycogen synthase kinase 3ß/ß-catenin signaling pathway, which ultimately promotes the proliferation of neural stem cells. Subsequently, we validated the effect of repetitive TMS on AKT phosphorylation. We found that repetitive TMS promoted Ca2+ influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway, thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3ß/ß-catenin pathway. These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+ influx-dependent phosphorylated AKT/glycogen synthase kinase 3ß/ß-catenin signaling pathway. This study has produced pioneering results on the intrinsic mechanism of repetitive TMS to promote neural function recovery after ischemic stroke. These results provide a strong scientific foundation for the clinical application of repetitive TMS. Moreover, repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications, but also provide an effective platform for the expansion of neural stem cells.

Preconditioning Exercise Inhibits Neuron Ferroptosis and Ameliorates Brain Ischemia Damage by Skeletal Muscle-Derived Exosomes via Regulating miR-484/ACSL4 Axis.

Aims: Although there is evidence that patients with stroke who exercise regularly before stroke have a better prognosis than those who do not exercise, the detailed mechanism remains unclear. Moreover, neuronal death plays a central role in neurological dysfunction caused by ischemic stroke. Thus, we investigated whether exercise could reduce stroke-induced neuronal death and its associated mediators in the current study. Results: Ferroptosis was the most dominant form of programmed cell death in neurons. Preconditioning exercise before stroke improved the neurological function and decreased the infarct area in rats with ischemic stroke. Preconditioning exercise attenuated stroke-induced ferroptosis by reducing lipid peroxidation (LPO) production, upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4). High-throughput sequencing and dual luciferase reporter assays revealed that exercise-induced exosomal miR-484 inhibits Acsl4 expression. Moreover, we showed that exercise-induced exosomal miR-484 is mainly derived from skeletal muscle, and the neuroprotective effect of preconditioning exercise is suppressed by inhibiting miR-484 production in skeletal muscle. Innovation: This study suggested that neuronal ferroptosis is the most dominant form of programmed cell death in a hypoxic environment. Moreover, we showed that the ferroptosis pathway is a potential therapeutic target in ischemic stroke and that preconditioning exercise could be an effective antioxidant intervention for cerebral ischemia. Conclusion: Our work revealed that preconditioning exercise before stroke exerts neuroprotective effects against brain ischemia by skeletal muscle-derived exosomal miR-484 via inhibiting ferroptosis.

Prediction of 6-month poststroke spasticity in patients with acute first-ever stroke by machine learning.

OBJECTIVE: Poststroke spasticity (PSS) reduces arm function and leads to low levels of independence. This study suggested applying machine learning (ML) from routinely available data to support the clinical management of PSS. DESIGN: 172 patients with acute first-ever stroke were included in this prospective cohort study. Twenty clinical information and rehabilitation assessments were obtained to train various ML algorithms for predicting 6-month PSS defined by a modified Ashworth scale (MAS) score ≥ 1. Factors significantly relevant were also defined. RESULTS: The study results indicated that multivariate adaptive regression spline (area under the curve (AUC) value: 0.916; 95% confidence interval (CI): 0.906-0.923), adaptive boosting (AUC: 0.962; 95% CI: 0.952-0.973), random forest (RF) (AUC: 0.975; 95% CI: 0.968-0.981), support vector machine (SVM) (AUC: 0.980; 95% CI: 0.970-0.989) outperformed the traditional logistic model (AUC: 0.897; 95% CI: 0.884-0.910) (P < 0.05). Among all of the algorithms, the RF and SVM models outperformed the others (P < 0.05). FMA score, days in hospital, age, stroke location, and paretic side were the most important features. CONCLUSION: These findings suggest that ML algorithms can help augment clinical decision-making processes for the assessment of PSS occurrence, which may enhance the efficacy of management for patients with PSS in the future.

Blood Brain Barrier-Crossing Delivery of Felodipine Nanodrug Ameliorates Anxiety-Like Behavior and Cognitive Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.