Analysis of m6A-regulated genes and subtype classification in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is the most common and severe clinical manifestation of systemic lupus erythematosus (SLE). N6-methyladenosine (m6A) is a reversible RNA modification and has been implicated in various biological processes. However, the roles of m6A regulators in LN are not fully demonstrated. METHODS: We downloaded the kidney tissue transcriptome dataset of LN patients and normal controls from the GEO database and extracted the expression levels of m6A regulators. We constructed and compared Random Forest (RF) and Support Vector Machine (SVM) models, and subsequently selected featured genes to develop nomogram models. The m6A subtypes were identified based on significantly differentially expressed m6A regulators, and the m6A gene subtypes were identified based on m6A-associated differential genes, and the two m6A modification patterns were comprehensively evaluated. RESULTS: We obtained the GSE32591 and GSE112943 datasets from the GEO database, including 78 LN samples and 36 normal control samples. We extracted the expression levels of 20 m6A regulators. By RF analysis we identified 7 characteristic m6A regulators and constructed nomogramh models with these 7 genes. We identified two m6A subtypes based on these seven important m6A regulators, and the immune cell infiltration levels of the two subtype clusters were significantly different. We identified two more m6A gene subtypes based on m6A-associated DEGs. We calculated the m6A scores using the principal component analysis (PCA) algorithm and found that the m6A scores of m6A cluster A and gene cluster A were lower than those of m6A cluster B and gene cluster B. In addition, we found that the levels of inflammatory factors were also significantly different between m6A clusters and gene clusters. CONCLUSION: This study confirms that m6A regulators are involved in the LN process through different modes of action and provide new diagnostic and therapeutic targets for LN.

The effect of corneal power on the accuracy of 14 IOL power formulas.

BACKGROUND: This study evaluates the impact of corneal power on the accuracy of 14 newer intraocular lens (IOL) calculation formulas in cataract surgery. The aim is to assess how these formulas perform across different corneal curvature ranges, thereby guiding more precise IOL selection. METHODS: In this retrospective case series, 336 eyes from 336 patients who underwent cataract surgery were studied. The cohort was divided into three groups according to preoperative corneal power. Key metrics analyzed included mean prediction error (PE), standard deviation of PE (SD), mean absolute prediction error (MAE), median absolute error (MedAE), and the percentage of eyes with PE within ± 0.25 D, 0.50 D, ± 0.75 D, ± 1.00 D and ± 2.00 D. RESULTS: In the flat K group (Km < 43 D), VRF-G, Emmetropia Verifying Optical Version 2.0 (EVO2.0), Kane, and Hoffer QST demonstrated lower SDs (± 0.373D, ± 0.379D, ± 0.380D, ± 0.418D, respectively) compared to the VRF formula (all P < 0.05). EVO2.0 and K6 showed significantly different SDs compared to Barrett Universal II (BUII) (all P < 0.02). In the medium K group (43 D ≤ Km < 46 D), VRF-G, BUII, Karmona, K6, EVO2.0, Kane, and Pearl-DGS recorded lower MAEs (0.307D to 0.320D) than Olsen (OLCR) and Castrop (all P < 0.03), with RBF3.0 having the second lowest MAE (0.309D), significantly lower than VRF and Olsen (OLCR) (all P < 0.05). In the steep K group (Km ≥ 46D), RBF3.0, K6, and Kane achieved significantly lower MAEs (0.279D, 0.290D, 0.291D, respectively) than Castrop (all P < 0.001). CONCLUSIONS: The study highlights the varying accuracy of newer IOL formulas based on corneal power. VRF-G, EVO2.0, Kane, K6, and Hoffer QST are highly accurate for flat corneas, while VRF-G, RBF3.0, BUII, Karmona, K6, EVO2.0, Kane, and Pearl-DGS are recommended for medium K corneas. In steep corneas, RBF3.0, K6, and Kane show superior performance.

Glycyrrhizin attenuates myocardial ischemia reperfusion injury by suppressing Inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway.

Ferroptosis, a form of regulated cell death process, play an important role in myocardial ischemia‒reperfusion (I/R) injury. Glycyrrhizin (GL), a natural glycoconjugate triterpene, has the property to improve growth rate, immune regulation, antioxidant, anti-inflammatory. However, whether GL can attenuate myocardial I/R injury by modulating ferroptosis or other mechanisms are still unclear. In this study, SD rats underwent in vivo myocardial ischemia/reperfusion (I/R) surgery, while H9C2 cells were subjected to the hypoxia/reoxygenation (H/R) model for in vitro experiments. In addition, TAK-242, a TLR4-specific antagonist, and GL were also used to evaluate the effect and mechanisms of GL on the cardiac function and expression of ferroptosis-related gene and protein in vivo and vitro. The results show that GL decreased not only the expression of the inflammation-related factors (HMGB1, TNF-α, IL-6, IL-18 and IL-1ß), but also reduced the number of TUNEL-positive cardiomyocytes, and mitigated pathological alterations in I/R injury. In addition, GL decreased the levels of MDA, promoted antioxidant capacity such as GSH, CAT, Cu/Zn-SOD, Mn-SOD, and SOD in vivo and vitro. More importantly, GL and TAK-242 regulate ferroptosis-related protein and gene expression in I/R and H/R model. Surprisingly, GL may ameliorate cardiomyocyte ferroptosis and ultimately improves cardiac function induced by H/R via the HMGB1-TLR4-GPX4 axis. Therefore, we have highlighted a novel mechanism by which GL regulates inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway to prevent myocardial I/R injury. GL appears to be a potentially applicable drug for the treatment of myocardial I/R injury.

Factors associated with progressive anisometropia after bilateral intraocular lens implantation in patients with pediatric cataract.

OBJECTIVES: To identify factors associated with progressive anisometropia after bilateral intraocular lens (IOL) implantation in patients with pediatric cataract. METHODS: Clinical and standardized questionnaire data were collected for Sixty-eight patients with pediatric cataract (136 eyes) who underwent bilateral IOL implantation and at least 1 year of follow-up. Univariate and multivariate linear regression models were used to identify factors associated with postoperative anisometropia. RESULTS: The median age at IOL implantation was 3.2 years (range: 1-12.4 years), and median follow-up time was 5.7 years (range: 1.1-14 years). At 1 month postoperatively and at the last follow-up, there were 19 (27%) and 31 (46%) cases of anisometropia ≥1 D, 9 (13%) and 15 (22%) cases of anisometropia ≥2 D, and 2 (3%) and 9 (13%) cases of anisometropia ≥3 D, respectively. Compared with 1 month postoperatively, the amount of anisometropia increased in 45 (67%) patients. Greater anisometropia one year or more after bilateral IOL implantation was associated with larger intereye difference in IOL power (P = 0.032, 95%CI 0.013 to 0.285), intereye difference in preoperative axial length (P = 0.018, 95%CI -1.247 to -0.123), presence of strabismus (P = 0.017, 95%CI 0.063-0.601), anisometropia at 1 month postoperatively (P = 0.001, 95%CI 0.126-0.478), and intereye difference in axial length at the last follow-up (P = 0.047, 95%CI 0.005-0.627). CONCLUSION: Anisometropia might progress after bilateral IOL implantation in patients with pediatric cataract. Greater intereye difference in IOL power, presence of strabismus might increase the potential of progressive anisometropia.

Multi-omic profiling of the developing human cerebral cortex at the single-cell level.

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements (CREs). We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across six broad developmental time points from fetus to adult. We identified cell type-specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at CREs precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell type-specific and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.

Effects of HMGB1/RAGE/cathespin B inhibitors on alleviating hippocampal injury by regulating microglial pyroptosis and caspase activation in neonatal hypoxic-ischemic brain damage.

Microglia play a crucial role in regulating neuroinflammation in the pathogenesis of neonatal hypoxic-ischemic brain damage (HIBD). Pyroptosis, an inflammatory form of programmed cell death, has been implicated in HIBD; however, its underlying mechanism remains unclear. We previously demonstrated that high-mobility group box 1 protein (HMGB1) mediates neuroinflammation and microglial damage in HIBD. In this study, we aimed to investigate the association between HMGB1 and microglial pyroptosis and elucidate the mechanism involved in rats with HIBD (both sexes were included) and in BV2 microglia subjected to oxygen-glucose deprivation. Our results showed that HMGB1 inhibition by glycyrrhizin (20 mg/kg) reduced the expression of microglial pyroptosis-related proteins, including caspase-1, the N-terminus fragment of gasdermin D (N-GSDMD), and pyroptosis-related inflammatory factors, such as interleukin (IL) -1ß and IL-18. Moreover, HMGB1 inhibition resulted in reduced neuronal damage in the hippocampus 72 h after HIBD and ultimately improved neurobehavior during adulthood, as evidenced by reduced escape latency and path length, as well as increased time and distance spent in the target quadrant during the Morris water maze test. These results revealed that HIBD-induced pyroptosis is mediated by HMGB1/receptor for advanced glycation end products (RAGE) signaling (inhibition by FPS-ZM1, 1 mg/kg) and the activation of cathespin B (cat B). Notably, cat B inhibition by CA074-Me (5 mg/kg) also reduced hippocampal neuronal damage by suppressing microglial pyroptosis, thereby ameliorating learning and memory impairments caused by HIBD. Lastly, we demonstrated that microglial pyroptosis may contribute to neuronal damage through the HMGB1/RAGE/cat B signaling pathway in vitro. In conclusion, these results suggest that HMGB1/RAGE/cat B inhibitors can alleviate hippocampal injury by regulating microglial pyroptosis and caspase activation in HIBD, thereby reducing the release of proinflammatory mediators that destroy hippocampal neurons and induce spatial memory impairments.

Mean Platelet Volume/Platelet Count Ratio as a Predictor of Both Incidence and Prognosis of Acute Ischemic Stroke in Hemodialysis Patients.

Purpose: This study aimed to explore whether the mean platelet volume/platelet count ratio (MPR) has predictive value for the occurrence and prognosis of acute ischemic stroke (AIS) in hemodialysis patients. Patients and Methods: A total of 402 patients undergoing maintenance hemodialysis were screened and 259 were enrolled in this study. The receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the predictive power of the models. The patients enrolled in this study were divided into three groups based on the tertiles of the MPR value (Q1, Q2, and Q3). Kaplan-Meier curves were used to investigate the association between the MPR and AIS-free survival in hemodialysis patients. Chi-square analysis was performed to explore the association between the MPR and AIS outcomes in hemodialysis patients. And the AIS outcome was assessed using the modified Rankin Scale (mRS). Results: MPR had a predictive value for the occurrence of AIS (AUC=0.814) in hemodialysis patients with a high sensitivity and specificity. AIS-free survival rates in the MPR Q1, MPR Q2, and MPR Q3 groups were 0.930, 0.701, and 0.360, respectively. The proportion of patients with good outcomes (mRS 0-2) was significantly greater among patients in the MPR Q1-Q2 group than in the MPR Q3 group (0.844 vs 0.745, p <0.001). Conclusion: The MPR can be used as a good predictor of AIS in patients undergoing hemodialysis. Patients on hemodialysis with increased MPR levels had a higher incidence of AIS and poorer functional outcomes than those with low MPR levels.

Cardioprotective effects of Schisantherin A against isoproterenol-induced acute myocardial infarction through amelioration of oxidative stress and inflammation via modulation of PI3K-AKT/Nrf2/ARE and TLR4/MAPK/NF-κB pathways in rats.

BACKGROUND AND AIMS: The scientific community is concerned about cardiovascular disease mortality and morbidity, especially myocardial infarction (MI). Schisantherin A (SCA), a dibenzocyclooctadiene lignan monomer found in S. chinensis fruits has cardiovascular advantages such as increasing NO production in isolated rat thoracic aorta and reducing heart damage caused by ischemia-reperfusion (I/R) through decreasing apoptosis. The present study was undertaken to explore the potential effects of SCA on ISO-induced myocardial infarction in rats. METHODS: Rats were randomly allocated to four groups: control; ISO-treated, and two additional groups of ISO + SCA (5 or 10 mg/kg body weight). All SCA-treated groups were administered with SCA for 20 days and all ISO groups were challenged with ISO on days 19 and 20. RESULTS: SCA significantly attenuated ISO-induced rise in heart/body weight ratio, myocardial infarct size, and cardiac functional biomarkers (CK-MB, cTnI and BNP). SCA pre- and co-treatment resulted in a significant reduction in oxidative stress (via MDA, NO and GSH and increased activities of SOD, CAT and GPx) and inflammation (via decreased levels of TNF-α, IL-6 and IL-1ß) markers when compared to the same levels in cardiac tissue of ISO-treated rats. This study also showed that SCA protects ISO-induced oxidative stress and inflammation by activating the PI3K-AKT/Nrf2/ARE pathway and suppressing TLR4/MAPK/NF-κB pathways. Furthermore, SCA treatment protected histopathological alterations observed in only ISO-treated cardiac transverse sections of rats. CONCLUSION: In conclusion, the findings of this study suggest that SCA protects against cardiac injury in the ISO-induced MI model of rats.

Single-cell RNA sequencing reveals new subtypes of lens superficial tissue in humans.

Although the cell atlas of the human ocular anterior segment of the human eye was revealed by single-nucleus RNA sequencing, whether subtypes of lens stem/progenitor cells exist among epithelial cells and the molecular characteristics of cell differentiation of the human lens remain unclear. Single-cell RNA sequencing is a powerful tool to analyse the heterogeneity of tissues at the single cell level, leading to a better understanding of the processes of cell differentiation. By profiling 18,596 cells in human lens superficial tissue through single-cell sequencing, we identified two subtypes of lens epithelial cells that specifically expressed C8orf4 and ADAMTSL4 with distinct spatial localization, a new type of fibre cells located directly adjacent to the epithelium, and a subpopulation of ADAMTSL4+ cells that might be lens epithelial stem/progenitor cells. We also found two trajectories of lens epithelial cell differentiation and changes of some important genes during differentiation.

Presurgical MRI-Based Radiomics Models for Predicting Cerebellar Mutism Syndrome in Children With Posterior Fossa Tumors.

BACKGROUND: Current studies have indicated that tumoral morphologic features are associated with cerebellar mutism syndrome (CMS), but the radiomics application in CMS is scarce. PURPOSE: To develop a model for CMS discrimination based on multiparametric MRI radiomics in patients with posterior fossa tumors. STUDY TYPE: Retrospective. POPULATION: A total of 218 patients (males 132, females 86) with posterior fossa tumors, 169 of which were included in the MRI radiomics analysis. The MRI radiomics study cohort (169) was split into training (119) and testing (50) sets with a ratio of 7:3. FIELD/SEQUENCE: All the MRI were acquired under 1.5/3.0 T scanners. T2-weighted image (T2W), T1-weighted (T1W), fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI). ASSESSMENT: Apparent diffusion coefficient (ADC) maps were generated from DWI. Each MRI dataset generated 1561 radiomics characteristics. Feature selection was performed with univariable logistic analysis, correlation analysis, and least absolute shrinkage and selection operator (LASSO) penalized logistic regression. Significant clinical features were selected with multivariable logistic analysis and used to constructed the clinical model. Radiomics models (based on T1W, T2W, FLAIR, DWI, ADC) were constructed with selected radiomics features. The mix model was based on the multiparametric MRI radiomics features. STATISTICAL TEST: Multivariable logistic analysis was utilized during clinical features selection. Models' performance was evaluated using the area under the receiver operating characteristic (AUC) curve. Interobserver variability was assessed using Cohen's kappa. Significant threshold was set as P < 0.05. RESULTS: Sex (aOR = 3.72), tumor location (aOR = 2.81), hydrocephalus (aOR = 2.14), and tumor texture (aOR = 5.08) were significant features in the multivariable analysis and were used to construct the clinical model (AUC = 0.79); totally, 33 radiomics features were selected to construct radiomics models (AUC = 0.63-0.93). Seven of the 33 radiomics features were selected for the mix model (AUC = 0.93). DATA CONCLUSION: Multiparametric MRI radiomics may be better at predicting CMS than single-parameter MRI models and clinical model. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: 2.

Long-term postoperative quality of life in childhood survivors with cerebellar mutism syndrome.

Background: To investigate the long-term quality of life (QoL) of children with cerebellar mutism syndrome (CMS) and explore the risk factors for a low QoL. Procedure: This cross-sectional study investigated children who underwent posterior fossa surgery using an online Pediatric Quality of Life Inventory questionnaire. CMS and non-CMS patients were included to identify QoL predictors. Results: Sixty-nine patients were included (male, 62.3%), 22 of whom had CMS. The mean follow-up time was 45.2 months. Children with CMS had a significantly lower mean QoL score (65.3 vs. 83.7, p < 0.001) and subdomain mean scores (physical; 57.8 vs. 85.3, p < 0.001; social: 69.5 vs. 85.1, p = 0.001; academic: p = 0.001) than those without CMS, except for the emotional domain (78.0 vs. 83.7, p = 0.062). Multivariable analysis revealed that CMS (coefficient = -14.748.61, p = 0.043), chemotherapy (coefficient = -7.629.82, p = 0.013), ventriculoperitoneal (VP) shunt placement (coefficient = -10.14, p = 0.024), and older age at surgery (coefficient = -1.1830, p = 0.007) were independent predictors of low total QoL scores. Physical scores were independently associated with CMS (coefficient = -27.4815.31, p = 0.005), VP shunt placement (coefficient = -12.86, p = 0.025), and radiotherapy (coefficient = -13.62, p = 0.007). Emotional score was negatively associated with age at surgery (coefficient = -1.92, p = 0.0337) and chemotherapy (coefficient = -9.11, p = 0.003). Social scores were negatively associated with male sex (coefficient = -13.68, p = 0.001) and VP shunt placement (coefficient = -1.36, p = 0.005), whereas academic scores were negatively correlated with chemotherapy (coefficient = -17.45, p < 0.001) and age at surgery (coefficient = -1.92, p = 0.002). Extent of resection (coefficient = 13.16, p = 0.021) was a good predictor of higher academic scores. Conclusion: CMS results in long-term neurological and neuropsychological deficits, negatively affecting QoL, and warranting early rehabilitation.

Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate.

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

Epidemiological characteristics, clinical presentations, and prognoses of pediatric brain tumors: Experiences of national center for children's health.

Background: We aimed to describe the epidemiological characteristics, clinical presentations, and prognoses in a national health center for children. Methods: From January 2015 to December 2020, 484 patients aged 0-16 years, who were diagnosed with brain tumors and received neurosurgery treatment, were enrolled in the study. Pathology was based on the World Health Organization 2021 nervous system tumor classification, and tumor behaviors were classified according to the International Classification of Diseases for Oncology, third edition. Results: Among the 484 patients with brain tumors, the median age at diagnosis was 4.62 [2.19, 8.17] years (benign tumors 4.07 [1.64, 7.13] vs. malignant tumors 5.36 [2.78, 8.84], p=0.008). The overall male-to-female ratio was 1.33:1(benign 1.09:1 vs. malignant 1.62:1, p=0.029). Nausea, vomiting, and headache were the most frequent initial symptoms. The three most frequent tumor types were embryonal tumors (ET, 22.8%), circumscribed astrocytic gliomas (20.0%), and pediatric-type diffuse gliomas (11.0%). The most common tumor locations were the cerebellum and fourth ventricle (38.67%), the sellar region (22.9%) and ventricles (10.6%). Males took up a higher proportion than females in choroid plexus tumors (63.6%), ET (61.1%), ependymal tumors (68.6%), and germ cell tumors (GCTs, 78.1%). Patients were followed for 1 to 82 months. The overall 5-year survival rate was 77.5%, with survival rates of 91.0% for benign tumors and 64.6% for malignant tumors. Conclusion: Brain tumors presented particularly sex-, age-, and regional-dependent epidemiological characteristics. Our results were consistent with previous reports and might reflect the real epidemiological status in China.

Apigenin alleviates oxidative stress-induced myocardial injury by regulating SIRT1 signaling pathway.

Apigenin is a natural flavonoid which is widely found in vegetables and fruits. However, the mechanism of apigenin in oxidative stress-induced myocardial injury has not been fully elucidated. We established an isoproterenol (Iso)-induced myocardial injury mouse model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell injury model, followed by pretreatment with apigenin to explore its protective effects. Apigenin can significantly alleviate isoproterenol-induced oxidative stress, cell apoptosis and myocardial remodeling in vivo. Apigenin pretreatment can also significantly improve cardiomyocyte morphology, decrease H/R induced oxidative stress, and attenuate cell apoptosis and inflammation in vitro. Further mechanism study revealed that apigenin treatment reversed isoprenaline and H/R-induced decrease of Sirtuin1 (SIRT1). Molecular docking results proved that apigenin can form hydrogen bond with 230 Glu, a key site of SIRT1 activation, indicating that apigenin is an agonist of SIRT1. Moreover, SIRT1 knockdown by siRNA significantly reversed the protective effect of apigenin in H/R-induced myocardial injury. In conclusion, apigenin protects cardiomyocyte function from oxidative stress-induced myocardial injury by modulating SIRT1 signaling pathway, which provides a new potential therapeutic natural compound for the clinical treatment of cardiovascular diseases.

A presurgical voxel-wise predictive model for cerebellar mutism syndrome in children with posterior fossa tumors.

BACKGROUND: This study aimed to investigate cerebellar mutism syndrome (CMS)-related voxels and build a voxel-wise predictive model for CMS. METHODS: From July 2013 to January 2022, 188 pediatric patients diagnosed with posterior fossa tumor were included in this study, including 38 from a prospective cohort recruited between 2020 and January 2022, and the remaining from a retrospective cohort recruited in July 2013-Aug 2020. The retrospective cohort was divided into the training and validation sets; the prospective cohort served as a prospective validation set. Voxel-based lesion symptoms were assessed to identify voxels related to CMS, and a predictive model was constructed and tested in the validation and prospective validation sets. RESULTS: No significant differences were detected among these three data sets in CMS rate, gender, age, tumor size, tumor consistency, presence of hydrocephalus and paraventricular edema. Voxels related to CMS were mainly located in bilateral superior and inferior cerebellar peduncles and the superior part of the cerebellum. The areas under the curves for the model in the training, validation and prospective validation sets were 0.889, 0.784 and 0.791, respectively. CONCLUSIONS: Superior and inferior cerebellar peduncles and the superior part of the cerebellum were related to CMS, especially the right side, and voxel-based lesion-symptom analysis could provide valuable predictive information before surgery.

Male Predisposition in Cerebellar Mutism Syndrome: a Cohort Study.

The aim of this study was to explore the association between sex and cerebellar mutism syndrome and to examine other potential risk factors. This ambispective cohort study examined 218 pediatric patients (132 boys) with a posterior fossa tumor who underwent tumor resection from July 2013 to March 2021. The patients' demographics and tumor characteristics were examined and statistically analyzed to explore the associations among the variables. Multivariable and subgroup analyses were conducted to validate the independent risk factors for cerebellar mutism syndrome (CMS). The male and female patients did not differ significantly in terms of age, tumor size, tumor location, tumor consistency, VP shunt placement before resection, extent of resection, or surgeon, as well as with respect to the presence of hydrocephalus or paraventricular edema. The overall incidence of CMS was 32.6%. The incidence of CMS was significantly higher in male patients than that in female patients (41.7% vs. 18.6%; P = 0.001). In the multivariable analysis, male sex (adjusted odds ratio [OR], 3.27; P = 0.001), solid tumor consistency (adjusted OR, 5.61; P = 0.001), midline location (adjusted OR, 3.78; P = 0.004), and hydrocephalus (adjusted OR, 2.56; P = 0.047) were independent risk factors for the CMS. Chi-square analysis revealed that solid tumor consistency and midline location were associated with medulloblastoma (P < 0.001). Male patients had a higher risk of developing CMS after a posterior fossa tumor resection. Midline location, solid tumor consistency, and hydrocephalus were independent risk factors for CMS.

Delphinidin induces autophagic flux blockage and apoptosis by inhibiting both multidrug resistance gene 1 and DEAD-box helicase 17 expressions in liver cancer cells.

OBJECTIVES: To investigate the function and regulatory mechanisms of delphinidin in the treatment of hepatocellular carcinoma. METHODS: HepG2 and HuH-7 cells were treated with different concentrations of delphinidin. Cell viability was analysed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell autophagy and autophagic flux were analysed by LC3b-green fluorescent protein (GFP)-Adv and LC3b-GFP-monomeric red fluorescent protein-Adv transfected HepG2 and HuH-7 cells, respectively. Cell apoptosis was analysed by Hoechst33342 staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and DNA laddering. Cell autophagy, apoptosis and survival related protein expressions were detected by Western blotting. KEY FINDINGS: After treatment with different concentrations of delphinidin, the cell survival rate was significantly decreased. Delphinidin could block the autophagic flux, resulting in a significant increase in autophagosomes, and led to an increase in cell apoptosis. The combined application of delphinidin and cisplatin could promote the antitumour effect and reduce the dose of cisplatin in tumour cells. Further mechanism studies reveal that delphinidin could inhibit the multidrug resistance gene 1 (MDR1) and the tumour-promoting transcription cofactor DEAD-box helicase 17 (DDX17) expression in tumour cells. Overexpression of DDX17 could reverse delphinidin's antitumor function in tumour cells. CONCLUSIONS: Delphinidin has a strong anti-tumour effect by inducing tumour cell autophagic flux blockage and apoptosis by inhibiting of both MDR1 and DDX17 expression.

High-mobility Group Box 1 Contributes to Hypoxic-Ischemic Brain Damage by Facilitating Imbalance of Microglial Polarization through RAGE-PI3K/Akt Pathway in Neonatal Rats.

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern integral for hypoxic-ischemic brain damage (HIBD) in neonatal rats since it regulates the phenotypic polarization of microglia, as depicted in our previous studies. Since this mechanism is not clear, this study establishes an oxygen-glucose deprivation (OGD) model of highly aggressively proliferating immortalized microglia while modulating the expression of HMGB1 by plasmid transfection. The M1/M2 microglial phenotype and receptor for advanced glycation end products-phosphoinositide 3-kinase/Akt (RAGE-PI3K/Akt) activation were evaluated, showing that HMGB1 promoted the polarization of microglia to the M1 phenotype under OGD conditions. Meanwhile, RAGE, which is the main receptor of HMGB1, was activated, and phosphorylation of PI3K/Akt was upregulated. However, knockdown or inhibition of HMGB1 can weaken the activation of RAGE and phosphorylation of PI3K/Akt. The inhibition of HMGB1 or RAGE-PI3K/Akt attenuated microglial polarization to the M1 phenotype and promoted M2 microglial polarization instead, reducing the release of pro-inflammatory factors. In the neonatal HIBD rat model, the RAGE-PI3K/Akt pathway was activated seven days after hypoxic-ischemic (HI) exposure, and the activation was partly inhibited after pretreatment with the HMGB1 inhibitor. Concurrently, inhibition of the HMGB1-RAGE-PI3K/Akt pathway alleviated neuronal damage in the hippocampus. These findings verified that HMGB1 could lead to an imbalance in M1/M2 microglial polarization through activation of the RAGE-PI3K/Akt signaling pathway under OGD conditions. Obstructing this pathway may attenuate the imbalanced polarization of microglia, enabling its utilization as a therapeutic strategy against brain injury in HIBD.

Postoperative MRI features of cerebellar mutism syndrome: a retrospective cohort study.

OBJECTIVE: In this study, the authors aimed to investigate the relationship between postoperative MRI features and cerebellar mutism syndrome. METHODS: A retrospective cohort of patients who underwent tumor resection from July 2013 to March 2021 for midline posterior fossa tumors was investigated. All patients were followed up at least once. Clinical data were extracted from medical records and follow-up databases. Two neuroradiologists independently reviewed preoperative and postoperative MRI. Univariable and multivariable analyses were performed to compare the postoperative cerebellar mutism syndrome (pCMS) and non-pCMS groups. Correlation analysis was performed using the Spearman correlation coefficient analysis. RESULTS: Of 124 patients, 47 (37.9%) developed pCMS. The median follow-up duration was 45.73 (Q1: 33.4, Q3: 64.0) months. The median duration of mutism was 45 days. The median tumor size was 48.8 (Q1: 42.1, Q3: 56.8) mm. In the univariable analysis, abnormal T2-weighted signal of the left dentate nucleus (DN) (74.5% in the pCMS group vs 36.4% in the non-pCMS group, p < 0.001), right DN (83.0% vs 40.3%, p < 0.001), left superior cerebellar peduncle (SCP) (74.5% vs 27.3%, p < 0.001), right SCP (63.8% vs 23.4%, p < 0.001), left middle cerebellar peduncle (MCP) (51.1% vs 26.0%, p = 0.008), and right MCP (61.7% vs 26.0%, p < 0.001); male sex (83.0% vs 45.5%, p < 0.001); vermis 3 impairment (49.4% vs 19.1%, p = 0.002); solid tumor (91.5% vs 72.7%, p = 0.022); and hydrocephalus (72.3% vs 45.5%, p = 0.006) were more frequent in the pCMS group than in the non-pCMS group. Multivariable logistic analysis showed that male sex (adjusted OR 4.08, p = 0.010) and the cerebro-cerebellar circuit score of T2-weighted images (adjusted OR 2.15, p < 0.001) were independent risk factors for pCMS. The cerebro-cerebellar circuit score positively correlated with the duration of mutism. In Cox regression analysis, the cerebro-cerebellar integrated circuit injury score of T2 (adjusted HR 0.790, 95% CI 0.637-0.980; p = 0.032) and injury of vermis 3 (adjusted HR 3.005, 95% CI 1.197-7.547; p = 0.019) were independently associated with the duration of mutism. CONCLUSIONS: Male sex and cerebro-cerebellar circuit damage are independent risk factors for pCMS. The cerebro-cerebellar circuit score indicates the duration of mutism.

Adiponectin Protects Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury by Suppressing Autophagy.

Adiponectin is a cytokine produced by adipocytes and acts as a potential cardioprotective agent and plays an important role in myocardial ischemia/reperfusion injury. In a myocardial hypoxia/reoxygenation model using neonatal rat ventricular myocytes, we investigated the contribution of adiponectin-mediated autophagy to its cardioprotective effects. Cardiomyocytes were exposed to hypoxia/reoxygenation pretreated with or without adiponectin in the presence of absence of rapamycin. Cell viability was analyzed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Western blotting assay was used to determine the expression levels of microtubule-associated proteins 1A/1B light chain 3B (LC3B), adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), p62/sequestosome 1, unc-51 like autophagy activating kinase 1 (ULK1), and Beclin-1. Autophagosome formation was detected by monodansylcadaverine staining. We found that hypoxia induced a time dependent decline in cardiomyocyte viability, and increase in autophagy and reoxygenation further augmented hypoxia-induced autophagy induction and consequently reduced cell viability. Adiponectin treatment alleviated hypoxia/reoxygenation-induced cellular damage and autophagy in cardiomyocytes. Adiponectin treatment also attenuated hypoxia/reoxygenation-promoted cardiomyocyte autophagy even in the presence of another autophagy stimulator rapamycin in part by inhibiting vacuolar hydron-adenosine triphosphatase. Additionally, autophagy suppression by adiponectin during hypoxia/reoxygenation was associated with the attenuated phosphorylation of AMPK and ULK1, augmented phosphorylation of mTOR, and the reduced protein expression levels of Beclin-1 in cardiomyocytes. Taken together, these results suggest that adiponectin protects ischemia/reperfusion-induced cardiomyocytes by suppressing autophagy in part through AMPK/mTOR/ULK1/Beclin-1 signaling pathway.