Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

The role of ATP in sleep-wake regulation: In adenosine-dependent and -independent manner.

ATP plays a crucial role as an energy currency in the body's various physiological functions, including the regulation of the sleep-wake cycle. Evidence from genetics and pharmacology demonstrates a strong association between ATP metabolism and sleep. With the advent of new technologies such as optogenetics, genetically encoded biosensors, and novel ATP detection methods, the dynamic changes in ATP levels between different sleep states have been further uncovered. The classic mechanism for regulating sleep by ATP involves its conversion to adenosine, which increases sleep pressure when accumulated extracellularly. However, emerging evidence suggests that ATP can directly bind to P2 receptors and influence sleep-wake regulation through both adenosine-dependent and independent pathways. The outcome depends on the brain region where ATP acts and the expression type of P2 receptors. This review summarizes the experimental evidence on the relationship between ATP levels and changes in sleep states and outlines the mechanisms by which ATP is involved in regulating the sleep-wake cycle through both adenosine-dependent and independent pathways. Hopefully, this review will provide a comprehensive understanding of the current research basis and progress in this field and promote further investigations into the specific mechanisms of ATP in regulating sleep.

[An analysis of clinical efficacy of microvascular decompression for 21 inpatients suffering from primary hemifacial spasm].

Objective:To assess the effectiveness of microvascular decompression（MVD） in treating inpatients suffering from primary hemifacial spasm（HFS）. Methods:A total of 21 inpatients with HFS underwent MVD. The clinical effect was follow up evaluated according to the clinical symptoms until post operative 6 months. Results:The effective rate of MVD for 1 day, 14 days, 1 month, 3 months and 6 months post-operation was 95.2%, 100%, 100%, 100% and 100%, respectively.one patient had transient tinnitus and the symptom disappeared within 6 days postoperatively.one patient developed postoperative incomplete facial paralysis（HB grade IV facial nerve function, grade Ⅱ） and recovered 6 days after surgery; There was no cerebrospinal fluid leakage, intracranial infection, death or disability occurred during follow-up. Conclusion:Microvascular decompression is a safe and effective method for the treatment of primary hemifacial spasm, which is worthy of clinical promotion.

Differences in Physiologic Endotypes Between Nonpositional and Positional OSA: Results From the Shanghai Sleep Health Study Cohort.

BACKGROUND: Positional OSA (POSA) is a recognized subtype of OSA that exhibits distinct endotypic characteristics when compared with nonpositional OSA (NPOSA). The basis for the disparity in endotypes between these subtypes remains poorly understood. RESEARCH QUESTION: (1) Do individuals with NPOSA and POSA have different underlying OSA endotypes? (2) Which endotypic characteristics are critical in determining NPOSA and POSA severity? STUDY DESIGN AND METHODS: Within the Shanghai Sleep Health Study cohort, individuals with OSA were recruited and classified as having POSA or NPOSA. Endotypes were calculated using polysomnography. RESULTS: Endotype analysis was conducted in 1,036 individuals with OSA. Compared with individuals with NPOSA, those with POSA had lower loop gain calculated during all sleep stages and all sleep positions (0.55; interquartile range [IQR], 0.46-0.66 vs 0.68, IQR, 0.52-0.90; P < .001), lower arousal threshold calculated during all sleep stages and all sleep positions (ArTHAll) (138.67; IQR, 118.94-180.87 percentage of the eupneic ventilation [%Veupnea] vs 189.00; IQR, 129.71-257.76 %Veupnea; P < .001), lower pharyngeal collapsibility calculated during all sleep stages and all sleep positions (VpassiveAll) (91.85; IQR, 83.13-95.15 %Veupnea vs 76.38; IQR, 23.77-92.08 %Veupnea; P < .001), and higher muscle compensation calculated during all sleep stages and all sleep positions (6.50; IQR, -6.77 to 16.39 %Veupnea vs 3.65; IQR, -10.47 to 12.14 %Veupnea; P = .003). Logistic regression analyses indicated that higher VpassiveAll was associated with increased odds of POSA vs NPOSA. In NPOSA, fully adjusted linear regression analyses indicated that VpassiveAll (ß = -0.55; 95% CI, -0.68 to -0.42; P < .001) and lower loop gain calculated during all sleep stages and all sleep positions (ß = 0.19; 95% CI, 0.08-0.30; P < .001) were significant independent predictors of the apnea hypopnea index, with VpassiveAll being the most critical factor. In contrast, in POSA, collapsibility appeared to be less influential (ß = -0.09; 95% CI, -0.21 to 0.03; P = .138). Nonanatomic endotypic characteristics (LGAll: ß = 0.29; 95% CI, 0.18-0.41; P < .001; arousal threshold in all sleep stages and all sleep positions: ß = 0.15; 95% CI, 0.01-0.28; P = .031; muscle compensation in all sleep stages and all sleep positions: ß = -0.21; 95% CI, -0.29 to -0.12; P < .001) were significant in determining the severity of POSA, with loop gain being the most crucial factor. INTERPRETATION: This study highlights the differences in endotypes between NPOSA and POSA. In Chinese individuals, anatomic factors were more significant in determining the severity of NPOSA, whereas nonanatomic traits were more likely to determine the severity of POSA. Future research should focus on developing personalized management strategies for individuals with NPOSA and POSA based on their endotypes. TRIAL REGISTRATION: Chinese Clinical Trial Registry; No.: ChiCTR1900025714; URL: https://www.chictr.org.cn/indexEN.html.

Single-cell RNA-Seq reveals the heterogeneity of fibroblasts within the tympanojugular paraganglioma microenvironment.

Tympanojugular paragangliomas (TJP) originate from the parasympathetic ganglia in the lateral base of the skull. Although the cellular composition and oncogenic mechanisms of paragangliomas have been evaluated, a comprehensive transcriptomic atlas specific to TJP remains to be established to facilitate further investigations. In this study, single-cell RNA sequencing and whole-exome sequencing were conducted on six surgically excised TJP samples to determine their cellular composition and intratumoral heterogeneity. Fibroblasts were sub-classified into two distinct groups: myofibroblasts and fibroblasts associated with bone remodeling. Additionally, an elaborate regulatory and cell-cell communication network was determined, highlighting the multifaceted role of fibroblasts, which varies depending on expression transitions. The Kit receptor (KIT) signaling pathway mediated interactions between fibroblasts and mast cells, whereas robust connections with endothelial and Schwann cell-like cells were facilitated through the platelet-derived growth factor signaling pathway. These findings establish a foundation for studying the mechanisms underlying protumor angiogenesis and the specific contributions of fibroblasts within the TJP microenvironment. IL6 signaling pathway of fibroblasts interacting with macrophages and endothelial cells may be involved in tumor regrowth. These results enhance our understanding of fibroblast functionality and provide a resource for future therapeutic targeting of TJP.

Global burden of head and neck cancers from 1990 to 2019.

Head and neck cancer (HNC) exerts a significant healthcare burden worldwide. Insufficient data impedes a comprehensive understanding of its global impact. Through analysis of the 2019 Global Burden of Disease (GBD) database, our secondary investigation unveiled a surging global incidence of HNC, yet a decline in associated mortality and disability-adjusted life years (DALYs) owing to enhanced prognosis. Particularly noteworthy is the higher incidence of escalation among females compared to males. Effective resource allocation, meticulous control of risk factors, and tailored interventions are imperative to curtail mortality rates among young individuals afflicted with HNC in underprivileged regions, as well as in elderly individuals grappling with thyroid cancer.

T266M variants of ANGPTL4 improve lipid metabolism by modifying their binding affinity to acetyl-CoA carboxylase in obstructive sleep apnea.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the ß-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. METHODS: This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured via ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA. RESULTS: Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, p = 6.02 × 10-16). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4. CONCLUSIONS: Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.

Cellular and Molecular Insights into the Divergence of Neural Stem Cells on Matrigel and Poly-l-lysine Interfaces.

Poly-l-lysine (PLL) and Matrigel, both classical coating materials for culture substrates in neural stem cell (NSC) research, present distinct interfaces whose effect on NSC behavior at cellular and molecular levels remains ambiguous. Our investigation reveals intriguing disparities: although both PLL and Matrigel interfaces are hydrophilic and feature amine functional groups, Matrigel stands out with lower stiffness and higher roughness. Based on this diversity, Matrigel surpasses PLL, driving NSC adhesion, migration, and proliferation. Intriguingly, PLL promotes NSC differentiation into astrocytes, whereas Matrigel favors neural differentiation and the physiological maturation of neurons. At the molecular level, Matrigel showcases a wider upregulation of genes linked to NSC behavior. Specifically, it enhances ECM-receptor interaction, activates the YAP transcription factor, and heightens glycerophospholipid metabolism, steering NSC proliferation and neural differentiation. Conversely, PLL upregulates genes associated with glial cell differentiation and amino acid metabolism and elevates various amino acid levels, potentially linked to its support for astrocyte differentiation. These distinct transcriptional and metabolic activities jointly shape the divergent NSC behavior on these substrates. This study significantly advances our understanding of substrate regulation on NSC behavior, offering novel insights into optimizing and targeting the application of these surface coating materials in NSC research.

Genetic variations of low-density lipoprotein cholesterol on metabolic disorders in obstructive sleep apnea.

BACKGROUND: The study aimed to explore the relationship between low-density lipoprotein cholesterol (LDL-C) genetic variants and obstructive sleep apnea (OSA) and its complications, including cardiovascular diseases (CVD), insulin resistance (IR), and metabolic syndrome (MS). METHOD: 4329 individuals with suspected OSA who underwent a comprehensive assessment of anthropometric, biochemical, and polysomnography (PSG) data, along with 30 LDL-C single nucleotide polymorphisms (SNPs) were enrolled. The 10-year Framingham CVD risk score (FRS), IR and MS were evaluated for each subject. Linear regression and logistic regression were utilized to examine the correlations among these variables. RESULTS: After the Benjamini-Hochberg correction, linear regression results indicated positive correlations between variants rs3741297 and rs629301 with FRS (ß = 0.031, PBH=0.002; ß = 0.026, PBH=0.015). Logistic regression revealed that rs3741297 increased MS risk among total subjects [OR = 1.67 (95% CI:1.369-2.038), PBH=1.32 × 10- 5] and increased IR risk in females [OR = 3.475 (95% CI:1.653-7.307), PBH=0.03]. In males, rs2642438 decreased MS risk [OR = 0.81 (95% CI:0.703-0.933), PBH=0.045]. CONCLUSIONS: The rs3741297 variant correlated with susceptibility to CVD, IR, and MS in the OSA population. OSA, CVD, IR and MS share a potentially common genetic background, which may promote precision medicine. CINICAL TRIAL REGISTRATION: The study protocol was registered with the Chinese Clinical Trial Registry (ChiCTR1900025714).

Association between multiple sleep dimensions in obstructive sleep apnea and an early sign of atherosclerosis.

STUDY OBJECTIVES: We investigated the associations between multiple sleep dimensions in obstructive sleep apnea (OSA) and carotid intima-media thickness (CIMT), an early sign of atherosclerosis, in participants from the Shanghai Sleep Health Study. METHODS: We performed secondary analysis of SSHS in a group of subjects who underwent ultrasound evaluation from 2018 to 2022. Multiple sleep dimensions were measured using standard polysomnography. CIMT was measured from ultrasound images as an early sign of atherosclerosis. Multivariable-adjusted linear regression and logistic regression analyses were performed to detect associations between sleep traits in OSA and CIMT. RESULTS: CIMT was found to increase with increasing severity of OSA (P < .001). When adjusted for conventional risk factors, microarousal index and hypoxic burden were positively correlated with CIMT, while slow-wave sleep and mean apnea-hypopnea event duration showed a negative correlation with CIMT (all P < .01). In binary logistic regression analysis, participants with a high microarousal index, less slow-wave sleep, higher hypoxic burden, and shorter mean apnea-hypopnea event duration showed a higher prevalence of thick CIMT with no evidence of interaction by age, sex, or body mass index (P-interaction > .05). CONCLUSIONS: Patients with more severe sleep fragmentation, more severe hypoxemia, and increased arousability were more likely to have increased CIMT after adjusting for potential confounders. It is important to evaluate novel indices of sleep fragmentation, hypoxemia, and arousability in OSA for early detection and prevention of cardiovascular disease, including stroke. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trial Registry; Name: Establishing Bio-bank and Cohort of OSAHS in Hospital-based Population; URL: http://www.chictr.org.cn/showproj.aspx?proj=43057; Identifier: ChiCTR1900025714. CITATION: Huang W, Zhou E, Zhang J, et al. Association between multiple sleep dimensions in obstructive sleep apnea and an early sign of atherosclerosis. J Clin Sleep Med. 2024;20(7):1093-1104.

Obstructive Sleep Apnea Syndrome Exacerbates NASH Progression via Selective Autophagy-Mediated Eepd1 Degradation.

Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non-alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH-exposed mice, which deviates from human responses. To address this issue, a pair-feeding investigation with CIH-exposed and normoxia-exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome-wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver-specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH-induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH-mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH-mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS.

Comparison of healing of acute total tympanic membrane perforation between rats with and without excision of the mallear handle.

Objective: We compared the histological changes and hearing restoration during the healing of acute total tympanic membrane (TM) perforations between Sprague-Dawley (SD) rats with and without excision of the mallear handle. Materials and methods: Bilateral, acute, and total TM perforations were created in 36 male SD rats. The mallear handle was preserved in the left ear (handle-preserved ear [HPE]) and excised from the right ear (handle-excised ear [HEE]). Endoscopical examination, auditory brainstem response (ABR) thresholds, histopathological, and scanning electron microscope (SEM) analysis were performed. Results: Endoscopic photographs showed that all perforations in the 18 SD rats were closed. The mean closure times were 6.83 ± 0.85 and 8.50 ± 0.71 days in the HPE and HEE groups, respectively (p < .001). SEM images showed radial arrangement of fiber bundles in a single direction in HPEs, although normal arrangement was not achieved. In contrast, HEEs showed disorganized arrangement. At 1 month after perforation closure, the ABR thresholds at high frequencies were significantly higher in the HEE group than in the HPE group (p = .029 and p = .017 for 16 and 32 kHz, respectively). Additionally, the changes in ABR threshold were significantly different at high frequencies (p = .011 and p = .017 for 16 and 32 kHz, respectively) before and 1 month after perforation closure between the HPE and HEE groups, although the differences were not statistically significant at the remaining frequencies. Conclusion: Although the malleus handle may not affect the closure of total perforation in SD rats, it contributes to accelerate the perforation closure by possible guide the migration of proliferative epithelial cell on the upper halves of the annulus. Additionally, resection of the malleus handle impairs high frequency hearing recovery following spontaneous closure of the TM.