Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.
Intervertebral Disc Displacement/metabolism* ; Humans ; Aging/pathology* ; Nucleus Pulposus/pathology* ; Male ; Female ; Transcriptome ; Middle Aged ; Lumbar Vertebrae/pathology* ; Adult ; Cellular Senescence ; Stem Cells/pathology* ; Aged ; Intervertebral Disc Degeneration/metabolism*

ObjectiveTo investigate the incidence rate of sarcopenia in patients with Wilson’s disease （WD）-related liver cirrhosis， as well as the risk factors for sarcopenia and their impact on clinical outcomes. MethodsA total of 140 patients with WD-related liver cirrhosis who were treated in The First Affiliated Hospital of Anhui University of Chinese Medicine from January 2019 to June 2020， and according to the third lumbar skeletal muscle mass index （L3 SMI）， the patients were divided into sarcopenia group and non-sarcopenia group. Nutritional risk screening， anthropometric measurements， and blood biochemical tests were performed for the patients to identify the influencing factors for sarcopenia. The patients were followed up for 36 — 48 months， and survival status and complications were compared between the two groups. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the chi-square test and the Mann-Whitney U rank sum test were used for comparison of categorical data between two groups. A binary Logistic regression analysis was used to investigate the influencing factors for sarcopenia， and univariate and multivariate Cox regression analyses were used to investigate the risk factors for the prognosis of patients with WD-related liver cirrhosis. The Kaplan-Meier survival curve was plotted， and the Log-rank test was used for comparison between groups. ResultsAmong the 140 patients with WD-related liver cirrhosis， 53 （37.9%） developed sarcopenia， with significantly lower body mass index （BMI） and L3 SMI than the patients without sarcopenia （t=10.550 and 3.982， both P<0.001）. The multivariate Logistic regression analysis showed that age （odds ratio ［OR］=2.243， 95% confidence interval ［CI］： 1.196 — 4.208， P=0.012）， sex （OR=0.450， 95%CI： 0.232 — 0.872， P=0.018）， BMI （OR=0.126， 95%CI： 0.089 — 0.294， P<0.001）， and hepatic encephalopathy （OR=8.367， 95%CI： 2.423 — 28.897， P<0.001） were the main influencing factors for sarcopenia in patients with WD-related liver cirrhosis. Compared with the non-sarcopenia group， the sarcopenia group had significantly higher mortality rate （χ²=6.158， P=0.019） and significantly higher incidence rates of infection （χ²=8.008， P=0.040）， recurrent abdominal/pleural efflux （χ²=17.742， P<0.001）， and hepatic encephalopathy （χ²=4.338， P=0.039）. The multivariate Cox regression analysis showed that sarcopenia （hazard ratio ［HR］=4.685， P=0.002） and hepatic encephalopathy （HR=19.156， P<0.001） were independent risk factors for death in patients with WD-related liver cirrhosis. The Kaplan-Meier survival curve analysis showed a significant reduction in survival rate in the patients with sarcopenia （P=0.003）. ConclusionSarcopenia is one of the manifestations of malnutrition in patients with WD-related liver cirrhosis， which increases the risk of mortality and other complications and has an adverse effect on prognosis. There is an increased risk of sarcopenia in male patients or patients with hepatic encephalopathy， a lower level of BMI or an older age.

Objective:To compare the localization accuracy of interictal 18F-FDG and 18F-flumazenil (FMZ) PET/CT imaging for focal cortical dysplasia (FCD). Methods:A retrospective analysis was conducted on 22 patients (12 males, 10 females; age 8-36 years) with pathologically confirmed FCD who underwent surgical resection at Huashan Hospital, Fudan University from July 2021 to June 2023. All patients underwent 18F-FDG and 18F-FMZ PET/CT scans before surgery. Surgical pathological diagnosis was used as the gold standard. Visual scoring was used to analyze the images. The accuracy of the two imaging methods in the localization of FCD was compared, and subgroup analysis (FCD Ⅱa, FCD Ⅱb) of different pathological type was further performed. Paired- t test, χ2 test or Fisher′s exact test was used to analyze the data. Results:The visual score of 18F-FMZ PET/CT was higher than that of 18F-FDG (3.00±0.82 vs 2.27±0.92; t=4.17, P=0.020). The accuracy of interictal 18F-FMZ PET/CT was 77.27%(17/22), which was higher than that of 18F-FDG PET/CT (36.36%, 8/22; χ2=7.50, P=0.006). Subgroup analysis showed that within the cohort of patients diagnosed with FCD Ⅱa ( n=18), 18F-FMZ PET/CT outperformed 18F-FDG in terms of accuracy for localization (15/18 vs 6/18; P=0.006). Conclusion:Compared to 18F-FDG, 18F-FMZ PET/CT demonstrates clearer and more accurate identification of lesion borders, and exhibits higher precision, which provides valuable guidance for preoperative localization.

Cough is a common symptom of several respiratory diseases. However, frequent coughing from acute to chronic often causes great pain to patients. It may turn into cough variant asthma, which seriously affects people's quality of life. For cough treatment, it is dominated by over-the-counter antitussive drugs, such as asmeton, but most currently available antitussive drugs have serious side effects. Thus, there is a great need for the development of new drugs with potent cough suppressant. BALB/c mice were used to construct mice model with cough to investigate the pharmacological effects of pectolinarigenin (PEC). Hematoxylin-eosin and Masson staining were used to assess lung injury and airway remodeling, and ELISA was used to assess the level of inflammatory factor release. In addition, inflammatory cell counts were measured to assess airway inflammation. Airway hyperresponsiveness assay was used to assess respiratory resistance in mice. Finally, we used Western blotting to explore the potential mechanisms of PEC. We found that PEC could alleviate lung tissue injury and reduce the release of inflammatory factors, inhibit of cough frequency and airway wall collagen deposition in mice model with cough. Meanwhile, PEC inhibited the Ras/ERK/c-Fos pathway to exhibit antitussive effect. Therefore, PEC may be a potential drug for cough suppression.

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.
Mesenchymal Stem Cells/physiology* ; Cellular Senescence ; Homeostasis ; Cell Cycle Proteins/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; Mitochondria/metabolism* ; Electron Transport Complex III/metabolism* ; Humans ; Cells, Cultured

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Mice ; Animals ; Transcriptome ; Aging/metabolism* ; Cochlea ; Stria Vascularis ; Presbycusis

Objective To develop a new model for predicting recurrence after liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria based on related preoperative and postoperative indicators. Methods A retrospective analysis was performed for the clinical data of the patients with HCC beyond Milan criteria who underwent orthotopic liver transplantation for the first time in Tianjin First Central Hospital from August 2014 to July 2018, and according to the presence or absence of recurrence during follow-up, the patients were divided into recurrence group and no-recurrence group. The t -test or the Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison of survival curves. Univariate and multivariate Cox proportional hazards regression analyses were used to identify the risk factors for recurrence-free survival after surgery. A new model was developed for recurrence after liver transplantation in the patients with HCC beyond Milan criteria based on the risk factors identified. The area under the receiver operating characteristic curve (AUC) was used to evaluate predictive performance, and the Hosmer-Lemeshow test was used to assess the goodness of fit of the model. Results A total of 117 patients with HCC beyond Milan criteria were enrolled in this study, with a median follow-up time of 24 (1-74) months. A total of 53 patients (45.3%) experienced recurrence after surgery, among whom 52 (98.1%) had recurrence within 3 years after surgery, with a median time to recurrence of 6 (1-52) months. The Cox proportional hazards regression analysis showed that preoperative serum alpha-fetoprotein (AFP) >769 ng/mL, neutrophil-lymphocyte ratio (NLR) >3.75, and ki67 index >0.25 were independent risk factors for recurrence-free survival after liver transplantation. The model established based on these three risk factors had an AUC of 0.843, with good sensitivity (88.7%) and specificity (70.3%). The optimal cut-off value was selected according to the maximization of Youden index, and then the patients were divided into low-risk group (0-1 point) and high-risk group (1.5-4 points). The log-rank test showed that the low-risk group had significantly higher 3-and 5-year recurrence-free survival rates than the high-risk group (84.1%/72.0% vs 10.9%/10.9%, χ 2 =29.425, P < 0.001). Conclusion Liver transplantation for HCC beyond Milan criteria should be performed with caution, and the predictive model established based on preoperative AFP, NLR, and ki67 index can accurately assess the indication for liver transplantation in such patients.

Humans ; Mechanistic Target of Rapamycin Complex 2/metabolism* ; Multiprotein Complexes/metabolism* ; Neural Stem Cells/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Rapamycin-Insensitive Companion of mTOR Protein/metabolism* ; TOR Serine-Threonine Kinases/metabolism*

Cell Cycle Proteins ; Microtubule-Associated Proteins