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*

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
Humans ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Transcription Factors/metabolism* ; Gene Expression Regulation ; Hypoxia/metabolism* ; Cell Hypoxia/physiology*

The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
Animals ; Male ; Testis ; Sertoli Cells/metabolism* ; Transcriptome ; Spermatogenesis/genetics* ; Primates ; Aging/genetics* ; Stem Cells

Animals ; Antlers ; Exosomes ; Mesenchymal Stem Cells ; Osteoarthritis/therapy*

Objective: To observe and evaluate the clinical efficacy of laparoscopic abdominoperineal intersphincteric resection com-bined with ileostomy for the treatment of ultra-low rectal cancer. Methods: Clinicopathologic data of 74 patients undergoing laparo-scopic radical resection for ultra-low rectal cancer at Coloproctology Hospital of Chengdu from January 2015 to June 2017 were retro-spectively analyzed. In total, 43 patients underwent laparoscopic abdominoperineal intersphincteric resection combined with ileosto-my (ISR group), and 31 patients underwent laparoscopic low anterior resection combined with ileostomy (LAR group). The periopera-tive condition, radical resection of tumor, and postoperative anal function were compared between the two groups. Results: There were no significant differences in blood loss, postoperative hospital stay, and postoperative complications between the groups (all P>0.05). The mean operative time was (306.6 ± 25.1) minutes in the ISR group and (239.7 ± 26.4) minutes in the LAR group (P=0.010). There were no significant differences in pT and pN between the groups (all P values>0.05). The coincidence rate of T stage diagnosis was 93.0% in the ISR group and 93.5% in the LAR group. The positive rate of circumferential resection margin in the two groups was 0. The mean distance of the distal margin was (2.3±0.1) cm in the ISR group and (1.4±0.3) cm in the LAR group (P<0.001). All patients were followed up for 12-42 (mean 23.4) months. The local recurrence rate was 0 in the ISR group and 12.9% (4/31) in the LAR group (P=0.027); no distant metastasis was observed in any of the groups. There was no significant difference in the results of the anorectal manometry test between the groups (P>0.05). The proportion of patients with good continence of anal function after closure of ileos- tomy was 83.7% in the ISR group and 87.1% in the LAR group (P>0.05). Conclusions: Laparoscopic abdominoperineal intersphincteric resection combined with ileostomy is safe and feasible for the treatment of ultra-low rectal cancer, and it leads to satisfactory anal function and a short-term curative effect.

Objective:To analyze the prognostic factors for survival in elderly patients with glioma.Methods:We performed a retrospective analysis of prognostic factors for elderly patients with glioma,who were treated by the same attending doctor during June 2014 and June 2016,to investigate the correlations of the age,dimension of pathology,histological grade,extent of resection,adjuvant therapy,preoperative Karnofsky Performance Scale (KPS) score,postoperative KPS score,molecular markers [isocitrate dehydrogenase-1 (IDHH-1),O6-methylguanine DNA-transferase (MGMT),epidermal growth factor receptor (EGFR),Ki-67] with the prognosis.Results:A total of 45 patients were included in the study.The median overall survival (OS) was 11 months.The median progression-free survival (PFS) was 6 months.Univariate analysis revealed that the age,gender,dimension ofpathology,histological grade and preoperative KPS score had no significant correlation with survival (P＞0.05).The gross total resection,higher postoperative KPS score,adjuvant therapy,lower Ki-67 index were significantly correlated with survival.The expressions of MGMT and EGFR were significant factors for survival.High postoperative KPS score (P=0.019),adjuvant therapy (P=0.024),and the expression of MGMT (P=0.026) were independent predictors for increased median OS in a multivariate regression model.Conclusion:The extent of resection,adjuvant therapy,postoperative KPS score and molecular markers are the influential factors for survival.Larger prospective studies are needed to confirm these findings.

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Aging ; genetics ; physiology ; DNA Helicases ; genetics ; Human Embryonic Stem Cells ; metabolism ; physiology ; Humans ; Kinetics ; Lamin Type A ; genetics ; Mesenchymal Stem Cells ; metabolism ; physiology ; Mutation ; Progeria ; genetics ; physiopathology ; Werner Syndrome ; genetics ; physiopathology

Objective To survey on the condition of critically ill children in emergency room (ER) for improving the care for them.Methods Data of 374 critically ill children in emergency intensive care unit (EICU) were recorded in the respects of mode of sending them to ER,rescue during transport,length of stay in ER,blood gas,electrolytes,accuracy of assessing pediatric critical illness score/neonate critical illness score (PCIS/NCIS) and Glasgow Coma Scale (GCS),correctness of determining SIRS,sepsis and septic shock.Results Of 374 patients,neonates were 29.9％,and the mean age of children patients not including neonate was 37.4 months.The mean length of ER stay was 4.7 hours (0.42-96 hours).Of 374 patients,those with infection diseases were 47.6％,and the main vehicles for transportation of patient sent to ER were Taxi (38.3％),ambulance (28.4％) and private cars (21.5％).Total fatality was 12.3％ and ER fatality ( 15.6％ ) was higher than in - hospital fatality ( 10.3％,P ＜0.01 ).The mean PCIS/NCIS of 374 patients were 81.92 ± 9.66,and the PCIS/NCIS ≤ 90 accounted for 81％.Of assessed GCSs of 172 patients,GCS≤8,GCS 9-12 and GCS 13-15 accounted for 35.5％,21.5％ and 43.0％ respectively,and fatalities were 26.23％,10.81％ and 5.41％ correspondingly (P ＜0.01 ).The PCIS values of GCS≤8 and GCS 9-12 patients were lower than those of GCS 13-15 patients (P ＜ 0.01 ).There was no significant difference in PCIS between GCS≤8 and GCS 9-12 ( P ＞ 0.05 ).PCIS and GCS were positively correlated (r=0.454,P=0.01).Of374 patients,41.7％ had SIRS,and 25.7％ had sepsis.Of 262 children not including neonates,43.5％ had shock,and 61.4％ of these shock children were septic shock.In 374 patients,those with hyponatremia accounted for 37.2％,and those with hyperkaliemia accounted for 22.0％.The rate of hypoglycemia found in neonates was 20.91％ and rate of hyperglycemia occurred in neonates was 29.1％.The rate of hypoglycemia found in children patients was 9％ and hyperglycemia was 66.7％.Patients with pH ＜ 7.35 accounted for 67.8％ and those with pH ＜ 7.2 were 33.1％.Conclusions The majority of children patients in pediatric ER were neonates and infants.The length of ER stay was short with mean value of 4.7 hours (0.42-96 hours).ER fatality was higher than in - hospital fatality,suggesting the critically ill children patients should be admitted as early as possible.The rate of using ambulance was only 28.4％.The Emergency Medical Service (EMS) should be improved to enhance the public sense of the EMS available.PCIS/NCIS can be used in ER for assessing the conditions and prognosis of critically ill children.GCS ≤8 and GCS 8-12 patients accounted for 57％ with majority of nontrauma brain injury.The values of PCIS in GCS≤8 and GCS 9-12 patients were much lower than those in GCS 13-15 patients.Patients with GCS ＜ 13 might be in critical settings.Majority of shock patients were septic shock (61.4％).Hyponatremia,hyperkalemia,hyperglycemia and hypoglycemia often occurred in critically ill pediatric patients and hypoglycemia not excepted in the neonates should have attention paid to.The main factor of acid -base balance disorder in critically ill children was acidosis (67.8％).