Activities of daily living and non-exercise physical activity in older adults: findings from the Chinese Longitudinal Healthy Longevity Survey.

OBJECTIVES: Studies have shown that good cognitive function can moderate the relationship between non-exercise physical activity (NEPA) and activities of daily living (ADLs) disability to some extent, and this study mainly explores the relationship between ADL and NEPA and cognitive function in Chinese older adults. SETTING AND PARTICIPANTS: Data came from a nationally representative sample of 2471 Chinese old adults (aged 65+) from the 2011, 2014 and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. PRIMARY AND SECONDARY OUTCOME MEASURES: A cross-lagged panel model combined with mediation analysis was used to determine the relationship between ADL and NEPA and the mediating effect of cognitive function on the ascertained ADL-NEPA relationship. RESULTS: The more frequently people over the age of 65 in China participate in NEPA, the lower the risk of ADL disability. Cognitive function partially mediated this expected relationship, accounting for 9.09% of the total NEPA effect on ADL. CONCLUSION: Participating in more NEPA could reduce the risk of ADL disability, and participating in NEPA may reduce the risk of ADL disability through cognitive function to some extent.

Autophagy regulation and protein kinase activity of PIK3C3 controls sertoli cell polarity through its negative regulation on SCIN (scinderin).

Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (PtdIns3K) plays core roles in macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which the gene encoding the catalytic subunit, Pik3c3, was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis which we identified a significant increase of the F-actin negative regulator SCIN (scinderin) and the reduced phosphorylation of HDAC6, an α-tubulin deacetylase. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disorder and disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate a new mechanism for PIK3C3 in maintaining the polarity of Sertoli cells, in which both its autophagy regulation or protein kinase activities are required for the stabilization of the actin cytoskeleton.Abbreviations: ACTB: actin, beta; AR: androgen receptor; ATG14: autophagy related 14; BafA1: bafilomycin A1; BECN1: beclin 1, autophagy related; BTB: blood-testis barrier; CASP3: caspase 3; CDC42: cell division cycle 42; CDH2: cadherin 2; CHX: cycloheximide; CTNNA1: catenin (cadherin associated protein), alpha 1; CYP11A1: cytochrome P450, family 11, subfamily A, polypeptide 1; EBSS: Earle's balanced salt solution; ES: ectoplasmic specialization; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCNA: germ cell nuclear acidic protein; GJA1: gap junction protein, alpha 1; H2AX: H2A.X variant histone; HDAC6: histone deacetylase 6; KIT: KIT proto-oncogene, receptor tyrosine kinase; LAMP1: lysosomal associated membrane protein 1; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; OCLN: occludin; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PNA: arachis hypogaea lectin; RAC1: Rac family small GTPase 1; SCIN: scinderin; SQSTM1/p62: sequestosome 1; SSC: spermatogonia stem cell; STK11: serine/threonine kinase 11; TJP1: tight junction protein 1; TubA: tubastatin A; TUBB3: tubulin beta 3 class III; TUNEL: TdT-mediated dUTP nick-end labeling; UB: ubiquitin; UVRAG: UV radiation resistance associated gene; VIM: vimentin; WT1: WT1 transcription factor; ZBTB16: zinc finger and BTB domain containing 16.

Development of rapid and effective risk prediction models for stroke in the Chinese population: a cross-sectional study.

OBJECTIVES: The purpose of this study was to use easily obtained and directly observable clinical features to establish predictive models to identify patients at increased risk of stroke. SETTING AND PARTICIPANTS: A total of 46 240 valid records were obtained from 8 research centres and 14 communities in Jiangxi province, China, between February and September 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: The area under the receiver operating characteristic curve (AUC), sensitivity, specificity and accuracy were calculated to test the performance of the five models (logistic regression (LR), random forest (RF), decision tree (DT), extreme gradient boosting (XGBoost) and gradient boosting DT). The calibration curve was used to show calibration performance. RESULTS: The results indicated that XGBoost (AUC: 0.924, accuracy: 0.873, sensitivity: 0.776, specificity: 0.916) and RF (AUC: 0.924, accuracy: 0.872, sensitivity: 0.778, specificity: 0.913) demonstrated excellent performance in predicting stroke. Physical inactivity, hypertension, meat-based diet and high salt intake were important prediction features of stroke. CONCLUSION: The five machine learning models all had good predictive and discriminatory performance for stroke. The performance of RF and XGBoost was slightly better than that of LR, which was easier to interpret and less prone to overfitting. This work provides a rapid and accurate tool for stroke risk assessment, which can help to improve the efficiency of stroke screening medical services and the management of high-risk groups.

Fasting blood glucose as a predictor of progressive infarction in men with acute ischemic stroke.

OBJECTIVE: Blood glucose is related to early neurological deterioration in acute ischemic stroke, but multiple mechanisms are involved in early neurological deterioration, such as progressive infarction. This study aimed to determine whether fasting blood glucose (FBG) is an independent predictor of progressive infarction. METHODS: From April 2017 to December 2020, we retrospectively enrolled 477 patients with acute ischemic stroke within 48 hours of onset. Demographic characteristics, clinical information, neuroimaging characteristics, and laboratory data were collected after admission. RESULTS: We found that 147 (30.8%) patients had progressive infarction. Multiple regression analysis showed that high FBG concentrations (>7.66 mmol/L) were independently associated with progressive infarction. Sex subgroup analysis showed that high FBG concentrations were an independent predictor of progressive infarction in male patients (odds ratio, 2.559; 95% confidence interval, 1.279-5.121). In a receiver operating characteristic curve analysis, FBG concentrations were a predictor of progressive infarction in all cases, especially in male patients. The cutoff value of FBG in all patients and men was 7.155 mmol/L. CONCLUSIONS: FBG is an independent predictor of progressive infarction in patients with acute ischemic stroke within 48 hours of onset, especially in men. Patients with FBG concentrations ≥7.155 mmol/L are more likely to develop progressive infarction.

A lesion extending three or more slices as a predictor of progressive infarction in anterior circulation small subcortical infarction.

Progressive infarction (PI) is common in small subcortical infarction and may lead to a poor outcome. The purpose of our study is to identify neuroimaging predictors for PI. From April 2017 to December 2020, we enrolled 86 patients with an anterior circulation subcortical infarction within 48 h after onset. Progressive infarction was defined by an increase of ≥ one point in motor power or ≥ two points in the total National Institute of Health Stroke Scale score within 7 days after admission and further confirmed by diffusion-weighted imaging (DWI). To identify predictors, demographic characteristics, clinical information, laboratory date, and neuroimaging characteristics were evaluated. The infarct size and infarct slice number were measured by DWI. We found that thirty-one patients (36%) had PI. In a univariate analysis, the patients with PI had higher levels of triglyceride, lower levels of blood urea nitrogen and prothrombin time, and a higher frequency of infarct slice number ≥ three compared to the patients without PI. After logistic regression stepwise adjustment for all considered relevant confounders, infarct slice number ≥ three slices proved to be independently associated with PI (OR = 4.781, 95% CI 1.677-13.627; OR = 4.867, 95% CI 1.6-14.864; OR = 3.584, 95% CI 1.034-12.420). Our study showed that a lesion extending ≥ three slices on DWI is an independent predictor for progressive infarction in patients with anterior circulation small subcortical infarction.

Lymphocyte-to-Monocyte Ratio Is Independently Associated with Progressive Infarction in Patients with Acute Ischemic Stroke.

Methods: From April 2017 to December 2020, we retrospectively recruited 477 patients with acute ischemic stroke (within 48 hours after onset). Progressive infarction was defined as an increase of ≥1 point in motor power or ≥2 points on the total National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission and extension of the original infarction were further confirmed by diffusion-weighted imaging. Demographic characteristics, clinical information, and neuroimaging characteristics were evaluated after admission. All blood draws and initial imaging were completed within 24 hours of admission. Results: PI occurred in 147 (30.8%) patients. Univariate analysis comparing the two groups revealed that hypertension, initial NIHSS score, discharge NIHSS score, modified Rankin scale score at 90 days, monocyte level, creatinine level, fasting glucose level, LMR, monocyte-to-high-density lipoprotein ratio (MHR), and lesion location were significantly different (P < 0.05). Multivariate logistic regression analysis showed that the odds ratio of PI increased as the quartile of LMR increased, with the lowest quartile as the reference value. Subgroup analyses showed that a high LMR was an independent predictor of PI only in large artery atherosclerosis (LAA) patients. The receiver operating characteristic (ROC) curve was drawn to estimate the predictive value of LMR for PI. For all cases, the area under the curve was 0.583 (95% CI 0.526-0.641), and the best predictive cutoff value was 3.506, with a sensitivity of 53.1% and a specificity of 63.9%. In patients with LAA, the area under the curve was 0.585 (95% CI 0.505-0.665), and the best predictive cutoff value was 3.944, with a sensitivity of 48.7% and a specificity of 72.8%. Conclusions: LMR was an independent predictor for progressive infarction in patients with acute ischemic stroke, especially in LAA cerebral infarction patients.

RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging.

There is increasing evidence that mitophagy, a specialized form of autophagy to degrade and clear long-lived or damaged mitochondria, is impaired in aging and age-related disease. Previous study has demonstrated the obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy. However, it remains unknown whether mitophagy functions in oocyte and what's the regulatory mechanism in oocyte aging. In the study, when fully grown oocytes were treated with CCCP, an uncoupling agent to induce mitophagy, we found the activation of the PRKN-mediated mitophagy pathway accompanied the blockage of meiosis at metaphase I stage. Our result then demonstrated its association with the decreased activity of RAB7 and all the observed defects in CCCP treated oocytes could be effectively rescued by microinjection of mRNA encoding active RAB7Q67L or treatment with the RAB7 activator ML098. Further study indicated PRKN protein level as a rate-limiting factor to facilitate degradation of RAB7 and its GEF (guanine nucleotide exchange factor) complex CCZ1-MON1 through the ubiquitin-proteasome system. In GV oocytes collected during ovarian aging, we found the age-related increase of PINK1 and PRKN proteins and a significant decrease of RAB7 which resulted in defects of mitophagosome formation and the accumulation of damaged mitochondria. The age-related retardation of female fertility was improved after in vivo treatment of ML098. Thus, RAB7 activity is required to maintain the balance between mitophagy and chromosome stability and RAB7 activator is a good candidate to ameliorate age-related deterioration of oocyte quality.Abbreviations: ATG9: autophagy related 9A; ATP: adenosine triphosphate; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CCZ1: CCZ1 vacuolar protein trafficking and biogenesis associated; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GAPs: GTPase-activating proteins; GEF: guanine nucleotide exchange factor; GV: germinal vesicle; GVBD: germinal vesicle breakdown; LAMP1: lysosomal-associated membrane protein 1; MI: metaphase I stage of meiosis; MII: metaphase II stage of meiosis; Mito: MitoTracker; mtDNA: mitochondrial DNA; MON1: MON1 homolog, secretory trafficking associated; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; TEM: transmission electron microscopy; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin, beta; UB: ubiquitin.

NEDD9 promotes invasion and migration of colorectal cancer cell line HCT116 via JNK/EMT.

Neural precursor cell-expressed, developmentally-downregulated 9 (NEDD9) is a multi-domain skeleton protein that serves an important role in the cell signaling process via modulating invasion, metastasis, proliferation and apoptosis of tumor cells. The present study identified that the expression levels of NEDD9 in colorectal cancer were elevated. Therefore, the effect of downregulating the expression of NEDD9 in terms of invasion and migration of colorectal cancer cells was investigated and the role of the JNK pathway in these processes was also investigated. The data revealed that downregulation of NEDD9 and JNK inhibitors suppressed invasion and migration, decreased expression levels of phosphorylated JNK, increased the expression levels of E-cadherin and decreased the expression levels of vimentin. In summary, NEDD9 promotes invasion and migration of colorectal cancer cells via the JNK pathway.