[A study on factors associated with age of Alzheimer's disease onset].

Objective: To understand the distribution characteristics of age of Alzheimer's disease (AD) onset and influencing factors. Methods: Based on the follow-up data of Alzheimer's Disease Neuroimaging Initiative from 2005 to 2022, participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline survey, and those with progression to AD during follow-up period were selected as study subjects. Univariate analysis and multiple linear regression analysis were performed to explore the associations of gender, race, number of ApoE ε4 genes carried, family history, years of education and marital status with the age of AD onset. Results: A total of 405 participants, with an average age of (74.0±6.9) years at baseline survey, progressed to AD during follow up period. The age of AD onset was (76.6±7.5) years, and age of onset in men was about 1.9 years later than women. Multiple linear regression analysis showed that for each increase in ApoE ε4 gene number, the age of AD onset was about 0.344 years earlier. The age of AD onset was 4.007 years earlier for those with MCI at baseline survey compared with those with CN. Years of education were not significantly associated with the age of onset of AD (P>0.05). Conclusion: Those who carry ApoE ε4 gene, and have MCI at baseline survey might have earlier age of AD onset.

[Mechanism of VPS26 gene promoting implant osseointegration through Wnt/ß-catenin pathway in hyperlipidemia rats].

Objective: To investigate the mechanism of VPS26 effect on osteogenesis and adipogenesis differentiation of rat bone marrow mesenchymal stem cells (BMSC) in high fat environment, and to explore the effect of VPS26 on implants osseointegration of high fat rats and ectopic osteogenesis in nude mice. Methods: BMSC were cultured under normal osteogenic induction (osteogenic group) and high-fat osteogenic induction (high-fat group).High-fat group was transfected with VPS26 enhancer and inhibitor, and the expression levels of osteogenesis related genes and adipogenesis related genes were examined. Osteogenesis and adipogenesis of BMSC were detected by alkaline phosphatase (ALP) staining and oil red O staining after 7 and 14 days of induction.In osteogenic group,the binding of VPS26 to ß-catenin was detected by immunofluorescence staining and immunoprecipitation, and dual luciferase reporter assay (TOP Flash) was used to analyze the TOP/FOP ratio. Eighteen male 12-week hyperlipidemic Wista rats (160-200 g) were implanted with implants, and six in each group were injected with VPS26 overexpression lentivirus (LV-VPS26 group), negative control lentivirus (LV-nc group) and saline (blank control group).Micro-CT analysis , HE and oil red O staining were used to evaluate the osseointegration of the implants and lipid droplets formation of the femur samples. Twenty female 6-week nude mice (30-40 g) were divided into five groups and subcutaneously implanted with osteogenic BMSC non-transfected and transfected LV-VPS26, LV-nc, shVPS26, and shscr lentivirus on the back. Samples were used to observe ectopic osteogenesis. Results: The mRNA expression levels of ALP in the high-fat group BMSC after overexpression of VPS26 (1.56±0.09) were significantly higher than those of the negative control (1.01±0.03) (t=10.09, P<0.001), while those of peroxisome proliferator-activated receptor-γ (PPAR-γ) (t=6.44, P<0.001) and fatty acid-binding protein4 (FABP4) (t=10.01, P<0.001) were lower than those of the negative control. Western blotting results showed that compared with the negative control, protein expression of ALP and Runt-related transcription gene 2 was enhanced in the high-fat group BMSC after overexpression of VPS26 while PPAR-γ and FABP4 were inhibited. ALP activity of BMSC in the high-fat group was stronger after overexpression of VPS26, and the formation of lipid droplets was weaker than that in negative control. The results of immunofluorescence, immunoprecipitation and dual luciferase reporter assays showed co-localization and interaction of VPS26 with ß-catenin and a significant 43.10% increase in the TOP/FOP ratio (t=-3.17, P=0.034). VPS26 overexpression enhanced osseointegration and decreased the number of lipid droplets in high-fat rat and enhanced ectopic osteogenesis of nude mice. Conclusions: VPS26 activated osteogenesis differentiation and inhibited adipogenic differentiation of BMSCs through Wnt/ß-catenin pathway, promoting osseointegration of high-fat rat implants and ectopic osteogenesis of nude mice.

[Multimorbidity developmental trajectory among middle-aged and older adults and its impact on new-onset disability in China].

Objective: To explore the developmental trajectory of multimorbidity and its impact on new-onset disability to identify homogeneous groups with similar multimorbidity developmental courses and to provide evidence for interventions for disability risk among middle-aged and older adults in China. Methods: Data was retrospectively collected from China Health and Retirement Longitudinal Study with four consecutive surveys (2011-2018). Group-based trajectory modeling was used to fit multimorbidity developmental trajectories, and the impact of multimorbidity trajectories on new-onset disability was analyzed using the time-dependent Cox regression model. Results: A total of 8 580 participants were included in current analysis, and four multimorbidity trajectories were identified: no multimorbidity (n=2 136, 24.90%), newly-developing (n=3 758, 43.80%), moderate-developing (n=2 270, 26.45%) and severe-developing (n=416, 4.85%). Participants who belong to moderate-developing and severe-developing tended to be female, single, overweight or obese, live in rural areas, have poorer self-rated health and high levels of annual per capita household expenditure, and developed a new-onset disability. After adjusting for demographic and behavioral covariates, compared to the newly-developing, the severe-developing(HR=3.132, 95%CI:1.884-5.207) had the highest risk of disability, followed by the moderate- developing (HR=1.400, 95%CI:1.026-1.909) and the risk for the no multimorbidity (HR=0.631, 95%CI:0.424-0.938) was the lowest. Conclusions: There was great heterogeneity in the developmental trajectory of multimorbidity among middle-aged and older adults in China. Data showed that the risk of disability in the developmental trajectory of multimorbidity increases with increasing levels. We think that the elevating developmental trajectory of multimorbidity is a risk factor for developing disability.

[Transition rules of cognitive frailty and influencing factors in the elderly in China].

Objective: To understand the transition rules of cognitive frailty and its influencing factors in the elderly in China and provide evidence for the early intervention of cognitive frailty. Methods: Data were retrospectively collected from China Health and Retirement Longitudinal Study with 3 round consecutive survey (2011, 2013, 2015) and the state of the subjects were classified into four categories: robust-normal cognitive, cognitive impairment, physical frailty, and cognitive frailty. A multi-state Markov model was established to explore the transition rules of cognitive frailty and its influencing factors. Results: A total of 3 470 older adults were included, and 350 (10.09%) had cognitive frailty at baseline. After two years, the probability of cognitive frailty in the cognitive impairment population was higher than that in people with physical frailty (31.6% vs. 7.6%). Persons with cognitive frailty were more likely to become physical frailty (29.7% vs. 15.6%). Being women (HR=1.599, 95%CI: 1.058-2.417), comorbidity (HR=3.035, 95%CI: 1.090-8.450), and depression (HR=1.678, 95%CI: 1.153-2.441) were the risk factors associated with cognitive frailty in the elderly, while being educated (HR=2.367, 95%CI: 1.567-3.575) was a protective factor for the transition of cognitive frailty to physical frailty. Conclusions: The prevalence of cognitive frailty is relatively high in the elderly in China. Those with cognitive impairment have a higher probability of cognitive frailty. Gender, education level, comorbidity, and depression are the main influencing factors for the occurrence and transition of cognitive frailty.

[Research on predicting the risk of mild cognitive impairment in the elderly based on the joint model].

Objective: To construct and compare the dynamic prediction models of the risk of mild cognitive impairment (MCI) in the elderly based on six different cognitive function scales. Methods: Based on longitudinal data from the Alzheimer's Disease Neuroimaging Initiative from 2005 to 2020, Mini-mental state examination (MMSE), functional activities questionnaire (FAQ), Alzheimer's disease assessment scale-cognitive (ADAS-Cog) 11, ADAS-Cog13, ADAS delayed word recall (ADASQ4), and Rey auditory verbal learning test (RAVLT)_immediate were used as longitudinal cognitive function evaluation indicators to assess the longitudinal changes in cognitive function. The joint model was used to analyze association between indicators variation trajectory and survival outcome MCI, and construct the risk prediction model of MCI in the elderly, the linear mixed model was constructed the longitudinal sub-model which described the evolution of a repeated measure over time, a proportional hazards model was constructed the survival sub-model, and the two sub-models were connected through the correlation parameter (α). The areas under the receiver operator characteristic curve (AUC) were used to evaluate the predictive efficacy of the model in the follow-up period of (t, t+Δt). The starting point t was selected at the 30th, 42nd, and 54th month, and the Δt was selected as 15 and 21 months. Based on the prediction model, an example of the research object was selected for dynamic individual predictions of the risk of MCI. Results: Finally, 544 older adults (aged 60 years and above) with normal baseline cognitive status were included, of which 119 cases (21.9%) had MCI during the follow-up process were regarded as the case group, and 425 cases remained normal as the control group. The joint model suggests that the longitudinal trajectories of the six evaluation indicators are all related to the risk of MCI (P<0.001). The risk of MCI decreased by 32.3% (HR=0.677, 95%CI: 0.541-0.846) and 10.8% (HR=0.892, 95%CI: 0.865-0.919) for each one-point increase of MMSE and RAVLT_immediate longitudinal scores. The risk of MCI increased by 53.2% (HR=1.532, 95%CI: 1.393-1.686), 36.2% (HR=1.362, 95%CI: 1.268-1.462), 23.2% (HR=1.232, 95%CI: 1.181-1.285), and 85.1% (HR=1.851, 95%CI:1.629-2.104) for each one-point increase of FAQ, ADAS-Cog11, ADAS-Cog13, and ADASQ4 longitudinal scores. AUC results show that RAVLT_immediate (0.760 2) and ADASQ4 (0.755 8) have higher average prediction efficiency, followed by ADAS-Cog13 (0.743 7), ADAS-Cog11 (0.715 3), FAQ (0.700 8) and MMSE (0.629 5). ADASQ4 joint model was used to provide a dynamic individual prediction of the risk of MCI. The average probability of MCI after five years of follow-up and ten years of follow-up in the example individuals were 8% and 40%, respectively. Conclusions: The RAVLT_immediate and ADASQ4 scales, which are only for memory tests, have high accuracy in predicting the risk of MCI. Using the RAVLT_immediate and ADASQ4 scales as longitudinal cognitive function evaluation indicators to construct a joint model, the results can provide a basis for realizing MCI risk prediction for the elderly.

[SNP Panel Analysis of Ancestry Inference in East Asian Populations].

ABSTRACT: Objective To develop an SNP Panel for East Asian population, which has a high individual identification rate and the capability of ancestry analysis. Methods The 55 SNP Panel by Professor KIDD of Yale University and the 128 SNP Panel by Professor SELDIN of Davis School of California University, 170 SNP Panel in total was used as the basis and its test data in the East Asian population was collected. The genetic parameters of SNP loci were calculated and combined with the results of heatmap analysis to screen SNP loci suitable for East Asian population. Some Tibetan and Han samples were tested. The possibility of using the SNP loci in ancestry inference was analyzed by means of STRUCTURE analysis, principal component analysis and heatmap analysis. Results A Panel with 45 SNPs （45 SNP Panel） was screened out, and the average genetic parameters of each SNP were better than 170 SNP Panel, with the same ancestry analysis and inference ability. Conclusion In terms of ancestry inference information, the 45 SNP Panel can completely replace the 170 SNP Panel and achieve the same ancestry analysis and inference ability. In genetic parameters, 45 SNP Panel is better than 170 SNP Panel in the East Asian population, which shows its important potential forensic application value.

Luteoloside Ameliorates Palmitic Acid-Induced in Vitro Model of Non-alcoholic Fatty Liver Disease via Activating STAT3-Triggered Hepatocyte Regeneration.

Luteoloside (Lute), a bioactive natural ingredient, widely exists in nature and possesses hepatoprotective and hepatocyte proliferation-promoting properties. This study aimed to investigate whether Lute could counteract non-alcoholic fatty liver disease (NAFLD)-caused hepatocyte damage via its stimulation of hepatocyte regeneration efficacy and to explore the involved mechanism. LO2 cells and primary hepatocytes were used to examine the hepatocyte proliferation effects of Lute under physiological conditions and in the palmitic acid (PA)- induced in vitro model of NAFLD. STAT3 and cell cycle-related proteins (cyclin D1, c-myc and p21) were evaluated by Western blot. Under physiological conditions, LO2 cells and primary hepatocytes treated with various concentration of Lute for 12 and 24 h showed increased hepatocyte proliferation, especially with 20 µM treatment for 24 h. More notably, under the model conditions, co-incubation with 20 µM of Lute also markedly reversed PA-induced inhibition of cell proliferation and viability in primary hepatocytes. Mechanistically, Lute could activate STAT3 and subsequently increase cyclin D1 and cmyc expression, which positively regulates cell cycle progression, and decrease expression of p21, an inhibitor of cell cycle progression. Furthermore, Luteinduced hepatocyte proliferation-promoting efficacy was abolished by STAT3 inhibitor stattic. Collectively, Lute can alleviate PA-induced hepatocyte damage via activating STAT3-mediated hepatocyte regeneration.

[Progress in research of association of adverse childhood experiences with prevalence of common chronic diseases in adulthood].

The effects of adverse childhood experiences on adult health has aroused increasing concern in the world in recent years, but limited studies have been conducted in China. This study synthesized the measurement of adverse childhood experiences, the association between adverse childhood experiences and the prevalence common chronic diseases in adulthood and possible mechanisms. It was found that though measurement range of adverse childhood experiences might be different among studies, current used measurement scales basically met the requirement of disease prevention. Most categories of adverse childhood experiences were positively related to risk of common chronic diseases, and the relationship was influenced by social economic status, sex and age. However, people with exposure to famine in childhood had lower prevalence of hypertension compared with those without the exposure. The possible mechanisms might be that the occurrence of adverse childhood experiences might damage physiological functions or increase the adoption of poor healthy behaviors and lifestyles, and finally increased the risk of chronic diseases directly or indirectly. While premature death due to adverse childhood experiences might reverse the association because of nonrandom selection. It is necessary for us to select appropriate indexes of adverse childhood experiences and conduct more studies to prove the association between adverse childhood experiences and prevalence of common chronic diseases in adulthood and explore the related mechanism for the better prevention of chronic diseases in China.

[Association between TV watching time and the cognitive functions among the elderly aged 60 years and above in Xiamen City].

Objective: To explore the cognitive functions of the elderly aged 60 years and above in Xiamen, and whether TV watching time would affect those functions. Methods: We conducted a cross-sectional study on 3 230 registered individuals aged 60 years and above in Xiamen from July to October in 2016 with a multi-stage random sampling method. Montreal Cognitive Assessment (MoCA) was used to measure cognitive functions and ordinal logistic regression was used to quantify their associations with TV watching time. Results: A total of 2 944 respondents were included in this study. The overall age of them was (70.14±7.81) years. 51.49% (n=1 516) of all participants were men. Overall, the mean scores of MoCA in general and each subdomain cognitive function were 18.65±6.43 (general), 5.43±1.17 (orientation), 2.33±1.95 (memory), 1.80±1.52 (visuospatial), 1.66±1.20 (executive), 4.54±1.71 (attention), and 4.09±1.64 (language). Compared to those who watched TV no more than 2 hours per day, the elderly who did not watch TV had a worse performance in general, orientation, memory, visuospatial, executive, attention, language function, with OR (95%CI) values about 0.50 (0.35-0.71), 0.52 (0.37-0.73), 0.68 (0.48-0.96), 0.67 (0.47-0.96), 0.48 (0.34-0.67), 0.56 (0.41-0.77) and 0.45 (0.33-0.62), respectively. As to respondents who watched TV more than 2 hours but no more than 4 hours per day, they had a better performance in general, executive, attention, language, and orientation function with respective OR (95%CI) values about 1.24 (1.05-1.47), 1.20 (1.02-1.41), 1.41 (1.19-1.67), 1.51 (1.28-1.77) and 1.33 (1.08-1.64). Conclusion: The elderly aged 60 years and above in Xiamen City with TV watching time between 2 and 4 hours per day had a good performance in cognitive functions compared to those with more or less TV watching time.

[Research on spatiotemporal spread of avian influenza A(H7N9) virus based on discrete geographic information].

Objective: To establish a dynamic spatiotemporal spread modes of influenza A (H7N9) virus by using discrete geographic information and explore the spatiotemporal transmission of the virus. Methods: The gene sequences of H7N9 virus isolated from human in China, which were available from Global Initiative on Sharing Avian Influenza Data (GISAID), were used in alignment by using software BioEdit 7.0. Spatiotemporal spread model of H7N9 virus was established in a Bayesian statistical framework by using software BEAST 1.8.2. The symmetric substitution model and Bayesian stochastic search variable selection (BSSVS) were used to infer and verify the historical transmission route of H7N9 virus. Finally the spatiotemporal transmission route was presented by Google Earth software. Results: The transmission of avian influenza A (H7N9) virus originated in Shanghai and Hangzhou, and can be dated back to October 2012. In March and April 2013, it began to spread to the neighboring provinces. The transmission speed up in August and September and affected more than ten geographic positions within 3 months. Conclusion: Based on gene sequences and spatial geographic information, the transmission route of H7N9 virus was traced, which would support the avian influenza prevention and control as well as avian influenza virus tracing.

Ensemble-based simultaneous emission estimates and improved forecast of radioactive pollution from nuclear power plant accidents: application to ETEX tracer experiment.

The accidental release of radioactive materials from nuclear power plant leads to radioactive pollution. We apply an augmented ensemble Kalman filter (EnKF) with a chemical transport model to jointly estimate the emissions of Perfluoromethylcyclohexane (PMCH), a tracer substitute for radionuclides, from a point source during the European Tracer Experiment, and to improve the forecast of its dispersion downwind. We perturb wind fields to account for meteorological uncertainties. We expand the state vector of PMCH concentrations through continuously adding an a priori emission rate for each succeeding assimilation cycle. We adopt a time-correlated red noise to simulate the temporal emission fluctuation. The improved EnKF system rapidly updates (and reduces) the excessively large initial first-guess emissions, thereby significantly improves subsequent forecasts (r = 0.83, p < 0.001). It retrieves 94% of the total PMCH released and substantially reduces transport error (>80% average reduction of the normalized mean square error).

The anti-tumoral efficacy of a docetaxel-loaded liposomal drug delivery system modified with transferrin for ovarian cancer.

To reduce the toxic effect on normal cells and improve the treatment effects of docetaxel, a novel transferrin modified docetaxel-loaded long circulating liposome for ovarian tumor was established for the first time. The transferrin-modified long-circulating liposomes loaded with docetaxel (TF-LP-DOC) were prepared by the post-insertion method and exhibited excellent characteristics in terms of particle size, encapsulation efficiency and stability. We investigated the targeting efficiencies of liposomes by the cellular uptake in vitro and biodistribution in vivo, and identified the therapeutic effects using cytotoxicity experiment (in vitro)and tumor growth inhibition (in vivo) on ovarian cancer. The in vitro and in vivo results showed that TF-LP-DOC were successfully established and presented an enhanced targeting ability. With decreased side effect and improved anti-tumor efficacy of chemotherapeutic drugs, TF-LP-DOC proved itself to be a very promising tumor targeted drug delivery system.