Objective:To explore the relationship between obesity indicators and DNA methylation clocks acceleration,and to analyze their temporal sequence.Methods:Data were obtained from two sur-veys conducted in 2013 and 2017-2018 by the Chinese National Twin Registry.Peripheral blood DNA methylation data were measured using the Illumina Infinium Human Methylation 450K BeadChip and EPIC BeadChip.DNA methylation clocks/acceleration metrics(GrimAA,PCGrimAA and Dunedin-PACE)were calculated using the DNA methylation online tool(https://dnamage.genetics.ucla.edu/)or R code provided by researchers.Obesity indicators included weight,body mass index(BMI),waist circumference,waist-hip ratio,and waist-height ratio.A total of 1 070 twin individuals were included in the cross-sectional analysis,comprising 378 monozygotic(MZ)twin pairs and 155 dizygotic(DZ)twin pairs for within-pair analysis.Mixed-effects models were used to examine the associations between obesity indicators and DNA methylation clocks,as well as their acceleration measures.The longitudinal analysis included 314 twin individuals,comprising 95 MZ twin pairs and 62 DZ twin pairs for within-pair analy-sis.Cross-lagged panel models were applied to further explore the temporal relationships between obesity and DNA methylation clock indicators.All analyses were conducted both in the full twin sample and separately within MZ and DZ twin pairs.Results:In the cross-sectional analysis population,monozygotic twins accounted for 71.0％,males for 68.0％,and the mean chronological age was(49.9±12.1)years.In the longitudinal analysis population,monozygotic twins accounted for 60.5％,males for 60.8％,with a mean baseline chronological age of(50.4±10.2)years and a mean follow-up duration of(4.6±0.6)years.Except for the waist-to-hip ratio,which was significantly higher at follow-up com-pared with baseline,no statistically significant differences were observed in the means of other obesity in-dicators between baseline and follow-up.Correlation analysis revealed that weight,BMI,waist circumfe-rence,waist-hip ratio(WHR),and waist-height ratio(WHtR)were positively correlated with Dunedin-PACE in all the twins,with WHtR showing the strongest association(β=0.21,95％CI:0.11 to 0.31).Weight and BMI were negatively associated with GrimAA(β=-0.03,95％CI:-0.05 to-0.01;β=-0.07,95％CI:-0.12 to-0.02),while weight was negatively associated with PCGrim-AA(β=-0.02,95％CI:-0.03 to 0.00).However,within-twin-pair analyses showed no statistically significant correlations.Cross-lagged panel model analysis indicated that higher baseline weight might lead to increased GrimAA at follow-up,while elevated baseline weight,BMI,and waist circumference might increase PCGrimAA.Higher baseline WHR was associated with increased DunedinPACE at follow-up.Conclusion:Obesity indicators correlate with DNA methylation clock acceleration metrics.Baseline obesity may influence changes in certain DNA methylation clock indicators over time,suggesting that obesity could exert long-term health effects by accelerating DNA methylation aging.However,these associations may be confounded by shared genetic or environmental factors among the twins.

Objective:To investigate the influencing factors of enlarged perivascular space (PVS) in relapsing-remitting multiple sclerosis (RRMS) patients and their relationship with cognitive function.Methods:Twenty-seven individuals with RRMS (RRMS group) and 27 healthy controls (healthy control group) who presented to the Department of Neurology, the Sixth Medical Center of People′s Liberation Army General Hospital from July 2022 to November 2024 underwent cognitive function assessments. PVS volume fractions, lesion volumes, and brain volumes were calculated using FreeSurfer, FSL, and other relevant softwares. Group differences in PVS volume fractions, lesion volumes, brain volumes, and cognitive function assessments were compared. Furthermore, correlations between PVS volume fractions and lesion volumes, brain volumes, and cognitive function assessments were analyzed within the RRMS group.Results:Compared with the healthy control group, the RRMS group exhibited significantly higher PVS volume fractions in white matter (PVS_w) (3.14‰±0.29‰ vs 2.91‰±0.30‰, t=2.877, P=0.006) and PVS volume fractions in deep gray matter (PVS_d) (2.25‰±0.10‰ vs 2.17‰±0.09‰, t=2.681, P=0.010), indicating an enlargement of the PVS. Compared with the healthy control group, the RRMS group showed a significant decrease in both white matter volumes [297.3 (274.3, 340.2) ml vs (324.2 (311.0, 350.0) ml, U=-2.085, P=0.037] and deep grey matter volumes [40.2 (34.9, 43.6) ml vs 42.7 (40.2, 44.8) ml, U=-2.292, P=0.022]. Compared with the healthy control group, the RRMS group showed significantly lower scores in cognitive function assessments ( P<0.05). Univariate analysis showed that PVS_w in the RRMS group was significantly positively correlated with age ( r=0.486), white matter lesion volumes ( r=0.437) and deep gray matter lesion volumes ( r=0.394;all P<0.05); PVS_d was also significantly positively correlated with white matter lesion volumes ( r=0.418) and deep gray matter lesion volumes ( r=0.480; both P<0.05). Multiple linear regression analysis showed that age ( B=0.011,95% CI 0.004-0.017), white matter lesion volumes ( B=0.026,95% CI 0.011-0.040) and deep gray matter lesion volumes ( B=0.401,95% CI 0.032-0.771) in the RRMS group were significantly positively correlated with PVS_w, while white matter lesion volumes ( B=0.007,95% CI 0.001-0.014) and deep gray matter lesion volumes ( B=0.204,95% CI 0.029-0.380) were significantly positively correlated with PVS_d (both P<0.05). Univariate analysis showed that immediate memory score in the RRMS group was significantly negatively correlated with PVS_d ( r=-0.428), and was significantly positively correlated with education level ( r=0.471), deep gray matter volumes ( r=0.530) and total brain volumes ( r=0.389; all P<0.05); short-term delayed memory score in the RRMS group was significantly negatively correlated with age ( r=-0.390), PVS_w ( r=-0.417) and white matter lesion volumes ( r=-0.438), and was significantly positively correlated with gender ( r=0.393), white matter volumes ( r=0.478), deep gray matter volumes ( r=0.579) and total brain volumes ( r=0.602;all P<0.05); verbal fluency test score in the RRMS group was significantly negatively correlated with PVS_d ( r=-0.409) and was significantly positively correlated with education level ( r=0.419) and total brain volumes ( r=0.400;all P<0.05). Multiple linear regression analysis revealed that PVS_d ( B=-5.572, 95% CI -11.513--0.368) and brain volumes ( B=0.012, 95% CI 0.001-0.023) in the RRMS group were both significant predictors of immediate recall score, while PVS_d ( B=-14.203,95% CI -27.514--0.891) was an independent predictor of verbal fluency test score (all P<0.05). Conclusions:The PVS is enlarged in individuals with RRMS compared with the healthy controls, and increased lesion volumes may be a significant predictor. Furthermore, enlarged PVS in the deep gray matter may be a significant predictor of impairment of verbal memory and verbal function in individuals with RRMS.

Objective:To investigate the sero-conversion rate of HIV antibody and influencing factors in cross-border couples in Dehong Dai and Jingpo Autonomous Prefecture(Dehong).Methods:A cohort design was used to recruit HIV-negative people in cross-border couples in Dehong in 2017. Follow-up was conducted in 2023, and questionnaire survey and HIV test were carried out to calculate the sero-conversion rate of HIV antibody. Univariate and multivariate logistic regression models were used to analyze the influence factors for HIV infections.Results:A total of 36 278 HIV-negative persons in cross-border couples were included in the 2017 baseline survey, of whom 22 438 (61.9%) were tested in follow-up in 2023. The sero-conversion rate between 2017 and 2023 was 0.51% (115/22 438). Multivariate logistic regression analysis showed that length of marriage <6 years, Jingpo ethnic group, education level of primary school or below, drug use, illegal marriage and HIV infected spouse were the risk factors of HIV infection in male spouses, and length of marriage <6 years, Jingpo ethnic group, illegal marriage and HIV infected spouse were the risk factors in female spouses.Conclusions:The sero-conversion rate of HIV antibody in cross-border couples in Dehong was relatively high. HIV infection was mainly caused by secondary transmission in the couples, and men might also be infected through drug use. It is necessary to strengthen the registration and management of cross-border couples, especially the couples with discordant HIV infection status, and the intervention in drug users to reduce the risk for secondary transmission of HIV in the cross-border couples.

Objective: To investigate the regional differences in the incidence of urothelial carcinoma among kidney transplant recipients between northern and southern China，so as to provide reference for early diagnosis of this disease. Methods: A comprehensive search was conducted across multiple databases，including CNKI，Wanfang，CBM，and PubMed，using the keywords “kidney transplantation” and “tumor” to collect clinical data from qualified kidney transplant centers.The latest and most complete literature data published by 17 transplant centers in northern China and 14 in southern China were included.Statistical analyses were performed to compare the incidence of post-transplant urothelial carcinoma and non-urothelial malignancies. Results: A total of 37 475 kidney transplant recipients were included，among whom 837 (2.23%) developed post-transplant malignancies，including urothelial carcinoma (366/837，43.73%)，non-urothelial carcinoma (444/837，53.05%)，and malignancies with unspecified pathology (27/837，3.23%).The incidence of malignancies was significantly higher in northern China than in southern China [(2.82±1.39)% vs. (1.67±0.83)%，P=0.011]，with a particularly pronounced difference in the incidence of urothelial carcinoma [(1.68±1.12)% vs. (0.32±0.32)%，P<0.001].No significant difference was observed in the incidence of non-urothelial carcinoma between the two regions [(1.11±0.56)% vs. (1.35±0.65)%，P=0.279].Additionally，female transplant recipients exhibited a higher incidence of malignancies than males in both regions (southern China：2.38% vs. 1.80%; northern China：8.93% vs. 2.52%). Conclusion: The incidence of urothelial carcinoma following kidney transplantation is significantly higher in northern China than in southern China，underscoring the importance of implementing regular tumor screening for kidney transplant recipients，particularly for female patients in northern China，to facilitate early diagnosis and timely intervention.

Objective:To investigate the sero-conversion rate of HIV antibody and influencing factors in cross-border couples in Dehong Dai and Jingpo Autonomous Prefecture(Dehong).Methods:A cohort design was used to recruit HIV-negative people in cross-border couples in Dehong in 2017. Follow-up was conducted in 2023, and questionnaire survey and HIV test were carried out to calculate the sero-conversion rate of HIV antibody. Univariate and multivariate logistic regression models were used to analyze the influence factors for HIV infections.Results:A total of 36 278 HIV-negative persons in cross-border couples were included in the 2017 baseline survey, of whom 22 438 (61.9%) were tested in follow-up in 2023. The sero-conversion rate between 2017 and 2023 was 0.51% (115/22 438). Multivariate logistic regression analysis showed that length of marriage <6 years, Jingpo ethnic group, education level of primary school or below, drug use, illegal marriage and HIV infected spouse were the risk factors of HIV infection in male spouses, and length of marriage <6 years, Jingpo ethnic group, illegal marriage and HIV infected spouse were the risk factors in female spouses.Conclusions:The sero-conversion rate of HIV antibody in cross-border couples in Dehong was relatively high. HIV infection was mainly caused by secondary transmission in the couples, and men might also be infected through drug use. It is necessary to strengthen the registration and management of cross-border couples, especially the couples with discordant HIV infection status, and the intervention in drug users to reduce the risk for secondary transmission of HIV in the cross-border couples.

Objective:To explore the relationship between obesity indicators and DNA methylation clocks acceleration,and to analyze their temporal sequence.Methods:Data were obtained from two sur-veys conducted in 2013 and 2017-2018 by the Chinese National Twin Registry.Peripheral blood DNA methylation data were measured using the Illumina Infinium Human Methylation 450K BeadChip and EPIC BeadChip.DNA methylation clocks/acceleration metrics(GrimAA,PCGrimAA and Dunedin-PACE)were calculated using the DNA methylation online tool(https://dnamage.genetics.ucla.edu/)or R code provided by researchers.Obesity indicators included weight,body mass index(BMI),waist circumference,waist-hip ratio,and waist-height ratio.A total of 1 070 twin individuals were included in the cross-sectional analysis,comprising 378 monozygotic(MZ)twin pairs and 155 dizygotic(DZ)twin pairs for within-pair analysis.Mixed-effects models were used to examine the associations between obesity indicators and DNA methylation clocks,as well as their acceleration measures.The longitudinal analysis included 314 twin individuals,comprising 95 MZ twin pairs and 62 DZ twin pairs for within-pair analy-sis.Cross-lagged panel models were applied to further explore the temporal relationships between obesity and DNA methylation clock indicators.All analyses were conducted both in the full twin sample and separately within MZ and DZ twin pairs.Results:In the cross-sectional analysis population,monozygotic twins accounted for 71.0％,males for 68.0％,and the mean chronological age was(49.9±12.1)years.In the longitudinal analysis population,monozygotic twins accounted for 60.5％,males for 60.8％,with a mean baseline chronological age of(50.4±10.2)years and a mean follow-up duration of(4.6±0.6)years.Except for the waist-to-hip ratio,which was significantly higher at follow-up com-pared with baseline,no statistically significant differences were observed in the means of other obesity in-dicators between baseline and follow-up.Correlation analysis revealed that weight,BMI,waist circumfe-rence,waist-hip ratio(WHR),and waist-height ratio(WHtR)were positively correlated with Dunedin-PACE in all the twins,with WHtR showing the strongest association(β=0.21,95％CI:0.11 to 0.31).Weight and BMI were negatively associated with GrimAA(β=-0.03,95％CI:-0.05 to-0.01;β=-0.07,95％CI:-0.12 to-0.02),while weight was negatively associated with PCGrim-AA(β=-0.02,95％CI:-0.03 to 0.00).However,within-twin-pair analyses showed no statistically significant correlations.Cross-lagged panel model analysis indicated that higher baseline weight might lead to increased GrimAA at follow-up,while elevated baseline weight,BMI,and waist circumference might increase PCGrimAA.Higher baseline WHR was associated with increased DunedinPACE at follow-up.Conclusion:Obesity indicators correlate with DNA methylation clock acceleration metrics.Baseline obesity may influence changes in certain DNA methylation clock indicators over time,suggesting that obesity could exert long-term health effects by accelerating DNA methylation aging.However,these associations may be confounded by shared genetic or environmental factors among the twins.

Objective:To investigate the influencing factors of enlarged perivascular space (PVS) in relapsing-remitting multiple sclerosis (RRMS) patients and their relationship with cognitive function.Methods:Twenty-seven individuals with RRMS (RRMS group) and 27 healthy controls (healthy control group) who presented to the Department of Neurology, the Sixth Medical Center of People′s Liberation Army General Hospital from July 2022 to November 2024 underwent cognitive function assessments. PVS volume fractions, lesion volumes, and brain volumes were calculated using FreeSurfer, FSL, and other relevant softwares. Group differences in PVS volume fractions, lesion volumes, brain volumes, and cognitive function assessments were compared. Furthermore, correlations between PVS volume fractions and lesion volumes, brain volumes, and cognitive function assessments were analyzed within the RRMS group.Results:Compared with the healthy control group, the RRMS group exhibited significantly higher PVS volume fractions in white matter (PVS_w) (3.14‰±0.29‰ vs 2.91‰±0.30‰, t=2.877, P=0.006) and PVS volume fractions in deep gray matter (PVS_d) (2.25‰±0.10‰ vs 2.17‰±0.09‰, t=2.681, P=0.010), indicating an enlargement of the PVS. Compared with the healthy control group, the RRMS group showed a significant decrease in both white matter volumes [297.3 (274.3, 340.2) ml vs (324.2 (311.0, 350.0) ml, U=-2.085, P=0.037] and deep grey matter volumes [40.2 (34.9, 43.6) ml vs 42.7 (40.2, 44.8) ml, U=-2.292, P=0.022]. Compared with the healthy control group, the RRMS group showed significantly lower scores in cognitive function assessments ( P<0.05). Univariate analysis showed that PVS_w in the RRMS group was significantly positively correlated with age ( r=0.486), white matter lesion volumes ( r=0.437) and deep gray matter lesion volumes ( r=0.394;all P<0.05); PVS_d was also significantly positively correlated with white matter lesion volumes ( r=0.418) and deep gray matter lesion volumes ( r=0.480; both P<0.05). Multiple linear regression analysis showed that age ( B=0.011,95% CI 0.004-0.017), white matter lesion volumes ( B=0.026,95% CI 0.011-0.040) and deep gray matter lesion volumes ( B=0.401,95% CI 0.032-0.771) in the RRMS group were significantly positively correlated with PVS_w, while white matter lesion volumes ( B=0.007,95% CI 0.001-0.014) and deep gray matter lesion volumes ( B=0.204,95% CI 0.029-0.380) were significantly positively correlated with PVS_d (both P<0.05). Univariate analysis showed that immediate memory score in the RRMS group was significantly negatively correlated with PVS_d ( r=-0.428), and was significantly positively correlated with education level ( r=0.471), deep gray matter volumes ( r=0.530) and total brain volumes ( r=0.389; all P<0.05); short-term delayed memory score in the RRMS group was significantly negatively correlated with age ( r=-0.390), PVS_w ( r=-0.417) and white matter lesion volumes ( r=-0.438), and was significantly positively correlated with gender ( r=0.393), white matter volumes ( r=0.478), deep gray matter volumes ( r=0.579) and total brain volumes ( r=0.602;all P<0.05); verbal fluency test score in the RRMS group was significantly negatively correlated with PVS_d ( r=-0.409) and was significantly positively correlated with education level ( r=0.419) and total brain volumes ( r=0.400;all P<0.05). Multiple linear regression analysis revealed that PVS_d ( B=-5.572, 95% CI -11.513--0.368) and brain volumes ( B=0.012, 95% CI 0.001-0.023) in the RRMS group were both significant predictors of immediate recall score, while PVS_d ( B=-14.203,95% CI -27.514--0.891) was an independent predictor of verbal fluency test score (all P<0.05). Conclusions:The PVS is enlarged in individuals with RRMS compared with the healthy controls, and increased lesion volumes may be a significant predictor. Furthermore, enlarged PVS in the deep gray matter may be a significant predictor of impairment of verbal memory and verbal function in individuals with RRMS.

Objective To investigate the effects and mechanism of modified Ditan Decoction in regulating miR-149 on liver injury in rats with chronic intermittent hypoxia.Methods Totally 18 male SD rats were randomly divided into control group,model group,and modified Ditan Decoction,with 6 rats in each group.The model group and the modified Ditan Decoction group were modeled in a low oxygen chamber.During the modeling period,the modified Ditan Decoction group was given gavage of the modified Ditan Decoction for 12 consecutive weeks.HE staining was used to observe the pathological changes of liver tissue;the ultrastructural changes of liver tissue were observed by transmission electron microscopy,TUNEL staining was used to observe hepatocyte apoptosis,the contents of ALT,AST,SOD and MDA in liver tissue were detected,the mRNA and protein expression of miR-149,ATF6,GRP78 and CHOP in liver tissue were detected by RT-qPCR and Western blot.The correlation between the mRNA transcription levels of miR-149 and ATF6 was analyzed.Results Compared with the control group,a small amount of inflammatory cell infiltration in liver tissue of the model group,with irregular arrangement of liver cells,varying degrees of edema,expansion of endoplasmic reticulum,ribosome shedding,mitochondrial membrane rupture,and apoptosis rate of liver cells increased(P<0.05),the contents of ALT,AST and MDA significantly increased(P<0.05),while the content of SOD significantly decreased(P<0.05),the expression of miR-149 mRNA in liver tissue decreased(P<0.05),while the mRNA and protein expression of ATF6,GRP78 and CHOP increased(P<0.05).Compared with the model group,no obvious edema or inflammatory cell infiltration was observed in liver tissue of rats in the modified Ditan Decoction group,the liver cells were arranged in a regular manner,with slightly expanded endoplasmic reticulum and more uniform distribution of ribosomes,the mitochondrial membrane was relatively intact,and the apoptosis rate of liver cells decreased(P<0.05),the contents of ALT,AST and MDA decreased(P<0.05),while the content of SOD increased(P<0.05),the expression of miR-149 mRNA in liver tissue significantly increased(P<0.05),while the mRNA and protein expression of ATF6,GRP78 and CHOP significantly decreased(P<0.05).The level of miR-149 mRNA was significantly negatively correlated with that of ATF6 mRNA(r=-0.766).Conclusion Modified Ditan Decoction may inhibit liver oxidative stress response in chronic intermittent hypoxia rats and improve liver injury by regulating the miR-149/ATF6 pathway.

Objective:To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function.Methods:Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains.Results:Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens ( P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment ( r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory ( r=0.45, P=0.047) and information processing speed impairment ( r=0.50, P=0.026). Conclusions:Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

OBJECTIVE: To screen for small molecular compounds with selective inhibitory activity against cutaneous melanoma cells with BAP1 deletion. METHODS: Cutaneous melanoma cells expressing wild-type BAP1 were selected to construct a BAP1 knockout cell model using CRISPR-Cas9 system, and small molecules with selective inhibitory activity against BAP1 knockout cells were screened from a compound library using MTT assay. Rescue experiment was carried out to determine whether the sensitivity of BAP1 knockout cells to the candidate compounds was directly related to BAP1 deletion. The effects of the candidate compounds on cell cycle and apoptosis were detected with flow cytometry, and the protein expressions in the cells were analyzed with Western blotting. RESULTS: The p53 activator RITA from the compound library was shown to selectively inhibit the viability of BAP1 knockout cells. Overexpression of wild-type BAP1 reversed the sensitivity of BAP1 knockout cells to RITA, while overexpression of the mutant BAP1 (C91S) with inactivated ubiquitinase did not produce any rescue effect. Compared with the control cells expressing wild-type BAP1, BAP1 knockout cells were more sensitive to RITA-induced cell cycle arrest and apoptosis (P < 0.0001) and showed an increased expression of p53 protein, which was further increased by RITA treatment (P < 0.0001). CONCLUSION Loss of BAP1 results in the sensitivity of cutaneous melanoma cells to p53 activator RITA. In melanoma cells, the activity of ubiquitinase in BAP1 is directly related to their sensitivity to RITA. An increased expression of p53 protein induced by BAP1 knockout is probably a key reason for RITA sensitivity of melanoma cells, suggesting the potential of RITA as a targeted therapeutic agent for cutaneous melanoma carrying BAP1-inactivating mutations.
Humans ; Melanoma ; Skin Neoplasms ; Tumor Suppressor Protein p53 ; Apoptosis ; Cell Division ; Tumor Suppressor Proteins/genetics* ; Ubiquitin Thiolesterase/genetics*