Integrated genetic and epigenetic analyses uncovered GLP1R association with metabolically healthy obesity.

BACKGROUND: Both genetic and epigenetic variations of GLP1R influence the development and progression of obesity. However, the underlying mechanism remains elusive. This study aims to explore the mediation roles of obesity-related methylation sites in GLP1R gene variants-obesity association. METHODS: A total of 300 Chinese adult participants were included in this study and classified into two groups: 180 metabolically healthy obesity (MHO) cases and 120 metabolically healthy normal-weight (MHNW) controls. Questionnaire investigation, physical measurement and laboratory examination were assessed in all participants. 18 single nucleotide polymorphisms (SNPs) and 31 CpG sites were selected for genotype and methylation assays. Causal inference test (CIT) was performed to evaluate the associations between GLP1R genetic variation, DNA methylation and MHO. RESULTS: The study found that rs4714211 polymorphism of GLP1R gene was significantly associated with MHO. Additionally, methylation sites in the intronic region of GLP1R (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 12.13; GLP1R-68-CpG 17; GLP1R-68-CpG 21) were associated with MHO, and two of these methylation sites (GLP1R-68-CpG 7.8.9; GLP1R-68-CpG 17) partially mediated the association between genotypes and MHO. CONCLUSIONS: Not only the gene polymorphism, but also the DNA methylation of GLP1R was associated with MHO. Epigenetic changes in the methylome may in part explain the relationship between genetic variants and MHO.

An epigenome-wide association study of waist circumference in Chinese monozygotic twins.

OBJECTIVES: Central obesity poses significant health risks because it increases susceptibility to multiple chronic diseases. Epigenetic features such as DNA methylation may be associated with specific obesity traits, which could help us understand how genetic and environmental factors interact to influence the development of obesity. This study aims to identify DNA methylation sites associated with the waist circumference (WC) in Northern Han Chinese population, and to elucidate potential causal relationships. METHODS: A total of 59 pairs of WC discordant monozygotic twins (ΔWC >0) were selected from the Qingdao Twin Registry in China. Generalized estimated equation model was employed to estimate the methylation levels of CpG sites on WC. Causal relationships between methylation and WC were assessed through the examination of family confounding factors using FAmiliaL CONfounding (ICE FALCON). Additionally, the findings of the epigenome-wide analysis were corroborated in the validation stage. RESULTS: We identified 26 CpG sites with differential methylation reached false discovery rate (FDR) < 0.05 and 22 differentially methylated regions (slk-corrected p < 0.05) strongly linked to WC. These findings provided annotations for 26 genes, with notable emphasis on MMP17, ITGA11, COL23A1, TFPI, A2ML1-AS1, MRGPRE, C2orf82, and NINJ2. ICE FALCON analysis indicated the DNA methylation of ITGA11 and TFPI had a causal effect on WC and vice versa (p < 0.05). Subsequent validation analysis successfully replicated 10 (p < 0.05) out of the 26 identified sites. CONCLUSIONS: Our research has ascertained an association between specific epigenetic variations and WC in the Northern Han Chinese population. These DNA methylation features can offer fresh insights into the epigenetic regulation of obesity and WC as well as hints to plausible biological mechanisms.

Distinct effects of SDC3 and FGFRL1 on selective neurodegeneration in AD and PD.

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-dependent neurodegenerative disorders. There is a profound neuronal loss in the basal forebrain cholinergic system in AD and severe dopaminergic deficiency within the nigrostriatal pathway in PD. Swedish APP (APPSWE ) and SNCAA53T mutations promote Aß generation and α-synuclein aggregation, respectively, and have been linked to the pathogenesis of AD and PD. However, the mechanisms underlying selective cholinergic and dopaminergic neurodegeneration in AD and PD are still unknown. We demonstrated that APPSWE mutation enhanced Aß generation and increased cell susceptibility to Aß oligomer in cholinergic SN56 cells, whereas SNCAA53T mutations promoted aggregates formation and potentiated mutant α-synuclein oligomer-induced cytotoxicity in MN9D cells. Furthermore, syndecan-3 (SDC3) and fibroblast growth factor receptor-like 1 (FGFRL1) genes were differentially expressed in SN56 and MN9D cells carrying APPSWE or SNCAA53T mutation. SDC3 and FGFRL1 proteins were preferentially expressed in the cholinergic nucleus and dopaminergic neurons of APPSWE and SNCAA53T mouse models, respectively. Finally, the knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA53T cells. The results demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA53T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.

USP25 contributes to defective neurogenesis and cognitive impairments.

Both Down syndrome (DS) individuals and animal models exhibit hypo-cellularity in hippocampus and neocortex indicated by enhanced neuronal death and compromised neurogenesis. Ubiquitin-specific peptidase 25 (USP25), a human chromosome 21 (HSA21) gene, encodes for a deubiquitinating enzyme overexpressed in DS patients. Dysregulation of USP25 has been associated with Alzheimer's phenotypes in DS, but its role in defective neurogenesis in DS has not been defined. In this study, we found that USP25 upregulation impaired cell cycle regulation during embryonic neurogenesis and cortical development. Overexpression of USP25 in hippocampus promoted the neural stem cells to glial cell fates and suppressed neuronal cell fate by altering the balance between cyclin D1 and cyclin D2, thus reducing neurogenesis in the hippocampus. USP25-Tg mice showed increased anxiety/depression-like behaviors and learning and memory deficits. These results suggested that USP25 overexpression resulted in defective neurogenesis and cognitive impairments, which could contribute to the pathogenesis of DS. USP25 may be a potential pharmaceutical target for DS.

Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.

BACKGROUND: The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. METHODS: An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2 h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24 h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). RESULTS: OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. CONCLUSIONS: This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

Association of seafood consumption with cardiovascular disease among adults in Qingdao, China.

BACKGROUND AND AIMS: The relationship between seafood consumption and cardiovascular disease (CVD) is controversial, and studies have not considered competing risk events. Our study examined the association between a full range of seafood consumption and CVD incidence and mortality based on the Qingdao Diabetes Prevention Program. METHODS AND RESULTS: We followed up 5285 participants without CVD at baseline until December 31, 2021. CVD cases and deaths were identified through record linkage with the Qingdao CVD Surveillance System and the Qingdao Death Surveillance System, respectively. Information on seafood consumption was obtained using a food frequency questionnaire. We used the Cox proportional hazard model and the competing risk model to evaluate the association between all types of seafood consumption and CVD incidence and mortality. During a median follow-up of 11.4 years, 122 CVD cases and 75 deaths occurred. After adjustment for potential confounders, compared with nonconsumers, seafood consumption of 300-500 and > 500 g/week was associated with a lower risk of CVD incidence [hazards ratio and 95 % confidence interval (CI): 0.54 (0.29-0.99) and 0.49 (0.26-0.91), respectively]. However, seafood consumption of >500 g/week had a significantly lower risk of CVD mortality [subdistribution hazard ratio and 95 % CI: 0.40 (0.17-0.95)], but it was insignificant in other groups. CONCLUSION: Seafood consumption of 300-500 g/week and >500 g/week was associated with a lower CVD incidence and mortality. Our findings provide evidence of the recommendations of the 2022 Dietary Guidelines for Chinese residents and may guide the promotion of strategies for CVD prevention.

Perceived risk of COVID-19 hurts mental health: the mediating role of fear of COVID-19 and the moderating role of resilience.

BACKGROUND: Depression and anxiety have been found prevalent during all phases of the COVID-19 pandemic. In late December 2022, almost all COVID-19 control measures were lifted in China, leading to a surge in COVID-19 infections. The public's perceived risk and fear of COVID-19 would be increased. This study aims to examine the prevalence of depression and anxiety in the Chinese general population and explores the mediating role of fear of COVID-19 between COVID-19 perceived risk and depression/anxiety and the moderating role of resilience between fear of COVID-19 and depression/anxiety. METHODS: A cross-sectional online survey was conducted in Wenzhou, China, immediately following almost all COVID-19 control measures lifted. The 9-item Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), the COVID-19 Risk Perception Scale, the Fear of COVID-19 Scale, and the Connor-Davidson Resilience Scale (CD-RISC) were used to evaluate depression, anxiety, COVID-19 perceived risk, fear of COVID-19, and resilience, respectively. Structural Equation Modeling (SEM) with Maximum Likelihood (ML) estimator and adjusted for significant background factors was performed to test the moderated mediation. Data obtained from 935 participants were analyzed. RESULTS: The prevalence of moderate to severe depression and anxiety was 23.7% and 9.5%, respectively. The present study revealed positive associations among COVID-19 perceived risk, fear of COVID-19 and depression/anxiety, and negative associations between resilience and fear of COVID-19/depression/anxiety. Fear of COVID-19 partially mediated the association between COVID-19 perceived risk and depression/anxiety. Furthermore, resilience significantly moderated the association between fear of COVID-19 and depression/anxiety. Two moderated mediation models were constructed. CONCLUSION: Depression and anxiety were prevalent among Chinese adults during the final phase of the pandemic in China. The significant mediation role of fear of COVID-19 implies that reducing fear of COVID-19 may effectively alleviate depression and anxiety symptoms. Moreover, enhancing public resilience during an epidemic crisis is crucial for promoting mental health.

The moderated-mediation role of risk perception and intolerance of uncertainty in the association between residual symptoms and psychological distress: a cross-sectional study after COVID-19 policy lifted in China.

BACKGROUND: A considerable number of individuals infected with COVID-19 experience residual symptoms after the acute phase. However, the correlation between residual symptoms and psychological distress and underlying mechanisms are scarcely studied. We aim to explore the association between residual symptoms of COVID-19 and psychological distress, specifically depression, anxiety, and fear of COVID-19, and examine the role of risk perception and intolerance of uncertainty in the association. METHODS: A cross-sectional survey was conducted by online questionnaire-based approach in mid-January 2023. Self-reported demographic characteristics, COVID-19-related information, and residual symptoms were collected. Depression, anxiety, fear, risk perception and intolerance of uncertainty were evaluated using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Fear of COVID-19 Scale (FCV-19S), COVID-19 Risk Perception Scale and Intolerance of Uncertainty Scale-12 (IUS-12), respectively. Linear regression analyses were conducted to explore the associations. A moderated mediation model was then constructed to examine the role of risk perception of COVID-19 and intolerance of uncertainty in the association between residual symptoms and psychological distress. RESULTS: 1735 participants effectively completed the survey. 34.9% of the patients experienced residual symptoms after acute phase of COVID-19. Psychological distress was markedly increased by COVID-19 infection, while residual symptoms had a significant impact on psychological distress (Ps < 0.001), including depression (ß = 0.23), anxiety (ß = 0.21), and fear of COVID-19 (ß = 0.14). Risk perception served as a mediator between residual symptoms and all forms of psychological distress, while intolerance of uncertainty moderated the effect of risk perception on depression and anxiety. CONCLUSION: A considerable proportion of patients experience residual symptoms after acute phase of COVID-19, which have a significant impact on psychological distress. Risk perception and intolerance of uncertainty play a moderated-mediation role in the association between residual symptoms and depression/anxiety. It highly suggests that effective treatment for residual symptoms, maintaining appropriate risk perception and improving intolerance of uncertainty are critical strategies to alleviate COVID-19 infection-associated psychological distress.

Genome-wide DNA methylation analysis of body composition in Chinese monozygotic twins.

BACKGROUND: Little is currently known about epigenetic alterations associated with body composition in obesity. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and three common traits of body composition as measured by body fat percentage (BF%), fat mass (FM) and lean body mass (LBM) among Chinese monozygotic twins. METHODS: Generalized estimated equation model was used to regress the methylation level of CpG sites on body composition. Inference about Causation Through Examination Of Familial Confounding was used to explore the evidence of a causal relationship. Gene expression analysis was further performed to validate the results of differentially methylated genes. RESULTS: We identified 32, 22 and 28 differentially methylated CpG sites (p < 10-5 ) as well as 20, 17 and eight differentially methylated regions (slk-corrected p < 0.05) significantly associated with BF%, FM and LBM which were annotated to 65 genes, showing partially overlapping. Causal inference demonstrated bidirectional causality between DNA methylation and body composition (p < 0.05). Gene expression analysis revealed significant correlations between expression levels of five differentially methylated genes and body composition (p < 0.05). CONCLUSIONS: These DNA methylation signatures will contribute to increased knowledge about the epigenetic basis of body composition and provide new strategies for early prevention and treatment of obesity and its related diseases.

Perceived parenting styles and incidence of major depressive disorder: results from a 6985 freshmen cohort study.

BACKGROUND: Even though a fair amount of studies focus on depression among college students, the effect of perceived parenting styles on the incidence of major depressive disorder (MDD) among representative freshmen in Chinese context is scarcely studied. The aim of this study is to investigate the effect of parenting styles on MDD in Chinese freshmen. METHODS: A total of 9,928 Chinese freshmen were recruited in 2018. 6985 valid questionnaires were collected at one-year follow-up. Composite International Diagnostic Interview 3.0 (CIDI-3.0) was used for the diagnosis of MDD. Egna Minnen Beträffande Uppfostran (EMBU) questionnaire and Beck Depression Inventory-II (BDI-II) were used to assess parenting styles and baseline depressive symptoms, respectively. The associations between parenting styles and MDD incidence was analyzed with logistic regression. RESULTS: The incidence of MDD in freshmen was 2.23% (95%CI: 1.91-2.60%). Maternal overprotection (OR = 1.03, 95%CI: 1.01-1.05) and disharmony relationship between parents (OR = 2.35, 95% CI: 1.42-3.89) increased the risk of new-onset MDD in freshmen, respectively. Mild depressive symptoms (OR = 2.06, 95%CI: 1.06-4.02), moderate (OR = 4.64, 95%CI: 2.55-8.44) and severe depressive symptoms (OR = 7.46, 95%CI: 2.71-20.52) at baseline increased the risk of new-onset MDD. CONCLUSIONS: Maternal overprotection, disharmony relationship between parents and baseline depressive symptoms are risk factors for new-onset MDD in Chinese freshmen.

COVID-19 vaccine uptake and vaccine hesitancy in rural-to-urban migrant workers at the first round of COVID-19 vaccination in China.

BACKGROUND: Migration can be linked to the transmission of COVID-19. COVID-19 vaccine uptake and hesitancy among rural-to-urban migrant workers in China, the largest group of internal migrants in the world, has not been characterized. OBJECTIVE: To investigate COVID-19 vaccine uptake and identify vaccine hesitancy-associated factors among rural-to-urban migrant workers in the first round of COVID-19 vaccination in China. METHODS: A cross-sectional questionnaire-based survey was conducted, including 14,917 participants. Socio-demographics, COVID-19 vaccine uptake, vaccine hesitancy and its associated factors based on Vaccine Hesitancy Determinants Matrix (VHDM) were applied for the survey. Data were principally analyzed by logistic regression analysis. RESULTS: The COVID-19 vaccine uptake and vaccine hesitancy rates were 7.1% and 57.7%, respectively. Vaccine hesitancy was strongly associated with VHDM, including individual factors (female, higher annual income and fewer medical knowledge), group factors (less family support, friend support and public opinion support), COVID-19 epidemic factors (lower fatality, infection and emotional distress) and vaccine factors (less vaccine necessity, vaccine safety, vaccine efficacy, vaccine importance and vaccine reliability). CONCLUSION: The VHDM model has the potential utility in efforts to reduce COVID-19 vaccine hesitancy. Greater efforts should be put into addressing positive predictors associated with vaccine hesitancy.

Serial multiple mediation of loneliness and depressive symptoms in the relationship between pain and cognitive function among older people.

OBJECTIVES: Although the negative effect of pain on cognitive function has been widely reported, it is unclear how the effect is mediated. The aim of this study is to analyze the mediating role of loneliness and depressive symptoms in the association between pain and cognitive function. METHODS: A total of 6,309 participants aged ≥50 years from 2012/13 (T1), 2014/15 (T2), 2016/17 (T3) and 2018/19 (T4) of the English Longitudinal Study of Aging (ELSA) were included. Of them, 55.8% were females, and the median age (rang) was 65 (50-99) years at T1. Serial mediation analysis was performed using Mplus 8.3. RESULTS: The mediation model explained 10.1% of the variance in loneliness, 22.1% of the variance of depressive symptoms, and 22.7% of the variance of cognitive function. Higher level pain was associated with poorer cognitive function (c: ß = -0.057; p < 0.001). The negative effect of pain on cognition was mediated separately and sequentially through loneliness and depressive symptoms, with loneliness and depressive symptoms explaining 8.8% of the total effect, respectively, and the pathway of loneliness and subsequent depression explaining 1.8%. CONCLUSIONS: Diversified interventions aimed at treating pain in older adults would be beneficial for their mental health and cognitive function.

The impact of self-efficacy on first onset and prognosis of major depressive disorder: findings from a longitudinal study in a sample of Chinese first-year university students.

BACKGROUND: Self-efficacy is a pivotal factor in the etiology and prognosis of major depression. However, longitudinal studies on the relationship between self-efficacy and major depressive disorder (MDD) are scarce. The objectives were to investigate: (1) the associations between self-efficacy and the 1-year and 2-year risks of first onset of MDD and (2) the associations between self-efficacy and the 1-year and 2-year risks of the persistence/recurrence of MDD, in a sample of first-year university students. METHODS: We followed 8079 first-year university students for 2 years from April 2018 to October 2020. MDD was ascertained by the Chinese version of the Composite International Diagnostic Interview (CIDI-3.0) based on self-report. Self-efficacy was measured by the 10-item General Self-efficacy (GSE) scale. Random effect logistic regression modeling was used to estimate the associations. RESULTS: Among participants without a lifetime MDD, the data showed that participants with high baseline GSE scores were associated with a higher risk of first onset of MDD over 2 years [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08]. Among those with a lifetime MDD, participants with high baseline GSE scores were less likely to have had a MDD over 2 years (OR 0.93, 95% CI 0.88-0.99) compared to others. CONCLUSIONS: A high level of GSE may be protective of the risk of persistent or recurrent MDD. More longitudinal studies in university students are needed to further investigate the impact of GSE on the first onset of MDD.

Associations of Sleep Quality with Gait Speed and Falls in Older Adults: The Mediating Effect of Muscle Strength and the Gender Difference.

INTRODUCTION: Although previous studies have reported the significant associations of sleep quality with gait speed and falls, the mechanisms underlying these associations are unclear. We aimed to examine the gender-specific associations of sleep quality with gait speed and falls among older adults and to explore the possible mediating effect of muscle strength on these relationships. METHODS: Data were taken from wave 6 (2012-2013) of the English Longitudinal Study of Aging (ELSA), including 7,664 participants aged 60 years and older. Sleep quality and falls were assessed by self-report. Gait speed was measured by the "timed walking test" and then adjusted by height. As an indicator of overall muscle strength, grip strength was measured by using the Smedley dynamometer. Baron and Kenny's causal steps and the Karlson/Holm/Breen method were used to examine the mediating effect. RESULTS: Higher sleep quality was associated with the higher level of gait speed (ß = 0.008, p = 0.031 in men; ß = 0.008, p = 0.017 in women) and with lower prevalence of falls (OR = 0.878, 95% CI: 0.773, 0.998 in men; OR = 0.874, 95% CI: 0.792, 0.965 in women). Grip strength mediated these associations in men but not in women, and the mediating effects of grip strength can explain 23.74 and 11.01% of the total effect of sleep quality on gait speed and falls, respectively. CONCLUSION: Our findings help explain the mechanism underlying the associations of sleep quality with gait speed and falls. Effort to maintain the mobility of the older men should focus on improving both sleep quality and muscle strength.

Nomogram for predicting the 12-year risk of ADL disability among older adults.

OBJECTIVES: Previous studies have identified plenty of risk factors for activities of daily living (ADL). However, there are no reliable and widely available prediction models for ADL disability up to now. This study aimed to develop and validate a nomogram for predicting the 12-year risk of ADL disability in older adults. METHODS: Data from 4,809 participants in the English Longitudinal Study of Ageing (ELSA) and 18,620 participants in the Survey of Health, Ageing and Retirement in Europe (SHARE) were used as training set and validation set, respectively. We used the least absolute shrinkage and selection operator (LASSO) and Cox regression to screen the predictors and develop the nomogram. The P value, concordance index (C-index), integrated area under the ROC (receiver operating characteristic) curve (AUC) and calibration curves were used to validate the nomogram. RESULTS: During 12 years, 30.0% (n = 1,441) participants developed ADL disability in the training set, while the corresponding percentages were 18.5% in the validation set (n = 3,445). After screening, 13 variables were contained in the final prediction model. In ADL nomogram, the C-index and AUC were 0.744 ± 0.013 and 0.793 in internal valid ation, respectively, while in external validation, the C-index and AUC were 0.755 ± 0.009 and 0.796. CONCLUSIONS: This study developed and validated a nomogram that predicts functional disability. The application of the predictive model could have important implications for patient prognosis and health care.

Analysis of genetic and environmental correlation between leisure activities and cognitive function in aging Chinese twins.

OBJECTIVE: Leisure activity has been shown to be beneficial to mental health and cognitive aging. The biological basis of the correlation is, however, poorly understood. This study aimed at exploring the genetic and environmental impacts on correlation between leisure activities and cognitive function in the Chinese middle- and old-aged twins. METHODS: Cognition measured using a screening test (Montreal Cognitive Assessment, MoCA) and leisure activities including intellectual and social activity were investigated on 379 complete twin pairs of middle- and old-aged twins. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in their variance and covariance. RESULTS: Moderate heritability was estimated for leisure activities and cognition (0.44-0.53) but insignificant for social activity. Common environmental factors accounted for about 0.36 of the total variance to social activity with no significant contribution to leisure activity, intellectual activity and cognition. Unique environmental factors displayed moderate contributions (0.47-0.64) to leisure activities and cognition. Bivariate analysis showed highly and positively genetic correlations between leisure activities and cognition (rG=0.80-0.96). Besides, intellectual activity and cognition presented low but significant unique environmental correlation (rE=0.12). CONCLUSIONS: Genetic factor had the moderate contribution to leisure activities and cognition. Cognitive function was highly genetically related to leisure activities. Intellectual activity and cognitive function may share some unique environmental basis.

A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling.

Presenilin-1 (PSEN1) is the catalytic subunit of the γ-secretase complex, and pathogenic mutations in the PSEN1 gene account for the majority cases of familial AD (FAD). FAD-associated mutant PSEN1 proteins have been shown to affect APP processing and Aß generation and inhibit Notch1 cleavage and Notch signaling. In this report, we found that a PSEN1 mutation (S169del) altered APP processing and Aß generation, and promoted neuritic plaque formation as well as learning and memory deficits in AD model mice. However, this mutation did not affect Notch1 cleavage and Notch signaling in vitro and in vivo. Taken together, we demonstrated that PSEN1S169del has distinct effects on APP processing and Notch1 cleavage, suggesting that Notch signaling may not be critical for AD pathogenesis and serine169 could be a critical site as a potential target for the development of novel γ-secretase modulators without affecting Notch1 cleavage to treat AD.

Association between coffee consumption and functional disability in older US adults.

The effect of coffee consumption on functional disability has been scarcely investigated. Thus, this study aimed to examine the association between coffee consumption and functional disability in older American adults. Participants (≥60 years old, n 7704) were from the National Health and Nutrition Examination Survey 2007-2016. Coffee consumption was assessed through two 24-h dietary recall interviews. Five domains of functional disability including lower extremity mobility (LEM), general physical activity (GPA), leisure and social activities (LSA), activities of daily living (ADL) and instrumental activities of daily living (IADL) were self-reported. Age- and multivariate-adjusted logistic regression models and restricted cubic spline analyses were used. Total coffee consumption was inversely associated with LEM, GPA, LSA and IADL disability. Compared with non-drinkers of total coffee, those who consumed ≥2 cups/d reported lower odds of LEM (OR 0·67, 95 % CI 0·50, 0·91), GPA (OR 0·65, 95 % CI 0·47, 0·88), LSA (OR 0·61, 95 % CI 0·45, 0·83) and IADL (OR 0·59, 95 % CI 0·44, 0·78) disability. The dose-response analyses confirmed these relationships. Intake of ≥2 cups/d caffeinated coffee was also inversely linked to GPA (OR 0·67, 95 % CI 0·48, 0·92), LSA (OR 0·66, 95 % CI 0·46, 0·93) and IADL (OR 0·57, 95 % CI 0·43, 0·75) disability, whereas the inverse association of 2+ cups/d decaffeinated coffee was only on LEM (OR 0·43, 95 % CI 0·23, 0·81) and LSA (OR 0·39, 95 % CI 0·16, 0·94) disability. The present study suggested that coffee consumption was inversely associated with functional disability in older American adults. Those associations of diverse coffee types differed across domains of functional disability.

Establishment of a nomogram model to predict macrosomia in pregnant women with gestational diabetes mellitus.

AIM: To establish a nomogram model to predict the risk of macrosomia in pregnant women with gestational diabetes mellitus in China. METHODS: We retrospectively collected the medical records of 783 pregnant women with gestational diabetes who underwent prenatal examinations and delivered at the Affiliated Hospital of Qingdao University from October 2019 to October 2020. The pregnant women were randomly divided into two groups in a 4:1 ratio to generate and validate the model. The independent risk factors for macrosomia in pregnant women with gestational diabetes mellitus were analyzed by multivariate logistic regression, and the nomogram model to predict the risk of macrosomia in pregnant women with gestational diabetes mellitus was established and verified by R software. RESULTS: Logistic regression analysis showed that prepregnancy body mass index, weight gain during pregnancy, fasting plasma glucose, triglycerides, biparietal diameter and amniotic fluid index were independent risk factors for macrosomia (P < 0.05). The areas under the ROC curve for internal and external validation of the model were 0.813 (95 % confidence interval 0.754-0.862) and 0.903 (95 % confidence interval 0.588-0.967), respectively. The calibration curve was a straight line with a slope close to 1. CONCLUSIONS: In this study, we constructed a nomogram model to predict the risk of macrosomia in pregnant women with gestational diabetes mellitus. The model has good discrimination and calibration abilities, which can help clinical healthcare staff accurately predict macrosomia in pregnant women with gestational diabetes mellitus.

RCAN1 in cardiovascular diseases: molecular mechanisms and a potential therapeutic target.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Considerable efforts are needed to elucidate the underlying mechanisms for the prevention and treatment of CVDs. Regulator of calcineurin 1 (RCAN1) is involved in both development/maintenance of the cardiovascular system and the pathogenesis of CVDs. RCAN1 reduction protects against atherosclerosis by reducing the uptake of oxidized low-density lipoproteins, whereas RCAN1 has a protective effect on myocardial ischemia/reperfusion injury, myocardial hypertrophy and intramural hematoma/aortic rupture mainly mediated by maintaining mitochondrial function and inhibiting calcineurin and Rho kinase activity, respectively. In this review, the regulation and the function of RCAN1 are summarized. Moreover, the dysregulation of RCAN1 in CVDs is reviewed. In addition, the beneficial role of RCAN1 reduction in atherosclerosis and the protective role of RCAN1 in myocardial ischemia/reperfusion injury, myocardial hypertrophy and intramural hematoma /aortic rupture are discussed, as well as underlying mechanisms. Furthermore, the therapeutic potential and challenges of targeting RCAN1 for CVDs treatment are also discussed.