Leading determinants of incident dementia among individuals with and without the apolipoprotein E ε4 genotype: a retrospective cohort study.

BACKGROUND: Little is known regarding the leading risk factors for dementia/Alzheimer's disease (AD) in individuals with and without APOE4. The identification of key risk factors for dementia/Alzheimer's disease (AD) in individuals with and without the APOE4 gene is of significant importance in global health. METHODS: Our analysis included 110,354 APOE4 carriers and 220,708 age- and sex-matched controls aged 40-73 years at baseline (between 2006-2010) from UK Biobank. Incident dementia was ascertained using hospital inpatient, or death records until January 2021. Individuals of non-European ancestry were excluded. Furthermore, individuals without medical record linkage were excluded from the analysis. Moderation analysis was tested for 134 individual factors. RESULTS: During a median follow-up of 11.9 years, 4,764 cases of incident all-cause dementia and 2065 incident AD cases were documented. Hazard ratios (95% CIs) for all-cause dementia and AD associated with APOE4 were 2.70(2.55-2.85) and 3.72(3.40-4.07), respectively. In APOE4 carriers, the leading risk factors for all-cause dementia included low self-rated overall health, low household income, high multimorbidity risk score, long-term illness, high neutrophil percentage, and high nitrogen dioxide air pollution. In non-APOE4 carriers, the leading risk factors included high multimorbidity risk score, low overall self-rated health, low household income, long-term illness, high microalbumin in urine, high neutrophil count, and low greenspace percentage. Population attributable risk for these individual risk factors combined was 65.1%, and 85.8% in APOE4 and non-APOE4 carriers, respectively. For 20 risk factors including multimorbidity risk score, unhealthy lifestyle habits, and particulate matter air pollutants, their associations with incident dementia were stronger in non-APOE4 carriers. For only 2 risk factors (mother's history of dementia, low C-reactive protein), their associations with incident all-cause dementia were stronger in APOE4 carriers. CONCLUSIONS: Our findings provide evidence for personalized preventative approaches to dementia/AD in APOE4 and non-APOE4 carriers. A mother's history of dementia and low levels of C-reactive protein were more important risk factors of dementia in APOE4 carriers whereas leading risk factors including unhealthy lifestyle habits, multimorbidity risk score, inflammation and immune-related markers were more predictive of dementia in non-APOE4 carriers.

Knockout of sws2a and sws2b in Medaka (Oryzias latipes) Reveals Their Roles in Regulating Vision-Guided Behavior and Eye Development.

The medaka (Oryzias latipes) is an excellent vertebrate model for studying the development of the retina. Its genome database is complete, and the number of opsin genes is relatively small compared to zebrafish. Short wavelength sensitive 2 (sws2), a G-protein-coupled receptor expressed in the retina, has been lost in mammals, but its role in eye development in fish is still poorly understood. In this study, we established a sws2a and sws2b knockout medaka model by CRISPR/Cas9 technology. We discovered that medaka sws2a and sws2b are mainly expressed in the eyes and may be regulated by growth differentiation factor 6a (gdf6a). Compared with the WT, sws2a-/- and sws2b-/- mutant larvae displayed an increase in swimming speed during the changes from light to dark. We also observed that sws2a-/- and sws2b-/- larvae both swam faster than WT in the first 10 s of the 2 min light period. The enhanced vision-guided behavior in sws2a-/- and sws2b-/- medaka larvae may be related to the upregulation of phototransduction-related genes. Additionally, we also found that sws2b affects the expression of eye development genes, while sws2a is unaffected. Together, these findings indicate that sws2a and sws2b knockouts increase vision-guided behavior and phototransduction, but on the other hand, sws2b plays an important role in regulating eye development genes. This study provides data for further understanding of the role of sws2a and sws2b in medaka retina development.

Role of short-wave-sensitive 1 (sws1) in cone development and first feeding in larval zebrafish.

Color vision is mediated by the expression of different major visual pigment proteins (opsins) on retinal photoreceptors. Vertebrates have four classes of cone opsins that are most sensitive to different wavelengths of light: short wavelength sensitive 1 (SWS1), short wavelength sensitive 2 (SWS2), medium wavelength sensitive (RH2), and long wavelength sensitive (LWS). UV wavelengths play important roles in foraging and communication. However, direct evidence provide links between sws1 and first feeding is lacking. Here, CRISPR/Cas9 technology was performed to generate mutant zebrafish lines with sws1 deletion. sws1 mutant zebrafish larvae exhibited decreased sws1, rh2-2, and lws1 expression, and increased rod gene (rho and gnat1) expression. Furthermore, the sws1-deficient larvae exhibited significantly reduced food intake, and the orexigenic genes npy and agrp signaling were upregulated at 6 days postfertilization (dpf). The transcription expression of sws1 and rh2-3 genes decreased in sws1-/- adults compared to wild type. Surprisingly, the results of feeding at the adult stage were not the same with larvae. sws1 deficiency did not affect food intake and appetite gene expression at adult stages. These results reveal a role for sws1 in normal cone development and first feeding in larval zebrafish.

Association of Retinal Age Gap With Arterial Stiffness and Incident Cardiovascular Disease.

BACKGROUND: Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for aging and mortality. Therefore, we aim to investigate associations of retinal age gap with arterial stiffness index and incident cardiovascular disease (CVD). METHODS: A deep learning model was trained based on 19 200 fundus images of 11 052 participants without any medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35 917 participants. Regression models were used to assess the association between retinal age gap and arterial stiffness index. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD. RESULTS: We found each 1-year increase in retinal age gap was associated with increased arterial stiffness index (ß=0.002 [95% CI, 0.001-0.003]; P<0.001). After a median follow-up of 5.83 years (interquartile range: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each 1-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio=1.03 [95% CI, 1.01-1.06]; P=0.014). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (hazard ratio=1.05 [95% CI, 1.00-1.10]; P-overall <0.0001; P-nonlinear=0.0681). CONCLUSIONS: We found that retinal age gap was significantly associated with arterial stiffness index and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.

Temporal trajectories of important diseases in the life course and premature mortality in the UK Biobank.

BACKGROUND: Little is known regarding life-course trajectories of important diseases. We aimed to identify diseases that were strongly associated with mortality and test temporal trajectories of these diseases before mortality. METHODS: Our analysis was based on UK Biobank. Diseases were identified using questionnaires, nurses' interviews, or inpatient data. Mortality register data were used to identify mortality up to January 2021. The association between 60 individual diseases at baseline and in the life course and incident mortality was examined using Cox proportional regression models. Those diseases with great contribution to mortality were identified and disease trajectories in life course were then derived. RESULTS: During a median follow-up of 11.8 years, 31,373 individuals (median age at death (interquartile range): 70.7 (65.3-74.8) years, 59.4% male) died of all-cause mortality (with complete data on diagnosis date of disease), with 16,237 dying with cancer and 6702 with cardiovascular disease (CVD). We identified 37 diseases including cancers and heart diseases that were associated with an increased risk of mortality independent of other diseases (hazard ratio ranged from 1.09 to 7.77). Among those who died during follow-up, 2.2% did not have a diagnosis of any disease of interest and 90.1% were diagnosed with two or more diseases in their life course. Individuals who were diagnosed with more diseases in their life course were more likely to have longer longevity. Cancer was more likely to be diagnosed following hypertension, hypercholesterolemia, CVD, or digestive disorders and more likely to be diagnosed ahead of CVD, chronic kidney disease (CKD), or digestive disorders. CVD was more likely to be diagnosed following hypertension, hypercholesterolemia, or digestive disorders and more likely to be diagnosed ahead of cancer or CKD. Hypertension was more likely to precede other diseases, and CKD was more likely to be diagnosed as the last disease before more mortality. CONCLUSIONS: There are significant interplays between cancer and CVD for mortality. Cancer and CVD were frequently clustered with hypertension, CKD, and digestive disorders with CKD highly being diagnosed as the last disease in the life course. Our findings underline the importance of health checks among middle-aged adults for the prevention of premature mortality.

Retinal age gap as a predictive biomarker of stroke risk.

BACKGROUND: The aim of this study is to investigate the association of retinal age gap with the risk of incident stroke and its predictive value for incident stroke. METHODS: A total of 80,169 fundus images from 46,969 participants in the UK Biobank cohort met the image quality standard. A deep learning model was constructed based on 19,200 fundus images of 11,052 disease-free participants at baseline for age prediction. Retinal age gap (retinal age predicted based on the fundus image minus chronological age) was generated for the remaining 35,917 participants. Stroke events were determined by data linkage to hospital records on admissions and diagnoses, and national death registers, whichever occurred earliest. Cox proportional hazards regression models were used to estimate the effect of retinal age gap on risk of stroke. Logistic regression models were used to estimate the predictive value of retinal age and well-established risk factors in 10-year stroke risk. RESULTS: A total of 35,304 participants without history of stroke at baseline were included. During a median follow-up of 5.83 years, 282 (0.80%) participants had stroke events. In the fully adjusted model, each one-year increase in the retinal age gap was associated with a 4% increase in the risk of stroke (hazard ratio [HR] = 1.04, 95% confidence interval [CI]: 1.00-1.08, P = 0.029). Compared to participants with retinal age gap in the first quintile, participants with retinal age gap in the fifth quintile had significantly higher risks of stroke events (HR = 2.37, 95% CI: 1.37-4.10, P = 0.002). The predictive capability of retinal age alone was comparable to the well-established risk factor-based model (AUC=0.676 vs AUC=0.661, p=0.511). CONCLUSIONS: We found that retinal age gap was significantly associated with incident stroke, implying the potential of retinal age gap as a predictive biomarker of stroke risk.

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank.

BACKGROUND: Plasma metabolomic profile is disturbed in dementia patients, but previous studies have discordant conclusions. METHODS: Circulating metabolomic data of 110,655 people in the UK Biobank study were measured with nuclear magnetic resonance technique, and incident dementia records were obtained from national health registers. The associations between plasma metabolites and dementia were estimated using Cox proportional hazard models. The 10-fold cross-validation elastic net regression models selected metabolites that predicted incident dementia, and a 10-year prediction model for dementia was constructed by multivariable logistic regression. The predictive values of the conventional risk model, the metabolites model, and the combined model were discriminated by comparison of area under the receiver operating characteristic curves (AUCs). Net reclassification improvement (NRI) was used to estimate the change of reclassification ability when adding metabolites into the conventional prediction model. RESULTS: Amongst 110,655 participants, the mean (standard deviation) age was 56.5 (8.1) years, and 51 186 (46.3%) were male. A total of 1439 (13.0%) developed dementia during a median follow-up of 12.2 years (interquartile range: 11.5-12.9 years). A total of 38 metabolites, including lipids and lipoproteins, ketone bodies, glycolysis-related metabolites, and amino acids, were found to be significantly associated with incident dementia. Adding selected metabolites (n=24) to the conventional dementia risk prediction model significantly improved the prediction for incident dementia (AUC: 0.824 versus 0.817, p =0.042) and reclassification ability (NRI = 4.97%, P = 0.009) for identifying high risk groups. CONCLUSIONS: Our analysis identified various metabolomic biomarkers which were significantly associated with incident dementia. Metabolomic profiles also provided opportunities for dementia risk reclassification. These findings may help explain the biological mechanisms underlying dementia and improve dementia prediction.

Retinal age gap as a predictive biomarker of future risk of Parkinson's disease.

INTRODUCTION: retinal age derived from fundus images using deep learning has been verified as a novel biomarker of ageing. We aim to investigate the association between retinal age gap (retinal age-chronological age) and incident Parkinson's disease (PD). METHODS: a deep learning (DL) model trained on 19,200 fundus images of 11,052 chronic disease-free participants was used to predict retinal age. Retinal age gap was generated by the trained DL model for the remaining 35,834 participants free of PD at the baseline assessment. Cox proportional hazards regression models were utilised to investigate the association between retinal age gap and incident PD. Multivariable logistic model was applied for prediction of 5-year PD risk and area under the receiver operator characteristic curves (AUC) was used to estimate the predictive value. RESULTS: a total of 35,834 participants (56.7 ± 8.04 years, 55.7% female) free of PD at baseline were included in the present analysis. After adjustment of confounding factors, 1-year increase in retinal age gap was associated with a 10% increase in risk of PD (hazard ratio [HR] = 1.10, 95% confidence interval [CI]: 1.01-1.20, P = 0.023). Compared with the lowest quartile of the retinal age gap, the risk of PD was significantly increased in the third and fourth quartiles (HR = 2.66, 95% CI: 1.13-6.22, P = 0.024; HR = 4.86, 95% CI: 1.59-14.8, P = 0.005, respectively). The predictive value of retinal age and established risk factors for 5-year PD risk were comparable (AUC = 0.708 and 0.717, P = 0.821). CONCLUSION: retinal age gap demonstrated a potential for identifying individuals at a high risk of developing future PD.

Association between dual sensory impairment and risk of mortality: a cohort study from the UK Biobank.

BACKGROUND: Dual sensory impairment is affecting over 10% of older adults worldwide. However, the long-term effect of dual sensory impairment (DSI) on the risk of mortality remains controversial. We aim to investigate the impact of single or/and dual sensory impairment on the risk of mortality in a large population-based sample of the adult in the UK with 14-years of follow-up. METHODS: This population-based prospective cohort study included participants aged 40 and over with complete records of visual and hearing functions from the UK Biobank study. Measurements of visual and hearing functions were performed at baseline examinations between 2006 and 2010, and data on mortality was obtained by 2021. Dual sensory impairment was defined as concurrent visual and hearing impairments. Cox proportional hazards regression models were employed to evaluate the impact of sensory impairment (dual sensory impairment, single visual or hearing impairment) on the hazard of mortality. RESULTS: Of the 113,563 participants included in this study, the mean age (standard deviation) was 56.8 (8.09) years, and 61,849 (54.5%) were female. At baseline measurements, there were 733 (0.65%) participants with dual sensory impairment, 2,973 (2.62%) participants with single visual impairment, and 13,560 (11.94%) with single hearing impairment. After a follow-up period of 14 years (mean duration of 11 years), 5,992 (5.28%) participants died from all causes. Compared with no sensory impairment, dual sensory impairment was significantly associated with an estimated 44% higher hazard of mortality (hazard ratio: 1.44 [95% confidence interval, 1.11-1.88], p = 0.007) after multiple adjustments. CONCLUSIONS: Individuals with dual sensory impairment were found to have an independently 44% higher hazard of mortality than those with neither sensory impairment. Timely intervention of sensory impairment and early prevention of its underlying causes should help to reduce the associated risk of mortality.

Effects of dietary carbohydrate to lipid ratios on growth, biochemical indicators, lipid metabolism, and appetite in Chinese perch (Siniperca chuatsi).

An 8-week feeding trial was conducted to evaluate the effects of dietary carbohydrate to lipid (CHO:L) ratios on growth performance, body composition, serum biochemical indexes, lipid metabolism, and gene expression of central appetite regulating factors in Chinese perch (Siniperca chuatsi) (mean initial weight: 12.86 ± 0.10 g). Five isonitrogenous and isoenergetic diets (fish meal, casein as main protein sources) were formulated to contain different graded CHO:L ratio diets ranging from 0.12, 0.86, 1.71, 3.29, and 7.19. Each diet was assigned to triplicate groups of 18 experimental fish. Our results revealed that final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR), and protein efficiency ratio (PER) increased with dietary CHO:L ratio from 0.12 to 1.71 and then decreased with further increases in dietary CHO:L ratio. A two-slope broken-line regression analysis based on WGR showed that the optimal dietary CHO:L level for maximum growth performance of fish was 1.60. Crude lipid and crude protein content in the liver and glycogen concentration in the muscle and liver were significantly influenced by the dietary CHO:L ratios (P < 0.05). The lowest crude lipid content in the liver was observed in fish fed the diet with a CHO:L ratio of 1.71(P < 0.05). Dietary CHO:L ratios significantly induced the glucose concentration of serum (P < 0.05). The relative expression levels of genes involved in lipid metabolism, such as srebp1 and fas in the liver, showed a trend of first decreased and then increased with the increase of dietary CHO:L ratio levels. Appropriate CHO:L ratio in the diet can effectively reduce the accumulation of liver fat. We observed in fish fed the 1.71 CHO:L ratio diet showed higher feed intake, up-regulated mRNA expression of neuropeptide Y (npy) and agouti gene-related protein (agrp), and down-regulated mRNA expression of cocaine- and amphetamine-regulated transcript (cart) and pro-opiomelanocorticoid (pomc) significantly as compared to control group. Thus, these results provide the theoretical basis for feed formulation to determine the appropriate CHO:L ratio requirement of Chinese perch.

mTOR - Mediated protein synthesis by inhibiting protein catabolism in Chinese perch (Siniperca chuatsi).

Activation of the mechanistic target of rapamycin (mTOR) pathway is known to promote protein synthesis by enhancing mRNA translation. However, there have been few literatures on the effect of mTOR on protein metabolism in non-mammals. The main source of ammonia in fish comes from protein catabolism. The key step of protein catabolism involves the deamination and/or transamination of amino acids. This study is aimed to explore the mechanism underlying mTOR pathway influencing protein retention from the perspective of protein catabolism. Chinese perch were fasted for 24 h and divided into 4 groups randomly before intracerebroventricular (ICV) injection: (1) control group for leucine; (2) leucine group; (3) control group for leucine and rapamycin; (4) leucine and rapamycin group. Food intake was equivalent between each control and treatment groups at each time point (0.5, 4, 12 and 24 h post-injection). Ammonia-N excretion rate, blood glucose, S6 phosphorylation level, and expression of relative genes of protein catabolism (GDH, AMPD, AST, ALT) were determined. The results indicated that the pS6 level was increased, and that the ammonia-N excretion rate, blood glucose, and mRNA level of protein catabolism genes (GDH and AMPD) were significantly decreased after injection with leucine, while those changes were reversed after injection with leucine and rapamycin. Our study not only reveals the mechanism by which mTOR mediates protein synthesis by inhibiting protein catabolism in Chinese perch, but also provides reference for improving the utilization of feed protein.

Identification of NOVA family proteins as novel ß-catenin RNA-binding proteins that promote epithelial-mesenchymal transition.

The NOVA (neuro-oncological ventral antigen) protein family, composed of two paralogs, NOVA1 and NOVA2, consists of RNA-binding proteins involving in processes such as alternative splicing and transport of some target mRNAs. The function of NOVA has been well studied, and increasing evidence has shown that NOVA proteins may be important contributors to carcinogenesis. However, the molecular mechanisms underlying the roles of NOVA proteins in carcinogenesis remain to be determined. Here, we have identified both NOVA1 and NOVA2 as novel ß-catenin RNA-binding proteins. The NOVA1/NOVA2 heterodimer positively regulates ß-catenin expression by enhancing ß-catenin mRNA stability. Furthermore, we demonstrated that NOVA1 and NOVA2 promote epithelial-mesenchymal transition via ß-catenin in breast cancer cells, as NOVA-induced upregulation of epithelial and mesenchymal marker expression was attenuated by restoring ß-catenin expression. Our results advance the current understanding of ß-catenin post-transcriptional regulation and shed light on the role of NOVA proteins in cancer, suggesting that NOVA proteins are potential therapeutic targets in breast cancer.

Activin A affects feeding by promoting the inner diameter and muscle development of the pharynx and oesophagus in zebrafish (Danio rerio) larvae.

Activin A belongs to the superfamily of transforming growth factor-ß and plays an important role in hormone regulation and tissue development. However, few research studies have been conducted on the effect of activin A on feeding organs in fish. In this study, the zebrafish (Danio rerio) larvae were treated with 1 ng ml-1 activin A for 8 days continuously. The haematoxylin and eosin (H&E) staining section results revealed that the transverse inner diameter of the pharynx and oesophagus significantly increased on the third and eighth days after treatment compared with the control group (P < 0.05). On the eighth day, the cross-sectional area of the pharyngeal muscle increased by 8638 µm2 compared to the control group (P < 0.05). The RNA in situ hybridization results also showed that the expression of skeletal muscle-specific genes (myog and myod) was significantly increased in pharyngeal muscle on the eighth day. Furthermore, the qRT-PCR results showed the expression of gh gene was significantly increased on the eighth day (P < 0.05). At the same time, more larvae in activin A group were able to feed larger brine shrimp (Artemia) than in the control group on the eighth day. In conclusion, activin A could affect feeding by promoting the inner diameter and muscle development of the pharynx and oesophagus in zebrafish larvae. This study is the first to report that the development of the pharynx and oesophagus can directly affect food intake in fish larvae, which provides a theoretical basis for the study of food intake of fish at an early stage.

Deoxynivalenol Exposure Suppresses Adipogenesis by Inhibiting the Expression of Peroxisome Proliferator-Activated Receptor Gamma 2 (PPARγ2) in 3T3-L1 Cells.

Deoxynivalenol (DON)-a type B trichothecene mycotoxin, mainly produced by the secondary metabolism of Fusarium-has toxic effects on animals and humans. Although DON's toxicity in many organs including the adrenal glands, thymus, stomach, spleen, and colon has been addressed, its effects on adipocytes have not been investigated. In this study, 3T3-L1 cells were chosen as the cell model and treated with less toxic doses of DON (100 ng/mL) for 7 days. An inhibition of adipogenesis and decrease in triglycerides (TGs) were observed. DON exposure significantly downregulated the expression of PPARγ2 and C/EBPα, along with that of other adipogenic marker genes in 3T3-L1 cells and BALB/c mice. The anti-adipogenesis effect of DON and the downregulation of the expression of adipogenic marker genes were effectively reversed by PPARγ2 overexpression. The repression of PPARγ2's expression is the pivotal event during DON exposure regarding adipogenesis. DON exposure specifically decreased the di-/trimethylation levels of Histone 3 at lysine 4 in 3T3-L1 cells, therefore weakening the enrichment of H3K4me2 and H3K4me3 at the Pparγ2 promoter and suppressing its expression. Conclusively, DON exposure inhibited PPARγ2 expression via decreasing H3K4 methylation, downregulated the expression of PPARγ2-regulated adipogenic marker genes, and consequently suppressed the intermediate and late stages of adipogenesis. Our results broaden the current understanding of DON's toxic effects and provide a reference for addressing the toxicological mechanism of DON's interference with lipid homeostasis.

Association of age at diagnosis of diabetes with subsequent risk of age-related ocular diseases and vision acuity.

BACKGROUND: The importance of age on the development of ocular conditions has been reported by numerous studies. Diabetes may have different associations with different stages of ocular conditions, and the duration of diabetes may affect the development of diabetic eye disease. While there is a dose-response relationship between the age at diagnosis of diabetes and the risk of cardiovascular disease and mortality, whether the age at diagnosis of diabetes is associated with incident ocular conditions remains to be explored. It is unclear which types of diabetes are more predictive of ocular conditions. AIM: To examine associations between the age of diabetes diagnosis and the incidence of cataract, glaucoma, age-related macular degeneration (AMD), and vision acuity. METHODS: Our analysis was using the UK Biobank. The cohort included 8709 diabetic participants and 17418 controls for ocular condition analysis, and 6689 diabetic participants and 13378 controls for vision analysis. Ocular diseases were identified using inpatient records until January 2021. Vision acuity was assessed using a chart. RESULTS: During a median follow-up of 11.0 years, 3874, 665, and 616 new cases of cataract, glaucoma, and AMD, respectively, were identified. A stronger association between diabetes and incident ocular conditions was observed where diabetes was diagnosed at a younger age. Individuals with type 2 diabetes (T2D) diagnosed at < 45 years [HR (95%CI): 2.71 (1.49-4.93)], 45-49 years [2.57 (1.17-5.65)], 50-54 years [1.85 (1.13-3.04)], or 50-59 years of age [1.53 (1.00-2.34)] had a higher risk of AMD independent of glycated haemoglobin. T2D diagnosed < 45 years [HR (95%CI): 2.18 (1.71-2.79)], 45-49 years [1.54 (1.19-2.01)], 50-54 years [1.60 (1.31-1.96)], or 55-59 years of age [1.21 (1.02-1.43)] was associated with an increased cataract risk. T2D diagnosed < 45 years of age only was associated with an increased risk of glaucoma [HR (95%CI): 1.76 (1.00-3.12)]. HRs (95%CIs) for AMD, cataract, and glaucoma associated with type 1 diabetes (T1D) were 4.12 (1.99-8.53), 2.95 (2.17-4.02), and 2.40 (1.09-5.31), respectively. In multivariable-adjusted analysis, individuals with T2D diagnosed < 45 years of age [ß 95%CI: 0.025 (0.009,0.040)] had a larger increase in LogMAR. The ß (95%CI) for LogMAR associated with T1D was 0.044 (0.014, 0.073). CONCLUSION: The younger age at the diagnosis of diabetes is associated with a larger relative risk of incident ocular diseases and greater vision loss.

Metabolomic age and risk of 50 chronic diseases in community-dwelling adults: A prospective cohort study.

It is unclear how metabolomic age is associated with the risk of a wide range of chronic diseases. Our analysis included 110,692 participants (training: n = 27,673; testing: n = 27,673; validating: n = 55,346) aged 39-71 years at baseline (2006-2010) from the UK Biobank. Incident chronic diseases were identified using inpatient records, or death registers until January 2021. Predicted metabolomic age was trained and tested based on 168 metabolomics. Metabolomic age was linked to the risk of 50 diseases in the validation dataset. The median follow-up duration for individual diseases ranged from 11.2 years to 11.9 years. After controlling for false discovery rate, chronological age-adjusted age gap (CAAG) was significantly associated with the incidence of 25 out of 50 chronic diseases. After adjustment for full covariates, associations with 15 chronic diseases remained significant. Greater CAAG was associated with increased risk of eight cardiometabolic disorders (including cardiovascular diseases and diabetes), some cancers, alcohol use disorder, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease and age-related macular degeneration. The association between CAAG and risk of peripheral vascular disease, other cardiac diseases, fracture, cataract and thyroid disorder was stronger among individuals with unhealthy diet than in those with healthy diet. The association between CAAG and risk of some conditions was stronger in younger individuals, those with metabolic disorders or low education. Metabolomic age plays an important role in the development of multiple chronic diseases. Healthy diet and high education may mitigate the risk for some chronic diseases due to metabolomic age acceleration.

Association of greenspace and natural environment with brain volumes mediated by lifestyle and biomarkers among urban residents.

OBJECTIVES: To examine the associaiton between environmental measures and brain volumes and its potential mediators. STUDY DESIGN: This was a prospective study. METHODS: Our analysis included 34,454 participants (53.4% females) aged 40-73 years at baseline (between 2006 and 2010) from the UK Biobank. Brain volumes were measured using magnetic resonance imaging between 2014 and 2019. RESULTS: Greater proximity to greenspace buffered at 1000 m at baseline was associated with larger volumes of total brain measured 8.8 years after baseline assessment (standardized ß (95% CI) for each 10% increment in coverage: 0.013(0.005,0.020)), grey matter (0.013(0.006,0.020)), and white matter (0.011(0.004,0.017)) after adjustment for covariates and air pollution. The corresponding numbers for natural environment buffered at 1000 m were 0.010 (0.004,0.017), 0.009 (0.004,0.015), and 0.010 (0.004,0.016), respectively. Similar results were observed for greenspace and natural environment buffered at 300 m. The strongest mediator for the association between greenspace buffered at 1000 m and total brain volume was smoking (percentage (95% CI) of total variance explained: 7.9% (5.5-11.4%)) followed by mean sphered cell volume (3.3% (1.8-5.8%)), vitamin D (2.9% (1.6-5.1%)), and creatinine in blood (2.7% (1.6-4.7%)). Significant mediators combined explained 18.5% (13.2-25.3%) of the association with total brain volume and 32.9% (95% CI: 22.3-45.7%) of the association with grey matter volume. The percentage (95% CI) of the association between natural environment and total brain volume explained by significant mediators combined was 20.6% (14.7-28.1%)). CONCLUSIONS: Higher coverage percentage of greenspace and environment may benefit brain health by promoting healthy lifestyle and improving biomarkers including vitamin D and red blood cell indices.

The Joint Effect of Social Comparison and Social Distance on Evaluation of Intertemporal Choice Outcomes in Event-related Potential Studies.

Intertemporal choice plays a crucial role in our daily lives, influencing decisions related to education, health, consumption, and investment. This research proposes an innovative experimental protocol that examines how social comparison and social distance jointly affect the neural processes involved in outcome assessment for intertemporal choices. The study is based on the theoretical framework of cognitive resource competition. This protocol enables researchers to dynamically establish an indifference point for each participant, effectively eliminating the influence of any biased indifference points on the assessment of intertemporal choices. Consequently, the study solely measures the combined impact of social comparison and social distance on how participants evaluate intertemporal choice outcomes. The findings reveal that individuals are more inclined to opt for immediate outcomes under negative unfair conditions. Moreover, compared to the fair and positive unfair conditions, people tend to undervalue delayed outcomes in the negative unfair condition. The strength of this approach lies in its dynamic indifference point setting, making it an effective method to investigate the influence of various external factors (such as social status and power level) on intertemporal decision-making. While the protocol is designed to measure electrophysiological events like event-related potentials, it can also be tailored for use with fMRI.

Single-cell RNA-seq uncovers distinct pathways and genes in endothelial cells during atherosclerosis progression.

Background: Atherosclerosis (AS) is a chronic inflammatory disease involving various cell types, cytokines, and adhesion molecules. Herein, we aimed to uncover its key molecular mechanisms by single-cell RNA-seq (scRNA-seq) analysis. Methods: ScRNA-seq data of cells from atherosclerotic human coronary arteries were analyzed using the Seurat package. Cell types were clustered, and differentially expressed genes (DEGs) were screened. GSVA (Gene Set Variation Analysis) scores of hub pathways were compared among different cell clusters. DEGs in endothelial cells between apolipoprotein-E (ApoE)-/- mice and specific TGFbR1/2 KO ApoE-/- mice fed with high-fat diet were overlapped with those from human AS coronary arteries. In fluid shear stress and AS, hub genes were determined based on the protein-protein interaction (PPI) network, which were verified in ApoE-/- mice. Finally, hub genes were validated in three pairs of AS coronary arteries and normal tissues by histopathological examination. Results: ScRNA-seq identified nine cell clusters in human coronary arteries, namely, fibroblasts, endothelial cells, macrophages, B cells, adipocytes, HSCs, NK cells, CD8+ T cells, and monocytes. Among them, endothelial cells had the lowest fluid shear stress and AS and TGF-beta signaling pathway scores. Compared to ApoE-/- mice fed with normal diet, fluid shear stress and AS and TGF-beta scores were both significantly lower in endothelial cells from TGFbR1/2 KO ApoE-/- mice fed with normal or high-fat diet. Furthermore, the two hub pathways had a positive correlation. Three hub genes (ICAM1, KLF2, and VCAM1) were identified, and their expression was distinctly downregulated in endothelial cells from TGFbR1/2 KO ApoE-/- mice fed with normal or high-fat diet than in those from ApoE-/- mice fed with a normal diet, which were confirmed in human AS coronary artery. Conclusion: Our findings clarified the pivotal impacts of pathways (fluid shear stress and AS and TGF-beta) and genes (ICAM1, KLF2, and VCAM1) in endothelial cells on AS progression.