Deep5hmC: Predicting genome-wide 5-Hydroxymethylcytosine landscape via a multimodal deep learning model.

5-hydroxymethylcytosine (5hmC), a critical epigenetic mark with a significant role in regulating tissue-specific gene expression, is essential for understanding the dynamic functions of the human genome. Using tissue-specific 5hmC sequencing data, we introduce Deep5hmC, a multimodal deep learning framework that integrates both the DNA sequence and the histone modification information to predict genome-wide 5hmC modification. The multimodal design of Deep5hmC demonstrates remarkable improvement in predicting both qualitative and quantitative 5hmC modification compared to unimodal versions of Deep5hmC and state-of-the-art machine learning methods. This improvement is demonstrated through benchmarking on a comprehensive set of 5hmC sequencing data collected at four time points during forebrain organoid development and across 17 human tissues. Notably, Deep5hmC showcases its practical utility by accurately predicting gene expression and identifying differentially hydroxymethylated regions in a case-control study of Alzheimer's disease.

Motor symptoms of Parkinson's disease are affected by temperature: A controlled pilot study.

PURPOSE: The motor symptoms (MS) of Parkinson's disease (PD) have been affecting the quality of life in patients. In clinical practice, most patients with PD report that MS are more severe in winter than in summer, and hyperthermic baths (HTB) could temporarily improve MS. The study aimed to evaluate the effects of seasonal variation and aquatic thermal environment of HTB on the MS of PD. PATIENTS AND METHODS: A cross-sectional study of 203 Chinese Han patients was performed. Univariate and multivariate analyses were performed to analyze seasonal variation in MS relative to baseline data (sex, age at onset, duration, season of birth, Hoehn and Yahr stage, family history, levodopa equivalent dose, and the effect of HTB on MS). Ten subjects participated in the HTB study, and one patient dropped out. The paired Wilcoxon rank test was used to assess the differences in the Movement Disorder Society-United Parkinson's disease Rating Scale (MDS-UPDRS) part III motor examination total scores and the modified Webster Symptoms Score between non-HTB and before HTB and between non-HTB and after HTB. RESULTS: The improvement of MS after HTB was an independent risk factor for seasonal variation in MS (OR, 25.203; 95% CI, 10.951-58.006; p = .000). Patients with PD had significant improvements in the MDS-UPDRS part III motor examination total scores, especially in bradykinesia (p = .043), rigidity (p = .008), posture (p = .038), and rest tremor amplitude (p = .047). CONCLUSION: Seasonal variation in temperature and water temperature of HTB may affect MS in some patients with PD. Simple HTB could be recommended as physiotherapy for patients with PD who report temperature-sensitive MS.

Longitudinal Profiling of Fasting Plasma Metabolome in Response to Weight-Loss Interventions in Patients with Morbid Obesity.

It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive medical intervention (IMI). The molecular mechanisms behind these observations, however, remain largely unknown. To identify the plasma metabolites associated with differential glycemic outcomes induced by weight-loss intervention, we studied 75 patients with severe obesity (25 each in RYGB, BAND, or IMI). Using untargeted metabolomics, we repeatedly measured 364 metabolites in plasma samples at baseline and 1-year after intervention. Linear regression was used to examine whether baseline metabolites or changes in metabolites are associated with differential glycemic outcomes in response to different types of weight-loss intervention, adjusting for sex, baseline age, and BMI as well as weight loss. Network analyses were performed to identify differential metabolic pathways involved in the observed associations. After correction for multiple testing (q < 0.05), 33 (RYGB vs. IMI) and 28 (RYGB vs. BAND) baseline metabolites were associated with changes in fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c). Longitudinal changes in 38 (RYGB vs. IMI) and 38 metabolites (RYGB vs. BAND) were significantly associated with changes in FPG or HbA1c. The identified metabolites are enriched in pathways involved in the biosynthesis of aminoacyl-tRNA and branched-chain amino acids. Weight-loss intervention evokes extensive changes in plasma metabolites, and the altered metabolome may underlie the differential glycemic outcomes in response to different types of weight-loss intervention, independent of weight loss itself.

Longitudinal Lipidomic Signature of Coronary Heart Disease in American Indian People.

BACKGROUND: Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large-scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting. METHODS AND RESULTS: Using an untargeted liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow-up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors. CONCLUSIONS: Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

Equilibrium points and their stability of COVID-19 in US.

This study aims to develop an advanced mathematic model and investigate when and how will the COVID-19 in the US be evolved to endemic. We employed a nonlinear ordinary differential equations-based model to simulate COVID-19 transmission dynamics, factoring in vaccination efforts. Multi-stability analysis was performed on daily new infection data from January 12, 2021 to December 12, 2022 across 50 states in the US. Key indices such as eigenvalues and the basic reproduction number were utilized to evaluate stability and investigate how the pandemic COVD-19 will evolve to endemic in the US. The transmissional, recovery, vaccination rates, vaccination effectiveness, eigenvalues and reproduction numbers ([Formula: see text] and [Formula: see text]) in the endemic equilibrium point were estimated. The stability attractor regions for these parameters were identified and ranked. Our multi-stability analysis revealed that while the endemic equilibrium points in the 50 states remain unstable, there is a significant trend towards stable endemicity in the US. The study's stability analysis, coupled with observed epidemiological waves in the US, suggested that the COVID-19 pandemic may not conclude with the virus's eradication. Nevertheless, the virus is gradually becoming endemic. Effectively strategizing vaccine distribution is pivotal for this transition.

Acupoint application therapy alleviates pain by regulating immune function through inhibiting TLR4/MyD88/NF-κB p65 signaling in a primary dysmenorrhea rat model. / 穴位贴敷通过TLR4/MyD88/NF-κBé€šè·¯è°ƒèŠ‚åŽŸå‘æ€§ç—›ç»å¤§é¼ çš„å ç–«åŠŸèƒ½.

OBJECTIVES: To investigate the effects of graphene-based warm uterus acupoint paste on uterine Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-kappa B p65 (NF-κB p65) signaling pathway and Th1/Th2 immune balance in primary dysmenorrhea ( PD ) model rats, so as to reveal its immunological mechanisms of relieving dysmenorrhea. METHODS: Thirty SD female rats were randomly divided into 3 groups：normal group, model group and acupoint paste group, with 10 rats in each group. PD rat model was established by subcutaneous injection of estradiol benzoate for 10 consecutive days. At the same time of modeling, graphene-based warm uterus acupoint paste was applied to the acupoints of "Guanyuan" (CV4), bilateral "Zigong" (EX-CA1) and "Sanyinjiao" (SP6) of rats in the acupoint paste group. The application was continuously applied once daily for 10 d, 5 h each time. On the 11th day, oxytocin was injected intraperitoneally to observe the writhing latency, writhing times within 30 min and writhing score of rats in each group. The spleen and thymus indexes were calculated. The pathological changes of spleen and thymus tissue were observed after HE staining. The contents of serum immunoglobulin (Ig) A, IgG, tumor necrosis factor-α (TNF-α), interleukin (IL)-2, interferon-γ (IFN-γ), IL-4 and IL-10 were detected by ELISA . The protein and mRNA expression levels of TLR4, MyD88 and NF-κB p65 in rat uterine tissue were detected by Western blot and real-time quantitative PCR, respectively. RESULTS: Compared with the normal group, the writhing times and writhing scores within 30 min of rats in the model group were significantly increased(P<0.001), and the rats showed writhing reaction (P<0.01). The spleen index and thymus index were significantly decreased(P<0.01, P<0.05). The spleen and thymus had obvious pathological changes. The contents of IgA, IgG, TNF-α, IL-2 and IFN-γ in serum were significantly increased, while the contents of serum IL-4 and IL-10 were significantly decreased(P<0.001, P<0.01). The expression levels of TLR4, MyD88, NF-κB p65 protein and corresponding mRNA in uterine tissue were significantly increased(P<0.001). Following intervention, compared with the model group, the writhing latency time of rats in the acupoint paste group was prolonged, and the writhing times and writhing scores within 30 min were significantly decreased (P<0.001). The spleen index and thymus index were significantly increased(P<0.01, P<0.05). The pathological changes of spleen and thymus were improved. The contents of serum IgA, IgG, TNF-α, IL-2 and IFN-γ were significantly decreased, while the contents of IL-4 and IL-10 were significantly increased(P<0.001, P<0.05, P<0.01). The expression of TLR4, MyD88, NF-κB p65 protein and the corresponding mRNA levels in uterine tissue were decreased(P<0.001, P<0.01). CONCLUSIONS: Graphene-based warm uterus acupoint paste can regulate the immune balance of Th1/ Th2 by regulating TLR4/ MyD88/ NF-κB p65 signaling pathway, repair the pathological damage of immune tissue, improve immune function, and effectively relieve the pain symptoms of PD rats.

Learning from vertically distributed data across multiple sites: An efficient privacy-preserving algorithm for Cox proportional hazards model with variable selection.

OBJECTIVE: To develop a lossless distributed algorithm for regularized Cox proportional hazards model with variable selection to support federated learning for vertically distributed data. METHODS: We propose a novel distributed algorithm for fitting regularized Cox proportional hazards model when data sharing among different data providers is restricted. Based on cyclical coordinate descent, the proposed algorithm computes intermediary statistics by each site and then exchanges them to update the model parameters in other sites without accessing individual patient-level data. We evaluate the performance of the proposed algorithm with (1) a simulation study and (2) a real-world data analysis predicting the risk of Alzheimer's dementia from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Moreover, we compared the performance of our method with existing privacy-preserving models. RESULTS: Our algorithm achieves privacy-preserving variable selection for time-to-event data in the vertically distributed setting, without degradation of accuracy compared with a centralized approach. Simulation demonstrates that our algorithm is highly efficient in analyzing high-dimensional datasets. Real-world data analysis reveals that our distributed Cox model yields higher accuracy in predicting the risk of Alzheimer's dementia than the conventional Cox model built by each data provider without data sharing. Moreover, our algorithm is computationally more efficient compared with existing privacy-preserving Cox models with or without regularization term. CONCLUSION: The proposed algorithm is lossless, privacy-preserving and highly efficient to fit regularized Cox model for vertically distributed data. It provides a suitable and convenient approach for modeling time-to-event data in a distributed manner.

Plasma lipidomic markers of diet quality are associated with incident coronary heart disease in American Indian adults: the Strong Heart Family Study.

BACKGROUND: Identifying lipidomic markers of diet quality is needed to inform the development of biomarkers of diet, and to understand the mechanisms driving the diet- coronary heart disease (CHD) association. OBJECTIVES: This study aimed to identify lipidomic markers of diet quality and examine whether these lipids are associated with incident CHD. METHODS: Using liquid chromatography-mass spectrometry, we measured 1542 lipid species from 1694 American Indian adults (aged 18-75 years, 62% female) in the Strong Heart Family Study. Participants were followed up for development of CHD through 2020. Information on the past year diet was collected using the Block Food Frequency Questionnaire, and diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI). Mixed-effects linear regression was used to identify individual lipids cross-sectionally associated with AHEI. In prospective analysis, Cox frailty model was used to estimate the hazard ratio (HR) of each AHEI-related lipid for incident CHD. All models were adjusted for age, sex, center, education, body mass index, smoking, alcohol drinking, level of physical activity, energy intake, diabetes, hypertension, and use of lipid-lowering drugs. Multiple testing was controlled at a false discovery rate of <0.05. RESULTS: Among 1542 lipid species measured, 71 lipid species (23 known), including acylcarnitine, cholesterol esters, glycerophospholipids, sphingomyelins and triacylglycerols, were associated with AHEI. Most of the identified lipids were associated with consumption of ω-3 (n-3) fatty acids. In total, 147 participants developed CHD during a mean follow-up of 17.8 years. Among the diet-related lipids, 10 lipids [5 known: cholesterol ester (CE)(22:5)B, phosphatidylcholine (PC)(p-14:0/22:1)/PC(o-14:0/22:1), PC(p-38:3)/PC(o-38:4)B, phosphatidylethanolamine (PE)(p-18:0/20:4)/PE(o-18:0/20:4), and sphingomyelin (d36:2)A] were associated with incident CHD. On average, each standard deviation increase in the baseline level of these 5 lipids was associated with 17%-23% increased risk of CHD (from HR: 1.17; 95% CI: 1, 1.36; to HR: 1.23; 95% CI: 1.05, 1.43). CONCLUSIONS: In this study, lipidomic markers of diet quality in American Indian adults are found. Some diet-related lipids are associated with risk of CHD beyond established risk factors.

Acupoint compatibility effect: increasing "effect value" and expanding "effect domain". / è §ç©´é ä¼æ•ˆåº”.

By summarizing and exploring the theoretic connotation, key of functions and effect mechanism of acupoint compatibility, the effect of acupoint compatibility is concluded as the increase of "effect value" and the expansion of "effect domain". The increase of "effect value" is the concrete embodiment by the value of medical assessment scale, the value of objective index detection in clinical trial and the value of index detection in experiment research. The expansion of "effect domain" is the increase of effect target and the extension of effect scope. The paper interprets the scientific connotation of acupoint compatibility therapy from a new perspective, and emphasizes the innovative approaches to research while bringing forth new ideas on the research method. It is anticipated that a novel breakthrough can be achieved in the study of acupoint compatibility and the improvement of acupuncture-moxibustion efficacy.

Shape recovery from fusion of polarization binocular vision and shading.

The shape from polarization can recover the fine texture of the target surface. However, the gradient field for shape recovery by polarization is ambiguous, which is caused by the multi-value of the azimuth angle. In response to the problem, a method of correcting the ambiguity by the fusion of polarization binocular vision and shading information is proposed in this paper. An iterative optimization algorithm is designed to estimate the direction of the light source, which provides the basis for the shading method to calculate the depth map. Additionally. the low-frequency depth map generated by binocular matching is used to correct the polarization gradient field. The polarization gradient field of the holes and small zenith angle regions in the binocular are corrected by the improved shading method. In the experiment, four different material target objects were used for shape recovery and compared with other methods. The results of the fusion method proposed are better in terms of fine texture. At the camera working distance of  700 mm, the resolving power performs well and demonstrates that changes in the depth of at least 0.1 mm can be distinguished from that recovery result.

Longitudinal lipidomic signature of carotid atherosclerosis in American Indians: Findings from the Strong Heart Family Study.

BACKGROUND AND AIMS: Dyslipidemia is an independent risk factor for atherosclerosis and atherosclerotic cardiovascular disease (ASCVD). To date, a comprehensive assessment of individual lipid species associated with atherosclerosis is lacking in large-scale epidemiological studies, especially in a longitudinal setting. We investigated the association of circulating lipid species and its longitudinal changes with carotid atherosclerosis. METHODS: Using liquid chromatograph-mass spectrometry, we repeatedly measured 1542 lipid species in 3687 plasma samples from 1918 unique American Indians attending two visits (mean ∼5 years apart) in the Strong Heart Family Study. Carotid atherosclerotic plaques were assessed by ultrasonography at each visit. We identified lipids associated with prevalence or progression of carotid plaques, adjusting age, sex, BMI, smoking, hypertension, diabetes, and eGFR. Then we examined whether longitudinal changes in lipids were associated with changes in cardiovascular risk factors. Multiple testing was controlled at false discovery rate (FDR) < 0.05. RESULTS: Higher levels of sphingomyelins, ether-phosphatidylcholines, and triacylglycerols were significantly associated with prevalence or progression of carotid plaques (odds ratios ranged from 1.15 to 1.34). Longitudinal changes in multiple lipid species (e.g., acylcarnitines, phosphatidylcholines, triacylglycerols) were associated with changes in cardiometabolic traits (e.g., BMI, blood pressure, fasting glucose, eGFR). Network analysis identified differential lipid networks associated with plaque progression. CONCLUSIONS: Baseline and longitudinal changes in multiple lipid species were significantly associated with carotid atherosclerosis and its progression in American Indians. Some plaque-related lipid species were also associated with risk for CVD events.

Graphical Learning and Causal Inference for Drug Repurposing.

Gene expression profiles that connect drug perturbations, disease gene expression signatures, and clinical data are important for discovering potential drug repurposing indications. However, the current approach to gene expression reversal has several limitations. First, most methods focus on validating the reversal expression of individual genes. Second, there is a lack of causal approaches for identifying drug repurposing candidates. Third, few methods for passing and summarizing information on a graph have been used for drug repurposing analysis, with classical network propagation and gene set enrichment analysis being the most common. Fourth, there is a lack of graph-valued association analysis, with current approaches using real-valued association analysis one gene at a time to reverse abnormal gene expressions to normal gene expressions. To overcome these limitations, we propose a novel causal inference and graph neural network (GNN)-based framework for identifying drug repurposing candidates. We formulated a causal network as a continuous constrained optimization problem and developed a new algorithm for reconstructing large-scale causal networks of up to 1,000 nodes. We conducted large-scale simulations that demonstrated good false positive and false negative rates. To aggregate and summarize information on both nodes and structure from the spatial domain of the causal network, we used directed acyclic graph neural networks (DAGNN). We also developed a new method for graph regression in which both dependent and independent variables are graphs. We used graph regression to measure the degree to which drugs reverse altered gene expressions of disease to normal levels and to select potential drug repurposing candidates. To illustrate the application of our proposed methods for drug repurposing, we applied them to phase I and II L1000 connectivity map perturbational profiles from the Broad Institute LINCS, which consist of gene-expression profiles for thousands of perturbagens at a variety of time points, doses, and cell lines, as well as disease gene expression data under-expressed and over-expressed in response to SARS-CoV-2.

Improving Photovoltaic Performance of All-Polymer Solar Cells by Adding an Amorphous B←N Embedded Polymer as the Third Component.

Currently, most of the disclosed ternary strategies to improve photovoltaic performance of all-polymer solar cells (all-PSCs) commonly focus on the guest polymers having similar structures with the host polymer donors or acceptors. Herein, this work develops a distinctive ternary method that adding an amorphous B←N embedded polymer named BN-Cl-2fT to a crystallized host polymer blend of PM6 (a commercialized polymer donor) and PY-TT (a copolymer of Y6 and thieno[3,2-b]thiophene). Although the structures between BN-Cl-2fT and PM6 and PY-TT are completely different, excellent miscibility is found between BN-Cl-2fT and both of the host PM6 and PY-TT, which can be interpreted by the crowded phenyl groups anchoring along the backbone of BN-Cl-2fT, leading to weak self-aggregation. Glazing incidence wide-angle X-ray diffraction (GIWAXS) measurements explicitly confirm the crystallization of PM6 and PY-TT and amorphous feature of BN-Cl-2fT. Furthermore, adding 10 wt% BN-Cl-2fT to PM6:PY-TT can significantly enhance the crystallization of the host polymers. Thus the ternary devices based on PM6:PY-TT:BN-Cl-2fT afford promote short-circuit current density (JSC , 23.29 vs. 21.80 mA cm-2 ), fill factor (FF, 62.4% vs. 60.0%), and power conversion efficiency (PCE, 13.70% vs. 12.23%) in contrast to these parameters of binary devices based on PM6:PY-TT. This work provides a unique and enlightening avenue to design high performance all-PSCs by adding amorphous B←N embedded polymers as guest component to enhance host-crystallization.

DNA methylation is differentially associated with glycemic outcomes by different types of weight-loss interventions: an epigenome-wide association study.

BACKGROUND: Alterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions. METHODS: Participants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n = 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors. RESULTS: Baseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND. CONCLUSIONS: Baseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.

Chitosan Microspheres Loaded with Curcumin and Gallic Acid: Modified Synthesis, Sustainable Slow Release, and Enhanced Biological Property.

Improving the utilization rate of loaded-drugs is of huge importance for generating chitosan-based (CS) micro-carriers. This study aims to fabricate a novel CS microspheres co-delivered curcumin (Cur) and gallic acid (Ga) to assess drug loading and release kinetics, the blood compatibility and anti-osteosarcoma properties. The present study observes the interaction between CS and Cur/Ga molecules and estimates the change in crystallinity and loading and release rate. In addition, blood compatibility and cytotoxicity of such microspheres are also evaluated. Cur-Ga-CS microspheres present high entrapment rate of (55.84 ± 0.34) % for Ga and (42.68 ± 0.11) % for Cur, possibly attributed to surface positive charge (21.76 ± 2.46) mV. Strikingly, Cur-Ga-CS microspheres exhibit slowly sustainable release for almost 7 days in physiological buffer. Importantly, these microspheres possess negligibly toxic to blood and normal BMSC cells, but strong anti-osteosarcoma effect on U2OS cells. Overall, Cur-Ga-CS microspheres are promising to become a novel anti-osteosarcoma agent or sustainable delivery carrier in biomedical applications.

Longitudinal Lipidomic Profile of Hypertension in American Indians: Findings From the Strong Heart Family Study.

BACKGROUND: Dyslipidemia is an important risk factor for hypertension and cardiovascular disease. Standard lipid panel cannot reflect the complexity of blood lipidome. The associations of individual lipid species with hypertension remain to be determined in large-scale epidemiological studies, especially in a longitudinal setting. METHODS: Using liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species in 3699 fasting plasma samples at 2 visits (1905 at baseline, 1794 at follow-up, ~5.5 years apart) from 1905 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with prevalent and incident hypertension, followed by replication of top hits in Europeans. We then conducted repeated measurement analysis to examine the associations of changes in lipid species with changes in systolic blood pressure, diastolic blood pressure, and mean arterial pressure. Network analysis was performed to identify lipid networks associated with the risk of hypertension. RESULTS: Baseline levels of multiple lipid species, for example, glycerophospholipids, cholesterol esters, sphingomyelins, glycerolipids, and fatty acids, were significantly associated with both prevalent and incident hypertension in American Indians. Some lipids were confirmed in Europeans. Longitudinal changes in multiple lipid species, for example, acylcarnitines, phosphatidylcholines, fatty acids, and triacylglycerols, were significantly associated with changes in blood pressure measurements. Network analysis identified distinct lipidomic patterns associated with the risk of hypertension. CONCLUSIONS: Baseline plasma lipid species and their longitudinal changes are significantly associated with hypertension development in American Indians. Our findings shed light on the role of dyslipidemia in hypertension and may offer potential opportunities for risk stratification and early prediction of hypertension.

Epigenome-wide association study identifies novel genes associated with ischemic stroke.

BACKGROUND: DNA methylation has previously been associated with ischemic stroke, but the specific genes and their functional roles in ischemic stroke remain to be determined. Here we aimed to identify differentially methylated genes that play a functional role in ischemic stroke in a Chinese population. RESULTS: Genome-wide DNA methylation assessed with the Illumina Methylation EPIC Array in a discovery sample including 80 Chinese adults (40 cases vs. 40 controls) found that patients with ischemic stroke were characterized by increased DNA methylation at six CpG loci (individually located at TRIM6, FLRT2, SOX1, SOX17, AGBL4, and FAM84A, respectively) and decreased DNA methylation at one additional locus (located at TLN2). Targeted bisulfite sequencing confirmed six of these differentially methylated probes in an independent Chinese population (853 cases vs. 918 controls), and one probe (located at TRIM6) was further verified in an external European cohort (207 cases vs. 83 controls). Experimental manipulation of DNA methylation in engineered human umbilical vein endothelial cells indicated that the identified differentially methylated probes located at TRIM6, TLN2, and FLRT2 genes may play a role in endothelial cell adhesion and atherosclerosis. CONCLUSIONS: Altered DNA methylation of the TRIM6, TLN2, and FLRT2 genes may play a functional role in ischemic stroke in Chinese populations.

Drooling disrupts the brain functional connectivity network in Parkinson's disease.

AIMS: This study aimed to investigate the causal interaction between significant sensorimotor network (SMN) regions and other brain regions in Parkinson's disease patients with drooling (droolers). METHODS: Twenty-one droolers, 22 PD patients without drooling (non-droolers), and 22 matched healthy controls underwent 3T-MRI resting-state scans. We performed independent component analysis and Granger causality analysis to determine whether significant SMN regions help predict other brain areas. Pearson's correlation was computed between imaging characteristics and clinical characteristics. ROC curves were plotted to assess the diagnostic performance of effective connectivity (EC). RESULTS: Compared with non-droolers and healthy controls, droolers showed abnormal EC of the right caudate nucleus (CAU.R) and right postcentral gyrus to extensive brain regions. In droolers, increased EC from the CAU.R to the right middle temporal gyrus was positively correlated with MDS-UPDRS, MDS-UPDRS II, NMSS, and HAMD scores; increased EC from the right inferior parietal lobe to CAU.R was positively correlated with MDS-UPDRS score. ROC curve analysis showed that these abnormal ECs are of great significance in diagnosing drooling in PD. CONCLUSION: This study identified that PD patients with drooling have abnormal EC in the cortico-limbic-striatal-cerebellar and cortio-cortical networks, which could be potential biomarkers for drooling in PD.

mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.

BACKGROUND: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk. METHODS: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term. RESULTS: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons. CONCLUSION: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings.

Longitudinal lipidomic signatures of all-cause and CVD mortality in American Indians: findings from the Strong Heart Study.

Dyslipidemia is an independent and modifiable risk factor for aging and age-related disorders. Routine lipid panel cannot capture all individual lipid species in blood (i.e., blood lipidome). To date, a comprehensive assessment of the blood lipidome associated with mortality is lacking in large-scale community-dwelling individuals, especially in a longitudinal setting. Using liquid chromatograph-mass spectrometry, we repeatedly measured individual lipid species in 3,821 plasma samples collected at two visits (~ 5.5 years apart) from 1,930 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with risks for all-cause mortality and CVD mortality (mean follow-up period: 17.8 years) in American Indians, followed by replication of top hits in European Caucasians in the Malmö Diet and Cancer-Cardiovascular Cohort (n = 3,943, mean follow-up period: 23.7 years). The model adjusted age, sex, BMI, smoking, hypertension, diabetes, and LDL-c at baseline. We then examined the associations between changes in lipid species and risk of mortality. Multiple testing was controlled by false discovery rate (FDR). We found that baseline levels and longitudinal changes of multiple lipid species, e.g., cholesterol esters, glycerophospholipids, sphingomyelins, and triacylglycerols, were significantly associated with risks of all-cause or CVD mortality. Many lipids identified in American Indians could be replicated in European Caucasians. Network analysis identified differential lipid networks associated with risk of mortality. Our findings provide novel insight into the role of dyslipidemia in disease mortality and offer potential biomarkers for early prediction and risk reduction in American Indians and other ethnic groups.