PharmGWAS: a GWAS-based knowledgebase for drug repurposing.

Leveraging genetics insights to promote drug repurposing has become a promising and active strategy in pharmacology. Indeed, among the 50 drugs approved by FDA in 2021, two-thirds have genetically supported evidence. In this regard, the increasing amount of widely available genome-wide association studies (GWAS) datasets have provided substantial opportunities for drug repurposing based on genetics discoveries. Here, we developed PharmGWAS, a comprehensive knowledgebase designed to identify candidate drugs through the integration of GWAS data. PharmGWAS focuses on novel connections between diseases and small-molecule compounds derived using a reverse relationship between the genetically-regulated expression signature and the drug-induced signature. Specifically, we collected and processed 1929 GWAS datasets across a diverse spectrum of diseases and 724 485 perturbation signatures pertaining to a substantial 33609 molecular compounds. To obtain reliable and robust predictions for the reverse connections, we implemented six distinct connectivity methods. In the current version, PharmGWAS deposits a total of 740 227 genetically-informed disease-drug pairs derived from drug-perturbation signatures, presenting a valuable and comprehensive catalog. Further equipped with its user-friendly web design, PharmGWAS is expected to greatly aid the discovery of novel drugs, the exploration of drug combination therapies and the identification of drug resistance or side effects. PharmGWAS is available at https://ngdc.cncb.ac.cn/pharmgwas.

TargetGene: a comprehensive database of cell-type-specific target genes for genetic variants.

Annotating genetic variants to their target genes is of great importance in unraveling the causal variants and genetic mechanisms that underlie complex diseases. However, disease-associated genetic variants are often located in non-coding regions and manifest context-specific effects, making it challenging to accurately identify the target genes and regulatory mechanisms. Here, we present TargetGene (https://ngdc.cncb.ac.cn/targetgene/), a comprehensive database reporting target genes for human genetic variants from various aspects. Specifically, we collected a comprehensive catalog of multi-omics data at the single-cell and bulk levels and from various human tissues, cell types and developmental stages. To facilitate the identification of Single Nucleotide Polymorphism (SNP)-to-gene connections, we have implemented multiple analytical tools based on chromatin co-accessibility, 3D interaction, enhancer activities and quantitative trait loci, among others. We applied the pipeline to evaluate variants from nearly 1300 Genome-wide association studies (GWAS) and assembled a comprehensive atlas of multiscale regulation of genetic variants. TargetGene is equipped with user-friendly web interfaces that enable intuitive searching, navigation and browsing through the results. Overall, TargetGene provides a unique resource to empower researchers to study the regulatory mechanisms of genetic variants in complex human traits.

COLOCdb: a comprehensive resource for multi-model colocalization of complex traits.

Large-scale genome-wide association studies (GWAS) have provided profound insights into complex traits and diseases. Yet, deciphering the fine-scale molecular mechanisms of how genetic variants manifest to cause the phenotypes remains a daunting task. Here, we present COLOCdb (https://ngdc.cncb.ac.cn/colocdb), a comprehensive genetic colocalization database by integrating more than 3000 GWAS summary statistics and 13 types of xQTL to date. By employing two representative approaches for the colocalization analysis, COLOCdb deposits results from three key components: (i) GWAS-xQTL, pair-wise colocalization between GWAS loci and different types of xQTL, (ii) GWAS-GWAS, pair-wise colocalization between the trait-associated genetic loci from GWASs and (iii) xQTL-xQTL, pair-wise colocalization between the genetic loci associated with molecular phenotypes in xQTLs. These results together represent the most comprehensive colocalization analysis, which also greatly expands the list of shared variants with genetic pleiotropy. We expect that COLOCdb can serve as a unique and useful resource in advancing the discovery of new biological mechanisms and benefit future functional studies.

Brain Catalog: a comprehensive resource for the genetic landscape of brain-related traits.

A broad range of complex phenotypes are related to dysfunctions in brain (hereafter referred to as brain-related traits), including various mental and behavioral disorders and diseases of the nervous system. These traits in general share overlapping symptoms, pathogenesis, and genetic components. Here, we present Brain Catalog (https://ngdc.cncb.ac.cn/braincatalog), a comprehensive database aiming to delineate the genetic components of more than 500 GWAS summary statistics datasets for brain-related traits from multiple aspects. First, Brain Catalog provides results of candidate causal variants, causal genes, and functional tissues and cell types for each trait identified by multiple methods using comprehensive annotation datasets (58 QTL datasets spanning 6 types of QTLs). Second, Brain Catalog estimates the SNP-based heritability, the partitioning heritability based on functional annotations, and genetic correlations among traits. Finally, through bidirectional Mendelian randomization analyses, Brain Catalog presents inference of risk factors that are likely causal to each trait. In conclusion, Brain Catalog presents a one-stop shop for the genetic components of brain-related traits, potentially serving as a valuable resource for worldwide researchers to advance the understanding of how GWAS signals may contribute to the biological etiology of brain-related traits.

Iron-modified biochars and their aging reduce soil cadmium mobility and inhibit rice cadmium uptake by promoting soil iron redox cycling.

Iron (Fe) modified biochar has been widely used for cadmium (Cd) contaminated soil remediation. However, the accompanying anions introduced during the modification process potentially affect the behavior of Cd in soil. In this study, we investigated the distinct Cd immobilization mechanisms by Fe2(SO4)3 modified biochar (FSBC) and Fe(NO3)3 modified biochar (FNBC) in a two-year pot experiment. Results showed that both FSBC and FNBC significantly reduced Cd concentrations in rice grains by 23%-42% and 30%-37% compared to pristine biochar (BC). Specifically, NFBC promoted the formation of amorphous Fe oxides by enhancing the NO3--reducing Fe(II) oxidation process, which significantly increased Fe/Mn oxide-bound Cd and decreased soil CaCl2-extractable Cd. For FSBC, the introduction of SO42- significantly promoted the formation of Fe plaques by enhancing the Fe(III) reduction process, which blocked the Cd transfer from the soil to the rice roots. More importantly, after two years of biochar application, an organo-mineral complex layer is formed on the biochar surface, which immobilized a large amount of Cd. The Cd immobilization on the surface of aged biochar could be due to the fixation by the secondary Fe oxides within the organo-mineral layer and the complexation by the surface functional groups. The result of laser ablation inductively coupled plasma mass spectrometry showed that the Cd content on aged FNBC and FSBC was 5.9 and 2.6 times higher than on aged BC. This might be attributed to the Fe-modified biochar's higher electron exchange capability (EEC), which promoted the development of organo-mineral complexes. Notably, the EEC of biochar was maintained during its aging process, which may keep the biochar surface active and facilitate continual Cd immobilization. This study revealed the complex mechanisms of soil Cd immobilization with Fe-modified biochar, providing new insights into sustainable biochar environmental remediation.

Vinculin Identified as a Potential Biomarker in Hand-Arm Vibration Syndrome Based on iTRAQ and LC-MS/MS-Based Proteomic Analysis.

Local vibration can induce vascular injuries, one example is the hand-arm vibration syndrome (HAVS) caused by hand-transmitted vibration (HTV). Little is known about the molecular mechanism of HAVS-induced vascular injuries. Herein, the iTRAQ (isobaric tags for relative and absolute quantitation) followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach was applied to conduct the quantitative proteomic analysis of plasma from specimens with HTV exposure or HAVS diagnosis. Overall, 726 proteins were identified in iTRAQ. 37 proteins upregulated and 43 downregulated in HAVS. Moreover, 37 upregulated and 40 downregulated when comparing severe HAVS and mild HAVS. Among them, Vinculin (VCL) was found to be downregulated in the whole process of HAVS. The concentration of vinculin was further verified by ELISA, and the results suggested that the proteomics data was reliable. Bioinformative analyses were used, and those proteins mainly engaged in specific biological processes like binding, focal adhesion, and integrins. The potential of vinculin application in HAVS diagnosis was validated by the receiver operating characteristic curve.

A Strategy for Accessing Trifluoromethyl Carbinol-Containing Chromones from o-Hydroxyaryl Enaminones and Trifluoroacetaldehyde/Ketone Derivatives.

Herein, we present a practical strategy for the direct construction of structurally diverse trifluoromethyl carbinol-containing compounds, especially CF3-substituted tertiary alcohol with chromone derivatives from easily available o-hydroxyaryl enaminones and trifluoroacetaldehyde/ketone derivatives under metal-free conditions. This reaction features a broad substrate scope with good yields and is easily scaled up. Notably, a one-pot in two-steps reaction of obtained products with amidines is also developed to provide a series of multi-substituted pyrimidine derivatives bearing two unique hydroxyls and one trifluoromethyl containing functional units.

The Relationship between the Serum NLRP1 Level and Coronary Lesions in Patients with Coronary Artery Disease.

Background: The pathogenesis of coronary artery disease is complex, and inflammation is one of the regulatory factors. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP1) plays an important role in the cellular inflammatory response, cell apoptosis, cell death, and autoimmune diseases. Whether the level of NLRP1 is related to the severity of coronary artery stenosis in patients with coronary artery disease (CAD) has not been reported. Objective: To test the serum level of NLRP1 in unstable angina (UA) patients and investigate the effect of NLRP1 on coronary stenosis severity of the coronary artery disease (CAD). Methods: 307 patients hospitalized in the Department of Cardiology of the Affiliated Hospital of Xuzhou Medical University for coronary angiography from January 1, 2021, to December 31, 2022 were included. We detect the level of NLRP1 in the serum of the included patients. Patients were divided into UA group and control group according to coronary angiography results and other clinical data. We use logistic regression to screen the influencing factors of UA. Then, subgroups were divided according to the Gensini score and the number of coronary artery lesions, and the difference of serum NLRP1 level between the groups was compared. Spearman correlation analysis was used to explore the correlation between the serum NLRP1 level and Gensini score. We analyze the diagnostic value of NLRP1 for UA by drawing ROC curve. Results: The median level of serum NLRP1 in patients with UA (n = 257) was 49.71 pg/ml, IQR 30.15, 80.21, and that in patients without UA (n = 50) was 24.75 pg/ml, IQR 13.49, 41.95. Serum NLRP1 levels were significantly different among different subgroups. The patient's Gensini score was correlated with the patient's serum NLRP1 level. Conclusion: The serum NLRP1 level is increased in patients with UA, which is increased with the increasing severity of coronary lesions.

Pear Recognition in an Orchard from 3D Stereo Camera Datasets to Develop a Fruit Picking Mechanism Using Mask R-CNN.

In orchard fruit picking systems for pears, the challenge is to identify the full shape of the soft fruit to avoid injuries while using robotic or automatic picking systems. Advancements in computer vision have brought the potential to train for different shapes and sizes of fruit using deep learning algorithms. In this research, a fruit recognition method for robotic systems was developed to identify pears in a complex orchard environment using a 3D stereo camera combined with Mask Region-Convolutional Neural Networks (Mask R-CNN) deep learning technology to obtain targets. This experiment used 9054 RGBA original images (3018 original images and 6036 augmented images) to create a dataset divided into a training, validation, and testing sets. Furthermore, we collected the dataset under different lighting conditions at different times which were high-light (9-10 am) and low-light (6-7 pm) conditions at JST, Tokyo Time, August 2021 (summertime) to prepare training, validation, and test datasets at a ratio of 6:3:1. All the images were taken by a 3D stereo camera which included PERFORMANCE, QUALITY, and ULTRA models. We used the PERFORMANCE model to capture images to make the datasets; the camera on the left generated depth images and the camera on the right generated the original images. In this research, we also compared the performance of different types with the R-CNN model (Mask R-CNN and Faster R-CNN); the mean Average Precisions (mAP) of Mask R-CNN and Faster R-CNN were compared in the same datasets with the same ratio. Each epoch in Mask R-CNN was set at 500 steps with total 80 epochs. And Faster R-CNN was set at 40,000 steps for training. For the recognition of pears, the Mask R-CNN, had the mAPs of 95.22% for validation set and 99.45% was observed for the testing set. On the other hand, mAPs were observed 87.9% in the validation set and 87.52% in the testing set using Faster R-CNN. The different models using the same dataset had differences in performance in gathering clustered pears and individual pear situations. Mask R-CNN outperformed Faster R-CNN when the pears are densely clustered at the complex orchard. Therefore, the 3D stereo camera-based dataset combined with the Mask R-CNN vision algorithm had high accuracy in detecting the individual pears from gathered pears in a complex orchard environment.

Characterization and complete genome analysis of Bacillus velezensis CB6 revealed ATP synthase subunit α against foodborne pathogens.

Given the serious threat of foodborne multidrug-resistant bacteria to animals and humans, finding an effective antibacterial compound has always been an important topic for scientists. Here, from the soil of Changbaishan, we have identified a bacterium that can inhibit the growth of Staphylococcus aureus. Nr genome database analysis and phylogenetic analysis showed that strain CB6 belongs to Bacillus velezensis. We found that the crude extract of strain CB6 has broad-spectrum antibacterial activity against foodborne pathogens. In addition, we showed that the crude extract loses antibacterial activity after treatment with papain. Next, strain CB6 was purified using ammonium sulfate precipitation, a Sephadex G-75 gel filtration column and high-performance liquid chromatography system (HPLC). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis indicated that the antibacterial compound was the protein ATP synthase subunit α (ATP-1), with a molecular weight of 55.397 KDa. Moreover, we reported the complete genome sequence of strain CB6, which is composed of a unique circular 3,963,507 bp chromosome with 3749 coding genes and a G + C content of 46.53%. The genome contained 12 gene clusters with antibacterial functions, which constituted over 20.947% of the complete genome. Of note, the amino acid sequence encoding the ATP-1 protein in the strain CB6 genome was identified. In addition to these findings, we speculate that the ATP-1 protein may provide energy for secondary metabolites, which in turn will improve the antibacterial activity of the secondary metabolites. All the above important features make the ATP-1 as a potential candidate for the development of new antibacterial drugs and food preservatives in the future.

Sleep deprivation and a non-24-h working schedule lead to extensive alterations in physiology and behavior.

Most organisms on Earth possess circadian rhythms in their physiology and behaviors that allow them to resonate with the cycling environment over a 24-h period. However, in human society, a substantial quantity of jobs requires non-24-h working and rest or shift schedules, which causes more or less misalignment in circadian rhythms and disorders as a consequence. In this work, we conducted a sleep deprivation (SD) and non-24-h working and rest schedule (8 h on and 4 h off) experiment over 10 d in total and measured the changes in a series of physiologic and cognitive parameters. The results show that although the subjects could sleep during the schedule, their sleepiness increased significantly. Actigraphy data suggest that a 12-h schedule might result in chronic SD. Along with the increased sleepiness revealed by the Karolinska Sleepiness Scale questionnaire, the neurobehavioral psychomotor vigilance test data reveal that, compared with the control period, the reaction time of the subjects was significantly delayed. The saliva insulin levels were significantly changed in the morning in SD and non-24-h cycles. Salivary biochemical parameters were also altered, including aspartate aminotransferase and K+. 16S rRNA-based analysis of the salivary microbiota showed differentially changed patterns in bacteria composition and concentration. Together, these data demonstrate that an abnormal working and rest schedule might produce comprehensive interference with circadian rhythms, metabolism, and cognition.-Ma, H., Li, Y., Liang, H., Chen, S., Pan, S., Chang, L., Li, S., Zhang, Y., Liu, X., Xu, Y., Shao, Y., Yang, Y., Guo, J. Sleep deprivation and a non-24-h working schedule lead to extensive alterations in physiology and behavior.

Crystallization Behavior and Mechanical Property of Biodegradable Poly(butylene succinate-co-2-methyl succinate)/Cellulose Nanocrystals Composites.

Biodegradable poly(butylene succinate-co-2-methyl succinate) (PBSMS)/cellulose nanocrystals (CNC) composites were successfully prepared at low CNC loadings with the aims of improving crystallization and mechanical properties and extending the practical application of PBSMS. CNC is finely dispersed in the PBSMS matrix without obvious aggregations. The low content of CNC obviously promoted the crystallization behavior of PBSMS under different conditions. The spherulitic morphology study revealed that CNC, as an effective heterogeneous nucleating agent, provided more nucleation sites during the melt crystallization process. In addition, the nucleation effect of CNC was quantitatively evaluated by the following two parameters, i.e., nucleation activity and nucleation efficiency. The crystal structure and crystallization mechanism of PBSMS remained unchanged in the composites. In addition, as a reinforcing nanofiller, CNC significantly increased Young's modulus and the yield strength of PBSMS. The crystallization behavior and mechanical properties of PBSMS were significantly improved by the low content of CNC, which should be interesting and essential from the perspective of biodegradable polymer composites.

One independent or many independent? The relationship among self-construal, number of brand endorsers, and brand attitudes.

Introduction: It was common for brands to use different numbers of endorsers in marketing practice. Nevertheless, research on brand endorsers' quantity has not yielded a uniform consensus. The previous research about brand endorsers mainly focuses on the appeal of endorsement, brand category, and endorser characteristics, paying less attention to the impact of cultural factors, particularly self-construal. This study delves into selecting brand endorsers across diverse cultural regions for the same brand. Methods: Drawing on the principles of self-consistency theory and self-construal theory, our research, conducted through three distinct experiments, reveals that consumers tend to hold more favorable opinions about brands endorsed by a single individual. Furthermore, self-consistency emerges as a crucial mediating factor in this phenomenon. Additionally, self-construal is an essential factor among consumers from various cultural backgrounds. Results: Consumers with an independent self-construal exhibit more favorable brand perceptions when it comes to single-endorser brands compared to their counterparts with an interdependent self-construal. Conversely, individuals with an interdependent self-construal demonstrate a more positive disposition towards brands with multiple endorsers than those with an independent self-construal. Discussion: This research not only enriches and extends our theoretical understanding of the impact of the number of brand endorsers on consumer brand attitudes but also provides valuable practical insights for optimizing the selection of brand endorsers for companies.

The Relationship Between the Serum NLRP3 and Adiponectin Levels and Coronary Lesions in Patients with Unstable Angina with Type 2 Diabetes.

Objective: To investigate the Levels of Nucleotide-binding, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) and Adiponectin (APN) and their relationship with the severity of coronary artery disease in patients with Unstable Angina (UA) and Type 2 Diabetes (T2D). Methods: Two hundred and thirty-one patients with UA were diagnosed by CAG in the Department of Cardiology of the Affiliated Hospital of Xuzhou Medical University from July 2022 to May 2023 were included, and 74 healthy subjects were included as the control group. The levels of NLRP3 and APN in each group were detected by ELISA and the Gensini score in each patient according to the results of CAG. The correlations between NLRP3, APN, and Gensini score were analyzed. According to whether complicated with T2D or not, we further analyze the effect of NLRP3 and APN levels of patients with UA and T2D on the severity of coronary artery stenosis. Results: The levels of NLRP3 in UA with T2D group were the highest, followed by simple UA group, and the lowest in the control group, and the level of APN was the opposite. Spearman Correlation analysis showed that the level of NLRP3 was positively correlated with Gensini score (ρ1=0.688, P<0.05) and the level of APN was negatively associated with Gensini score (ρ2= -0.515, P<0.05). There was a negative correlation between NLRP3 and the level of APN (ρ3= -0.366, P<0.05). High NLRP3 and low APN levels are the risk factors for atherosclerosis. Conclusion: The NLRP3 and APN were abnormally expressed in patients with UA complicated with T2D. With the aggravation of atherosclerosis, the level of NLRP3 increased and the level of APN decreased.

Microvascular abnormalities induced by hand-transmitted vibration reflects in finger systolic blood pressure: a cross-sectional study in China.

OBJECTIVE: Local vibration can cause microcirculatory abnormalities such as blood stasis and symmetrical intermittent digital artery vasospasm. Finger SBP (FSBP) measurement is a potential way of assessing vascular components. This study aims to comprehensively investigate the relationship between the occurrence of the vibration-induced white finger (VWF) and changes in FSBP and then set the application value of FSBP measurements in the early diagnosis of VWF. METHODS: All samples were judgmental sampling from one factory. Totally 50 patients with VWF were the case group, while 50 without occupational hand-transmitted vibration exposure were the control group. FSBP measurements and epidemiological feature investigations were taken. RESULTS: There were significant reductions in FSBP level and %FSBP index at both 10 °C and 30 °C in fingers reported VWF ( P  < 0.05). The %FSBP abnormal rate of the index, ring and little finger in the VWF group was higher than the control (44.00% vs. 18.00%, 78.00% vs. 26.00%, 64.00% vs. 8.00%). The %FSBP of the ring and little finger had a relatively high application value (area under curve = 0.902, 0.737), while their standard regression coefficients were -0.23 and -0.412. The diagnostic cutoff value of the ring finger was 77.60%, while the sensitivity and specificity were 86.67%. CONCLUSION: FSBP measurements were proven helpful in monitoring and diagnosing VWF prospectively and proved to have great application value in our study. %FSBP of the ring finger was the appropriate diagnostic index in FSBP measurements, while its abnormal value could be set as 80.00%.

Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension in rats by inhibiting purine metabolism and polyamine synthesis-associated vascular remodeling.

Ensuring the homeostatic integrity of pulmonary artery endothelial cells (PAECs) is essential for combatting pulmonary arterial hypertension (PAH), as it equips the cells to withstand microenvironmental challenges. Spermidine (SPD), a potent facilitator of autophagy, has been identified as a significant contributor to PAECs function and survival. Despite SPD's observed benefits, a comprehensive understanding of its protective mechanisms has remained elusive. Through an integrated approach combining metabolomics and molecular biology, this study uncovers the molecular pathways employed by SPD in mitigating PAH induced by monocrotaline (MCT) in a Sprague-Dawley rat model. The study demonstrates that SPD administration (5 mg/kg/day) significantly corrects right ventricular impairment and pathological changes in pulmonary tissues following MCT exposure (60 mg/kg). Metabolomic profiling identified a purine metabolism disorder in MCT-treated rats, which SPD effectively normalized, conferring a protective effect against PAH progression. Subsequent in vitro analysis showed that SPD (0.8 mM) reduces oxidative stress and apoptosis in PAECs challenged with Dehydromonocrotaline (MCTP, 50 µM), likely by downregulating purine nucleoside phosphorylase (PNP) and modulating polyamine biosynthesis through alterations in S-adenosylmethionine decarboxylase (AMD1) expression and the subsequent production of decarboxylated S-adenosylmethionine (dcSAM). These findings advocate SPD's dual inhibitory effect on PNP and AMD1 as a novel strategy to conserve cellular ATP and alleviate oxidative injuries, thus providing a foundation for SPD's potential therapeutic application in PAH treatment.

Polyacrylamide/sodium alginate/sodium chloride photochromic hydrogel with high conductivity, anti-freezing property and fast response for information storage and electronic skin.

Photochromic hydrogels have promising prospects in areas such as wearable device, information encryption technology, optoelectronic display technology, and electronic skin. However, there are strict requirements for the properties of photochromic hydrogels in practical engineering applications, especially in some extreme application environments. The preparation of photochromic hydrogels with high transparency, high toughness, fast response, colour reversibility, excellent electrical conductivity, and anti-freezing property remains a challenge. In this study, a novel photochromic hydrogel (PAAm/SA/NaCl-Mo7) was prepared by loading ammonium molybdate (Mo7) and sodium chloride (NaCl) into a dual-network hydrogel of polyacrylamide (PAAm) and sodium alginate (SA) using a simple one-pot method. PAAm/SA/NaCl-Mo7 hydrogel has excellent conductivity (175.9 S/cm), water retention capacity and anti-freezing properties, which can work normally at a low temperature of -28.4 °C. In addition, the prepared PAAm/SA/NaCl-Mo7 hydrogel exhibits fast response (<15 s), high transparency (>70 %), good toughness (maximum elongation up to 1500 %), good cyclic compression properties at high compressive strains (60 %), good biocompatibility (78.5 %), stable reversible discolouration and excellent sensing properties, which can be used for photoelectric display, information storage and motion monitoring. This work provides a new inspiration for the development of flexible electronic skin devices.

The Serum NLRP1 Level and Coronary Artery Calcification: From Association to Development of a Risk-Prediction Nomogram.

Background: To investigate the correlation between inflammasomes and coronary artery calcification (CAC), and develop and validating a nomogram for predicting the risk of CAC in patients with coronary artery disease (CAD). Methods: A total of 626 patients with CAD at the Affiliated Hospital of Xuzhou Medical University were enrolled in this study. The patients were divided into the calcification group and the non-calcification group based on the assessment of coronary calcification. We constructed a training set and a validation set through random assignment. The least absolute shrinkage and selection operator (LASSO) regression and multivariate analysis were performed to identify independent risk factors of CAC in patients with CAD. Based on these independent predictors, we developed a web-based dynamic nomogram prediction model. The area under the receiver operating characteristic curve (AUC-ROC), calibration curves, and decision curve analysis (DCA) were used to evaluate this nomogram. Results: Age, smoking, diabetes mellitus (DM), hyperlipidemia, the serum level of nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP1), alkaline phosphatase (ALP) and triglycerides (TG) were identified as independent risk factors of CAC. The AUC-ROC of the nomogram is 0.881 (95% confidence interval (CI): 0.850-0.912) in the training set and 0.825 (95% CI: 0.760-0.876) in the validation set, implying high discriminative ability. Satisfactory performance of this model was confirmed using calibration curves and DCA. Conclusions: The serum NLRP1 level is an independent predictor of CAC. We established a web-based dynamic nomogram, providing a more accurate estimation and comprehensive perspective for predicting the risk of CAC in patients with CAD.

Hydroxy-Safflower Yellow A Mitigates Vascular Remodeling in Rat Pulmonary Arterial Hypertension.

Purpose: The underlying causes of pulmonary arterial hypertension (PAH) often remain obscure. Addressing PAH with effective treatments presents a formidable challenge. Studies have shown that Hydroxysafflor yellow A (HSYA) has a potential role in PAH, While the mechanism underlies its protective role is still unclear. The study was conducted to investigate the potential mechanisms of the protective effects of HSYA. Methods: Using databases such as PharmMapper and GeneCards, we identified active components of HSYA and associated PAH targets, pinpointed intersecting genes, and constructed a protein-protein interaction (PPI) network. Core targets were singled out using Cytoscape for the development of a model illustrating drug-component-target-disease interactions. Intersection targets underwent analysis for Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Selected components were then modeled for target interaction using Autodock and Pymol. In vivo validation in a monocrotaline-induced PAH (MCT-PAH) animal model was utilized to substantiate the predictions made by network pharmacology. Results: We associated HSYA with 113 targets, and PAH with 1737 targets, identifying 34 mutual targets for treatment by HSYA. HSYA predominantly affects 9 core targets. Molecular docking unveiled hydrogen bond interactions between HSYA and several PAH-related proteins such as ANXA5, EGFR, SRC, PPARG, PGR, and ESR1. Conclusion: Utilizing network pharmacology and molecular docking approaches, we investigated potential targets and relevant human disease pathways implicating HSYA in PAH therapy, such as the chemical carcinogenesis receptor activation pathway and the cancer pathway. Our findings were corroborated by the efficacious use of HSYA in an MCT-induced rat PAH model, confirming its therapeutic potential.

Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits.

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.