Insights into effects of conventional and biodegradable microplastics on organic carbon decomposition in different soil aggregates.

The impacts of microplastics on soil ecological functions such as carbon recycling and soil structure maintenance have been extensively focused. However, the mechanisms underlying the impacts of microplastics on soil carbon transformation and soil microbial community at soil aggregate scale have not been clarified yet. In this work, the effects and action mechanisms of traditional microplastic polypropylene (PP) and degradable microplastic polylactic acid (PLA) on carbon transformation in three sizes of soil aggregates were investigated. The results showed that both PP and PLA promoted CO2 emission, and the effect depended on the type and content of microplastics, and the size of soil aggregates. Changes in soil carbon stocks were mainly driven by changes in organic carbon associated with macroaggregates. For macroaggregates, PP microplastics decreased soil organic carbon (SOC) as well as dissolved organic carbon (DOC). These changes were reversed in microaggregates and silt and clay. Interestingly, PLA increased the SOC, DOC and CO2 emissions in bulk soil and all three aggregates with a dose-effect response. These changes were associated with soil microbes, functional genes and enzymes associated with the degradation of labile and recalcitrant carbon fractions. Furthermore, PP and PLA reduced bacterial community diversities and shifted bacterial community structures in both the three aggregates and in bulk soil. Alterations of functional genes induced by microplastics were the key driving factors of their impacts on carbon transformation in soil aggregates. This research opened up a new insight into the mechanisms underlying the impacts of microplastics on soil carbon transformation, and helped us make rational assessments of the risks and the disturbances of microplastics on soil carbon cycling.

Mechanical network motifs as targets for mechanomedicine.

The identification and analysis of network motifs has been widely used in the functional analysis of signaling components, disease discovery and other fields. The positive feedback loop (PFL) is a simple but important network motif. The formation of a PFL is regulated by mechanical cues such as substrate stiffness, fiber stretching and cell compression in the cell microenvironment. Here, we propose a new term, 'mechanical PFL', and analyze the mechanisms of mechanical PFLs at molecular, subcellular and cellular scales. More and more therapies are being targeted against mechanosignaling pathways at the experimental and preclinical stages, and exploring mechanical PFLs as potential mechanomedicine targets could be a new direction for disease treatment.

Causal relationship between gut microbiota and childhood obesity: A Mendelian randomization study and case-control study.

BACKGROUND: Gut microbiota and obesity are deeply interconnected. However, the causality in the relationship between these factors remains unclear. Therefore, this study aimed to elucidate the genetic relationship between gut microbiota and childhood obesity. METHODS: Genetic summary statistics for the gut microbiota were obtained from the MiBioGen consortium. Genome-wide association studies (GWAS) summary data for childhood obesity were obtained from North American, Australian, and European collaborative genome-wide meta-analyses. Mendelian randomization (MR) analyses were performed using the inverse variance weighting method. 16 children with obesity and 16 without obesity were included for clinical observation, and their weight, body mass index, blood lipid levels, and gut microbiology were assessed. Paired t-test was the primary method of data analysis, and statistical significance was set at P < 0.05. RESULTS: MR identified 16 causal relationships between the gut microbiome and childhood obesity. In the case-control study, we found that five gut microorganisms differed between children with and without obesity, whereas three gut microorganisms changed after weight loss in children with obesity. CONCLUSION: Our study provides new insights into the genetic mechanisms underlying gut microbiota and childhood obesity. TRIAL REGISTRATION NUMBER: ChiCTR2300072179. NAME OF REGISTRY: Change of intestinal flora and plasma metabolome in obese children and their weight loss intervention: a randomized controlled tria URL OF REGISTRY: https://www.chictr.org.cn/showproj.html. DATE OF REGISTRATION: 2023-06-06. DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 2023-06-07.

The effects of diet quality, eating behavior, and sleep on the academic performance among elementary school students.

The academic success of children contributes to their income, social status, and public health. This study was conducted with 217 elementary school students from western China. Scores on the Chinese Children Dietary Index (CCDI), Dietary Approaches to Stop Hypertension (DASH), adjusted DASH, and KIDMED index were calculated to evaluate diet quality. Eating behavior and sleep quality were assessed using the Children's Eating Behavior Questionnaire (CEBQ) and Children's Sleep Habits Questionnaire (CHSQ), respectively. Academic achievement was measured using school-provided average grades. Higher CCDI scores, longer sleep time, lower total CHSQ scores, and lower subscores on "satiety responsiveness," "slowness in eating," "emotional undereating," and "food fussiness" dimensions of the CEBQ were associated with high academic achievement. In conclusion, good diet quality, sleep quality, healthy eating behaviors, and adequate sleep duration were associated with better academic performance. Interventions are recommended to be developed in education system to improve healthy diets and lifestyles, enhancing academic achievement.

Serum stromal cell-derived factor-1 concentrations are increased and associated with nonalcoholic fatty liver disease in children with obesity.

INTRODUCTION: Stromal cell-derived factor-1 (SDF-1) is a newly discovered small molecule adipocytokine, and research has shown that it is closely related to the occurrence and development of obesity. However, there are currently few research reports on SDF-1 in childhood obesity and nonalcoholic fatty liver disease (NAFLD), and this study aims to explore the relationship between SDF-1 and obesity related indicators in obese children. METHODS: Serum SDF-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data were collected, such as body mass index (BMI), waist and hip circumference, blood pressure, liver enzymes, cholesterol, and fasting insulin. Children with NAFLD or not were evaluated through Color Doppler Ultrasound. RESULTS: Serum SDF-1 concentrations were significantly higher in obese subjects than in non-obese subjects (P < 0.05), and were elevated in the NAFLD obese subjects than in the non-NAFLD obese subjects (P < 0.05). SDF-1 was positively correlated with BMI, waist-to-hip ratio, systolic blood pressure, body fat percentage (BFP), basal metabolic rate (BMR), alanine transaminase (ALT), aspartate transaminase (AST), glutyltranspeptidase (GT), and homoeostasis model of HOMA-IR, independent of their uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), gender and age. BFP and BMR were associated with the serum SDF-1 concentrations in multivariable linear regression analysis. CONCLUSION: These results suggest that SDF-1 levels are elevated in obese children and are associated with NAFLD, indicating that SDF-1 may play a role in the development of childhood obesity and metabolic disorders.

Metabolomics of cerebrospinal fluid reveals candidate diagnostic biomarkers to distinguish between spinal muscular atrophy type II and type III.

AIMS: Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to identify metabolic markers in the cerebrospinal fluid (CSF) of children with SMA types II and III. METHODS: CSF samples were collected from 40 patients with SMA (27 with type II and 13 with type III) and analyzed for metabolites. RESULTS: We identified 135 metabolites associated with SMA types II and III. These were associated with lysine degradation and arginine, proline, and tyrosine metabolism. We identified seven metabolites associated with the Hammersmith Functional Motor Scale: 4-chlorophenylacetic acid, adb-chminaca,(+/-)-, dodecyl benzenesulfonic acid, norethindrone acetate, 4-(undecan-5-yl) benzene-1-sulfonic acid, dihydromaleimide beta-d-glucoside, and cinobufagin. Potential typing biomarkers, N-cyclohexylformamide, cinobufagin, cotinine glucuronide, N-myristoyl arginine, 4-chlorophenylacetic acid, geranic acid, 4-(undecan-5-yl) benzene, and 7,8-diamino pelargonate, showed good predictive performance. Among these, N-myristoyl arginine was unaffected by the gene phenotype. CONCLUSION: This study identified metabolic markers are promising candidate prognostic factors for SMA. We also identified the metabolic pathways associated with the severity of SMA. These assessments can help predict the outcomes of screening SMA classification biomarkers.

The effect of high altitude on ephedrine content and metabolic variations in two species of Ephedra.

Ephedra is an important plant in Chinese medicine; however, there are few reports on two species of Ephedra which are distributed at high altitudes from 3000 to 5200 meters. We collected a total of 84 individuals representing five Ephedra gerardiana and nine Ephedra saxatilis populations respectively located from 3158 to 5200 meters altitude, and determined the relative content of 213 metabolites using UHPLC-MS/MS (Ultra-High-Performance Liquid Chromatography-tandem mass spectrometry). 37 Chemical compositions were annotated using the KEGG (Kyoto Encyclopaedia of Genes and Genomes) database. From the top five significant enrichments in metabolic KEGG pathway analysis, we found a total of 166 compounds belonging to phenylpropanoids, 123 flavonoids, 67 metabolites carried by ABC transporters, and 61 in purine metabolism. We identified the top 8 altitude-related compounds in two species. Ephedrine and pseudoephedrine were found to be associated with altitude in both E. saxatilis and E. gerardiana. To verify which environmental factors influenced the metabolic content, the soil moisture and temperature of each population site were collected, and quantitative analysis of ephedrine and pseudoephedrine was performed using UHPLC-MS (Ultra-High-Performance liquid chromatography-tandem mass spectrometry). After detection, soil moisture ranged from 0.074 to 0.177 mm3/mm3, and temperature ranged from 9.7°C to 23.9°C. The content of ephedrine ranged from (0.84 ± 0.49)% to (2.01 ± 0.41)% in E. saxatilis, which was positively correlated with soil moisture; the content of pseudoephedrine ranged from (0.72 ± 0.45)% to (1.11 ± 0.57)% and was negatively correlated with soil moisture. In contrast to these results, in E. gerardiana, the content of ephedrine and pseudoephedrine was negatively correlated with soil moisture. Furthermore, the trends of alkaloid contents in two kinds of Ephedra were similar when the temperature was lower than 17°C even if the sum was various. With the increase in soil moisture and temperature, the total alkaloid content of E. saxatilis was higher than that of E. gerardiana. When the soil moisture was lower, the alkaloid content of the two Ephedra species was higher. These results provide useful data for the future separation of new compounds, and for seed homogeneous growth to determine artificial breeding of Ephedra located at high altitudes.

Ephedrine and pseudoephedrine in Ephedra saxatilis on the vertical altitude gradient changed in southern Tibet Plateau, China.

Ephedra is one of the world's most important plants, used in medicine, plants and ecology. Most Ephedra grows in plain areas and is stable. But the plateau environment is special, with the change of altitude, the variety difference of plateau Ephedra saxatilis is very obvious. E. saxatilis metabolism on the Tibetan Plateau is not only affected by altitude, but also environmental conditions such as climate conditions and different soil components. However, the change mechanism of E. saxatilis alkaloids in special ecological environment is still unclear. Therefore, we analyzed the metabolic and altitude of E. saxatilis species in the Tibetan Plateau. Through the functional analysis of Kyoto Metabolism and Metabolomic Encyclopedia (KEGG), we can determine that the number of E. saxatilis metabolites decreases with the increase of altitude, and there are differences in metabolism among the three mountains. This was confirmed by univariate analysis of the top five metabolic pathways. Based on the analysis of soil and metabolomics, it was found that soil water content was also a factor affecting E. saxatilis metabolism. According to the difference of vertical height gradient, ephedrine and pseudephedrine showed the same change in vertical altitude under different mountains. Ephedrine increased as the altitude gradient increased, and pseudoephedrine decreased as the altitude gradient decreased. Our results provide valuable information for further study of metabolic mechanism and efficacy stability. It provides useful reference for the research of E. saxatilis planting in special area.

Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis.

Epilepsy is a severe neurological condition affecting 50-65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWASfdr < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWASfdr < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (Pcgsea < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets.

Single-cell transcriptomic analysis of normal and pathological tissues from the same patient uncovers colon cancer progression.

The aim of the present study was to elucidate the evolutionary trajectory of colon cells from normal colon mucosa, to adenoma, then to carcinoma in the same microenvironment. Normal colon, adenoma and carcinoma tissues from the same patient were analyzed by single-cell sequencing, which perfectly simulated the process of time-dependent colon cancer due to the same microenvironment. A total of 22 cell types were identified. Results suggest the presence of dominant clones of same cells including C2 goblet cell, epithelial cell subtype 1 (Epi1), enterocyte cell subset 0 (Entero0), and Entero5 in carcinoma. Epi1 and Entero0 were Co-enriched in antibacterial and IL-17 signaling, Entero5 was enriched in immune response and mucin-type O-glycan biosynthesis. We discovered new colon cancer related genes including AC007952.4, NEK8, CHRM3, ANO7, B3GNT6, NEURL1, ODC1 and KCNMA1. The function of TBC1D4, LTB, C2CD4A, AND GBP4/5 in T cells needs to be clarified. We used colon samples from the same person, which provide new information for colon cancer therapy.

miR-199a-5p Reduces Chondrocyte Hypertrophy and Attenuates Osteoarthritis Progression via the Indian Hedgehog Signal Pathway.

Osteoarthritis (OA), the most common type of arthritis, is an age-associated disease, characterized by the progressive degradation of articular cartilage, synovial inflammation, and degeneration of subchondral bone. Chondrocyte proliferation is regulated by the Indian hedgehog (IHH in humans, Ihh in animals) signaling molecule, which regulates hypertrophy and endochondral ossification in the development of the skeletal system. microRNAs (miRNAs, miRs) are a family of about 22-nucleotide endogenous non-coding RNAs, which negatively regulate gene expression. In this study, the expression level of IHH was upregulated in the damaged articular cartilage tissues among OA patients and OA cell cultures, while that of miR-199a-5p was the opposite. Further investigations demonstrated that miR-199a-5p could directly regulate IHH expression and reduce chondrocyte hypertrophy and matrix degradation via the IHH signal pathway in the primary human chondrocytes. The intra-articular injection of synthetic miR-199a-5p agomir attenuated OA symptoms in rats, including the alleviation of articular cartilage destruction, subchondral bone degradation, and synovial inflammation. The miR-199a-5p agomir could also inhibit the Ihh signaling pathway in vivo. This study might help in understanding the role of miR-199a-5p in the pathophysiology and molecular mechanisms of OA and indicate a potential novel therapeutic strategy for OA patients.

Identification of candidate genes and pathways associated with juvenile idiopathic arthritis by integrative transcriptome-wide association studies and mRNA expression profiles.

AIM: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, with genetic susceptibility and pathological processes such as autoimmunity and autoinflammation, but its pathogenesis is unclear. We conducted a transcriptome-wide association study (TWAS) using expression interpolation from a large-scale genome-wide association study (GWAS) dataset to identify genes, biological pathways, and environmental chemicals associated with JIA. METHODS: We obtained published GWAS data on JIA for TWAS and used mRNA expression profiling to validate the genes identified by TWAS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A protein-protein interaction (PPI) network was generated, and central genes were obtained using Molecular Complex Detection (MCODE). Finally, chemical gene expression datasets were obtained from the Comparative Toxicogenomics database for chemical genome enrichment analysis. RESULTS: TWAS identified 1481 genes associated with JIA, and 154 differentially expressed genes were identified based on mRNA expression profiles. After comparing the results of TWAS and mRNA expression profiles, we obtained eight overlapping genes. GO and KEGG enrichment analyses of the genes identified by TWAS yielded 163 pathways, and PPI network analysis as well as MCODE resolution identified a total of eight clusters. Through chemical gene set enrichment analysis, 287 environmental chemicals associated with JIA were identified. CONCLUSION: By integrating TWAS and mRNA expression profiles, genes, biological pathways, and environmental chemicals associated with JIA were identified. Our findings provide new insights into the pathogenesis of JIA, including candidate genetic and environmental factors contributing to its onset and progression.

Reproducibility and Validity of a Semi-Quantitative Food Frequency Questionnaire for Children Aged 6-12 in Western China.

The Food Frequency Questionnaire (FFQ) is often used to assess dietary intake in large-scale epidemiological studies. This study aimed to evaluate the reproducibility and validity of the FFQ newly developed for children aged 6 to 12 in western China. A total of 133 children were included in the analysis, and all the children and their caregivers completed the FFQs twice with a three-month interval period, and three 24 h recalls were carried out one month after the first FFQ. We assessed the relative validity and reproducibility using various methods, such as the Spearman correlation coefficient, intra-class correlation coefficient, weighed Kappa, quartile agreement, and Bland-Altman analysis. The Spearman correlation coefficients for food ranged from 0.30 to 0.84, and for nutrients from 0.46 to 0.82 regarding reproducibility. The food intra-class correlation coefficients ranged from 0.20 to 0.85, while nutrients' ranged from 0.37 to 0.75. In terms of relative validity, the average Spearman correlation coefficients for food were 0.20, and 0.30 for energy and nutrients. The energy-adjusted and de-attenuation coefficients were calculated. Moreover, the average percentage of participants misclassified into the extreme quartile for food and nutrients was 8.0% and 7.0%, respectively. Weighted Kappa values indicated acceptable agreement between the FFQs and 24 h recalls. Furthermore, the percentage of results in the limits of agreement (LOA) were all above 93.0%. In conclusion, The FFQ showed good reproducibility and acceptable relative validity for assessing the dietary intake of children aged 6-12 in western China.

Efficacy and mechanism of intermittent fasting in metabolic associated fatty liver disease based on ultraperformance liquid chromatography-tandem mass spectrometry.

Objectives: Drug treatment of metabolic associated fatty liver disease (MAFLD) remains lacking. This study analyzes the efficacy and mechanism underlying intermittent fasting combined with lipidomics. Methods: Thirty-two male rats were randomly divided into three groups: Normal group, administered a standard diet; MAFLD group, administered a 60% high-fat diet; time-restricted feeding (TRF) group, administered a 60% high-fat diet. Eating was allowed for 6 h per day (16:00-22:00). After 15 weeks, liver lipidomics and other indicators were compared. Results: A total of 1,062 metabolites were detected. Compared with the Normal group, the weight, body fat ratio, aspartate aminotransferase, total cholesterol, low-density cholesterol, fasting blood glucose, uric acid, and levels of 317 lipids including triglycerides (TG) (17:0-18:1-20:4) were upregulated, whereas the levels of 265 lipids including phosphatidyl ethanolamine (PE) (17:0-20:5) were downregulated in the MAFLD group (P < 0.05). Compared with the MAFLD group, the weight, body fat ratio, daily food intake, and levels of 253 lipids including TG (17:0-18:1-22:5) were lower in the TRF group. Furthermore, the levels of 82 lipids including phosphatidylcholine (PC) (20:4-22:6) were upregulated in the TRF group (P < 0.05), while serum TG level was increased; however, the increase was not significant (P > 0.05). Enrichment analysis of differential metabolites showed that the pathways associated with the observed changes mainly included metabolic pathways, regulation of lipolysis in adipocytes, and fat digestion and absorption, while reverse-transcription polymerase chain reaction showed that TRF improved the abnormal expression of FAS and PPARα genes in the MAFLD group (P < 0.05). Conclusion: Our results suggest that 6 h of TRF can improve MAFLD via reducing food intake by 13% and improving the expression of genes in the PPARα/FAS pathway, thereby providing insights into the prevention and treatment of MAFLD.

Identifying celiac disease-related chemicals by transcriptome-wide association study and chemical-gene interaction analyses.

Celiac disease (CeD) is one of the most common intestinal inflammatory diseases, and its incidence and prevalence have increased over time. CeD affects multiple organs and systems in the body, and environmental factors play a key role in its complex pathogenesis. Although gluten exposure is known to be the causative agent, many unknown environmental factors can trigger or exacerbate CeD. In this study, we investigated the influence of genetic and environmental factors on CeD. Data from a CeD genome-wide association study that included 12,041 CeD cases and 12,228 controls were used to conduct a transcriptome-wide association study (TWAS) using FUSION software. Gene expression reference data were obtained for the small intestine, whole blood, peripheral blood, and lymphocytes. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significant genes identified by the TWAS and conducted a protein-protein interaction network analysis based on the STRING database to detect the function of TWAS-identified genes for CeD. We also performed a chemical-related gene set enrichment analysis (CGSEA) using the TWAS-identified genes to test the relationships between chemicals and CeD. The TWAS identified 8,692 genes, including 101 significant genes (p adjusted < 0.05). The CGSEA identified 2,559 chemicals, including 178 chemicals that were significantly correlated with CeD. This study performed a TWAS (for genetic factors) and CGSEA (for environmental factors) and identified several CeD-associated genes and chemicals. The findings expand our understanding of the genetic and environmental factors related to immune-mediated diseases.

Pulmonary embolism and 529 human blood metabolites: genetic correlation and two-sample Mendelian randomization study.

BACKGROUND: The incidence of pulmonary embolism complications in the literature ranges from 10 to 50%, with a 0.5-10% risk of fatal pulmonary embolism. However, the biological cause of pulmonary embolism is unknown. METHODS: This study used data from the Genome-Wide Association Study (GWAS) of Pulmonary Embolism and Human Blood Metabolites from the UK Biobank, and the data from subjects of European ancestry were analyzed. We explored the relationship between pulmonary embolism and blood metabolites in three ways. We first analyzed the genetic correlation between pulmonary embolism and human blood metabolites using the linkage disequilibrium score regression (LDSC) and then analyzed the causal relationship between pulmonary embolism and meaningful blood metabolites obtained from the LDSC, a procedure for which we used Mendelian randomization analysis. Finally, we obtained transcriptome sequencing data for patients with a pulmonary embolism from the GEO database, analyzed differentially expressed genes (DEGs) in patients with pulmonary embolism versus healthy populations, and compared the DEGs with the resulting blood metabolite genes to further validate the relationship between pulmonary embolism and blood metabolites. RESULT: We found six human blood metabolites genetically associated with pulmonary embolism, stearic acid glycerol phosphate ethanolamine (correlation coefficient = 0.2582, P = 0.0493), hydroxytryptophan (correlation coefficient = 0.2894, P = 0.0435), and N1-methyladenosine (correlation coefficient = 0.0439, P = 0.3728), and a significant causal relationship was discovered between hydroxytryptophan and pulmonary embolism. After screening microarray data from the GEO database, we performed differential gene analysis on the GSE19151 dataset and screened a total of 22,216 genes with P values less than 0.05, including 17,361 upregulated genes and 4854 downregulated genes. By comparing the resulting differentially expressed genes with six genes encoding blood metabolites, LIPC and NAT2 were found to be differentially expressed in association with pulmonary embolism.

Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of death in stroke patients and a severe health burden worldwide. There is a pressing need to understand the mechanisms by which it occurs and to identify at-risk patients efficiently and accurately. METHODS: First, based on data from GWAS in European populations, we performed a linkage disequilibrium score regression (LDSC) analysis of plasma proteins and PE in 3,283 individuals and additionally analyzed the genetic association between PE and fracture. Then, we performed a TWAS on PE GWAS data using skeletal muscle and blood for gene expression references. Finally, we validated the genetic correlation between PE and human plasma proteins by co-matching the genes encoding the identified proteins and those identified using TWAS with the differentially expressed genes obtained from mRNA expression profiling of PE. RESULTS: We identified five plasma proteins associated with PE, including hydroxycarboxylic acid receptor 2, defensin 118, and bone morphogenetic protein (BMP) 7, as well as a relationship between PE and fracture. Comparison of genes encoding these proteins with genes obtained from TWAS and then with differentially expressed genes obtained from PE mRNA expression profiling revealed that PE was highly correlated with the BMP family of genes.

Transcriptome-Wide Association Studies and Integration Analysis of mRNA Expression Profiles Identify Candidate Genes and Pathways Associated With Ankylosing Spondylitis.

This study aimed to identify susceptibility genes and pathways associated with ankylosing spondylitis (AS) by integrating whole transcriptome-wide association study (TWAS) analysis and mRNA expression profiling data. AS genome-wide association study (GWAS) summary data from the large GWAS database were used. This included data of 1265 AS patients and 452264 controls. A TWAS of AS was conducted using these data. The analysis software used was FUSION, and Epstein-Barr virus-transformed lymphocytes, transformed fibroblasts, peripheral blood, and whole blood were used as gene expression references. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed for the important genes identified via TWAS. Protein-protein interaction (PPI) network analysis based on the STRING database was also performed to detect genes shared by TWAS and mRNA expression profiles in AS. TWAS identified 920 genes (P <0.05) and analyzed mRNA expression profiles to obtain 1183 differential genes. Following comparison of the TWAS results and mRNA expression characteristics, we obtained 70 overlapping genes and performed GO and KEGG enrichment analyses of these genes to obtain 16 pathways. Via PPI network analysis, we obtained the protein interaction network and performed MCODE analysis to acquire the HUB genes. Similarly, we performed GO and KEGG analyses on the genes identified by TWAS, obtained 98 pathways after screening, and analyzed protein interactions via the PPI network. Through the integration of TWAS and mRNA expression analysis, genes related to AS and GO and KEGG terms were determined, providing new evidence and revealing the pathogenesis of AS. Our AS TWAS work identified novel genes associated with AS, as well as suggested potential tissues and pathways of action for these TWAS AS genes, providing a new direction for research into the pathogenesis of AS.

Identifying Environmental Endocrine Disruptors Associated With the Age at Menarche by Integrating a Transcriptome-Wide Association Study With Chemical-Gene-Interaction Analysis.

Menarche is the first occurrence of menstrual bleeding and one of the most important events of female puberty. Alarmingly, over the last several decades, the mean age at menarche (AAM) has decreased. Environmental endocrine disruptors (EEDs) are chemicals that may interfere with the endocrine system, resulting in adverse developmental, immunological, neurological, and reproductive effects in humans. Thus, the effects of EEDs on fertility and reproduction are growing concerns in modern societies. In this study, we aimed to determine the influence of genetic and environmental factors on AAM. We used data from an AAM genome-wide association study of 329,345 women to conduct a transcriptome-wide association study (TWAS) with FUSION software. As references, we determined the gene-expression levels in the hypothalamus, pituitary gland, ovaries, uterus, and whole blood. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significantly dysregulated genes identified by the TWAS. Using the STRING database, we also generated a protein-protein-interaction network to analyze common AAM-specific genes identified by the TWAS with different tissues. We performed chemical-related gene set enrichment analysis (CGSEA) and identified significant TWAS genes to uncover relationships between different chemicals and AAM. The TWAS identified 9,848 genes; among these, 1580 genes were significant (P < 0.05), and 11 genes were significant among the hypothalamus, pituitary, ovary, uterus, and whole blood. CGSEA identified 1,634 chemicals, including 120 chemicals significantly correlated with AAM. In summary, we performed a TWAS (for genetic factors) and CGSEA (for environmental factors) focusing on AAM and identified several AAM-associated genes and EEDs. The results of this study expand our understanding of genetic and environmental factors related to the onset of female puberty.

Comprehensive analysis of alfa defensin expression and prognosis in human colorectal cancer.

Introduction: Colorectal cancer (CRC) is a serious threat to human health. Screening new biomarkers can provide basis for improving the prognosis and individualized treatment of CRC. Although some members of the defensin family were found increased in pancreatic cancer and CRC, their exact function and clinical significance remain unclear. Methods: In this study, the expression, correlation, mutation, and functional enrichment of several defensin family members in pancreatic cancer and CRC were analyzed using tumor public databases and verified in several patients. Results: Results showed no significant correlation between the expression levels of DEFA1-4 and CRC. The expression levels of DEFA5 and DEFA6 significantly increased in CRC tissues compared with those in normal tissues. DEFA5 may be associated with better prognosis of CRC, while DEFA6 may be associated with poor prognosis. Immunohistochemistry (IHC) experiments showed that the expression of DEFA6 was significantly higher in adenoma than in normal mucosa and slightly higher in carcinoma than in normal mucosa. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that DEFAs were closely related to hsa05202: transcriptional misregulation in cancer and Hsa04015: Rap1 signaling pathway. DEFA5 may be a stable and good prognostic marker, and DEFA6 may be a poor prognostic marker in CRC of metastasis. Conclusion: Overall, DEFA5 and DEFA6 have a certain degree of sensitivity and specificity in predicting CRC.