Admixed populations offer a unique opportunity for mapping diseases that have large disease allele frequency differences between ancestral populations. However, association analysis in such ...populations is challenging because population stratification may lead to association with loci unlinked to the disease locus.
We show that local ancestry at a test single nucleotide polymorphism (SNP) may confound with the association signal and ignoring it can lead to spurious association. We demonstrate theoretically that adjustment for local ancestry at the test SNP is sufficient to remove the spurious association regardless of the mechanism of population stratification, whether due to local or global ancestry differences among study subjects; however, global ancestry adjustment procedures may not be effective. We further develop two novel association tests that adjust for local ancestry. Our first test is based on a conditional likelihood framework which models the distribution of the test SNP given disease status and flanking marker genotypes. A key advantage of this test lies in its ability to incorporate different directions of association in the ancestral populations. Our second test, which is computationally simpler, is based on logistic regression, with adjustment for local ancestry proportion. We conducted extensive simulations and found that the Type I error rates of our tests are under control; however, the global adjustment procedures yielded inflated Type I error rates when stratification is due to local ancestry difference.
Accumulation of microplastics (MPs) in soil is a serious environmental concern. Addition of exogenous MPs can alter structure and physicochemical properties of and material transport in soil. MPs are ...particularly toxic to earthworms, which are soil ecosystem engineers, and exacerbate ecological risks; however, there is a lack of comprehensive and in-depth analyses of how MPs exhibit toxicity to/towards earthworms. In this study, we report a bibliometric analysis of 77 peer-reviewed papers published before December 2021 to systematically analyze how the addition of exogenous MPs contributes to earthworm toxicity and clarify the historical development and research hotspots in this field. We found that first, polyethylene and polystyrene are the most common materials used to study the toxic effects of MPs on earthworms. Second, the toxic mechanisms of MPs on earthworms mainly involve histopathological damage and oxidative stress, as well as serving as carriers of complex pollutants (e.g., heavy metals and organic pollutants) through combined adsorption–desorption. Third, oxidative stress is the typical reaction process of MPs toxicity in earthworms. When the content of MPs in soil exceeds 0.1%, earthworm growth is affected, and oxidative stress is induced, resulting in neural and DNA damage. Based on published studies, the prospects for future research on the ecological risks posed by MPs to earthworms have also been discussed. Overall, our findings help clarify the ecological risk of soil MPs toxicity to earthworms, reveal the mechanism of their toxic effects, and provide a theoretical basis for future studies focusing on establishing a healthy and ecologically sustainable soil environment.
Background Anthracycline-induced cardiomyopathy is a leading cause of premature death in childhood cancer survivors, presenting a need to understand the underlying pathogenesis. We sought to examine ...differential blood-based mRNA expression profiles in anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Methods and Results We designed a matched case-control study (Children's Oncology Group-ALTE03N1) with mRNA sequencing on total RNA from peripheral blood in 40 anthracycline-exposed survivors with cardiomyopathy (cases) and 64 matched survivors without (controls). DESeq2 identified differentially expressed genes. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analyses determined the potential roles of altered genes in biological pathways. Functional validation was performed by gene knockout in human-induced pluripotent stem cell-derived cardiomyocytes using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) technology. Median age at primary cancer diagnosis for cases and controls was 8.2 and 9.7 years, respectively. Thirty-six differentially expressed genes with fold change ≥±2 were identified; 35 were upregulated. IPA identified "hepatic fibrosis" and "iron homeostasis" pathways to be significantly modulated by differentially expressed genes, including toxicology functions of myocardial infarction, cardiac damage, and cardiac dilation. Leading edge analysis from Gene Set Enrichment Analyses identified lactate dehydrogenase A (
) and cluster of differentiation 36 (
) genes to be significantly upregulated in cases. Interleukin 1 receptor type 1, 2 (
,
), and matrix metalloproteinase 8, 9 (
) appeared in multiple canonical pathways.
-knockout human-induced pluripotent stem cell-derived cardiomyocytes showed increased sensitivity to doxorubicin. Conclusions We identified differential mRNA expression profiles in peripheral blood of anthracycline-exposed childhood cancer survivors with and without cardiomyopathy. Upregulation of
and
genes suggests metabolic perturbations in a failing heart. Dysregulation of proinflammatory cytokine receptors
and
and matrix metalloproteinases,
and
indicates structural remodeling that accompanies the clinical manifestation of symptomatic cardiotoxicity.
Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile ...metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways.
Here, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls.
We employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways.
PLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism.
Our findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.
The process of hematopoiesis, characterized by long-term self-renewal and multi-potent lineage differentiation, has been shown to be regulated in part by the ligand-activated transcription factor ...known as the aryl hydrocarbon receptor (AHR). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous contaminant and the most potent AHR agonist, also modulates regulation of adult hematopoietic stem and progenitor cell (HSC/HPC) homeostasis. However, the effect of developmental TCDD exposure on early life hematopoiesis has not been fully explored. Given the inhibitory effects of TCDD on hematopoiesis and lymphocyte development, we hypothesized that in utero exposure to TCDD would alter the functional capacity of fetal HSC/HPCs to complete lymphocyte differentiation. To test this hypothesis, we employed a co-culture system designed to facilitate the maturation of progenitor cells to either B or T lymphocytes. Furthermore, we utilized an innovative limiting dilution assay to precisely quantify differences in lymphocyte differentiation between HSC/HPCs obtained from fetuses of dams exposed to 3μg/kg TCDD or control. We found that the AHR is transcribed in yolk sac hematopoietic cells and is transcriptionally active as early as gestational day (GD) 7.5. Furthermore, the number of HSC/HPCs present in the fetal liver on GD 14.5 was significantly increased in fetuses whose mothers were exposed to TCDD throughout pregnancy. Despite this increase in HSC/HPC cell number, B and T lymphocyte differentiation is decreased by approximately 2.5 fold. These findings demonstrate that inappropriate developmental AHR activation in HSC/HPCs adversely impacts lymphocyte differentiation and may have consequences for lymphocyte development in the bone marrow and thymus later in life.
In this work, the CuO@Ta2O5 nanocomposite was synthesized, and the chemical stability and sensing capabilities of the CuO@Ta2O5 nanocomposite as a chrysin sensor were improved. The nanocomposite was ...electrodeposited on a glassy carbon electrode (GCE), and structural analyses using SEM and XRD indicated that the GCE was uniformly coated with high porosity CuO@Ta2O5 nanoparticles. The amperometry and cyclic voltammetry experiments showed the high sensitive, selective, stable and accurate response of CuO@Ta2O5/GCE to chrysin determination because of the formation of a hetero-interface between CuO and Ta2O5 nanostructures, which facilitates charge migration and enhances the catalytic activity of CuO@Ta2O5/GCE. Results showed that the linear range, detection limit and sensitivity were obtained at 10 to 100μM, 0.008μM and 0.92921μA/μM, respectively. The practicality of the proposed electrochemical sensor in real samples was studied and results indicated the obtained recovery (96.00% to 98.00%) and RSD (2.77% to 3.11%) values were acceptable, illustrating that CuO@Ta2O5/GCE can be used as a practical sensor to detect chrysin in pharmaceutical and biological samples.
Triglycerides are an important measure of heart health. Although more than 90 genes have been found to be associated to lipids, they only explain 12 to 15% of the variance in lipid levels. Evidence ...suggests that age may interact with the genetic effect on lipid levels. Existing methods to detect the main effect of rare variants cannot be readily applied for testing the gene environment interaction effect of rare variants, as those methods either have unstable results or inflated Type I error rates when the main effect exists. To overcome these difficulties, we developed two statistical methods: testing of optimally weighted combination of single-nucleotide polymorphism (SNP) environment interaction (TOW-SE) and a variable weight TOW-SE (VW-TOW-SE) to test the gene environment interaction effect of rare variants by grouping SNPs into biologically meaningful SNP-sets (SNPs in a gene or pathway) to improve power and interpretability. The proposed methods can be applied to either continuous or binary environmental variables, and to either continuous or binary outcomes. Simulation studies show that Type I error rates of the proposed methods are under control. Comparing the two methods with the existing interaction sequence kernel association test (iSKAT), the VW-TOW-SE is the most powerful test and the TOW-SE is the second most powerful test when gene environment interaction effect exists for both rare and common variants. The three tests were applied to the GAW20 simulated data, among the five regions in which the main effect of common SNPs was simulated and the gene-age interaction effect was not included. As expected, none of the tests indicated positive results.
OBJECTIVE—The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA ...sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).
METHODS AND RESULTS—We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study n=916 and the Penn Coronary Artery Calcification sample n=2061). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10.
CONCLUSION—A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.
It has not been well understood that the influences of pH and accompanying anions on the toxicity of selenate (Se(VI)). The influences of pH and major anions on Se(VI) toxicity to wheat root ...elongation were determined and modeled based on the biotic ligand model (BLM) and free ion activity model (FIAM) concepts. Results showed that EC50Se(VI)T values increased from 162 to 251 μM as the pH values increased from 4.5 to 8.0, indicating that the pH increases alleviated the Se(VI) toxicity. The EC50{SeO42−} values increased from 133 to 203 μM while the EC50{HSeO4−} values sharply decreased from 210 to 0.102 nM with the pH increasing from 4.5 to 8.0. The effect of pH on Se(VI) toxicity could be explained by the changes of Se(VI) species in different pH solutions as SeO42− and HSeO4−were differently toxic to wheat root elongation. The toxicity of Se(VI) decreased with the increasing activities of H2PO4− and SO42− but not for NO3− and Cl− activities, indicating that only H2PO4− and SO42− had competitive effects with Se(VI) on the binding sites. An extended BLM was developed to consider effects of pH, phosphate and sulphate, and stability constants of SeO42−, HSeO4−, H2PO4− and SO42− to the binding sites were obtained: logKSeO4BL = 3.45, logKHSeO4BL = 5.98, logKH2PO4BL = 2.05, logKSO4BL = 1.85. Results implied that BLM performed much better than FIAM in the wheat root elongation prediction when coupling with toxic species SeO42− and HSeO4−, and the competitions of H2PO4− and SO42− for the binding sites while developing the Se(VI)-BLM.
•SeO42− and HSeO4− were the two main toxic species contributed to Se(VI) toxicity.•HSeO4− had a greater binding affinity than SeO42−.•Se(VI) toxicity was described by H2PO4− and SO42− protection and speciation effect.•An extended BLM can predict the Se(VI) toxicity to wheat root elongation.
Microplastic (MP) pollution in terrestrial ecosystems has aroused great concern. However, little is known regarding the distribution of MPs in Sand Land soils and their associated destinies. We ...investigated the MPs pollution in different areas, different vegetation cover and restoration years in Mu Us Sand Land soils. The results clearly showed that the soils of Mu Us Sand Land contain a relatively higher MPs abundance. The significant differences of MPs abundance were demonstrated among soil from sand, grassland and woodland, which the total MP abundance of sand soil was higher than that of grassland and woodland. The distribution of MP size in the woodland area primarily from 0 to 0.50 mm, which is significantly higher than that other areas. In addition, the highest concentration of MP collected was found at Salix tree (ST), followed by Poplar tree (PT) and Chinese pine (CP), while the lowest concentration was at Pinus sylvestris (PSs) and Jujube tree (JT). It is worth noting that the abundance of MPs decreases with restoration years increased, whether it is PT or PSs. We speculate that the tree disturbance in the sampling area might affect the distribution of microplastics and then be conducive to plastic fragmentation.
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•The abundance of microplastics exhibited exceptionally high level of MPs.
•The microplastic abundance of sand was higher than that of grassland and woodland.
•Microplastics size decreased gradually with the enhancement of repair degree.
•Different types of cover vegetation may influence the distribution of microplastic.
•Microplastics disturbance may be related to the history of restoration years.
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