In recent times, machine learning has become increasingly prominent in predictive toxicology as it has shifted from in vivo studies toward in silico studies. Currently, in vitro methods together with ...other computational methods such as quantitative structure–activity relationship modeling and absorption, distribution, metabolism, and excretion calculations are being used. An overview of machine learning and its applications in predictive toxicology is presented here, including support vector machines (SVMs), random forest (RF) and decision trees (DTs), neural networks, regression models, naïve Bayes, k-nearest neighbors, and ensemble learning. The recent successes of these machine learning methods in predictive toxicology are summarized, and a comparison of some models used in predictive toxicology is presented. In predictive toxicology, SVMs, RF, and DTs are the dominant machine learning methods due to the characteristics of the data available. Lastly, this review describes the current challenges facing the use of machine learning in predictive toxicology and offers insights into the possible areas of improvement in the field.
Emissions from gasoline and diesel vehicles are predominant anthropogenic sources of reactive gas-phase organic carbon and key precursors to secondary organic aerosol (SOA) in urban areas. Their ...relative importance for aerosol formation is a controversial issue with implications for air quality control policy and public health. We characterize the chemical composition, mass distribution, and organic aerosol formation potential of emissions from gasoline and diesel vehicles, and find diesel exhaust is seven times more efficient at forming aerosol than gasoline exhaust. However, both sources are important for air quality; depending on a region’s fuel use, diesel is responsible for 65% to 90% of vehicular-derived SOA, with substantial contributions from aromatic and aliphatic hydrocarbons. Including these insights on source characterization and SOA formation will improve regional pollution control policies, fuel regulations, and methodologies for future measurement, laboratory, and modeling studies.
Alternative splicing (AS) allows generation of cell type–specific mRNA transcripts and contributes to hallmarks of cancer. Genome‐wide analysis for AS in human hepatocellular carcinoma (HCC), ...however, is limited. We sought to obtain a comprehensive AS landscape in HCC and define tumor‐associated variants. Single‐molecule real‐time long‐read RNA sequencing was performed on patient‐derived HCC cells, and presence of splice junctions was defined by SpliceMap‐LSC‐IDP algorithm. We obtained an all‐inclusive map of annotated AS variants and further discovered 362 alternative spliced variants that are not previously reported in any database (neither RefSeq nor GENCODE). They were mostly derived from intron retention and early termination codon with an in‐frame open reading frame in 81.5%. We corroborated many of these predicted unannotated and annotated variants to be tumor specific in an independent cohort of primary HCC tumors and matching nontumoral liver. Using the combined Sanger sequencing and TaqMan junction assays, unique and common expressions of spliced variants including enzyme regulators (ARHGEF2, SERPINH1), chromatin modifiers (DEK, CDK9, RBBP7), RNA‐binding proteins (SRSF3, RBM27, MATR3, YBX1), and receptors (ADRM1, CD44v8‐10, vitamin D receptor, ROR1) were determined in HCC tumors. We further focused functional investigations on ARHGEF2 variants (v1 and v3) that arise from the common amplified site chr.1q22 of HCC. Their biological significance underscores two major cancer hallmarks, namely cancer stemness and epithelial‐to‐mesenchymal transition–mediated cell invasion and migration, although v3 is consistently more potent than v1. Conclusion: Alternative isoforms and tumor‐specific isoforms that arise from aberrant splicing are common during the liver tumorigenesis. Our results highlight insights gained from the analysis of AS in HCC.
1. Functional trait diversity can reveal mechanisms of species coexistence in plant communities. Few studies have tested whether functional diversity for foliar traits related to resource-use ...strategy increases or decreases with declining soil phosphorus (P) in forest communities. 2. We quantified tree basal area and four foliar functional traits (i. e. nitrogen (N), phosphorus (P), thickness and tissue density) for all woody species along the c. 120 000 year Franz Josef soil chronosequence in cool temperate rain forest, where strong shifts occur in light and soil nutrient availability (i. e. total soil P declines from 805 to 100 mg kg⁻¹). We combined the abundance and trait data in functional diversity indices to quantify trait convergence and divergence, in an effort to determine whether mechanisms of coexistence change with soil fertility. 3. Relationships between species trait means and total soil N and P were examined using multiple regression, with and without weighting of species abundances. We used Rao's quadratic entropy to quantify functional diversity at the plot scale, then compared this with random expectation, using a null model that randomizes abundances across species within plots. Taxonomic diversity was measured using Simpson's Diversity. Relationships between functional and taxonomic diversity and total soil P were examined using jackknife linear regression. 4. Leaf N and P declined and leaf thickness and density increased monotonically with declining total soil P along the sequence; these relationships were unaffected by abundance weighting of species in the analyses. Inclusion of total soil N did not improve predictions of trait means. All measures of diversity calculated from presence/absence data were unrelated to total soil N and P. There was no evidence for a relationship between Rao values using quantitative abundances and total soil P. However, there was a strong positive relationship between Rao, expressed relative to random expectation, and total soil P, indicating trait convergence of dominant species as soil P declined. 5. Synthesis: Our results demonstrate that at high fertility locally dominant species differ in resource-use strategy, but as soil fertility declines over the long term, dominant species increasingly converge on a resource-retentive strategy. This suggests that differentiation in resource-use strategy is required for coexistence at high-fertility but not in low-fertility ecosystems.
Motor vehicles are major sources of primary organic aerosol (POA), which is a mixture of a large number of organic compounds that have not been comprehensively characterized. In this work, we apply a ...recently developed gas chromatography mass spectrometry approach utilizing “soft” vacuum ultraviolet photoionization to achieve unprecedented chemical characterization of motor vehicle POA emissions in a roadway tunnel with a mass closure of >60%. The observed POA was characterized by number of carbon atoms (N C), number of double bond equivalents (N DBE) and degree of molecular branching. Vehicular POA was observed to predominantly contain cycloalkanes with one or more rings and one or more branched alkyl side chains (≥80%) with low abundances of n-alkanes and aromatics (<5%), similar to “fresh” lubricating oil. The gas chromatography retention time data indicates that the cycloalkane ring structures are most likely dominated by cyclohexane and cyclopentane rings and not larger cycloalkanes. High molecular weight combustion byproducts, that is, alkenes, oxygenates, and aromatics, were not present in significant amounts. The observed carbon number and chemical composition of motor vehicle POA was consistent with lubricating oil being the dominant source from both gasoline and diesel-powered vehicles, with an additional smaller contribution from unburned diesel fuel and a negligible contribution from unburned gasoline.
There is much interest in the tissue of origin of circulating DNA in plasma. Data generated using DNA methylation markers have suggested that hematopoietic cells of white cell lineages are important ...contributors to the circulating DNA pool. However, it is not known whether cells of the erythroid lineage would also release DNA into the plasma.
Using high-resolution methylation profiles of erythroblasts and other tissue types, 3 genomic loci were found to be hypomethylated in erythroblasts but hypermethylated in other cell types. We developed digital PCR assays for measuring erythroid DNA using the differentially methylated region for each locus.
Based on the methylation marker in the ferrochelatase gene, erythroid DNA represented a median of 30.1% of the plasma DNA of healthy subjects. In subjects with anemia of different etiologies, quantitative analysis of circulating erythroid DNA could reflect the erythropoietic activity in the bone marrow. For patients with reduced erythropoietic activity, as exemplified by aplastic anemia, the percentage of circulating erythroid DNA was decreased. For patients with increased but ineffective erythropoiesis, as exemplified by β-thalassemia major, the percentage was increased. In addition, the plasma concentration of erythroid DNA was found to correlate with treatment response in aplastic anemia and iron deficiency anemia. Plasma DNA analysis using digital PCR assays targeting the other 2 differentially methylated regions showed similar findings.
Erythroid DNA is a hitherto unrecognized major component of the circulating DNA pool and is a noninvasive biomarker for differential diagnosis and monitoring of anemia.
The ratio of early transmitral velocity to tissue Doppler mitral annular early diastolic velocity (E/Ea) has been correlated with pulmonary capillary wedge pressure (PCWP) in a wide variety of ...cardiac conditions. The objective of this study was to determine the reliability of mitral E/Ea for predicting PCWP in patients admitted for advanced decompensated heart failure.
Prospective consecutive patients with advanced decompensated heart failure (ejection fraction < or =30%, New York Heart Association class III to IV symptoms) underwent simultaneous echocardiographic and hemodynamic evaluation on admission and after 48 hours of intensive medical therapy. A total of 106 patients were included (mean age, 57+/-12 years; ejection fraction, 24+/-8%; PCWP, 21+/-7 mm Hg; mitral E/Ea ratio, 20+/-12). No correlation was found between mitral E/Ea ratio and PCWP, particularly in those with larger left ventricular volumes, more impaired cardiac indexes, and the presence of cardiac resynchronization therapy. Overall, the mitral E/Ea ratio was similar among patients with PCWP >18 and < or =18 mm Hg, and sensitivity and specificity for mitral E/Ea ratio >15 to identify a PCWP >18 mm Hg were 66% and 50%, respectively. Contrary to prior reports, we did not observe any direct association between changes in PCWP and changes in mitral E/Ea ratio.
In decompensated patients with advanced systolic heart failure, tissue Doppler-derived mitral E/Ea ratio may not be as reliable in predicting intracardiac filling pressures, particularly in those with larger LV volumes, more impaired cardiac indices, and the presence of cardiac resynchronization therapy.
CRISPR/Cas9-based therapeutics hold the possibility for permanent treatment of genetic disease. The potency and specificity of this system has been used to target dominantly inherited conditions ...caused by heterozygous missense mutations through inclusion of the mutated base in the short-guide RNA (sgRNA) sequence. This research evaluates a novel approach for targeting heterozygous single-nucleotide polymorphisms (SNPs) using CRISPR/Cas9. We determined that a mutation within KRT12, which causes Meesmann's epithelial corneal dystrophy (MECD), leads to the occurrence of a novel protospacer adjacent motif (PAM). We designed an sgRNA complementary to the sequence adjacent to this SNP-derived PAM and evaluated its potency and allele specificity both in vitro and in vivo. This sgRNA was found to be highly effective at reducing the expression of mutant KRT12 mRNA and protein in vitro. To assess its activity in vivo we injected a combined Cas9/sgRNA expression construct into the corneal stroma of a humanized MECD mouse model. Sequence analysis of corneal genomic DNA revealed non-homologous end-joining repair resulting in frame-shifting deletions within the mutant KRT12 allele. This study is the first to demonstrate in vivo gene editing of a heterozygous disease-causing SNP that results in a novel PAM, further highlighting the potential for CRISPR/Cas9-based therapeutics.
Abstract Background Trimethylamine- N -oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and ...betaine, in heart failure (HF). Methods and Results In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6–12.1) μmol/L, 10.9 (8.4–14.0) μmol/L, and 43.8 (37.1–53.0) μmol/L, respectively, and were correlated with each other (all P < .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 4.9–13.2 vs 4.8 3.4–9.8 μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 4.7–14.8 vs 4.7 3.4–11.3 μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio HR 1.64, 95% CI 1.22–2.20; P = .001), betaine (HR 1.51, 95% CI 1.10–2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10–1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03–2.14; P = .03). Conclusion Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices.
Objectives This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF). ...Background Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. Methods In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. Results In our study cohort (age 57 ± 14 years, left ventricular ejection fraction LVEF 26 ± 6%, median N-terminal pro-B-type natriuretic peptide NT-proBNP 1,158 pg/ml), the mean GLS was −7.1 ± 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = −0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s': r = −0.30, p < 0.0001), and RV diastolic function (RV e'/a': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS ≥−6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011). Conclusions In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF.
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