AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Discovery of 18 Organophosphate Esters and 3 Organophosphite Antioxidants in Food Contact Materials Using Suspect and Nontarget Screening: Implications for Human Exposure

In this study of extracts of 100 food contact material (FCM) samples collected from South China, we identified 21 organophosphate esters (OPEs) by suspect screening and seven novel OPEs by characteristic fragments-based nontarget screening. Six organophosphite antioxidants (OPAs) were further identified using a suspect list derived from these identified OPEs. Of these compounds, 18 OPEs and 3 OPAs were found for the first time in the extracts of FCMs. (Semi-)quantification revealed that seven of the OPEs [triphenyl phosphate, tris(2,4-di-tert-butylphenyl) phosphate (TDtBPP), bis(2,4-di-tert-butylphenyl) methyl phosphate, (2,4-di-tert-butylphenyl)pentaerythritol phosphate, triethyl phosphate, 2-ethylhexyl-diphenyl phosphate, and trimethyl phosphate] and two of the OPAs [tris(2,4-di-tert-butylphenyl) phosphite (TDtBPPi) and pentabutylated triphenyl phosphite] were present in more than 50 FCM samples and that TDtBPP and TDtBPPi were the dominant OPE and OPA in FCMs, respectively [with median concentrations of 7260 ng/g (range: <8.50–103,879 ng/g) and 31,920 ng/g (range: <9.80–657,399 ng/g), respectively]. A migration test revealed that the migration efficiencies of compounds from a plastic coffee cup to food simulants in the cup increased as the ethanol/water ratio in the food simulants increased. This study significantly enhanced our understanding on the diversity and occurrences of OPEs and OPAs in FCMs used in China and their FCM-to-food migration risk

Placental transfer of bisphenol diglycidyl ethers (BDGEs) and its association with maternal health in a population in South of China

Despite high production and usage, little is known about exposure to bisphenol diglycidyl ethers (BDGEs) and their derivatives in pregnant women and fetuses. In this study, we determined nine BDGEs in 106 paired maternal and cord serum samples collected from e-waste dismantling sites in South of China. Bisphenol A bis (2,3-dihydroxypropyl) glycidyl ether (BADGE·2H2O), bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) glycidyl ether (BADGE·HCl·H2O), and bisphenol F diglycidyl ether (BFDGE) were the major BDGEs, with median concentrations of 0.57, 4.07, and 1.60 ng/mL, respectively, in maternal serum, and of 3.58, 5.61, and 0.61 ng/mL, respectively, in cord serum. The transplacental transfer efficiencies (TTEs) were estimated for BDGEs found in samples, and median values were in the range of 0.98 (BFDGE) to 5.91 (BADGE·2H2O). Our results suggested that passive diffusion plays a role in the placental transfer of BADGE·HCl·H2O and BFDGE, whereas several mechanisms contribute to the high accumulation of BADGE·2H2O in cord serum. Multiple linear regression analysis indicated significant associations between maternal serum concentrations of BDGEs and blood clinical biomarkers, especially those related to liver injuries, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and adenosine deaminase (ADA) (P < 0.05). To our knowledge, this is the first study to report the occurrence of BDGEs in paired maternal–fetal serum samples and provide new insights into prenatal and fetal exposures. The newly discovered TTEs in maternal–fetal pairs contribute to a fuller inventory of the transmission activity of pollutants in the human body, ultimately adding to a more significant comprehensive risk evaluation

Urinary parabens in children from South China: Implications for human exposure and health risks

Parabens are extensively applied in cosmetics, drugs or food as preservatives and have become common pollutants in environmental media. However, data on human exposure to these chemicals is still limited, especially for children. This study aimed to investigate parabens in urine samples of children and to evaluate the cumulative risk of paraben exposure. Five short-chain parabens were measured in 255 urine samples collected from children in a kindergarten and elementary schools from South China. Methyl paraben (MeP), ethyl paraben (EtP) and n-propyl paraben (PrP) were widely detected in urine samples (detection rates > 94.9%), indicating their widespread exposure. The urinary median concentrations of MeP, EtP and PrP were 2.25, 0.33 and 0.50 mu g/L, respectively. Significantly positive correlations (p < 0.01) were observed between MeP and PrP in urine, suggesting similar sources and/or metabolic pathways of these two chemicals. The median estimated daily intakes (EDIs) of parabens were determined to be 18.1 and 9.79 mu g/kg-bw/day for kindergarten children and elementary school students, respectively. Estimation of human intake and exposure risks indicated potential risks of PrP exposure for elementary school students. This is the first study addressing paraben exposure in South China children. (C) 2019 Elsevier Ltd. All rights reserved

Assessing Neurobehavioral Alterations Among E-waste Recycling Workers in Hong Kong

Background: E-waste workers in Hong Kong are handling an unprecedented amount of e-waste, which contains various neurotoxic chemicals. However, no study has been conducted to evaluate the neurological health status of e-waste workers in Hong Kong. This study aimed to evaluate the prevalence of neurobehavioral alterations and to identify the vulnerable groups among Hong Kong e-waste workers. Methods: We recruited 109 Hong Kong e-waste workers from June 2021 to September 2022. Participants completed standard questionnaires and wore a GENEActiv accelerometer for seven days. Pittsburgh Sleep Quality Index and Questionnaire 16/18 (Q16/18) were used to assess subjective neurobehavioral alterations. The GENEActiv data generated objective sleep and circadian rhythm variables. Workers were grouped based on job designation and entity type according to the presumed hazardous level. Unconditional logistic regression models measured the associations of occupational characteristics with neurobehavioral alterations after adjusting for confounders. Results: While dismantlers/repairers and the workers in entities not funded by the government were more likely to suffer from neurotoxic symptoms in Q18 (adjusted odds ratio: 3.18 [1.18–9.39] and 2.77 [1.10–7.46], respectively), the workers from self-sustained recycling facilities also have poor performances in circadian rhythm. Results also showed that the dismantlers/repairers working in entities not funded by the government had the highest risk of neurotoxic symptoms compared to the lowest-risk group (i.e., workers in government-funded companies with other job designations). Conclusion: This timely and valuable study emphasizes the importance of improving the working conditions for high-risk e-waste workers, especially the dismantlers or repairers working in facilities not funded by the government

Shrinkage Reduction in Nanopore-Rich Cement Paste Based on Facile Organic Modification of Montmorillonite

The organic modification of montmorillonite was successfully achieved using cetyltrimethyl ammonium bromide under facile conditions. The modified montmorillonite was subsequently used for the fabrication of montmorillonite-induced nanopore-rich cement paste (MNCP), and the shrinkage behavior and fundamental performance of MNCP were also investigated. The results indicate that alkali cations on a montmorillonite layer surface were exchanged by using CTAB under 80 °C, successfully achieving the organic modification of montmorillonite. As a pore-forming agent, the modified montmorillonite caused a reduction in shrinkage: the 28-day autogenous shrinkage at a design density of 400 kg/m3 and 800 kg/m3 was reduced to 2.05 mm/m and 0.24 mm/m, and the highest reduction percentages during the 28-day drying shrinkage were 68.1% and 62.2%, respectively. The enlarged interlamellar pores and hydrophobic effects caused by the organic modification of montmorillonite aided this process. Organic-modified montmorillonite had a minor influence on dry density and thermal conductivity and could contribute to an enhancement of strength in MNCP