Bridging the Gap between Target-Based and Cell-Based Drug Discovery with a Graph Generative Multitask Model.

The development of new drugs is crucial for protecting humans from disease. In the past several decades, target-based screening has been one of the most popular methods for developing new drugs. This method efficiently screens potential inhibitors of a target protein in vitro, but it frequently fails in vivo due to insufficient activity of the selected drugs. There is a need for accurate computational methods to bridge this gap. Here, we present a novel graph multi-task deep learning model to identify compounds with both target inhibitory and cell active (MATIC) properties. On a carefully curated SARS-CoV-2 data set, the proposed MATIC model shows advantages compared with the traditional method in screening effective compounds in vivo. Following this, we investigated the interpretability of the model and discovered that the learned features for target inhibition (in vitro) or cell active (in vivo) tasks are different with molecular property correlations and atom functional attention. Based on these findings, we utilized a Monte Carlo-based reinforcement learning generative model to generate novel multiproperty compounds with both in vitro and in vivo efficacy, thus bridging the gap between target-based and cell-based drug discovery. The tool is freely accessible at https://github.com/SIAT-code/MATIC.

Assessment on the cumulative effect of pollutants and the evolution of micro-ecosystems in bioretention systems with different media.

Bioretention system is one of the most used green stormwater infrastructures (GSI), and its media is a key factor in reducing runoff water volume and purifying water quality. Many studies have investigated media improvement to enhance the pollutant removal capacity. However, the long-term cumulative effect and microbial effect of pollutants in the modified-media bioretention system is less known. This study investigated the cumulative effect of pollutants and their influence on microbial characteristics in conventional and modified media bioretention system. The addition of modifiers increased the background content of pollutants in the media, and the accumulation of pollutants in planting soil (PS) and bioretention soil mixing + water treatment residuals (BSM+WTR) was relatively higher after the simulated rainfall experiment. The accumulation of pollutants led to a decrease in dehydrogenase activity, and an increase in urease and invertase activities. Ten dominant bacterial species at the phylum level were found in all bioretention systems. The relative abundances of the bacteria with good viability under low nutritional conditions decreased, while the species which could live in the pollutant-rich environment increased. The accumulation of pollutants in the bioretention system led to the extinction of some functional microorganisms. The better the effects of modified media on pollutant removal showed, the more obvious effect on the media micro-ecosystem was. To ensure the long-term efficient and stable operation of the modified-media bioretention system, we recommend balancing the pollutant removal efficiency and cumulative effect in modified-media bioretention systems.

An assessment system for evaluating the severity of thoracolumbar osteoporotic fracture and its clinical application: A retrospective study of 381 cases.

OBJECTIVE: We put forward an assessment system of thoracolumbar osteoporotic fracture (ASTLOF) evaluating the severity of thoracolumbar osteoporotic fracture. This study was to investigate its efficacy in guiding clinical practice. METHODS: Three hundred and eighty-one patients with thoracolumbar vertebral osteoporosis fracture admitted to the hospital from January 2010 to December 2011 were enrolled in the study. All cases were evaluated by ASTLOF including evaluation of morphological changes, MRI, bone mineral density and pain. The patients were treated with different methods according to ASTLOF score. All patients were followed up on a regular basis. The treatment results were assessed by VAS and ODI. RESULTS: All patients were followed up with an average of 20.1 (range: 6-30) months. There were 91 cases of ASTLOF score<4 points. Their average VAS score decreased from 8.0 ± 1.7 points to 2.0 ± 1.3 with statistical significance (P<0.05) and the average ODI score decreased from 69.5 ± 2.8 to 38.1 ± 1.5 (P<0.05). One hundred and thirty-two cases were with ASTLOF score=4, with the average VAS score decreased from 8.2 ± 1.4 to 1.9 ± 1.2 (P<0.05) and the average ODI score decreased from 71.5 ± 3.7 to 36.2 ± 2.5 (P<0.05). There were 158 cases of ASTLOF score ≥ 5, with the VAS score decreased from 8.0 ± 1.7 to 2.0 ± 1.3 and the ODI score decreased from 69.5 ± 2.8 to 38.1 ± 1.5. CONCLUSIONS: ASTLOF based on the severity of thoracolumbar osteoporotic fracture was suggested to be helpful in guiding clinical practice.

A comprehensive investigation and assessment of mercury in intertidal sediment in continental coast of Shanghai.

The aims of this paper were to survey the total Hg levels and distribution character in intertidal sediment in continental coast of Shanghai, and identify the environment factors that might influence the sediment Hg concentrations, and to assess the pollution degree and potential ecological risk of Hg in sediment. Eighty-eight surface sediment samples and 18 sediment cores were collected for Hg contamination analysis. Physicochemical properties including Eh, particle size, content of total organic carbon (TOC), and acid volatile sulfide (AVS) were also measured. Index of geo-accumulation (I geo) and potential ecological risk index were used respectively to assess the pollution levels and the ecological risk of sediment Hg. The average of total Hg concentrations in surface sediments was 107.4 ± 90.9 ng/g with the range from 0 to 465.9 ng/g. Higher Hg concentrations were generally found in surface sediments near sewage outfalls and the mouth of rivers. Total Hg concentrations were significantly correlated with TOC (p < 0.05) both in surface (r = 0.24) and core (r = 0.29) sediments, but not with the other environment factors (Eh, AVS, and particle size). Geo-accumulation index indicated that Hg contamination in intertidal sediments was generally at none to moderate degree, while potential ecological risk index demonstrated that the risk caused by Hg were at moderate to considerable level. Intertidal sediment in continental coast of Shanghai has generally been contaminated by Hg, and it might pose moderate to considerable risk to the local ecosystem. The Hg contamination is related more to the coastal pollution sources and complicated hydrodynamic and sedimentary conditions than the other environment factors studied.

Toxic heavy metal contamination and risk assessment of street dust in small towns of Shanghai suburban area, China.

The aims of this paper were to quantify the heavy metal concentrations in street dust of small towns in Shanghai suburban area compared with those in urban area, and examine their seasonal and spatial variations, and to assess their risks to water environment and local populations. Street dust samples were collected from three small towns and urban area in Shanghai in different seasons. Levels of heavy metals were determined by atomic adsorption spectrophotometer analyzer. The method of potential ecological risk index and the health risk assessment model were used to evaluate the potential risks to water bodies and local residents, respectively. The mean metal concentrations in street dust of small towns were far above soil background values but still lower than those in the urban area. No significant seasonal change was observed except for Cr, Ni, and Zn concentrations. Higher metal concentrations tended to be located in central area of towns and township roads. The integrated metal contamination was high and posed a strong potential ecological risk. Children had greater health risk than adults. The carcinogenic risk probabilities were under the acceptable level. The hazard index values to children were close to the safe level. Street dust from the studied area has been contaminated by heavy metals. The contamination of these elements is related more to the pollution source than seasonal change. The combination of the six metals may threaten the water environment and has non-cancer health risk to children, but not to adults.

Heavy Metal Contamination and Assessment of Roadside and Foliar Dust along the Outer-Ring Highway of Shanghai, China.

Foliar and roadside dust samples were collected from five sites along the outer-ring highway of Shanghai, one of the biggest metropolitan areas of China, to assess heavy/toxic metal contamination. Concentrations of Zn, Cu, Ni, As, and Hg in foliar dust were higher than in roadside dust, whereas concentrations of Pb and Cd were higher in roadside dust. In the roadside dust, average concentrations of all metals except As in foliar and roadside dust samples were significantly above the background values of soil in Shanghai: the ratios between the average of samples and background values of Shanghai were in the order: Cd (25.1) > Zn (12.2) > Cu (6.16) > Pb (5.74) > Ni (5.50) > Hg (5.18) > As (1.05). By using the geo-accumulation index, the pollution grades of seven heavy metals at five sampling sites were calculated. Roadside dust was heavily to extremely contaminated with Cd; moderately to heavily contaminated with Zn; and moderately contaminated with Cu, Hg, Pb, and Ni. Foliar dust was heavily contaminated with Cd; moderately to heavily contaminated with Zn and Cu; and moderately contaminated with Hg, Pb, and Ni. The contamination level of heavy metals in the Puxi area was greater than that in the Pudong area, which might be related to the industrial distribution and land use. Combined with correlation analysis, hierarchical cluster analysis indicated that atmospheric deposition is the main source of Cd, Hg, As, and Pb in dust and that Cu and Zn in dust are mainly from heavy traffic on the highway. A portion of Ni in dust also comes from the parent soil.

Preclinical assessment of drug-induced proarrhythmias: role of the arterially perfused rabbit left ventricular wedge preparation.

Drug-induced torsade de pointes (TdP) is a rare but lethal side effect of many cardiovascular and non-cardiovascular drugs. It has led to black box warnings or even withdrawal of many useful compounds from the market and is one of the major stumbling blocks for new drug development. The critical need for a better test that can predict the TdP liability of a candidate drug has led to the development of multiple preclinical models. Each of these models has it own merits and limitations in preclinical testing for TdP liability; however, most of these models have not been adequately validated, so their precise sensitivity and specificity remain largely unknown. Recent blinded validation studies have demonstrated that the rabbit left ventricular wedge preparation can predict drug-induced TdP with an extremely high sensitivity and specificity. As a matter of fact, the wedge technique was initially developed primarily for studying the electrical heterogeneity of myocardium and the cellular basis of QT prolongation and TdP. Naturally then, the electrophysiological data obtained from the wedge takes into account every critical factor associated with the development of TdP. The TdP scores generated using the wedge technique have been shown to assess the torsadogenic potential of the drugs in a predictable fashion. This review elaborates on the current and prospective role of the rabbit left ventricular wedge preparation in preclinical assessment of drug-induced proarrhythmias including but not limited to TdP.