Comprehensive Toxicological Assessment of Halobenzoquinones in Drinking Water at Environmentally Relevant Concentration.

Halobenzoquinones (HBQs), an emerging unregulated category of disinfection byproduct (DBP) in drinking water, have aroused an increasing concern over their potential health risks. However, the chronic toxicity of HBQs at environmentally relevant concentrations remains largely unknown. Here, the occurrence and concentrations of 13 HBQs in drinking water from a northern megacity in China were examined using ultrahigh performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UHPLC-MS/MS). Four HBQs, including 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), 2,3,6-trichloro-1,4-benzoquinone (TriCBQ), and 2,5-dibromo-1,4-benzoquinone (2,5-DBBQ), were detected beyond 50% occurrence frequency and at median concentrations from 4 to 50 ng/L. The chronic toxicity of these four HBQs to normal human colon and liver cells (FHC and THLE-2) was investigated at these concentrations. After 90 days of exposure, 2,5-DBBQ and 2,6-DCBQ induced the highest levels of oxidative stress and deoxyribonucleic acid (DNA) damage in colon and liver cells, respectively. Moreover, 2,5-DBBQ and 2,6-DCBQ were also found to induce epithelial-mesenchymal transition (EMT) in normal human liver cells via the extracellular signal regulated kinase (ERK) signaling pathway. Importantly, heating to 100 °C (boiling) was found to efficiently reduce the levels of these four HBQs in drinking water. These results suggested that environmentally relevant concentrations of HBQs could induce cytotoxicity and genotoxicity in normal human cells, and boiling is a highly efficient way of detoxification for HBQs.

Optical Coherence Tomography Assessment of Coronary Lesions Associated With Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Microvascular reperfusion following percutaneous coronary intervention (PCI) is associated with the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We investigated how plaque characteristics detected by optical coherence tomography (OCT) in STEMI patients affect the status of the microcirculation during PCI.Methods and Results: This retrospective, single-center study was a post hoc analysis basedon the multicenter SALVAGE randomized control trial (NCT03581513) that enrolled 629 STEMI patients, and finally we enrolled 235 patients who underwent PCI and pre-intervention OCT. Microvascular perfusion was evaluated using the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion frame count (TMPFC). Patients were divided into 3 groups based on the change in TMPFC from before to after PCI: improving TMPFC (n=11; 4.7%), stable TMPFC (n=182; 77.4%), and worsening TMPFC group (n=42; 17.9%). The proportion of patients with a microcirculation dysfunction before reperfusion was 11.9%, which increased significantly by (P=0.079) 8.5% to 20.4% after reperfusion. Compared with plaque characteristics in the stable and worsening TMPFC groups, the improving TMPFC group had fewer thrombi (90.7% and 90.5% vs. 89.4%, respectively; P=0.018), a lower proportion of plaque rupture (66.5% and 66.3% vs. 54.5%, respectively; P=0.029), and a lower proportion of lipid-rich plaques (89.6% and 88.1% vs. 63.6%, respectively; P=0.036). CONCLUSIONS: PCI may not always achieve complete myocardial reperfusion. Thrombi, plaque rupture, and lipid-rich plaques detected by OCT can indicate microcirculation dysfunction during the reperfusion period.

Assessment of the therapeutic potential of probiotics against carbon quantum dots-induced neurotoxicity in common carp (Cyprinus carpio).

Carbon quantum dots (CQDs) have received increasing attention in recent years for their potential toxicity. However, little is known about their neurobehavioral toxicity. This study aimed to investigate the potential mechanisms by which probiotics reduce CQDs neurotoxicity from a brain-gut axis perspective by exposing carp to CQDs and/or probiotics for five weeks. The results showed that CQDs accumulation in the brain reduces the expression of blood-brain-barrier (BBB) related genes in carp, leading to brain damage. In addition, CQDs impaired motor behavior and inhibited acetylcholinesterase activity. These abnormalities were alleviated by probiotic supplementation. Microbiomic analysis showed that probiotics improved the imbalance of intestinal flora caused by CQDs and increased the abundance of Firmicutes. Serum metabolomic analysis showed that probiotic supplementation restored the abnormal metabolic levels associated with neurological, inflammatory, and apoptotic cell death caused by CQDs. Overall, probiotic supplementation improved the CQDs-induced changes in brain damage, gut microbiology, and systemic metabolism. These results suggests that CQDs may cause neurotoxicity via the brain-gut microbial axis.

Soil potentially toxic element pollution at different urbanization intensities: Quantitative source apportionment and source-oriented health risk assessment.

Potentially toxic element (PTE) pollution of urban soils has become the focus of social concern, but the differences of the sources, pollution levels and source-oriented human health risks (HHR) of PTE in urban soils among different urban intensity areas is rarely known. This study explored a comprehensive scheme that combined positive matrix factorization model and source-oriented assessment to quantitatively assess the priority pollution sources and HHR in urban soils from areas with different urbanization intensities. All the average values for PTE concentrations, except for Cr, were higher than their corresponding background values. The contributions made by the four sources (atmospheric deposition, agricultural activities, traffic activities, and natural sources) were relatively similar (22.29-29.89%) in the low urbanization intensity (LUI) area, whereas traffic activities and atmospheric deposition made the greatest contributions in the medium urbanization intensity (MUI) (29.12%) and the high urbanization intensity (HUI) (38.97%) areas, respectively. The geo-accumulation index results revealed that Cd was the most polluting element and the HUI area had the highest pollution levels. The content-oriented assessment of HHR demonstrated that the non-carcinogenic risks were acceptable, but the carcinogenic risks were unacceptable. According to the source-oriented HHR assessment, among the anthropogenic activities, atmospheric deposition contributed the most to carcinogenic risk of children in all areas, and atmospheric deposition, traffic activities and agricultural activities contributed the most to the carcinogenic risk of adults in HUI, MUI and LUI, respectively. This suggest that control measures need to be tailored to the appropriate urbanization intensity to effectively curb PTE pollution caused by anthropogenic activities.

Research on Risk and Resilience Evaluation of Urban Underground Public Space.

High urban density, land scarcity, rapid population growth, and traffic congestion have restricted urban development. In response, selected multiple functions have increasingly been integrated into the underground public space (UPS) to maximize the 3D utilization of precious urban space. The accelerated intensity of UPS use has alerted safety concerns. UPS with enclosed and confined natures, complex building structures, locations usually in cramped areas, and limited emergency exits are potentially more prone to heavy casualties and losses in natural or human-made disasters. As research on UPS safety is limited and focused on single risks, we attempted to fill the knowledge gap by developing an integrated risk analysis of UPS to understand risk resilience and improve risk management. From the perspective of the UPS system, four latent factors were identified: natural environment, economic environment, facilities and equipment, and physical structure. Seventeen resilience indicators subsumed under the factors were selected based on resilience concepts. A questionnaire was designed to gather opinions on the relative importance rating of the resilience indicators. SPSS and AMOS software were enlisted to build a structural equation model (SEM), validate the data and model, and calculate the path coefficients and index weights to test four hypotheses. The SEM model results were employed to develop a holistic resilience enhancement strategy under a four-phase framework: before, during, after, and long-term, and under four latent factors. The resilience enhancements can optimize UPS disaster prevention, rescue and evacuation, mitigation, and response management.

Preclinical safety assessment of toxicity and biodistribution of oncolytic virus HSV-1 expressing human PD-1 antibody in mice.

HSV-1/hPD-1 is composed of engineered herpes simplex virus type-1 and two inserted copies of the human PD-1 antibody sequence. It is a novel oncolytic virus product designed to cure malignancies. The objective of this study was to estimate its toxicity in mice. In the single-dose toxicity study, no mortality and abnormal symptoms were observed in animals injected with 4.0 × 107 pfu/mouse dose. In the repeat-dose toxicity study, HSV-1/hPD-1 in animals intramuscularly treated with 1.0 × 107, 2.0 × 107, or 4.0 × 107 pfu/mouse doses was well tolerated in terms of clinical observation, body weight, food consumption, hematology and biochemistry indexes, T lymphocyte counting, immune reaction, and organ weight, except for some histopathological changes, such as the irreversible degeneration of the sciatic nerve, which was considered related to the adopted administration route. Synchronously, a biodistribution study in mice was performed to examine whether HSV-1/hPD-1 could spread to the injection site, gonads, liver, lung, heart, mesenteric and inguinal lymph nodes, skin, dorsal root ganglia, and blood, and then be gradually eliminated. Thus, two safety dose levels-the maximum tolerance dose of 4.0 × 107 pfu/mouse and the no-observed-adverse-effect-level dose of 1.0 × 107 pfu/mouse-were determined to help design patients' dose regimens. Our research data have been successfully accepted for investigational new drug (IND) application in China.

Exponential synchronization of neural networks with time-varying delays and stochastic impulses.

This paper concentrates on the exponential synchronization problem of the delayed neural networks (DNNs) with stochastic impulses. First, the impulsive Halanay differential inequality is further extended to the case that the impulsive strengths are random variables. Then, based on the generalized inequalities, synchronization criteria are respectively proposed for DNNs with two kinds of stochastic impulses, i.e., impulses with independent property/Markovian property. It should be pointed out that only some basic statistical characteristics are needed to verify the proposed criteria. Numerical examples are provided to show the validation of the obtained theoretical results at the end of this paper.

Efficient and Low-Cost Error Removal in DNA Synthesis by a High-Durability MutS.

Enzyme-based error correction is a key step in de novo DNA synthesis, yet the inherent instability of error-correction enzymes such as MutS has hindered the throughput and efficiency of DNA synthesis workflows. Here we introduce a process called Improved MICC (iMICC), in which all error-correction steps of oligos and fragments within a complete gene-synthesis cycle are completed in a simple, efficient, and low-cost manner via a MutS protein engineered for high durability. By establishing a disulfide bond of L157C-G233C, full-activity shelf life of E. coli MutS (eMutS) was prolonged from 7 to 49 days and was further extended to 63 days via cellulose-bound 4 °C storage. In synthesis of 10 Cas9 homologues in-solution and 10 xylose reductase (XR) homologues on-chip, iMICC reduced error frequency to 0.64/Kb and 0.41/Kb, respectively, with 72.1% and 86.4% of assembled fragments being error-free. By elevating base accuracy by 37.6-fold while avoiding repetitive preparation of fresh enzymes, iMICC is more efficient and robust than the wild-type eMutS, and it is 6.6-fold more accurate and 26.7-fold cheaper than CorrectASE. These advantages promise its broad applications in industrial DNA synthesis.

The prevalence of colistin resistance in Escherichia coli and Klebsiella pneumoniae isolated from food animals in China: coexistence of mcr-1 and blaNDM with low fitness cost.

Increasing colistin resistance is a global concern because colistin is used as a last resort for the treatment of carbapenem-resistant Enterobacteriaceae infections. The plasmid-mediated colistin resistance gene, mcr-1 was found in distinct bacterial species isolated from humans, animals, and the environment. In this study, farms in four different agricultural provinces in China were investigated to determine the occurrence of the antimicrobial resistance and related genes. A total of 373 Escherichia coli and 54 Klebsiella pneumoniae were isolated from 510 non-duplicated samples. Of the E. coli and K. pneumoniae isolates, 72.7% and 66.7%, respectively, were susceptible to colistin. Isolates resistant to colistin comprised 46.6% of the samples isolated from Shandong, and 17.8% and 16.4% of the samples from Jilin and Henan, respectively. Twenty-six carbapenem-resistant E. coli isolates were resistant to colistin, in which both mcr-1 and blaNDM were present. Specifically, the co-existence was found in isolates from animals and sewage. Most of the resistance genes were located on plasmids and were 40-244 kilobases. Growth curves of transconjugants carrying mcr-1, blaNDM-1, blaNDM-4, blaNDM-5, and blaNDM-9 showed a low fitness cost compared with the recipient. In conclusion, mcr-1 was widespread in E. coli and K. pneumoniae isolated from farms in China. Co-existence of mcr-1 and blaNDM-9 was identified in different sequence types of E. coli with low fitness cost from various origins, indicating an urgent need to take measures for decreasing dissemination.