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The question of whether long-term chronic exposure to microplastics (MPs) could induce dose- and size-dependent adverse effects in mammals remains controversial and poorly understood. Our study explored potential health risks from dietary exposure to environmentally relevant doses of polystyrene (PS) MPs, through a mouse model and integrated analyses of the interruptions of fecal microbial metagenomes and plasma lipidomes. After 21 weeks of exposure to the MPs (40-100 μm), mice mainly exhibited gut microbiota dysbiosis, tissue inflammation, and plasma lipid metabolism disorder, although no notable accumulation of MPs was observed in the gut or liver. The change of the relative abundance of microbiota was strongly associated with the exposure dose and size of MPs while less significant effects were observed in gut damage and abnormal lipid metabolism. Moreover, multiomics data suggested that the host abnormal lipid metabolism was closely related to bowel function disruptions, including gut microbiota dysbiosis, increased gut permeability, and inflammation induced by MPs. We revealed for the first time that even without notable accumulation in mouse tissues, long-term exposure to MPs at environmentally relevant doses could still induce widespread health risks. This raises concern on the health risks from the exposure of humans and other mammals to environmentally relevant dose MPs.

Artesunate (ART) has been indicated as a candidate drug for hepatocellular carcinoma (HCC). Glucosylceramidase (GBA) is required for autophagic degradation. Whether ART regulates autophagic flux by targeting GBA in HCC remains to be defined. Herein, our data demonstrated that the dramatic overexpression of GBA was significantly associated with aggressive progression and short overall survival times in HCC. Subsequent experiments revealed an association between autophagic activity and GBA expression in clinical HCC samples, tumor tissues from a rat model of inflammation-induced HCC and an orthotopic mouse model, and human HCC cell lines. Interestingly, probe labeling identified GBA as an ART target, which was further verified by both a glutathione-S-transferase pulldown assay and surface plasmon resonance analysis. The elevated protein expression of LC3B, the increased numbers of GFP-LC3B puncta and double-membrane vacuoles, and the enhanced expression of SQSTM1/p62 indicated that the degradation of autophagosomes in HCC cells was inhibited by ART treatment. Both the in vitro and in vivo data revealed that autophagosome accumulation through targeting of GBA was responsible for the anti-HCC effects of ART. In summary, this preclinical study identified GBA as one of the direct targets of ART, which may have promising potential to inhibit lysosomal autophagy for HCC therapy.

Sanitary landfills and uncontrolled dumpsites are plastic wastes (PWs) reservoirs containing ∼60% of all the plastics ever made, amounting to 5,000 × 106 tons as of 2017. The distribution, long-term behavior, and release of macro- and microplastics (MPs) from disposal sites are critical to global plastics pollution, but are poorly understood and lack systematic assessments. We review comprehensively the available knowledge in the three aspects herein. The spatial and temporal distribution of PW in 616 municipal solid waste (MSW) samples retrieved from 275 disposal sites in 56 countries are summarized. The weight percentages of PW (%PW) generally decrease with increasing year of disposal and disposal depth. Other influential factors are disposal duration and country income level. The %PW values in different disposal sites show high regionality and spatial variability and heterogeneity. Disposal sites mostly have harsh temperature and stress, reactive liquids, and microbial activities, which are conducive to long-term processes of PW and MPs. The major processes are chemical degradation, dissolution, leaching and adsorption, biological degradation, mechanical wearing, pneumatic and hydrological transport and deposition, and conglomeration. PW leaves disposal sites via recycling, scavenging, mining, wind and surface runoff, coastal erosion and flooding, and slope failure. The release and removal pathways of PW from disposal sites have been recognized only qualitatively. In addition, the sources, presences, and secondary generation of MPs in disposal sites have been studied occasionally, whereas the transport and fate of MPs within and from disposal sites remain largely unstudied. Economic Development Board (EDB) Nanyang Technological University The authors would like to acknowledge Nanyang Technological University (NTU, Singapore), Nanyang Environment and Water Research Institute (Singapore), and Economic Development Board (Singapore) for the financial support and scholarships of this research. Xunchang Fei thanks the supports from Debris of the Anthropocene to Resources (DotA2) Lab at NTU. Jun Ma was supported by the China Scholarship Council (Grant No. 201904910309).

Since the phase-out of traditional halogenated flame retardants (HFRs), interests of research are gradually being shifted to organophosphate flame retardants (OPFRs), and this can be reflected by the increasing number of publications on OPFRs year by year. Here, an extensive survey is conducted in an attempt to generate a list of OPFRs that are being produced in factories, and to investigate the annual production volume (APV). This survey suggests that at least n = 56 OPFR monomers and n = 62 OPFR mixtures are being currently produced in 367 factories around the world, and 201 out of them are in Mainland China. APV of OPFRs was estimated as 598,422 metric tons, and this number could be underestimated due to the limitation of available information. We also notice that current researches are confined to a limited number of OPFRs, especially for OP esters (OPEs), and other OPFRs with different structures from OPEs has been rarely studied. Based on all the collected datasets, we provide five recommendations for how to proceed with future research to more comprehensively understand the currently-produced OPFRs in the environment. This research was supported by the National Natural Science Foundation of China (Grant 21976088), and the Fundamental Research Funds for the Central Universities (Grant No. 30919011101).

In this paper, we study the unicity of meromorphic functions concerning differences and small functions and mainly prove two results: 1. Let f f be a transcendental entire function of finite order with a Borel exceptional entire small function a ( z ) a\left(z) , and let η \eta be a constant such that Δ η 2 f ≢ 0 {\Delta }_{\eta }^{2}\hspace{0.25em}f\not\equiv 0 . If Δ η 2 f {\Delta }_{\eta }^{2}\hspace{0.25em}f and Δ η f {\Delta }_{\eta }\hspace{0.25em}f share Δ η a {\Delta }_{\eta }a CM, then a ( z ) a\left(z) is a constant a a and f ( z ) = a + B e A z f\left(z)=a+B{e}^{Az} , where A , B A,B are two nonzero constants; 2. Let f f be a transcendental meromorphic function with ρ 2 ( f ) < 1 {\rho }_{2}(f)\lt 1 , let a 1 {a}_{1} , a 2 {a}_{2} be two distinct small functions of f f , let L ( z , f ) L\left(z,f) be a linear difference polynomial, and let a 1 ≢ L ( z , a 2 ) {a}_{1}\not\equiv L\left(z,{a}_{2}) . If δ ( a 2 , f ) > 0 \delta \left({a}_{2},f)\gt 0 , and f f and L ( z , f ) L\left(z,f) share a 1 {a}_{1} and ∞ \infty CM, then L ( z , f ) − a 1 f − a 1 = c , \frac{L\left(z,f)-{a}_{1}}{f-{a}_{1}}=c, for some constant c ≠ 0 c\ne 0 . The results improve some results following C. X. Chen and R. R. Zhang [Uniqueness theorems related difference operators of entire functions, Chinese Ann. Math. Ser. A 42 (2021), no. 1, 11–22] and R. R. Zhang, C. X. Chen, and Z. B. Huang [Uniqueness on linear difference polynomials of meromorphic functions, AIMS Math. 6 (2021), no. 4, 3874–3888].

In this paper, we study a uniqueness question of meromorphic functions concerning fixed points and mainly prove the following theorem: Let $ f $ and $ g $ be two nonconstant meromorphic functions, let $ n, k $ be two positive integers with $ n > 3k+10.5-\Theta_{\min}(k+6.5) $, if $ \Theta_{\min}\geq \frac{2.5}{k+6.5} $, otherwise $ n > 3k+8 $, and let $ (f^{n})^{(k)} $ and $ (g^{n})^{(k)} $ share $ z $ CM, $ f $ and $ g $ share $ \infty $ IM, then one of the following two cases holds: If $ k = 1 $, then either $ f(z) = c_{1}e^{cz^{2}} $, $ g(z) = c_{2}e^{-cz^{2}} $, where $ c_{1}, c_{2} $ and $ c $ are three constants satisfying $ 4n^{2}(c_{1}c_{2})^{n}c^{2} = -1 $, or $ f = tg $ for a constant $ t $ such that $ t^{n} = 1 $; if $ k\geq2 $, then $ f = tg $ for a constant $ t $ such that $ t^{n} = 1 $. Our results extend and improve some results due to [8,9,19,24].

Humans and wildlife are exposed to complex environmental mixtures. Identifying causal toxic pollutants in environmental samples remains challenging because of the high complexity of sample mixtures and the unknown nature of the potential toxicants. In the field of environmental chemistry and toxicology, this pursuit of causal toxicants leads us to the method of effect-directed analysis (EDA), an integrated method comprised of three iterative modules: (1) bioassays to guide component prioritization; (2) fractionation to reduce the mixture complexity; and (3) chemical analysis to identify the toxicants. In this commentary review, we try to provide a concise guideline for EDA beginners by summarizing good practices from successful EDA studies, categorized by sample-toxicity pair selection, efficient separation, and chemical analysis. We also discussed the practical challenges faced with current EDA practices. Based on these above, we try to provide suggestions and perspectives for future EDA studies. Specifically, we discussed the potential of applying EDA on human biological examples to identify the environmental causes of human diseases. We proposed future collaboration between environmental chemists and toxicologists, environmental health scientists, epidemiologists, physicians, and social scientists.

In this article, we study some results on the value distribution of differential polynomials and mainly prove the following theorem: suppose that P P is a polynomial with deg P ≥ 3 {\rm{\deg }}\hspace{0.33em}P\ge 3 and f f is a transcendental meromorphic function. Let α \alpha be a small function of f f . If α \alpha is a constant, we also require that there exists a constant A ≠ α A\ne \alpha such that P ( z ) − A P\left(z)-A has a zero of multiplicity at least 3. Then, for any 0 < ε < 1 0\lt \varepsilon \lt 1 , we have T ( r , f ) ≤ k N ¯ r , 1 P ( f ) − α + S ( r , f ) , T\left(r,f)\le k\overline{N}\left(r,\frac{1}{P(f)-\alpha }\right)+S\left(r,f), where if P ′ ( z ) P^{\prime} \left(z) has only one zero, then k = 1 deg P − 2 k=\frac{1}{{\rm{\deg }}\hspace{0.33em}P-2} ; if P ′ ( z ) P^{\prime} \left(z) has two distinct zeros a a and b b with P ( a ) ≠ P ( b ) P\left(a)\ne P\left(b) and α \alpha is nonconstant, then k = 1 1 − ε k=\frac{1}{1-\varepsilon } ; otherwise k = 1 k=1 .

Exposome has become the hotspot of next-generation health studies. To date, there is no available effective platform to standardize the analysis of exposomic data. In this study, we aim to propose one new framework of exposomic analysis and build up one novel integrated platform “ExposomeX” to expediate the discovery of the “Exposure-Biology-Disease” nexus. We have developed 13 standardized modules to accomplish six major functions including statistical learning (E-STAT), exposome database search (E-DB), mass spectrometry data processing (E-MS), meta-analysis (E-META), biological link via pathway integration and protein-protein interaction (E-BIO) and data visualization (E-VIZ). Using ExposomeX, we can effectively analyze the multiple-dimensional exposomics data and investigate the “Exposure-Biology-Disease” nexus by exploring mediation and interaction effects, understanding statistical and biological mechanisms, strengthening prediction performance, and automatically conducting meta-analysis based on well-established literature databases. The performance of ExposomeX has been well validated by re-analyzing two previous multi-omics studies. Additionally, ExposomeX can efficiently help discover new associations, as well as relevant in-depth biological pathways via protein-protein interaction and gene ontology network analysis. In sum, we have proposed a novel framework for standardized exposomic analysis, which can be accessed using both R and online interactive platform (http://www.exposomex.cn/).

Although the risks of microplastics in environmental exposure and human health are being increasingly studied, little is known about the behavior of “eco-friendly” bioplastics in humans, especially their effects on our gastrointestinal tract. Here we demonstrate that enzymatic hydrolysis of bio-based polylactic acid (PLA) microplastics rapidly generates an excess of nanoplastic particles by competing for triglyceride-degrading lipase during gastrointestinal processes. These tiny nanoparticles are oligomers formed by hydrophobic-driven self-aggregation, and upon exposure the oligomers and their associated nanoparticles can bioaccumulate in in vitro and several in vivo organs, including the liver, intestine, and even in the brain. Severe intestinal damage and inflammation are also observed, the toxic effect of which is mostly pronounced from hydrolyzed oligomer products. Furthermore, the oligomers’ potential protein target screening using large scale pharmacophore model reveals that oligomers can interact with matrix metallopeptidase 12 protein (MMP12), which is further validated using protein binding assay. A close mechanistic study reveals high binding affinity of oligomers to the catalytic zinc ion finger domain, leading to MMP12 inactivation and mediating the adverse bowel inflammatory effect following PLA oligomer exposure. Since biodegradable plastics are highly proposed as one solution for the global plastic problem, understanding the gastrointestinal fate and toxicity of bioplastics, will provide ground-breaking data on bioplastics as a substantial risk to human health.

Tandem mass spectral (MS/MS) data in liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis are often contaminated as the selection of precursor ions is based on a low-resolution quadrupole mass filter. In this work, we developed a strategy to differentiate contamination fragment ions (CFIs) from true fragment ions (TFIs) in an MS/MS spectrum. The rationale is that TFIs should coelute with their parent ions, but CFIs should not. To assess coelution, we performed a parallel LC-MS/MS analysis in data-independent acquisition (DIA) with all-ion-fragmentation (AIF) mode. Using the DIA (AIF) data, peak-peak correlation (PPC) score is calculated between the extracted ion chromatogram (EIC) of the fragment ion using the MS/MS scans and the EIC of the precursor ion using the MS1 scans. A high PPC score is an indication of TFIs, and a low PPC score is an indication of CFIs. Tested using metabolomics data generated by high resolution QTOF and Orbitrap MS from various vendors in different LC-MS configurations, we found that more than 70% of the fragment ions have PPC scores < 0.8 and identified three common sources of CFIs, including (1) solvent contamination, (2) adjacent chemical contamination, and (3) undetermined signals from artifacts and noise. Combining PPC scores with other precursor and fragment ion information, we further developed a machine learning model that can robustly and conservatively predict CFIs. Incorporating the machine learning model, we created an R program, MS2Purifier, to automatically recognize CFIs and clean MS/MS spectra of metabolic features in LC-MS/MS data with high sensitivity and specificity.

We used online secondary electrospray ionization mass spectrometry to measure venlafaxine (VEN), a nonvolatile drug, in the exhaled air of mice intraperitoneally treated with VEN. The breath pharmacokinetic (PK) profile of VEN was recorded, which was in good agreement with that of the blood. Combined with online collection of exhaled breath particles (EBPs), it was shown that VEN existed as part of EBPs rather than gas molecules in the breath. Linear free-energy relationship analysis confirmed that almost completely ionized VEN at physiological conditions unlikely partition from the lung lining fluid (LLF) into breath air. This implies that the occurrence of VEN in exhaled air accompanies the formation of EBPs from the LLF. By comparison with the low breath signals of VEN metabolites, passive membrane permeability and lung/blood partition coefficient are suggested as the main influencing factors for the levels of drugs in the breath. This study advances our knowledge on the mechanism by which nonvolatile drugs are transferred from blood into exhaled breath, providing guidance for breath test-based therapeutic drug monitoring.

The identification of target proteins for small molecules is of great importance in drug discovery and for understanding the cellular mode of action (MOA) of toxicants. Herein, a "bottom-up" oriented target finding strategy is proposed based on the principle that the targeted enzymes can be inferred according to their phenotypic changes at the metabolome level. Meanwhile, computer-assisted in silico molecular docking analysis was performed to evaluate the binding affinities between the chemicals and the target enzymes to further rank the possible targets. In this study, triphenyl phosphate (TPhP) was used as an example to illustrate the workflow. After a comprehensive metabolome and lipidome analysis, 51 related metabolic enzymes were selected for ranking binding energies, wherein 25 proteins exhibited a higher affinity for TPhP than for their endogenous substrates. Two proteins, hydroxyacyl-coenzyme A dehydrogenase (HADH) and 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10), were further confirmed by surface phasma resonance (SPR) and isothermal titration calorimetry (ITC) analysis, displayed Kd values at low micromolar levels for TPhP. Overall, the proposed strategy has provided a feasible means for discovering enzymatic targets for the large-scale small-molecule sets, with the advantages of closely associating with the phenotype change, reducing the cost of groping, and improving the accuracy of target prediction.

In this paper, we study the unicity of entire functions concerning their shifts and derivatives and prove: Let f be a non-constant entire function of hyper-order less than 1, let c be a non-zero finite value, and let a, b be two distinct finite values. If $$f'(z)$$ and $$f(z+c)$$ share a, b IM, then $$f'(z)\equiv f(z+c)$$ . This improves some results due to Qi and Yang (Comput Methods Funct Theory 20:159–178, 2020).

The objective of this study was to evaluate the effect of sample presentation (tissue type) and maturity (ripe and unripe) on the classification of banana (Musa Cavendish) samples sourced from two different geographical regions and analysed using mid infrared (MIR) spectroscopy. The coefficient of determination (R2) and the standard error of cross‐validation (SECV) obtained using partial least squares discriminant analysis were 0.83 (0.33), 0.75 (0.25) and 0.94 (0.19) for the prediction of maturity, geographical origin and tissue type, respectively. No effect of either of type of tissue (e.g. pulp or peel) or maturity was observed. The results of this study demonstrated that MIR spectroscopy might be used to classify the origin of the banana samples at different degrees of ripeness. However, one of the limitations of this study is on the number of samples analysed and further validation must be recommended using samples from other sources, regions and harvest seasons.

In this paper, we study the unicity of entire functions and their derivatives and obtain the following result: letffbe a non-constant entire function, leta1{a}_{1},a2{a}_{2},b1{b}_{1}, andb2{b}_{2}be four small functions offfsuch thata1≢b1{a}_{1}\not\equiv {b}_{1},a2≢b2{a}_{2}\not\equiv {b}_{2}, and none of them is identically equal to∞\infty. Ifffandf(k){f}^{\left(k)}share(a1,a2)\left({a}_{1},{a}_{2})CM and share(b1,b2)\left({b}_{1},{b}_{2})IM, then(a2−b2)f−(a1−b1)f(k)≡a2b1−a1b2\left({a}_{2}-{b}_{2})f-\left({a}_{1}-{b}_{1}){f}^{\left(k)}\equiv {a}_{2}{b}_{1}-{a}_{1}{b}_{2}. This extends the result due to Li and Yang [Value sharing of an entire function and its derivatives, J. Math. Soc. Japan.51(1999), no. 7, 781–799].

Printers are everyday devices in both our homes and workplaces. We have previously found high occupational exposure levels to toner-based printer emitted nanoparticles (PEPs) at printing centers. To elucidate the potential health effects from exposure to PEPs, a total of 124 human serum samples were collected from 32 workers in the printing centers during the repeated follow-up measurements, and global serum metabolomics were analyzed in three ways: correlation between metabolic response and personal exposure (dose response exposure); metabolite response changes between Monday and Friday of a work week (short-term exposure), and metabolite response in relation to length of service in a center (long-term exposure). A total of 52 key metabolites changed significantly in relation to nanoparticle exposure levels. The primary dysregulated pathways included inflammation and immunity related arginine and tryptophan metabolism. Besides, some distinct metabolite expression patterns were found to occur during the transition from short-term to long-term exposures, suggesting cumulative effect of PEPs exposure. These findings, for the first time, highlight the inhalation exposure responses to printer emitted nanoparticles at the metabolite level, potentially serving as pre-requisites for whole organism and population responses, and are inline with emerging findings on potential health effects. Nanyang Technological University Submitted/Accepted version This study was supported by Nanyang Technological University – Harvard School of Public Health Initiative for Sustainable Nanotechnology (NTU-Harvard SusNano; Ref. No. NTU-HSPH 17001). This work was also funded by the Engineered Nanomaterials Resource and Coordination Core established at Harvard T. H. Chan School of Public Health (NIH grant # U24ES026946) as part of the Nanotechnology Health Implications Research (NHIR) Consortium.

In this article, two results concerning the periodic points and normality of meromorphic functions are obtained: (i) the exact lower bound for the numbers of periodic points of rational functions with multiple fixed points and zeros is proven by letting R(z) be a non-polynomial rational function, and if all zeros and poles of R(z) − z are multiple, then Rk(z) has at least k + 1 fixed points in the complex plane for each integer k ≥ 2; (ii) a complete solution to the problem of normality of meromorphic functions with periodic points is given by letting ℱ be a family of meromorphic functions in a domain D, and letting k ≥ 2 be a positive integer. If, for each f ∈ ℱ, all zeros and poles of f(z) − z are multiple, and its iteration fk has at most k distinct fixed points in D, then ℱ is normal in D. Examples show that all of the conditions are the best possible.

Humans are exposed to many xenobiotics simultaneously, but little is known about the toxic effects based on chemical-chemical interactions. This study aims at evaluating the binary interactions between 13 common environmental organic compounds (resulting in 78 pairs) by observing their cytotoxicity on HepG2 cells. Among all of the tested pairs, the combination of flame-retardant triphenyl phosphate (TPP) and tris(1,3-dichloro-2-propyl)phosphate (TDCPP) exhibited one of the most significant synergistic effects. We further characterized the transcriptome and metabolome after combined exposure to TPP and TDCPP and individual exposure. The results suggested that the coexposure caused many more changes in gene expressions and cellular activities. The transcriptome data showed that the coexposure triggered significant pathway changes including "cholesterol biosynthesis" and "ATF6-Alpha activated chaperone genes", together with distinct gene ontology (GO) terms such as the "negative regulation of the ERK1 and ERK2 cascade". Additionally, coexposure enhanced the biological activity of liver X receptors and nuclear factor erythroid 2-related factor 2 (Nrf2). The metabolome data showed that coexposure significantly elevated oxidative stress and affected the purine and pyrimidine metabolism. Overall, this study showed that interactions, which may enhance or suppress the biological processes, are common among environmental chemicals, although their environmental relevance should be studied in the future.

Naturally occurring hydrazones are rare despite the ubiquitous usage of synthetic hydrazones in the preparation of organic compounds and functional materials. In this study, we discovered a family of novel microbial metabolites (tasikamides) that share a unique cyclic pentapeptide scaffold. Surprisingly, tasikamides A-C (

A set of highly branched imidazolium-functionalized poly(arylene ether sulfone)s copolymer bearing with flexible alkyl side chains of different lengths are designed and synthesized. The ion exchange capacity (IEC), ionic conductivity, water uptake, thermal stability, mechanical property and alkaline resistance of the anion exchange membranes (AEMs) were evaluated in detail. Atomic force microscopy and small-angle X-ray scattering are used to study morphology which reveals that the branched membrane with an alkyl side chain (6 carbons) achieves the highest conductivity (up to 115.8 mS cm−1 at 80 °C) due to the well-developed hydrophilic/hydrophobic phase separation. In addition, the branched co-polymer AEM with a longer alkyl side chain (12 carbons) exhibit the best robust alkaline stability, it decreases only 27% of ionic conductivity after 550 h in 1 M KOH. Therefore, this study provides a comprehensive insight into the tuneable membrane properties of highly branched copolymers as a change in the length of flexible alkyl side chains.

Bisphenol analogues (BPs) are widely used in plastics, food packaging and other commercial products as non safer alternative of BPA. As emerging environmental contaminants, BPs have received considerable attention for their adverse effects on human health. However, their effects on liver metabolisms are only marginally understood. In this study, high-resolution mass spectrometry-based global metabolomics and extracellular flux (XF) analysis were applied to characterize the cellular metabolome alterations and reveal the possible mechanisms of the metabolic disorders associated with BPs-induced toxicity in HepG2 cells. BPE, BPB and BPAP with similar chemical structures were selected to compare their interference with different metabolic pathways. A total of 61 key metabolite profiles were significantly altered after exposure to the three BPs. Overall, BPs altered metabolites which are associated with energy metabolism, oxidative stress, cell proliferation and nucleotides synthesis. The primary dysregulated pathways included energy and nucleotides synthesis related Purine and Glycolysis/Gluconeogenesis metabolism. In addition, attenuated mitochondrial function and enhanced glycolysis were found under BPB and BPAP treatment. While attenuated glycolysis was observed under BPE treatment. These findings may provide potential biomarkers indicating the cytotoxicity of BPs and prompt a deeper understanding of the intramolecular metabolic processes induced by BPs exposure. Economic Development Board (EDB) This work is funded by the Economic Development Board - Singapore (S16-1309-NRF-Water-RCFS).

Objective — To investigate the effects of angiotensin 1-7 (Ang1-7) on plasma membrane ATPase isoform 1 (PMCA1) in salt-sensitive hypertensive rats. Methods — Thirty newborn male Wistar rats were selected to establish the salt-sensitive hypertensive rat model with sensory nerve injury, which were then randomly divided into 5 groups (n=5), including model group, Telmisartan group, Ramipril group, Ang1-7 group, and A-779 group. Another normal control group was established (n=5). After 4 weeks of intervention, the tail blood pressure of rats in each group was measured, and then the apical tissue of left ventricle was cut. The contents of AngⅡ and Ang1-7 in cardiomyocytes were detected by enzyme-linked immunosorbent assay. The expression of PMCA1 mRNA and protein in heart of salt-sensitive hypertensive rats were detected by RT-PCR and immunohistochemistry. Results — (1) Compared with the normal control group, the concentration of AngⅡ in the myocardium of salt-sensitive hypertensive rats increased (P < 0.05), which decreased after the intervention of Telmisartan and Ramipril (P < 0.05), and no change occurred after the intervention of Ang1-7 in concentration (P＞0.05). (2) Compared with the normal control group, the concentration of myocardial Ang1-7 in salt-sensitive hypertensive rats decreased (P < 0.05), and increased after the intervention of telmisartan and ramipril (P < 0.05), and increased after the intervention of A-779 (P < 0.05). (3) The expression of PMCA1 mRNA and protein in salt-sensitive hypertensive rats was increased compared with the normal control group (P < 0.05), and the expression of Ang-(1-7), telmisartan and ramipril was decreased compared with the model group (P < 0.05). The expression of p38MAPK mRNA and p-p38MAPK protein in the myocardium of salt-sensitive hypertensive rats was increased compared with that in the normal control group (P < 0.05), and the expression of Ang-(1-7), Telmisartan and Ramipril was decreased compared with that in the model group (P < 0.05). Conclusion — Ang-(1-7) may be involved in the regulation of cardiac calcium pump, inhibiting its overcompensation and delaying the occurrence of calcium pump inhibition in the early stage of salt-sensitive hypertension. Ang-(1-7) can inhibit the activity of p38MAPK and protect the heart, and its regulation on PMCA1 may be mediated by the expression of p38MAPK pathway.

Carbon capture has become an important technology to mitigate ever-increasing CO2 emissions worldwide, and alkali waste is a potential source of CO2 capture material. Slagging-gasification is a novel technology for treating municipal solid waste (MSW), and the gasification fly ash (GFA) is the only solid residue that is not reused at present due to its high heavy metal content. GFA contains high amounts of Ca(OH)2 and Ca(OH)Cl, making it protentional for CO2 capture. In this study, GFA and washed gasification fly ash (WGFA) were treated with CO2 for different treatment periods. Weight changes of samples were recorded to evaluate the efficiency of CO2 capture. To assess the properties of treated GFA, pH value, leached heavy metal concentration, mineral composition, and microscopic morphology were studied. The results revealed that GFA and WGFA could adsorb 18.8% and 23.7% CO2 of their weights, respectively. Carbonation could immobilize heavy metals including Pb, Zn, and Cu when a proper treatment period was applied. An excessive treatment period decreased the efficiency of heavy metal immobilization. Pre-washing is recommended as a pre-treatment method for GFA carbonation, which increased the efficiency to adsorb CO2, improved the pH of carbonated GFA, and enhanced the effect to immobilize heavy metals. Ministry of Education (MOE) This research is supported by the Ministry of Education, Singapore, under its Academic Research Fund Tier 1 grant (RG139/20).

Secondary electrospray ionization coupled with high resolution mass spectrometry (SESI-HRMS) is a direct mass spectrometry technique, which can identify trace volatile organic compounds (VOCs) in real time without sample pretreatment and chromatographic separation. SESI-HRMS has been successfully applied in multiple applications, including breath analysis, animals and plants VOCs emissions, analysis of headspace of cell cultures and indoor and outdoor air. The range of areas where the technique can potentially have a substantial impact is very broad. However, one critical aspect that requires further development to consolidate the technique is absolute quantification. Therefore, in this study we aim to develop a quantitative method for eight representative VOCs, including ketones (acetone, 2-butanone and 2-pentanone), alkenes (isoprene and α-terpinene) and aromatics (toluene, styrene and mesitylene). The mass spectrometric platform includes a commercial SESI source hyphenated with a Q-Exactive hybrid quadrupole Orbitrap high resolution mass spectrometer. Within the concentration range of 0–100 ppbv studied, the optimal coefficient of determination for linear regression (R2 = 0.993–0.999) between signal intensity and concentration is obtained in the range of 0–10 ppbv for all eight VOCs. The detection limits range between 3 (2-Pentanone) and 15 (Acetone) pptv. The intra-day (n = 10) and inter-day (n = 30) coefficients of variation (CV) are ≤ 6% and ≤10%, respectively. Finally the method is applied for the fast evaluation (

We are constantly exposed to a variety of environmental contaminants and hormones, including those mimicking endogenous estrogens. These highly heterogeneous molecules are collectively referred to as xenoestrogens and hold the potential to affect and alter the delicate hormonal balance of the human body. To monitor exposure and investigate potential health implications, comprehensive analytical methods covering all major xenoestrogen classes are needed but not available to date. Herein, we describe a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of multiple classes of endogenous as well as exogenous estrogens in human urine, serum, and breast milk to enable proper exposure and risk assessment. In total, 75 analytes were included, whereof a majority was successfully in-house validated in the three matrices. Extraction recoveries of validated analytes ranged from 71% to 110% and limits of quantification from 0.015 to 5 μg/L, 0.03 to 14 μg/L, and 0.03 to 4.6 μg/L in urine, serum, and breast milk, respectively. The applicability of the novel method was demonstrated in proof-of-principle experiments by analyzing urine from Austrian individuals and breast milk from Austrian and Nigerian individuals. Thereby, we proved the methods' feasibility to identify and quantify different classes of xenoestrogens simultaneously. The results illustrate the general importance of multiclass exposure assessment in the context of the exposome paradigm. Specifically, they highlight the need for estimating total estrogenic burden rather than single analyte or chemical class measurements and its potential impact in endocrine disruption and hormone related diseases including cancers.

Infants and children under 6 years old spend most of daily time in Child Care Centers (CCCs), especially in the tropical regions like Singapore. Environmental exposure and associated risk during this early critical developmental stage is of great public concern. In this study, seven representative volatile organic compounds (VOCs) and five typical phthalates were analyzed in the indoor and outdoor air samples collected from 32 Singapore CCCs. The median of total VOC and phthalate concentration in indoor air was 19.03 and 5.41 μg m-3; respectively. For both indoors and outdoors environment, benzene, toluene and xylene were the dominant VOC contributors (more than 68%). For indoor air phthalates, di(2-ethylhexyl) phthalate and di-butyl phthalate (DBP) accounts for 60-76%. The level of both VOCs and phthalates in indoor environment was significantly higher than that in outdoor, with an average indoor/outdoor ratio of 1.24 and 1.45; respectively. A strong correlation (r > 0.50, p < 0.05) was observed between indoor and outdoor air compounds. VOC and phthalate levels have no significant difference between CCCs with split-unit and centrally ventilated air conditioners. Monte Carlo simulation was used to estimate exposure uncertainty and variability for the risk assessment. Overall, the concentrations of VOC were below the healthy reference values from either EPA Integrated Risk Information System (IRIS) or Singapore guideline. However, similar to other countries' report, benzene, DBP, ethylbenzene and naphthalene were at levels that could exceed the stringent standards such as Office of Environmental Health Hazard Assessment (OEHHA) cancer and reproductive health-based benchmarks. National Environmental Agency (NEA) This work was funded by Singapore National Environment Agency Fund (M4061617) “Assessing the Public Health Risks and Enhancing the Health of Singapore's Built Environment”.

Bohai Bay, in the western region of northeastern China's Bohai Sea, receives water from large rivers containing various pollutants including dioxin-like compounds (DLCs). This study used the established zebrafish (Danio rerio) model, its known developmental toxicity endpoints and sensitive molecular analyses to evaluate sediments near and around an industrial effluent site in Bohai Bay. The primary objective was to assess the efficacy of rapid biological detection methods as an addition to chemical analyses. Embryos were exposed to various concentrations of sediment extracts as well as a 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) positive control. Exposure to sediment extract nearest the discharge site (P1) resulted in the most severe- and highest rates of change in embryos and larvae, suggesting that DLC contaminated sediment probably did not occur much beyond it. P1 extract resulted in concentration dependent increases in mortality and pericardial edema. Its highest concentration caused up-regulation of P-450 (CYP)-1A1(CYP1A) mRNA expression at 72 h post fertilization (hpf), an increase in its expression in gill arches as observed by whole mount in situ hybridization, and an increased signal in the Tg(cyp1a: mCherry) transgenic line. The pattern and magnitude of response was very similar to that of TCDD and supported the presence of DLCs in these sediment samples. Follow-up chemical analysis confirmed this presence and identified H7CDF, O8CDF and O8CDD as the main components in P1 extract. This study validates the use of biological assays as a rapid, sensitive, and cost-effective method to evaluate DLCs and their effects in sediment samples. Additionally, it provides support for the conclusion that DLCs have limited remobilization capacity in marine sediments. This work was funded by the National Natural Science Foundation of China (21267015, 21567019, 81360508, 41807352, 41877366, 641722110 and 41571474), Inner Mongolia University for Nationalities, China (MDXK008), and the Open Project Program of Inner Mongolia Key Laboratory of Toxicant Monitoring and Toxicology, China (MDK2017012, MDK2017014 and MDK2018027). The authors are grateful for the supports from the Three Hundred Leading Talents in Scientific and Technological Innovation Program of Chongqing, China (No. CSTCCXLJRC201714 to D.S.P.).

Let f be a nonconstant meromorphic function, c ∊ ℂ, and let a(z)(≢ 0) ∊ S(f) be a meromorphic function. If f(z) and P(z, f(z)) share the sets {a(z), −a(z)}, {0} CM almost and share {∞} IM almost, where P(z, f(z)) is defined as (1.1), then f(z) ≡ ±P(z, f(z)) or f(z)P(z, f(z)) ≡ ±a2(z). This extends the results due to Chen and Chen (2013), Liu (2009) and Yi (1987).

Bisphenol A diglycidy ether (BADGE) and its derivatives are epoxy resins and widely used as emerging plasticizers in food packages and material coating. Though known as endocrine disruptors, little information is available on their occurrence, exposure routes and toxicity. Besides, the analysis of BADGE and its derivatives has always been a challenge due to their reactive chemical properties and the background contamination. Therefore, we firstly developed a novel water-free method to analyze BADGE and its derivatives in dust samples together with other two typical plasticizers bisphenol A (BPA) and bisphenol S (BPS). In order to investigate the levels in paired dust and urine samples, 33 paired samples were collected from Singapore. In both dust and urine samples, the predominant compounds were BPA, BADGE-2H2O and BPS. A significantly positive correlation of BPA levels in paired dust and urine samples was observed in this small-scale study. To tentatively explore the human health effect from exposure to these bisphenol plasticizers, we assessed the correlation between the urinary concentrations of these compounds and oxo-2’-deoxyguanosine (8-OHdG), an oxidative stress biomarker. The result showed that 8-OHdG levels in urine samples was positively correlated with urinary BPA level and body mass index (BMI), suggesting that elevated oxidative stress might be associated with BPA exposure and obesity. In the future, a larger scale study is warranted due to the limited sample size in this study. Building and Construction Authority (BCA) Ministry of Education (MOE) Nanyang Technological University National Environmental Agency (NEA) We appreciate the contributions of all volunteers in this study. This work was funded by Singapore Ministry of Education Academic Research Fund Tier 1 (M4011732.030), Start-Up Grant of Nanyang Technological University (M4081915, M060030008), Singapore National Environment Agency (M4061617) and Singapore Building and Construction Authority (M4062065).

The thermostability and wettability of a separator play key roles in improving the safety and electrochemical properties of lithium-ion batteries (LIBs). Poly(ether ether ketone) (PEEK) exhibits excellent thermostability, and fluorinated polymers show improved wettability. However, the use of a fluorinated poly(ether ether ketone) (FPEEK) as a separator for LIBs has not been reported until now. In this work, a series of FPEEK polymers were successfully synthesized and further fabricated into porous LIB separators by an electrospinning method for the first time. The structure, thermal stability, morphology, mechanical strength, liquid electrolyte uptake, porosity, contact angle, ionic conductivity and electrochemical performance of the FPEEK separators were investigated. The FPEEK separators showed much stronger anti-shrinkage properties than the commercial polypropylene separator at 150 °C over 1 h. The FPEEK separator also exhibited superior electrolyte uptake (559%), strong mechanical properties (27.7 MPa), high porosity (88%), and great ionic conductivity (3.12 mS cm−1). More importantly, the cell assembled with this FPEEK separator presented outstanding cycle and C rate performances. The discharge capacity retention of the cell was 85.4% after 300 cycles at 60 °C. Hence, the obtained FPEEK separator improved the safety and electrochemical properties of the corresponding LIB.

It is a known uniqueness result that if f is a transcendental meromorphic function of finite order with two Borel excetional values $$a \ne \infty , b$$ and its first order difference operator $${\triangle }_c f\not \equiv 0$$ , for some complex number c, and if f and $${\triangle }_c f$$ share a, b CM, then $$a=0, b=\infty $$ and $$f=\exp (Az+B)$$ , where $$A\ne 0, B \in {\mathbb {C}} $$ . This type of results has its origin dating back to Csillag-Tumura’s uniqueness theorems. In this paper, by using completely different methods, we shall show that the result holds for arbitrary higher order difference operators. Examples are provided to show that this result is not valid for meromorphic functions with infinite order, which also shows a distinction between the derivatives and the difference operators of meromorphic functions, in view of Csillag-Tumura type uniqueness theorems.

Over the course of the continual phase-outs of toxic halogenated flame retardants (HFRs), there has been an increasing demand for organophosphate esters (OPEs) in global FR markets. OPE-FRs have largely been identified as OP triesters, which have a basic chemical structure of O = P(OR)3. In addition to OP triesters, OPEs can refer to another class of related substances, namely, OP diesters that have a typical chemical structure of O = P(OR)2(OH)). OP diesters are known as biotic or abiotic degradation products of OP triesters. In recent years, environmental scientists have proven that OP diesters widely exist in a variety of environmental matrices and biotic samples around the world, implying the potential risks from OP diester exposure to biota and humans in the environment. Here, we have reviewed the scientific literature for studies involving OP diesters and up to the end of 2020. The aim of the present review is to assess the present understanding of the physicochemical properties, sources (industrial production and degradation), environmental occurrence of OP diesters, and adverse effects to exposed organisms. Based on the literature in the Web of Science core collection, we found that at least 23 OP diesters have been reported as contaminants in various environments or as degradation products of OP triesters. The physicochemical properties of OP diesters vary depending on their specific chemical structures. OP diesters containing halogen atoms and aryl groups seem to be more persistent (with greater estimated half-life (t1/2) values) in environmental matrices. There were multiple sources of OP diesters, including industrial production and biotic or abiotic degradation from OP triesters. Specifically, we found that ten OP diesters are produced somewhere in the world, and the total annual output was estimated to be 17,050 metric tons (this number is underestimated due to the limitation of the available information). In addition, the wide application of OP triesters worldwide makes the degradation of OP triesters another critical source of OP diesters to the environment and to organisms. Current monitoring studies have demonstrated that some OP diesters were detectable in the human body (via both blood and urine samples), indoor dust, wastewater, or sewage sludge worldwide. The highest concentrations of diphenyl phosphate (DPHP) in human urine have been reported as high as 727 ng/mL (children (aged 0–5 years) urine samples from Australia). In addition, adverse effects following direct or indirect exposure to 11 OP diesters in organisms (including animals, bacteria, and algae) have been reported, and the recorded adverse outcomes following exposure to OP diesters included developmental toxicity, alteration of gene expression, and disturbance of nuclear receptor activity. Biomonitoring studies regarding human samples have frequently reported statistically significant associations between the concentrations of OP diesters and markers of human health (mainly related to reproductive toxicity). Finally, on the basis of current knowledge on OP diesters, we propose prospects for related research directions in future studies.

The identification of target proteins for small molecules is of great importance in drug discovery and for understanding the cellular mode of action (MOA) of toxicants. Herein, a "bottom-up" oriented target finding strategy is proposed based on the principle that the targeted enzymes can be inferred according to their phenotypic changes at the metabolome level. Meanwhile, computer-assisted

Background: Humans are constantly being exposed to various xenobiotics at relatively low concentrations. To date, limited evidence is available to ascertain whether a complex xenobiotic mixture at human-relevant levels causes any health effect. Moreover, there is no effective method to pinpoint the contribution of each chemical toward such an effect. Objectives: This study aims to understand the responses of cells to a mixture containing 23 xenobiotics at human-relevant levels and develop a feasible method to decipher the chemical(s) that contribute significantly to the observed effect. Methods: We characterized the metabolome and transcriptome of breast cancer cells (MCF-7) before and after exposure to the mixture at human-relevant levels; preexposure levels were derived from existing large-scale biomonitoring data. A high-throughput metabolomics-based “leave-one-out” method was proposed to understand the relative contribution of each component by comparing the metabolome with and without the particular chemical in the mixture. Results: The metabolomic analysis suggested that the mixture altered metabolites associated with cell proliferation and oxidative stress. For the transcriptomes, gene ontology terms and pathways including “cell cycle,” “cell proliferation,” and “cell division” were significantly altered after mixture exposure. The mixture altered genes associated with pathways such as “genotoxicity” and “nuclear factor erythroid 2-related factor 2 (Nrf2).” Through joint pathways analysis, metabolites and genes were observed to be well-aligned in pyrimidine and purine metabolisms. The leave-one-out results showed that many chemicals made their contributions to specific metabolic pathways. The overall metabolome pattern of the absence of 2,4-dihyroxybenzophenone (DHB) or bisphenol A (BPA) showed great resemblance to controls, suggesting their higher relative contribution to the observed effect. Discussion: The omics results showed that exposure to the mixture at human-relevant levels can induce significant in vitro cellular changes. Also, the leave one out method offers an effective approach for deconvoluting the effects of the mixture. Ministry of Health (MOH) Nanyang Technological University National Medical Research Council (NMRC) Published version This work was funded by NTU-Harvard SusNano (M4082370.030) and Singapore Ministry of Health’s National Medical Research Council under its Clinician-Scientist Individual Research Grant (CS-IRG) (MOH-000,141) and Open Fund−Individual Research Grant (OFIRG/0076/2018).

Let c be a nonzero constant and n a positive integer, let f be a transcendental meromorphic function of finite order, and let R be a nonconstant rational function. Under some conditions, we study the relationships between the exponent of convergence of zero points of $f-R$ f − R , its shift $f(z+nc)$ f ( z + n c ) and the differences $\Delta _{c}^{n} f$ Δ c n f .