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Polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) emissions in fly ash from multiple-field electrostatic precipitators in different sized sintering plants were studied. The monochlorinated-trichlorinated and tetrachlorinated-octachlorinated PCDD/F concentrations were higher for small plants (90 m2) than for medium (91-180 m2) and large (>180 m2) plants. The PCDD/F concentrations and less-chlorinated PCDD/F contributions to the total PCDD/F concentrations increased as the fly ash particle size decreased moving through the precipitator stages; the abundance of monochlorinated-trichlorinated PCDD/F congeners and homologues also increased. The ash particle size and surface area can be directly used to indicate monochlorinated-trichlorinated PCDD/Fs and toxic equivalents (TEQs). Previously ignored PCDD/F emissions in discarded fly ash were identified. Estimated total monochlorinated-trichlorinated PCDD/F and TEQ emissions in discarded fly ash were 155 and 1.979 kg TEQ, respectively, in 2003-2014, and the ratio between annual PCDD/F emissions in discarded fly ash and flue gases has gradually increased. Reductions in monochlorinated-trichlorinated PCDD/F emitted in flue gas and fly ash in 2003-2014 were 28 and 40 kg, respectively, because of the phasing out of small-scale plants. Reductions in TEQs emitted in flue gas and fly ash in 2003-2014 were 7476 and 180 g TEQ, respectively.

Anion exchange membrane (AEM) fuel cells are promising for efficient and environmentally benign electrochemical energy conversion. However, the development of high-performance fuel cells requires new AEMs tailored for high conductivity and alkaline stability. In this work, poly(arylene ether sulfone)s with different branching degrees were synthesized as AEM materials. The effect of the branching degree on the properties of the copolymers was investigated in detail. The bulky rigid three-pronged branched structure introduced into the copolymer backbone increased the free volume in the corresponding AEM. As a result, the branched AEM demonstrated markedly improved ionic conductivity (up to 126 mS cm−1) compared with that of the linear copolymer AEM (96 mS cm−1) at 80 °C. The highly branched comb-shaped copolymer AEM also exhibited robust alkaline stability and dimensional stability. Furthermore, a platinum-catalyzed fuel cell based on a highly branched comb-shaped copolymer AEM achieved a peak power density of 160 mW cm−2, which was higher than that of the linear copolymer AEM (111 mW cm−2). These results suggest that introduction of a branched structure is an effective strategy to fabricate AEMs with high performance suitable for alkaline fuel cell applications.

Summary The current human exposome primarily emphasizes the total environmental exposure during an entire life. The characteristics of “lifelong” and “all environmental factors” make it very challenging to bring the exposomic study into real-life applications. Herein, we mainly discuss the typical application scenarios of exposomics and how to conduct an exposomic study to establish relationships between the exposome and human health. To increase the feasibility and efficiency, we propose that (1) an exposomic study can start with health events during critical-window periods; (2) both data- and hypothesis-driven exposomics should be combined to prioritize the risk of environmental factors; and (3) reliable statistical analysis of high-dimensional data of external and internal exposure factors are urgently needed. With standardization of the exposomic study, it will be critical to build a “wonderland” for human health.

Polycyclic aromatic hydrocarbons (PAHs) are among the most health-relevant air pollutants. Herein, we conducted meta-analysis and experimental validation to evaluate PAHs in our surroundings and carcinogenic risks. We summarized the occurrence of PAHs in outdoors and indoors from 131 studies with 6,766 samples collected in different countries in 1989-2019. The global weighted-median concentration in outdoor air, indoor air and dust of ΣPAHs were 142 ng/m3, 369 ng/m3 and 10,201 ng/g; respectively. ΣPAHs have decreased in indoor air but remained steady in outdoor air and indoor dust. More carcinogenic PAHs in indoor/outdoor air was observed in Asia, while in dust was North America. Monte-Carlo simulation further showed indoor sources for children's exposure from dust and air can exceed outdoor. To further validate the health effect of PAHs from indoors, 15 more recent indoor dust samples were collected to examine their mutagenicity. The results showed that ΣPAHs were found to be significantly correlated with mutagenicity potency in the dust sample metabolically activated with liver S9 subcellular fraction and likely accounted for 0.42-0.50 of the mutagenic activity. Our findings indicated that PAHs are still likely to have carcinogenic activity in indoor environments and exposure risk of children to indoor dust should be emphasized. Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University National Environmental Agency (NEA) This work is supported by the Singapore Ministry of Education Academic Research Fund Tier 1 (04MNP000567C120), NTU-Harvard SusNano (M4082370.030), the National Environment Agency - Singapore Naph Any Ane Fle Phe Ant P y r F la B (a)A Chry B(b)F B (k)F B(a)P I(cd)P D(ah)A B (ghi)P 1 10 100 1000 10000 ng/g 0.0 0.2 0.4 0.6 0.8 1.0 Indoor Dus t (n=15) Contribution (%) Naph Any Ane Fle P he Ant Fla Pyr B(a)A C hry B(b)F B(k)F B(a)P I(cd)P D(ah)A B(ghi)P A B C 600 6000 1000 10000 Mutagenic potency (revertants /g) PAH concentration (ng g) / R 2 =0.50, p < 0.05 B2 PAH PAH R 2 =0.42, p < 0.05 Fig. 5. Concentrations of individual PAHs (A) in box plot and profiling (B) of PAHs in indoor dust from this study (n = 15). Correlations between the total B2 PAHs, ΣPAHs and the mutagenic potency of house dust on TA98 with S9 activation (C). Nap = Naphthalene, Any = acenaphthylene, Ane = acenaphthene, Flu = fluorene, Phe = phenanthrene, Ant = anthracene, Fla = fluoranthene, Pyr = pyrene, B[a]A = benzo[a]anthracene, Chry = chrysene, B[b]F = benzo[b]fluoranthene, B[k] F = benzo[k]fluoranthene, B[a]P = benzo[a]pyrene, I(cd)P = indeno[1,2,3-c,d]pyrene, D[ah]A = dibenz[a,h]anthracene (D[ah]A), and B[ghi]P = benzo[g,h, i]perylene. M. Wang et al. Journal of Hazardous Materials 409 (2021) 124531 7 (04SBS000714N025), and Singapore Ministry of Health’s National Medical Research Council under its Clinician-Scientist Individual Research Grant (CS-IRG) (MOH-000141) and Open Fund-Individual Research Grant (OFIRG/0076/2018).

In this paper, we studied a normality criterion concerning Hayman’s question and proved: let $$n({\ge }2),k({\ge }1), m({\ge }0)$$ be three integers, let $$h(z)({\not \equiv } 0)$$ be a holomorphic function in a domain D with all zeros that have multiplicity at most m, and let $$\mathcal {F}$$ be a family of functions meromorphic in a domain D, all of whose zeros have multiplicity at least $$k+m$$ . If, for any two functions $$f, g\in \mathcal {F}$$ , $$f^nf^{(k)}$$ and $$g^ng^{(k)}$$ share h(z) in D, then $$\mathcal {F}$$ is normal in D. The result gets rid of two conditions “all zeros of h(z) have multiplicity divisible by $$n+1$$ ” and “all poles of f(z) have multiplicity at least $$m+1$$ ” in the result due to Meng and Hu (Bull Malays Math Sci Soc 38:1331–1347, 2015).

Let {fn} be a sequence of functions meromorphic in a domain D, let {hn} be a sequence of holomorphic functions in D, such that \({h_n}\left( z \right)\mathop \Rightarrow \limits^\chi h\left( z \right)\) , where h(z) ≢ 0 is holomorphic in D, and let k be a positive integer. If for each n ∈ ℕ+, fn(z) ≠ 0 and fn(k) − hn(z) has at most k distinct zeros (ignoring multiplicity) in D, then {fn} is normal in D.

The speed and throughput of analytical platforms has been a driving force in recent years in the "omics" technologies and while great strides have been accomplished in both chromatography and mass spectrometry, data analysis times have not benefited at the same pace. Even though personal computers have become more powerful, data transfer times still represent a bottleneck in data processing because of the increasingly complex data files and studies with a greater number of samples. To meet the demand of analyzing hundreds to thousands of samples within a given experiment, we have developed a data streaming platform, XCMS Stream, which capitalizes on the acquisition time to compress and stream recently acquired data files to data processing servers, mimicking just-in-time production strategies from the manufacturing industry. The utility of this XCMS Online-based technology is demonstrated here in the analysis of T cell metabolism and other large-scale metabolomic studies. A large scale example on a 1000 sample data set demonstrated a 10 000-fold time savings, reducing data analysis time from days to minutes. Further, XCMS Stream has the capability to increase the efficiency of downstream biochemical dependent data acquisition (BDDA) analysis by initiating data conversion and data processing on subsets of data acquired, expanding its application beyond data transfer to smart preliminary data decision-making prior to full acquisition.

Author(s): Li, Jiayu; Wan, Man Pun; Schiavon, Stefano; Tham, Kwok Wai; Zuraimi, Sultan; Xiong, Jinwen; Fang, Mingliang; Gall, Elliott | Abstract: This study evaluated the interrelations between indoor and outdoor bioaerosols in a bedroom under a living condition. Two wideband integrated bioaerosol sensors were utilized to measure indoor and outdoor particulate matter (PM) and fluorescent biological airborne particles (FBAPs), which were within a size range of 0.5-20 μm. Throughout this one-month case study, the median proportion of FBAPs in PM by number was 19% (5%; the interquartile range, hereafter) and 17% (3%) for indoors and outdoors, respectively, and those by mass were 78% (12%) and 55% (9%). According to the size-resolved data, FBAPs dominated above 2 and 3.5 μm indoors and outdoors, respectively. Comparing indoor upon outdoor ratios among occupancy and window conditions, the indoor FBAPs larger than 3.16 μm was dominated by indoor sources, while non-FBAPs were mainly from outdoors. The occupant dominated the indoor source of both FBAPs and non-FBAPs. Under awake and asleep, count- and mass-based mean emission rates were 45.9 and 18.7 × 106 #/h and 5.02 and 2.83 mg/h, respectively. Based on indoor activities and local outdoor air quality in Singapore, this study recommended opening the window when awake and closing it during sleep to lower indoor bioaerosol exposure.

Humans are inevitably exposed to a complex mixture of organic contaminants (i.e., xenobiotics) through diet, environment, and behavior. Biotransformation makes key contributions to the elimination of xenobiotics and greatly mediates the toxicity. However, most biotransformation studies were conducted using individual chemical, and whether coexposure of multiple environmental chemicals will affect each other's fate in the human body is still in its infancy. In this study, bisphenol A (BPA) was selected as a model compound. Its biotransformation was investigated under single exposure/coexposure to other phenolic xenobiotics (triclosan, tetrabromobisphenol A, and bisphenol S) in liver microsome and cell models. The result shows that binary exposures exhibit significant inhibitory effects on the BPA metabolism, especially the sulfate conjugation. In combination of analysis on inhibition models and enzyme activity, the inhibition effect was suggested to be primarily driven by competition for metabolizing enzymes. A mixture with 22 phenolic chemicals was further examined to disrupt BPA at various human-relevant levels. Again, the result demonstrates significant inhibition on the BPA metabolism, indicating the possible natural existence of our finding. Overall, our results show that biotransformation of phenolic xenobiotics can be significantly altered by coexposure, which provides referential evidence on underestimated risks of simultaneous exposure to environmental toxicants.

Summary Human pluripotent stem cell-derived kidney organoids recapitulate developmental processes and tissue architecture, but intrinsic limitations, such as lack of vasculature and functionality, have greatly hampered their application. Here we establish a versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, producing a correlative level of vascular endothelial growth factor A (VEGFA) to define a resident vascular network. Single-cell RNA sequencing identifies a subset of nephron progenitor cells as a potential source of renal vasculature. These kidney organoids undergo further structural and functional maturation upon implantation. Using this kidney organoid platform, we establish an in vitro model of autosomal recessive polycystic kidney disease (ARPKD), the cystic phenotype of which can be effectively prevented by gene correction or drug treatment. Our studies provide new avenues for studying human kidney development, modeling disease pathogenesis, and performing patient-specific drug validation.

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 urgently needed but still not available. Herein, we describe an 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, respec-tively. The applicability of the novel method was demonstrated in proof of principle experiments by analyzing urine from Austrian, 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 multi-class 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.

Human exposure to hundreds of chemicals, a primary component of the exposome, has been associated with many diseases. Urinary biomarkers of these chemicals are commonly monitored to quantify their exposure. However, because of low concentrations and the great variability in physicochemical properties of exposure biomarkers, exposome research has been limited by low-throughput and costly methods. Here, we developed a sensitive and high-throughput exposome analytical platform (CIL-EXPOSOME) by isotopically labeling urinary biomarkers with common functional groups (phenolic hydroxyl/carboxyl/primary amine). After a simple cleanup, we used mass spectrometry to perform a screening for both targeted and untargeted biomarkers, which was further processed by an automatic computational pipeline method for qualification and quantification. This platform has effectively introduced an isotope tag for the absolute quantification of biomarkers and has improved sensitivity of 2−1184 fold compared to existing methods. For putative identification, we built a database of 818 urinary biomarkers with MS/MS fragmentation information from either standards or in silico predictions. Using this platform, we have found 671 urinary exposure biomarker candidates from a 2 mL pooled urine sample. The exposome data acquisition and analysis time has also been greatly shortened. The results showed that CILEXPOSOME is a useful tool for global exposome analysis of complex samples. MOE (Min. of Education, S’pore) Accepted version

The human gut microbiome (GM) in healthy people is chronically exposed to tetracycline (TET) via environmental exposure and dietary uptake. However, limited information is available on its effect on the GM metabolome and effect on the host, especially at the dietary exposure level. Here, we investigated how TET at both sub-pharmaceutical and dietary exposure levels affects the metabolome and the secretome-induced host immune response by studying several representative gut bacteria. Interestingly, the metabolome showed a highly species-specific pattern with a distinct dose-response relationship. B. fragilis was highly sensitive to TET and vitamin, nucleotide, and amino acid metabolism pathways were the most vulnerable metabolic pathways at dietary exposure level. For key metabolite short chain fatty acids, TET significantly induced the synthesis of butyrate in B. fragilis, rather than C. sporogenes and E. coli. Furthermore, TET induced the release of lipopolysaccharides (LPS) in E. coli and enhanced the immune response; however, there was no obvious effect on B. fragilis. Interestingly, the overall immune response modulation with TET exposure relied on the ratio between E. coli and B. fragilis, possibly due to the neutralization of active LPS from E. coli by the LPS from B. fragilis. Overall, our results showed that the effect of TET from environmental exposure on the host health would be highly dependent on the GM composition, especially for the gut bacterial metabolome and secretome induced immune response. MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Published version

This study presented an experimental analysis to investigate the influence of the RH on PM2.5 concentration in a typical residential building in Tianjin, China. PM2.5 concentrations were measured using an aerosol monitor in different conditions of three RH scenarios, two pollutant sources and two initial pollutant concentrations. It was observed that about 95% of the size of particles produced by cigarette and wormwood are smaller than 1μm, and the particulate matters produced by wormwood has smaller particle size than that produced by cigarette. Results shows humidification is a practicable method to accelerate the deposition rate of PM2.5. Furthermore, the larger the particle size, and the higher initial pollutant concentration, the more significant influences of the RH on PM2.5 concentration. Considering the requirement of human comfort, the RH is recommended to be controlled at the range of 60%-70% when the indoor PM2.5 pollution is serious. Although humidification can reduce indoor PM2.5 concentration to a certain extent, it cannot reduce the PM2.5 concentration to the permissible range in a short period of time. Therefore, it is recommended to use RH control together with purification device.

Multiple reaction monitoring (MRM) mode using liquid-chromatography tandem mass spectrometry (e.g., LC-QqQ-MS/MS) has been extensively employed in the small molecule analysis with trace levels in complex samples owing to its high sensitivity. However, most of the reported MRM methods are developed using authentic standards, which are often costly yet not readily available. To address this question, a practical platform for the MRM method transfer between different LC-QqQ-MS/MS instruments, assisted by the high-resolution mass spectrometry (LC-HRMS) and retention time (RT) prediction, has been developed in this study. The reported platform can take advantage of both the high sensitivity of LC-MRM method and ion transition pairs from the previous publications. LC-HRMS can provide the accurate mass measurement of the compounds, though high-quality MS/MS fragments are usually difficult to obtain for chemicals at trace levels. Retention time matching and peaks matching between both instrumental platforms rule out isobaric candidates. With an additional retention time prediction filter from quantitative structure retention relationship (QSRR) model based on random forest feature selection (Pearson r2 = 0.63), identification of small molecules is achieved at a high confidence level without using authentic standards. The developed platform has been validated with robustness by examining spiked environmental chemicals in sludge water samples, biological urine, and cell extracts. Ministry of Education (MOE) Nanyang Technological University National Environmental Agency (NEA) This work is funded by Singapore Ministry of Education Academic Research Fund Tier 1 (M4011732.030), Start-Up Grant of Nanyang Technological University (M4081915, M060030008) and Singapore National Environment Agency (M4061617).

In this paper, we study the uniqueness problems of meromorphic functions and their difference operators. Our main result is a difference analogue of a result of Jank–Mues–Volkmann, which is concerned with the uniqueness of an entire function sharing one finite value with its derivatives. Some recent papers studied the case of entire functions of finite order sharing a periodic small function to f. We consider the case of meromorphic functions of finite order sharing a polynomial, which is a more popular case. Examples are provided for our results.

Polybenzimidazole membrane exhibits a promising application prospect in the high-performance and safe operation of lithium-ion batteries (LIBs). However, the relevant characterization and analysis of their safety mechanism is extremely lacking. Herein, a poly(aryl ether benzimidazole) (OPBI) non-woven fabric is prepared by electrospinning technology as a highly safe separator of LIBs. The characterization and analysis of safety mechanism in terms of thermostability, flame resistance, electrochemical stability, as well as dendrite growth, are investigated. The OPBI membrane shows excellent stability, such as no shrinkage at 200 °C, remaining weight above 54% at 800 °C, even no combustion on fire, electrochemical stability window exceeding 5.75 V vs. Li+/Li. Compared with Celgard 2400 separator, the Li dendrite growth is effectively suppressed by the OPBI membrane due to the excellent interface compatibility with Li anode. The Li/LiFePO4 cells using OPBI membrane deliver outstanding cycling stability (a specific capacity retention rate of 94% over 300 cycles) and excellent rate capacity. The results indicate that the OPBI nanofiber membrane is an intriguing candidate for high-performance and safe LIBs.

Flame retardants are widely used in polyurethane foam materials including gymnastics safety equipment such as pit cubes and landing mats. We previously reported elevated concentrations of flame retardants in the air and dust of a U.S. gymnastics training facility and elevated PentaBDE in the serum of collegiate gymnasts. Our objective in this pilot study was to compare urinary biomarkers of exposure to other flame retardants and additives of polyurethane foam including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), triphenyl phosphate (TPHP) and 2-ethylhexyl- 2,3,4,5-tetrabromobenzoate (EH-TBB) in samples collected from 11 collegiate gymnasts before and after a gymnastics practice (n = 53 urine samples total). We identified a 50% increase in the TPHP biomarker (p = 0.03) from before to after practice, a non-significant 22% increase in the TDCIPP biomarker (p = 0.14) and no change for the EH-TBB biomarker. These preliminary results indicate that the gymnastics training environment can be a source of recreational exposure to flame retardants. Such exposures are likely widespread, as we identified flame retardants in 89% of foam samples collected from gyms across the U.S. Keywords: Flame retardants, Gymnastics

Mass spectrometry has traditionally been the technology of choice for small molecule analysis, making significant inroads into metabolism, clinical diagnostics, and pharmacodynamics since the 1960s. In the mid-1980s, with the discovery of electrospray ionization (ESI) for biomolecule analysis, a new door opened for applications beyond small molecules. Initially, proteins were widely examined, followed by oligonucleotides and other nonvolatile molecules. Then in 1991, three intriguing studies reported using mass spectrometry to examine noncovalent protein complexes, results that have been expanded on for the last 25 years. Those experiments also raised the questions: How soft is ESI, and can it be used to examine even more complex interactions? Our lab addressed these questions with the analyses of viruses, which were initially tested for viability following electrospray ionization and their passage through a quadrupole mass analyzer by placing them on an active medium that would allow them to propagate. This observation has been replicated on multiple different systems, including experiments on an even bigger microbe, a spore. The question of analysis was also addressed in the early 2000s with charge detection mass spectrometry. This unique technology could simultaneously measure mass-to-charge and charge, allowing for the direct determination of the mass of a virus. More recent experiments on spores and enveloped viruses have given us insight into the range of mass spectrometry's capabilities (reaching 100 trillion Da), beginning to answer fundamental questions regarding the complexity of these organisms beyond proteins and genes, and how small molecules are integral to these supramolecular living structures. Graphical Abstract ᅟ.

Halogenated carbazoles are increasingly identified as a novel class of environmental contaminants. However, no in vivo acute toxicity information on those compounds was available. In the present study, an in vivo zebrafish embryonic model (Danio rerio) was used to investigate the developmental toxicity of those halogenated carbazoles. The results suggested that acute toxicity was structure-dependent. Two of the 6 tested carbazoles, 2,7-dibromocarbazole (27-DBCZ) and 2,3,6,7-tetrachlorocarbazole, showed obvious developmental toxicity at nanomolar levels. The typical phenotypes were similar to dioxin-induced cardiotoxicity, including swollen yolk sac, pericardial sac edema, elongated and unlooped heart, and lower jaw shortening. During embryonic development 27-DBCZ also induced a unique pigmentation decrease. Gene expression and protein staining of cytochrome P4501A (CYP1A) showed that both halogenated carbazoles could induce CYP1A expression at the micromolar level and primarily in the heart area, which was similar to dioxin activity. Further, aryl hydrocarbon receptor-(AhR)2 gene knockdown with morpholino confirmed that the acute cardiotoxicity is AhR-dependent. In conclusion, the results demonstrate that halogenated carbazoles represent yet another class of persistent organic pollutants with dioxin-like activity in an in vivo animal model. Environ Toxicol Chem 2016;35:2523-2529. © 2016 SETAC.

The sluggish oxygen evolution reaction (OER) is a pivotal process for renewable energy technologies, such as water splitting. The discovery of efficient, durable, and earth-abundant electrocatalysts for water oxidation is highly desirable. Here, a novel trimetallic nitride compound grown on nickel foam (CoVFeN @ NF) is demonstrated, which is an ultra-highly active OER electrocatalyst that outperforms the benchmark catalyst, RuO, and most of the state-of-the-art 3D transition metals and their compounds. CoVFeN @ NF exhibits ultralow OER overpotentials of 212 and 264 mV at 10 and 100 mA cm in 1 m KOH, respectively, together with a small Tafel slop of 34.8 mV dec. Structural characterization reveals that the excellent catalytic activity mainly originates from: 1) formation of oxyhydroxide species on the surface of the catalyst due to surface reconstruction and phase transition, 2) promoted oxygen evolution possibly activated by peroxo-like (O) species through a combined lattice-oxygen-oxidation and adsorbate escape mechanism, 3) an optimized electronic structure and local coordination environment owing to the synergistic effect of the multimetal system, and 4) greatly accelerated electron transfer as a result of nitridation. This study provides a simple approach to rationally design cost-efficient and highly catalytic multimetal compound systems as OER catalysts for electrochemical energy devices.

Hydrogen evolution reaction (HER) is a vital step for electrochemical energy conversion technologies. However, developing cost-efficient electrocatalysts remains a huge challenge. Here, we report that Cr-doped NiSx (Cr-NiSx) in situ grown on Ni foam via a hydrothermal sulfurization reaction can be an ultra-highly efficient and low-cost electrocatalyst for HER in alkaline condition. We find that the Cr-doping can trigger the formation of NiS and NiS1.19, leading to the suppression of Ni3S2 in the nanostructure. We show that Cr-NiSx exhibits an excellent HER activity with an ultralow overpotential of 81 mV at 10 mA cm−2, better than those of most nickel sulfide catalysts, and good stability. Our combined experimental and computational study reveals that the excellent performance is contributed by: (1) stabilized NiSx phase, (2) strongly improved conductivity, (3) greatly enhanced active sites, and (4) reduced Gibbs free energy for hydrogen adsorption (ΔGH) due to the Cr-doping. We believe that this work provides a simple approach to design cost-effective and ultra-highly efficient HER electrocatalysts for practical applications.

The application of phosphoric acid (PA)-doped polybenzimidazoles (PBIs) in high-temperature proton exchange membrane fuel cells (HTPEMFCs) requires optimal proton conductivity and fuel cell performance. Recently, we found that branched PBIs could absorb more PA due to their large free volume, and block PBIs could yield obvious nanophase-separated structures, both of which were beneficial to proton transportation. Herein, by constructing a branched PBI core block with another derived PBI structure, a novel membrane with a star-shaped, branched block matrix was prepared for the first time. The dendritic polymer backbone with a phase separation path endows the membranes with high PA doping capacity and high-efficiency proton transmission. Noticeably, a high proton conductivity (0.15 S cm−1, 160 °C) and low activation energy (5.6 kJ mol−1) were obtained under anhydrous conditions, and the peak power density of the single-cell test was as high as 713 mW cm−2 at 160 °C. The results indicate that the combination of branching and a block structure is promising for actual use in HTPEMFCs.

Attenuation of trace organic chemicals (TOrCs), including pesticides, by reverse osmosis (RO) membrane treatment is critical for ensuring public health protection in potable water reuse. This study aimed to elucidate the mechanisms underlying the poor rejection of small pesticides by polyamide-based RO membranes. Rejection of the selected TOrCs (four N-nitrosamines and 158 pesticides) was primarily governed by size exclusion, charge interactions, and dipolar interactions when evaluated at high water temperatures. Further investigation indicated that small and uncharged secondary amide pesticides showed low and highly variable rejections, compared to similarly sized counterparts with no amide functional groups. Remarkably, three secondary amide pesticides that have no other atoms holding a high partial negative charge showed very low rejections (34–65%), likely due to the cooperativity of hydrogen bonding which occurs between amide functional groups of the pesticides and RO membranes. In contrast, secondary amide pesticides that have an atom holding a high partial negative charge showed higher rejections (72–98%), likely due to the inducted electrostatic repulsion. This study proposed that secondary amide pesticides that have no other atoms holding a high partial negative charge can be poorly rejected. The findings are useful to predict the rejection level of unregulated TOrCs.

The human gut microbiome experiences long-term exposure to numerous organic contaminants (e.g., xenobiotics) in the digestive tract, and the possible consequences have rarely been characterized. To date, very few studies have investigated the metabolic variation from different species of gut bacteria in response to xenobiotic mixtures. In this study, we applied liquid chromatography mass spectrometry-based global metabolomics, coupled with targeted metabolomics, to characterize the model gut bacterial responses toward the xenobiotic mixture, covering diverse classes of compounds at human relevant concentrations. The xenobiotic "cocktail" will not likely affect the growth or morphological properties of model bacteria at human relevant concentrations. However, the metabolic results were distinct between four model bacteria and dose levels, showing species-specific and dose-dependent responsive patterns among different commensal gut bacteria. The key metabolites responsive to xenobiotic exposure are mainly involved in amino acid metabolism and central carbon metabolism, including sulfur-containing amino acids, aromatic amino acids, amino sugars, neurotransmitters, and energy-related metabolic pathways. Many of those metabolites also play an important role in the host's health. In summary, our results show that the gut microbiome can be significantly perturbed by exposure to xenobiotic mixtures at human relevant levels, providing key information on susceptibilities of individuals with diverse gut microbial structures.

Thiram, a pesticide in the dithiocarbamate chemical family, is widely used to prevent fungal disease in seeds and crops. Its off-site movement to surface waters occurs and may place aquatic organisms at potential harm. Zebrafish embryos were used for investigation of acute (1 h) thiram exposure (0.001–10 µM) at various developmental stages. Survival decreased at 1 µM and 10 µM and hatching was delayed at 0.1 µM and 1 µM. Notochord curvatures were seen at 0.1 and 1 μM thiram when exposure was initiated at 2 and at 10 hpf. Similar notochord curvatures followed exposure to the known TPO inhibitor, methimazole (MMI). Changes were absent in embryos exposed at later stages, i.e., 12 hpf. In embryos exposed to 0.1 or 1 μM at 10 hpf, levels of the thyroid enzyme, Deiodinase 3, increased by 12 hpf. Thyroid peroxide (TPO), important in T4 synthesis, decreased by 48 hpf in embryos exposed to 1 µM at 10 hpf. Thiram toxicity was stage-dependent and early life stage exposure may be responsible for adverse effects seen later. These effects may be due to impacts on the thyroid via regulation of specific thyroid genes including TPO and Deiodinase 3.

Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected by long-acting slow effective release ART. Indeed, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS). To address this, dolutegravir (Tivicay, DTG), a potent and durable HIV integrase inhibitor used effectively in combination ART was tested. Rodents were administered parenteral 45-mg/kg doses. DTG-associated changes in CNS homeostasis were assessed by measuring brain metabolic activities. After antiretroviral treatment, brain subregions were dissected and screened by mass spectrometry-based metabolomics. Metabolic drug-related dysregulation of energy and oxidative stress were readily observed within the cerebellum and frontal cortex following native drug administrations. Each was associated with alterations in neural homeostasis and depleted canonical oxidation protection pools that included glutathione and ascorbic acid. Surprisingly, the oxidative stress-related metabolites were completely attenuated when DTG was administered as nanoformulations. These data demonstrate the importance of formulation design in control of DTG or perhaps other antiretroviral drug-associated CNS events.

Background: The relationship between the levels of various environmental chemicals and the high prevalence of neural tube defects (NTDs) in north China remains unclear. This study aimed to classify the associations of maternal exposure to polycyclic aromatic hydrocarbons (PAHs), passive smoking, and widely concerned trace metal elements with NTD risk. Methods: Our case-control study recruited a total of 828 subjects: 285 women who delivered a fetus with NTDs (cases) and 543 women a healthy newborn without NTDs (controls). We measured the concentrations of PAHs, nicotine/cotinine, and various trace metal elements in two hair sections grown near the early pregnancy. Findings: Overall, no significant associations were found between the risk of any NTD subtypes and the hair levels of PAHs, nicotine/cotinine, and some metals (i.e., Cd, Sb, Pb, Cr, Mn, Fe, Ni, Co, and Cu). According to the cross-validation results for the two hair sections, hair concentrations of Mo and Sn were inversely associated with anencephaly risk, and the hair concentration of Zn was inversely associated with the risk of spina bifida. Interpretation: We concluded that maternal exposure to either PAHs or passive smoking was not a significant risk factor for NTDs, whereas the maternal less intake of certain trace metal elements may contribute to the high NTD prevalence in north China. It suggested that much effort should be spent to improve the dietary quality of various essential trace metal elements to reduce NTD risk for population living in North China. Funding: This research was supported by grants from the National Key Research and Development Program, P.R. China (Grant No. 2016YFC1000501) and the National Natural Science Foundation of China (No. 41771527 and 81373014). Conflict of Interest: The authors declare they have no actual or potential competing financial interests. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board of Peking University (PU-IRB) and the signed consent was obtained from all subjects.

Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame retardants that are ubiquitously detected in the environment and associated with adverse health outcomes. 6-OH-BDE-47 is a metabolite of the flame retardant, 2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47), and there is increasing concern regarding its developmental neurotoxicity and endocrine disrupting properties. In this study, we report that early life exposure in zebrafish (Danio rerio) embryos to 6-OH-BDE-47 (50 and 100 nM) resulted in higher coiling frequency and significantly increased apoptotic cells in the brain. These effects were partially rescued by overexpression of thyroid hormone receptor β (THRβ) mRNA. Moreover, exposure to 100 nM 6-OH-BDE-47 significantly reduced the number of hypothalamic 5-hydroxytryptamine (5-HT, serotonin)-immunoreactive (5-HT-ir) neurons and the mRNA expression of tryptophan hydroxylase 2 (TPH2). These results indicate that 6-OH-BDE-47 affected thyroid hormone regulation through THRβ and negatively impacted the nervous system, in turn, affecting coiling behavior. Correlations of these endpoints suggest that coiling frequency could be used as an indicator of neurotoxicity in embryos.

Thermal processes are widely used in small molecule chemical analysis and metabolomics for derivatization, vaporization, chromatography, and ionization, especially in gas chromatography mass spectrometry (GC/MS). In this study the effect of heating was examined on a set of 64 small molecule standards and, separately, on human plasma metabolite extracts. The samples, either derivatized or underivatized, were heated at three different temperatures (60, 100, and 250 °C) at different exposure times (30 s, 60 s, and 300 s). All the samples were analyzed by liquid chromatography coupled to electrospray ionization mass spectrometry (LC/MS) and the data processed by XCMS Online ( xcmsonline.scripps.edu ). The results showed that heating at an elevated temperature of 100 °C had an appreciable effect on both the underivatized and derivatized molecules, and heating at 250 °C created substantial changes in the profile. For example, over 40% of the molecular peaks were altered in the plasma metabolite analysis after heating (250 °C, 300s) with a significant formation of degradation and transformation products. The analysis of 64 small molecule standards validated the temperature-induced changes observed on the plasma metabolites, where most of the small molecules degraded at elevated temperatures even after minimal exposure times (30 s). For example, tri- and diorganophosphates (e.g., adenosine triphosphate and adenosine diphosphate) were readily degraded into a mono-organophosphate (e.g., adenosine monophosphate) during heating. Nucleosides and nucleotides (e.g., inosine and inosine monophosphate) were also found to be transformed into purine derivatives (e.g., hypoxanthine). A newly formed transformation product, oleoyl ethyl amide, was identified in both the underivatized and derivatized forms of the plasma extracts and small molecule standard mixture, and was likely generated from oleic acid. Overall these analyses show that small molecules and metabolites undergo significant time-sensitive alterations when exposed to elevated temperatures, especially those conditions that mimic sample preparation and analysis in GC/MS experiments.

Motivation: Metabolite databases provide a unique window into metabolome research allowing the most commonly searched biomarkers to be catalogued. Omic scale metabolite profiling, or metabolomics, is finding increased utility in biomarker discovery largely driven by improvements in analytical technologies and the concurrent developments in bioinformatics. However, the successful translation of biomarkers into clinical or biologically relevant indicators is limited. Results: With the aim of improving the discovery of translatable metabolite biomarkers, we present search analytics for over one million METLIN metabolite database queries. The most common metabolites found in METLIN were cross-correlated against XCMS Online, the widely used cloud-based data processing and pathway analysis platform. Analysis of the METLIN and XCMS common metabolite data has two primary implications: these metabolites, might indicate a conserved metabolic response to stressors and, this data may be used to gauge the relative uniqueness of potential biomarkers. Availability and implementation. METLIN can be accessed by logging on to: https://metlin.scripps.edu Contact: siuzdak@scripps.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Recently, we reported that several semi-volatile compounds (SVOCs) were competitive ligands for human peroxisome proliferator-activated nuclear receptor gamma (PPARγ1). We also observed significant binding from chemicals extracted from house dust at a concentration of 3 mg dust/mL in the dosing medium. To follow up on this study, a commercially available reporter gene assay (GeneBLAzer PPARγ1 non-DA Assay, Invitrogen) was used to investigate the PPARγ1 activation by 30 common SVOCs (e.g., brominated flame retardants, organophosphates, and phthalates) and in house dust extracts. Twenty-eight SVOCs or their metabolites were either confirmed or for the first time were found to be weak or moderate PPARγ1 agonists. We also observed activation in 15 of 25 dust extracts examined. In some cases, activation was as high as 50% of the activation of the positive control (rosiglitazone). Furthermore, there was a significant and positive correlation (r = 0.7, p < 0.003) between data collected from this reporter assay and our previous ligand binding assay tested on the same dust extracts. Our results suggest that many SVOCs ubiquitous in house dust, or their metabolites, are possible PPARγ1 agonists. Also, chemical mixtures present in house dust at environmentally relevant levels can activate human PPARγ1 in a transfected cell culture system, and further research is needed to identify the primary chemical(s) driving this activity.

Background: Accumulating evidence has shown that some environmental contaminants can alter adipogenesis and act as obesogens. Many of these contaminants act via the activation of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor. Objectives: Our goal was to determine the PPARγ ligand binding potency of several major flame retardants, including polybrominated diphenyl ethers (PBDEs), halogenated phenols and bisphenols, and their metabolites. Ligand binding activity of indoor dust and its bioactivated extracts were also investigated. Methods: We used a commercially available fluorescence polarization ligand binding assay to investigate the binding potency of flame retardants and dust extracts to human PPARγ ligand-binding domain. Rosiglitazone was used as a positive control. Results: Most of the tested compounds exhibited dose-dependent binding to PPARγ. Mono(2-ethylhexyl) tetrabromophthalate, halogenated bisphenols and phenols, and hydroxylated PBDEs were found to be potent PPARγ ligands. The most potent compound was 3-OH-BDE-47, with an IC50 (concentration required to reduce effect by 50%) of 0.24 μM. The extent of halogenation and the position of the hydroxyl group strongly affected binding. In the dust samples, 21 of the 24 samples tested showed significant binding potency at a concentration of 3 mg dust equivalent (DEQ)/mL. A 3–16% increase in PPARγ binding potency was observed following bioactivation of the dust using rat hepatic S9 fractions. Conclusion: Our results suggest that several flame retardants are potential PPARγ ligands and that metabolism may lead to increased binding affinity. The PPARγ binding activity of house dust extracts at levels comparable to human exposure warrants further studies into agonistic or antagonistic activities and their potential health effects. Citation: Fang M, Webster TF, Ferguson PL, Stapleton HM. 2015. Characterizing the peroxisome proliferator-activated receptor (PPARγ) ligand binding potential of several major flame retardants, their metabolites, and chemical mixtures in house dust. Environ Health Perspect 123:166–172; http://dx.doi.org/10.1289/ehp.1408522

In the present study, effect-directed analysis was used to identify teratogenic compounds in porewater collected from a Superfund site along the Elizabeth River estuary (VA, USA). Zebrafish (Danio rerio) exposed to the porewater displayed acute developmental toxicity and cardiac teratogenesis, presumably because of elevated sediment levels of polycyclic aromatic hydrocarbons (PAHs) from historical creosote use. Pretreatment of porewater with several physical and chemical particle removal methods revealed that colloid-bound chemicals constituted the bulk of the observed toxicity. Size-exclusive chromatography and normal-phase high-performance liquid chromatography were used to fractionate Elizabeth River porewater. Acute toxicity of porewater extracts and extract fractions was assessed as the pericardial area in embryonic zebrafish. The most toxic fraction contained several known aryl hydrocarbon receptor (AhR) agonists (e.g., 1,2-benzofluorene and 1,2-benzanthracene) and cytochrome P450 A1 (CPY1A) inhibitors (e.g., dibenzothiophene and fluoranthene). The second most toxic fraction contained known AhR agonists (e.g., benzo[a]pyrene and indeno[1,2,3-cd]pyrene). Addition of a CYP1A inhibitor, fluoranthene, increased toxicity in all active porewater fractions, suggesting synergism between several contaminants present in porewaters. The results indicate that the observed acute toxicity associated with Elizabeth River porewater results from high concentrations of AhR agonistic PAHs and mixture effects related to interactions between compounds co-occurring at the Elizabeth River site. However, even after extensive fractionation and chemical characterization, it remains plausible that some active compounds in Elizabeth River porewater remain unidentified.

Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e., the "exposome", and their specific biological effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technology. We demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biological effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700 000 chemical structures to now include more than 950 000 unique small molecules. More importantly, we demonstrate how the XCMS/METLIN platform now allows for the readout of the biological effect of a toxicant through metabolomic-derived pathway analysis, and further, artificial intelligence provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the methodological challenges current exposomics research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.

Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e. theexposome, and their specific biological effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technology. We demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biological effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700,000 chemical structures to now include more than 950,000 unique small molecules. More importantly, we demonstrate how the XCMS/METLIN platform now allows for the readout of the biological effect of a toxicant through metabolomic-derived pathway analysis and further, cognitive computing provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the outstanding methodological challenges current exposome research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.

Systems biology is the study of complex living organisms, and as such, analysis on a systems-wide scale involves the collection of information-dense data sets that are representative of an entire phenotype. To uncover dynamic biological mechanisms, bioinformatics tools have become essential to facilitating data interpretation in large-scale analyses. Global metabolomics is one such method for performing systems biology, as metabolites represent the downstream functional products of ongoing biological processes. We have developed XCMS Online, a platform that enables online metabolomics data processing and interpretation. A systems biology workflow recently implemented within XCMS Online enables rapid metabolic pathway mapping using raw metabolomics data for investigating dysregulated metabolic processes. In addition, this platform supports integration of multi-omic (such as genomic and proteomic) data to garner further systems-wide mechanistic insight. Here, we provide an in-depth procedure showing how to effectively navigate and use the systems biology workflow within XCMS Online without a priori knowledge of the platform, including uploading liquid chromatography (LCLC)–mass spectrometry (MS) data from metabolite-extracted biological samples, defining the job parameters to identify features, correcting for retention time deviations, conducting statistical analysis of features between sample classes and performing predictive metabolic pathway analysis. Additional multi-omics data can be uploaded and overlaid with previously identified pathways to enhance systems-wide analysis of the observed dysregulations. We also describe unique visualization tools to assist in elucidation of statistically significant dysregulated metabolic pathways. Parameter input takes 5–10 min, depending on user experience; data processing typically takes 1–3 h, and data analysis takes ~30 min.

Background: The use of alternative flame retardants has increased since the phase out of pentabromodiphenyl ethers (pentaBDEs). One alternative, Firemaster® 550 (FM550), induces obesity in rats. Triphenyl phosphate (TPP), a component of FM550, has a structure similar to that of organotins, which are obesogenic in rodents. Objectives: We tested the hypothesis that components of FM550 are biologically active peroxisome proliferator-activated receptor γ (PPARγ) ligands and estimated indoor exposure to TPP. Methods: FM550 and its components were assessed for ligand binding to and activation of human PPARγ. Solvent mapping was used to model TPP in the PPARγ binding site. Adipocyte and osteoblast differentiation were assessed in bone marrow multipotent mesenchymal stromal cell models. We estimated exposure of children to TPP using a screening-level indoor exposure model and house dust concentrations determined previously. Results: FM550 bound human PPARγ, and binding appeared to be driven primarily by TPP. Solvent mapping revealed that TPP interacted with binding hot spots within the PPARγ ligand binding domain. FM550 and its organophosphate components increased human PPARγ1 transcriptional activity in a Cos7 reporter assay and induced lipid accumulation and perilipin protein expression in BMS2 cells. FM550 and TPP diverted osteogenic differentiation toward adipogenesis in primary mouse bone marrow cultures. Our estimates suggest that dust ingestion is the major route of exposure of children to TPP. Conclusions: Our findings suggest that FM550 components bind and activate PPARγ. In addition, in vitro exposure initiated adipocyte differentiation and antagonized osteogenesis. TPP likely is a major contributor to these biological actions. Given that TPP is ubiquitous in house dust, further studies are warranted to investigate the health effects of FM550. Citation: Pillai HK, Fang M, Beglov D, Kozakov D, Vajda S, Stapleton HM, Webster TF, Schlezinger JJ. 2014. Ligand binding and activation of PPARγ by Firemaster® 550: effects on adipogenesis and osteogenesis in vitro. Environ Health Perspect 122:1225–1232; http://dx.doi.org/10.1289/ehp.1408111

In this study, Dechlorane Plus (DP) concentrations were analyzed in marine sediments (depth: ~10cm) from two Korean industrial bays. Two sediments were fractionated into 5 sizes by using gravitational split-flow thin fractionation technique and DP distribution was investigated in different particle size fractions. Elevated DP levels in surface sediments were observed at the site closest to land and industrial area. The highest concentrations of DP were detected in the finest grain-size (

We prove a unicity theorem of entire functions that share two distinct small functions with their shifts. The corollary of the theorem confirms the conjecture posed by Li and Gao (2011).

Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (∼20-fold) during the course of oligodendrocyte differentiation and maturation. When added exogenously at physiologically relevant concentrations, taurine was found to dramatically enhance the processes of drug-induced in vitro OPC differentiation and maturation. Mechanism of action studies suggest that the oligodendrocyte-differentiation-enhancing activities of taurine are driven primarily by its ability to directly increase available serine pools, which serve as the initial building block required for the synthesis of the glycosphingolipid components of myelin that define the functional oligodendrocyte cell state.