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In the process of growth, apples' ripening, storage, transportation, and processing, the appearance and internal physiological characteristics will have some changes because of the effect of time and physical attributes. A series of problems, such as the false ripeness and putrefaction of fruit, will bring huge economic losses to fruit vendors and harm to consumers. In this paper, an odor recognition system has been designed for the fast evaluation of the freshness characteristics of apples, which is based on the freshness characteristics of Fuji apple. A series of apple-air mixture with equivalent model was established by studying the change of gas concentration during the growth and storage of apples. The continuous projection algorithm (Successive Projections Algorithm, SPA) is used to optimize the sensor array to solve the problems of collinearity and overlap and also to eliminate the abnormal and redundant sensors. ZigBee wireless sensor network is adopted to send data to host computer, and BP (Error Backpropagation) neural network algorithm optimized by SFLA (shuffled complex evolution, SCE + Particle Swarm Optimization, PSO) algorithm is used to recognize gas data, which greatly improves the training speed and precision of neural network. The experimental results show that the detection accuracy of the Fuji apples freshness is 98.67% and can quickly and comprehensively identify the freshness of apples. [ABSTRACT FROM AUTHOR]

This paper addresses the event-triggered output-feedback stabilization for a class of uncertain nonlinear systems. Essentially different from the related literature, the systems under investigation allow large uncertainties (whose size is unknown) coupling to unmeasurable states, which requires to integrate a comprehensive output-feedback compensation mechanism into the event-triggered philosophy and would bring substantial challenges to the event-triggered control. To solve the problem, a novel scheme of adaptive event-triggered output-feedback control is established for the systems. Specifically, an adaptive dynamic gain is introduced not only to counteract the large uncertainties but also to cope with the execution/sampling error. Then, an adaptive event-triggered output-feedback controller based on dynamic-gain observer is constructed to guarantee global convergence for the resulting closed-loop system while reducing execution/sampling. Particularly, the event-triggering mechanism involved is delicately designed by fully exploiting the dynamic gain, to enable the negative influence of the gain through the execution error to be counteracted (no matter how large the gain becomes) while precluding infinitely fast execution which violates the implementation of event-triggered controller in practice. Correspondingly, a distinctive analysis pattern is implemented for the closed-loop performance, due to the coupling of the dynamic-gain compensation mechanism and the event-triggering mechanism. Moreover, for more efficient resource saving, we further show the feasibility of adaptive dynamic event-triggering mechanism for the desired stabilization. [ABSTRACT FROM AUTHOR]

This paper considers the global output-feedback stabilization for a class of uncertain strict-feedback nonlinear systems. Besides the unavailability of system state, the nonlinear systems allow unknown control directions and non-parametric uncertainties, which are both arguably the most severe structural uncertainties. Even so, a refined stabilization objective with prescribed convergence rate is pursued in this paper. To solve the control problem, a new output-feedback scheme is established by introducing delicate time-varying gains and utilizing a filtered transformation, where the time-varying gains are pivotal for counteracting the structural uncertainties and guaranteeing the prescribed performance. By forcing certain system signals to evolve within a pre-specified funnel, the designed output-feedback controller can guarantee the system state to converge to zero with prescribed rate. Moreover, unlike the common backstepping design for strict-feedback systems, the established scheme can effectively prevent the computation complexity for controller construction from extremely increasing with system dimension. [ABSTRACT FROM AUTHOR]

This paper investigates the event-triggered stabilization for a class of uncertain nonlinear systems. Remarkably, the systems allow not only inherent nonlinearities but also the large uncertainties (whose size is unknown). The two ingredients together really challenge the event-triggered control design, partly because for the latter, certain compensation mechanism is necessary but hard to incorporate in the nonlinear event-triggered paradigm. To solve the problem, a new switching event-triggered control scheme is proposed in this paper by incorporating a logic-based switching mechanism which can instantly adjust controller parameter/structure and hence has strong adaptive capability to large uncertainties. The key point of the scheme is how to flexibly couple the event-triggering mechanism and the switching varying mechanism, determining not only when to sample/execute but also when to switch the design parameter, such that the switching event-triggered controller can effectively dominate/counteract the nonlinearities, the uncertainties and the sampling error, and thus can achieve the global stabilization of the systems. Owing to the introduction of switching varying mechanism, the performance analysis of the closed-loop system is a bit complicated, especially showing the nonoccurrence of infinite switchings or infinitely fast sampling/execution. Extended investigations are particularly performed for the switching event-triggered controller for its reliable implementability and broad application: By strengthening the switching varying and event-triggering mechanisms, the modified controller can additionally guarantee the pre-evaluation of sampling/execution rate and the tolerance to more types of disturbances, respectively. A simulation example on controlled Chua's circuit demonstrates the effectiveness of the proposed approach. [ABSTRACT FROM AUTHOR]

In view of the problems of large consumption of communication and computing resources in the control process, this paper studies a fundamental property for a class of multi-agent systems under event-triggered strategy: the S-stabilizability of a group of multi-agent systems with general linear dynamics under weakly connected directed topology. The results indicate that the S-stabilizability can be described in some way that the stabilizability region and feedback gain can evaluate the performance of the protocol. Firstly, a new distributed event-triggered protocol is proposed. Under this protocol, a kind of hybrid static and dynamic event-triggered strategy are presented, respectively. In particular, by using Lyapunov stability theory and graph partition tool, it is proved that the proposed event-triggered control strategy can guarantee the closed-loop system achieve S-stabilizability effectively, if at least one vertex in each iSCC (independent strongly connected component) cell receives information from the leader, which reflects the ability of distributed control law. Further, we demonstrate that the stabilizability can be realized if the initial system matrix A is Hurwitz. Moreover, it is confirmed that the designed static event-triggered condition is a limit case of dynamic event condition and can guarantee Zeno-free behavior. Finally, the validity of the theoretical results is proved by numerical simulation. [ABSTRACT FROM AUTHOR]

Summary: This paper studies the problem of global practical tracking by output feedback for a class of uncertain nonlinear systems with unmeasured state‐dependent growth and unknown time‐varying control coefficients. Compared with the closely related works, the remarkableness of this paper is that the upper and lower bounds of unknown control coefficients are not required to be known a priori. Motivated by our recent works, by combining the methods of universal control and deadzone with the backstepping technique and skillfully constructing a novel Lyapunov function, we propose a new adaptive tracking control scheme with appropriate design parameters. The new scheme guarantees that the state of the resulting closed‐loop system is globally bounded while the tracking error converges to a prescribed arbitrarily small neighborhood of the origin after a finite time. Two examples, including a practical example, are given to illustrate the effectiveness of the theoretical results. [ABSTRACT FROM AUTHOR]

Carbamazepine (CBZ, an antiepileptic) is metabolized by multiple CYP enzymes to its epoxide and hydroxides; however, whether it is genotoxic remains unclear. In this study, molecular docking (CBZ to CYPs) and cytogenotoxic toxicity assays were employed to investigate the activation of CBZ for mutagenic effects, in various mammalian cell models. Docking results indicated that CBZ was valid as a substrate of human CYP2B6 and 2E1, while not for CYP1A1, 1A2, 1B1 or 3A4. In the Chinese hamster (V79) cell line and its derivatives genetically engineered for the expression of human CYP1A1, 1A2, 1B1, 2E1 or 3A4 CBZ (2.5 ~ 40 μM) did not induce micronucleus, while in human CYP2B6-expressing cells CBZ significantly induced micronucleus formation. In a human hepatoma C3A cell line, which endogenously expressed CYP2B6 twofold higher than in HepG2 cells, CBZ induced micronucleus potently, which was blocked by 1-aminobenzotriazole (inhibitor of CYPs) and ticlopidine (specific CYP2B6 inhibitor). In HepG2 cells CBZ did not induce micronucleus; however, pretreatment of the cells with CICTO (CYP2B6 inducer) led to micronucleus formation by CBZ, while rifampicin (CYP3A4 inducer) or PCB126 (CYP1A inducer) did not change the negative results. Immunofluorescent assay showed that CBZ selectively induced centromere-free micronucleus. Moreover, CBZ induced double-strand DNA breaks (γ-H2AX elevation, by Western blot) and PIG-A gene mutations (by flowcytometry) in C3A (threshold being 5 μM, lower than its therapeutic serum concentrations, 17 ~ 51 μM), with no effects in HepG2 cells. Clearly, CBZ may induce clastogenesis and gene mutations at its therapeutic concentrations, human CYP2B6 being a major activating enzyme. [ABSTRACT FROM AUTHOR]

Pentachlorophenol (PCP) is a ubiquitous environmental contaminant commonly existing as its sodium salt (NaPCP), which enters the human body primarily through long term but low-level dietary exposure. PCP contributes to chemical carcinogenesis and teratogenesis. In this study, the probabilistic risk of dietary exposure to PCP in Guangzhou citizens was investigated. In total, 923 food samples in the categories of pork, livestock (beef and lamb), poultry, offal, eggs, and freshwater fish (considered to be relatively susceptible to PCP contamination) were collected from various markets in Guangzhou and tested for PCP. Probabilistic risk assessment model calculations for PCP dietary exposure and margin of exposure (MOE) values were performed using @RISK software, based on a Monte Carlo simulation with 10,000 iterations. The overall detection rate of PCP (above 1 μg kg−1, the detection limit) was 19.9% (184/923), with an average of 7.9 μg kg−1. The highest rate of PCP detection, 28.2%, was in livestock (beef and lamb). The MOE value for dietary PCP exposure in general Guangzhou residents averaged 400, which was far below 5,000 (the borderline for judging a health risk). The lowest MOE value, 190, was observed in the 3- to-6-year old population and indicates a significant risk. In conclusion, this study suggests that PCP exposure in Guangzhou residents is of considerable health risk, especially for the pre-school young children. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is a human procarcinogen known to be activated by cytochrome P450 (CYP) 1A2 and 3A4. In a previous study AFB1 caused chromosomal rearrangement in a yeast strain genetically engineered for stably expressing human CYP1B1. Yet, further verification of the effect of AFB1 in human cells, a potential role of the aryl hydrocarbon receptor (AhR), and CYP1B1-catalyzed AFB1 metabolism remain unidentified. In this study, a human hepatocyte (L-02) line and a human lymphoblastoid (TK6) cell line were genetically engineered for the expression of human CYP1B1, producing L-02-hCYP1B1 and TK6-hCYP1B1, respectively. They were exposed to AFB1 and analyzed for the formation of micronucleus and elevation of γ-H2AX (indicating double-strand DNA breaks); the metabolites formed by CYP1B1 from AFB1 after incubation of AFB1 with human CYP1B1 isoenzyme microsomes were determined by LC-MS. The results showed significantly more potent induction of micronucleus by AFB1 in L-02-hCYP1B1 and TK6-hCYP1B1 than in the parental (L-02 and TK6) cells, and the effects were reduced by (E)− 2,3′,4,5′-tetramethoxystilbene, a specific CYP1B1 inhibitor. In the AFB1- CYP1B1 microsomes incubations AFM1, a known stable metabolite of AFB1, was detected. Moreover, in L-02 and TK6 cells, AFB1 apparently increased the protein levels of AhR, ANRT and CYP1B1, and caused the nuclear translocation of AhR and ARNT, the latter effect being blocked by BAY-218 (an inhibitor of AhR). In conclusion, this study indicates that human CYP1B1 is capable of metabolically activating AFB1 through the AhR signaling pathway. [Display omitted] • Human CYP1B1 activates aflatoxin B1 (AFB1) for potent DNA/chromosome damage. • AFM1 is formed by AFB1 incubated with S9 fractions expressing human CYP1B1. • Aryl hydrocarbon receptor mediates AFB1-induced nuclear translocation of CYP1B1. [ABSTRACT FROM AUTHOR]

As an efficient collective response of multi-agent systems, the realization of stabilizability needs appropriate information transfer among agents, thus the topology structure is paramount. To investigate the influences of network topology on stabilizability, the concept of quotient graph (equivalent transformation of original graph) is proposed to realize the stabilizability of large-scale network systems which can be reduced to a small-scale quotient graph. As a cornerstone of topology graph transformation, N S i graph division, which is proposed for the first time in this paper, plays a crucial role in stabilizability analysis and has far-reaching impact. It establishes an equivalent connection between the stabilizability of the original topology graph and the quotient graph. Results reveal a nontrivial relationship between stabilizability of uncontrollable multi-agent systems and network topology (i.e., the stabilizability of uncontrollable multi-agent systems is not only related to the selection of leaders, but also depends on uncontrollable modes.), which is established by quotient graph as a visual generalization of the original network topology. Surprisingly, structural balance is not always good, and unbalance has a positive effect on the stabilizability of the system. Finally, the simulation experiments demonstrate the effectiveness of the theoretical results. [ABSTRACT FROM AUTHOR]

This paper researches the fixed-time leader-following consensus problem for nonlinear multi-agent systems (MASs) affected by unknown disturbances under the jointly connected graph. In order to achieve control goal, this paper designs a fixed-time consensus protocol, which can offset the unknown disturbances and the nonlinear item under the jointly connected graph, simultaneously. In this paper, the states of multiple followers can converge to the state of the leader within a fixed time regardless of the initial conditions rather than just converging to a small neighborhood near the leader state. Finally, a simulation example is given to illustrate the theoretical result. [ABSTRACT FROM AUTHOR]

Benzene is a recognized environmental leukemogen, however, the mechanisms for its carcinogenesis have not been fully elucidated. Recently, miR-221, a suggested oncogene involved in a number of malignancies, has been detected with elevated expression levels in blood cells of patients with leukemia. To explore whether benzene exposure has an effect on the expression of miR-221, a population based cross-sectional study was conducted in southern China, with 97 petrol station attendants as the exposure group and 103 general residents as the control group. Plasma benzene was analyzed by using GC∖MS. miR-221 in peripheral blood lymphocytes were measured by qRT-PCR and the ΔCt value for each sample was calculated by normalizing the Ct value for miR-221 with U6 RNA (i.e., ΔCt = Ct miR-221 − Ct U6 ). Potential confounding factors were taken into account. Pearson correlation, univariate and multivariate logistic regression were performed in statistical analysis. The results showed that the air concentrations of benzene were significantly higher in petrol stations than in control sites ( P < 0.05); The levels of benzene and miR-221 in exposure group were both significantly higher than in control group ( P < 0.05) and there was a significant positive correlation between the two indexes ( r = 0.851, P < 0.05); An association between benzene levels and the ΔCt values for miR-221 was identified by univariate and multivariate logistic analysis (OR 0.274; 95%CI 0.117, 0.396). Our investigation indicates that benzene exposure may be related to elevated miR-221 expression in human lymphocytes. [ABSTRACT FROM AUTHOR]

Tris(2-butoxyethyl) phosphate (TBOEP) is an organophosphorus flame retardant ubiquitously present in the environment and even the human body. TBOEP is toxic in multiple tissues, which forms dealkylated and hydroxylated metabolites under incubation with human hepatic microsomes; however, the impact of TBOEP metabolism on its toxicity, particularly mutagenicity (typically requiring metabolic activation), is left unidentified. In this study, the mutagenicity of TBOEP in human hepatoma cell lines (HepG2 and C3A) and the role of specific CYPs were studied. Through molecular docking, TBOEP bound to human CYP1A1, 1B1, 2B6 and 3A4 with energies and conformations favorable for catalyzing reactions, while the conformations of its binding with human CYP1A2 and 2E1 appeared unfavorable. In C3A cells (endogenous CYPs being substantial), TBOEP exposing for 72 h (2-cell cycle) at low micromolar levels induced micronucleus, which was abolished by 1-aminobenzotriazole (inhibitor of CYPs); in HepG2 cells (CYPs being insufficient) TBOEP did not induce micronucleus, whose effect was however potentiated by pretreating the cells with PCB126 (CYP1A1 inducer) or rifampicin (CYP3A4 inducer). TBOEP induced micronucleus in Chinese hamster V79-derived cell lines genetically engineered for stably expressing human CYP1A1 and 3A4, but not in cells expressing the other CYPs. In C3A cells, TBOEP selectively induced centromere protein B-free micronucleus (visualized by immunofluorescence) and PIG-A gene mutations, and elevated γ-H2AX rather than p-H3 (by Western blot) which indicated specific double-strand DNA breaks. Therefore, this study suggests that TBOEP may induce DNA/chromosome breaks and gene mutations in human cells, which requires metabolic activation by CYPs, primarily CYP1A1 and 3A4. [Display omitted] • Tris(2-butoxyethyl) phosphate (TBOEP) induced DNA breaks and gene mutations. • TBOEP formed micronuclei in human hepatoma C3A cells by a clastogenic mechanism. • Mutagenicity of TBOEP was dependent on metabolic activation by human CYP1A1 and 3A4. • Pretreating HepG2 cells with AhR and PXR activators potentiated the effect of TBOEP. [ABSTRACT FROM AUTHOR]

N -nitrosonornicotine (NNN) and N -nitrosoanabasine (NAB) are both tobacco-specific nitrosamines bearing two heterocyclic amino groups, NAB bearing an extra -CH 2 - group (conferring a hexa- rather than penta-membered cycle) but with significantly decreased carcinogenicity. However, their activating enzymes and related mutagenicity remain unclear. In this study, the chemical-CYP interaction was analyzed by molecular docking, thus the binding energies and conformations of NNN for human CYP2A6, 2A13, 2B6, 2E1 and 3A4 appeared appropriate as a substrate, so did NAB for human CYP1B1, 2A6, 2A13 and 2E1. The micronucleus test in human hepatoma (HepG2) cells with each compound (62.5–1000 μM) exposing for 48 h (two-cell cycle) was negative, however, pretreatment with bisphenol AF (0.1–100 nM, CYPs inducer) and ethanol (0.2% v:v, CYP2E1 inducer) potentiated micronucleus formation by both compounds, while CITCO (1 μM, CYP2B6 inducer) selectively potentiated that by NNN. In C3A cells (endogenous CYPs enhanced over HepG2) both compounds induced micronucleus, which was abolished by 1-aminobenzotriazole (60 μM, CYPs inhibitor) while unaffected by 8-methoxypsoralen (1 μM, CYP2A inhibitor). Consistently, NNN and NAB induced micronucleus in V79-derived recombinant cell lines expressing human CYP2B6/2E1 and CYP1B1/2E1, respectively, while negative in those expressing other CYPs. By immunofluorescent assay both compounds selectively induced centromere-free micronucleus in C3A cells. In PIG-A assays in HepG2 cells NNN and NAB were weakly positive and simply negative, respectively; however, in C3A cells both compounds significantly induced gene mutations, NNN being slight more potent. Conclusively, both NNN and NAB are mutagenic and clastogenic, depending on metabolic activation by partially different CYP enzymes. [Display omitted] • Two tobacco-specific nitrosamines induced genotoxic effect in mammalian cells. • Genotoxicity of NNN was activated by human CYP2B6/2E1, and NAB by CYP1B1/2E1. • Pretreating HepG2 cells with bisphenol AF potentiated the effects of NNN and NAB. • The mode of chromosome damage by NNN and NAB were consistently pure clastogenesis. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is a commonly used antitumor drug. However, it may cause severe cardiotoxicity, apoptosis being a major change. A recent report indicates that miR-147 expression is decreased in the myocardium of a myocardial infarction model, suggesting a potential role of this miRNA in DOX-induced cardiomyocyte toxicity. In this study, freshly isolated neonatal pig cardiomyocytes were used; following transfection of a miR-147-y mimic, the cell death induced by DOX was alleviated, represented by augmented mitophagy [indicated by a decrease in P62, and increases in LC3, PINK1, parkin mRNA, LC3Ⅱ/Ⅰ, beclin-1, PINK1, and parkin including p-parkin (Ser65) protein expression], prohibited cell apoptosis as determined by TUNEL staining, and the suppression of caspase-3 transcription and cleaved caspase-3 translation. In cells transfected with an miR-147-y inhibitor, DOX-induced mitophagy was decreased, while apoptosis was increased. Additionally, RAPTOR gene silencing in cardiomyocytes exposed to DOX increased the rate of mitophagy and decreased that of apoptosis as compared with the treatment with DOX alone. Moreover, RAPTOR overexpression downregulated the rate of mitophagy and increased that of apoptosis in cells exposed to DOX. RAPTOR was confirmed as the target gene of miR-147-y based on the results of luciferase reporter gene assays and the opposite effects of the miR-147-y mimic and miR-147-y inhibitor on RAPTOR expression. In summary, our study suggests that miR-147-y mediates DOX-induced cardiomyocyte mitophagy while suppresses apoptosis by targeting RAPTOR, thus playing a protective role in DOX-induced cardiomyocyte damage. • Doxorubicin (DOX)-induced cardiomyocyte death was alleviated by miR-147-y. • Mitophagy and apoptosis in DOX-treated cells were oppositely altered by miR-147-y. • The effect of miR-147-y on cardiomyocytes was attained by targeting on Raptor. [ABSTRACT FROM AUTHOR]

This paper is devoted to the stabilization of a class of uncertain reaction–diffusion equations with dynamic boundary condition. Remarkably, the dynamics of boundary condition at control end are considered while unknown parameters are contained in both the intra-domain and the dynamic boundary. This greatly relaxes the restrictions on boundary dynamics and system uncertainties of the related literature where dynamic boundary condition is neglected or considered but unknown parameters are only contained in the dynamic boundary or even completely excluded from the whole system. To solve the control problem, a novel control framework is established by infinite-dimensional backstepping method combining with adaptive compensation technique based on passive identifier. Then, an adaptive state-feedback controller is explicitly constructed which guarantees that all the states of the resulting closed-loop system are bounded while those of the original system converge to zero. A simulation example is provided to validate the effectiveness of the proposed theoretical results. • The restrictions of the existing literature imposed on boundary dynamics and system uncertainties are greatly relaxed since a dynamic boundary condition at control end is considered while unknown parameters are allowed in both the intra-domain and the dynamic boundary in the paper. • A novel passive identifier is designed, combining which with the infinite-dimensional backstepping method, a novel control framework is established that can compensate both the boundary dynamics and system uncertainties, and in turn to stabilize the system under investigation. [ABSTRACT FROM AUTHOR]

In this paper, the influences of negative weights on the consensus problems of multi-agent systems are investigated. While the system is subject to external attacks or agents in the system break down, there are errors in information transmission between agents. As a result, for non-negative systems, the connection weights between agents may change, or even change from positive to negative. In this paper, we provide a unified approach to deal with the problem of how to ensure the consensus of the system when the connection weight becomes negative. It is found that the consensus of multi-agent systems and general linear multi-agent systems will be guaranteed while the weights change to a certain extent without changing the protocol and feedback gains. We obtain a necessary and sufficient condition to ensure that the system can still reach asymptotic consensus when the connection weight is negative. The result is applicable to first-order, high-order integrator type of multi-agent systems as well as the general linear multi-agent system. [ABSTRACT FROM AUTHOR]

In this paper, the structural controllability of leader–follower systems over digraphs is discussed. Firstly, with the aid of leader–follower partition, we analyze the topological characteristics of systems without dilations. Moreover, we divide the digraph into the leader subgraph and the follower subgraph. By analyzing the topological characteristics of the follower subgraph, a sufficient condition to ensure the system structurally controllable is given. Furthermore, some special topologies of follower graphs are analyzed, such as unidirectional cycle graphs and directed paths, and the corresponding sufficient conditions of structural controllability are given. Meanwhile, a method to construct digraphs with structural controllability is presented. Finally, the strong structural controllability of directed tree graphs is considered, as well as the selection mechanism of leaders and the lower bound of the number of leaders under strong structural controllability are given. The above results reflect the effects of topologies on strong (or weak) structural controllability. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is the most toxic mycotoxin and a proven human carcinogen that requires metabolic activation, known by cytochrome P450 (CYP) 1A2 and 3A4. Previous evidence showed that AFB1 is activated by human recombinant CYP1A1 expressed in budding yeast. Yet, the toxicity, in particular the genotoxicity of the reactive metabolites formed from AFB1 remains unclear. Humans could be exposed to both AFB1 and benzo(a)pyrene (BaP) simultaneously, thus we were interested in their combined genotoxic effects subsequent to metabolic activation by CYP1A1. In this study, molecular docking of AFB1 to human CYP1A1 indicated that AFB1 is valid as a substrate. In the incubations with AFB1 in human CYP1A1-expressed microsomes, AFM1 as a marking metabolite of AFB1 was detected. Moreover, AFB1 induced micronucleus formation in a Chinese hamster V79-derived cell line and in a human lung epithelial BEAS-2B cell line, both expressing recombinant human CYP1A1, V79-hCYP1A1 and 2B-hCYP1A1 cells, respectively. Immunofluorescence of centromere protein B stained micronuclei was dominant in AFB1-treated BEAS-2B cells exposed to AFB1, suggesting an aneugenic effect. Moreover, AFB1 elevated the levels of ROS, 8-OHdG, AFB1-DNA adduct, and DNA breaks in 2B-hCYP1A1 cells, compared with those in the parental BEAS-2B cells. Meanwhile, AFB1 increased CYP1A1, RAD51, and γ-H2AX protein levels in 2B-hCYP1A1 cells, which were attenuated by the CYP1A1 inhibitor bergamottin. Co-exposure of AFB1 with BaP increased 8-OHdG, RAD51, and γ-H2AX levels (indicating DNA damage). In conclusion, AFB1 could be activated by human CYP1A1 for potent aneugenicity, which may be further enhanced by co-exposure to BaP. • AFB1 could be activated by human CYP1A1 for potent aneugenicity. • AFM1 is formed by AFB1 incubated in human CYP1A1-expressed microsomes. • AFB1 and BaP coexposure enhanced the genotoxic effects associated with human CYP1A1 activity. [ABSTRACT FROM AUTHOR]

This paper investigates the stabilization of an uncertain wave equation which describes the vibration dynamics of a flexible string. All the system parameters are unknown while the disturbance with unknown bound and period is allowed which lead to more serious uncertainties than the related literature, and hence result into the incapability of the traditional schemes. To solve the control problem, a novel condition-based adaptive control framework is developed in the paper. Specifically, as preparation for the adaptive control design, a state-feedback controller is first designed under the assumption that all the system parameters are known. Then, an adaptive controller, together with two continuous adaptive laws and a condition-based updating mechanism for the online tuning of the controller parameters, is proposed for the original uncertain system. Finally, it is proven that the updating of controller parameters under the proposed condition-based updating mechanism stops at a finite time instant, then the proposed controller guarantees the stability of the resulting closed-loop system. The proposed theoretical results are validated by a simulation example. [ABSTRACT FROM AUTHOR]

Abstract: V79-hCYP2E1-hSULT1A1, a V79-derived cell line co-expressing both human CYP2E1 and SULT1A1, has been constructed and efficiently used in detection of the mutagenic activities of a number of promutagens. 2-Nitropropane (2-NP) and N-nitrosodimethylamine (NDMA), both being hepatocarcinogenic to animals but inactive in standard genotoxicity assays in vitro, are activated to mutagenic metabolites by human SULT1A1 and CYP2E1, respectively. Nevertheless, little is known about the chromosomal effects of these two carcinogens. In the present study, we investigated the effects of 2-NP and NDMA on frequencies of micronucleated (F mi) and multinucleated cells (F mu) in V79-hCYP2E1-hSULT1A1 cells. The results showed induction of both F mi and F mu by 2-NP and NDMA individually, and this effect was completely suppressed by relatively specific inhibitor of SULT1A1 and CYP2E1, i.e., pentachlorophenol and 1-aminobenzotriazole, respectively. The F mu/F mi ratio in 2-NP groups was significantly higher than NDMA groups, probably indicating an aneugenic activity of 2-NP based on proposed F mu/F mi ratio as a simple index to discriminate aneugens from clastogens. The present study has established biotransformation enzyme-dependent formation of multinuclei and micronuclei induced by 2-NP and NDMA. [Copyright &y& Elsevier]

Abstract: We recently constructed a Chinese hamster V79-derived cell line that stably expresses human cytochrome P450 (CYP) 2E1 and human sulphotransferase (SULT) 1A1. These enzymes are involved in the bioactivation of numerous promutagens/procarcinogens, but are not taken into account in standard in vitro mutagenicity assays. Various carbohydrate pyrolysis products and other food contaminants that induce tumours or preneoplastic lesions in laboratory animals are inactive or only weakly active in standard in vitro genotoxicity assays. This is the case for acrylamide, furan, 5-hydroxymethylfurfural, nitrofen and N-nitrosodimethylamine. These compounds were investigated for induction of sister chromatid exchange (SCE) in V79-hCYP2E1-hSULT1A1 cells. All test compounds showed positive results over a wide concentration range, starting at 0.01μM for N-nitrosodimethylamine, 3μM for furan, 12.5μM for nitrofen, 20μM for 5-hydroxymethylfurfural, and 200μM for acrylamide. The concentration–response curve of furan was unusual, as this compound induced a statistically significant, but rather constant and weak increase in SCE over an extremely wide concentration range (3–16,000μM). Furan was slightly less active, whereas the remaining compounds were much less active in the parental V79 cell line than in V79-hCYP2E1-hSULT1A1 cells. Compared to many other genotoxic effects, the study of SCE only requires small numbers of cells (and incubation volumes) and usually is detected even at low concentrations of the genotoxicant. Therefore, induction of SCE in V79-hCYP2E1-hSULT1A1 cells may be useful in the genotoxicity testing of preparations of heated food and in their bioassay-directed fractionation. [Copyright &y& Elsevier]

[Display omitted] • BPF promotes glycolysis and the secretion of pro-inflammatory cytokines in macrophages. • Enhanced glycolysis promotes the secretion of pro-inflammatory cytokines induced by BPF. • The PI3K-AKT pathway is involved in BPF induced glycolysis and the secretion of pro-inflammatory cytokines of macrophages. • Estrogen receptor (ER) mediates the activation of PI3K-AKT signaling pathway induced by BPF. Bisphenol F (BPF) is a member of endocrine disrupting chemicals (EDCs). As a substitute of bisphenol A (BPA), BPF is widely used in various consumer products, leading to an increased risk of people's exposure. However, there are few studies on the immunotoxicity and mechanism of BPF. This study aimed to investigate the effect of BPF on the secretion of pro-inflammatory cytokines by macrophages and explore its mechanism. In our study, RAW264.7 macrophages were treated with different concentrations of BPF (0, 5, 10 and 20 μM) for 24 h. The results showed that the secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) and the production of lactate were increased in a dose-dependent manner. BPFalso led to the activation of the PI3K-AKT signaling pathway. After pretreatment with glycolysis inhibitor (2-DG) and exposure to BPF (20 μM), the secretion of pro-inflammatory cytokines induced by BPF was inhibited. PI3K inhibitor (LY294002) and estrogen receptor (ER) antagonist (ICI 182,780) could also inhibit the above effects induced by BPF (20 μM). In conclusion, our results suggested that BPF can enhance glycolysis through ER mediated PI3K-AKT signaling pathway, and the enhanced glycolysis further promoted the secretion of pro-inflammatory cytokines. Our research provides basic data for future studies on bisphenol exposure and immunotoxicity. [ABSTRACT FROM AUTHOR]

• SET might regulate expression of 53BP1 through suppressing H3K18/27ac • SET might participate in multiple cellular processes of malignant transformed 16HBE cells, including proliferation, apoptosis, and cell cycle distribution, through regulating 53BP1-H3K18/27ac cascade. • The SET-H3K18/27ac-53BP1 regulatory axis might be a specific characteristic regarding Cr(VI)-induced malignant transformation in 16HBE cells. Hexavalent chromium (Cr(VI)) is a well-established human carcinogen with DNA damaging effects. Recently we established a Cr(VI)-induced malignant transformation model from a human bronchial epithelial (16HBE) cell line, and in the transformed (16HBE-T) cells reduced levels of 53BP1 (critical for DNA repair) and the acetylated histone H3K18/27 (H3K18/27ac) were observed. In 16HBE-T cells SET (a multifunctional protein) was elevated by Cr(VI) through quantitative proteomics analysis. In the present study, we further explore the involvement of SET in the H3K18/27ac/53BP1 cascade in the 16HBE-T model, primarily by knockdown of SET. Bioinformatic analysis of the differentially expressed proteins indicated enrichment in histone modifications, in which SET was a major regulator. In 16HBE cells SET expression was enhanced by Cr(VI) in a concentration- and exposure duration-dependent manner. In 16HBE-T cells, SET knockdown showed the following effects: reversal of H3K18/27ac and 53BP1 levels, enhanced enrichment H3K18/27ac in 53BP1′s promotor region, increase rate of apoptosis and cell cycle G0/G1 arrest (with or without Cr(VI) treatment), and reduced colony-forming efficiency. Finally, In comparison with benzo(a)pyrene-transformed (malignant, 16HBE-B) cells from 16HBE where no changes in H3K18/27ac, 53BP1 or SET were observed, while the H3K18/27ac/53BP1 cascade was downregulated and SET upregulated in 16HBE-T cells, as compared with the parental 16HBE cells; thus the changes in 16HBE-T might be a specific effect of Cr(VI). In conclusion, our results suggest that SET may be involved in the malignant cell transformation, through inhibiting the H3K18/27ac/53BP1 cascade, at least in the 16HBE cell model. [ABSTRACT FROM AUTHOR]

1-Methylpyrene (1-MP) is a common environmental pollutant and animal carcinogen. After sequential activation by cytochromes P450 and sulfotransferases, it induced gene mutations and micronuclei in mammalian cells. The type of micronuclei formed, entire chromosomes or fragments, was not analysed. In this study, 1-MP and its primary metabolite, 1-hydroxymethylpyrene (1-HMP), were investigated for the induction of centromere-positive and -negative micronuclei in the human hepatoma cell line HepG2 and its derivative C3A, expressing relevant enzymes at higher levels. Under a short-exposure (9 h)/long-recovery regime (2 cell cycles in total), 1-MP and 1-HMP provided negative test results in HepG2 cells. However, they induced micronuclei in C3A cells, the effect being blocked by 1-aminobenzotriazole (inhibitor of cytochromes P450s) and reduced by pentachlorophenol (inhibitor of sulfotransferases). Immunofluorescence staining of centromere protein B in the micronuclei revealed purely clastogenic effects under this regime. Unexpectedly, 1-MP and 1-HMP at concentrations 1/5–1/4 of that required for micronuclei formation led to mitotic arrest and spindle aberrations, as detected by immunofluorescence staining of β- and γ-tubulin. Following extended exposure (72 h, 2 cell cycles, no recovery), damage to the spindle apparatus and centrosomes was detected at even lower concentrations, with concurrent formation of micronuclei. At low concentrations (1–8 µM 1-MP, 0.25–0.5 µM 1-HMP), the micronuclei induced were unexceptionally centromere-positive. Thus, the chromosome-damaging mechanism of 1-MP was regime and concentration dependent: potently aneugenic under persistent exposure, while clastogenic at higher concentrations following a short-exposure/long-recovery regime. This is a convincing evidence for the existence of metabolic activation-dependent aneugens. [ABSTRACT FROM AUTHOR]

The land surface temperature (LST) changes in North America are very abnormal recently, but few studies have systematically researched these anomalies from several aspects, especially the influencing forces. After reconstructing higher quality MODIS monthly LST data (0.05° * 0.05°) in 2002–2018, we analyzed the LST changes especially anomalous changes and their driving forces in North America. Here we show that North America warmed at the rate of 0.02 °C/y. The LST changes in three regions, including frigid region in the northwestern (0.12 °C/y), the west coast from 20°N–40°N (0.07 °C/y), and the tropics south of 20°N (0.04 °C/y), were extremely abnormal. The El Nino and La Nina were the main drivers for the periodical highest and lowest LST, respectively. The North Atlantic Oscillation was closed related to the opposite change of LST in the northeastern North America and the southeastern United States, and the warming trend of the Florida peninsula in winter was closely related to enhancement of the North Atlantic Oscillation index. The Pacific Decadal Oscillation index showed a positive correlation with the LST in most Alaska. Vegetation and atmospheric water vapor also had a profound influence on the LST changes, but it had obvious difference in latitude. [ABSTRACT FROM AUTHOR]

Background: Postpartum depression (PPD) is prevalent and may present major adverse impacts on mother and child health. According to previous studies, mostly from the western society, PPD may have complicated etiologies, such as genetic, social and psychological factors. The aim of this study was to explore the associations of some social and clinical factors, particularly those unique in Chinese, with significant PPD symptoms.Methods: A sample of 556 pregnant women in their 36th to 40th gestational week were randomly recruited in a cross-sectional study using a self-reported questionnaire, which collected maternal sociodemographic and clinical information. During their 2nd to 4th postpartum months, 522 participants responded to our screening of significant PPD symptoms, based on a score of Edinburgh Postnatal Depression Scale ≥9.Results: A total of 90 (17.3%) participants were identified with significant PPD symptoms, and the following factors were observed more frequently in women with significant PPD symptoms (PPD+) than with fewer symptoms (PPD-): intensive involvement of parents-in-law in a participant's life (living together with her, taking care of her, or discriminating against a female baby), lack of support from husband, cesarean delivery, and breast milk insufficiency (supplemented with formula). After multiple logistic regression analysis, parents-in-law's preference to baby boy while devaluing baby girl, dissatisfaction with husband's support, cesarean delivery, and mixed feeding were strongly associated with significant PPD symptoms.Conclusion: The potential risk factors for significant PPD symptoms, i.e., "son preference" custom, cesarean delivery and mixed feeding, deserve confirmation in continued, especially clinical diagnosis-based longitudinal studies. [ABSTRACT FROM AUTHOR]

Heavy metals, such as cadmium and lead, are ubiquitously present as single substances and compounds in the environment. These substances have various and overlapping health effects. Consumption of contaminated foods is the main pathway of the human exposure, however, estimation of their dietary exposure in combination with health risk analysis, particularly at various endpoints, has rarely been reported. In this study, we integrated relative potency factor (RPF) analysis into the margin of exposure (MOE) model to evaluate the health risk of combined heavy metal (including cadmium, arsenic, lead, chromium, and nickel) exposure in the residents in Guangzhou, China, after quantifying the heavy metals in various food samples and estimating their dietary exposure. The results indicated that rice, rice products and leafy vegetables contributed primarily to the dietary exposure of all metals except arsenic, which exposed the population largely through consumption of sea-foods. With all the five metals contributing to nephro- and neurotoxicity, the 95% confidence limits of MOE for the residents were clearly below 1.0 in the 3∼6-year group, suggesting a recognizable risk to young children. This study provides substantial evidence for the non-negligible health risk in young children due to increased heavy metal exposure,at least on some toxicity targets. [Display omitted] • Relative potency factor and margin of exposure were used for risk analysis of metals. • Rice/rice products/leafy vegetables contributed largely to Cd, Pb, Cr & Ni exposure. • Multiple toxicity endpoints were evaluated based on combined metal exposure. • Children at 3–6 years were especially prone to dietary metal-associated health risks. [ABSTRACT FROM AUTHOR]

Summary: This paper investigates event‐triggered output feedback H∞ control for a networked control system. Transmitted through a network under an event‐triggered scheme, the sample outputs of the plant are used to drive the dynamical output feedback controller to generate a new control signal in the discrete‐time domain. The discrete‐time control signals are also transmitted through the network to drive the plant. As a result of two types of transmission delays, the controlled plant and the dynamical output feedback controller are driven by the discrete‐time outputs and control signals at different instants of time. An interval decomposition method is introduced to place the controlled plant and the output feedback controller into the same updated time interval but with updated signals at different instants. Based on a proper Lyapunov‐Krasovskii functional, sufficient conditions are derived to ensure H∞ performance for the controlled plant. Finally, numerical simulations are used to demonstrate the practical utility of the proposed method. [ABSTRACT FROM AUTHOR]

Abstract Polychlorinated biphenyls (PCBs) as a group of persistent organic pollutants are confirmed human carcinogens; however, their mutagenicity remains mostly unknown. We have reported the mutagenicity of some PCBs with one to four chlorines in mammalian cells expressing human CYP2E1. To further explore the structural requirements for the mutagenicity of PCBs, eight tri- and tetrachlorobiphenyls untested before were investigated for the induction of gene mutations and micronuclei in a V79-derived cell line expressing both human CYP2E1 and sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1), with SULT1A1 activity inhibited by pentachlorophenol, a potent SULT1 inhibitor. 2,2′,6-Tri-, 2,3′,6-tri, 2,4′,6-tri-, and 2,2′,5-trichlorobiphenyls (PCBs 19, 27, 32, and 18, respectively) induced micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells, at potencies slightly higher than 2,6-dichlorobiphenyl, but one order of magnitude below that by 2,3,3′- and 2,3,4′-trichlorobiphenyls as reported recently; in the parental V79-Mz cells, they were nonmutagenic and weak in micronuclei induction. Among the four tetrachlorobiphenyls with varying number of ortho chlorines, 2,3,3′,4′-tetrachlorobiphenyl (PCB 56) induced both micronuclei and gene mutations in V79-hCYP2E1-hSULT1A1 cells with a potency greater than the above compounds; however, 2,2′,3,3′-tetrachlorobiphenyl was equivocal and 2,2′,3,6′-tetra- and 2,2′,6,6′-tetrachlorobiphenyls inactive in V79-hCYP2E1-hSULT1A1 cells. Immunofluorescent staining of micronuclei formed by PCBs 32 and 56 in V79-hCYP2E1-hSULT1A1 cells with centromere protein B antibodies indicated that they were predominantly whole chromosomes, implying aneugenic potentials. This study suggests that tri- and tetrachlorobiphenyls with a single ortho chlorine can be most mutagenic under activation by human CYP2E1, and greater numbers of ortho chlorines may cause a drastic decline in the activity, especially for tetrachlorobiphenyls. Highlights • Activation of tetra-Cl-PCBs by CYP2E1 is limited by the increase in ortho chlorines. • Distinct structure-mutagenicity relationships exist between tri- and tetra-Cl-PCBs. • Human CYP2E1 can activate some noncoplanar PCBs for aneugenic potentials. [ABSTRACT FROM AUTHOR]

As a new-type flame retardant and toxic substance, triphenyl phosphate (TPP) is a ubiquitous pollutant present even in human blood. TPP is transformed by human CYP enzymes to oxidized/dealkylated metabolites. The impact of TPP metabolism on its toxicity, however, remains unclear. In this study, the genotoxicity of TPP in several mammalian cell lines and its relevance to CYP/sulfortransferase (SULT) activities were investigated. The results indicated that TPP induced micronucleus formation at ≥1 μM concentrations in a human hepatoma (C3A, endogenous CYPs being substantial) cell line, which was abolished by 1-aminobenzotriazole (CYPs inhibitor). In cell line HepG2 (parental to C3A with lower CYP expression) TPP was inactive up to 10 μM, while pretreatment with ethanol (CYP2E1 inducer), PCB 126 (CYP1A inducer), or rifampicin (CYP3A inducer) led to micronucleus formation by TPP. In V79-Mz and V79-derived cells expressing human CYP1A1 TPP was inactive (up to 32 μM), and in cells expressing human CYP1B1, 2B6 and 3A4 it induced micronucleus weakly (positive only at 32 μM). However, TPP induced micronucleus potently in V79-derived cells expressing human CYP1A2, while this effect was drastically reduced by human SULT1A1 co-expression; likewise, TPP was inactive in cells expressing both human CYP2E1 and SULT1A1, but became positive with pentachlorophenol (inhibitor of SULT1) co-exposure. Moreover, in C3A cells TPP selectively induced centromere-free micronucleus (immunofluorescent assay), and TPP increased γ-H2AX (by Western blot, indicating double-strand DNA breaks). In conclusion, this study suggests that TPP is potently clastogenic, human CYP1A2 and 2E1 being major activating enzymes while SULT1A1 involved in detoxification. • Triphenyl phosphate (TPP) induced genotoxic effect in mammalian cells. • The genotoxicity of TPP depended on metabolic activation by human CYP enzymes. • Human CYP1A2 and 2E1 were the major metabolic enzymes involved in activating TPP. • The mode of TPP-induced chromosome damage appeared to be purely clastogenesis. [ABSTRACT FROM AUTHOR]

In this paper, we investigate global-exponential stabilisation of a class of nonlinear networked control systems. The network-induced delays are assumed to be random and significantly smaller than the sampling period. First, sufficient conditions are presented to ensure global-exponential stability for a class of hybrid systems with time delay. Then, the networked control systems are modelled as the hybrid systems with time delay. By the techniques of adding a power integrator and a recursive argument, a sampled-data state feedback control law is presented. Sufficient conditions are given to ensure global-exponential stability of the closed-loop system by constructing a Lyapunov–Krasovskii function. Finally, a numerical example is presented to show the validity of the new methods. [ABSTRACT FROM AUTHOR]

The standard procedure for the micronucleus test in cell lines requires a short exposure (≤0.5 cell cycle) to the test compounds followed by a long recovery (≥1.5 cell cycle), and in case of negative or equivocal results, a second test with extended exposure (≥2 cell cycles) without or with a recovery time. In general the two procedures are advantageous for detecting clastogens and aneugens, respectively. However, whether the recommended procedures apply to micronucleus tests with promutagens in cell lines genetically engineered for expressing biotransformation enzymes has not been identified. In this study, several promutagens dependent on cytochrome P450 (CYP) 2E1 and/or sulfotransferase (SULT) 1A1 were used in the micronucleus test in a Chinese hamster V79-derived cell line expressing human CYP2E1 and SULT1A1 (V79-hCYP2E1-hSULT1A1), with varying exposure/recovery schedules: 3 h/21 h, 6 h/18 h, 12 h/12 h, 18 h/6 h, and 24 h/0 h, in comparison with known clastogens and aneugens in V79 control cells. The results showed peaked micronuclei induction by mitomycin C and bleomycin (clastogens) at the 12 h/12 h schedule, while colchicine and vinblastine (aneugens) showed the strongest effect at 24 h/0 h. Catechol and trihydroxybenzene (activated by CYP2E1) induced micronuclei most strongly at 6 h/18 h, whereas somewhat longer exposures were optimal for hydroquinone, another compound activated by CYP2E1. 1-Hydroxymethylpyrene (activated by SULT1A1) and 1-methylpyrene (activated sequentially by CYP2E1 and SULT1A1) produced the highest response with the 18 h/6 h treatment regimen. Moreover, mitotic arrest by 1-hydroxymethylpyrene was observed in V79-hCYP2E1-hSULT1A1 cells but not in V79 cells, and 1-methylpyrene arrested mitosis in V79-hCYP2E1-hSULT1A1 more strongly than in V79 cells. Our study suggests that intracellular bioactivation of promutagens may not delay the induction of micronuclei in the present model, and 1-methylpyrene and 1-hydroxymethylpyrene may be activated to mitosis-arresting metabolites. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants with confirmed carcinogenicity to humans. Metabolic activation of lower chlorinated PCBs to genotoxic metabolites may involve hydroxylation and further oxidation, and some hydroxylated metabolites may be sulfo-conjugated. However, the genotoxicity of individual PCB compounds is largely unknown. In this study, 15 mono- and dichlorobiphenyls were investigated for genotoxicity using the micronucleus and Hprt mutagenicity assays in a Chinese hamster V79-derived cell line expressing both human cytochrome P450 (CYP) 2E1 and human sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1). All tested compounds were inactive in both assays in V79 control cells. However, eight dichlorobiphenyls strongly induced micronuclei and other congeners were weakly positive for this endpoint in V79-hCYP2E1-hSULT1A1 cells. The effects of each PCB in V79-hCYP2E1-hSULT1A1 cells were abolished or reduced in the presence of a CYP2E1 inhibitor (1-aminobenzotriazole), or enhanced by pretreatment of the cells with (CYP2E1-inducing) ethanol, while the genotoxicity was not significantly affected by a SULT1 inhibitor (pentachlorophenol). As representative dichlorobiphenyls, PCB 5, 10, 8 and 11 (2,3-, 2,5-, 2,4ʹ- and 3,3ʹ-dichlorobiphenyl, respectively) strongly induced Hprt gene mutations in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner. This is the first indication that human CYP2E1 is capable of converting a series of dichlorobiphenyls to strong mutagens. [ABSTRACT FROM AUTHOR]

[Display omitted] Bisphenol A (BPA) induces neurotoxicity via enhancing cell apoptosis and inflammation potently (effective at nanomolar concentrations), but its mechanisms remain unidentified. In this study, human neuroblastoma cell lines, IMR-32 and SK-N-SH cells, isolated from a male and a female subject, respectively, were exposed to BPA at various concentrations, with epigallocatechin gallate (EGCG, an antioxidant from green tea), Z-YVAD-FMK (a caspase-1 inhibitor), and ICI182.780 [an estrogen receptor (ER) inhibitor] as modulators. The results showed that BPA increased the mRNA levels of IL-18, ASC, GSDMD and protein levels of NLRP3, caspase-1 and GSDMD in both cell lines in a nonlinear manner. Noticeably, the direction of changes in the mRNA levels of caspase-1 and IL-1β were opposite, so did each of them in different cell lines: caspase-1 was enhanced in IMR-32 cells but suppressed in SK-N-SH cells, while IL-1β was suppressed in IMR-32 cells but enhanced in SK-N-SH cells. The level of GSDMD in situ increased along with the leakage of IL-1β, IL-18, caspase-1 and lactate dehydrogenase (LDH). Moreover, all the above effects of BPA were reversed by Z-YVAD-FMK, ICI182.780, and EGCG. Besides, BPA significantly increased reactive oxygen species production, LDH leakage and apoptosis, with reduced cell viability and mitochondrial membrane potential, in both cell lines, whereas Z-YVAD-FMK and ICI182.780 significantly alleviated the induction of Bak1, Bax, Bcl-2 and caspase-3 proteins by BPA. In summary, BPA may induce pyroptosis in neuroblastoma cells through NLRP3/caspase-1/GSDMD pathway, as mediated by ER; caspase-1-dependent pyroptosis may also contribute to BPA-induced apoptosis, an effect alleviated by EGCG. [ABSTRACT FROM AUTHOR]

Benzene is a ubiquitous environmental pollutant and a confirmed human carcinogen, which requires metabolic activation, primarily by CYP2E1, for most of its biological actions. Chromosome damages in benzene-exposed workers and rodents have been observed, and in their urine sulfo- and glucuronide-conjugates of phenol and hydroquinone were present. Yet, direct evidence for human CYP2E1-activated mutagenicity of benzene and the exact significance of phase II metabolism for inactivating benzene metabolites are still missing. In the present study, benzene and its oxidized metabolites (phenol, hydroquinone, catechol, 1,2,4-trihydroxybenzene and 1,4-benzoquinone) were investigated for induction of micronuclei in a V79-derived cell line genetically engineered for expression of both human CYP2E1 and human sulfotransferase (SULT) 1A1 (indicated by active micronuclei induction by 1-hydroxymethylpyrene). The results demonstrated concentration-dependent induction of micronuclei by benzene and phenol, though with lower potency or efficacy than the other metabolites. Inhibition of CYP2E1 by 1-aminobenzotriazole did not change the effect of benzoquinone, but completely abolished that of benzene and phenol, and attenuated that of the other compounds. Moreover, inhibition of SULT1A1 by pentachlorophenol potentiated the effects of benzene, hydroquinone, catechol and trihydroxybenzene. Ascorbic acid, a reducing and free radical-scavenging agent, significantly lowered the effects of hydroquinone, catechol, trihydroxybenzene as well as N -nitrosodimethylamine (a known CYP2E1-dependent promutagen), with that of benzoquinone unaffected. These results suggest that in addition to activating benzene and phenol, human CYP2E1 may further convert hydroquinone, catechol and trihydroxybenzene to more genotoxic metabolites, and sulfo-conjugation of the multi-hydroxylated metabolites of benzene by human SULT1A1 may represent an important detoxifying pathway. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the relationship between dietary habits, physical activity and cognitive views and the risk of gestational diabetes mellitus (GDM) in Chinese women.DesignA cross-sectional study to explore the potential risk factors of GMD through the International Physical Activity Questionnaire, an FFQ and a self-designed structured questionnaire, respectively.SettingGuangzhou, Guangdong Province, China.SubjectsChinese pregnant women (n 571) who underwent a 75-g oral glucose tolerance test at their 24th to 28th gestational week.ResultsThirteen per cent of the investigated women were identified as having GDM, and an increased intake of local featured foods and lower physical activity were observed in the GDM-positive group v. the GDM-negative group. Women who regarded early-pregnancy morning sickness as relevant to fetal abnormalities and those with unlimited dietary intake after the ending of morning sickness both had an increased risk for GDM (P = 0·018 and P = 0·038, respectively). After multiple logistic regression analysis, cognitive views for unlimited food intake subsequent to morning sickness, increased consumption of energy-dense snack foods and high-glycaemic-index fruits were strongly associated with the risk of GDM (OR = 1·911, P = 0·032; OR = 1·050, P = 0·001; and OR = 1·002, P = 0·017, respectively).ConclusionsLocal featured foods and incorrect cognitive views on pregnancy-related health were closely related to the risk of GDM in Chinese women. Intensive health education about pregnancy physiology and reasonable dietary and physical exercise behaviours should be strengthened for the control of GDM. [ABSTRACT FROM AUTHOR]

Bisphenol compounds (BPs) are ubiquitously existing pollutants. Recent evidence shows that they may be activated by human CYP1A1 for clastogenic effects; however, factors that influence/mediate CYP1A1-activated 4,4′-(hexafluoroisopropylidene)diphenol (BPAF) toxicity, particularly the aryl hydrocarbon receptor (AhR), sulfotransferase (SULT) 1A1 [known to conjugate 2,2-bis(4-hydroxyphenol)-propane (BPA)] and reactive oxygen species (ROS), remain unclear. In this study, a human hepatoma (HepG2) cell line was genetically engineered for the expression of human CYP1A1 and SULT1A1, producing HepG2-hCYP1A1 and HepG2-hSULT1A1, respectively. They were used in the micronucleus test and γ-H2AX analysis (Western blot) (indicating double-strand DNA breaks) with BPAF; the role of AhR in mediating BPAF toxicity was investigated by coexposure of AhR modulators in HepG2 and its derivative C3A (with no genetic modifications but enhanced CYP expression). The results indicated induction of micronuclei by BPAF (≥ 2.5 µM, for 2-cell cycle) in HepG2-hCYP1A1 and C3A, while inactive in HepG2 and HepG2-hSULT1A1; however, BPAF induced micronuclei in HepG2 pretreated with 3,3′,4,4′,5-pentachlorobiphenyl (PCB126, AhR activator), and BAY-218 (AhR inhibitor) blocked the effect of BPAF in C3A. In HepG2-hCYP1A1 BPAF selectively induced centromere-free micronuclei (immunofluorescent assay) and double-strand DNA breaks. In HepG2 cells receiving conditional medium from BPAF-HepG2-hCYP1A1 incubation micronuclei were formed, while negative in HepG2-hSULT1A1. Finally, the intracellular levels of ROS, superoxide dismutase and reduced glutathione in C3A and HepG2-hCYP1A1 exposed to BPAF were all moderately increased, while unchanged in HepG2 cells. In conclusion, like other BPs BPAF is activated by human CYP1A1 for potent clastogenicity, and this effect is enhanced by AhR while alleviated by SULT1A1. [Display omitted] • Bisphenol AF (BPAF) induces chromosome/DNA breaks in human cells. • BPAF is activated by human CYP1A1 while detoxified by SULT1A1. • Activation of aromatic hydrocarbon receptor enhances genotoxicity of BPAF. • Reactive oxygen species seems insignificant in CYP1A1-activated BPAF genotoxicity. [ABSTRACT FROM AUTHOR]

Polybrominated biphenyl ethers (PBDEs) are a group of persistent organic pollutants with endocrine-disrupting, neurotoxic, tumorigenic and DNA-damaging activities. They are hydroxylated by human liver microsomal CYP enzymes, however, their mutagenicity remains unknown. In this study, 2,2′,4,4′-tetrabromobiphenyl ether (BDE-47, relatively abundant in human tissues) was investigated for micronuclei induction and DNA damage in mammalian cells. The results indicated that BDE-47 up to 80 μM under a 6 h/18 h (exposure/recovery, covering 2 cell cycles) regime did not induce micronuclei in V79-Mz and V79-derived cell lines expressing human CYP1A1 or 1A2, while it was moderately positive in human CYP2B6-, 2E1-and 3A4-expressing cell lines (V79-hCYP2B6, V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4-hOR, respectively). Following 24 h exposure, BDE-47 induced micronuclei in V79-hCYP2E1-hSULT1A1 and V79-hCYP3A4 cells at increased potencies. In the human hepatoma (HepG2) cells BDE-47 (48 h exposure) was inactive up to 40 μM, however, pretreatment of the cells with ethanol (0.2%, v:v, inducer of CYP2E1) or rifampicin (10 μM, inducer of CYP3A4) led to significant micronuclei formation by BDE-47; pretreatment with bisphenol AF (100 nM) also potentiated BDE-47-induced micronuclei formation (which was blocked by a CYP2E1 inhibitor trans -1,2-dichloroethylene or a CYP3A inhibitor (ketoconazole). Immunofluorescent staining of centromere protein B with the micronuclei formed by BDE-47 in HepG2 cells pretreated with ethanol or rifampicin demonstrated selective formation of centromere-containing micronuclei. The increased phosphorylation of both histones H2AX and H3 in HepG2 by BDE-47 also indicated an aneugenic potential. Therefore, this study suggests that BDE-47 is an aneugen activated by several human CYP enzymes. [Display omitted] • 2,2′,4,4′-Tetrabromobiphenyl ether (BDE-47) is aneugenic in mammalian cells. • The aneugenicity of BDE-47 depends on metabolic activation by human CYP enzymes. • Human CYP3A4 and 2E1 might be the major enzymes activating BDE-47. [ABSTRACT FROM AUTHOR]

A new, sensitive and fast method for the simultaneous determination of pyrazinamide, isoniazid, streptomycin, ethambutol, and rifampicin in human plasma was developed and validated. The method required only 100 μL of plasma and one step for sample preparation by protein precipitation. The drugs were separated by using a hydrophilic interaction liquid chromatography (HILIC) column. The mobile phase was methanol and water (0.1 % formic acid and 5 mM ammonium acetate, pH 3.0 ± 0.1) in a ratio of 65:35 (v/v), which was eluted at an isocratic flow rate of 0.5 mL/min. Tandem mass spectrometry was performed with a triple-quadrupole tandem mass spectrometer. By use of the HILIC column, the detection was free of ion-pair reagents in the mobile phase, with no significant matrix effects. The total run time was less than 2 min for each sample. The method was validated by evaluating its selectivity, sensitivity, linearity, accuracy, and precision according to US Food and Drug Administration guidelines. The lower limit of quantification was 4.0 ng/mL for pyrazinamide, isoniazid, and rifampicin, 0.5 ng/mL for ethambutol, and 10.0 ng/mL for streptomycin. The intraday precision and interday precision were less than 9 %, with the accuracy ranging between −9.3 and 7.3 %. The method was successfully applied to therapeutic drug monitoring of 33 patients with tuberculosis after administration of standard antituberculosis drugs. The method has been proved to meet the high-throughput requirements in therapeutic drug monitoring. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

1-Methylpyrene (1-MP) is a ubiquitous environmental pollutant and rodent carcinogen. Its mutagenic activity depends on sequential activation by various CYP and sulfotransferase (SULT) enzymes. Previously we have observed induction of micronuclei and mitotic arrest by 1-MP in a Chinese hamster (V79)-derived cell line expressing both human CYP1A2 and SULT1A1 (V79-hCYP1A2-hSULT1A1), however, the mode of chromosome damage and the involvement of mitotic tubulin structures have not been clarified. In this study, we used immunofluorescent staining of centromere protein B (CENP-B) with the formed micronuclei, and that of β- and γ-tubulin reflecting the structures of mitotic spindle and centrioles, respectively, in V79-hCYP1A2-hSULT1A1 cells. The results indicated that 1-MP induced micronuclei in V79-hCYP1A2-hSULT1A1 cells from 0.125 to 2 μM under a 24 h/0 h (exposure/recovery) regime, while in the parental V79-Mz cells micronuclei were induced by 1-MP only at concentrations ≥ 8 μM; in both cases, the micronuclei induced by 1-MP were predominantly CENP-B positive. Following 54 h of exposure, 1-MP induced mitotic spindle non-congression and centrosome amplification (multipolar mitosis) in V79-hCYP1A2-hSULT1A1 cells, and anaphase/telophase retardation, at concentrations ≥ 0.125 μM with concentration-dependence; while in V79-Mz cells it was inactive up to 8 μM. This study suggests that in mammalian cells proficient in activating enzymes 1-MP may induce chromosome loss and mitotic disturbance, probably by interfering with the mitotic spindle and centrioles. 1-Methylpyrene is potently aneugenic in metabolism-proficient mammalian cells. 1-Methylpyrene may disrupt mitotic apparatus by interfering with tubulin. 1-Methylpyrene may retard mitotic progression. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are persistent organic pollutants with human carcinogenicity. Many lower chlorinated and non-dioxin-like PCBs have been observed to be mutagenic following activation by human CYP2E1, while activation of dioxin-like (DL-) PCBs by this enzyme has never been evidenced. In this study, each DL-PCB was analyzed by molecular docking to human CYP2E1 protein for predicting a substrate interaction. All compounds demonstrated high affinities with the active site of human CYP2E1, binding energy being −8.7 ∼ −9.7 kcal/mol. However, most compounds demonstrated ligand-heme distances as ≥ 6.8 Å, while the values for 2,3,3′,4,4′- (PCB 105) and 2,3′,4,4′,5-pentachlorobiphenyl (PCB 118) were 5.3 and 5.4 Å, respectively (valid for electron transfer). Experimentally, both PCB 105 and 118 induced micronuclei in a V79-derived cell line engineered for expression of human CYP2E1 at low micromolar concentrations, while inactive or weakly positive in V79-Mz control cells; these effects were blocked or reduced by 1-aminobenzotriazole, a suicide CYP inhibitor. However, DL-PCBs 77, 81 and 126 were all negative in both cell lines. In a human hepatoma (C3A) cell line, PCB 105 and 118 induced micronuclei marginally, while with ethanol pretreatment (to stabilize CYP2E1) both compounds induced micronuclei efficiently, and co-exposure to trans -1,2-dichloroethylene (a selective CYP2E1 inhibitor) led to clearly negative results with both compounds. Finally, both PCB 105 and 118 induced PIG-A gene mutations in C3A cells, which was blocked by trans -1,2-dichloroethylene. In summary, in silico and experimental results consistently suggest that DL- PCBs 105 and 118 may be activated by human CYP2E1 for mutagenic activities. [ABSTRACT FROM AUTHOR]

• Subchronic arsenic exposure via food changes the gut microbiome. • Feces might be the main excreting pathway for arsenic from food exposure. • The toxicity of arsenic in staples should be comprehensively evaluated. • Gut microbiome interaction might be disturbed by arsenic. • Arsenic exposure would disturb carbohydrates, lipid, and amino acids metabolism of gut bacteria. Arsenic, a global pollutant and a threshold-free primary carcinogen, can accumulate in rice. Previous studies have focused on arsenic poisoning in drinking water and the effects on gut microbes. The research on arseniasis through food, which involves the bio-transformation of arsenic, and the related changes in gut microbiome is insufficient. Mice were exposed from animal feed prepared with four arsenic species (iAsIII, iAsV, MMA, and DMA) at a dose of 30 mg/kg according to the arsenic species proportion in rice for 30 days and 60 days. The levels of total arsenic (tAs) and arsenic species in mice feces and urine samples were determined using ICP-MS and HPLC-ICP-MS, respectively. 16S rRNA and ITS gene sequencing were conducted on microbial DNA extracted from the feces samples. At 30 days and 60 days exposure, the tAs levels excreted from urine were 0.0092 and 0.0093 mg/day, and tAs levels in feces were 0.0441 and 0.0409 mg/day, respectively. We found significant differences in arsenic species distribution in urine and feces (p < 0.05). In urine, the predominant arsenic species were iAsIII (23% and 14%, respectively), DMA (55% and 70%, respectively), and uAs (unknown arsenic, 14% and 10%, respectively). In feces, the proportion of major arsenic species (iAsV, 26% and 21%; iAsIII, 16% and 15%; MMA, 14% and 14%; DMA, 19% and 19%; and uAs, 22% and 29%, respectively) were evenly distributed. Microbiological analysis (MRPP test, α- and β-diversities) showed that diversity of gut bacteria was significantly related to arsenic exposure through food, but diversity of gut fungi is less affected. Manhattan plot and LEfSe analysis showed that arsenic exposure significantly changes microbial taxa, which might be directly associated with arsenic metabolism and diseases mediated by arsenic exposure, such as Deltaproteobacteria , Polynucleobacter , Saccharomyces , Candida , Amanitaceae, and Fusarium. Network analysis was used to identify the changing hub taxa in feces along with arsenic exposure. Function predicting analysis indicated that arsenic exposure might also significantly increase differential metabolic pathways and would disturb carbohydrates, lipid, and amino acids metabolism of gut bacteria. The results demonstrate that subchronic arsenic exposure via food significantly changes the gut microbiome, and the toxicity of arsenic in food, especially in staples, should be comprehensively evaluated in terms of the disturbance of microbiome, and feces might be the main pathway through which arsenic from food exposure is excreted and bio-transformed, providing a new insight into the investigation of bio-detoxification for arseniasis. [ABSTRACT FROM AUTHOR]

• BPF promotes RAW264.7 macrophages M1 polarization. • The JAK2/STAT3/SOCS3 pathway is involved in BPF-promoted macrophage M1 polarization. • Estrogen receptor participates in BPF-promoted macrophage M1 polarization. As an alternative to bisphenol A (BPA), bisphenol F (BPF) has been increasingly used in manufacturing various consumer products. Exposured to BPF may lead to imbalanced immune homeostasis, yet the underlying mechanisms have not been fully elucidated. The present study was aimed to investigate the effects of BPF on macrophages and the underlying mechanism in regard to its association with estrogen receptor (ER), janus kinase 2/signal transducer and activator of transcription 3/suppressor of cytokine signaling 3 (JAK2/STAT3/SOCS3) pathway. In this study, after treatment of RAW264.7 macrophages with BPF (0, 5, 10, 20 μM), the macrophage M1 polarization was promoted, and the gene expression of M1 functional markers and pro-inflammatory cytokines was upregulated, which suggested the involvement of a vicious circle associated with chronic inflammation. Moreover, BPF facilitated SOCS3 expression in the cells in a dose-dependent manner, via activation of the JAK2/STAT3 signaling pathway, which may promote the transcription of many pro-inflammatory factors. Additionally, the above effects of BPF were blocked by either JAK2/STAT3 inhibitor AG490 (10 μM) or ER antagonist ICI 182,780 (10 μM). Taken together, the results of this study indicate that BPF promotes macrophage polarization toward pro-inflammatory M1 subtype, through activation of the ER-JAK2/STAT3/SOCS3 signaling pathway. Our finding may provide a new insight into the link between bisphenol exposure and immune dysfunction. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are persistent organic pollutants and human carcinogens. It was reported that rat CYP1A1 and catfish CYP1A can hydroxylate 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 3,3',4,4'-tetrachlorobiphenyl (PCB 77), while potential roles of other CYP1 enzymes in the metabolism of dioxin-like (DL) PCBs remain unconfirmed. In this study, three representative DL-PCBs, i.e., PCB 77, PCB 126, and 3,4,4',5-tetrachlorobiphenyl (PCB 81), were investigated on their genotoxicity in Chinese hamster V79-derived cell lines genetically engineered for the expression of human CYP1A1, 1A2 and 1B1, and in the human hepatoma C3A cell line, which endogenously expresses various CYPs. Under both 6 h/18 h and 18 h/6 h (exposure/recovery) regimes, PCB 77 and 81 induced micronuclei in V79-hCYP1B1 cells at micromolar levels, with slightly higher potency in the latter regime, while they were inactive in the parental V79-Mz cells and the V79-derived cell lines expressing human CYP1A1 and 1A2. However, PCB 126 was negative in each cell line. Likewise, PCB 77 and 81 induced micronuclei formation in C3A cells, which expressed CYP1B1. This effect was blocked by co-exposure to tetramethoxystilbene (30 nM), a selective CYP1B1 inhibitor. Immuno-fluorescent staining of centromere protein B in the micronuclei in PCB-treated cultures showed a predominance of centromere-negative micronuclei, which indicated a clastogenic effect. Moreover, all three PCBs elevated the level of γ-H2AX protein (indicating DNA double-strand breaks) in C3A cells, and these effects were blocked by tetramethoxystilbene (10 nM). This study demonstrates that some DL-PCBs are clastogenic in mammalian cells following metabolic activation by human CYP1B1. [ABSTRACT FROM AUTHOR]