The Ah receptor (AhR) is a ligand-dependent transcription factor that mediates a wide range of biological and toxicological effects that result from exposure to a structurally diverse variety of synthetic and naturally occurring chemicals. Although the overall mechanism of action of the AhR has been extensively studied and involves a classical nuclear receptor mechanism of action (i.e., ligand-dependent nuclear localization, protein heterodimerization, binding of liganded receptor as a protein complex to its specific DNA recognition sequence and activation of gene expression), details of the exact molecular events that result in most AhR-dependent biochemical, physiological, and toxicological effects are generally lacking. Ongoing research efforts continue to describe an ever-expanding list of ligand-, species-, and tissue-specific spectrum of AhR-dependent biological and toxicological effects that seemingly add even more complexity to the mechanism. However, at the same time, these studies are also identifying and characterizing new pathways and molecular mechanisms by which the AhR exerts its actions and plays key modulatory roles in both endogenous developmental and physiological pathways and response to exogenous chemicals. Here we provide an overview of the classical and nonclassical mechanisms that can contribute to the differential sensitivity and diversity in responses observed in humans and other species following ligand-dependent activation of the AhR signal transduction pathway.
The aryl hydrocarbon (dioxin) receptor (AhR) is a ligand-dependent transcription factor that produces a wide range of biological and toxic effects in many species and tissues. Whereas the best-characterized high-affinity ligands include structurally related halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs), the AhR is promiscuous and can also be activated by structurally diverse exogenous and endogenous chemicals. However, little is known about how these diverse ligands actually bind to and activate the AhR. Utilizing AhR ligand binding, DNA binding, and reporter gene expression assays, we have identified a novel ligand-selective antagonist (CH223191) that preferentially inhibits the ability of some classes of AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and related HAHs), but not others (PAHs, flavonoids, or indirubin), to bind to and/or activate the AhR and AhR signal transduction. HAH-specific antagonism of AhR-dependent reporter gene expression by CH223191 was observed with mouse, rat, human, and guinea pig cell lines. Ligand- and species-selective antagonism was also observed with the AhR antagonists 3'-methoxy-4'-nitroflavone and 6,2',4',-trimethoxyflavone. Our results suggest that the differences in the binding by various ligands to the AhR contribute to the observed structural diversity of AhR ligands and could contribute in ligand-specific variation in AhR functionality and the toxic and biological effects of various classes of AhR agonists.
Tuning the catalytic active sites plays a crucial role in developing low cost and highly durable oxygen electrode catalysts with precious metal-competitive activity. In an attempt to engineer the active sites in crystalline structure of Co 3 O 4 spinel for oxygen electrocatalysis in alkaline electrolyte, we provide herein controllable synthesis of surface-tailored Co 3 O 4 nanocrystals including nanocube (NC), nanotruncated octahedron (NTO), and nanopolyhedron (NP) anchored on nitrogen-doped reduced graphene oxide (N-rGO), through a facile and template-free hydrothermal strategy. The as-synthesized Co 3 O 4 NC, NTO and NP nanostructures are predominantly enclosed by {001}, {001}+{111}, and {112} crystal planes, which expose different surface atomic configurations of Co 2+ and Co 3+ active sites. Electrochemical results indicate that the unusual {112} plane enclosed Co 3 O 4 -NP/N-rGO with abundant Co 3+ sites exhibits superior bifunctional activity for dual oxygen reduction and evolution reactions, as well as significantly enhanced metal-air battery performance in comparison with other counterparts. Further experimental and theoretical simulation studies demonstrate that the surface atomic arrangement of Co 2+ /Co 3+ active sites, especially the existence of octahedrally coordinated Co 3+ sites (Co 3+Oh ), optimizes the adsorption, activation, and desorption features of oxygen species, thus contributing to the distinct electrocatalytic properties of different facets enclosed Co 3 O 4 nanocrystals. This work paves the way to obtain highly active, durable and cost-effective electrocatalysts for practical clean energy devices through regulating the surface atomic configuration and catalytic active sites.
All large-scale graphene films contain extended topological defects dividing graphene into domains or grains. Here, we spatially map electronic transport near specific domain and grain boundaries in both epitaxial graphene grown on SiC and CVD graphene on Cu subsequently transferred to a SiO 2 substrate, with one-to-one correspondence to boundary structures.Boundaries coinciding with the substrate step on SiC exhibit a significant potential barrier for electron transport of epitaxial graphene due to the reduced charge transfer from the substrate near the step edge. Moreover, monolayer-bilayer boundaries exhibit a high resistance that can change depending on the height of substrate step coinciding at the boundary. In CVD graphene, the resistance of a grain boundary changes with the width of the disordered transition region between adjacent grains. A quantitative modeling of boundary resistance reveals the increased electron Published in ACS Nano 7, 7956 (2013).
The morphology of graphene formed on the ( 1 000 ) surface (the C-face) and the (0001) surface (the Si-face) of SiC, by annealing in ultra-high vacuum or in an argon environment, is studied by atomic force microscopy (AFM) and low-energy electron microscopy (LEEM). The graphene forms due to preferential sublimation of Si from the surface. In vacuum, this sublimation occurs much more rapidly for the C-face than the Si-face, so that 150°C lower annealing temperatures are required for the C-face to obtain films of comparable thickness. The evolution of the morphology as a function of graphene thickness is examined, revealing significant differences between the C-face and the Si-face. For annealing near 1320°C, graphene films of about 2 monolayers (ML) thickness are formed on the Si-face, but 16 ML is found for the C-face. In both cases, step bunches are formed on the surface and the films grow continuously (carpet-like) over the step bunches. For the Si-face in particular, layer-by-layer growth of the graphene is observed in areas between the step bunches. At 1170°C, for the C-face, a more 3-dimensional type of growth is found. The average thickness is then about 4 ML, but with a wide variation in local thickness (2 -7 ML) over the surface. The spatial arrangement of constant-thickness domains are found to be correlated with step bunches on the surface, which form in a more restricted manner than at 1320°C. It is argued that these domains are somewhat disconnected, so that no strong driving force for planarization of the film exists. In a 1-atm argon environment, permitting higher growth temperatures, the graphene morphology for the Si-face is found to become more layer-by-layer-like even for graphene thickness as low as 1 ML. However, for the C-face the morphology becomes much worse, with the surface displaying markedly inhomogeneous nucleation of the graphene. It is demonstrated that these surfaces are unintentionally oxidized, which accounts for the inhomogeneous growth.
We fabricate transistors from chemical vapor deposition-grown monolayer MoS2 crystals and demonstrate excellent current saturation at large drain voltages (Vd). The low-field characteristics of these devices indicate that the electron mobility is likely limited by scattering from charged impurities. The current-voltage characteristics exhibit variable range hopping at low Vd and evidence of velocity saturation at higher Vd. This work confirms the excellent potential of MoS2 as a possible channel-replacement material and highlights the role of multiple transport phenomena in governing its transistor action.
Pyrethroids are highly toxic to fish at parts per billion or parts per trillion concentrations. Their intended mechanism is prolonged sodium channel opening, but recent studies reveal that pyrethroids such as permethrin and bifenthrin also have endocrine activity. Additionally, metabolites may have greater endocrine activity than parent compounds. We evaluated the in vivo concentration-dependent ability of bifenthrin and permethrin to induce choriogenin (an estrogen-responsive protein) in Menidia beryllina, a fish species known to reside in pyrethroid contaminated aquatic habitats. We then compared the in vivo response to an in vitro assay: CALUX (Chemical Activated Luciferase Gene Expression). Juvenile Menidia beryllina exposed to bifenthrin (1, 10, 100 ng/L), permethrin (0.1, 1, 10 µg/L), and ethinylestradiol (1, 10, 50 ng/L) had significantly higher ng/mL choriogenin (Chg) measured in whole body homogenate than controls. While Chg expression in fish exposed to ethinylestradiol (EE2) exhibited a traditional sigmoidal concentration-response, curves fit to Chg expressed in fish exposed to pyrethroids suggest a unimodal response, decreasing slightly as concentration increases. While the in vivo response indicated that bifenthrin and permethrin or their metabolites act as estrogen agonists, the CALUX assay demonstrated estrogen antagonism by the pyrethroids. Our results, supported by evidence from previous studies, suggest that bifenthrin and permethrin, and/or their metabolites, appear to act as estrogen receptor (ER) agonists in vivo, and that the unmetabolized pyrethroids, particularly bifenthrin, act as an ER antagonists in cultured mammalian cells.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene-based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts.
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