A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

Modelling (001) surfaces of II-VI semiconductors

First, we present a two-dimensional lattice gas model with anisotropic interactions which explains the experimentally observed transition from a dominant c(2x2) ordering of the CdTe(001) surface to a local (2x1) arrangement of the Cd atoms as an equilibrium phase transition. Its analysis by means of transfer-matrix and Monte Carlo techniques shows that the small energy difference of the competing reconstructions determines to a large extent the nature of the different phases. Then, this lattice gas is extended to a model of a three-dimensional crystal which qualitatively reproduces many of the characteristic features of CdTe which have been observed during sublimation and atomic layer epitaxy.Comment: 5 pages, 3 figure

Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context

The aryl hydrocarbon receptor (AhR) mediates the induction of a variety of xenobiotic metabolism genes. Activation of the AhR occurs through binding to a group of structurally diverse compounds, most notably dioxins, which are exogenous ligands. Isoflavones are part of a family which include some well characterised endogenous AhR ligands. This paper analysed a novel family of these compounds, based on the structure of 2-amino-isoflavone. Initially two luciferase-based cell models, mouse H1L6.1c2 and human HG2L6.1c3, were used to identify whether the compounds had AhR agonistic and/or antagonistic properties. This analysis showed that some of the compounds were weak agonists in mouse and antagonists in human. Further analysis of two of the compounds, Chr-13 and Chr-19, was conducted using quantitative real-time PCR in rat H4IIE and human MCF-7 cells. The results indicated that Chr-13 was an agonist in rat but an antagonist in human cells. Chr-19 was shown to be an agonist in rat but more interestingly, a partial agonist in human. Luciferase induction results not only revealed that subtle differences in the structure of the compound could produce species-specific differences in response but also dictated the ability of the compound to be an AhR agonist or antagonist. Substituted 2-amino-isoflavones represent a novel group of AhR ligands that must differentially interact with the AhR ligand binding domain to produce their species-specific agonist or antagonist activity and future ligand binding analysis and docking studies with these compounds may provide insights into the differential mechanisms of action of structurally similar compounds

Statistical physics and practical training of soft-committee machines

Equilibrium states of large layered neural networks with differentiable activation function and a single, linear output unit are investigated using the replica formalism. The quenched free energy of a student network with a very large number of hidden units learning a rule of perfectly matching complexity is calculated analytically. The system undergoes a first order phase transition from unspecialized to specialized student configurations at a critical size of the training set. Computer simulations of learning by stochastic gradient descent from a fixed training set demonstrate that the equilibrium results describe quantitatively the plateau states which occur in practical training procedures at sufficiently small but finite learning rates.Comment: 11 pages, 4 figure

Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers

Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR\u27s target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively - xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases. © Akishina et al

Modelling sublimation and atomic layer epitaxy in the presence of competing surface reconstructions

We present a solid-on-solid model of a binary AB compound, where atoms of type A in the topmost layer interact via anisotropic interactions different from those inside the bulk. Depending on temperature and particle flux, this model displays surface reconstructions similar to those of (001) surfaces of II-VI semiconductors. We show, that our model qualitatively reproduces mamy of the characteristic features of these materials which have been observed during sublimation and atomic layer epitaxy. We predict some previously unknown effects which might be observed experimentally.Comment: 4 pages, 2 figures. New title, additional figures, minor changes in the text. See http://theorie.physik.uni-wuerzburg.de/~ahr/AB/ for surface images and MPEG movie

Relationship between the molecular composition, visible light absorption, and health-related properties of smoldering woodsmoke aerosols

Organic aerosols generated from the smoldering combustion of wood critically impact air quality and health for billions of people worldwide; yet, the links between the chemical components and the optical or biological effects of woodsmoke aerosol (WSA) are still poorly understood. In this work, an untargeted analysis of the molecular composition of smoldering WSA, generated in a controlled environment from nine types of heartwood fuels (African mahogany, birch, cherry, maple, pine, poplar, red oak, redwood, and walnut), identified several hundred compounds using gas chromatography mass spectrometry (GCMS) and nano-electrospray high-resolution mass spectrometry (HRMS) with tandem multistage mass spectrometry (MSn). The effects of WSA on cell toxicity as well as gene expression dependent on the aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) were characterized with cellular assays, and the visible mass absorption coefficients (MACvis) of WSA were measured with ultraviolet-visible spectroscopy. The WSAs studied in this work have significant levels of biological and toxicological activity, with exposure levels in both an outdoor and indoor environment similar to or greater than those of other toxicants. A correlation between the HRMS molecular composition and aerosol properties found that phenolic compounds from the oxidative decomposition of lignin are the main drivers of aerosol effects, while the cellulose decomposition products play a secondary role; e.g., levoglucosan is anticorrelated with multiple effects. Polycyclic aromatic hydrocarbons (PAHs) are not expected to form at the combustion temperature in this work, nor were they observed above the detection limit; thus, biological and optical properties of the smoldering WSA are not attributed to PAHs. Syringyl compounds tend to correlate with cell toxicity, while the more conjugated molecules (including several compounds assigned to dimers) have higher AhR activity and MACvis. The negative correlation between cell toxicity and AhR activity suggests that the toxicity of smoldering WSA to cells is not mediated by the AhR. Both mass-normalized biological outcomes have a statistically significant dependence on the degree of combustion of the wood. In addition, our observations support the fact that the visible light absorption of WSA is at least partially due to charge transfer effects in aerosols, as previously suggested. Finally, MACvis has no correlation with toxicity or receptor signaling, suggesting that key chromophores in this work are not biologically active on the endpoints tested