Evidence for direct-acting oxidative genotoxicity by reduction products of azo dyes.

The intestinal flora forms a complex ecosystem that metabolizes dietary and endogenous nutrients under primarily anaerobic conditions. The ingestion of azo dyes has been proposed as one source of potential genotoxic agents. Many intestinal bacteria are able to reduce the azo bond (termed azofission), which liberates the substituted naphthol compounds. The standard Ames test has not demonstrated mutagenicity either by various common food colorings or by their reduced end products in Salmonella typhimurium strains TA98 and TA100. In contrast, genetic toxicity was demonstrated in the Escherichia coli differential kill assay and in S. typhimurium TA102 for the reduced dyes. The superoxide free radical was produced by the azo dyes only after reduction by the intestinal bacteria Enterococcus faecalis and Bacteroides thetaiotaomicron

Evaluation of ITER MSE Viewing Optics

The Motional Stark Effect (MSE) diagnostic on ITER determines the local plasma current density by measuring the polarization angle of light resulting from the interaction of a high energy neutral heating beam and the tokamak plasma. This light signal has to be transmitted from the edge and core of the plasma to a polarization analyzer located in the port plug. The optical system should either preserve the polarization information, or it should be possible to reliably calibrate any changes induced by the optics. This LLNL Work for Others project for the US ITER Project Office (USIPO) is focused on the design of the viewing optics for both the edge and core MSE systems. Several design constraints were considered, including: image quality, lack of polarization aberrations, ease of construction and cost of mirrors, neutron shielding, and geometric layout in the equatorial port plugs. The edge MSE optics are located in ITER equatorial port 3 and view Heating Beam 5, and the core system is located in equatorial port 1 viewing heating beam 4. The current work is an extension of previous preliminary design work completed by the ITER central team (ITER resources were not available to complete a detailed optimization of this system, and then the MSE was assigned to the US). The optimization of the optical systems at this level was done with the ZEMAX optical ray tracing code. The final LLNL designs decreased the ''blur'' in the optical system by nearly an order of magnitude, and the polarization blur was reduced by a factor of 3. The mirror sizes were reduced with an estimated cost savings of a factor of 3. The throughput of the system was greater than or equal to the previous ITER design. It was found that optical ray tracing was necessary to accurately measure the throughput. Metal mirrors, while they can introduce polarization aberrations, were used close to the plasma because of the anticipated high heat, particle, and neutron loads. These mirrors formed an intermediate image that then was relayed out of the port plug with more ideal (dielectric) mirrors. Engineering models of the optics, port plug, and neutral beam geometry were also created, using the CATIA ITER models. Two video conference calls with the USIPO provided valuable design guidelines, such as the minimum distance of the first optic from the plasma. A second focus of the project was the calibration of the system. Several different techniques are proposed, both before and during plasma operation. Fixed and rotatable polarizers would be used to characterize the system in the no-plasma case. Obtaining the full modulation spectrum from the polarization analyzer allows measurement of polarization effects and also MHD plasma phenomena. Light from neutral beam interaction with deuterium gas (no plasma) has been found useful to determine the wavelength of each spatial channel. The status of the optical design for the edge (upper) and core (lower) systems is included in the following figure. Several issues should be addressed by a follow-on study, including whether the optical labyrinth has sufficient neutron shielding and a detailed polarization characterization of actual mirrors

Mapping Drug Physico-Chemical Features to Pathway Activity Reveals Molecular Networks Linked to Toxicity Outcome

The identification of predictive biomarkers is at the core of modern toxicology. So far, a number of approaches have been proposed. These rely on statistical inference of toxicity response from either compound features (i.e., QSAR), in vitro cell based assays or molecular profiling of target tissues (i.e., expression profiling). Although these approaches have already shown the potential of predictive toxicology, we still do not have a systematic approach to model the interaction between chemical features, molecular networks and toxicity outcome. Here, we describe a computational strategy designed to address this important need. Its application to a model of renal tubular degeneration has revealed a link between physico-chemical features and signalling components controlling cell communication pathways, which in turn are differentially modulated in response to toxic chemicals. Overall, our findings are consistent with the existence of a general toxicity mechanism operating in synergy with more specific single-target based mode of actions (MOAs) and provide a general framework for the development of an integrative approach to predictive toxicology

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

© Cuzick et al. Open Access article distributed under the terms of CC BY.http://dx.doi.org/10.1016/S1470-2045(14)71171-

Nuclear Isotopic Dilution of Highly-Enriched Uranium-235 and Uranium-233 by Dry Blending via the RM-2 Mill Technology

The United States Department of Energy has initiated numerous activities to identify strategies to disposition various excess fissile materials. Two such materials are the off-specification highly enriched uranium-235 oxide powder and the uranium-233 contained in unirradiated nuclear fuel both currently stored at the Idaho National Engineering and Environmental Laboratory. This report describes the development of a technology that could dilute these materials to levels categorized as low-enriched uranium, or further dilute the materials to a level categorized as waste. This dilution technology opens additional pathways for the disposition of these excess fissile materials as existing processing infrastructure continues to be retired

A New Bayesian Test to Test for the Intractability-Countering Hypothesis

We present a new test of hypothesis in which we seek the probability of the null conditioned on the data, where the null is a simplification undertaken to counter the intractability of the more complex model, that the simpler null model is nested within. With the more complex model rendered intractable, the null model uses a simplifying assumption that capacitates the learning of an unknown parameter vector given the data. Bayes factors are shown to be known only up to a ratio of unknown data-dependent constants--a problem that cannot be cured using prescriptions similar to those suggested to solve the problem caused to Bayes factor computation, by non-informative priors. Thus, a new test is needed in which we can circumvent Bayes factor computation. In this test, we undertake generation of data from the model in which the null hypothesis is true and can achieve support in the measured data for the null by comparing the marginalised posterior of the model parameter given the measured data, to that given such generated data. However, such a ratio of marginalised posteriors can confound interpretation of comparison of support in one measured data for a null, with that in another data set for a different null. Given an application in which such comparison is undertaken, we alternatively define support in a measured data set for a null by identifying the model parameters that are less consistent with the measured data than is minimally possible given the generated data, and realising that the higher the number of such parameter values, less is the support in the measured data for the null. Then, the probability of the null conditional on the data is given within an MCMC-based scheme, by marginalising the posterior given the measured data, over parameter values that are as, or more consistent with the measured data, than with the generated data.Comment: Accepted for publication in JAS