Competitive androgen receptor antagonism as a factor determining the predictability of cumulative antiandrogenic effects of widely used pesticides

Copyright @ 2012 National Institute of Environmental Health Sciences.This article has been made available through the Brunel Open Access Publishing Fund.Background: Many pesticides in current use have recently been revealed as in vitro androgen receptor (AR) antagonists, but information about their combined effects is lacking.
Objective: We investigated the combined effects and the competitive AR antagonism of pesticide mixtures.
Methods: We used the MDA-kb2 assay to test a combination of eight AR antagonists that did not also possess AR agonist properties (“pure” antagonists; 8 mix: fludioxonil, fenhexamid, ortho-­phenylphenol, imazalil, tebuconazole, dimetho­morph, methiocarb, pirimiphos-methyl), a combina­tion of five AR antagonists that also showed agonist activity (5 mix: cyprodinil, pyrimethanil, vinclozolin, chlor­propham, linuron), and all pesticides combined (13 mix). We used concentration addition (CA) and independent action (IA) to formu­late additivity expectations, and Schild plot analyses to investigate competitive AR antagonism.
Results: A good agreement between the effects of the mixture of eight “pure” AR antagonists and the responses predicted by CA was observed. Schild plot analysis revealed that the 8 mix acted by competi­tive AR antagonism. However, the observed responses of the 5 mix and the 13 mix fell within the “prediction window” boundaries defined by the predicted regression curves of CA and IA. Schild plot analysis with these mixtures yielded anomalous responses incompatible with competitive receptor antagonism.
Conclusions: A mixture of widely used pesticides can, in a predictable manner, produce combined AR antagonist effects that exceed the responses elicited by the most potent component alone. Inasmuch as large populations are regularly exposed to mixtures of anti­androgenic pesticides, our results underline the need for considering combination effects for these substances in regulatory practice.
This article is made available through the Brunel Open Access Publishing Fund. This work was funded by the European Commission, FP7 programme (CONTAMED, grant 212502).

A novel instrument to measure differential ablation of meteorite samples and proxies: The Meteoric Ablation Simulator (MASI)

On entering the Earth’s atmosphere, micrometeoroids partially or completely ablate, leaving behind layers of metallic atoms and ions. The relative concentration of the various metal layers is not well explained by current models of ablation. Furthermore, estimates of the total flux of cosmic dust and meteoroids entering the Earth’s atmosphere vary over two orders of magnitude. To better constrain these estimates and to better model the metal layers in the mesosphere, an experimental meteoric Ablation Simulator (MASI) has been developed. Interplanetary Dust Particle (IDP) analogs are subjected to temperature profiles simulating realistic entry heating, to ascertain the differential ablation of relevant metal species. MASI is the first ablation experiment capable of simulating detailed mass, velocity, and entry angle-specific temperature profiles whilst simultaneously tracking the resulting gas-phase ablation products in a time resolved manner. This enables the determination of elemental atmospheric entry yields which consider the mass and size distribution of IDPs. The instrument has also enabled the first direct measurements of differential ablation in a laboratory setting

SINR Analysis of Opportunistic MIMO-SDMA Downlink Systems with Linear Combining

Opportunistic scheduling (OS) schemes have been proposed previously by the authors for multiuser MIMO-SDMA downlink systems with linear combining. In particular, it has been demonstrated that significant performance improvement can be achieved by incorporating low-complexity linear combining techniques into the design of OS schemes for MIMO-SDMA. However, this previous analysis was performed based on the effective signal-to-interference ratio (SIR), assuming an interference-limited scenario, which is typically a valid assumption in SDMA-based systems. It was shown that the limiting distribution of the effective SIR is of the Frechet type. Surprisingly, the corresponding scaling laws were found to follow $\epsilon\log K$ with $0<\epsilon<1$, rather than the conventional $\log\log K$ form. Inspired by this difference between the scaling law forms, in this paper a systematic approach is developed to derive asymptotic throughput and scaling laws based on signal-to-interference-noise ratio (SINR) by utilizing extreme value theory. The convergence of the limiting distribution of the effective SINR to the Gumbel type is established. The resulting scaling law is found to be governed by the conventional $\log\log K$ form. These novel results are validated by simulation results. The comparison of SIR and SINR-based analysis suggests that the SIR-based analysis is more computationally efficient for SDMA-based systems and it captures the asymptotic system performance with higher fidelity.Comment: Proceedings of the 2008 IEEE International Conference on Communications, Beijing, May 19-23, 200

Structure of a human replisome shows the organisation and interactions of a DNA replication machine.

The human replisome is an elaborate arrangement of molecular machines responsible for accurate chromosome replication. At its heart is the CDC45-MCM-GINS (CMG) helicase, which, in addition to unwinding the parental DNA duplex, arranges many proteins including the leading-strand polymerase Pol ε, together with TIMELESS-TIPIN, CLASPIN and AND-1 that have key and varied roles in maintaining smooth replisome progression. How these proteins are coordinated in the human replisome is poorly understood. We have determined a 3.2 Å cryo-EM structure of a human replisome comprising CMG, Pol ε, TIMELESS-TIPIN, CLASPIN and AND-1 bound to replication fork DNA. The structure permits a detailed understanding of how AND-1, TIMELESS-TIPIN and Pol ε engage CMG, reveals how CLASPIN binds to multiple replisome components and identifies the position of the Pol ε catalytic domain. Furthermore, the intricate network of contacts contributed by MCM subunits and TIMELESS-TIPIN with replication fork DNA suggests a mechanism for strand separation