The underlying challenges that arise when analysing short-chain chlorinated paraffins in environmental matrices

As short-chain chlorinated paraffins (SCCPs) are listed on several monitoring programs, validated methods are essential. However, their complexity and the lack of commercially available certified reference materials (RMs) hinder a proper validation of methods. Instead, one method is usually ‘validated’ by evaluating performances and results of spiked materials with that of one other method, which could easily lead to unreliable results. This study evaluated four analytical methods with different principles (i.e. comprehensive two dimensional GC coupled to a micro electron capture detector, developed for this study, chloride enhanced atmospheric pressure chemical ionization triple quadrupole time of flight MS (APCI-QToF-HRMS), GC coupled to an electron capture negative ion low resolution MS (GC–ECNI–LRMS) and carbon skeleton GC–MS), investigated the comparability in SCCP determination in spiked and naturally contaminated samples and determined SCCP amounts in candidate RMs for possible certification. The results cast doubt on the use of the most commonly applied method (i.e. GC–ECNI–LRMS), as well as using spiked materials for method validation. The APCI-QToF-HRMS method was found most promising as it achieves the required MS resolution (>21,000), is relatively fast and can detect also other CPs. The suitable identified SCCP levels in the candidate RMs and the agreement in results between the methods bring the first certification of a RM for SCCPs within reach

Search for the evidence of endocrine disruption in the aquatic environment; Lessons to be learned from joint biological and chemical monitoring in the European project COMPREHEND

Between January 1999 and December 2001, the European Community project COMPREHEND was performed. The overall aim of COMPREHEND was to assess endocrine disruption in the aquatic environment in Europe, consequent to effluent discharge, with emphasis on estrogenic activity. COMPREHEND demonstrated the widespread occurrence of estrogenic effluents across Europe and presented evidence of impacts on a range of wild fish species. Using a variety of bioassays in combination with chemical analytical methods, estrogenic steroids of human origin from domestic wastewater effluents were identified as the most pervasive problem, although alkylphenols may be important estrogenic components of some industrial effluents. New tools have been developed for the identification of estrogenic effluents, and recommendations are made for the improvement of existing techniques. We have shown that individual fish within natural populations may be feminized to varying degrees, but it has not been possible to show, using traditional fish population parameters, that the survival of fish populations is threatened. However, laboratory-based fish life-cycle studies demonstrate the sensitivity of fish to estrogen (and androgen) exposure and how this might lead to complex (and potentially damaging) genetic changes at the population level. New approaches to this problem, utilizing recent advances made in the field of molecular and population genetics, are recommended. Finally, a study of estrogenic and androgenic activity of waste waters during the treatment process has shown that some of the existing wastewater treatment technologies have the potential to eliminate or minimize the hormonal activity of the final effluen

High resolution mapping of a novel late blight resistance gene Rpi-avll, from the wild Bolivian species Solanum avilesii

Both Mexico and South America are rich in Solanum species that might be valuable sources of resistance (R) genes to late blight (Phytophthora infestans). Here, we focus on an R gene present in the diploid Bolivian species S. avilesii. The genotype carrying the R gene was resistant to eight out of 10 Phytophthora isolates of various provenances. The identification of a resistant phenotype and the generation of a segregating population allowed the mapping of a single dominant R gene, Rpi-avl1, which is located in an R gene cluster on chromosome 11. This R gene cluster is considered as an R gene “hot spot”, containing R genes to at least five different pathogens. High resolution mapping of the Rpi-avl1 gene revealed a marker co-segregating in 3890 F1 individuals, which may be used for marker assisted selection in breeding programs and for further cloning of Rpi-avl

Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia

Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation (FAPESP), Takeda, and Wellcome Trust (092809/Z/10/Z). P.F., S.P., and C.-Y.W. were supported by a Wellcome Career Development Fellowship (095751/Z/11/Z). A.-C.G. is the Canada Research Chair in Functional Proteomics and the Lea Reichmann Chair in Cancer Proteomics and was supported by the Canadian Institutes of Health Research (foundation grant FDN143301). J.-P.L. was supported by a Cancer Research Society (Canada) Scholarship for the Next Generation of Scientists

Avoidance of tobacco health warnings? An eye-tracking approach.

Aims: Among three eye-tracking studies, we examined how cigarette pack features affected visual attention and self-reported avoidance of and reactance to warnings. Design: Study 1: smoking status × warning immediacy (short-term versus long-term health consequences) × warning location (top versus bottom of pack). Study 2: smoking status × warning framing (gain-framed versus loss-framed) × warning format (text-only versus pictorial). Study 3: smoking status × warning severity (highly severe versus moderately severe consequences of smoking). Setting: University of Bristol, UK, eye-tracking laboratory. Participants: Study 1: non-smokers (n = 25), weekly smokers (n = 25) and daily smokers (n = 25). Study 2: non-smokers (n = 37), smokers contemplating quitting (n = 37) and smokers not contemplating quitting (n = 43). Study 3: non-smokers (n = 27), weekly smokers (n = 26) and daily smokers (n = 26). Measurements: For all studies: visual attention, measured as the ratio of the number of fixations to the warning versus the branding, self-reported predicted avoidance of and reactance to warnings and for study 3, effect of warning on quitting motivation. Findings: Study 1: greater self-reported avoidance [mean difference (MD) = 1.14; 95% confidence interval (CI) = 0.94, 1.35, P  0.25). Study 3: greater self-reported avoidance of (MD = 0.37; 95% CI = 0.25, 0.48, P < 0.001, η p 2 = 0.33) and reactance to (MD = 0.14; 95% CI = 0.05, 0.23, P = 0.003, η p 2 = 0.11) highly severe warnings but findings were inconclusive as to whether there was a difference in visual attention (MD = –0.55; 95% CI = –1.5, 0.41, P = 0.24, η p 2 = 0.02). Conclusions: Subjective and objective (eye-tracking) measures of avoidance of health warnings on cigarette packs produce different results, suggesting these measure different constructs. Visual avoidance of warnings indicates low-level disengagement with warnings, while self-reported predicted avoidance reflects higher-level engagement with warnings

Demonstrating the reliability of in vivo metabolomics based chemical grouping:towards best practice

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography–mass spectrometry (LC–MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice

Left gaze bias in humans, rhesus monkeys and domestic dogs

While viewing faces, human adults often demonstrate a natural gaze bias towards the left visual field, that is, the right side of the viewee’s face is often inspected first and for longer periods. Using a preferential looking paradigm, we demonstrate that this bias is neither uniquely human nor limited to primates, and provide evidence to help elucidate its biological function within a broader social cognitive framework. We observed that 6-month-old infants showed a wider tendency for left gaze preference towards objects and faces of different species and orientation, while in adults the bias appears only towards upright human faces. Rhesus monkeys showed a left gaze bias towards upright human and monkey faces, but not towards inverted faces. Domestic dogs, however, only demonstrated a left gaze bias towards human faces, but not towards monkey or dog faces, nor to inanimate object images. Our findings suggest that face- and species-sensitive gaze asymmetry is more widespread in the animal kingdom than previously recognised, is not constrained by attentional or scanning bias, and could be shaped by experience to develop adaptive behavioural significance