Dr. Doodle: A diagrammatic theorem prover

This paper presents the Dr.Doodle system, an interactive theorem prover that uses diagrammatic representations. The assumption underlying this project is that, for some domains (principally geometry) , diagrammatic reasoning is easier to understand than conventional algebraic approaches -- at least for a significant number of people. The Dr.Doodle system was developed for the domain of metric-space analysis (a geometric domain, but traditionally taught using a dry algebraic formalism). Pilot experiments were conducted to evaluate its potential as the basis of an educational tool, with encouraging results

Assessing binary mixture effects from genotoxic and endocrine disrupting environmental contaminants using infrared spectroscopy

Benzo[a]pyrene (B[a]P), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent contaminants and concern has arisen over co-exposure of organisms when the chemicals exist in mixtures. Herein, attenuated total reflection Fouriertransform infrared (ATR-FTIR) spectroscopy was used to identify biochemical alterations induced in cells by single and binary mixtures of these environmental chemicals. It was also investigated as a method to identify if interactions are occurring in mixtures and as a possible tool to predict mixture effects. Mallard fibroblasts were treated with single and binary mixtures of B[a]P, PCB126, PCB153, BDE47 and BDE209. Comparison of observed spectra from cells treated with binary mixtures with expected additive spectra, which were created from individual exposure spectra, indicated that in many areas of the spectrum, less-than-additive binary mixture effects may occur. However, possible greater-than-additive alterations were identified in the 1650-1750 cm-1 lipid region and may demonstrate a common mechanism of B[a]P and PCBs or PBDEs, which can enhance toxicity in mixtures

Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse sertoli cells, evidence of binding at the cox-2 active site, and implications for endocrine disruption

Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. Results: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos- methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances—o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)— showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. Conclusions: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrinedisrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action

Did the Hilda collisional family form during the late heavy bombardment?

We model the long-term evolution of the Hilda collisional family located in the 3/2 mean-motion resonance with Jupiter. Its eccentricity distribution evolves mostly due to the Yarkovsky/YORP effect and assuming that: (i) impact disruption was isotropic, and (ii) albedo distribution of small asteroids is the same as for large ones, we can estimate the age of the Hilda family to be $4_{-1}^{+0}\,{\rm Gyr}$. We also calculate collisional activity in the J3/2 region. Our results indicate that current collisional rates are very low for a 200\,km parent body such that the number of expected events over Gyrs is much smaller than one. The large age and the low probability of the collisional disruption lead us to the conclusion that the Hilda family might have been created during the Late Heavy Bombardment when the collisions were much more frequent. The Hilda family may thus serve as a test of orbital behavior of planets during the LHB. We tested the influence of the giant-planet migration on the distribution of the family members. The scenarios that are consistent with the observed Hilda family are those with fast migration time scales $\simeq 0.3\,{\rm Myr}$ to $3\,{\rm Myr}$, because longer time scales produce a family that is depleted and too much spread in eccentricity. Moreover, there is an indication that Jupiter and Saturn were no longer in a compact configuration (with period ratio $P_{\rm S}/P_{\rm J} > 2.09$) at the time when the Hilda family was created

Transthyretin-Binding Activity of Complex Mixtures Representing the Composition of Thyroid-Hormone Disrupting Contaminants in House Dust and Human Serum

Background: House dust contains many organic contaminants that can compete with the thyroid hormone (TH) thyroxine (T4) for binding to transthyretin (TTR). How these contaminants work together at levels found in humans and how displacement from TTR in vitro relates to in vivoT4-TTR binding is unknown. Objectives: Our aims were to determine the TTR-binding potency for contaminant mixtures as found in house dust, maternal serum, and infant serum; to study whether the TTR-binding potency of the mixtures follows the principle of concentration addition; and to extrapolate the in vitro TTR-binding potency to in vivo inhibition levels of T4-TTR binding in maternal and infant serum. Methods: Twenty-five contaminants were tested for their in vitro capacity to compete for TTR-binding with a fluorescent FITC-T4 probe. Three mixtures were reconstituted proportionally to median concentrations for these chemicals in house dust, maternal serum, or infant serum from Nordic countries. Measured concentration–response curves were compared with concentration–response curves predicted by concentration addition. For each reconstituted serum mixture, its inhibitor–TTR dissociation constant (Ki) was used to estimate inhibition levels of T4-TTR binding in human blood. Results: The TTR-binding potency of the mixtures was well predicted by concentration addition. The ∼20% inhibition in FITC-T4 binding observed for the mixtures reflecting median concentrations in maternal and infant serum was extrapolated to 1.3% inhibition of T4-TTR binding in maternal and 1.5% in infant blood. For nontested mixtures reflecting high-end serum concentrations, these estimates were 6.2% and 4.9%, respectively. Discussion: The relatively low estimated inhibition levels at median exposure levels may explain why no relationship between exposure to TTR-binding compounds and circulating T4 levels in humans has been reported, so far. We hypothesize, however, that 1.3% inhibition of T4-TTR binding may ultimately be decisive for reaching a status of maternal hypothyroidism or hypothyroxinemia associated with impaired neurodevelopment in children. https://doi.org/10.1289/EHP5911The MiSSE project ( https://www.aces.su.se/misse/) was funded by the Swedish Research Council FORMAS (project 210-2012-131). The authors acknowledge Å. Bergman (Stockholm University) for the initial coordination of the MiSSE project, M. Lamoree (Vrije Universiteit Amsterdam), and J. Kamstra (Vrije Universiteit Amsterdam, currently Utrecht University) for adopting and optimizing the FITC-T4 TTR-binding assay in our laboratory, and J. Norrgran Engdahl (Stockholm University) for supporting the compilation of the mixtures

Dispelling urban myths about default uncertainty factors in chemical risk assessment - Sufficient protection against mixture effects?

© 2013 Martin et al.; licensee BioMed Central LtdThis article has been made available through the Brunel Open Access Publishing Fund.Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. © 2013 Martin et al.; licensee BioMed Central Ltd.Oak Foundatio

Where are the Uranus Trojans?

The area of stable motion for fictitious Trojan asteroids around Uranus' equilateral equilibrium points is investigated with respect to the inclination of the asteroid's orbit to determine the size of the regions and their shape. For this task we used the results of extensive numerical integrations of orbits for a grid of initial conditions around the points L4 and L5, and analyzed the stability of the individual orbits. Our basic dynamical model was the Outer Solar System (Jupiter, Saturn, Uranus and Neptune). We integrated the equations of motion of fictitious Trojans in the vicinity of the stable equilibrium points for selected orbits up to the age of the Solar system of 5 billion years. One experiment has been undertaken for cuts through the Lagrange points for fixed values of the inclinations, while the semimajor axes were varied. The extension of the stable region with respect to the initial semimajor axis lies between 19.05 < a < 19.3 AU but depends on the initial inclination. In another run the inclination of the asteroids' orbit was varied in the range 0 < i < 60 and the semimajor axes were fixed. It turned out that only four 'windows' of stable orbits survive: these are the orbits for the initial inclinations 0 < i < 7, 9 < i < 13, 31 < i < 36 and 38 < i < 50. We postulate the existence of at least some Trojans around the Uranus Lagrange points for the stability window at small and also high inclinations.Comment: 15 pages, 12 figures, submitted to CMD

Genotoxic mixtures and dissimilar action: Concepts for prediction and assessment

This article has been made available through the Brunel Open Access Publishing Fund. This article is distributed under the terms of the creative commons Attribution license which permits any use, distribution, and reproduction in any medium, provided the original author(s)and the source are credited.Combinations of genotoxic agents have frequently been assessed without clear assumptions regarding their expected (additive) mixture effects, often leading to claims of synergisms that might in fact be compatible with additivity. We have shown earlier that the combined effects of chemicals, which induce micronuclei (MN) in the cytokinesis-block micronucleus assay in Chinese hamster ovary-K1 cells by a similar mechanism, were additive according to the concept of concentration addition (CA). Here, we extended these studies and investigated for the first time whether valid additivity expectations can be formulated for MN-inducing chemicals that operate through a variety of mechanisms, including aneugens and clastogens (DNA cross-linkers, topoisomerase II inhibitors, minor groove binders). We expected that their effects should follow the additivity principles of independent action (IA). With two mixtures, one composed of various aneugens (colchicine, flubendazole, vinblastine sulphate, griseofulvin, paclitaxel), and another composed of aneugens and clastogens (flubendazole, doxorubicin, etoposide, melphalan and mitomycin C), we observed mixture effects that fell between the additivity predictions derived from CA and IA. We achieved better agreement between observation and prediction by grouping the chemicals into common assessment groups and using hybrid CA/IA prediction models. The combined effects of four dissimilarly acting compounds (flubendazole, paclitaxel, doxorubicin and melphalan) also fell within CA and IA. Two binary mixtures (flubendazole/paclitaxel and flubendazole/doxorubicin) showed effects in reasonable agreement with IA additivity. Our studies provide a systematic basis for the investigation of mixtures that affect endpoints of relevance to genotoxicity and show that their effects are largely additive.UK Food Standards Agenc

A case study of neurodevelopmental risks from combined exposures to lead, methyl-mercury, inorganic arsenic, polychlorinated biphenyls, polybrominated diphenyl ethers and fluoride

We performed a mixture risk assessment (MRA) case study of dietary exposure to the food contaminants lead, methylmercury, inorganic arsenic (iAs), fluoride, non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs), all substances associated with declines in cognitive abilities measured as IQ loss. Most of these chemicals are frequently measured in human biomonitoring studies. A component-based, personalised modified reference point index (mRPI) approach, in which we expressed the exposures and potencies of our chosen substances as lead equivalent values, was applied to perform a MRA for dietary exposures. We conducted the assessment for four different age groups (toddlers, children, adolescents, and women aged 18–45 years) in nine European countries. Populations in all countries considered exceeded combined tolerable levels at median exposure levels. NDL-PCBs in fish, other seafood and dairy, lead in grains and fruits, methylmercury in fish and other seafoods, and fluoride in water contributed most to the combined exposure. We identified uncertainties for the likelihood of co-exposure, assessment group membership, endpoint-specific reference values (ESRVs) based on epidemiological (lead, methylmercury, iAs, fluoride and NDL-PCBs) and animal data (PBDE), and exposure data. Those uncertainties lead to a complex pattern of under- and overestimations, which would require probabilistic modelling based on expert knowledge elicitation for integration of the identified uncertainties into an overall uncertainty estimate. In addition, the identified uncertainties could be used to refine future MRA for cognitive decline.European Union’s Horizon 2020 research and innovation programme under grant agreement number 874583—the Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project. The author Mousumi Chatterjee is grateful for a Daphne Jackson Trust (UK) fellowship. The authors would like to thank EFSA providing the food consumption databases, data owners for giving permission to use the data, and Gerda van Donkersgoed and Matthijs Sam (RIVM) for organising the food consumption data and chemical concentration data