Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

The XMAP215-family protein DdCP224 is required for cortical interactions of microtubules

BACKGROUND: Interactions of peripheral microtubule tips with the cell cortex are of crucial importance for nuclear migration, spindle orientation, centrosome positioning and directional cell movement. Microtubule plus end binding proteins are thought to mediate interactions of microtubule tips with cortical actin and membrane proteins in a dynein-dependent manner. XMAP215-family proteins are main regulators of microtubule plus end dynamics but so far they have not been implicated in the interactions of microtubule tips with the cell cortex. RESULTS: Here we show that overexpression of an N-terminal fragment of DdCP224, the Dictyostelium XMAP215 homologue, caused a collapse of the radial microtubule cytoskeleton, whereby microtubules lost contact with the cell cortex and were dragged behind like a comet tail of an unusually motile centrosome. This phenotype was indistinguishable from mutants overexpressing fragments of the dynein heavy chain or intermediate chain. Moreover, it was accompanied by dispersal of the Golgi apparatus and reduced cortical localization of the dynein heavy chain indicating a disrupted dynein/dynactin interaction. The interference of DdCP224 with cortical dynein function is strongly supported by the observations that DdCP224 and its N-terminal fragment colocalize with dynein and coimmunoprecipitate with dynein and dynactin. CONCLUSIONS: Our data show that XMAP215-like proteins are required for the interaction of microtubule plus ends with the cell cortex in interphase cells and strongly suggest that this function is mediated by dynein

Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution December 1999Aryl hydrocarbon receptor (AHR) expression and activity was characterized in the teleost hepatoma cell line, PLHC-1. This work was carried out in order to gain insights into mechanisms of halogenated aromatic hydrocarbon (HAH) toxicity. The results improve our ability to characterize the risks posed by HAH exposure as well as further demonstrate the application of cultured cells to questions of AHR function. Cell proliferation, the cell cycle, and DNA sequences for an AHR2 and β-actin were all characterized in PLHC-1. Serum withdrawal of early-passage cells reduced AHR expression and consequently TCDD-induced induction of cytochrome P4501A (CYF1A), which is mediated by the AHR. Serum in cell culture medium was found to reduce bioavailability ofAHR agonists and significantly alter relative potencies of CYP1A induction, raising the possibility of artificial differences in measured potencies among cell types and laboratories. A quantitative pharmacological approach was used to show that both AHR binding affinity and intrinsic efficacy ofligands contribute to observed CYF1A induction potencies. These data also demonstrate the existence of "spare receptors" in this system. Non-additive effects of low-efficacy ligands call into question the utility of the "toxic equivalency factor" approach currently used for HAH risk assessment.I must also thank the National Science Foundation for believing in and supporting my potential and the Environmental Protection Agency, National Institutes of Health and Sea Grant for funding this research

Does the Provision of Information on their Skills Affect Students' Enrollment Choices?

This study assesses the impact of a French educational policy reform aimed at improving the match between students and their chosen field of study at university. As part of this reform, upon applying for entry to an undergraduate degree course, students are informed about their likelhood of succeeding given their observed skills. To examine the effect of the feedback they receive on students' choices, we compare students applying to different departments within the same university, some implementing the policy, providing candidates with feedback, whereas others do not. We find among those receiving a negative feedback that the proportion of students who decide to register for the degree course in question is reduced by about 7 percentage points but marginally significant at 10 percent level. Effects are heterogeneous according to students' origin and the type of high school they attended

Does the Provision of Information on their Skills Affect Students' Enrollment Choices?

This study assesses the impact of a French educational policy reform aimed at improving the match between students and their chosen field of study at university. As part of this reform, upon applying for entry to an undergraduate degree course, students are informed about their likelhood of succeeding given their observed skills. To examine the effect of the feedback they receive on students' choices, we compare students applying to different departments within the same university, some implementing the policy, providing candidates with feedback, whereas others do not. We find among those receiving a negative feedback that the proportion of students who decide to register for the degree course in question is reduced by about 7 percentage points but marginally significant at 10 percent level. Effects are heterogeneous according to students' origin and the type of high school they attended

Does the Provision of Information on their Skills Affect Students' Enrollment Choices?

This study assesses the impact of a French educational policy reform aimed at improving the match between students and their chosen field of study at university. As part of this reform, upon applying for entry to an undergraduate degree course, students are informed about their likelhood of succeeding given their observed skills. To examine the effect of the feedback they receive on students' choices, we compare students applying to different departments within the same university, some implementing the policy, providing candidates with feedback, whereas others do not. We find among those receiving a negative feedback that the proportion of students who decide to register for the degree course in question is reduced by about 7 percentage points but marginally significant at 10 percent level. Effects are heterogeneous according to students' origin and the type of high school they attended

Does the Provision of Information on their Skills Affect Students' Enrollment Choices?

This study assesses the impact of a French educational policy reform aimed at improving the match between students and their chosen field of study at university. As part of this reform, upon applying for entry to an undergraduate degree course, students are informed about their likelhood of succeeding given their observed skills. To examine the effect of the feedback they receive on students' choices, we compare students applying to different departments within the same university, some implementing the policy, providing candidates with feedback, whereas others do not. We find among those receiving a negative feedback that the proportion of students who decide to register for the degree course in question is reduced by about 7 percentage points but marginally significant at 10 percent level. Effects are heterogeneous according to students' origin and the type of high school they attended