Advancing the use of new approach methodologies for assessing teratogenicity: Building a tiered approach.

Many New Approach Methodologies (NAMs) have been developed for the safety assessment of new ingredients. Research into reproductive toxicity and teratogenicity is a particularly high priority, especially given their mechanistic complexity. Forty-six non-teratogenic and 39 teratogenic chemicals were screened for teratogenic potential using the in silico DART model from the OECD QSAR Toolbox; the devTox quickPredict™ (devTox assay) test and the Zebrafish Embryotoxicity Test (ZET). The sensitivity and specificity were 94.7% and 84.1%, respectively, for the DART tree (83 chemicals), 86.1% and 35.6% for the devTox (81 chemicals) and 77.8% and 76.7% for the ZET (57 chemicals). Fifty-three chemicals were tested in all three assays and when results were combined and based on a "2 out of 3 rule", the sensitivity and specificity were 96.0% and 71.4%, respectively. The specificity of the devTox assay for a sub-set of 43 chemicals was increased from 26.1% to 82.6% by incorporating human plasma concentrations into the assay interpretation. When all 85 chemicals were assessed in a decision tree approach, there was an excellent predictivity and assay robustness of 90%. In conclusion, all three models exhibited a good sensitivity and specificity, especially when outcomes from all three were combined or used in "2 out of 3" or a tiered decision tree approach. The latter is an interesting predictive approach for evaluating the teratogenic potential of new chemicals. Future investigations will extend the number of chemicals tested, as well as explore ways to refine the results and obtain a robust Integrated Testing Strategy to evaluate teratogenic potential.

Boost-HiC: computational enhancement of long-range contacts in chromosomal contact maps.

MOTIVATION: Genome-wide chromosomal contact maps are widely used to uncover the 3D organization of genomes. They rely on collecting millions of contacting pairs of genomic loci. Contacts at short range are usually well measured in experiments, while there is a lot of missing information about long-range contacts. RESULTS: We propose to use the sparse information contained in raw contact maps to infer high-confidence contact counts between all pairs of loci. Our algorithmic procedure, Boost-HiC, enables the detection of Hi-C patterns such as chromosomal compartments at a resolution that would be otherwise only attainable by sequencing a hundred times deeper the experimental Hi-C library. Boost-HiC can also be used to compare contact maps at an improved resolution. AVAILABILITY AND IMPLEMENTATION: Boost-HiC is available at https://github.com/LeopoldC/Boost-HiC. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Scanning probe microscopies applied to the study of the domain wall in a ferroelectric crystal.

Scanning near-field optical microscopy is capable of measuring the topography and optical signals at the same time. This fact makes this technique a valuable tool in the study of materials at nanometric scale and, in particular, of ferroelectric materials, as it permits the study of their domains structure without the need of chemical etching and, therefore, not damaging the surface (as will be demonstrated later). We have measured the scanning near-field optical microscopy transmission, as well as the topography, of an RbTiOPO(4) single crystalline slab, which exhibits two different of macroscopic ferroelectric domains. A chemical selective etching has been performed to distinguish between them, obtaining areas with a noticeable roughness (C(-) domain) in comparison with the original flat aspect of the other ones (C(+) domain). The effects of the selective chemical etching have been quantified in topographic images obtained by means of our fibre tip probe, and have been compared to topographic images obtained by Atomic Force Microscopy, with a better resolution. The near-field optical transmission images recorded have been obtained under different excitation wavelengths. These images are modulated by the light scattering due to the grains at the rough surface, which depends on the excitation wavelength used. In addition, they show a significant optical contrast due to the variations of the dielectric constant on the proximity of the ferroelectric domain wall.

Excitations of the orbital order in RMnO3 manganites: light scattering experiments.

Raman spectroscopy was used to seek out the orbital excitations in orbitally ordered RMnO3. The high energy Raman peaks are found to correspond to second and third order phonons which couple in some degree to the orbital order. Franck-Condon-type Raman resonance of multiphonons is observed but the cross sections are smaller than expected. A surging emission band at 1.5 eV, detected at high temperatures, disappears when the orbital order is established. The crossing of the configurational coordinate diagrams of the localized 3d Mn lowest levels, in the orbitally ordered state, originates the nonradiative relaxation and the quenching of the luminescence.

Behavioral effects of intraventricularly administered (-)-nicotine on fixed ratio schedules of food presentation in rats.

The behavioral effects of intraventricularly (IVT) administered (-)-nicotine on food-maintained behavior were studied. Rats responded by pressing a lever under various fixed ratio (FR) schedules. Infusion of 5 microgram of (-)-nicotine suppressed responding under an FR 16 schedule for 11-13 min. The effect was inversely related to the ratio size (16, 32, 64 responses per food delivery), but it was directly related to the infused (-)-nicotine dose (0.312, 0.624, 1.25, 2.5, 5.0, 10.0 microgram) when ratio size was held constant. Responses rates following the (-)-nicotine-induced suppression were similar to those obtained prior to infusion. The behavioral effects of (-)-nicotine were blocked, in a dose-related manner, by the centrally acting nicotinic-cholinergic antagonist, mecamylamine (0.05-3.0 mg/kg) but not by ther peripherally acting antagonist, hexamethonium (0.5-3.0 mg/kg), suggesting that the behavioral effects of IVT infusions of (-)-nicotine are mediated by central nicotine-cholinergic receptors.