Using Molecular Initiating Events to Develop a Structural Alert Based Screening Workflow for Nuclear Receptor Ligands Associated with Hepatic Steatosis

In silico models are essential to the development of integrated alternative methods to identify organ level toxicity and lead towards the replacement of animal testing. These models include (quantitative) structure-activity relationships ((Q)SARs) and, importantly, the identification of structural alerts associated with defined toxicological endpoints. Structural alerts are able both to predict toxicity directly and assist in the formation of categories to facilitate read-across. They are particularly important to decipher the myriad mechanisms of action that result in organ level toxicity. The aim of this study was to develop novel structural alerts for nuclear receptor (NR) ligands that are associated with inducing hepatic steatosis. Current knowledge on NR agonists was extended with data from the ChEMBL database of bioactive molecules and from studying NR ligand-binding interactions within the protein data base (PBD). A computational structural alerts based workflow was developed using KNIME from these data using molecular fragments and other relevant chemical features. In total 214 structural features were recorded computationally as SMARTS strings and, therefore, they can be used for grouping and screening during drug development and risk assessment and provide knowledge to anchor adverse outcome pathways (AOP)

Characterization of the recently detected cathinone N-cyclohexyl butylone: From structure elucidation to in silico supported pharmacological/ toxicological considerations

One of the most widely consumed new psychoactive substances (NPS) families in Europe are synthetic cathinones. Cathinone structure can be easily modified resulting in new derivatives that rapidly reach drug markets. In this work, the recently detected synthetic cathinone N-cyclohexyl butylone has been characterized by gas chromatography coupled to mass spectrometry (GC–MS), liquid chromatography coupled to high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) and Fourier-transformed infrared (FTIR) spectroscopy, using research chemicals samples collected by the drug analysis service Energy Control from anonymous users. Compound identification was performed by the combination of HRMS and NMR data. The elemental composition and putative moieties of the compound were determined based on the accurate-mass ions observed by HRMS. Then, different NMR experiments, including bidimensional, allowed the establishment of the chemical structure and confirmation of compound identity. Furthermore, FTIR spectrum was also acquired in order to provide a complete analytical characterization of the novel cathinone. Finally, pharmacological/toxicological characterization was attempted using in silico methods. Based on these predictions, N-cyclohexyl butylone probably has similar effects to stimulants like MDMA

NvPrdm14d-expressing neural progenitor cells contribute to non-ectodermal neurogenesis in Nematostella vectensis

Neurogenesis has been studied extensively in the ectoderm, from which most animals generate the majority of their neurons. Neurogenesis from non-ectodermal tissue is, in contrast, poorly understood. Here we use the cnidarian Nematostella vectensis as a model to provide new insights into the molecular regulation of non-ectodermal neurogenesis. We show that the transcription factor NvPrdm14d is expressed in a subpopulation of NvSoxB(2)-expressing endodermal progenitor cells and their NvPOU4-expressing progeny. Using a new transgenic reporter line, we show that NvPrdm14d-expressing cells give rise to neurons in the body wall and in close vicinity of the longitudinal retractor muscles. RNA-sequencing of NvPrdm14d::GFP-expressing cells and gene knockdown experiments provide candidate genes for the development and function of these neurons. Together, the identification of a population of endoderm-specific neural progenitor cells and of previously undescribed putative motoneurons in Nematostella provide new insights into the regulation of non-ectodermal neurogenesis.publishedVersio

A Preliminary Analysis of Long-Term Changes in the Value of Landings by French Fishing Fleets Operating in the North-East Atlantic

Recent work in the domain of fisheries ecology has shown that major changes are occurring in fish communities exploited by commercial fisheries. Selective fishing pressure on more highly valued components of fish communities, and its indirect effects via trophic interactions, are amongst the key factors proposed to explain these changes. Under de facto open access conditions, it is suggested that sequential overharvesting of higher valued fish and/or fish species leads to modifications in the structure of both fish communities, and fisheries landings. An important question is the implication of such changes in terms of the total value of landings from a given fish community. The aim of this paper is to present a preliminary analysis of this question in the context of French commercial fisheries. The analysis focuses on trends observed in the landings of fishing fleets operating in the North East Atlantic, over the last three decades. It is based on data concerning annual quantities landed and prices of 85 species, compiled by the authors from French official landings records. Changes in total quantity and total value landed are presented, as well as changes in the structure of landings in terms of the ecological characteristics of species landed. Using the economic theory of index numbers allows to separate volume and price variations, and to analyze their respective contributions to variations in gross turnover. Key drivers of these variations are then discussed.Keywords: Price Fluctuations, Catch Composition, Long Term Trends in Landings, Ecological Impacts of Fishing and Climate ChangeKeywords: Price Fluctuations, Catch Composition, Long Term Trends in Landings, Ecological Impacts of Fishing and Climate Chang

Hydrodynamic simulations of merging clusters of galaxies

We present the results of high-resolution AP3M+SPH simulations of merging clusters of galaxies. We find that the compression and shocking of the core gas during a merger can lead to large increases in bolometric X-ray luminosities and emission-weighted temperatures of clusters. Cooling flows are completely disrupted during equal-mass mergers, with the mass deposition rate dropping to zero as the cores of the clusters collide. The large increase in the cooling time of the core gas strongly suggests that cooling flows will not recover from such a merger within a Hubble time. Mergers with subclumps having one eighth of the mass of the main cluster are also found to disrupt a cooling flow if the merger is head-on. However, in this case the entropy injected into the core gas is rapidly radiated away and the cooling flow restarts within a few Gyr of the merger. Mergers in which the subcluster has an impact parameter of 500 kpc do not disrupt the cooling flow, although the mass deposition rate is reduced by ∼30 per cent. Finally, we find that equal mass, off-centre mergers can effectively mix gas in the cores of clusters, while head on mergers lead to very little mixing. Gas stripped from the outer layers of subclumps results in parts of the outer layers of the main cluster being well mixed, although they have little effect on the gas in the core of the cluster. None of the mergers examined here resulted in the intracluster medium being well mixed globally

Modelling Shear Flows with SPH and Grid Based Methods

Given the importance of shear flows for astrophysical gas dynamics, we study the evolution of the Kelvin-Helmholtz instability (KHI) analytically and numerically. We derive the dispersion relation for the two-dimensional KHI including viscous dissipation. The resulting expression for the growth rate is then used to estimate the intrinsic viscosity of four numerical schemes depending on code-specific as well as on physical parameters. Our set of numerical schemes includes the Tree-SPH code VINE, an alternative SPH formulation developed by Price (2008), and the finite-volume grid codes FLASH and PLUTO. In the first part, we explicitly demonstrate the effect of dissipation-inhibiting mechanisms such as the Balsara viscosity on the evolution of the KHI. With VINE, increasing density contrasts lead to a continuously increasing suppression of the KHI (with complete suppression from a contrast of 6:1 or higher). The alternative SPH formulation including an artificial thermal conductivity reproduces the analytically expected growth rates up to a density contrast of 10:1. The second part addresses the shear flow evolution with FLASH and PLUTO. Both codes result in a consistent non-viscous evolution (in the equal as well as in the different density case) in agreement with the analytical prediction. The viscous evolution studied with FLASH shows minor deviations from the analytical prediction.Comment: 16 pages, 17 figure

Radio galaxy selected clusters at high redshift and associated ERO overdensities

Galaxy clusters at high redshift present a superb opportunity to study galaxy evolution, with large galaxy samples at fixed distances. Several lines of evidence point towards large formation redshifts and passive evolution for cluster ellipticals. At redshifts larger than z~0.8, this picture rests on data from only a handful of rich clusters. We have observed four potential clusters to sample sparser environments in a critical redshift range, 0.8 < z < 1.2. We compare the photometric evolution and radial density profiles in our clusters with more massive clusters studied in a similar manner. We also highlight the overdense ERO (I-K>5) population, significantly redder than the old elliptical population at the cluster redshift. We discuss the implications of our clusters at high redshift, and possible differences in environment from richer clusters at similar redshifts selected through X-ray or optical techniques.Comment: 13 pages, 7 figures, accepted in the Astronomical Journal, Oct2000 issu

Data quality in the human and environmental health sciences: Using statistical confidence scoring to improve QSAR/QSPR modeling

A greater number of toxicity data are becoming publicly available allowing for in silico modeling. However, questions often arise as how to incorporate data quality and how to deal with contradicting data if more than a single datum point is available for the same compound. In this study, two well-known and studied QSAR/QSPR models for skin permeability and aquatic toxicology have been investigated in the context of statistical data quality. In particular, the potential benefits of the incorporation of the statistical Confidence Scoring (CS) approach within modelling and validation. As a result, robust QSAR/QSPR models for the skin permeability coefficient and the toxicity of nonpolar narcotics to Aliivibrio fischeri assay were created. CSweighted linear regression for training and CS-weighted root mean square error (RMSE) for validation were statistically superior compared to standard linear regression and standard RMSE. Strategies are proposed as to how to interpret data with high and low CS, as well as how to deal with large datasets containing multiple entries

Flow-Driven Cloud Formation and Fragmentation: Results From Eulerian and Lagrangian Simulations

The fragmentation of shocked flows in a thermally bistable medium provides a natural mechanism to form turbulent cold clouds as precursors to molecular clouds. Yet because of the large density and temperature differences and the range of dynamical scales involved, following this process with numerical simulations is challenging. We compare two-dimensional simulations of flow-driven cloud formation without self-gravity, using the Lagrangian Smoothed Particle Hydrodynamics (SPH) code VINE and the Eulerian grid code Proteus. Results are qualitatively similar for both methods, yet the variable spatial resolution of the SPH method leads to smaller fragments and thinner filaments, rendering the overall morphologies different. Thermal and hydro-dynamical instabilities lead to rapid cooling and fragmentation into cold clumps with temperatures below 300K. For clumps more massive than 1 Msun/pc, the clump mass function has an average slope of -0.8. The internal velocity dispersion of the clumps is nearly an order of magnitude smaller than their relative motion, rendering it subsonic with respect to the internal sound speed of the clumps, but supersonic as seen by an external observer. For the SPH simulations most of the cold gas resides at temperatures below 100K, while the grid-based models show an additional, substantial component between 100 and 300K. Independently of the numerical method our models confirm that converging flows of warm neutral gas fragment rapidly and form high-density, low-temperature clumps as possible seeds for star formation.Comment: 9 pages, 8 figures, MNRAS accepte

Extensive Variation in Chromatin States Across Humans

The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans