Substantiate a read-across hypothesis by using transcriptome data—A case study on volatile diketones

This case study explores the applicability of transcriptome data to characterize a common mechanism of action within groups of short-chain aliphatic α-, β-, and γ-diketones. Human reference in vivo data indicate that the α-diketone diacetyl induces bronchiolitis obliterans in workers involved in the preparation of microwave popcorn. The other three α-diketones induced inflammatory responses in preclinical in vivo animal studies, whereas beta and gamma diketones in addition caused neuronal effects. We investigated early transcriptional responses in primary human bronchiolar (PBEC) cell cultures after 24 h and 72 h of air-liquid exposure. Differentially expressed genes (DEGs) were assessed based on transcriptome data generated with the EUToxRisk gene panel of Temp-O-Seq®. For each individual substance, genes were identified displaying a consistent differential expression across dose and exposure duration. The log fold change values of the DEG profiles indicate that α- and β-diketones are more active compared to γ-diketones. α-diketones in particular showed a highly concordant expression pattern, which may serve as a first indication of the shared mode of action. In order to gain a better mechanistic understanding, the resultant DEGs were submitted to a pathway analysis using ConsensusPathDB. The four α-diketones showed very similar results with regard to the number of activated and shared pathways. Overall, the number of signaling pathways decreased from α-to β-to γ-diketones. Additionally, we reconstructed networks of genes that interact with one another and are associated with different adverse outcomes such as fibrosis, inflammation or apoptosis using the TRANSPATH-database. Transcription factor enrichment and upstream analyses with the geneXplain platform revealed highly interacting gene products (called master regulators, MRs) per case study compound. The mapping of the resultant MRs on the reconstructed networks, visualized similar gene regulation with regard to fibrosis, inflammation and apoptosis. This analysis showed that transcriptome data can strengthen the similarity assessment of compounds, which is of particular importance, e.g., in read-across approaches. It is one important step towards grouping of compounds based on biological profiles

Air–Liquid Interface In Vitro Models for Respiratory Toxicology Research: Consensus Workshop and Recommendations

In vitro air–liquid interface (ALI) cell culture models can potentially be used to assess inhalation toxicology endpoints and are usually considered, in terms of relevancy, between classic (i.e., submerged) in vitro models and animal-based models. In some situations that need to be clearly defined, ALI methods may represent a complement or an alternative option to in vivo experimentations or classic in vitro methods. However, it is clear that many different approaches exist and that only very limited validation studies have been carried out to date. This means comparison of data from different methods is difficult and available methods are currently not suitable for use in regulatory assessments. This is despite inhalation toxicology being a priority area for many governmental organizations. In this setting, a 1-day workshop on ALI in vitro models for respiratory toxicology research was organized in Paris in March 2016 to assess the situation and to discuss what might be possible in terms of validation studies. The workshop was attended by major parties in Europe and brought together more than 60 representatives from various academic, commercial, and regulatory organizations. Following plenary, oral, and poster presentations, an expert panel was convened to lead a discussion on possible approaches to validation studies for ALI inhalation models. A series of recommendations were made and the outcomes of the workshop are reported

Ambient-noise tomography of the wider Vienna Basin region

We present a new 3-D shear-velocity model for the top 30 km of the crust in the wider Vienna Basin region based on surface waves extracted from ambient-noise cross-correlations. We use continuous seismic records of 63 broad-band stations of the AlpArray project to retrieve interstation Green’s functions from ambient-noise cross-correlations in the period range from 5 to 25 s. From these Green’s functions, we measure Rayleigh group traveltimes, utilizing all four components of the cross-correlation tensor, which are associated with Rayleigh waves (ZZ, RR, RZ and ZR), to exploit multiple measurements per station pair. A set of selection criteria is applied to ensure that we use high-quality recordings of fundamental Rayleigh modes. We regionalize the interstation group velocities in a 5 km × 5 km grid with an average path density of ∼20 paths per cell. From the resulting group-velocity maps, we extract local 1-D dispersion curves for each cell and invert all cells independently to retrieve the crustal shear-velocity structure of the study area. The resulting model provides a previously unachieved lateral resolution of seismic velocities in the region of ∼15 km. As major features, we image the Vienna Basin and Little Hungarian Plain as low-velocity anomalies, and the Bohemian Massif with high velocities. The edges of these features are marked with prominent velocity contrasts correlated with faults, such as the Alpine Front and Vienna Basin transfer fault system. The observed structures correlate well with surface geology, gravitational anomalies and the few known crystalline basement depths from boreholes. For depths larger than those reached by boreholes, the new model allows new insight into the complex structure of the Vienna Basin and surrounding areas, including deep low-velocity zones, which we image with previously unachieved detail. This model may be used in the future to interpret the deeper structures and tectonic evolution of the wider Vienna Basin region, evaluate natural resources, model wave propagation and improve earthquake locations, among others

Arrival angles of teleseismic fundamental mode Rayleigh waves across the AlpArray

The dense AlpArray network allows studying seismic wave propagation with high spatial resolution. Here we introduce an array approach to measure arrival angles of teleseismic Rayleigh waves. The approach combines the advantages of phase correlation as in the two-station method with array beamforming to obtain the phase-velocity vector. 20 earthquakes from the first two years of the AlpArray project are selected, and spatial patterns of arrival-angle deviations across the AlpArray are shown in maps, depending on period and earthquake location. The cause of these intriguing spatial patterns is discussed. A simple wave-propagation modelling example using an isolated anomaly and a Gaussian beam solution suggests that much of the complexity can be explained as a result of wave interference after passing a structural anomaly along the wave paths. This indicates that arrival-angle information constitutes useful additional information on the Earth structure, beyond what is currently used in inversions

Crustal Thinning From Orogen to Back-Arc Basin: The Structure of the Pannonian Basin Region Revealed by P-to-S Converted Seismic Waves

We present the results of P-to-S receiver function analysis to improve the 3D image of the sedimentary layer, the upper crust, and lower crust in the Pannonian Basin area. The Pannonian Basin hosts deep sedimentary depocentres superimposed on a complex basement structure and it is surrounded by mountain belts. We processed waveforms from 221 three-component broadband seismological stations. As a result of the dense station coverage, we were able to achieve so far unprecedented spatial resolution in determining the velocity structure of the crust. We applied a three-fold quality control process; the first two being applied to the observed waveforms and the third to the calculated radial receiver functions. This work is the first comprehensive receiver function study of the entire region. To prepare the inversions, we performed station-wise H-Vp/Vs grid search, as well as Common Conversion Point migration. Our main focus was then the S-wave velocity structure of the area, which we determined by the Neighborhood Algorithm inversion method at each station, where data were sub-divided into back-azimuthal bundles based on similar Ps delay times. The 1D, nonlinear inversions provided the depth of the discontinuities, shear-wave velocities and Vp/Vs ratios of each layer per bundle, and we calculated uncertainty values for each of these parameters. We then developed a 3D interpolation method based on natural neighbor interpolation to obtain the 3D crustal structure from the local inversion results. We present the sedimentary thickness map, the first Conrad depth map and an improved, detailed Moho map, as well as the first upper and lower crustal thickness maps obtained from receiver function analysis. The velocity jump across the Conrad discontinuity is estimated at less than 0.2 km/s over most of the investigated area. We also compare the new Moho map from our approach to simple grid search results and prior knowledge from other techniques. Our Moho depth map presents local variations in the investigated area: the crust-mantle boundary is at 20–26 km beneath the sedimentary basins, while it is situated deeper below the Apuseni Mountains, Transdanubian and North Hungarian Ranges (28–33 km), and it is the deepest beneath the Eastern Alps and the Southern Carpathians (40–45 km). These values reflect well the Neogene evolution of the region, such as crustal thinning of the Pannonian Basin and orogenic thickening in the neighboring mountain belts

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Entwicklung eines Systems zur Untersuchung der biologischen Aktivität atmosphärischer Gase in vitro

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