Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126.

Chemical pollutant exposure is a risk factor contributing to the growing epidemic of non-alcoholic fatty liver disease (NAFLD) affecting human populations that consume a western diet. Although it is recognized that intoxication by chemical pollutants can lead to NAFLD, there is limited information available regarding the mechanism by which typical environmental levels of exposure can contribute to the onset of this disease. Here, we describe the alterations in gene expression profiles and metabolite levels in the human HepaRG liver cell line, a validated model for cellular steatosis, exposed to the polychlorinated biphenyl (PCB) 126, one of the most potent chemical pollutants that can induce NAFLD. Sparse partial least squares classification of the molecular profiles revealed that exposure to PCB 126 provoked a decrease in polyunsaturated fatty acids as well as an increase in sphingolipid levels, concomitant with a decrease in the activity of genes involved in lipid metabolism. This was associated with an increased oxidative stress reflected by marked disturbances in taurine metabolism. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. These changes in metabolome and transcriptome profiles were observed even at the lowest concentration (100 pM) of PCB 126 tested. A decrease in docosatrienoate levels was the most sensitive biomarker. Overall, our integrated multi-omics analysis provides mechanistic insight into how this class of chemical pollutant can cause NAFLD. Our study lays the foundation for the development of molecular signatures of toxic effects of chemicals causing fatty liver diseases to move away from a chemical risk assessment based on in vivo animal experiments

a-Synuclein and lipids in erythrocytes of Gaucher disease carriers and patients before and after enzyme replacement therapy

It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson's disease. A plethora of evidence suggests that disturbed alpha-Synuclein homeostasis is the link between Gaucher disease and Parkinson's disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated alpha-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of alpha-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized alpha-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating alpha-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of alpha-Synuclein oligomerization in this system.Medical Biochemistr

Testing a Spectral Model of Tonal Affinity with Microtonal Melodies and Inharmonic Spectra

Tonal affinity is the perceived goodness of fit of successive tones. It is important because a preference for certain intervals over others would likely influence preferences for, and prevalences of, “higher-order” musical structures such as scales and chord progressions. We hypothesize that two psychoacoustic (spectral) factors—harmonicity and spectral pitch similarity—have an impact on affinity. The harmonicity of a single tone is the extent to which its partials (frequency components) correspond to those of a harmonic complex tone (whose partials are a multiple of a single fundamental frequency). The spectral pitch similarity of two tones is the extent to which they have partials with corresponding, or close, frequencies. To ascertain the unique effect sizes of harmonicity and spectral pitch similarity, we constructed a computational model to numerically quantify them. The model was tested against data obtained from 44 participants who ranked the overall affinity of tones in melodies played in a variety of tunings (some microtonal) with a variety of spectra (some inharmonic). The data indicate the two factors have similar, but independent, effect sizes: in combination, they explain a sizeable portion of the variance in the data (the model-data squared correlation is r2 = .64). Neither harmonicity nor spectral pitch similarity require prior knowledge of musical structure, so they provide a potentially universal bottom-up explanation for tonal affinity. We show how the model—as optimized to these data—can explain scale structures commonly found in music, both historical and contemporary, and we discuss its implications for experimental microtonal and spectral music

The major geoeffective solar eruptions of 2012 March 7: comprehensive Sun-to-Earth analysis

During the interval 2012 March 7-11 the geospace experienced a barrage of intense space weather phenomena including the second largest geomagnetic storm of solar cycle 24 so far. Significant ultra-low-frequency wave enhancements and relativistic-electron dropouts in the radiation belts, as well as strong energetic-electron injection events in the magnetosphere were observed. These phenomena were ultimately associated with two ultra-fast (>2000 kms-1) coronal mass ejections (CMEs), linked to two X-class flares launched on early 2012 March 7. Given that both powerful events originated from solar active region NOAA 11429 and their onsets were separated by less than an hour, the analysis of the two events and the determination of solar causes and geospace effects are rather challenging. Using satellite data from a flotilla of solar, heliospheric and magnetospheric missions a synergistic Sun-to-Earth study of diverse observational solar, interplanetary and magnetospheric data sets was performed. It was found that only the second CME was Earth-directed. Using a novel method, we estimated its near-Sun magnetic field at 13R⊙ to be in the range [0.01, 0.16] G. Steep radial fall-offs of the near-Sun CME magnetic field are required to match the magnetic fields of the corresponding interplanetary CME (ICME) at 1 AU. Perturbed upstream solar-wind conditions, as resulting from the shock associated with the Earth-directed CME, offer a decent description of its kinematics. The magnetospheric compression caused by the arrival at 1 AU of the shock associated with the ICME was a key factor for radiation-belt dynamics.Publisher PDFPeer reviewe

Effect of Interlaminar Epidural Steroid Injection in Acute and Subacute Pain Due to Lumbar Disk Herniation: A Randomized Comparison of 2 Different Protocols

In order to assess the efficacy of epidural steroid injections (ESI) in acute and subacute pain due to lumbar spine disk herniation, we conducted a randomized trial, comparing 2 different protocols. Fourty patients with radicular pain due to L4-L5 and L5-S1 disc herniation were assigned to receive either 3 consecutive ESI every 24 hours through a spinal catheter (group A) or 3 consecutive ESI every 10 days with an epidural needle (group B). All patients had improved Oswestry Disabilty Index (ODI) and the Visual Analog Scale (VAS) for pain scores at 1 month of follow-up compared to baseline, while no significant differences were observed between the 2 groups. The scores for group B were statistically significant lower at 2 months of follow-up compared to those of group A. The improvement in the scores of group B was continuous since the mean scores at 2 months of follow up were lower compared to the respective scores at 1 month. Protocol B (3 consecutive ESI every 10 days) was found more effective in the treatment of subacute pain compared to Protocol A (3 consecutive ESI every 24 hours) with statistically significant differences in the ODI and VAS scores at 2 months of follow-up

Analysis of information gain and Kolmogorov complexity for structural evaluation of cellular automata configurations

Shannon entropy fails to discriminate structurally different patterns in two-dimensional images. We have adapted information gain measure and Kolmogorov complexity to overcome the shortcomings of entropy as a measure of image structure. The measures are customised to robustly quantify the complexity of images resulting from multi-state cellular automata (CA). Experiments with a two-dimensional multi-state cellular automaton demonstrate that these measures are able to predict some of the structural characteristics, symmetry and orientation of CA generated patterns