Chronic ethanol feeding alters miRNA expression dynamics during liver regeneration.

BACKGROUND: Adaptation to chronic ethanol (EtOH) treatment of rats results in a changed functional state of the liver and greatly inhibits its regenerative ability, which may contribute to the progression of alcoholic liver disease. METHODS: In this study, we investigated the effect of chronic EtOH intake on hepatic microRNA (miRNA) expression in male Sprague-Dawley rats during the initial 24 hours of liver regeneration following 70% partial hepatectomy (PHx) using miRNA microarrays. miRNA expression during adaptation to EtOH was investigated using RT-qPCR. Nuclear factor kappa B (NFκB) binding at target miRNA promoters was investigated with chromatin immunoprecipitation. RESULTS: Unsupervised clustering of miRNA expression profiles suggested that miRNA expression was more affected by chronic EtOH feeding than by the acute challenge of liver regeneration after PHx. Several miRNAs that were significantly altered by chronic EtOH feeding, including miR-34a, miR-103, miR-107, and miR-122 have been reported to play a role in regulating hepatic metabolism and the onset of these miRNA changes occurred gradually during the time course of EtOH feeding. Chronic EtOH feeding also altered the dynamic miRNA profile during liver regeneration. Promoter analysis predicted a role for NFκB in the immediate-early miRNA response to PHx. NFκB binding at target miRNA promoters in the chronic EtOH-fed group was significantly altered and these changes directly correlated with the observed expression dynamics of the target miRNA. CONCLUSIONS: Chronic EtOH consumption alters the hepatic miRNA expression profile such that the response of the metabolism-associated miRNAs occurs during long-term adaptation to EtOH rather than as an acute transient response to EtOH metabolism. Additionally, the dynamic miRNA program during liver regeneration in response to PHx is altered in the chronically EtOH-fed liver and these differences reflect, in part, differences in miRNA expression between the EtOH-adapted and control livers at the baseline state prior to PHx

A Common Origin for Quasar Extended Emission-Line Regions and Their Broad-Line Regions

We present a correlation between the presence of luminous extended emission-line regions (EELRs) and the metallicity of the broad-line regions (BLRs) of low-redshift quasars. The result is based on ground-based [O III] 5007 narrow-band imaging and Hubble Space Telescope UV spectra of 12 quasars at 0.20 < z < 0.45. Quasars showing luminous EELRs have low-metallicity BLRs (Z < 0.6 Z_Solar), while the remaining quasars show typical metal-rich gas (Z > Z_Solar). Previous studies have shown that EELRs themselves also have low metallicities (Z < 0.5 Z_Solar). The correlation between the occurrence of EELRs and the metallicity of the BLRs, strengthened by the sub-Solar metallicity in both regions, indicates a common external origin for the gas, almost certainly from the merger of a gas-rich galaxy. Our results provide the first direct observational evidence that the gas from a merger can indeed be driven down to the immediate vicinity (< 1 pc) of the central black hole.Comment: Accepted for publication in ApJ Letters. 4 pages, 1 figure, 1 tabl

Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin.

The extracellular matrix is a master regulator of tissue homeostasis in health and disease. Here we examined how the small, leucine-rich, extracellular matrix proteoglycan decorin regulates cardiomyocyte metabolism during fasting in vivo. First, we validated in Dcn-/- mice that decorin plays an essential role in autophagy induced by fasting. High-Throughput metabolomics analyses of cardiac tissue in Dcn-/- mice subjected to fasting revealed striking differences in the hexosamine biosynthetic pathway resulting in aberrant cardiac O-β-N-Acetylglycosylation as compared with WT mice. Functionally, Dcn-/- mice maintained cardiac function at a level comparable with nonfasted animals whereas fasted WT mice showed reduced ejection fraction. Collectively, our results suggest that reduced sensing of nutrient deprivation in the absence of decorin preempts functional adjustments of cardiac output associated with metabolic reprogramming. © 2018 Gubbiotti et al

Computational modeling analysis of mitochondrial superoxide production under varying substrate conditions and upon inhibition of different segments of the electron transport chain.

A computational mechanistic model of superoxide (O2•-) formation in the mitochondrial electron transport chain (ETC) was developed to facilitate the quantitative analysis of factors controlling mitochondrial O2•- production and assist in the interpretation of experimental studies. The model takes into account all individual electron transfer reactions in Complexes I and III. The model accounts for multiple, often seemingly contradictory observations on the effects of ΔΨ and ΔpH, and for the effects of multiple substrate and inhibitor conditions, including differential effects of Complex III inhibitors antimycin A, myxothiazol and stigmatellin. Simulation results confirm that, in addition to O2•- formation in Complex III and at the flavin site of Complex I, the quinone binding site of Complex I is an additional superoxide generating site that accounts for experimental observations on O2•- production during reverse electron transfer. However, our simulation results predict that, when cytochrome c oxidase is inhibited during oxidation of succinate, ROS production at this site is eliminated and almost all superoxide in Complex I is generated by reduced FMN, even when the redox pressure for reverse electron transfer from succinate is strong. In addition, the model indicates that conflicting literature data on the kinetics of electron transfer in Complex III involving the iron-sulfur protein-cytochrome bL complex can be resolved in favor of a dissociation of the protein only after electron transfer to cytochrome bH. The model predictions can be helpful in understanding factors driving mitochondrial superoxide formation in intact cells and tissues

Reconstruction methods — P&#8254;ANDA focussing-light guide disc DIRC

The Focussing-Lightguide Disc DIRC will provide crucial Particle Identification (PID) information for the P&#8254;ANDA experiment at FAIR, GSI. This detector presents a challenging environment for reconstruction due to the complexity of the expected hit patterns and the operating conditions of the P&#8254;ANDA experiment. A discussion of possible methods to reconstruct PID from this detector is given here. Reconstruction software is currently under development

The evolution of the stellar populations in low surface brightness galaxies

We investigate the star formation history and chemical evolution of low surface brightness (LSB) disk galaxies by modelling their observed spectro-photometric and chemical properties using a galactic chemical and photometric evolution model incorporating a detailed metallicity depen dent set of stellar input data. For a large fraction of the LSB galaxies in our sample, observed properties are best explained by models incorporating an exponentially decreasing global star formation rate (SFR) ending at a present-day gas fraction (M_{gas}/(M_{gas}+M_{stars}) = 0.5 for a galaxy age of 14 Gyr. For some galaxies small amplitude star formation bursts are required to explain the contribution of the young (5-50 Myr old) stellar population to the galaxy integrated luminosity. This suggests that star formation has proceeded in a stochastic manner. The presence of an old stellar population in many late-type LSB galaxies suggests that LSB galaxies roughly follow the same evolutionary history as HSB galaxies, except at a much lower rate. In particular, our results imply that LSB galaxies do not form late, nor have a delayed onset of star formation, but simply evolve slowly.Comment: To be published in A&

Temporal and functional profile of the transcriptional regulatory network in the early regenerative response to partial hepatectomy in the rat

<p>Abstract</p> <p>Background</p> <p>The goal of these studies was to characterize the transcriptional network regulating changes in gene expression in the remnant liver of the rat after 70% partial hepatectomy (PHx) during the early phase response including the transition of hepatocytes from the quiescent (G₀) state and the onset of the G₁phase of the cell cycle.</p> <p>Results</p> <p>The transcriptome of remnant livers was monitored at 1, 2, 4, and 6 hours after PHx using cDNA microarrays. Differentially regulated genes were grouped into six clusters according their temporal expression profiles. Promoter regions of genes in these clusters were examined for shared transcription factor binding sites (TFBS) by comparing enrichment of each TFBS relative to a reference set using the Promoter Analysis and Interaction Network Toolset (PAINT).</p> <p>Analysis of the gene expression time series data using ANOVA resulted in a total of 309 genes significantly up- or down-regulated at <it>any </it>of the four time points at a 20% FDR threshold. Sham-operated animals showed no significant differential expression. A subset of the differentially expressed genes was validated using quantitative RT-PCR. Distinct sets of TFBS could be identified that were significantly enriched in each one of the different temporal gene expression clusters. These included binding sites for transcription factors that had previously been recognized as contributing to the onset of regeneration, including NF-κB, C/EBP, HNF-1, CREB, as well as factors, such as ATF, AP-2, LEF-1, GATA and PAX-6, that had not yet been recognized to be involved in this process. A subset of these candidate TFBS was validated by measuring activation of corresponding transcription factors (HNF-1, NK-κB, CREB, C/EBP-α and C/EBP-β, GATA-1, AP-2, PAX-6) in nuclear extracts from the remnant livers.</p> <p>Conclusion</p> <p>This analysis revealed multiple candidate transcription factors activated in the remnant livers, some known to be involved in the early phase of liver regeneration, and several not previously identified. The study describes the predominant temporal and functional elements to which these factors contribute and demonstrates the potential of this novel approach to define the functional correlates of the transcriptional regulatory network driving the early response to partial hepatectomy.</p