Variability of disk emission in pre-main sequence and related stars. II. Variability in the gas and dust emission of the Herbig Fe star SAO 206462

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We present 13 epochs of near-infrared (0.8-5 μm) spectroscopic observations of the pre-transitional, "gapped" disk system in SAO 206462 (=HD 135344B). In all, six gas emission lines (Brα, Brγ, Paβ, Paγ, Paδ, Paepsilon, and the 0.8446 μm line of O I) along with continuum measurements made near the standard J, H, K, and L photometric bands were measured. A mass accretion rate of approximately 2 × 10–8 M ☉ yr–1 was derived from the Brγ and Paβ lines. However, the fluxes of these lines varied by a factor of over two during the course of a few months. The continuum also varied, but by only ~30%, and even decreased at a time when the gas emission was increasing. The H I line at 1.083 μm was also found to vary in a manner inconsistent with that of either the hydrogen lines or the dust. Both the gas and dust variabilities indicate significant changes in the region of the inner gas and the inner dust belt that may be common to many young disk systems. If planets are responsible for defining the inner edge of the gap, they could interact with the material on timescales commensurate with what is observed for the variations in the dust, while other disk instabilities (thermal, magnetorotational) would operate there on longer timescales than we observe for the inner dust belt. For SAO 206462, the orbital period would likely be 1-3 years. If the changes are being induced in the disk material closer to the star than the gap, a variety of mechanisms (disk instabilities, interactions via planets) might be responsible for the changes seen. The He I feature is most likely due to a wind whose orientation changes with respect to the observer on timescales of a day or less. To further constrain the origin of the gas and dust emission will require multiple spectroscopic and interferometric observations on both shorter and longer timescales that have been sampled so far.This work was supported by NASA ADP grants NNH06CC28C and NNX09AC73G, Hubble Space Telescope grants HST-GO-10764 and HST-GO-10864, Chilean National TAC grants CNTAC-010A-064

Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted. Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRA

A Kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

© 2020, The Author(s). Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI

Bioinformatic Analysis and Post-Translational Modification Crosstalk Prediction of Lysine Acetylation

Recent proteomics studies suggest high abundance and a much wider role for lysine acetylation (K-Ac) in cellular functions. Nevertheless, cross influence between K-Ac and other post-translational modifications (PTMs) has not been carefully examined. Here, we used a variety of bioinformatics tools to analyze several available K-Ac datasets. Using gene ontology databases, we demonstrate that K-Ac sites are found in all cellular compartments. KEGG analysis indicates that the K-Ac sites are found on proteins responsible for a diverse and wide array of vital cellular functions. Domain structure prediction shows that K-Ac sites are found throughout a wide variety of protein domains, including those in heat shock proteins and those involved in cell cycle functions and DNA repair. Secondary structure prediction proves that K-Ac sites are preferentially found in ordered structures such as alpha helices and beta sheets. Finally, by mutating K-Ac sites in silico and predicting the effect on nearby phosphorylation sites, we demonstrate that the majority of lysine acetylation sites have the potential to impact protein phosphorylation, methylation, and ubiquitination status. Our work validates earlier smaller-scale studies on the acetylome and demonstrates the importance of PTM crosstalk for regulation of cellular function

Confrontation of fibroblasts with cancer cells in vitro: Gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth

Background: There is growing evidence that emerging malignancies in solid tissues might be kept under control by physical intercellular contacts with normal fibroblasts. Methods: Here we characterize transcriptional landscapes of fibroblasts that confronted cancer cells. We studied four pairs of in vitro and ex vivo fibroblast lines which, within each pair, differed in their capacity to inhibit cancer cells. The natural process was modeled in vitro by confronting the fibroblasts with PC-3 cancer cells. Fibroblast transcriptomes were recorded by Affymetrix microarrays and then investigated using network analysis. Results: The network enrichment analysis allowed us to separate confrontation- and inhibition-specific components of the fibroblast transcriptional response. Confrontation-specific differences were stronger and were characterized by changes in a number of pathways, including Rho, the YAP/TAZ cascade, NF-kB, and TGF-beta signaling, as well as the transcription factor RELA. Inhibition-specific differences were more subtle and characterized by involvement of Rho signaling at the pathway level and by potential individual regulators such as IL6, MAPK8, MAP2K4, PRKCA, JUN, STAT3, and STAT5A. Conclusions: We investigated the interaction between cancer cells and fibroblasts in order to shed light on the potential mechanisms and explain the differential inhibitory capacity of the latter, which enabled both a holistic view on the process and details at the gene/protein level. The combination of our methods pointed to proteins, such as members of the Rho pathway, pro-inflammatory signature and the YAP1/TAZ cascade, that warrant further investigation via tools of experimental perturbation. We also demonstrated functional congruence between the in vitro and ex vivo models. © 2015 Alexeyenko et al