Increased expression of fibroblast activation protein-alpha in keloid fibroblasts: implications for development of a novel treatment option.

Keloid scars are common benign fibroproliferative reticular dermal lesions with unknown etiology and ill-defined management with high rate of recurrence post surgery. The progression of keloids is characterized by increased deposition of extracellular matrix proteins, invasion into the surrounding healthy skin and inflammation. Fibroblasts are considered to be the key cellular mediators of fibrogenesis in keloid scars. Fibroblast activation protein alpha (FAP-a) and dipeptidyl peptidase IV (DPPIV) are proteases located at the plasma membrane promoting cell invasiveness and tumor growth and have been previously associated with keloid scars. Therefore, in this study we analyzed in further detail the expression of FAP-a in keloid fibroblasts compared to control skin fibroblasts. Dermal fibroblasts were obtained from punch-biopsies from the active margin of four keloids and four control skin samples. Flow cytometry was used to analyze FAP-a expression and the CytoSelect(®) 24-Well Collagen I Cell Invasion Assay was applied to study fibroblast invasion. Secretion of extracellular matrix (ECM) proteins was investigated by multiplexed particle-based flow cytometric assay and enzyme-linked immunosorbent assay. We found an increased expression of FAP-a in keloid fibroblasts compared to control skin fibroblasts (p

On-line Emotion Recognition in a 3-D Activation-Valence-Time Continuum using Acoustic and Linguistic Cues

For many applications of emotion recognition, such as virtual agents, the system must select responses while the user is speaking. This requires reliable on-line recognition of the user’s affect. However most emotion recognition systems are based on turnwise processing. We present a novel approach to on-line emotion recognition from speech using Long Short-Term Memory Recurrent Neural Networks. Emotion is recognised frame-wise in a two-dimensional valence-activation continuum. In contrast to current state-of-the-art approaches, recognition is performed on low-level signal frames, similar to those used for speech recognition. No statistical functionals are applied to low-level feature contours. Framing at a higher level is therefore unnecessary and regression outputs can be produced in real-time for every low-level input frame. We also investigate the benefits of including linguistic features on the signal frame level obtained by a keyword spotter.

hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase

Mammalian cells respond to nutrient deprivation by inhibiting energy consuming processes, such as proliferation and protein synthesis, and by stimulating catabolic processes, such as autophagy. p70 S6 kinase (S6K1) plays a central role during nutritional regulation of translation. S6K1 is activated by growth factors such as insulin, and by mammalian target of rapamycin (mTOR), which is itself regulated by amino acids. The Class IA phosphatidylinositol (PI) 3-kinase plays a well recognized role in the regulation of S6K1. We now present evidence that the Class III PI 3-kinase, hVps34, also regulates S6K1, and is a critical component of the nutrient sensing apparatus. Overexpression of hVps34 or the associated hVps15 kinase activates S6K1, and insulin stimulation of S6K1 is blocked by microinjection of inhibitory anti-hVps34 antibodies, overexpression of a FYVE domain construct that sequesters the hVps34 product PI(3) P, or small interfering RNA-mediated knock-down of hVps34. hVps34 is not part of the insulin input to S6K1, as it is not stimulated by insulin, and inhibition of hVps34 has no effect on phosphorylation of Akt or TSC2 in insulin-stimulated cells. However, hVps34 is inhibited by amino acid or glucose starvation, suggesting that it lies on the nutrient-regulated pathway to S6K1. Consistent with this, hVps34 is also inhibited by activation of the AMP-activated kinase, which inhibits mTOR/S6K1 in glucose-starved cells. hVps34 appears to lie upstream of mTOR, as small interfering RNA knock- down of hVps34 inhibits the phosphorylation of another mTOR substrate, eIF4E-binding protein-1 (4EBP1). Our data suggest that hVps34 is a nutrient-regulated lipid kinase that integrates amino acid and glucose inputs to mTOR and S6K1.

Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation

Background: Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.

Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation

The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.

Activation of Alkanes by Gold-Modified Lanthanum Oxide

Functionalization of alkanes is much sought after for the production of fine and bulk chemicals. In particular, the oxidative activation of alkanes and their conversion to ethene and propene has been studied extensively, owing to the use of these alkenes in polymerization reactions. The greater reactivity of the products in comparison with the reactants has proven a major issue in this reaction as this can result in overoxidation, producing CO and CO2 and, therefore, reducing the alkene yield. Herein, the first application of supported gold catalysts for the direct activation of C2+ aliphatic alkanes with oxygen to form alkenes is demonstrated. This catalyst is particularly notable as it is highly active, selective to propene and ethene, and stable on stream over a 48 h period. Maintaining cationic gold is thought to be critical for the stability and this catalyst design provides the possibility of applying gold-based catalysts over a much wider temperature range than has been reported.