The Antioxidant Protein Peroxiredoxin 4 Is Epigenetically Down Regulated in Acute Promyelocytic Leukemia

The antioxidant peroxiredoxin (PRDX) protein family comprises 6 members, which are implicated in a variety of cellular responses, including growth factor signal transduction. PRDX4 resides in the endoplasmic reticulum (ER), where it locally controls oxidative stress by reducing H2O2levels. We recently provided evidence for a regulatory function of PRDX4 in signal transduction from a myeloid growth factor receptor, the granulocyte colony-stimulating factor receptor (G-CSFR). Upon activation, the ligand-induced G-CSFR undergoes endocytosis and routes via the early endosomes where it physically interacts with ER-resident PRDX4. PRDX4 negatively regulates G-CSFR mediated signaling. Here, we investigated whether PRDX4 is affected in acute myeloid leukemia (AML); genomic alterations and expression levels of PRDX4 were investigated. We show that genomic abnormalities involving PRDX4 are rare in AML. However, we find a strong reduction in PRDX4 expression levels in acute promyelocytic leukemia (APL) compared to normal promyelocytes and different molecular subtypes of AML. Subsequently, the possible role of DNA methylation and histone modifications in silencing of PRDX4 in APLs was investigated. We show that the reduced expression is not due to methylation of the CpG island in the promoter region of PRDX4 but correlates with increased trimethylation of histone 3 lysine residue 27 (H3K27me3) and lysine residue 4 (H3K4me3) at the transcriptional start site (TSS) of PRDX4, indicative of a bivalent histone code involved in transcriptional silencing. These findings suggest that the control of G-CSF responses by the antioxidant protein PRDX4 may be perturbed in APL

Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish

Cellular metabolism provides various sources of hydrogen peroxide (H2O2) in different organelles and compartments. The suitability of H2O2 as an intracellular signaling molecule therefore also depends on its ability to pass cellular membranes. The propensity of the membranous boundary of the endoplasmic reticulum (ER) to let pass H2O2 has been discussed controversially. In this essay, we challenge the recent proposal that the ER membrane constitutes a simple barrier for H2O2 diffusion and support earlier data showing that (i) ample H2O2 permeability of the ER membrane is a prerequisite for signal transduction, (ii) aquaporin channels are crucially involved in the facilitation of H2O2 permeation, and (iii) a proper experimental framework not prone to artifacts is necessary to further unravel the role of H2O2 permeation in signal transduction and organelle biology. © 2016 Elsevier Inc

Optimization of Cutting Parameters using the RSM-Desirability Approach in the MQL-Assisted Turning of AISI 4130

In this study, the main task is to identify the best cutting parameters to improve the machining performance during MQL-turning with various cutting fluids like coconut oil, ground nut oil, sunflower oil, soyabean oil, and blassocut oil. Cutting temperature and surface roughness were used as performance metrics, with the goal of minimizing these responses. To construct an experimental plan for turning AISI4130 with uncoated brazed carbide, full factorial design for three levels and three factors (33) design of experiments was used. The optimal cutting parameter was identified using the response surface approach. Aiming to discover the optimum possible cutting settings, the desirability function method was utilized. It was discovered that the best cutting speed, depth of cut, and feed rate for minimizing the temperature and surface roughness are 72.38 m/min, 0.5 mm, and 0.35 mm/rev respectively. According to the ANOVA findings, the feed and depth of cut have a substantial impact on the tool temperature for MQL-soyabean oil

An Overview Of Herring Bone & Smooth Wavy Fin Heat Exchanger For Hydraulic Oil Cooling System

 Power from hydraulics is very important and researchers have started acting on the energy conservation from this, the energy conservation was limited to electrical till 20th century. At the start of 21st century researcher have understood there are other ideas from where also we can save some energy. The major thing must be kept in mind that when we think of power saving it must be carried out for without compromise of reliable operation and low maintenance. Above stated factors should not be compromised. The major aspect of the hydraulic system design was to prevent hydraulic oil heating while in operation. The reason behind heating of hydraulic oil it is a reason of inefficiencies of oil, these inefficiencies results in the losses of input power, this power loss is converted into the heat. If the total input power lost to heat is greater than the heat dissipated, the hydraulic system will eventually overheat. Coolers are frequently used while designing temperatureoptimized hydraulic systems. This is used for keeping oil temperatures within a tolerable range. Such circuits are basic prerequisites for cost-efficient operation, as they provide a number of performance, economic, and environmental benefits

Bivalent H3K27me3 and H3K4me3 marks are present at the TSS of <i>PRDX4.</i>

<p>ChIP using αH3K27me3 and an IgG control (<b>A</b>) and αH3K4me3 and an IgG control (<b>B</b>) showing an enrichment of both H3K27me3 and H3K4me3 at the TSS of <i>PRDX4</i> in APL cells. To rule out a possible involvement of X-inactivation, and thereby H3K27me3, in silencing of <i>PRDX4</i> expression, male APL samples are compared to a male AML control and female APL samples are compared to a female AML control.</p

Reduced PRDX4 protein and transcript levels in APL.

<p><b>A</b>. Lysates of APL and AML samples were analyzed for PRDX4 protein levels. Because human <i>PRDX4</i> gene is located on the X-chromosome, male samples and female samples were compared with male and female AML control samples respectively to rule out the possibility of X-inactivation involvement. Patient number followed by F indicates female sample while patient number followed by M indicates male sample. <b>B. Upper panel</b>: Western blot analysis of PRDX4 expression in different normal bone marrow fractions (myeloblasts, promyelocytes, neutrophils). <b>Lower panel</b>: Micrographs of May Grunwald Giemsa stained fractions of cells used for Western blotting.</p

Expression of PRDX transcripts in AML and APL.

<p><b>A</b>. Graphical representation of expression of PRDX family members in APL patients clustered based on expression of ∼2000 genes as described <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0016340#pone.0016340-Valk1" target="_blank">[24]</a>. Cluster 12 is exclusively formed by APL patients, as indicated by the red bars indicating the presence of t(15;17). Cluster 11 comprises AML patients with normal karyotype and an underlying NPM1 mutation. Cluster 13 is formed by AML patients with t(8;21). Histograms represent MAS5-normalized expression values. <b>B</b>. Expression levels of the peroxiredoxin gene family in APL (n = 22) were compared to transcript levels in AML (n = 439). Significant differences were calculated using a Wilcoxon test. *  =  p-value <0.001, **  =  p-value <0.0001.</p