Reactive oxygen species regulate context-dependent inhibition of NFAT5 target genes

The activation of nuclear factor of activated T cells 5(NFAT5), a well-known osmoprotective factor, can be induced by isotonic stimuli, such as activated Toll-like receptors (TLRs). It is unclear, however, how NFAT5 discriminates between isotonic and hypertonic stimuli. In this study we identified a novel context-dependent suppression of NFAT5 target gene expression in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) or a high salt (NaCl) concentration. Although LPS and NaCl both used NFAT5 as a core transcription factor, these stimuli mutually inhibited distinct sets of NFAT5 targets within the cells. Although reactive oxygen species (ROS) are essential for this inhibition, the source of ROS differed depending on the context: mitochondria for high salt and xanthine oxidase for TLRs. Specifically, the high salt-induced suppression of interleukin-6 (IL-6) production was mediated through the ROS-induced inhibition of NFAT5 binding to the IL-6 promoter. The context-dependent inhibition of NFAT5 target gene expression was also confirmed in mouse spleen and kidney tissues that were cotreated with LPS and high salt. Taken together, our data suggest that ROS function as molecular sensors to discriminate between TLR ligation and osmotic stimuli in RAW 264.7 macrophages, directing NFAT5 activity toward proinflammatory or hypertonic responses in a context-dependent manner.open3

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Design of microstructure for achieving high strength in an Fe-10Mn-3Al-0.2C based alloy

Yielding and work hardening behaviors were studied using α+γ and α' +γ fine lamellar structures in an Fe-10Mn-3Al-0.2C based alloy. An alloy of Fe-10.62Mn-2.84Al-0.17C-0.5Mo (wt. %) steel was prepared by vacuum induction melting. The ingot was homogenized at 1150 °C for 2 h, then hot-rolled to 4-mm-thick plates. The plates were solution-treated at 900 °C for 20 min then quenched with water. To obtain the α + γ lamellar structure, intercritical annealing was performed at 550 °C for 16 h (Fig. 1). A plate was then annealed at 800 °C for 1 min and cooled in air. Another plate was annealed at 850 °C for 3 min and water-quenched. Yielding in α'+γ lamellar structure occurred much faster than that in α+γ lamellar structure. After yielding, α'+γ lamellar structure showed abrupt increase of strength compared to gradual work hardening of α+γ lamellar structure. The origin of two different yielding and work hardening behavior was investigated using a transmission electron microscopy (TEM). TEM results demonstrate the importance of neighboring phase contacting with soft and mechanical stability of for yielding. Abrupt work hardening in α' +γ lamellar structure was related with deformation induced martensitic transformation of γ lamella. When γ lamella is mechanically stable, yielding occurs by the propagation of pile-up dislocations in α to γ or α' to γ. To understand this yielding mechanism, the stress for the propagation of pile-up dislocations in one phase into another phase is calculated using Hall-Petch behaviors of corresponding phases. Effective grain size of a lamella is determined to calculate the contribution of each boundary of a lamella to dislocation pile-up. Comparison of stresses required to drive α-to-γ and γ-to-α, and α'-to-γ and γ-to-α' propagations of pile-up dislocations suggests that α+γ and α'+γ lamellar structures yield by propagation of pile-up dislocations in α lamella to γ lamella or α' lamella to γ lamella. Based on the experimental results, the concept for achieving high strength was developed.1

The Twin and Twin System in FCT L1<SUB>0</SUB> &theta;-MnNi Phase in an Equiatomic Mn-Ni Alloy

This study examined the twinning mechanism and operating twin system of a face centered tetragonal (FCT) L10 θ-MnNi phase in an equiatomic Mn-Ni alloy using detailed TEM analysis (electron diffraction, high resolution imaging, and HAADF (Z-contrast) imaging techniques) of the structure of the twins formed during the β (B2, bcc) to θ (L10, fct) phase transformation. In addition to the well-documented {111}1⁄6⟨112] deformation twinning system in L10 crystals, {111}1⁄6⟨211]* type pseudo-twin systems were also observed. The Z-contrast image of the twins showed that no atomic shuffling occurred during twinning in the θ-MnNi phase and atomic order was maintained in the {111}1⁄6⟨112] type true-twins. *in ⟨ijk], i and j are interchangeable in the tetragonal system but k is not.11Nscopu

Correlation between carbide reaction and anomalous interfacial segregation of solutes under tensile stress in heat-resistant steels

Depending on the phosphorus bulk content, the phosphorus segregation profile at the grain boundary/carbide interface of heat-resistant ferritic steels is composed of a convex profile or two maximum peaks and one minimum peak during rupture test at 650 degrees C. In the higher phosphorus bulk content steel, the smaller pre-formed non-equilibrium M3C carbides, which arise from the higher phosphorus segregation concentration at the carbide interface and thus its carbide growth retardation, are massively dissolved into the matrix after the first maximum peak. While the dissolved carbon is consumed in forming the equilibrium M7C3 carbides, the carbon segregates at the same time to the grain boundary/formed M7C3 carbide interface and the matrix/formed M7C3 carbide interface, resulting in a strong repulsive segregation between carbon and phosphorus. However, because the transformation of the thermally unstable M3C carbides to the M7C3 carbides is very early finished in the lower phosphorus bulk content steel, such a repulsive segregation is not observed. Meanwhile, the decrease in phosphorus segregation concentration after the second maximum segregation peak in the former steel or a plateau in segregation concentration of the latter steel is due to the formation of equilibrium MX carbides which results in the increase in total interface area. Due to the finer and denser MX particles formed on the M7C3 carbide surface of the former steel, the phosphorus segregation concentration decreases abruptly with increasing rupture time after the second maximum. The difference in rupture behavior of the steels is understood from the viewpoint of such a correlation. (C) 2014 Elsevier B.V. All rights reserved.X1156sciescopu

Anomalous Segregation Kinetics of Phosphorus and Carbon Governed by Carbide Reactions in 2.25Cr-1.5W Heat-resistant Steel

In a 2.25Cr-1.5W heat-resistant steel containing V and Nb, the formation sequence of carbides are detailed. Such carbide reactions determine directly the anomalous segregation kinetics of phosphorus and carbon at the grain boundary/carbide interface. The anomalous segregation kinetics of phosphorus consists of two maximum segregation peaks and one minimum peak corresponding to the high segregation concentration of carbon. The roles of the carbide reactions on the anomalous segregation kinetics of the solutes are fully understood from the viewpoint of the dissolution of unstable carbides into the matrix for forming the stable carbides, the active segregation of the dissolved carbon into the newly formed carbide interface for the growth and the resultant repulsive segregation between carbon and phosphorus.X1144Ysciescopu