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

Stroke awareness decreases prehospital delay after acute ischemic stroke in korea

BACKGROUND: Delayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea. METHODS: A prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay. RESULTS: Among the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival. CONCLUSIONS: In Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.ope

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

A Strategy for Phase Identification of Precipitates in High Al-containing Austenitic and Ferritic Steels Using Electron Diffraction

22Ykc

Accurate determination of orientation relationship between ferrite and (Fe, Mn)(3)AlC in an Fe-Mn-Al-C eutectoid alloy

The orientation relationship between ferrite and (Fe,Mn)(3)AlC has been investigated in an Fe-3.5Mn-5.8Al-1.05C based eutectoid alloy. Electron diffraction pattern analysis shows two possible orientation relationships between both phases. Accurate analysis using convergent beam electron diffraction reveals the deviation of [001](ferrite) pole from [110]((Fe,Mn)3AlC) pole in Nishiyama-Wasserman orientation relationship and the coincidence of [111](ferrite) and [110] ((Fe,Mn)3AlC) poles in Kurdjumov-Sachs orientation relationship. Transmission Kikuchi diffraction resolves the orientation of several tens nanometer scales of ferrite +(Fe,Mn)(3)AlC lamellar. Kurdjumov-Sachs orientation relationship between ferrite and (Fe,Mn)(3)AlC is clarified by the comparison of deviation angle from both orientation relationships. Coherency at the interphase boundaries is further discussed. (C) 2020 Elsevier B.V. All rights reserved.11Nsciescopu

Precipitation and fracture behaviour of Fe–Mn–Ni–Al alloys

The effects of Al addition on the precipitation and fracture behaviour of Fe-Mn-Ni alloys were investigated. With the increasing of Al concentration, the matrix and grain boundary precipitates changed from L1(0)-MnNi to B2 Ni2MnAl phase, which is coherent and in cube-to-cube orientation relationship with the -matrix. Due to the suppression of the -MnNi precipitates at prior austenite grain boundaries (PAGBs), the fracture mode changed from intergranular to transgranular cleavage fracture. Further addition of Al resulted in the discontinuous growth of Ni2MnAl precipitates in the alloy containing 4.2wt.% Al and fracture occurred by void growth and coalescence, i.e. by ductile dimple rupture. The transition of the fracture behaviour of the Fe-Mn-Ni-Al alloys is discussed in relation to the conversion of the precipitates and their discontinuous precipitation behaviour at PAGBs.11Nsciescopu

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