Thermal barrier coatings (TBCs) are increasingly susceptible to degradation by molten calcium-magnesium alumino silicate (CMAS) deposits in advanced engines that operate at higher temperatures and in environments laden with siliceous debris. This paper investigates the thermochemical aspects of the degradation phenomena using a model CMAS composition and ZrO 2 -7.6%YO 1.5 (7YSZ) grown by vapor deposition on alumina substrates. The changes in microstructure and chemistry are characterized after isothermal treatments of 4 h at 12001-14001C. It is found that CMAS rapidly penetrates the open structure of the coating as soon as melting occurs, whereupon the original 7YSZ dissolves in the CMAS and reprecipitates with a different morphology and composition that depends on the local melt chemistry. The attack is minimal in the bulk of the coating but severe near the surface and the interface with the substrate, which is also partially dissolved by the melt. The phase evolution is discussed in terms of available thermodynamic information.

The thermochemical interaction between a Gd2Zr2O7 thermal barrier coating synthesized by electron‐beam physical vapor deposition and a model 33CaO–9MgO–13AlO3/2–45SiO2 (CMAS) melt with a melting point of ∼1240°C was investigated. A dense, fine‐grained, ∼6‐μm thick reaction layer formed after 4 h of isothermal exposure to 1300°C. It consisted primarily of an apatite phase based on Gd8Ca2(SiO4)6O2 and fluorite ZrO2 with Gd and Ca in a solid solution. Remarkably, melt infiltration into the intercolumnar gaps was largely suppressed, with penetration rarely exceeding ∼30 μm below the original surface. The microstructural evidence suggests a mechanism in which CMAS infiltration is arrested by rapid filling of the gaps with crystalline reaction products, followed by slow attack of the column tips.

Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

Continuous fiber ceramic composites (CFCCs) based on oxides are of interest for high-temperature applications owing to their inherent oxidative stability. An enabling element is a matrix with an optimum combination of toughness and strength, which may be achieved by incorporating a controlled amount of fine, well-distributed porosity. Implementation of this concept by vacuum infiltration of aqueous mullite-alumina slurries into two-dimensional woven preforms of alumina fibers has been investigated. Evaluation of these materials shows stress-strain characteristics similar to other CFCCs, especially carbon-matrix composites. Moreover, promising notch and creep properties have been found. Microstructural and processing issues relevant to the attainment of these behaviors are discussed.

ObjectiveDeficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain.DesignExpression of miR-574-5p, Qki5/6/7/7b splicing variants, β-catenin and p27Kip1 was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on β-catenin/p27Kip1 signalling, cell cycle progression, proliferation, migration, invasion and tumour growth.ResultsIn the CRC tissues of C57BL/6-Apcmin/+ mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of β-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in β-catenin and p27Kip1, increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice.ConclusionsTogether, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.

Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.

OREBP (osmotic response element-binding protein), also called TonEBP or NFAT5, is thought to induce the expression of genes that increase the accumulation of organic osmolytes to protect cells against a hypertonic environment. To investigate the consequences of lacking OREBP activity, transgenic (Tg) mice that overexpress OREBPdn (dominant negative form of OREBP) specifically in the epithelial cells of the renal collecting tubules were generated. These mice showed impairment in their urine concentrating mechanism, most likely due to reduced expression of the aquaporin AQP2 and the urea transporter UT-A1 and UT-A2 mRNAs. When deprived of water or after the administration of a vasopressin analogue, urine osmolality of the Tg mice was significantly increased but not to the same extent as that of the wild type mice. The expression of AQP2 and UT-A1, but not UT-A2 mRNAs, was increased to the same level as that of the wild type mice in the water deprivation state, indicating that the vasopressin regulatory mechanism was not affected by OREBPdn. These data indicate that in addition to vasopressin, OREBP is another essential regulator of the urine concentrating mechanism. Furthermore, the OREBPdn Tg mice developed progressive hydronephrosis soon after weaning, confirming the osmoprotective function of OREBP implicated by the in vitro experiments.The mammalian kidney plays an important role in maintaining the homeostasis of osmolality and the electrolyte concentrations of the circulating fluid. The osmolality of the kidney inner medulla is highly hypertonic to facilitate the reabsorption of water from the urine. The cells in the collecting tubules guard against hypertonic stress by increasing the synthesis or import of several organic "compatible" osmolytes. These include sorbitol, which is synthesized by the enzyme aldose reductase, and betaine, myo-inositol, and taurine, which are imported by the betaine/␥-aminobutyric acid transporter, the Na ϩ -dependent myo-inositol transporter, and taurine transporter, respectively (1). The transcription of these genes is induced by a hypertonic medium and regulated by a protein called the osmotic response element-binding protein (OREBP) 1 (2) or tonicity element-binding protein (TonEBP) (3). This protein is also called NFAT5 because of its homology to the NFAT family of transcription factors (4).OREBP consists of a nuclear localization signal near the N terminus followed by a DNA binding domain, a dimerization domain, and a transactivation domain at the carboxyl end. Upon stimulation by hypertonicity, it is rapidly translocated into the nucleus and binds to the osmotic response elements (OREs) (5) in the promoter region of the osmoprotective genes (2) to stimulate transcription. OREBP is highly expressed in the inner medulla as well as in the inner stripe of the outer medulla in the rat kidney (6). In response to water loading, OREBP in the initial portion of the inner medullary collecting ducts (IMCDs) is primarily located in the cytoplasm of the epithelial cells. In dehydrated a...

Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3′-untranslated region of OREBP (OREBP-3′UTR). Furthermore, overexpression of OREBP-3′UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR-717 being most significantly down-regulated. Moreover, increased miR-200b or miR-717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA–3′UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR-200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells.