Acute Hypercapnia/Ischemia Alters the Esterification of Arachidonic Acid and Docosahexaenoic Acid Epoxide Metabolites in Rat Brain Neutral Lipids.

In the brain, approximately 90% of oxylipins are esterified to lipids. However, the significance of this esterification process is not known. In the present study, we (1) validated an aminopropyl solid phase extraction (SPE) method for separating esterified lipids using 100 and 500 mg columns and (2) applied the method to quantify the distribution of esterified oxylipins within phospholipids (PL) and neutral lipids (NL) (i.e. triacylglycerol and cholesteryl ester) in rats subjected to head-focused microwave fixation (controls) or CO2 -induced hypercapnia/ischemia. We hypothesized that oxylipin esterification into these lipid pools will be altered following CO2 -induced hypercapnia/ischemia. Lipids were extracted from control (n = 8) and CO2 -asphyxiated (n = 8) rat brains and separated on aminopropyl cartridges to yield PL and NL. The separated lipid fractions were hydrolyzed, purified with hydrophobic-lipophilic-balanced SPE columns, and analyzed with ultra-high-pressure liquid chromatography coupled to tandem mass spectrometry. Method validation showed that the 500 mg (vs 100 mg) aminopropyl columns yielded acceptable separation and recovery of esterified fatty acid epoxides but not other oxylipins. Two epoxides of arachidonic acid (ARA) were significantly increased, and three epoxides of docosahexaenoic acid (DHA) were significantly decreased in brain NL of CO2 -asphyxiated rats compared to controls subjected to head-focused microwave fixation. PL-bound fatty acid epoxides were highly variable and did not differ significantly between the groups. This study demonstrates that hypercapnia/ischemia alters the concentration of ARA and DHA epoxides within NL, reflecting an active turnover process regulating brain fatty acid epoxide concentrations

Activation of the Transient Receptor Potential Ion Channel TRMP8 Mediates Upregulation 0f Profibrotic Genes, A New Pathway to Tissue Fibrosis

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Deficiency of Phosphoinositide 3-Kinase Enhancer Protects Mice From Diet-Induced Obesity and Insulin Resistance

OBJECTIVE: Phosphoinositide 3-kinase enhancer A (PIKE-A) is a proto-oncogene that promotes tumor growth and transformation by enhancing Akt activity. However, the physiological functions of PIKE-A in peripheral tissues are unknown. Here, we describe the effect of PIKE deletion in mice and explore the role of PIKE-A in obesity development. RESEARCH DESIGN AND METHODS: Whole-body PIKE knockout mice were generated and subjected to high-fat–diet feeding for 20 weeks. The glucose tolerance, tissue-specific insulin sensitivity, adipocyte differentiation, and lipid oxidation status were determined. The molecular mechanism of PIKE in the insulin signaling pathway was also studied. RESULTS: We show that PIKE-A regulates obesity development by modulating AMP-activated protein kinase (AMPK) phosphorylation. PIKE-A is important for insulin to suppress AMPK phosphorylation. The expression of PIKE-A is markedly increased in adipose tissue of obese mice, whereas depletion of PIKE-A inhibits adipocyte differentiation. PIKE knockout mice exhibit a prominent phenotype of lipoatrophy and are resistant to high-fat diet–induced obesity, liver steatosis, and diabetes. PIKE knockout mice also have augmented lipid oxidation, which is accompanied by enhanced AMPK phosphorylation in both muscle and adipose tissue. Moreover, insulin sensitivity is improved in PIKE-A–deficient muscle and fat, thus protecting the animals from diet-induced diabetes. CONCLUSIONS: Our results suggest that PIKE-A is implicated in obesity and associated diabetes development by negatively regulating AMPK activity

Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.

Clear cell renal cell carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133+). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor-2 (TNFR2) signaling promotes the cell cycle entry of ccRCC-CD133+CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, we describe a TNFR2-activated signaling pathway in ccRCC-CD133+CSCs that is required for cell survival. Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI-3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase-like (MLKL). Pretreatment with necrostatin-1 is more protective than z-VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial-mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC

Lepton Flavor Violation in Supersymmetric SO(10) Grand Unified Models

The study for lepton flavor violation combined with the neutrino oscillation may provide more information about the lepton flavor structure of the grand unified theory. In this paper, we study two lepton flavor violation processes, $\tau\to \mu\gamma$ and $Z\to \tau\mu$, in the context of supersymmetric SO(10) grand unified models. We find the two processes are both of phenomenological interest. In particular the latter may be important in some supersymmetric parameter space where the former is suppressed. Thus, Z-dacay may offer another chance for looking for lepton flavor violation.Comment: 26 pages, 10 figure

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease

Math1 Is Essential for the Development of Hindbrain Neurons Critical for Perinatal Breathing

SummaryMice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with congenital central hypoventilation syndrome (CCHS). We generated a Math1-GFP fusion allele to trace the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified Math1-dependent neurons and their projections near the pre-Bötzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration

Immittance Matching for Multi-dimensional Open-system Photonic Crystals

An electromagnetic (EM) Bloch wave propagating in a photonic crystal (PC) is characterized by the immittance (impedance and admittance) of the wave. The immittance is used to investigate transmission and reflection at a surface or an interface of the PC. In particular, the general properties of immittance are useful for clarifying the wave propagation characteristics. We give a general proof that the immittance of EM Bloch waves on a plane in infinite one- and two-dimensional (2D) PCs is real when the plane is a reflection plane of the PC and the Bloch wavevector is perpendicular to the plane. We also show that the pure-real feature of immittance on a reflection plane for an infinite three-dimensional PC is good approximation based on the numerical calculations. The analytical proof indicates that the method used for immittance matching is extremely simplified since only the real part of the immittance function is needed for analysis without numerical verification. As an application of the proof, we describe a method based on immittance matching for qualitatively evaluating the reflection at the surface of a semi-infinite 2D PC, at the interface between a semi-infinite slab waveguide (WG) and a semi-infinite 2D PC line-defect WG, and at the interface between a semi-infinite channel WG and a semi-infinite 2D PC slab line-defect WG.Comment: 8 pages, 6 figure

New Yellow Ba\u3csub\u3e0.93\u3c/sub\u3eEu\u3csub\u3e0.07\u3c/sub\u3eAl\u3csub\u3e2\u3c/sub\u3eO\u3csub\u3e4\u3c/sub\u3e

Phosphor-converted white light-emitting diodes for indoor illumination need to be warm-white (i.e., correlated color temperature \u3c4000 \u3eK) with good color rendition (i.e., color rendering index \u3e80). However, no single-phosphor, single-emitting-center-converted white light-emitting diodes can simultaneously satisfy the color temperature and rendition requirements due to the lack of sufficient red spectral component in the phosphors’ emission spectrum. Here, we report a new yellow Ba0.93Eu0.07Al2O4phosphor that has a new orthorhombic lattice structure and exhibits a broad yellow photoluminescence band with sufficient red spectral component. Warm-white emissions with correlated color temperature 80 were readily achieved when combining the Ba0.93Eu0.07Al2O4 phosphor with a blue light-emitting diode (440–470 nm). This study demonstrates that warm-white light-emitting diodes with high color rendition (i.e., color rendering index \u3e80) can be achieved based on single-phosphor, single-emitting-center conversion