Sample records for tak kuen mau

  1. TAK1 regulates skeletal muscle mass and mitochondrial function

    PubMed Central

    Hindi, Sajedah M.; Sato, Shuichi; Xiong, Guangyan; Bohnert, Kyle R.; Gibb, Andrew A.; Gallot, Yann S.; McMillan, Joseph D.; Hill, Bradford G.

    2018-01-01

    Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β–activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy. Phosphorylation and enzymatic activity of AMPK are increased, whereas levels of phosphorylated mTOR and p38 MAPK are diminished upon inducible inactivation of TAK1 in skeletal muscle. In addition, targeted inactivation of TAK1 leads to the accumulation of dysfunctional mitochondria and oxidative stress in skeletal muscle of adult mice. Inhibition of TAK1 does not attenuate denervation-induced muscle wasting in adult mice. Finally, TAK1 activity is highly upregulated during overload-induced skeletal muscle growth, and inactivation of TAK1 prevents myofiber hypertrophy in response to functional overload. Overall, our study demonstrates that TAK1 is a key regulator of skeletal muscle mass and oxidative metabolism. PMID:29415881

  2. The carboxyl group of Glu113 is required for stabilization of the diferrous and bis-FeIV states of MauG

    PubMed Central

    Tarboush, Nafez Abu; Yukl, Erik T.; Shin, Sooim; Feng, Manliang; Wilmot, Carrie M.; Davidson, Victor L.

    2013-01-01

    The diheme enzyme MauG catalyzes a six-electron oxidation required for posttranslational modification of a precursor of methylamine dehydrogenase (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. Crystallographic studies have implicated Glu113 in the formation of the bis-FeIV state of MauG, in which one heme is FeIV=O and the other is FeIV with His-Tyr axial ligation. An E113Q mutation had no effect on the structure of MauG, but significantly altered its redox properties. E113Q MauG could not be converted to the diferrous state by reduction with dithionite, but was only reduced to a mixed valence FeII/FeIII state, which is never observed in wild-type (WT) MauG. Addition of H2O2 to E113Q MauG generated a high valence state that formed more slowly and was less stable than the bis-FeIV state of WT MauG. E113Q MauG exhibited no detectable TTQ biosynthesis activity in a steady-state assay with preMADH as the substrate. It did catalyze the steady-state oxidation of quinol MADH to the quinone, but 1000-fold less efficiently than WT MauG. Addition of H2O2 to a crystal of the E113Q MauG-preMADH complex resulted in partial synthesis of TTQ. Extended exposure of these crystals to H2O2 resulted in hydroxylation of Pro107 in the distal pocket of the high-spin heme. It is concluded that the loss of the carboxylic group of Glu113 disrupts the redox cooperativity between hemes that allows rapid formation of the diferrous state, and alters the distribution of high-valence species that participate in charge-resonance stabilization of the bis-FeIV redox state. PMID:23952537

  3. Mauá Working to Become an Educator City

    ERIC Educational Resources Information Center

    Malachias, Rosangela; dos Santos, Maria E. Rosa; de Aguiar, Lairce Rodrigues

    2015-01-01

    This essay presents the Educational Policy from Mauá, which has been, as the epigraph says, built and organized by articulating thoughts from different people and institutions. At the level of democratic and popular governments of city, the women's leadership in education has been essential to identify the needs of the population and the educators.

  4. TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair

    PubMed Central

    Ogura, Yuji; Hindi, Sajedah M.; Sato, Shuichi; Xiong, Guangyan; Akira, Shizuo; Kumar, Ashok

    2015-01-01

    Satellite cells are resident adult stem cells that are required for regeneration of skeletal muscle. However, signalling mechanisms that regulate satellite cell function are less understood. Here we demonstrate that transforming growth factor-β-activated kinase 1 (TAK1) is important in satellite stem cell homeostasis and function. Inactivation of TAK1 in satellite cells inhibits muscle regeneration in adult mice. TAK1 is essential for satellite cell proliferation and its inactivation causes precocious differentiation. Moreover, TAK1-deficient satellite cells exhibit increased oxidative stress and undergo spontaneous cell death, primarily through necroptosis. TAK1 is required for the activation of NF-κB and JNK in satellite cells. Forced activation of NF-κB improves survival and proliferation of TAK1-deficient satellite cells. Furthermore, TAK1-mediated activation of JNK is essential to prevent oxidative stress and precocious differentiation of satellite cells. Collectively, our study suggests that TAK1 is required for maintaining the pool of satellite stem cells and for regenerative myogenesis. PMID:26648529

  5. Hunting Apprenticeship as Indigenous Form of Education for Sustainable Conservation of Wildlife in Mau Forest of Kenya

    ERIC Educational Resources Information Center

    Ronoh, T. K.; Makori, G.; Ayub, M.

    2016-01-01

    Mau Forest, the home of the majority of the Ogiek people is located in the Rift Valley Province and straddles Kericho, Nakuru, Narok and Bomet districts. Traditionally, the Ogiek as hunter-gatherers have distinctive histories of interaction with the natural environment. Over the years, the Ogiek have inhabited in the Mau Forest with little impact…

  6. MUC1-C ACTIVATES THE TAK1 INFLAMMATORY PATHWAY IN COLON CANCER

    PubMed Central

    Takahashi, Hidekazu; Jin, Caining; Rajabi, Hasan; Pitroda, Sean; Alam, Maroof; Ahmad, Rehan; Raina, Deepak; Hasegawa, Masanori; Suzuki, Yozo; Tagde, Ashujit; Bronson, Roderick T.; Weichselbaum, Ralph; Kufe, Donald

    2015-01-01

    The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-κB pathway. The TGF-β-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-κB signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1+/−/IL-10−/− mouse model of colitis and colon tumorigenesis. We show that MUC1-C promotes NF-κB-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-κB signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-κB. Targeting MUC1-C thus suppresses the TAK1→NF-κB pathway, downregulates BCL-XL, and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1→NF-κB signaling contributes to intestinal inflammation and colon cancer progression. PMID:25659581

  7. Pharmacokinetics of TAK-475, a Squalene Synthase Inhibitor, in Rats and Dogs.

    PubMed

    Ebihara, T; Teshima, K; Kondo, T; Tagawa, Y; Moriwaki, T; Asahi, S

    2016-06-01

    The pharmacokinetics of TAK-475 (lapaquistat acetate), a squalene synthase inhibitor, was investigated in rats and dogs. After oral administration of (14)C-labeled TAK-475 ([(14)C]TAK-475) to rats and dogs at a dose of 10 mg/kg, the bioavailability (BA) was relatively low at 3.5 and 8.2%, respectively. The main component of the radioactivity in the plasma was M-I, which has a comparable pharmacological activity to TAK-475 in vitro. The radioactivity in the portal plasma after intraduodenal administration of [(14)C]TAK-475 to portal vein-cannulated rat was also mainly M-I, suggesting that most of the TAK-475 was hydrolyzed to M-I during the permeable process in the intestine. The concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration of [(14)C]TAK-475 to rats. The main elimination route of the radioactivity was fecal excretion after oral administration of [(14)C]TAK-475 to rats and dogs, and the absorbed radioactivity was mainly excreted via the bile as M-I in rats. M-I excreted into the bile was partially subjected to enterohepatic circulation. These results suggest that although the BA values of TAK-475 are low, M-I can exert compensatory pharmacological effects in the animals. These pharmacokinetic characteristics in animals were also confirmed in the clinical studies. The evaluation of M-I disposition is important for the pharmacokinetics, pharmacodynamics and toxicity of TAK-475 in animals and humans. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063.

    PubMed

    Tohyama, Kimio; Sudo, Miyako; Morohashi, Akio; Kato, Suguru; Takahashi, Junzo; Tagawa, Yoshihiko

    2018-06-01

    TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC 50 values of 8.4, 12 and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020). © 2018 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  9. TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation.

    PubMed

    Morioka, Sho; Broglie, Peter; Omori, Emily; Ikeda, Yuka; Takaesu, Giichi; Matsumoto, Kunihiro; Ninomiya-Tsuji, Jun

    2014-02-17

    TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8-mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)-dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.

  10. Development, validation and application of the liquid chromatography tandem mass spectrometry method for simultaneous quantification of azilsartan medoxomil (TAK-491), azilsartan (TAK-536), and its 2 metabolites in human plasma.

    PubMed

    Kuze, Yoji; Kogame, Akifumi; Jinno, Fumihiro; Kondo, Takahiro; Asahi, Satoru

    2015-09-15

    Azilsartan medoxomil potassium salt (TAK-491) is an orally administered angiotensin II type 1 receptor blocker for the treatment of hypertension and is an ester-based prodrug that is rapidly hydrolyzed to the pharmacologically active moiety, azilsartan (TAK-536), during absorption. TAK-536 is biotransformed to the 2 metabolites M-I by decarboxylation and M-II by dealkylation. In this study, we developed and validated a LC/MS/MS method which can simultaneously determine 4 analytes, TAK-491, TAK-536, M-I and M-II. The bioanalytical method can be outlined as follows: two structural analogues are used as the internal standards. The analytes and the IS are extracted from human plasma using solid phase extraction. After evaporating, the residue is reconstituted and injected into a LC/MS/MS system with an ESI probe and analyzed in the positive ion mode. Separation is performed through a conventional reversed-phase column with a mobile phase of water/acetonitrile/acetic acid (40:60:0.05, v/v/v) mixture at a flow rate of 0.2mL/min. The total run time is 8.5min. The calibration range is 1-2500ng/mL in human plasma for all the analytes. Instability issues of the prodrug, TAK-491, were overcome and all the validation results met the acceptance criteria in accordance with the regulatory guideline/guidance. As a result of the clinical study, the human PK profiles of TAK-536, M-I and M-II were successfully obtained and also it was confirmed that TAK-491 was below the LLOQ (1ng/mL) in the human plasma samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. TAK1 in brain endothelial cells mediates fever and lethargy

    PubMed Central

    Ridder, Dirk A.; Lang, Ming-Fei; Salinin, Sergei; Röderer, Jan-Peter; Struss, Marcel; Maser-Gluth, Christiane

    2011-01-01

    Systemic inflammation affects the brain, resulting in fever, anorexia, lethargy, and activation of the hypothalamus–pituitary–adrenal axis. How peripheral inflammatory signals reach the brain is still a matter of debate. One possibility is that, in response to inflammatory stimuli, brain endothelial cells in proximity to the thermoregulatory centers produce cyclooxygenase 2 (COX-2) and release prostaglandin E2, causing fever and sickness behavior. We show that expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for interleukin 1β (IL-1β)–induced COX-2 production. Exploiting the selective expression of the thyroxine transporter Slco1c1 in brain endothelial cells, we generated a mouse line allowing inducible deletion of Tak1 specifically in brain endothelium. Mice lacking the Tak1 gene in brain endothelial cells showed a blunted fever response and reduced lethargy upon intravenous injection of the endogenous pyrogen IL-1β. In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior. PMID:22143887

  12. Drug evaluation: TAK-475--an oral inhibitor of squalene synthase for hyperlipidemia.

    PubMed

    Burnett, John R

    2006-09-01

    Takeda Pharmaceutical Co Ltd is developing TAK-475, a squalene synthetase inhibitor from a series of 4,1-benzoxazepine-3-acetic acid derivatives, for the potential oral treatment of hyperlipidemia. By March 2005, TAK-475 was undergoing phase III clinical trials in the US and Europe.

  13. Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro.

    PubMed

    Nishimoto, Tomoyuki; Amano, Yuichiro; Tozawa, Ryuichi; Ishikawa, Eiichiro; Imura, Yoshimi; Yukimasa, Hidefumi; Sugiyama, Yasuo

    2003-07-01

    1. Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED(50), 2.9 mg kg(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3. In marmosets, TAK-475 (30, 100 mg kg(-1), p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg(-1), p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4. TAK-475 (60 mg kg(-1), p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5. In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of (125)I-low-density lipoprotein (LDL) to LDL receptors. 6. These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.

  14. Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro

    PubMed Central

    Nishimoto, Tomoyuki; Amano, Yuichiro; Tozawa, Ryuichi; Ishikawa, Eiichiro; Imura, Yoshimi; Yukimasa, Hidefumi; Sugiyama, Yasuo

    2003-01-01

    Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED50, 2.9 mg kg−1) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. In marmosets, TAK-475 (30, 100 mg kg−1, p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg−1, p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. TAK-475 (60 mg kg−1, p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of 125I-low-density lipoprotein (LDL) to LDL receptors. 6 These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia. PMID:12839864

  15. Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males

    PubMed Central

    Shi, Hongliang; Faessel, Hélène M.; Saad, Fred

    2015-01-01

    Context: TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment. Objective: The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone. Design, Setting, and Participants: This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. Interventions: Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40–75 years. Main Outcome Measures: Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone. Results: Oral TAK-385 was readily absorbed, and steady state was reached in ≤14 days. Food reduced TAK-385 systemic exposure by 47–52%. Mean serum testosterone levels declined ≤6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥7 to <3 days. TAK-385 doses ≥80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤2). Conclusions: Oral TAK-385 (40–180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d. PMID:26502357

  16. Brain endothelial TAK1 and NEMO safeguard the neurovascular unit

    PubMed Central

    Ridder, Dirk A.; Wenzel, Jan; Müller, Kristin; Töllner, Kathrin; Tong, Xin-Kang; Assmann, Julian C.; Stroobants, Stijn; Weber, Tobias; Niturad, Cristina; Fischer, Lisanne; Lembrich, Beate; Wolburg, Hartwig; Grand’Maison, Marilyn; Papadopoulos, Panayiota; Korpos, Eva; Truchetet, Francois; Rades, Dirk; Sorokin, Lydia M.; Schmidt-Supprian, Marc; Bedell, Barry J.; Pasparakis, Manolis; Balschun, Detlef; D’Hooge, Rudi; Löscher, Wolfgang; Hamel, Edith

    2015-01-01

    Inactivating mutations of the NF-κB essential modulator (NEMO), a key component of NF-κB signaling, cause the genetic disease incontinentia pigmenti (IP). This leads to severe neurological symptoms, but the mechanisms underlying brain involvement were unclear. Here, we show that selectively deleting Nemo or the upstream kinase Tak1 in brain endothelial cells resulted in death of endothelial cells, a rarefaction of brain microvessels, cerebral hypoperfusion, a disrupted blood–brain barrier (BBB), and epileptic seizures. TAK1 and NEMO protected the BBB by activating the transcription factor NF-κB and stabilizing the tight junction protein occludin. They also prevented brain endothelial cell death in a NF-κB–independent manner by reducing oxidative damage. Our data identify crucial functions of inflammatory TAK1–NEMO signaling in protecting the brain endothelium and maintaining normal brain function, thus explaining the neurological symptoms associated with IP. PMID:26347470

  17. Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice.

    PubMed

    Qi, Bing; Cong, Qian; Li, Ping; Ma, Gang; Guo, Xizhi; Yeh, James; Xie, Min; Schneider, Michael D; Liu, Huijuan; Li, Baojie

    2014-11-24

    Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1-/- monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.

  18. TAK1 (MAP3K7) inhibition promotes apoptosis in KRAS-dependent colon cancers

    PubMed Central

    Singh, Anurag; Sweeney, Michael F.; Yu, Min; Burger, Alexa; Greninger, Patricia; Benes, Cyril; Haber, Daniel A.; Settleman, Jeff

    2012-01-01

    Summary Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS-mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC-mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived “TAK1-dependency signature” is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation. PMID:22341439

  19. Ablation of Tak1 in osteoclast progenitor leads to defects in skeletal growth and bone remodeling in mice

    PubMed Central

    Qi, Bing; Cong, Qian; Li, Ping; Ma, Gang; Guo, Xizhi; Yeh, James; Xie, Min; Schneider, Michael D.; Liu, Huijuan; Li, Baojie

    2014-01-01

    Tak1 is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-κB and JNK/p38 MAPKs. Tak1 is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Tak1 is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Tak1 deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Tak1 knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Tak1 deficiency altered the signaling of NF-κB, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Tak1 regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Tak1 mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Tak1−/− monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Tak1 functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners. PMID:25418008

  20. MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling.

    PubMed

    McNew, Kelsey L; Whipple, William J; Mehta, Anita K; Grant, Trevor J; Ray, Leah; Kenny, Connor; Singh, Anurag

    2016-12-01

    MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway-dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, codependencies of MEK, TAK1, and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacologic studies and cell-cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G 1 accumulation, in a distinct subset of cell lines. Furthermore, TAK1 inhibition causes G 2 -M cell-cycle blockade and polyploidy in many of the cell lines. MEK plus TAK1 inhibition causes reduced G 2 -M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1-dependent cell lines as well as a subset of BRAF-mutant cells. Mechanistically, sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation, which promote expression of NF-κB-dependent proinflammatory cytokines, driving tumor cell survival and proliferation. MEK/TAK1 inhibition causes reduced mTOR, Wnt, and NF-κB signaling in TAK1/MEK-dependent cell lines concomitant with apoptosis. A Wnt/NF-κB transcriptional signature was derived that stratifies primary tumors into three major subtypes: Wnt-high/NF-κB-low, Wnt-low/NF-κB-high and Wnt-high/NF-κB-high, designated W, N, and WN, respectively. These subtypes have distinct characteristics, including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype. Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines. Therefore, N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics. This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to

  1. Deletion of TAK1 in the Myeloid Lineage Results in the Spontaneous Development of Myelomonocytic Leukemia in Mice

    PubMed Central

    Lamothe, Betty; Lai, YunJu; Hur, Lana; Orozco, Natalia Martin; Wang, Jing; Campos, Alejandro D.; Xie, Min; Schneider, Michael D.; Lockworth, Cynthia R.; Jakacky, Jared; Tran, Diep; Ho, Michael; Dawud, Sity; Dong, Chen; Lin, Hui-Kuan; Hu, Peter; Estrov, Zeev; Bueso-Ramos, Carlos E.; Darnay, Bryant G.

    2012-01-01

    Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells’ increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1’s role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1’s role in leukemogenesis. PMID:23251462

  2. Thermal effects on shearing resistance of fractures in Tak granite

    NASA Astrophysics Data System (ADS)

    Khamrat, S.; Thongprapha, T.; Fuenkajorn, K.

    2018-06-01

    Triaxial shear tests have been performed on tension-induced fractures and smooth saw-cut surfaces in Tak granite under temperatures up to 773 K. The objective is to gain an understanding of the movement of shallow faults that cause seismic activities in the Tak batholith in the north of Thailand. The results indicate that the peak and residual shear strengths and fracture dilations notably decrease as the temperatures increase. The thermal effect is enhanced under higher confining pressures. The areas of the sheared-off asperities increase with temperature and confining pressure. A power equation can describe the increase of shear strengths with normal stress where the normal stress exponent is a linear function of the temperature. The strain energy principle is applied to incorporate the principal stresses and strains into a strength criterion. A linear relation between the distortional strain energy (Wd) and the mean strain energy (Wm) of the fractures is obtained. The Wd-Wm slope depends on the fracture roughness and strength of the asperities, which can be defined as a function of shear and mean strains and dilation of the fractures. This may allow predicting the peak strength of the shallow faults in the Tak batholith.

  3. Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development.

    PubMed

    Song, Zhongchen; Liu, Chao; Iwata, Junichi; Gu, Shuping; Suzuki, Akiko; Sun, Cheng; He, Wei; Shu, Rong; Li, Lu; Chai, Yang; Chen, YiPing

    2013-04-12

    Cleft palate represents one of the most common congenital birth defects in humans. TGFβ signaling, which is mediated by Smad-dependent and Smad-independent pathways, plays a crucial role in regulating craniofacial development and patterning, particularly in palate development. However, it remains largely unknown whether the Smad-independent pathway contributes to TGFβ signaling function during palatogenesis. In this study, we investigated the function of TGFβ activated kinase 1 (Tak1), a key regulator of Smad-independent TGFβ signaling in palate development. We show that Tak1 protein is expressed in both the epithelium and mesenchyme of the developing palatal shelves. Whereas deletion of Tak1 in the palatal epithelium or mesenchyme did not give rise to a cleft palate defect, inactivation of Tak1 in the neural crest lineage using the Wnt1-Cre transgenic allele resulted in failed palate elevation and subsequently the cleft palate formation. The failure in palate elevation in Wnt1-Cre;Tak1(F/F) mice results from a malformed tongue and micrognathia, resembling human Pierre Robin sequence cleft of the secondary palate. We found that the abnormal tongue development is associated with Fgf10 overexpression in the neural crest-derived tongue tissue. The failed palate elevation and cleft palate were recapitulated in an Fgf10-overexpressing mouse model. The repressive effect of the Tak1-mediated noncanonical TGFβ signaling on Fgf10 expression was further confirmed by inhibition of p38, a downstream kinase of Tak1, in the primary cell culture of developing tongue. Tak1 thus functions to regulate tongue development by controlling Fgf10 expression and could represent a candidate gene for mutation in human PRS clefting.

  4. Evaluation of the Parent-Implemented Communication Strategies (PiCS) Project Using the Multiattribute Utility (MAU) Approach

    ERIC Educational Resources Information Center

    Stoner, Julia B.; Meadan, Hedda; Angell, Maureen E.; Daczewitz, Marcus

    2012-01-01

    We conducted a multiattribute utility (MAU) evaluation to assess the Parent-Implemented Communication Strategies (PiCS) project which was funded by the Institute of Education Sciences (IES). In the PiCS project parents of young children with developmental disabilities are trained and coached in their homes on naturalistic and visual teaching…

  5. Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia.

    PubMed

    Amano, Yuichiro; Nishimoto, Tomoyuki; Tozawa, Ryu ichi; Ishikawa, Eiichiro; Imura, Yoshimi; Sugiyama, Yasuo

    2003-04-11

    The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.

  6. Reno-protective effects of TAK-242 on acute kidney injury in a rat model.

    PubMed

    Mohammad, Bassim I; Raheem, Abdulla K; Hadi, Najah R; Jamil, Dina A; Al-Aubaidy, Hayder A

    2018-06-13

    Acute kidney inschemia/reperfusion (I/R) injury is characterized by an abrupt loss of kidney function, resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. Despite the advances in therapeutic techniques, the mortality and morbidity of patients remain high and have not appreciably improved. This study aims to evaluate the potential protective effect of TAK-242 on renal ischemia/reperfusion injury using an animal model. Thirty-five adult male Sprague-dawely rats (weighing 200-300), were assigned randomly into the following experimental groups (n = 7 in each group), Control (I/R), Sham (negative control), TAK-242 (5 mg/kg body weight), TAK-242 (10 mg/kg body weight) and Vehicle (DMSO). Rats were exposed to a 30 min of ischemia then 3 h of reperfusion. At the end of reperfusion phase, rats were sacrificed then plasma, serum and tissue samples were obtained to measure markers of kidney oxidative stress and inflammation. Plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), and tissue levels of interleukin-18 (IL-18) and malondialdehyde (MDA) were significantly lower in TAK-242 pretreated groups than the vehicle group and the control group (p < 0.05). Furthermore; serum levels of urea and creatinine were significantly lower in the TAK-242 pretreated groups as compared to the control group (p < 0.05). We conclude that administration of TAK-242 can be useful preventive method in attenuating the degree of acute kidney injury during ischemic reperfusion process as shown by a significant reduction of urinary inflammatory markers as well as significant reduction of urea and creatinine levels. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice

    NASA Technical Reports Server (NTRS)

    Zhang, D.; Gaussin, V.; Taffet, G. E.; Belaguli, N. S.; Yamada, M.; Schwartz, R. J.; Michael, L. H.; Overbeek, P. A.; Schneider, M. D.

    2000-01-01

    The transforming-growth-factor-beta-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor beta. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo, cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, 'fetal' gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

  8. Bone bonding in bioactive glass ceramics combined with a new synthesized agent TAK-778.

    PubMed

    Kato, H; Neo, M; Tamura, J; Nakamura, T

    2001-11-01

    We studied the stimulatory effects of TAK-778, a new synthetic 3-benzothiepin derivative that promotes osteoblast differentiation, in the bonding of bone to bioactive glass ceramic implants in rabbit tibiae. Smooth-surfaced, rectangular plates (15 x 10 x 2 mm) made of apatite-wollastonite-containing glass ceramic were implanted bilaterally into the proximal metaphyses of rabbit tibiae. Sustained-release microcapsules containing TAK-778 were packed into the medullary cavity in one limb and untreated microcapsules were packed into the contralateral limb to serve as a paired control. At 4, 8, and 16 weeks after implantation, bonding at the bone/implant interfaces was evaluated using a detaching test and histological examination of undecalcified specimens. The tensile failure load increased during weeks 4 to 16 in both groups; the tensile failure load in the TAK-778-treated group was significantly greater than that in the control group at each interval after implantation. Histologically, the TAK-778-treated specimens showed greater active new bone formation mainly in the medullary cavity and more extensive bonding between the implant and bone than the untreated specimens. The results of this study suggest that adding the bone formation-promoting TAK-778 to bioactive glass ceramic implants may significantly accelerate bone apposition to the implants and improve the bonding process at the interface. This would help to establish earlier and stronger bonding of orthopedic ceramic implants to the surrounding bone tissue. Copyright 2001 John Wiley & Sons, Inc.

  9. TGF-β Coordinately Activates TAK1/MEK/AKT/NFkB and Smad Pathways to Promote Osteoclast Survival

    PubMed Central

    Gingery, Anne; Bradley, Elizabeth W.; Pederson, Larry; Ruan, Ming; Horwood, Nikki J.; Oursler, Merry Jo

    2008-01-01

    To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFκB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IκB, and NFκB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFκB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFκB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclXL expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFκB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival. PMID:18586026

  10. Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xu, Jianmin; Walsh, Stephanie B.; Verney, Zoe M.

    Research highlights: {yields} Organ transplant recipients are highly susceptible to early skin cancer development. {yields} CsA-mediated TGFB1-dependent TAK1/TAB1 signaling augments invasive tumor growth. {yields} CsA enhances accumulation of upstream kinases, ZMP, AMPK and IRAK to activate TAK1. {yields} TAK1 mediates enhanced proliferation and reduced apoptosis via CsA-dependent NF{kappa}B. -- Abstract: Cyclosporine A (CsA) is an immunosuppressive drug commonly used for maintaining chronic immune suppression in organ transplant recipients. It is known that patients receiving CsA manifest increased growth of aggressive non-melanoma skin cancers. However, the underlying mechanism by which CsA augments tumor growth is not fully understood. Here, we showmore » that CsA augments the growth of A431 epidermoid carcinoma xenograft tumors by activating tumor growth factor {beta}-activated kinase1 (TAK1). The activation of TAK1 by CsA occurs at multiple levels by kinases ZMP, AMPK and IRAK. TAK1 forms heterodimeric complexes with TAK binding protein 1 and 2 (TAB1/TAB2) which in term activate nuclear factor {kappa}B (NF{kappa}B) and p38 MAP kinase. Transcriptional activation of NF{kappa}B is evidenced by IKK{beta}-mediated phosphorylation-dependent degradation of I{kappa}B and consequent nuclear translocation of p65. This also leads to enhancement in the expression of its transcriptional target genes cyclin D1, Bcl2 and COX-2. Similarly, activation of p38 leads to enhanced inflammation-related signaling shown by increased phosphorylation of MAPKAPK2 and which in turn phosphorylates its substrate HSP27. Activation of both NF{kappa}B and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs.« less

  11. Lack of TAK1 in dendritic cells inhibits the contact hypersensitivity response induced by trichloroethylene in local lymph node assay

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yao, Pan; Hongqian, Chu; Qinghe, Meng

    Trichloroethylene (TCE) is a ubiquitous environmental contaminant. Occupational TCE exposure has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder. The development of CHS depends on innate and adaptive immune functions. Transforming growth factor-β activated kinase-1 (TAK1) controls the survival of dendritic cells (DCs) that affect the immune system homeostasis. We aimed to investigate the role of TAK1 activity in DC on TCE-induced CHS response. Control mice and DC-specific TAK1 deletion mice were treated with 80% (v/v) TCE using local lymph node assay (LLNA) to establish a TCE-induced CHS model. The draining lymph nodes (DLNs) were excised and themore » lymphocytes were measure for proliferation by BrdU-ELISA, T-cell phenotype analysis by flow cytometry and signaling pathway activation by western blot. The ears were harvested for histopathological analysis. Control mice in the 80% TCE group displayed an inflammatory response in the ears, increased lymphocyte proliferation, elevated regulatory T-cell and activated T-cell percentages, and more IFN-γ producing CD8{sup +} T cells in DLNs. In contrast to control mice, DC-specific TAK1 deletion mice in the 80% TCE group showed an abolished CHS response and this was associated with defective T-cell expansion, activation and IFN-γ production. This effect may occur through Jnk and NF-κB signaling pathways. Overall, this study demonstrates a pivotal role of TAK1 in DCs in controlling TCE-induced CHS response and suggests that targeting TAK1 function in DCs may be a viable approach to preventing and treating TCE-related occupational health hazards. - Highlights: • Lack of TAK1 in DC caused an abolished TCE-induced CHS response. • TAK1 in DCs was essential to maintain the homeostasis of T cells in TCE-induced CHS. • Intact TAK1 in DCs was critical to promote T-cell priming in TCE-induced CHS. • DC-specific TAK1 deficiency abolished the TCE-mediated phosphorylation of Jnk.« less

  12. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model

    PubMed Central

    Takashima, K; Matsunaga, N; Yoshimatsu, M; Hazeki, K; Kaisho, T; Uekata, M; Hazeki, O; Akira, S; Iizawa, Y; Ii, M

    2009-01-01

    Background and purpose: TAK-242, a novel synthetic small-molecule, suppresses production of multiple cytokines by inhibiting Toll-like receptor (TLR) 4 signalling. In this study, we investigated the target molecule of TAK-242 and examined its therapeutic effect in a mouse sepsis model. Experimental approach: Binding assay with [3H]-TAK-242 and nuclear factor-κB reporter assay were used to identify the target molecule and binding site of TAK-242. Bacillus calmette guerin (BCG)-primed mouse sepsis model using live Escherichia coli was used to estimate the efficacy of TAK-242 in sepsis. Key results: TAK-242 strongly bound to TLR4, but binding to TLR2, 3, 5, 9, TLR-related adaptor molecules and MD-2 was either not observed or marginal. Mutational analysis using TLR4 mutants indicated that TAK-242 inhibits TLR4 signalling by binding to Cys747 in the intracellular domain of TLR4. TAK-242 inhibited MyD88-independent pathway as well as MyD88-dependent pathway and its inhibitory effect was largely unaffected by lipopolysaccharide (LPS) concentration and types of TLR4 ligands. TAK-242 had no effect on the LPS-induced conformational change of TLR4-MD-2 and TLR4 homodimerization. In mouse sepsis model, although TAK-242 alone did not affect bacterial counts in blood, if co-administered with ceftazidime it inhibited the increases in serum cytokine levels and improved survival of mice. Conclusions and implications: TAK-242 suppressed TLR4 signalling by binding directly to a specific amino acid Cys747 in the intracellular domain of TLR4. When co-administered with antibiotics, TAK-242 showed potent therapeutic effects in an E. coli-induced sepsis model using BCG-primed mice. Thus, TAK-242 may be a promising therapeutic agent for sepsis. PMID:19563534

  13. Effect of TAK1 on osteogenic differentiation of mesenchymal stem cells by regulating BMP-2 via Wnt/β-catenin and MAPK pathway.

    PubMed

    Yang, Hongpeng; Guo, Yue; Wang, Dawei; Yang, Xiaofei; Ha, Chengzhi

    2018-01-02

    Mesenchymal stem cells (MSCs) have the ability to differentiate into osteoblasts and chondrocytes. In vitro osteogenic differentiation is critical but the molecular mechanism has yet to be further clarified. The role of TGF-β activated kinase 1 (TAK1) in MSCs osteogenesis differentiation has not been reported. By adding si-TAK1 and rhTAK1, the osteogenic differentiation of MSCs was measured. Expression levels of the osteoblastic marker genes during osteogenic differentiation of MSCs were checked. As well as molecules involved in BMP and Wnt/β-catenin signaling pathways. The phosphorylation of p38 and JNK was also checked. TAK1 is essential for mineralization of MSCs at low concentration, but excessive rhTAK1 inhibits mineralization of MSCs. It up regulates the expression levels of bone sialoprotein (BSP), osteocalcin (OSC), Alkaline phosphatase (ALP), and RUNX2 during osteogenic differentiation of MSCs. It can also promote TGF-β/BMP-2 gene expression and β-catenin expression, and down regulate GSK-3β expression. Meanwhile, TAK1 promotes the phosphorylation of p38 and JNK. Additionally, TAK1 up regulates the expression of BMP-2 at all concentration under the inhibition of p38 and JNK. Our results suggested that TAK1 is essential in MSCs osteogenesis differentiation, and functions as a double-edged sword, probably through regulation of β-catenin and p38/JNK.

  14. Innate immunity kinase TAK1 phosphorylates Rab1 on a hotspot for posttranslational modifications by host and pathogen.

    PubMed

    Levin, Rebecca S; Hertz, Nicholas T; Burlingame, Alma L; Shokat, Kevan M; Mukherjee, Shaeri

    2016-08-16

    TGF-β activated kinase 1 (TAK1) is a critical signaling hub responsible for translating antigen binding signals to immune receptors for the activation of the AP-1 and NF-κB master transcriptional programs. Despite its importance, known substrates of TAK1 are limited to kinases of the MAPK and IKK families and include no direct effectors of biochemical processes. Here, we identify over 200 substrates of TAK1 using a chemical genetic kinase strategy. We validate phosphorylation of the dynamic switch II region of GTPase Rab1, a mediator of endoplasmic reticulum to Golgi vesicular transport, at T75 to be regulated by TAK1 in vivo. TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. Previous studies established that the pathogen Legionella pneumophila is capable of hijacking Rab1 function through posttranslational modifications of the switch II region. Here, we present evidence that Rab1 is regulated by the host in a similar fashion, and that the innate immunity kinase TAK1 and Legionella effectors compete to regulate Rab1 by switch II modifications during infection.

  15. Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury

    PubMed Central

    Zhu, Andy Z. X.; Johnson, Mike; Yu, Shaoxia; Moriya, Yuu; Ebihara, Takuya; Csizmadia, Vilmos; Grieves, Jessica; Paton, Martin; Liao, Mingxiang; Gemski, Christopher; Pan, Liping; Vakilynejad, Majid; Dragan, Yvonne P.; Chowdhury, Swapan K.; Kirby, Patrick J.

    2017-01-01

    Abstract Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs. PMID:28108665

  16. An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK.

    PubMed

    Ono, K; Ohtomo, T; Sato, S; Sugamata, Y; Suzuki, M; Hisamoto, N; Ninomiya-Tsuji, J; Tsuchiya, M; Matsumoto, K

    2001-06-29

    TAK1, a member of the MAPKKK family, is involved in the intracellular signaling pathways mediated by transforming growth factor beta, interleukin 1, and Wnt. TAK1 kinase activity is specifically activated by the TAK1-binding protein TAB1. The C-terminal 68-amino acid sequence of TAB1 (TAB1-C68) is sufficient for TAK1 interaction and activation. Analysis of various truncated versions of TAB1-C68 defined a C-terminal 30-amino acid sequence (TAB1-C30) necessary for TAK1 binding and activation. NMR studies revealed that the TAB1-C30 region has a unique alpha-helical structure. We identified a conserved sequence motif, PYVDXA/TXF, in the C-terminal domain of mammalian TAB1, Xenopus TAB1, and its Caenorhabditis elegans homolog TAP-1, suggesting that this motif constitutes a specific TAK1 docking site. Alanine substitution mutagenesis showed that TAB1 Phe-484, located in the conserved motif, is crucial for TAK1 binding and activation. The C. elegans homolog of TAB1, TAP-1, was able to interact with and activate the C. elegans homolog of TAK1, MOM-4. However, the site in TAP-1 corresponding to Phe-484 of TAB1 is an alanine residue (Ala-364), and changing this residue to Phe abrogates the ability of TAP-1 to interact with and activate MOM-4. These results suggest that the Phe or Ala residue within the conserved motif of the TAB1-related proteins is important for interaction with and activation of specific TAK1 MAPKKK family members in vivo.

  17. TAK1 regulates NF-{Kappa}B and AP-1 activation in airway epithelial cells following RSV infection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Dey, Nilay; Liu Tianshuang; Garofalo, Roberto P.

    2011-09-30

    Respiratory syncytial virus (RSV) is the most common cause of epidemic respiratory diseases in infants and young children. RSV infection of airway epithelial cells induces the expression of immune/inflammatory genes through the activation of a subset of transcription factors, including Nuclear Factor-{kappa}B (NF-{kappa}B) and AP-1. In this study, we have investigated the signaling pathway leading to activation of these two transcription factors in response to RSV infection. Our results show that IKK{beta} plays a key role in viral-induced NF-{kappa}B activation, while JNK regulates AP-1-dependent gene transcription, as demonstrated by using kinase inactive proteins and chemical inhibitors of the two kinases.more » Inhibition of TAK1 activation, by overexpression of kinase inactive TAK1 or using cells lacking TAK1 expression, significantly reduced RSV-induced NF-{kappa}B and AP-1 nuclear translocation and DNA-binding activity, as well as NF-{kappa}B-dependent gene expression, identifying TAK1 as an important upstream signaling molecule regulating RSV-induced NF-{kappa}B and AP-1 activation. - Highlights: > IKK{beta} is a major kinase involved in RSV-induced NF-{kappa}B activation. > JNK regulates AP-1-dependent gene transcription in RSV infection. > TAK1 is a critical upstream signaling molecule for both pathways in infected cells.« less

  18. Synergistic effect of a factor Xa inhibitor, TAK-442, and antiplatelet agents on whole blood coagulation and arterial thrombosis in rats.

    PubMed

    Konishi, Noriko; Hiroe, Katsuhiko; Kawamura, Masaki

    2010-08-01

    Activated platelets facilitate blood coagulation by providing factor V and a procoagulant surface for prothrombinase. Here, we investigated the potential synergy of a potent factor Xa/prothrombinase inhibitor, TAK-442, plus aspirin or clopidogrel in preventing arterial thrombosis and whole blood coagulation. Thrombus formation was initiated by FeCl(3)-induced rat carotid injury. Bleeding time was evaluated with the rat tail transection model. Whole blood coagulation was assessed by thromboelastographic examination (TEG) for which blood obtained from control, aspirin-, or clopidogrel-treated rats was transferred to a TEG analyzer containing, collagen or adenosine diphosphate (ADP), and TAK-442 or vehicle. TAK-442 (3mg/kg, po), aspirin (100mg/kg, po) or clopidogrel (3mg/kg, po) alone had no significant effect on thrombus formation, whereas the combination of TAK-442 with aspirin and clopidogrel remarkably prolonged the time to thrombus formation without additional significant prolongation of bleeding time. TEG demonstrated that the onset of collagen-induced blood coagulation were slightly longer in aspirin-treated rats than control; however, when the blood from aspirin-treated rats was subsequently treated in vitro with 100 nM TAK-442, the onset of clotting was significantly prolonged. In contrast, only marginal prolongation was observed with TAK-442 treatment of blood from control animals. The onset time of ADP-induced blood coagulation was slightly longer in clopidogrel-treated rats compared with control, and it was further extended by TAK-442 treatment. These results demonstrate that blood coagulation can be markedly delayed by the addition of TAK-442 to antiplatelets treatment which could contribute to synergistic antithrombotic efficacy in these settings. (c) 2010 Elsevier Ltd. All rights reserved.

  19. Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist-Induced Rat Models of Schizophrenia.

    PubMed

    Nakashima, Masato; Imada, Haruka; Shiraishi, Eri; Ito, Yuki; Suzuki, Noriko; Miyamoto, Maki; Taniguchi, Takahiko; Iwashita, Hiroki

    2018-04-01

    The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, ( N -{(1 S )-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3- b ]pyrazine-4(1 H )-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  20. Electronic structure and properties of MAu and MOH, where M = Tl and Nh: New data

    NASA Astrophysics Data System (ADS)

    Pershina, V.; Iliaš, M.

    2018-02-01

    Properties of the MAu and MOH (M = Tl and element 113, Nh) molecules were calculated using the 2c-DFT method. The obtained data are needed for evaluation of reactivity of Nh studied by gas-phase chromatography experiments. Results show that Nh should be less reactive (or more volatile) than Tl, both with respect to gold and the hydroxyl group. The reason for that are strong relativistic effects on the valence 7s and 7p electron shells. In difference to the atoms, NhOH may be less volatile than TlOH due to its larger both dipole moment and anisotropic polarizability.

  1. Lack of TAK1 in dendritic cells inhibits the contact hypersensitivity response induced by trichloroethylene in local lymph node assay.

    PubMed

    Yao, Pan; Hongqian, Chu; Qinghe, Meng; Lanqin, Shang; Jianjun, Jiang; Xiaohua, Yang; Xuetao, Wei; Weidong, Hao

    2016-09-15

    Trichloroethylene (TCE) is a ubiquitous environmental contaminant. Occupational TCE exposure has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder. The development of CHS depends on innate and adaptive immune functions. Transforming growth factor-β activated kinase-1 (TAK1) controls the survival of dendritic cells (DCs) that affect the immune system homeostasis. We aimed to investigate the role of TAK1 activity in DC on TCE-induced CHS response. Control mice and DC-specific TAK1 deletion mice were treated with 80% (v/v) TCE using local lymph node assay (LLNA) to establish a TCE-induced CHS model. The draining lymph nodes (DLNs) were excised and the lymphocytes were measure for proliferation by BrdU-ELISA, T-cell phenotype analysis by flow cytometry and signaling pathway activation by western blot. The ears were harvested for histopathological analysis. Control mice in the 80% TCE group displayed an inflammatory response in the ears, increased lymphocyte proliferation, elevated regulatory T-cell and activated T-cell percentages, and more IFN-γ producing CD8(+) T cells in DLNs. In contrast to control mice, DC-specific TAK1 deletion mice in the 80% TCE group showed an abolished CHS response and this was associated with defective T-cell expansion, activation and IFN-γ production. This effect may occur through Jnk and NF-κB signaling pathways. Overall, this study demonstrates a pivotal role of TAK1 in DCs in controlling TCE-induced CHS response and suggests that targeting TAK1 function in DCs may be a viable approach to preventing and treating TCE-related occupational health hazards. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor.

    PubMed

    Tsai, Max; Chrones, Lambros; Xie, Jinhui; Gevorkyan, Hakop; Macek, Thomas A

    2016-10-01

    Schizophrenia is a complex neuropsychiatric disorder characterized, in part, by impaired dopamine signaling. TAK-063 is a selective inhibitor of phosphodiesterase 10A, a key regulator of intracellular signaling pathways that is highly expressed in the striatum. Safety, tolerability, and pharmacokinetics of TAK-063 were evaluated in a phase 1 study. Healthy Japanese and non-Japanese volunteers were randomized into dose cohorts of 3, 10, 30, 100, 300, and 1000 mg. Each fasting volunteer randomly received a single dose of TAK-063 or placebo. Individuals from the 100-mg cohort also received a post-washout, 100-mg dose under fed conditions. A total of 84 volunteers enrolled (14 per cohort). The most common drug-related adverse events (AEs) were somnolence (33.3 %), orthostatic tachycardia (19.7 %), and orthostatic hypotension (9.1 %). The three severe AEs recorded occurred at the highest doses: orthostatic hypotension (n = 1; 300 mg) and somnolence (n = 2; 1000 mg). There were no deaths, serious AEs, or discontinuations due to AEs. TAK-063 exposure increased in a dose-dependent manner. Median T max was reached 3 to 4 h postdose. Fed conditions slowed absorption (T max =  6 h) and increased oral bioavailability. Renal elimination was negligible. Safety and pharmacokinetic parameters were similar between Japanese and non-Japanese subjects. Impairments in cognitive function consistent with the effects of other sedative or hypnotic agents were detected using a validated, computerized cognition battery, CNS Vital Signs. TAK-063 was safe and well tolerated at doses up to 1000 mg and demonstrated a pharmacokinetic profile supporting once-daily dosing. Further evaluation of the clinical safety and efficacy of TAK-063 is warranted.

  3. TAK-242 treatment ameliorates liver ischemia/reperfusion injury by inhibiting TLR4 signaling pathway in a swine model of Maastricht-category-III cardiac death.

    PubMed

    Shao, Zigong; Jiao, Baoping; Liu, Tingting; Cheng, Ying; Liu, Hao; Liu, Yongfeng

    2016-12-01

    This study aims to test the effects of TAK-242 on liver transplant viability in a model of swine Maastricht-category-III cardiac death. A swine DCD Maastricht-III model of cardiac death was established, and TAK-242 was administered prior to the induction of cardiac death. The protein and mRNA level of TLR4 signaling pathway molecules and cytokines that are important in mediating immune and inflammatory responses were assessed at different time points following the induction of cardiac death. After induction of cardiac death, both the mRNA and protein levels of key molecules (TLR4, TRAF6, NF-ϰB, ICAM-1, MCP-1 and MPO), TNF-α and IL-6 increased significantly. Infusion of TAK-242 1h before induction of cardiac death blocked the increase of immune and inflammatory response molecules. However, the increase of TLR4 level was not affected by infusion of TAK-242. Histology study showed that infusion of TAK-242 protect liver tissue from damage during cardiac death. These results indicates that TLR4 signaling pathway may contribute to ischemia/reperfusion injury in the liver grafts, and blocking TLR4 pathway with TAk-242 may reduce TLR4-mediated tissue damage. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the omega-3 fatty acids randomized double-blind (ORD) study.

    PubMed

    Tatsuno, Ichiro; Saito, Yasushi; Kudou, Kentarou; Ootake, Jun

    2013-01-01

    Hypertriglyceridemia is a risk factor for cardiovascular disease, and clinical practice guidelines advocate treatment to reduce triglyceride (TG) levels. In Japan, an EPA-E (eicosapentaenoic acid-ethyl ester) product has been used clinically for treating dyslipidemia. We investigated the TG-lowering effects of TAK-085 (EPA-E + docosahexaenoic acid-ethyl ester) in comparison with EPA-E in Japanese patients with hypertriglyceridemia (TG ≥150 mg/dL and <750 mg/dL). In this multicenter, 12-week, double-blind study, subjects were stratified for coadministration of a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor then randomized to TAK-085 2 g once daily (n = 205), TAK-085 2 g twice daily (n = 210), or EPA-E 0.6 g three times daily (n = 195). Each one gram of fatty acid in TAK-085 contains approximately 465 mg of EPA plus 375 mg of docosahexaenoic acid-ethyl as ethyl esters. Guidance on lifestyle modifications was provided throughout. The primary end point was the percent change in TG levels (baseline from end of treatment), which was -10.8 ± 22.6, -22.9 ± 23.1, and -11.2 ± 25.7 in the TAK-085 2 g/day, TAK-085 4 g/day, and EPA-E 1.8 g/day groups, respectively. TAK-085 4 g/day produced a significantly greater reduction in TG than EPA-E 1.8 g/day (P < .0001), whereas TAK-085 2 g/day was not inferior to EPA-E 1.8 g/day. Changes in other lipid parameters were relatively modest. There were no notable safety or tolerability differences between the groups. In Japanese patients with modest hypertriglyceridemia who also underwent lifestyle intervention, TAK-085 4 g/day reduced TG more than EPA-E 1.8 g/day. TAK-085 2 g/day had similar effects on TG as EPA-E 1.8 g/day. TAK-085 was well-tolerated. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  5. Altered cerebellar development in nuclear receptor TAK1/ TR4 null mice is associated with deficits in GLAST(+) glia, alterations in social behavior, motor learning, startle reactivity, and microglia.

    PubMed

    Kim, Yong-Sik; Harry, G Jean; Kang, Hong Soon; Goulding, David; Wine, Rob N; Kissling, Grace E; Liao, Grace; Jetten, Anton M

    2010-09-01

    Previously, deficiency in the expression of the nuclear orphan receptor TAK1 was found to be associated with delayed cerebellar granule cell migration and Purkinje cell maturation with a permanent deficit in foliation of lobules VI–VII, suggesting a role for TAK1 in cerebellum development. In this study, we confirm that TAK1-deficient (TAK1(−/−)) mice have a smaller cerebellum and exhibit a disruption of lobules VI–VII. We extended these studies and show that at postnatal day 7, TAK1(−/−) mice exhibit a delay in monolayer maturation of dysmorphic calbindin 28K-positive Purkinje cells. The astrocyte-specific glutamate transporter (GLAST) was expressed within Bergmann fibers and internal granule cell layer at significantly lower levels in the cerebellum of TAK1(−/−) mice. At PND21, Golgi-positive Purkinje cells in TAK1(−/−) mice displayed a smaller soma (18%) and shorter distance to first branch point (35%). Neuronal death was not observed in TAK1(−/−) mice at PND21; however, activated microglia were present in the cerebellum, suggestive of earlier cell death. These structural deficits in the cerebellum were not sufficient to alter motor strength, coordination, or activity levels; however, deficits in acoustic startle response, prepulse startle inhibition, and social interactions were observed. Reactions to a novel environment were inhibited in a light/dark chamber, open-field, and home-cage running wheel. TAK1(−/−) mice displayed a plateau in performance on the running wheel, suggesting a deficit in learning to coordinate performance on a motor task. These data indicate that TAK1 is an important transcriptional modulator of cerebellar development and neurodevelopmentally regulated behavior.

  6. Long-term safety and efficacy of TAK-085 in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the omega-3 fatty acids randomized long-term (ORL) study.

    PubMed

    Tatsuno, Ichiro; Saito, Yasushi; Kudou, Kentarou; Ootake, Jun

    2013-01-01

    TAK-085 is an omega-3 preparation that contains eicosapentaenoic acid ethyl-ester (EPA-E) and docosahexaenoic acid-ethyl ester used in the management of hypertriglyceridemia. The aim of the study was to evaluate the long-term safety (adverse events [AEs], laboratory parameters, vital signs, weight, and electrocardiograms) and effects on lipid profiles, especially triglyceride levels, of TAK-085 in Japanese patients with hypertriglyceridemia (triglyceride levels ≥150 mg/dL and <750 mg/dL). In this multicenter, open-label, randomized study, adults with hypertriglyceridemia undergoing lifestyle modification received TAK-085 2 g (2 g once daily; n = 165) or 4 g (2 g twice daily; n = 171), or EPA-E 1.8 g (0.6 g three times daily; n = 167) for 52 weeks. Patients were stratified for co-administration of a statin. TAK-085 was well tolerated throughout the 52-week study. Overall, no substantial differences were found in the tolerability of TAK-085 2 g, TAK-085 4 g, and EPA-E 1.8 g with incidence rates for AEs of 83.6%, 86.0%, and 89.2%, respectively. Most AEs were mild or moderate in severity. Triglyceride levels decreased from baseline in all groups by week 4, and the decreases were maintained throughout the study. At week 52 the reduction in triglycerides with TAK-085 2 g (-13.9%) was similar to that with EPA-E 1.8 g (-12.1%), whereas the reduction seen with TAK-085 4 g (-25.5%) was greater than that with EPA-E 1.8 g, as assessed by point estimates and 95% confidence intervals. TAK-085 was safe and well tolerated for up to 52 weeks of treatment in Japanese patients with hypertriglyceridemia undergoing lifestyle modification. Reductions in triglyceride levels achieved after 4 weeks were maintained at 52 weeks. Copyright © 2013 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  7. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Bing, E-mail: wangbin69@yahoo.com; Wang, Xin-bao; Chen, Li-yu

    2013-07-19

    Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancermore » cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.« less

  8. Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.

    PubMed

    Nakata, Daisuke; Masaki, Tsuneo; Tanaka, Akira; Yoshimatsu, Mie; Akinaga, Yumiko; Asada, Mari; Sasada, Reiko; Takeyama, Michiyasu; Miwa, Kazuhiro; Watanabe, Tatsuya; Kusaka, Masami

    2014-01-15

    TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Parental Perceptions of the Effects of the High-Stakes TAKS Test on the Home Lives of At-Risk Fifth Grade Students

    ERIC Educational Resources Information Center

    Westfall, Dawn M.

    2010-01-01

    In Texas, fifth grade students are required to pass both the reading and math sections of the Texas Assessment of Knowledge and Skills, or TAKS test, in order to be promoted to the next grade level. The purpose of this study is to describe parents' perceptions of the influence of the high-stakes TAKS test on the family lives of at-risk fifth grade…

  10. HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways

    PubMed Central

    Berth, Sarah H.; Mesnard-Hoaglin, Nichole; Wang, Bin; Kim, Hajwa; Song, Yuyu; Sapar, Maria; Morfini, Gerardo

    2016-01-01

    Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP. PMID:27872270

  11. TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study

    PubMed Central

    Bang, Yung-Jue; Takano, Toshimi; Lin, Chia-Chi; Fasanmade, Adedigbo; Yang, Huyuan; Danaee, Hadi; Asato, Takayuki; Kalebic, Thea; Wang, Hui; Doi, Toshihiko

    2018-01-01

    Purpose This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). Materials and Methods Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. Results Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. Conclusion TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose. PMID:28494535

  12. Identifying the impacts of land use on water and nutrient cycling in the South-West Mau, Kenya

    NASA Astrophysics Data System (ADS)

    Jacobs, Suzanne; Weeser, Björn; Breuer, Lutz; Butterbach-Bahl, Klaus; Rufino, Mariana

    2016-04-01

    The Mau Forest is the largest closed canopy forest system and indigenous montane forest in Kenya, covering approximately 400,000 ha. It is the source of twelve major rivers in the Rift Valley and Western Kenya and one of Kenya's five 'water towers' that provide around 10 million people with fresh water. Significant areas have been affected by deforestation and land use changes in the past decades, resulting in a loss of approx. 25% of the forest area. Recent changes in downstream water supply are discussed to be attributed to land use change, though compelling scientific evidence is still lacking. The study area is located in the South-West Mau as a part of the Sondu River basin that drains into Lake Victoria. This area has suffered a forest loss of 25% through conversion of natural forest to smallholder agriculture and tea/tree plantations. A nested catchment approach has been applied, whereby automatic measurement equipment for monitoring discharge, turbidity, nitrate, total and dissolved organic carbon, electrical conductivity and water temperature at a 10 minute interval has been set up at the outlets of three sub-catchments of 27 - 36 km² and the outlet of the 1023 km² major catchment. The dominant land use in the sub-catchments is either natural forest, tea/tree plantation or smallholder agriculture. The river data is complemented by six precipitation gauging stations and three climate stations, that all measure at the same interval. Installed during October 2014, the systems have collected high resolution data for one and a half year now. The high resolution dataset is being analysed for patterns in stream flow and water quality during dry and wet seasons as well as diurnal cycling of nitrate. The results of the different sub-catchments are compared to identify the role of land use in water and nutrient cycling. First results of the high temporal resolution data already indicate that the different types of land use affect the stream nitrate concentration

  13. A Study of the Relationship between Levels of Technology Implementation (LoTi) and Student Performance on Texas Assessment of Knowledge and Skills (TAKS) Scores

    ERIC Educational Resources Information Center

    Berkeley-Jones, Catherine Spotswood

    2012-01-01

    The purpose of this study was to examine teacher Levels of Technology Implementation (LoTi) self-ratings and student Texas Assessment of Knowledge and Skills (TAKS) scores. The study assessed the relationship between LoTi ratings and TAKS scores of 6th, 7th, and 8th grade students as reported in student records at Alamo Heights Independent School…

  14. Anti-inflammatory and cytoprotective effects of a squalene synthase inhibitor, TAK-475 active metabolite-I, in immune cells simulating mevalonate kinase deficiency (MKD)-like condition.

    PubMed

    Suzuki, Nobutaka; Ito, Tatsuo; Matsui, Hisanori; Takizawa, Masayuki

    2016-01-01

    TAK-475 (lapaquistat acetate) and its active metabolite-I (TAK-475 M-I) inhibit squalene synthase, which catalyzes the conversion of farnesyl diphosphate (FPP) to squalene. FPP is a substrate for synthesis of other mevalonate-derived isoprenoids (MDIs) such as farnesol (FOH), geranlygeranyl diphosphate (GGPP), and geranylgeraniol. In patients with MKD, a rare autosomal recessive disorder, defective activity of mevalonate kinase leads to a shortage of MDIs. MDIs especially GGPP are required for prenylation of proteins, which is a posttranslation modification necessary for proper functioning of proteins like small guanosine triphosphatases. Malfunction of prenylation of proteins results in upregulation of the inflammatory cascade, leading to increased production of proinflammatory cytokines like interleukin-1β (IL-1β), eventually leading to episodic febrile attacks. In vitro, TAK-475 M-I incubation in a concentration dependent manner increased levels of FPP, GGPP, and FOH in human monocytic THP-1 cells. In subsequent experiments, THP-1 cells or human peripheral blood mononuclear cells (PBMCs) were incubated with simvastatin, which inhibits hydroxymethylglutaryl-coenzyme A reductase and thereby decreases levels of the precursors of MDIs, leading to the depletion of MDIs as expected in MKD patients. Increased levels of GGPP and FPP attenuated lipopolysaccharide (LPS)-induced IL-1β production in THP-1 cells and human PBMCs in statin-treated conditions. The MDIs also significantly reduced the damaged cell ratio in this active MKD-like condition. Moreover, TAK-475 M-I directly inhibited LPS-induced IL-1β production from statin-treated THP-1 cells. These results show anti-inflammatory and cytoprotective effects of MDIs via TAK-475 M-I treatment in statin-treated immune cells, suggesting that possible therapeutic effects of TAK-475 treatment in MKD patients.

  15. Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)

    PubMed Central

    2015-01-01

    We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors. PMID:25075558

  16. An Integrated Learning System: Impact on At-Risk Students' Ninth Grade TAKS Mathematics Achievement

    ERIC Educational Resources Information Center

    Harris, Tina D.

    2011-01-01

    The purpose of this study was to determine the impact of an integrated learning system on students who were considered at-risk of academic failure on the Texas Assessment of Knowledge and Skills (TAKS) mathematics assessment. Voyager Math (VMath), an integrated learning system had been implemented to address the needs of students at-risk of…

  17. Organic pollution and salt intrusion in Cai Nuoc District, Ca Mau Province, Vietnam.

    PubMed

    Tho, Nguyen; Vromant, Nico; Hung, Nguyen Thanh; Hens, Luc

    2006-07-01

    In Ca Mau, Vietnam, farmers converted from rice to shrimp farming, while ignoring the degradation of the aquatic environment. We assessed the seasonal variations in organic pollution of the surface water and salt intrusion in one district and assessed the difference in chemical characteristics of the surface water of shrimp ponds and canals. Several variables reflecting salinity and organic pollution were measured in the wet and dry season. The results show that in the dry season salinity increased to 37.36-42.73 g l(-1) and COD and suspended solids increased to a maximum of 268.7 mg l(-1) and 1312.0 mg l(-1), respectively. In the wet season salinity values of 8.16 to 10.60 g l(-1) were recorded, indicating that salinity could no longer be washed out completely in this season. It is concluded that salinity and suspended solids in the aquatic environment in the Cai Nuoc district are increased by shrimp monoculture, whereas organic pollution is contributed by human population pressure.

  18. TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipidinduced inflammation and insulin resistance in muscle cells

    PubMed Central

    Hussey, Sophie E.; Liang, Hanyu; Costford, Sheila R.; Klip, Amira; DeFronzo, Ralph A.; Sanchez-Avila, Alicia; Ely, Brian; Musi, Nicolas

    2012-01-01

    Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action. PMID:23050932

  19. Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tan, Li; Nomanbhoy, Tyzoon; Gurbani, Deepak

    Here, we developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16more » and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. Lastly, a 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.« less

  20. Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)

    DOE PAGES

    Tan, Li; Nomanbhoy, Tyzoon; Gurbani, Deepak; ...

    2014-07-17

    Here, we developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16more » and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. Lastly, a 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.« less

  1. Shrimp TAB1 interacts with TAK1 and p38 and activates the host innate immune response to bacterial infection.

    PubMed

    Wang, Sheng; Li, Mengqiao; Yin, Bin; Li, Haoyang; Xiao, Bang; Lǚ, Kai; Huang, Zhijian; Li, Sedong; He, Jianguo; Li, Chaozheng

    2017-08-01

    Mammalian TAB1 has been previously identified as transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) binding protein, which functions as the activator of TAK1 and p38. This report, for the first time, identified and characterized the homolog of TAB1 in shrimp, to be specific, the homolog gene from Litopenaeus vannamei, containing a 1560-bp open reading frame (ORF) that encoded a putative protein of 519 amino acids with the conserved PP2Cc (Serine/threonine phosphatases, family 2C, catalytic) domain in N-terminal and a TAK1 binding motif in C-terminus, has been cloned and named LvTAB1. LvTAB1 was most abundant in gills and its expression could respond significantly to a series of stimuli, including LPS, Vibrio parahemolyticus and Staphylococcus aureus. Moreover, Co-immunoprecipitation (Co-IP) experiments showed that LvTAB1 could combine with LvTAK1 as well as Lvp38, two members of IMD-NF-κB/MAPK pathway, which meant LvTAB1 could have a role in regulating the activities of these kinases. Over-expression of LvTAB1 in drosophila S2 cells could improve the transcriptional levels of antimicrobial peptide genes (AMPs) such as Diptericin (Dpt), the hallmark of drosophila NF-κB activated genes, indicating its activation effect on NF-κB pathway. Furthermore, suppression of LvTAB1 expression in vivo by RNA-interference increased the sensibility of shrimps to V. parahaemolyticus infection, implying its protective role against bacterial infection. In conclusion, these results provide some insight into the function of LvTAB1 during bacterial infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling.

    PubMed

    Ii, Masayuki; Matsunaga, Naoko; Hazeki, Kaoru; Nakamura, Kazuyo; Takashima, Katsunori; Seya, Tsukasa; Hazeki, Osamu; Kitazaki, Tomoyuki; Iizawa, Yuji

    2006-04-01

    Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-alpha induced by LPS and interferon-gamma in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1beta-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.

  3. TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.

    PubMed

    Hussey, Sophie E; Liang, Hanyu; Costford, Sheila R; Klip, Amira; DeFronzo, Ralph A; Sanchez-Avila, Alicia; Ely, Brian; Musi, Nicolas

    2012-11-30

    Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.

  4. Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.

    PubMed

    Ebihara, T; Takeuchi, T; Moriya, Y; Tagawa, Y; Kondo, T; Moriwaki, T; Asahi, S

    2016-06-01

    TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 μmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 μmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Repositioning Of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice.

    PubMed

    Marcuzzi, Annalisa; Loganes, Claudia; Celeghini, Claudio; Kleiner, Giulio

    2017-09-11

    Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase (MK), due to a mutation in the MVK gene, leads to the shortage of mevalonate-derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-1 (IL-1) can significantly reduce inflammation, they cannot completely control the clinical symptoms that affects the nervous system. For this reason, MKD can still be considered an orphan drug disease. Cellular models for MKD can be obtained by biochemical inhibition of mevalonate-derived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase (SQS) able to increase the availability of isoprenoids intermediates upstream the enzymatic block. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. HTLV-1 Tax Stimulates Ubiquitin E3 Ligase, Ring Finger Protein 8, to Assemble Lysine 63-Linked Polyubiquitin Chains for TAK1 and IKK Activation.

    PubMed

    Ho, Yik-Khuan; Zhi, Huijun; Bowlin, Tara; Dorjbal, Batsukh; Philip, Subha; Zahoor, Muhammad Atif; Shih, Hsiu-Ming; Semmes, Oliver John; Schaefer, Brian; Glover, J N Mark; Giam, Chou-Zen

    2015-08-01

    Human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, impacts a multitude of cellular processes, including I-κB kinase (IKK)/NF-κB signaling, DNA damage repair, and mitosis. These activities of Tax have been implicated in the development of adult T-cell leukemia (ATL) in HTLV-1-infected individuals, but the underlying mechanisms remain obscure. IKK and its upstream kinase, TGFβ-activated kinase 1 (TAK1), contain ubiquitin-binding subunits, NEMO and TAB2/3 respectively, which interact with K63-linked polyubiquitin (K63-pUb) chains. Recruitment to K63-pUb allows cross auto-phosphorylation and activation of TAK1 to occur, followed by TAK1-catalyzed IKK phosphorylation and activation. Using cytosolic extracts of HeLa and Jurkat T cells supplemented with purified proteins we have identified ubiquitin E3 ligase, ring finger protein 8 (RNF8), and E2 conjugating enzymes, Ubc13:Uev1A and Ubc13:Uev2, to be the cellular factors utilized by Tax for TAK1 and IKK activation. In vitro, the combination of Tax and RNF8 greatly stimulated TAK1, IKK, IκBα and JNK phosphorylation. In vivo, RNF8 over-expression augmented while RNF8 ablation drastically reduced canonical NF-κB activation by Tax. Activation of the non-canonical NF-κB pathway by Tax, however, is unaffected by the loss of RNF8. Using purified components, we further demonstrated biochemically that Tax greatly stimulated RNF8 and Ubc13:Uev1A/Uev2 to assemble long K63-pUb chains. Finally, co-transfection of Tax with increasing amounts of RNF8 greatly induced K63-pUb assembly in a dose-dependent manner. Thus, Tax targets RNF8 and Ubc13:Uev1A/Uev2 to promote the assembly of K63-pUb chains, which signal the activation of TAK1 and multiple downstream kinases including IKK and JNK. Because of the roles RNF8 and K63-pUb chains play in DNA damage repair and cytokinesis, this mechanism may also explain the genomic instability of HTLV-1-transformed T cells and ATL cells.

  7. HTLV-1 Tax Stimulates Ubiquitin E3 Ligase, Ring Finger Protein 8, to Assemble Lysine 63-Linked Polyubiquitin Chains for TAK1 and IKK Activation

    PubMed Central

    Ho, Yik-Khuan; Zhi, Huijun; Bowlin, Tara; Dorjbal, Batsukh; Philip, Subha; Zahoor, Muhammad Atif; Shih, Hsiu-Ming; Semmes, Oliver John; Schaefer, Brian; Glover, J. N. Mark; Giam, Chou-Zen

    2015-01-01

    Human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, impacts a multitude of cellular processes, including I-κB kinase (IKK)/NF-κB signaling, DNA damage repair, and mitosis. These activities of Tax have been implicated in the development of adult T-cell leukemia (ATL) in HTLV-1-infected individuals, but the underlying mechanisms remain obscure. IKK and its upstream kinase, TGFβ-activated kinase 1 (TAK1), contain ubiquitin-binding subunits, NEMO and TAB2/3 respectively, which interact with K63-linked polyubiquitin (K63-pUb) chains. Recruitment to K63-pUb allows cross auto-phosphorylation and activation of TAK1 to occur, followed by TAK1-catalyzed IKK phosphorylation and activation. Using cytosolic extracts of HeLa and Jurkat T cells supplemented with purified proteins we have identified ubiquitin E3 ligase, ring finger protein 8 (RNF8), and E2 conjugating enzymes, Ubc13:Uev1A and Ubc13:Uev2, to be the cellular factors utilized by Tax for TAK1 and IKK activation. In vitro, the combination of Tax and RNF8 greatly stimulated TAK1, IKK, IκBα and JNK phosphorylation. In vivo, RNF8 over-expression augmented while RNF8 ablation drastically reduced canonical NF-κB activation by Tax. Activation of the non-canonical NF-κB pathway by Tax, however, is unaffected by the loss of RNF8. Using purified components, we further demonstrated biochemically that Tax greatly stimulated RNF8 and Ubc13:Uev1A/Uev2 to assemble long K63-pUb chains. Finally, co-transfection of Tax with increasing amounts of RNF8 greatly induced K63-pUb assembly in a dose-dependent manner. Thus, Tax targets RNF8 and Ubc13:Uev1A/Uev2 to promote the assembly of K63-pUb chains, which signal the activation of TAK1 and multiple downstream kinases including IKK and JNK. Because of the roles RNF8 and K63-pUb chains play in DNA damage repair and cytokinesis, this mechanism may also explain the genomic instability of HTLV-1-transformed T cells and ATL cells. PMID:26285145

  8. Computer Modeling of the Instructionally Insensitive Nature of the Texas Assessment of Knowledge and Skills (TAKS) Exam

    ERIC Educational Resources Information Center

    Pham, Vinh Huy

    2009-01-01

    Stakeholders of the educational system assume that standardized tests are transparently about the subject content being tested and therefore can be used as a metric to measure achievement in outcome-based educational reform. Both analysis of longitudinal data for the Texas Assessment of Knowledge and Skills (TAKS) exam and agent based computer…

  9. The Effects of CSCOPE on Student Achievement as Measured by Both TAKS and STAAR Test Results

    ERIC Educational Resources Information Center

    Helm, Maricela Robledo

    2013-01-01

    The purpose of this study was to examine the effects of CSCOPE curriculum on student achievement. CSCOPE is a curriculum management system used in 750 of the 1,039 school districts in the state of Texas. Student achievement is based on the results acquired from the Texas Assessment of Knowledge and Skills (TAKS) and the new version of the state…

  10. Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling in Drosophila

    PubMed Central

    Stronach, Beth; Lennox, Ashley L.; Garlena, Rebecca A.

    2014-01-01

    A highly diverse set of protein kinases functions as early responders in the mitogen- and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-β activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate, the JNK kinase Hep. Tak1 C-terminal domain-containing constructs were inhibitory in Tak1 signaling contexts, including tumor necrosis factor-dependent cell death and innate immune signaling; however, depressing antimicrobial gene expression did not necessarily cause phenotypic susceptibility to infection. These same constructs were neutral in the context of Slpr-dependent developmental signaling, reflecting differential subcellular protein localization and by inference, point of activation. Altogether, our findings suggest that the selective deployment of a particular MAP3K can be attributed in part to its inherent sequence differences, cellular localization, and binding partner availability. PMID:24429281

  11. Barriers to immunization among children of migrant workers from Myanmar living in Tak province, Thailand.

    PubMed Central

    Plugge, Emma; Suwanjatuporn, Suporn; Sombatrungjaroen, Suteera; Nosten, François

    2011-01-01

    Abstract Problem Immunization is a cost-effective means of improving child survival but implementation of programmes in low- and middle-income countries is variable. Children of migrants are less likely to be immunized. Approach The qualitative study aimed to identify barriers to the successful implementation of migrant immunization programmes in Tak province, Thailand. We ran a total of 53 focus groups involving 371 participants in three sites. Local setting Tak province in Thailand borders Myanmar and has an estimated 200 000 migrants from Myanmar. Vaccine-preventable diseases are a documented cause of morbidity in this population but there is no systematic or coordinated immunization programme in the area. Relevant changes As a result of the findings, the subsequent immunization campaign targeted children in school to overcome those barriers of distance to immunization services, fear of arrest, not remembering immunization appointments, and the disruption of parental work. The campaigns also included immunization education for both parents and teachers. Lessons learnt Migrant parents identified similar barriers to accessing childhood immunization programmes as migrant populations elsewhere in the world, although a unique barrier identified by parents from Myanmar was “fear of arrest”. The subsequent school-based strategy to overcome these barriers appears to be effective. PMID:21734767

  12. The PPARβ/δ agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFκB pathway in rats.

    PubMed

    Su, Xuesong; Zhou, Guangyu; Wang, Yanqiu; Yang, Xu; Li, Li; Yu, Rui; Li, Detian

    2014-06-01

    Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARβ/δ agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25% PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516-containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-α, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-β-activated kinase 1 (TAK1), and nuclear factor kappa B (NFκB) signaling pathway (TAK1-NFκB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1-NFκB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD.

  13. Access to free or low-cost tuberculosis treatment for migrants and refugees along the Thailand-Myanmar border in Tak province, Thailand.

    PubMed

    Tschirhart, Naomi; Nosten, Francois; Foster, Angel M

    2016-07-07

    In Tak province, Thailand migrants and refugees from Myanmar navigate a pluralistic healthcare system to seek Tuberculosis (TB) care from a variety of government and non-governmental providers. This multi-methods qualitative study examined access to TB, TB/HIV and multidrug-resistant tuberculosis (MDR-TB) treatment with an emphasis on barriers to care and enabling factors. In the summer and fall of 2014, we conducted 12 key informant interviews with public health officials and TB treatment providers. We also conducted 11 focus group discussions with migrants and refugees who were receiving TB, TB/HIV and MDR-TB treatment in Tak province as well as non-TB patients. We analyzed these data through thematic analysis using both predetermined and emergent codes. As a second step in the qualitative analysis, we explored the barriers and enabling factors separately for migrants and refugees. We found that refugees face fewer barriers to accessing TB treatment than migrants. For both migrants and refugees, legal status plays an important intermediary role in influencing the population's ability to access care and eligibility for treatment. Our results suggest that there is a large geographical catchment area for migrants who seek TB treatment in Tak province that extends beyond provincial boundaries. Migrant participants described their ability to seek care as linked to the financial and non-financial resources required to travel and undergo treatment. Patients identified language of health services, availability of free or low cost services, and psychosocial support as important health system characteristics that affect accessibility. Access to TB treatment for migrants and refugees occurs at the interface of health system accessibility, population ability and legal status. In Tak province, migrant patients draw upon their social networks and financial resources to navigate a pathway to treatment. We revised a conceptual framework for access to healthcare to incorporate

  14. Social Marketing in Malaysia: Cognitive, Affective, and Normative Mediators of the TAK NAK Antismoking Advertising Campaign.

    PubMed

    Lee, Wonkyong Beth; Fong, Geoffrey T; Dewhirst, Timothy; Kennedy, Ryan D; Yong, Hua-Hie; Borland, Ron; Awang, Rahmat; Omar, Maizurah

    2015-01-01

    Antismoking mass media campaigns are known to be effective as part of comprehensive tobacco control programs in high-income countries, but such campaigns are relatively new in low- and middle-income countries and there is a need for strong evaluation studies from these regions. This study examines Malaysia's first national antismoking campaign, TAK NAK. The data are from the International Tobacco Control Malaysia Survey, which is an ongoing cohort survey of a nationally representative sample of adult smokers (18 years and older; N = 2,006). The outcome variable was quit intentions of adult smokers, and the authors assessed the extent to which quit intentions may have been strengthened by exposure to the antismoking campaign. The authors also tested whether the impact of the campaign on quit intentions was related to cognitive mechanisms (increasing thoughts about the harm of smoking), affective mechanisms (increasing fear from the campaign), and perceived social norms (increasing perceived social disapproval about smoking). Mediational regression analyses revealed that thoughts about the harm of smoking, fear arousal, and social norms against smoking mediated the relation between TAK NAK impact and quit intentions. Effective campaigns should prompt smokers to engage in both cognitive and affective processes and encourage consideration of social norms about smoking in their society.

  15. Momordica charantia Inhibits Inflammatory Responses in Murine Macrophages via Suppression of TAK1.

    PubMed

    Yang, Woo Seok; Yang, Eunju; Kim, Min-Jeong; Jeong, Deok; Yoon, Deok Hyo; Sung, Gi-Ho; Lee, Seungihm; Yoo, Byong Chul; Yeo, Seung-Gu; Cho, Jae Youl

    2018-01-01

    Momordica charantia known as bitter melon is a representative medicinal plant reported to exhibit numerous pharmacological activities such as antibacterial, antidiabetic, anti-inflammatory, anti-oxidant, antitumor, and hypoglycemic actions. Although this plant has high ethnopharmacological value for treating inflammatory diseases, the molecular mechanisms by which it inhibits the inflammatory response are not fully understood. In this study, we aim to identify the anti-inflammatory mechanism of this plant. To this end, we studied the effects of its methanol extract (Mc-ME) on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Specifically, we evaluated nitric oxide (NO) production, mRNA expression of inflammatory genes, luciferase reporter gene activity, and putative molecular targets. Mc-ME blocked NO production in a dose-dependent manner in RAW264.7 cells; importantly, no cytotoxicity was observed. Moreover, the mRNA expression levels of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 were decreased by Mc-ME treatment in a dose-dependent manner. Luciferase assays and nuclear lysate immunoblotting analyses strongly indicated that Mc-ME decreases the levels of p65 [a nuclear factor (NF)-[Formula: see text]B subunit] and c-Fos [an activator protein (AP)-1 subunit]. Whole lysate immunoblotting assays, luciferase assays, and overexpression experiments suggested that transforming growth factor [Formula: see text]-activated kinase 1 (TAK1) is targeted by Mc-ME, thereby suppressing NF-[Formula: see text]B and AP-1 activity via downregulation of extracellular signal-regulated kinases (ERKs) and AKT. These results strongly suggest that Mc-ME exerts its anti-inflammatory activity by reducing the action of TAK1, which also affects the activation of NF-[Formula: see text]B and AP-1.

  16. Kokua Mau: a statewide effort to improve end-of-life care.

    PubMed

    Braun, Kathryn L; Zir, Ana; Crocker, Joanna; Seely, Marilyn R

    2005-04-01

    Many Americans die in pain, without hospice, and without regard to advance directives, suggesting a need to improve end-of-life (EOL) awareness and services. This paper describes Kokua Mau, a community-state partnership to improve EOL in Hawaii funded by The Robert Wood Johnson Foundation (RWJF). Coalition activities were guided by innovation-diffusion theory, targeting "innovators" and "change agents" within communities and organizations willing to learn about and facilitate improvements to EOL care. Evaluation of a community-wide intervention to improve EOL care. Honolulu, Hawaii. We tracked dissemination of campaign messages by counting numbers of coalition members (including innovators and change agents to carry on the work), individuals reached through awareness and educational offerings, and new EOL projects initiated during and after the initial 3-year RWJF funding. To measure change, we counted the number of legislative policies that were modified by the coalition as well as indicators of hospice utilization, advance directive (AD) completion, support for physician-assisted death, and place of death. In the first 3 years of the project: coalition membership grew to 350 members; EOL care curricula were developed and offered to various target audiences; 17,000 individuals attended educational events; policy changes were facilitated; decreases were seen in proportions of residents supporting physician-assisted suicide; and increases were seen in advance directive completion rates and hospice utilization. Most importantly, after the grant period, coalition members went on to develop and implement new programs to improve care to the dying. Although it will take several years to effect comprehensive and sustained changes in the way death is perceived and the dying process is facilitated, findings suggest that programs based on innovation-diffusion theory can increase EOL awareness and help develop the change agents and role models needed to affect community

  17. Effects of TGF-β1 on plasminogen activation in human dental pulp cells: Role of ALK5/Smad2, TAK1 and MEK/ERK signalling.

    PubMed

    Chang, Mei-Chi; Chang, Hsiao-Hua; Lin, Po-Shuan; Huang, Yu-An; Chan, Chiu-Po; Tsai, Yi-Ling; Lee, Shen-Yang; Jeng, Po-Yuan; Kuo, Han-Yueh; Yeung, Sin-Yuet; Jeng, Jiiang-Huei

    2018-04-01

    Transforming growth factor-β1 (TGF-β1) plays an important role in the pulpal repair and dentinogenesis. Plasminogen activation (PA) system regulates extracellular matrix turnover. In this study, we investigated the effects of TGF-β1 on PA system of dental pulp cells and its signalling pathways. Dental pulp cells were treated with different concentrations of TGF-β1. MTT assay, reverse transcription-polymerase chain reaction, Western blotting and enzyme-linked immunosorbant assay (ELISA) were used to detect the effect of TGF-β1 on cell viability, mRNA and protein expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1) as well as their secretion. The phosphorylation of Smad2 and TAK1 was analysed by Pathscan ELISA or Western blotting. Cells were pretreated with SB431542 (ALK5/Smad2/3 inhibitor), 5z-7-oxozeaenol (TAK1 inhibitor) and U0126 (MEK/ERK inhibitor) for examining the related signalling. TGF-β1 slightly inhibited cell growth that was reversed by SB431542. TGF-β1 upregulated both RNA and protein expression of PAI-1 and uPAR, whereas it downregulated uPA expression. Accordingly, TGF-β1 stimulated PAI-1 and soluble uPAR (suPAR) secretion of pulp cells, whereas uPA secretion was inhibited. TGF-β1 induced the phosphorylation of Smad2 and TAK1. In addition, SB431542, 5z-7-oxozeaenol and U0126 attenuated the TGF-β1-induced secretion of PAI-1 and suPAR. These results indicate that TGF-β1 is possibly involved in the repair/regeneration and inflammatory processes of dental pulp via regulation of PAI-1, uPA and uPAR. These effects of TGF-β1 are related to activation of ALK5/Smad2, TAK1 and MEK/ERK signalling pathways. Clarifying the signal transduction for the effects of TGF-β1 is helpful for pulpo-dentin regeneration and tissue engineering. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Prevalence of latent tuberculous infection among adults in the general population of Ca Mau, Viet Nam.

    PubMed

    Marks, G B; Nhung, N V; Nguyen, T A; Hoa, N B; Khoa, T H; Son, N V; Phuong, N T B; Tin, D M; Ho, J; Fox, G J

    2018-03-01

    The study was conducted in a randomly selected sample of persons aged 15 years living in Ca Mau Province, southern Viet Nam. To estimate the prevalence of latent tuberculous infection (LTBI) in the general adult population of this province of Viet Nam. The secondary objective was to examine age and sex differences in prevalence. A cross-sectional survey was conducted in a cluster-random sample of the population. Clusters were subcommunes. The presence of LTBI was assessed using the QuantiFERON®-TB Gold In-Tube test system. QuantiFERON tests were performed among 1319 persons aged 15 years (77.7% of those selected). The overall prevalence of positive tests was 36.8% (95%CI 33.4-40.3). The prevalence of a positive test was lower in females than in males (31.0% vs. 44.7%, OR 0.57, 95%CI 0.45-0.72, P < 0.0001). The prevalence of positive tests increased with increasing age quintile (P < 0.0001). More than one third of the general adult population in a province in southern Viet Nam have evidence of LTBI. Although LTBI prevalence is higher in males, the sex difference is not as great as that for TB notification rates.

  19. AC Power at Power Frequencies: Bilateral comparison between SASO NMCC and TÜBİTAK UME

    NASA Astrophysics Data System (ADS)

    Çaycı, Hüseyin; Yılmaz, Özlem; AlRobaish, Abdullah M.; AlAnazi, Shafi S.; AlAyali, Ahmed R.; AlRumie, Rashed A.

    2018-01-01

    A supplementary bilateral comparison measurement on AC Power at 50/60 Hz between SASO NMCC (GULFMET) and TÜBİTAK UME (EURAMET) was performed with the primary power standards of each partner. Measurement methods and setups which are very similar of the participants, measurement results, calculation of differences in the results, evaluation of uncertainties are given within this report. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  20. Characterization of Pressure Fields of Focused Transducers at TÜBİTAK UME

    NASA Astrophysics Data System (ADS)

    Karaböce, B.; Şahin, A.; İnce, A. T.; Skarlatos, Y.

    Field radiated by HIFU (High Intensity Focused Ultrasound) has been investigated by measuring its pressure field and mapping in 2-D and 3-D. A new ultrasound pressure measurement system has been designed and constructed at TÜBİTAK UME (The Scientific and Technological Research Council of Turkey, the National Metrology Institute). System consists of a water tank, positioning system, measurement devices and a controlling program. The hydrophone was attached to a 3-axis, computer-controlled positioning system for alignment with the ultrasound source. The signal was captured and analyzed by the commercially available LabVIEW 8.1 software. The measurements of the ultrasound field were carried out with a needle hydrophone. For each waveform, p, p+ and p-pressures have been calculated. Wave behaviors produced by the KZK model and from experiments look like similar in general. In p, p+, p- the focal point, zero point after the primary peak (focus) and extremum points in the near field well match.

  1. Characteristical analysis of high school astronomy's learning in Rio Grande da Serra, Ribeirão Pires and Mauá

    NASA Astrophysics Data System (ADS)

    Faria, R. Z.; Voelzke, M. R.

    Even though astronomy is one of the oldest science that contributes to the human and thecnological development, its concepts are rarely taught for students of high school. The present research discusses two aspects related to the teaching of astronomy. The first aspect is to know whether astronomy is discussed in high school classes and the second on is related to the way how teachers approach astronomy. In order to find out this, a questionnaire was applied for the teachers who teach physics classes and work in state schools in Rio Grande da Serra, Ribeirão Pires and Mauá in São Paulo. From 66.2% of the teachers who answered to the questionnaire in the three chosen cities, 57.4% did not discuss any subject about astronomy, 89.4% did not use any kind of computer program, 70.2% did not use laboratory, 83.0% never took the students for museums or observatories and 38.3% did not indicate any kind magazine or book about astronomy. Although the majority of the teachers admit that the astronomy content influences the education of the student, they do not include the subject in their planning.

  2. Insights in public health: Community strengthening through canoe culture: Ho'omana'o Mau as method and metaphor.

    PubMed

    Ho-Lastimosa, Ilima; Hwang, Phoebe W; Lastimosa, Bob

    2014-12-01

    Historical trauma occurs across generations and is evidenced by indigenous disparities. Efforts made to address this issue commonly utilize European ethnocentric methods. Rather, a community-based approach should be used to empower indigenous communities. God's Country Waimanalo (GCW) is a grassroots organization developed by Native Hawaiians for Native Hawaiians. Its wa'a (canoe) project, Ho'omana'o Mau (everlasting memories; abbreviated Ho'o) is meant to perpetuate pre-colonial Hawaiian practices by educating Native Hawaiian communities and its partners through hands on experience. Since 2012, GCW has opened its wa'a curricula to educators, counselors, and students from the University of Hawai'i at Manoa, Queen Lili'uokalani Children's Center, Alu Like, Hina Mauka, and the Youth Correctional Facility and contributed to Waimanalo based events such as funeral ash scattering and the papio fishing tournament. As metaphor, Ho'o is viewed as the catalyst to engage the next generation of Hawaiians to remember where they descend from, the lineage of chiefs and royalty, while establishing a solid foundation of independence and enhancing their ability to become self-sustaining. As a method, Ho'o is viewed as a classroom, a hands-on learning environment, and an ocean vessel, assembled according to traditional Hawaiian knowledge. Through this knowledge and practice, both indigenous and non-indigenous communities can work together in empowering Native Hawaiians to overcome historical trauma and reduce health disparities.

  3. Thyroid hormone activates rat liver adenosine 5,-monophosphate-activated protein kinase: relation to CaMKKb, TAK1 and LKB1 expression and energy status.

    PubMed

    Vargas, R; Ortega, Y; Bozo, V; Andrade, M; Minuzzi, G; Cornejo, P; Fernandez, V; Videla, L A

    2013-01-01

    AMP-activated protein kinase (AMPK) is a sensor of energy status supporting cellular energy homeostasis that may represent the metabolic basis for 3,3,,5-triiodo-L-thyronine (T3) liver preconditioning. Functionally transient hyperthyroid state induced by T3 (single dose of 0.1 mg/kg) in fed rats led to upregulation of mRNA expression (RT-PCR) and protein phosphorylation (Western blot) of hepatic AMPK at 8 to 36 h after treatment. AMPK Thr 172 phosphorylation induced by T3 is associated with enhanced mRNA expression of the upstream kinases Ca2+ -calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) and transforming growth-factor-beta-activated kinase-1 (TAK1), with increased protein levels of CaMKKbeta and higher TAK1 phosphorylation, without changes in those of the liver kinase B1 (LKB1) signaling pathway. Liver contents of AMP and ADP were augmented by 291 percent and 44 percent by T3 compared to control values (p less than 0.05), respectively, whereas those of ATP decreased by 64% (p less than 0.05), with no significant changes in the total content of adenine nucleotides (AMP + ADP + ATP) at 24 h after T3 administration. Consequently, hepatic ATP/ADP content ratios exhibited 64 percent diminution (p less than 0.05) and those of AMP/ATP increased by 425 percent (p less than 0.05) in T3-treated rats over controls. It is concluded that in vivoT3 administration triggers liver AMPK upregulation in association with significant enhancements in AMPK mRNA expression, AMPK phosphorylation coupled to CaMKKbeta and TAK1 activation, and in AMP/ATP ratios, which may promote enhanced AMPK activity to support T3-induced energy consuming processes such as those of liver preconditioning.

  4. Myostatin induces interstitial fibrosis in the heart via TAK1 and p38.

    PubMed

    Biesemann, Nadine; Mendler, Luca; Kostin, Sawa; Wietelmann, Astrid; Borchardt, Thilo; Braun, Thomas

    2015-09-01

    Myostatin, a member of the TGF-β superfamily of secreted growth factors, is a negative regulator of skeletal muscle growth. In the heart, it is expressed at lower levels compared to skeletal muscle but up-regulated under disease conditions. Cre recombinase-mediated inactivation of myostatin in adult cardiomyocytes leads to heart failure and increased mortality but cardiac function of surviving mice is restored after several weeks probably due to compensatory expression in non-cardiomyocytes. To study long-term effects of increased myostatin expression in the heart and to analyze the putative crosstalk between cardiomyocytes and fibroblasts, we overexpressed myostatin in cardiomyocytes. Increased expression of myostatin in heart muscle cells caused interstitial fibrosis via activation of the TAK-1-MKK3/6-p38 signaling pathway, compromising cardiac function in older mice. Our results uncover a novel role of myostatin in the heart and highlight the necessity for tight regulation of myostatin to maintain normal heart function.

  5. Changes in mangrove vegetation area and character in a war and land use change affected region of Vietnam (Mui Ca Mau) over six decades

    NASA Astrophysics Data System (ADS)

    Van, T. T.; Wilson, N.; Thanh-Tung, H.; Quisthoudt, K.; Quang-Minh, V.; Xuan-Tuan, L.; Dahdouh-Guebas, F.; Koedam, N.

    2015-02-01

    Aerial photographs and satellite images have been used to determine land cover changes during the period 1953 to 2011 in the Mui Ca Mau, Vietnam, especially in relation to changes in the mangrove area. The mangrove area declined drastically from approximately 71,345 ha in 1953 to 33,083 ha in 1992, then rose to 46,712 ha in 2011. Loss due to herbicide attacks during the Vietnam War, overexploitation, and conversion into agriculture and aquaculture encouraged by land management policies are being partially counteracted by natural regeneration and replanting, especially a gradual increase in plantations as part of integrated mangrove-shrimp farming systems. The nature of the mangrove vegetation has markedly been transformed over this period. The results are valuable for management planning to understand and improve the contribution of mangrove forests to the provision of ecosystem services and resources, local livelihood and global interest.

  6. Characteristical Analysis of High School Astronomy's Teaching in Rio Grande da Serra, Ribeirão Pires and Mauá

    NASA Astrophysics Data System (ADS)

    Faria, R. Z.

    2008-08-01

    Considering that Astronomy is one of the oldest science that contributes to the human and technological development, its concepts are rarely taught for students of High School. The present research argues two aspects related to the method of teaching Astronomy. The first aspect is if it has been discussed in the classes by teachers of High School, and the second one treats of the way it has been taught by these teachers. In order to find out this, a questionnaire was applied for the teachers who teach Physics classes and work in state schools in Rio Grande da Serra, Ribeirão Pires and Mauá in São Paulo. From 66.2% of the teachers who answered to the questionnaire in the three cities researched, 57.4% did not give any subject about Astronomy, 89.4% did not use any kind of computer program, 70.2% did not use laboratory, 83.0% never took the students for museums or observatories and 38.3% did not indicate any kind of magazine or book about Astronomy. Although the majority of the teachers admit that the Astronomy influence the education of the student, they do not include the subject in their planning.

  7. Computer Modeling of the Instructionally Insensitive Nature of the Texas Assessment of Knowledge and Skills (TAKS) Exam

    NASA Astrophysics Data System (ADS)

    Pham, Vinh Huy

    Stakeholders of the educational system assume that standardized tests are transparently about the subject content being tested and therefore can be used as a metric to measure achievement in outcome-based educational reform. Both analysis of longitudinal data for the Texas Assessment of Knowledge and Skills (TAKS) exam and agent based computer modeling of its underlying theoretical testing framework have yielded results that indicate the exam only rank orders students on a persistent but uncharacterized latent trait across domains tested as well as across years. Such persistent rank ordering of students is indicative of an instructionally insensitive exam. This is problematic in the current atmosphere of high stakes testing which holds teachers, administrators, and school systems accountable for student achievement.

  8. Hydrodynamic Impacts on Coastal Erosion and Deposition Processes in Cu Lao Dung (Soc Trang) and Rach Goc (Ca Mau)

    NASA Astrophysics Data System (ADS)

    Vo-Luong, H. P.; Phong, N. H.; Tran, D. X.; Ogston, A. S.

    2016-02-01

    Coastal mangrove forests are special and unique vegetation found in the tropics. They are classified as the most vulnerable ecosystem in coastal ecosystems. Moreover, mangrove forests are dynamic systems that directly influence coastal erosion and deposition processes. Cu Lao Dung (Soc Trang province) and Rach Goc (Ca Mau province) are chosen as studied sites. Although they both belong to the Mekong Delta on the eastern coast of Viet Nam, coastal erosion and deposition processes are different: Cu Lao Dung tends to be aggradational while the Rach Goc area is seriously erosional. This study aims to focus on the impact of hydrodynamics in the coastal processes at the Cu Lao Dung and Rach Goc sites. As part of field measurements in NE and SW monsoons (2014-2015), wave, current, river discharge, suspended sediment concentration, and bathymetry were measured. These data were collected in shallow sub-tidal water, on the muddy flat and within the mangrove forest. The observed data show that waves and current are dissipated quickly from shallow coastal water into the mangroves. They also depend on topography changes, characteristic in mangroves. Suspended sediment concentration increases from shallow water into the mangroves, and fluctuates according to tides, waves and currents. The analyzed data in Cu Lao Dung and Rach Goc are compared and from that, the main factors causing the erosion and deposition in these studied sites are explained.

  9. Mau Mau War: British Counterinsurgency In Colonial Kenya

    DTIC Science & Technology

    2016-05-26

    administration, sensationalized these events and used them to dehumanize the Kikuyu.8 This... dehumanization process colored opinion of Kenya’s political elite and paved the way for brutal political repression that would develop in response to the

  10. The comorbidity of increased arterial stiffness and microalbuminuria in a survey of middle-aged adults in China.

    PubMed

    Miao, Rujia; Wu, Liuxin; Ni, Ping; Zeng, Yue; Chen, Zhiheng

    2018-05-04

    Increased arterial stiffness (iAS) and microalbuminuria (MAU), which may occur simultaneously or separately in the general population and share similar risk factors, are markers of macro- and microvascular injuries. Our research investigated the comorbidity of iAS and MAU in the middle-aged population and examined the heterogeneous effects of metabolic risk factors on iAS and MAU. We selected 11,911 individuals aged 45 to 60 years who underwent a health examination at the 3rd Xiangya Hospital between 2010 and 2014. Metabolic syndrome (MetS) was determined according to IDF/NHLBI/AHA-2009 criteria. Multinomial logistic regression was applied to evaluate the influence of MetS, components of MetS and clusters of MetS on the co-occurrence (MAU(+)/iAS(+)) or non-co-occurrence (MAU(+)/iAS(-) and MAU(-)/iAS(+)) of MAU and iAS. Reference group was MAU(-)/iAS(-). A positive effect of MetS on the presence of MAU(+)/iAS(-), MAU(-)/iAS(+), or MAU(+)/iAS(+) is listed in ascending order based on odds ratios (ORs = 2.11, 2.41, 4.61, respectively; P < 0.05). Compared with MAU(+)/iAS(-), Elevated blood pressure (BP) (OR = 1.62 vs. 4.83, P < 0.05), triglycerides(TG) (OR = 1.20 vs. 1.37, P < 0.05) were more strongly associated with MAU(-)/iAS(+), whereas fasting blood glucose (FBG) was less associated (OR = 1.37 vs. 1.31, P < 0.05). Decreased high-density lipoprotein cholesterol(HDL-c) (OR = 1.84, P < 0.01) and elevated waist circumference(WC) (OR = 1.28 P < 0.01) were the most strongly associated with MAU(+)/iAS(-). Compared with the individuals without MetS, individuals with the elevated BP, FBG, TG and decreased HDL-c cluster had the greatest likelihood of presenting a MAU(-)/iAS(+) (OR = 5.98, P < 0.01) and MAU(+)/iAS(+) (OR = 13.17, P < 0.01), these likelihood was even greater than the cluster with simultaneous alteration in all five MetS components (OR = 3.89 and 10.77, respectively, P < 0.01), which showed the

  11. Optimizing care for acute medical patients: the Australasian Medical Assessment Unit Survey.

    PubMed

    McNeill, G B S; Brand, C; Clark, K; Jenkins, G; Scott, I; Thompson, C; Jenkins, P

    2011-01-01

    To ascertain the design and operational characteristics of acute Medical Assessment Units (MAU) located within Australasian hospitals, and to compare these with formal standards promulgated by the Internal Medicine Society of Australia and New Zealand (IMSANZ).   Descriptive study based on responses to questionnaires mailed to clinical and nursing leads of MAU in March 2009 with follow-up reminders over 3months. Hospitals that had an MAU that met predefined criteria were identified from an IMSANZ directory of sites based on recent contact with IMSANZ members and health department personnel and interrogation of hospital websites and attendance lists at recent MAU workshops.   Questionnaires were returned from 32 of 50 hospitals (response rate 64%). Most MAU (15/22; 68%) were less than 2years old. MAU were smaller than recommended by IMSANZ. Sixty-eight per cent were located over a 5-min walk from the emergency department (ED). Delay in transfer of patients from the ED to the MAU was common. The medical service to the majority of MAU was provided by General Medicine physicians and cover was reduced at weekends. In the majority of MAU the emphasis on function was facilitating discharge of patients rather than managing patients with high acuity of illness.   Our survey suggests that despite some variation in staffing and procedures, MAU seem to be well established and a promising means of decreasing ED access block. Future comparative study is required to evaluate further the effect of MAU on ED access block and ED length of stay. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

  12. Identifying patients with type 2 diabetes at high risk of microalbuminuria: results of the DEMAND (Developing Education on Microalbuminuria for Awareness of reNal and cardiovascular risk in Diabetes) Study.

    PubMed

    Rossi, Maria C E; Nicolucci, Antonio; Pellegrini, Fabio; Comaschi, Marco; Ceriello, Antonio; Cucinotta, Domenico; Giorda, Carlo; Valentini, Umberto; Vespasiani, Giacomo; De Cosmo, Salvatore

    2008-04-01

    We evaluated to what extent the presence of risk factors and their interactions increased the likelihood of microalbuminuria (MAU) among individuals with type 2 diabetes. Fifty-five Italian diabetes outpatient clinics enrolled a sample of patients with type 2 diabetes, without urinary infections and overt diabetic nephropathy. A morning spot urine sample was collected to centrally determine the urinary albumin/creatinine ratio (ACR). A tree-based regression technique (RECPAM) and multivariate analyses were performed to investigate interaction between correlates of MAU. Of the 1841 patients recruited, 228 (12.4%) were excluded due to the presence of urinary infections and 56 (3.5%) for the presence of macroalbuminuria. Overall, the prevalence of MAU (ACR = 30-299 mg/g) was of 19.1%. The RECPAM algorithm led to the identification of seven classes showing a marked difference in the likelihood of MAU. Non-smoker patients with HbA1c <7% and waist circumference MAU (7.5%), and represented the reference class. Patients with retinopathy, waist circumference >98 cm and HbA1c >8% showed the highest likelihood of MAU (odds ratio = 13.7; 95% confidence intervals 6.8-27.6). In the other classes identified, the risk of MAU ranged between 3 and 5. Age, systolic blood pressure, HDL cholesterol levels and diabetes treatment represented additional, global correlates of MAU. The likelihood of MAU is strongly related to the interaction between diabetes severity, smoking habits and several components of the metabolic syndrome. In particular, abdominal obesity, elevated blood pressure levels and low HDL cholesterol levels substantially increase the risk of MAU. It is of primary importance to monitor MAU in high-risk individuals and aggressively intervene on modifiable risk factors.

  13. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

    PubMed

    Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

    2016-06-01

    The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. © 2016 Wiley Periodicals, Inc.

  14. Sorption characteristics of cadmium in a clay soil of Mae Ku creek, Tak Province, Thailand

    NASA Astrophysics Data System (ADS)

    Thunyawatcharakul, P.; Chotpantarat, S.

    2018-05-01

    Mae Sot is a district in Tak province, the northern part of Thailand where has encountered with cadmium (Cd) contaminated in soils. Exposure of Cd can lead to severe health effect, for examples, bone softening, osteoporosis, renal dysfunction, and Itai-Itai disease. This study aims at elucidating sorption behavior of Cd in the contaminated soil collected from Mae Ku creek, Mae Sot district, Thailand. Batch sorption experiment was conducted in order to investigate sorption characteristics of Cd onto the contaminated soil. The soil sample taken from the study area consists of 26% sand, 16% silt 58% clay, which categorized as a clay soil, based on USDA classification. Soil pH is slightly alkaline (pH∼7.7) and organic matter in the soil is 2.93%. The initial concentration in the batch sorption experiment was in the range from 0- 200 ppm. The result from the batch sorption experiment showed that soil sample can adsorb Cd up to 173.5 ppm and the sorption behavior of the soil sample can be well described by Freundlich isotherm, indicating the multilayer sorption (R2 = 0.9964), with Freundlich constants of 0.312 and 1.760 L g-1 for 1/n and Kf, respectively.

  15. Prevalence of microalbuminuria in the general population of Seychelles and strong association with diabetes and hypertension independent of renal markers.

    PubMed

    Pruijm, Menno T; Madeleine, George; Riesen, Walter F; Burnier, Michel; Bovet, Pascal

    2008-05-01

    Few studies have examined microalbuminuria (MAU) in non-western populations. We assessed the prevalence of MAU in the general population of a middle-income country in the African region and relationships between MAU and selected cardiovascular risk factors. An examination survey was conducted in a sample representative of the entire population aged 25-64 years in the Seychelles. MAU adjusted for urine creatinine concentration was measured on the second morning urine using a semiquantitative point-of-care analyzer. A total of 1255 persons attended the survey (participation rate of 80.2%). The age-adjusted prevalence of MAU was 11.4%. At age 25-64 years, the prevalence of MAU was 5% in persons without diabetes and hypertension, 20% in persons with either condition and 41% in persons with both conditions. The overall prevalence of stages 3-4 chronic kidney disease was low at 3.2%. In multivariate analysis, MAU was associated with age [odds ratio (OR) 1.24 for a 10-year increase; 95% confidence interval (CI): 1.02-1.52], hypertension stage I (2.0; 1.1-3.8) and stage II (4.5; 2.3-8.6), obesity (1.7; 1.0-2.8) and diabetes (3.0; 1.9-4.9). These associations were virtually unchanged upon further adjustment for markers of renal function such as serum creatinine, serum cystatin C and calculated renal function. The prevalence of MAU was high in this population, and MAU was strongly associated with several cardiovascular risk factors independently of renal function markers. These findings suggest that MAU could be a useful marker of cardiovascular risk in this population and help identify persons in need of a specific cardiovascular risk management.

  16. Preliminary study on assessment of lead exposure in Thai children aged between 3-7 years old who live in Umphang district, Tak Province.

    PubMed

    Neesanan, Naiyana; Kasemsup, Rachada; Ratanachuaeg, Suntree; Kojaranjit, Puangporn; Sakulnoom, Kim; Padungtod, Chantana

    2011-08-01

    Centers of Disease Control of the United States of America (CDC) informs Ministry of Public Health, Thailand that up to 13% of Burmese refugee children who are transferred to the United States of America during 2007-2009 have elevated blood lead levels (EBLL, Blood Lead Level > or = 10 microg/dl). These are children from a number of refugee camps in Tak Province; two camps are near Umphang but other camps are not. In June 2008, CDC, the result of investigation of Centers for Disease Control/Thailand Ministry of Public Health Collaboration (CDC/TUC) and International Organization for Migration, Thailand indicates that 33 of 64 children aged 6 months to 15 years (5.1%) who live in Mae La, Umpiem and Nupo camps have elevated blood lead level. However, no study on how Thai children who live nearby those camps are exposed to lead. Subsequently, Queen Sirikit National Institute of Child Health, Bangkok, Thailand contacts relevant organizations in Tak Province in order to investigate lead exposure and evaluate health status of Thai children who live close to Burmese refugee camps. 1) Evaluation of lead exposure of Thai children who live nearby Burmese refugee camps; 2) Assessment of risk factors on lead exposure of the children as mentioned above. The present study adopts a retrospective study based on information gathered from health assessment on 213 Thai children aged between 3-7 years old who live nearby Burmese refugee camps. The health assessment was conducted from April 30th, 2010 to May 5th, 2010. The information is from 3 sources. The first source is from blood sampling in order to assess lead level and ferritin level. The next source is from interview of persons who provide primary care in order to identify risk factors on lead exposure of target children. The last source is from physical examination and developmental assessment conducted by pediatricians and special nurses for child development in order to identify health and developmental problems. The

  17. Evaluation of cotton stalk hydrolysate for xylitol production.

    PubMed

    Sapcı, Burcu; Akpinar, Ozlem; Bolukbasi, Ufuk; Yilmaz, Levent

    2016-07-03

    Cotton stalk is a widely distributed and abundant lignocellulosic waste found in Turkey. Because of its rich xylose content, it can be a promising source for the production of xylitol. Xylitol can be produced by chemical or biotechnological methods. Because the biotechnological method is a simple process with great substrate specificity and low energy requirements, it is more of an economic alternative for the xylitol production. This study aimed to use cotton stalk for the production of xylitol with Candida tropicalis Kuen 1022. For this purpose, the combined effects of different oxygen concentration, inoculum level and substrate concentration were investigated to obtain high xylitol yield and volumetric xylitol production rate. Candida tropicalis Kuen 1022 afforded different concentrations of xylitol depending on xylose concentration, inoculum level, and oxygen concentration. The optimum xylose, yeast concentration, and airflow rate for cotton stalk hydrolysate were found as 10.41 g L(-1), 0.99 g L(-1), and 1.02 vvm, respectively, and under these conditions, xylitol yield and volumetric xylitol production rate were obtained as 36% and 0.06 g L(-1) hr(-1), respectively. The results of this study show that cotton stalk can serve as a potential renewable source for the production of xylitol.

  18. C-terminal polymorphism of Plasmodium falciparium merozoite surface protein-1 (MSP-1) from Tak Province, Thailand.

    PubMed

    Viputtigul, Kwanjai; Tungpukdee, Noppadon; Ruangareerate, Toon; Luplertlop, Natthanej; Wilairatana, Polrat; Gaywee, Jariyanart; Krudsood, Srivicha

    2013-01-01

    This study was undertaken to ascertain the extent of polymorphism in the C-terminal region of Plasmodium falciparum merozoite surface protein (MSP-1) from 119 malaria patients in Tak Province on the western border of Thailand, who were admitted to the Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. P. falciparum infection was confirmed by microscopic examination of peripheral blood smears. Clinical manifestations were categorized into 2 groups: uncomplicated (94 cases) and complicated/severe (25 cases). A 1,040 basepair fragment of P. falciparum MSP-1 gene was compared with MSP-1 of reference strains retrieved from GenBank. The consensus sequences of MSP-1 block 16 showed it belonged to MAD20 genotype, which is the major allele of falciparum malaria from the western border of Thailand. MSP-1 block 16 amino acid fragment could be separated into 2 groups: similar and dissimilar to reference sequence. Four variations in MSP-1 block 16 were -1494K, D1510G, D1556N, and K1696I. MSP-1 block 16 diversity is not significantly associated with clinical manifestation although MAD 20 genotype is the predominant genotype in this area. The genetic data of MSP1 gene of faciparum malaria isolated from western Thai border contribute to the existing genetic database of Thai P. falciparum strain.

  19. A herbal formula comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos inhibits the production of inflammatory mediators and the IRAK-1/TAK1 and TBK1/IRF3 pathways in RAW 264.7 and THP-1 cells.

    PubMed

    Cheng, Brian Chi Yan; Yu, Hua; Su, Tao; Fu, Xiu-Qiong; Guo, Hui; Li, Ting; Cao, Hui-Hui; Tse, Anfernee Kai-Wing; Kwan, Hiu-Yee; Yu, Zhi-Ling

    2015-11-04

    As documented in the Chinese Materia Medica Grand Dictionary (), a herbal formula (RL) consisting of Rosae Multiflorae Fructus (multiflora rose hips) and Lonicerae Japonicae Flos (Japanese honeysuckle flowers) has traditionally been used in treating inflammatory disorders. RL was previously reported to inhibit the expression of various inflammatory mediators regulated by NF-κB and MAPKs that are components of the TLR4 signalling pathways. This study aims to provide further justification for clinical application of RL in treating inflammatory disorders by further delineating the involvement of the TLR4 signalling cascades in the effects of RL on inflammatory mediators. RL consisting of Rosae Multiflorae Fructus and Lonicerae Japonicae Flos (in 5:3 ratio) was extracted using absolute ethanol. We investigated the effect of RL on the production of cytokines and chemokines that are regulated by three key transcription factors of the TLR4 signalling pathways AP-1, NF-κB and IRF3 in LPS-stimulated RAW264.7 cells using the multiplex biometric immunoassay. Phosphorylation of AP-1, NF-κB, IRF3, IκB-α, IKKα/β, Akt, TAK1, TBK1, IRAK-1 and IRAK-4 were examined in LPS-stimulated RAW264.7 cells and THP-1 cells using Western blotting. Nuclear localizations of AP-1, NF-κB and IRF3 were also examined using Western blotting. RL reduced the secretion of various pro-inflammatory cytokines and chemokines regulated by transcription factors AP-1, NF-κB and IRF3. Phosphorylation and nuclear protein levels of these transcription factors were decreased by RL treatment. Moreover, RL inhibited the activation/phosphorylation of IκB-α, IKKα/β, TAK1, TBK1 and IRAK-1. Suppression of the IRAK-1/TAK1 and TBK1/IRF3 signalling pathways was associated with the effect of RL on inflammatory mediators in LPS-stimulated RAW264.7 and THP-1 cells. This provides further pharmacological basis for the clinical application of RL in the treatment of inflammatory disorders. Copyright © 2015 Elsevier

  20. Innate immune signaling in Drosophila is regulated by transforming growth factor β (TGFβ)-activated kinase (Tak1)-triggered ubiquitin editing

    PubMed Central

    Chen, Li; Paquette, Nicholas; Mamoor, Shahan; Rus, Florentina; Nandy, Anubhab; Leszyk, John; Shaffer, Scott A.; Silverman, Neal

    2017-01-01

    Coordinated regulation of innate immune responses is necessary in all metazoans. In Drosophila the Imd pathway detects Gram-negative bacterial infections through recognition of diaminopimelic acid (DAP)-type peptidoglycan and activation of the NF-κB precursor Relish, which drives robust antimicrobial peptide gene expression. Imd is a receptor-proximal adaptor protein homologous to mammalian RIP1 that is regulated by proteolytic cleavage and Lys-63-polyubiquitination. However, the precise events and molecular mechanisms that control the post-translational modification of Imd remain unclear. Here, we demonstrate that Imd is rapidly Lys-63-polyubiquitinated at lysine residues 137 and 153 by the sequential action of two E2 enzymes, Ubc5 and Ubc13-Uev1a, in conjunction with the E3 ligase Diap2. Lys-63-ubiquitination activates the TGFβ-activated kinase (Tak1), which feeds back to phosphorylate Imd, triggering the removal of Lys-63 chains and the addition of Lys-48 polyubiquitin. This ubiquitin-editing process results in the proteasomal degradation of Imd, which we propose functions to restore homeostasis to the Drosophila immune response. PMID:28377500

  1. CXC195 suppresses proliferation and inflammatory response in LPS-induced human hepatocellular carcinoma cells via regulating TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Yiting; Tu, Qunfei; Yan, Wei

    Highlights: • CXC195 exhibited significant anti-proliferative effect and induced cell cycle arrest in LPS-induced HepG2 cells. • CXC195 suppressed the release of pro-inflammatory mediators in LPS-induced HepG2 cells. • CXC195 regulated TLR4-MyD88-TAK1-mediated NF-κB and MAPK pathway in LPS-induced HepG2 cells. - Abstract: CXC195 showed strong protective effects in neuronal apoptosis by exerting its antioxidant activity. However, the anti-cancer effects of CXC195 is still with limited acquaintance. Here, we investigated the role of CXC195 in lipopolysaccharide (LPS)-induced human hepatocellular carcinoma (HCC) cells lines (HepG2) and the possible signaling pathways. CXC195 exhibited significant anti-proliferative effect and induced cell cycle arrest in LPS-inducedmore » HepG2 cells. In addition, CXC195 suppressed the release of pro-inflammatory mediators in LPS-induced HepG2 cells, including TNF-α, iNOS, IL-1β, IL-6, CC chemokine ligand (CCL)-2, CCL-22 and epidermal growth factor receptor (EGFR). Moreover, CXC195 inhibited the expressions and interactions of TLR4, MyD88 and TAK1, NF-κB translocation to nucleus and its DNA binding activity, phosphorylation of ERK1/2, p38 and JNK. Our results suggested that treatment with CXC195 could attenuate the TLR4-mediated proliferation and inflammatory response in LPS-induced HepG2 cells, thus might be beneficial for the treatment of HCC.« less

  2. Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.

    PubMed

    Fujimoto, Takuya; Imaeda, Yasuhiro; Konishi, Noriko; Hiroe, Katsuhiko; Kawamura, Masaki; Textor, Garret P; Aertgeerts, Kathleen; Kubo, Keiji

    2010-05-13

    Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

  3. Dissolved inorganic carbon dynamics in the waters surrounding forested mangroves of the Ca Mau Province (Vietnam)

    NASA Astrophysics Data System (ADS)

    Koné, Y. J.-M.; Borges, A. V.

    2008-04-01

    Dissolved inorganic carbon (DIC) and ancillary data were obtained during the dry and rainy seasons in the waters surrounding two 10-year-old forested mangrove sites (Tam Giang and Kiên Vàng) located in the Ca Mau Province (South-West Vietnam). During both seasons, the spatial variations of partial pressure of CO 2 (pCO 2) were marked, with values ranging from 704 ppm to 11481 ppm during the dry season, and from 1209 ppm to 8136 ppm during the rainy season. During both seasons, DIC, pCO 2, total alkalinity (TAlk) and oxygen saturation levels (%O 2) were correlated with salinity in the mangrove creeks suggesting that a combination of lower water volume and longer residence time (leading to an increase in salinity due to evaporation) enhanced the enrichment in DIC, pCO 2 and TAlk, and an impoverishment in O 2. The low O 2 and high DIC and pCO 2 values suggest that heterotrophic processes in the water column and sediments controlled these variables. The latter processes were meaningful since the high DIC and TAlk values in the creek waters were related to some extent to the influx of pore waters, consistent with previous observations. This was confirmed by the stochiometric relationship between TAlk and DIC that shows that anaerobic processes control these variables, although this approach did not allow identifying unambiguously the dominant diagenetic carbon degradation pathway. During the rainy season, dilution led to significant decreases of salinity, TAlk and DIC in both mangrove creeks and adjacent main channels. In the Kiên Vàng mangrove creeks a distinct increase of pCO 2 and decrease of %O 2 were observed. The increase of TSM suggested enhanced inputs of organic matter probably from land surrounding the mangrove creeks, that could have led to higher benthic and water column heterotrophy. However, the flushing of water enriched in dissolved CO 2 originating from soil respiration and impoverished in O 2 could also have explained to some extent the patterns

  4. Decision analysis for a data collection system of patient-controlled analgesia with a multi-attribute utility model.

    PubMed

    Lee, I-Jung; Huang, Shih-Yu; Tsou, Mei-Yung; Chan, Kwok-Hon; Chang, Kuang-Yi

    2010-10-01

    Data collection systems are very important for the practice of patient-controlled analgesia (PCA). This study aimed to evaluate 3 PCA data collection systems and selected the most favorable system with the aid of multiattribute utility (MAU) theory. We developed a questionnaire with 10 items to evaluate the PCA data collection system and 1 item for overall satisfaction based on MAU theory. Three systems were compared in the questionnaire, including a paper record, optic card reader and personal digital assistant (PDA). A pilot study demonstrated a good internal and test-retest reliability of the questionnaire. A weighted utility score combining the relative importance of individual items assigned by each participant and their responses to each question was calculated for each system. Sensitivity analyses with distinct weighting protocols were conducted to evaluate the stability of the final results. Thirty potential users of a PCA data collection system were recruited in the study. The item "easy to use" had the highest median rank and received the heaviest mean weight among all items. MAU analysis showed that the PDA system had a higher utility score than that in the other 2 systems. Sensitivity analyses revealed that both inverse and reciprocal weighting processes favored the PDA system. High correlations between overall satisfaction and MAU scores from miscellaneous weighting protocols suggested a good predictive validity of our MAU-based questionnaire. The PDA system was selected as the most favorable PCA data collection system by the MAU analysis. The item "easy to use" was the most important attribute of the PCA data collection system. MAU theory can evaluate alternatives by taking into account individual preferences of stakeholders and aid in better decision-making. Copyright © 2010 Elsevier. Published by Elsevier B.V. All rights reserved.

  5. Relationship between a fragmented QRS and microalbuminuria in patients with type 2 diabetes mellitus.

    PubMed

    Cetin, Sukru; Yıldız, Suleyman Sezai; Mazı, Emrah Erkan; Keskin, Kudret; Cetinkal, Gokhan; Gurdal, Ahmet; Karabay, Umut; Orta Kilickesmez, Kadriye

    2017-11-01

    Microalbuminuria (MAU), a complication of diabetes, is closely related to cardiovascular events. A fragmented QRS (fQRS) in the electrocardiogram (ECG) was found to be strongly associated to cardiovascular morbidity and mortality. The aim of this study was to assess the association between a fQRS and MAU in patients with type 2 diabetes mellitus (T2DM). One hundred and twenty-seven patients (mean age, 50.49 years; 44.01% male) with T2DM of at least six months duration and at least two urine albumin/creatinine ratios (ACRs) available were enrolled into the study between December 2015 and May 2016. All patients underwent ECG and echocardiography, and were taken blood and urine samples. Patients were divided into two groups according to presence of fQRS (group 1) or absence of fQRS (group 2). Both groups had similar baseline characteristics. MAU and glycosylated hemoglobin (HbA1c) levels and left ventricular end-diastolic diameter (LVEDd) were increased in patients with a fQRS in the ECG (p=0.002, p=0.02, and p=0.007, respectively). Univariate and multivariate logistic regression analysis showed MAU and an increased LVEDd to be independent risk factors for the presence of a fQRS in the ECG of T2DM patients. In this study, a fQRS was associated to MAU. In T2DM, MAU may be related to subclinical diastolic and systolic dysfunction. Copyright © 2017. Publicado por Elsevier España, S.L.U.

  6. Compilation of References and Bibliography. Volume 1. An Annotated Bibliography on Low Intensity Conflict Taken from the Joint Low- Intensity Conflict Project Final Report of 1 August 1986. CLIC PAPERS.

    DTIC Science & Technology

    1987-08-01

    conditions--especially in rural areas. Moreover, the author recognizes a continued dependence upon the army in various matters. Some of these are electoral ...Mau Mau revolt in Kenya in East Africa, and the period of the " violencia " in Colombia. 54. Book, Insurgency, COIN. Wesson, Robert, editor, Communism

  7. Hypertension, poor glycemic control, and microalbuminuria in Cuban Americans with type 2 diabetes.

    PubMed

    Zarini, Gustavo G; Exebio, Joel C; Gundupalli, Deva; Nath, Subrata; Huffman, Fatma G

    2011-01-01

    To investigate to what degree the presence of hypertension (HTN) and poor glycemic control (GC) influences the likelihood of having microalbuminuria (MAU) among Cuban Americans with type 2 diabetes (T2D). A cross-sectional study conducted in Cuban Americans (n = 179) with T2D. Participants were recruited from a randomly generated mailing list purchased from Knowledge-Base Marketing, Inc. Blood pressure (BP) was measured twice and averaged using an adult size cuff. Glycosylated hemoglobin (A1c) levels were measured from whole blood samples with the Roche Tina-quant method. First morning urine samples were collected from each participant to determine MAU by a semiquantitative assay (ImmunoDip). MAU was present in 26% of Cuban Americans with T2D. A significantly higher percentage of subjects with MA had HTN (P = 0.038) and elevated A1C (P = 0.002) than those with normoalbuminuria. Logistic regression analysis showed that after controlling for covariates, subjects with poor GC were 6.76 times more likely to have MAU if they had hypertension compared with those without hypertension (P = 0.004; 95% confidence interval [CI]: 1.83, 23.05). The clinical significance of these findings emphasizes the early detection of MAU in this Hispanic subgroup combined with BP and good GC, which are fundamentals in preventing and treating diabetes complications and improving individuals' renal and cardiovascular outcomes.

  8. Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury.

    PubMed

    Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

    2016-01-01

    Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury.

  9. Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury

    PubMed Central

    Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

    2016-01-01

    Introduction Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. Methods We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. Results We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). Conclusion The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury. PMID:27642395

  10. Interleukin 1 β-induced SMAD2/3 linker modifications are TAK1 dependent and delay TGFβ signaling in primary human mesenchymal stem cells.

    PubMed

    van den Akker, Guus G; van Beuningen, Henk M; Vitters, Elly L; Koenders, Marije I; van de Loo, Fons A; van Lent, Peter L; Blaney Davidson, Esmeralda N; van der Kraan, Peter M

    2017-12-01

    was performed to identify kinases involved in SMAD2/3 linker modifications. We identified TAK1 kinase activity as crucial for IL1β-induced SMAD2 linker modifications and CAGA 12 -luciferase activity. TGFβ and IL1β signaling interact at the SMAD2/3 level in human primary MSC. Down-stream TGFβ target genes were repressed by IL1β independent of C-terminal SMAD2 phosphorylation. We demonstrate that SMAD2/3 linker modifications are required for this interplay and identified TAK1 as a crucial mediator of IL1β-induced TGFβ signal modulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Factors affecting delay in seeking treatment among malaria patients along Thailand-Myanmar border in Tak Province, Thailand.

    PubMed

    Sonkong, Krit; Chaiklieng, Sunisa; Neave, Penny; Suggaravetsiri, Pornnapa

    2015-01-07

    Malaria is a major health problem in Thailand, especially in areas adjacent to the borders of Myanmar. Delay in seeking treatment is an important factor in the development of severe complications, death and the transmission of the disease. This study aimed to investigate factors affecting delays in seeking treatment of malaria patients. A cross-sectional analytic study was conducted in 456 malaria patients along the Thailand-Myanmar border. Patients were selected by stratified sampling from 11 malaria clinics and five public hospitals in Tak Province, Thailand. Data were collected by the use of a structured interview questionnaire and from patient's medical records. The majority of patients were categorized with an ethnicity of 'hill tribe' (65.8%), followed by Thai (34.2%). Seventy-nine per cent of patients delayed seeking treatment. A simple logistic regression identified significant factors affecting delays in seeking treatment: people of "hill tribe" ethnicity; plasmodium species; self-treatment; visiting sub-district health promotion hospital/malaria post before visiting a malaria clinic or public hospital; and low to medium social support. After being subjected to multivariate analysis, factors significantly associated with the delay were "hill tribe" ethnicity (ORadj = 2.32, 95% CI: 1.34-4.04); infection with P.vivax (ORadj=2.02, 95% CI: 1.19-3.41; self-treatment (ORadj = 1.73, 95% CI: 1.04-2.85); and receiving a low degree of social support (ORadj = 2.58, 95% CI: 1.24-5.35). Emphasis should be placed on need for early diagnosis and treatment in malaria patients as well as on ensuring the first facility for detection and treatment of malaria is a malaria clinic or public hospital, and the promotion of social support. These are especially important issues for the health of hill tribe people.

  12. Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nishimoto, Tomoyuki; Ishikawa, Eiichiro; Anayama, Hisashi

    2007-08-15

    High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485,more » and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.« less

  13. Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs.

    PubMed

    Nishimoto, Tomoyuki; Ishikawa, Eiichiro; Anayama, Hisashi; Hamajyo, Hitomi; Nagai, Hirofumi; Hirakata, Masao; Tozawa, Ryuichi

    2007-08-15

    High-dose statin treatment has been recommended as a primary strategy for aggressive reduction of LDL cholesterol levels and protection against coronary artery disease. The effectiveness of high-dose statins may be limited by their potential for myotoxic side effects. There is currently little known about the molecular mechanisms of statin-induced myotoxicity. Previously we showed that T-91485, an active metabolite of the squalene synthase inhibitor lapaquistat acetate (lapaquistat: a previous name is TAK-475), attenuated statin-induced cytotoxicity in human skeletal muscle cells [Nishimoto, T., Tozawa, R., Amano, Y., Wada, T., Imura, Y., Sugiyama, Y., 2003a. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A. Biochem. Pharmacol. 66, 2133-2139]. In the current study, we investigated the effects of lapaquistat administration on statin-induced myotoxicity in vivo. Guinea pigs were treated with either high-dose cerivastatin (1 mg/kg) or cerivastatin together with lapaquistat (30 mg/kg) for 14 days. Treatment with cerivastatin alone decreased plasma cholesterol levels by 45% and increased creatine kinase (CK) levels by more than 10-fold (a marker of myotoxicity). The plasma CK levels positively correlated with the severity of skeletal muscle lesions as assessed by histopathology. Co-administration of lapaquistat almost completely prevented the cerivastatin-induced myotoxicity. Administration of mevalonolactone (100 mg/kg b.i.d.) prevented the cerivastatin-induced myotoxicity, confirming that this effect is directly related to HMG-CoA reductase inhibition. These results strongly suggest that cerivastatin-induced myotoxicity is due to depletion of mevalonate derived isoprenoids. In addition, squalene synthase inhibition could potentially be used clinically to prevent statin-induced myopathy.

  14. TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation

    PubMed Central

    Lee, So-Young; Wang, Zhibo; Ding, Yan; Haque, Nadeem; Zhang, Jiwang; Zhou, Jing

    2014-01-01

    TGF-β–activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-β or inflammatory cytokines, such as TNF-α and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre+:Tak1fx/fx; Tak1∆/∆). Targeted deletion of Tak1 in podocytes resulted in perinatal lethality, with approximately 50% of animals dying soon after birth and 90% of animals dying within 1 week of birth. Tak1∆/∆ mice developed proteinuria from P1 and exhibited delayed glomerulogenesis and reduced expression of Wilms’ tumor suppressor 1 and nephrin in podocytes. Compared with Tak1fx/fx mice, Tak1∆/∆ mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1∆/∆ mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4- and 7-week-old Tak1∆/∆ mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms’ tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis. PMID:24652804

  15. Implementation of the incremental scheme for one-electron first-order properties in coupled-cluster theory.

    PubMed

    Friedrich, Joachim; Coriani, Sonia; Helgaker, Trygve; Dolg, Michael

    2009-10-21

    A fully automated parallelized implementation of the incremental scheme for coupled-cluster singles-and-doubles (CCSD) energies has been extended to treat molecular (unrelaxed) first-order one-electron properties such as the electric dipole and quadrupole moments. The convergence and accuracy of the incremental approach for the dipole and quadrupole moments have been studied for a variety of chemically interesting systems. It is found that the electric dipole moment can be obtained to within 5% and 0.5% accuracy with respect to the exact CCSD value at the third and fourth orders of the expansion, respectively. Furthermore, we find that the incremental expansion of the quadrupole moment converges to the exact result with increasing order of the expansion: the convergence of nonaromatic compounds is fast with errors less than 16 mau and less than 1 mau at third and fourth orders, respectively (1 mau=10(-3)ea(0)(2)); the aromatic compounds converge slowly with maximum absolute deviations of 174 and 72 mau at third and fourth orders, respectively.

  16. An evaluation of multiple trauma severity indices created by different index development strategies.

    PubMed

    Gustafson, D H; Fryback, D G; Rose, J H; Prokop, C T; Detmer, D E; Rossmeissl, J C; Taylor, C M; Alemi, F; Carnazzo, A J

    1983-07-01

    Evaluation of the effectiveness of emergency trauma care systems is complicated by the need to adjust for the widely variable case mix found in trauma patient populations. Several strategies have been advanced to construct the severity indices that can control for these population differences. This article describes a validity and reliability comparison of trauma severity indices developed under three different approaches: 1) use of a multi-attribute utility (MAU) model; 2) an actuarial approach relying on empirical data bases; and 3) an "ad hoc" approach. Seven criteria were identified to serve as standards of comparison for four different indices. The study's findings indicate that the index developed using the MAU theory approach associates most closely with physician judgments of trauma severity. When correlated with a morbidity outcome measure, the MAU-based index shows higher levels of agreement than the other indices. The index development approach based on the principles of MAU theory has several advantages and it appears to be a powerful tool in the creation of effective severity indices.

  17. Mapping between 6 Multiattribute Utility Instruments.

    PubMed

    Chen, Gang; Khan, Munir A; Iezzi, Angelo; Ratcliffe, Julie; Richardson, Jeff

    2016-02-01

    Cost-utility analyses commonly employ a multiattribute utility (MAU) instrument to estimate the health state utilities, which are needed to calculate quality-adjusted life years. Different MAU instruments predict significantly different utilities, which makes comparison of results from different evaluation studies problematical. This article presents mapping functions ("crosswalks") from 6 MAU instruments (EQ-5D-5L, SF-6D, Health Utilities Index 3 [HUI 3], 15D, Quality of Well-Being [QWB], and Assessment of Quality of Life 8D [AQoL-8D]) to each of the other 5 instruments in the study: a total of 30 mapping functions. Data were obtained from a multi-instrument comparison survey of the public and patients in 7 disease areas conducted in 6 countries (Australia, Canada, Germany, Norway, United Kingdom, and United States). The 8022 respondents were administered each of the 6 study instruments. Mapping equations between each instrument pair were estimated using 4 econometric techniques: ordinary least squares, generalized linear model, censored least absolute deviations, and, for the first time, a robust MM-estimator. Goodness-of-fit indicators for each of the results are within the range of published studies. Transformations reduced discrepancies between predicted utilities. Incremental utilities, which determine the value of quality-related health benefits, are almost perfectly aligned at the sample means. Transformations presented here align the measurement scales of MAU instruments. Their use will increase confidence in the comparability of evaluation studies, which have employed different MAU instruments. © The Author(s) 2015.

  18. Revisited HLA and non-HLA genetics of Takayasu arteritis--where are we?

    PubMed

    Terao, Chikashi

    2016-01-01

    Takayasu arteritis (TAK) is an immune-mediated vasculitis affecting large arteries first reported in 1908 from Japan. Case reports of familial onset of TAK from Japan and other countries indicated genetic contribution to TAK onset beyond ethnicity. Genetic studies of TAK have been performed mainly addressing the human leukocyte antigen (HLA) locus. HLA genetic studies of TAK that have previously been reported are reviewed in this manuscript. HLA-B*52:01 is associated with TAK beyond population. Many of the associations other than HLA-B*52:01 can be explained by a haplotype with HLA-B*52:01. HLA-B*67:01 is a novel susceptibility HLA-B allele to TAK confirmed in the Japanese population. Further independent associations are suggested in the HLA locus. Involvement of the 171st and 67th amino acid residues with TAK onset has been indicated. The 67th amino acid may explain the difference in susceptibility effects to TAK and Behçet's disease between HLA-B*52:01 and *51:01. HLA-B*52:01 is associated not only with TAK susceptibility but also with clinical phenotypes. Recent genome-wide association studies of TAK revealed multiple non-HLA susceptibility genes. In particular, the IL12B region seems to have a central role in TAK onset and its progression. Whether TAK and giant cell arteritis (GCA), the other vasculitis affecting large arteries, are the same disease is an interesting question to address in spite of different clinical manifestations between the two diseases. GCA is associated with HLA-DR4, which is not associated with TAK. GCA is not associated with HLA-Bw52. These two diseases seem not to share non-HLA susceptibility loci based on the recent genetic studies.

  19. Identification of TGF-β-activated kinase 1 as a possible novel target for renal cell carcinoma intervention

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meng, Fandong; Li, Yan; Tian, Xin

    Highlights: • Inhibition of TAK1 kinase activity suppresses NF-κB activation and RCC cell survival. • TAK1 inhibitors induces apoptotic cytotoxicity against RCC cells. • RCC cells with TAK1 depletion show reduced cell viability and increased apoptosis. • TAK1 and p-NF-κB are both over-expressed in human RCC tissues. • Inhibition or depletion of TAK1 enhances the activity of vinblastine sulfate. - Abstract: Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitorsmore » (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention.« less

  20. Transforming growth factor β-activated kinase 1 transcriptionally suppresses hepatitis B virus replication.

    PubMed

    Pang, Jinke; Zhang, Geng; Lin, Yong; Xie, Zhanglian; Liu, Hongyan; Tang, Libo; Lu, Mengji; Yan, Ran; Guo, Haitao; Sun, Jian; Hou, Jinlin; Zhang, Xiaoyong

    2017-01-03

    Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect. By screening TAK1-associated signaling pathways with inhibitors and siRNAs, we found that the MAPK-JNK pathway was involved in TAK1-mediated HBV suppression. Moreover, TAK1 knockdown or JNK pathway inhibition induced the expression of farnesoid X receptor α, a transcription factor that upregulates HBV transcription. Finally, ectopic expression of TAK1 in a HBV hydrodynamic injection mouse model resulted in lower levels of HBV DNA and antigens in both liver and serum. In conclusion, our data suggest that TAK1 inhibits HBV primarily at viral transcription level through activation of MAPK-JNK pathway, thus TAK1 represents an intrinsic host restriction factor for HBV replication in hepatocytes.

  1. Recent advances in Takayasu arteritis.

    PubMed

    Terao, Chikashi; Yoshifuji, Hajime; Mimori, Tsuneyo

    2014-03-01

    Takayasu arteritis (TAK) is a relatively rare systemic vasculitis mainly affecting the aorta and its large branches. While patients with TAK are more frequently observed in Asian countries, we can find patients with TAK all over the world. This limited number of patients has made it difficult to collect large numbers of patients and perform detailed studies. However, recent progresses have led to the identification of susceptibility genes and novel susceptibility human leukocyte antigen (HLA) alleles as well as accumulation of clues for the pathophysiology of TAK. IL12B was shown to be a susceptibility gene beyond ethnicity. MLX and FCGR2A/3A were shown to be associated with TAK in Japanese and Turkish/American populations, respectively. HLA-B*52:01 and *67:01 are susceptibility alleles to TAK, and the 171st and 67th amino acid residues of HLA-B protein are suggested important for TAK susceptibility. HLA-DQB1/DRB1 is recently reported as an independent susceptibility locus. Although there are no standardized serum markers or composite measures for disease activity of TAK, Japanese and Italian groups showed pentraxin 3 as a novel biomarker for detecting and monitoring patients with TAK. Recently, an Indian group proposed a novel scoring system called ITAS to evaluate disease activity of TAK. Standardization of assessing disease activity would lead to clinical studies with high quality. Several groups reported results of treatment for refractory TAK with biological agents targeting tumor necrosis factor or interleukin-6R. The recent accumulation of research data should improve understanding of the basic pathophysiology of TAK and lead to better management of patients with TAK. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  2. Takayasu arteritis and ulcerative colitis: high rate of co-occurrence and genetic overlap.

    PubMed

    Terao, Chikashi; Matsumura, Takayoshi; Yoshifuji, Hajime; Kirino, Yohei; Maejima, Yasuhiro; Nakaoka, Yoshikazu; Takahashi, Meiko; Amiya, Eisuke; Tamura, Natsuko; Nakajima, Toshiki; Origuchi, Tomoki; Horita, Tetsuya; Matsukura, Mitsuru; Kochi, Yuta; Ogimoto, Akiyoshi; Yamamoto, Motohisa; Takahashi, Hiroki; Nakayamada, Shingo; Saito, Kazuyoshi; Wada, Yoko; Narita, Ichiei; Kawaguchi, Yasushi; Yamanaka, Hisashi; Ohmura, Koichiro; Atsumi, Tatsuya; Tanemoto, Kazuo; Miyata, Tetsuro; Kuwana, Masataka; Komuro, Issei; Tabara, Yasuharu; Ueda, Atsuhisa; Isobe, Mitsuaki; Mimori, Tsuneyo; Matsuda, Fumihiko

    2015-05-01

    Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 × 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10(-10) ). UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence. © 2015, American College of Rheumatology.

  3. Military Police Operations and Counterinsurgency

    DTIC Science & Technology

    2008-03-01

    that deceitfully advertised PRUs as assassination squads. In reality most PRU operations ended in the successful capture and prosecution of VCI...and neutralize Kimathi whose capture " virtually ended Mau Mau resistence" (Asprey, 886). This campaign analysis will use the following categories to...for special access programs. , 3.10. Employs specialized investigative techniques to include forensic and t:>ehavioral sciencell and hypnosis . 3.11

  4. Transforming growth factor β-activated kinase 1 inhibitor suppresses the proliferation in triple-negative breast cancer through TGF-β/TGFR pathway.

    PubMed

    Zhang, Liangyu; Fu, Zelong; Li, Xia; Tang, Haitao; Luo, Jiesi; Zhang, Dehui; Zhuang, Yongzhi; Han, Zhiyang; Yin, Mingzhu

    2017-09-01

    Breast cancer is one of the most invasive cancer types in female population. The functional activity of Transforming growth factor β-activated kinase 1 (TAK1) in breast cancer progression increasingly attracts attention as it provides a potential target for antibreast cancer drug development. However, the fundamental role of TAK1 for triple-negative breast cancer (TNBC) progression and the effect of potential anti-TAK1 drug candidate needs to be further evaluated. Herein, we focused on the role of TAK1 in human breast cancer cells, and we hypothesized that the inhibition of TAK1 activation can repress the growth of human TNBC cells. We found that the TAK1 is robustly activated within cancer cell population of clinic-derived TNBC samples and the human breast cancer cell lines in culture. Furthermore, we determined the effect of 5Z-7-oxozeaenol (5Z-O), a TAK1-specific small molecule inhibitor, on proliferation of human TNBC cell line. 5Z-O treatment significantly suppressed the proliferation of human TNBC cells. Collectively, these demonstrate the role of TAK1 in human breast cancer and the antiproliferate effect of TAK1 inhibitor. Our study sets the stage for further research on TAK1 as a promising target for development of anti-TNBC drugs and therapeutic strategies. © 2017 John Wiley & Sons A/S.

  5. Effects of 5,14-HEDGE, a 20-HETE mimetic, on lipopolysaccharide-induced changes in MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway and circulating miR-150, miR-223, and miR-297 levels in a rat model of septic shock

    PubMed Central

    Sari, A. Nihal; Korkmaz, Belma; Serin, Mehmet Sami; Kacan, Meltem; Unsal, Demet; Buharalioglu, C. Kemal; Firat, Seyhan Sahan; Manhati, Vijay L.; Falck, John R.; Malik, Kafait U.; Tunctan, Bahar

    2014-01-01

    Objectives We have previously demonstrated that a stable synthetic analog of 20-hydroxyeicosatetraenoic acid (20-HETE), N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), which mimics the effects of endogenously produced 20-HETE, prevents vascular hyporeactivity, hypotension, tachycardia, inflammation, and mortality in a rodent model of septic shock. The present study was performed to determine whether decreased renal and cardiovascular expression and activity of myeloid differentiation factor 88 (MyD88)/transforming growth factor-activated kinase 1 (TAK1)/inhibitor of κB (IκB) kinase β (IKKβ)/IκB-α/nuclear factor-κB (NF-κB) pathway and reduced circulating microRNA (miR)-150, miR-223, and miR-297 expression levels participate in the protective effect of 5,14-HEDGE against hypotension, tachycardia, and inflammation in response to systemic administration of lipopolysaccharide (LPS). Methods Conscious male Wistar rats received saline (4 ml/kg) or LPS (10 mg/kg) at time 0. Blood pressure and heart rate were measured using a tail-cuff device. Separate groups of LPS-treated rats were given 5,14-HEDGE (30 mg/kg) 1 h after injection of saline or LPS. The rats were sacrificed 4 h after LPS challenge and blood, kidney, heart, thoracic aorta, and superior mesenteric artery were collected for measurement of the protein expression. Results LPS-induced fall in blood pressure and rise in heart rate were associated with increased MyD88 expression and phosphorylation of TAK1 and IκB-α in cytosolic fractions of the tissues. LPS also caused an increase in both unphosphorylated and phosphorylated NF-κB p65 proteins in the cytosolic and nuclear fractions as well as nuclear translocation of NF-κB p65. In addition, serum miR-150, miR-223, and miR-297 expression levels were increased in LPS-treated rats. These effects of LPS were prevented by 5,14-HEDGE. Conclusions These results suggest that downregulation of MyD88/TAK1/IKKβ/IκB-α/NF-κB pathway as well as

  6. GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice.

    PubMed

    Yang, Xu; Kume, Shinji; Tanaka, Yuki; Isshiki, Keiji; Araki, Shin-ichi; Chin-Kanasaki, Masami; Sugimoto, Toshiro; Koya, Daisuke; Haneda, Masakazu; Sugaya, Takeshi; Li, Detian; Han, Ping; Nishio, Yoshihiko; Kashiwagi, Atsunori; Maegawa, Hiroshi; Uzu, Takashi

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(-). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases.

  7. GW501516, a PPARδ Agonist, Ameliorates Tubulointerstitial Inflammation in Proteinuric Kidney Disease via Inhibition of TAK1-NFκB Pathway in Mice

    PubMed Central

    Yang, Xu; Kume, Shinji; Tanaka, Yuki; Isshiki, Keiji; Araki, Shin-ichi; Chin-Kanasaki, Masami; Sugimoto, Toshiro; Koya, Daisuke; Haneda, Masakazu; Sugaya, Takeshi; Li, Detian; Han, Ping; Nishio, Yoshihiko; Kashiwagi, Atsunori; Maegawa, Hiroshi; Uzu, Takashi

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism. Mice fed with a control diet or GW501516-containing diet were intraperitoneally injected with free fatty acid (FFA)-bound albumin or PBS(−). In the control group, protein overload caused tubular damages, macrophage infiltration and increased mRNA expression of MCP-1 and TNFα. These effects were prevented by GW501516 treatment. In proteinuric kidney diseases, excess exposure of proximal tubular cells to albumin, FFA bound to albumin or cytokines such as TNFα is detrimental. In vitro studies using cultured proximal tubular cells showed that GW501516 attenuated both TNFα- and FFA (palmitate)-induced, but not albumin-induced, MCP-1 expression via direct inhibition of the TGF-β activated kinase 1 (TAK1)-NFκB pathway, a common downstream signaling pathway to TNFα receptor and toll-like receptor-4. In conclusion, we demonstrate that GW501516 has an anti-inflammatory effect in renal tubular cells and may serve as a therapeutic candidate to attenuate tubulointerstitial lesions in proteinuric kidney diseases. PMID:21966476

  8. Loss of Par-1a/MARK3/C-TAK1 kinase leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis.

    PubMed

    Lennerz, Jochen K; Hurov, Jonathan B; White, Lynn S; Lewandowski, Katherine T; Prior, Julie L; Planer, G James; Gereau, Robert W; Piwnica-Worms, David; Schmidt, Robert E; Piwnica-Worms, Helen

    2010-11-01

    Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a(-/-) but not in control or Par-1b(-/-) mice. The intercrossing of Par-1a(-/-) with Par-1b(-/-) mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a(-/-) mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b(-/-) mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice.

  9. The British in Kenya (1952-1960): Analysis of a Successful Counterinsurgency Campaign

    DTIC Science & Technology

    2005-06-01

    East Africa to seek their riches in cattle , coffee, mining, and selling safaris to tourists. While the other colonial powers set their sights on...violence on a large scale by early 1952. Cattle on white settlements were being destroyed and standing crops and haystacks set on fire, particularly...Guards used pliers to castrate Mau Mau prisoners. Whatever the method and level of brutality, by the latter half of the 1950s most Kikuyu had turned

  10. Live imaging of transforming growth factor-β activated kinase 1 activation in Lewis lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyinosinic:polycytidylic acid.

    PubMed

    Takaoka, Saori; Kamioka, Yuji; Takakura, Kanako; Baba, Ai; Shime, Hiroaki; Seya, Tsukasa; Matsuda, Michiyuki

    2016-05-01

    Transforming growth factor-β activated kinase 1 (TAK1) has been shown to play a crucial role in cell death, differentiation, and inflammation. Here, we live-imaged robust TAK1 activation in Lewis lung carcinoma 3LL cells implanted into the s.c. tissue of syngeneic C57BL/6 mice and treated with polyinosinic:polycytidylic acid (PolyI:C). First, we developed and characterized a Förster resonance energy transfer-based biosensor for TAK1 activity. The TAK1 biosensor, named Eevee-TAK1, responded to stress-inducing reagents such as anisomycin, tumor necrosis factor-α, and interleukin1-β. The anisomycin-induced increase in Förster resonance energy transfer was abolished by the TAK1 inhibitor (5z)-7-oxozeaenol. Activity of TAK1 in 3LL cells was markedly increased by PolyI:C in the presence of macrophages. 3LL cells expressing Eevee-TAK1 were implanted into mice and observed through imaging window by two-photon excitation microscopy. During the growth of tumor, the 3LL cells at the periphery of the tumor showed higher TAK1 activity than the 3LL cells located at the center of the tumor, suggesting that cells at the periphery of the tumor mass were under stronger stress. Injection of PolyI:C, which is known to induce regression of the implanted tumors, induced marked and homogenous TAK1 activation within the tumor tissues. The effect of PolyI:C faded within 4 days. These observations suggest that Eevee-TAK1 is a versatile tool to monitor cellular stress in cancer tissues. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  11. Biological treatments in giant cell arteritis & Takayasu arteritis.

    PubMed

    Samson, Maxime; Espígol-Frigolé, Georgina; Terrades-García, Nekane; Prieto-González, Sergio; Corbera-Bellalta, Marc; Alba-Rovira, Roser; Hernández-Rodríguez, José; Audia, Sylvain; Bonnotte, Bernard; Cid, Maria C

    2018-04-01

    Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the two main large vessel vasculitides. They share some similarities regarding their clinical, radiological and histological presentations but some pathogenic processes in GCA and TAK are activated differently, thus explaining their different sensitivity to biological therapies. The treatment of GCA and TAK essentially relies on glucocorticoids. However, thanks to major progress in our understanding of their pathogenesis, the role of biological therapies in the treatment of these two vasculitides is expanding, especially in relapsing or refractory diseases. In this review, the efficacy, the safety and the limits of the main biological therapies ever tested in GCA and TAK are discussed. Briefly, anti TNF-α agents appear to be effective in treating TAK but not GCA. Recent randomized placebo-controlled trials have reported on the efficacy and safety of abatacept and mostly tocilizumab in inducing and maintaining remission of GCA. Abatacept was not effective in TAK and robust data are still lacking to draw any conclusions concerning the use of tocilizumab in TAK. Furthermore, ustekinumab appears promising in relapsing/refractory GCA whereas rituximab has been reported to be effective in only a few cases of refractory TAK patients. If a biological therapy is indicated, and in light of the data discussed in this review, the first choice would be tocilizumab in GCA and anti-TNF-α agents (mainly infliximab) in TAK. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  12. [Susceptibility HLA alleles and amino acids to Takayasu arteritis].

    PubMed

    Terao, Chikashi; Yoshifuji, Hajime; Mimori, Tsuneyo; Matsuda, Fumihiko

    2014-01-01

    Takayasu arteritis (TAK) is a systemic vasculitis affecting aorta and its large branches which were firstly reported from Japan. TAK develops mainly in young females and the number of patients with TAK in Japan is estimated about 6,000 to 10,000. This low prevalence has made genetic studies of TAK difficult to elucidate its genetic background. The HLA region, especially HLA-B locus, is the strongest susceptibility locus to TAK. The association between TAK and HLA-B*52:01 has been established beyond ethnicity. Recently, two different Japanese research groups identified HLA-B67:01, a relatively rare allele in East Asian population, as a novel susceptibility allele. At the same time, two amino acid variations, namely, histidine at position 171 and phenylalanine at position 67 were reported as susceptibility and protective variations, respectively. Since these positions of amino acid are in the peptide binding grooves of HLA-B protein, changes of peptide-binding in MHC class I seem to play a critical role on susceptibility to TAK. Furthermore, the importance of these two amino acid variations would explain the lack of susceptibility effect of HLA-B*51:01 to TAK, which shares most of amino acid sequences with HLA-B*52:01 except for two amino acids including the position 67.

  13. The saline load test of the knee redefined: a test to detect traumatic arthrotomies and rule out periarticular wounds not requiring surgical intervention.

    PubMed

    Konda, Sanjit R; Howard, Daniel; Davidovitch, Roy I; Egol, Kenneth A

    2013-09-01

    To describe the use of the saline load test (SLT) using a new definition that more adequately characterizes its use in the emergency department (ED) setting. Retrospective review. Level I trauma center. Fifty consecutive patients who underwent an SLT of the knee in the ED and had a minimum of 14 days follow-up. Saline Load Test. Positive traumatic arthrotomy of the knee (+TAK) defined as operating room (OR) confirmation of an arthrotomy (assumed to develop a septic knee) or -SLT with follow-up revealing a septic knee. Periarticular wound equivalent to no traumatic arthrotomy of the knee [pw = (-TAK)] defined as OR evaluation revealing no arthrotomy (assumed not to develop a septic knee) or -SLT whose follow-up revealed no septic knee. Development of a septic knee was considered the gold standard for determining true positives/negatives and false positives/negatives. The mean wound size was 3.9 ± 4.3 cm and the mean saline load volume was 74.9 ± 28.2 cm. There were 19 +SLTs of which there were 16 +TAK and 3 pw = (-TAK). The 3 pw = (-TAK) in the +SLT group were evaluated in the OR where inspection of the joint capsule revealed the absence of a traumatic arthrotomy. There were 31 -SLTs of which there were 1 +TAK and 30 pw = (-TAK). The SLT has a sensitivity of 94% and a specificity of 91% for detecting +TAKs and ruling out periarticular wounds not requiring surgical intervention [pw = (-TAK)]. The false-positive rate of the SLT to detect +TAK is 9%. Using +TAK and pw = (-TAK) as the newly defined measures of the SLT, we report the sensitivity (94%) and specificity (91%) of the SLT in the ED setting while still maintaining the clinical relevancy of the test. Based on a small sample size, knees with small periarticular wounds and a -SLT and no other radiographic or clinical evidence of an arthrotomy appear to have an infection rate of 0% with nonoperative management. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

  14. Association of Takayasu arteritis with HLA-B 67:01 and two amino acids in HLA-B protein.

    PubMed

    Terao, Chikashi; Yoshifuji, Hajime; Ohmura, Koichiro; Murakami, Kosaku; Kawabata, Daisuke; Yurugi, Kimiko; Tazaki, Junichi; Kinoshita, Hideyuki; Kimura, Akinori; Akizuki, Masashi; Kawaguchi, Yasushi; Yamanaka, Hisashi; Miura, Yasuo; Maekawa, Taira; Saji, Hiroo; Mimori, Tsuneyo; Matsuda, Fumihiko

    2013-10-01

    Takayasu arteritis (TAK) is a rare autoimmune arteritis that affects large arteries. Although the association between TAK and HLA-B 52:01 is established, the other susceptibility HLA-B alleles are not fully known. We performed genetic association studies to determine independent HLA-B susceptibility alleles other than HLA-B 52:01 and to identify important amino acids of HLA-B protein in TAK susceptibility. One hundred patients with TAK and 1000 unrelated healthy controls were genotyped for HLA-B alleles in the first set, followed by a replication set containing 73 patients with TAK and 1000 controls to compare the frequencies of HLA-B alleles. Step-up logistic regression analysis was performed to identify susceptibility amino acids of HLA-B protein. Strong associations of susceptibility to TAK with HLA-B 52:01 and HLA-B 67:01 were observed (P = 1.0 × 10(-16) and 9.5 × 10(-6), respectively). An independent susceptibility effect of HLA-B 67:01 from HLA-B 52:01 was also detected (P = 1.8 × 10(-7)). Amino acid residues of histidine at position 171 and phenylalanine at position 67, both of which are located in antigen binding grooves of the HLA-B protein, were associated with TAK susceptibility (P ≤ 3.8 × 10(-5)) with a significant difference from other amino acid variations (ΔAIC ≥ 9.65). HLA-B 67:01 is associated with TAK independently from HLA-B 52:01. Two amino acids in HLA-B protein are strongly associated with TAK susceptibility.

  15. Protective effects of prescription n-3 fatty acids against impairment of spatial cognitive learning ability in amyloid β-infused rats.

    PubMed

    Hashimoto, Michio; Tozawa, Ryuichi; Katakura, Masanori; Shahdat, Hossain; Haque, Abdul Md; Tanabe, Yoko; Gamoh, Shuji; Shido, Osamu

    2011-07-01

    Deposition of amyloid β peptide (Aβ) into the brain causes cognitive impairment. We investigated whether prescription pre-administration of n-3 fatty acids improves cognitive learning ability in young rats and whether it protects against learning ability impairments in an animal model of Alzheimer's disease that was prepared by infusion of Aβ(1-40) into the cerebral ventricles of rats. Pre-administration of TAK-085 (highly purified and concentrated n-3 fatty acids containing eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester) at 300 mg kg(-1) day(-1) for 12 weeks significantly reduced the number of reference memory errors in an 8-arm radial maze, suggesting that long-term administration of TAK-085 improves cognitive leaning ability in rats. After pre-administration, the control group was divided into the vehicle and Aβ-infused groups, whereas the TAK-085 pre-administration group was divided into the TAK-085 and TAK-085 + Aβ groups (TAK-085-pre-administered Aβ-infused rats). Aβ(1-40) or vehicle was infused into the cerebral ventricle using a mini osmotic pump. Pre-administration of TAK-085 to the Aβ-infused rats significantly suppressed the number of reference and working memory errors and decreased the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and hippocampus of Aβ-infused rats, suggesting that TAK-085 increases antioxidative defenses. The present study suggests that long-term administration of TAK-085 is a possible therapeutic agent for protecting against Alzheimer's disease-induced learning deficiencies. This journal is © The Royal Society of Chemistry 2011

  16. Loss of Par-1a/MARK3/C-TAK1 Kinase Leads to Reduced Adiposity, Resistance to Hepatic Steatosis, and Defective Gluconeogenesis ▿

    PubMed Central

    Lennerz, Jochen K.; Hurov, Jonathan B.; White, Lynn S.; Lewandowski, Katherine T.; Prior, Julie L.; Planer, G. James; Gereau, Robert W.; Piwnica-Worms, David; Schmidt, Robert E.; Piwnica-Worms, Helen

    2010-01-01

    Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a−/− but not in control or Par-1b−/− mice. The intercrossing of Par-1a−/− with Par-1b−/− mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a−/− mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b−/− mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice. PMID:20733003

  17. Blocking RhoA/ROCK inhibits the pathogenesis of pemphigus vulgaris by suppressing oxidative stress and apoptosis through TAK1/NOD2-mediated NF-κB pathway.

    PubMed

    Liang, Junqin; Zeng, Xuewen; Halifu, Yilinuer; Chen, Wenjing; Hu, Fengxia; Wang, Peng; Zhang, Huan; Kang, Xiaojing

    2017-12-01

    Oxidative stress and apoptosis play critical roles in pemphigus vulgaris (PV). The main aim of the present study was to investigate the effects of RhoA/ROCK signaling on UVB-induced oxidative damage, and to delineate the molecular mechanisms involved in the UVB-mediated inflammatory and apoptotic response. In HaCaT cells, we observed that blockage of RhoA/ROCK signaling with the inhibitor CT04 or Y27632 greatly inhibited the UVB-mediated increase in intracellular reactive oxygen species (ROS). Additionally, inhibition of RhoA/ROCK signaling reduced UVB-induced apoptosis, as exemplified by a reduction in DNA fragmentation, and also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic protein Bax, caspase-3 cleavage and decreased PARP-1 protein. The release of inflammatory mediators TNF-α, IL-1β, and IL-6 was also attenuated. Mechanically, we observed that blockage of RhoA/ROCK repressed the TAK1/NOD2-mediated NF-κB pathway in HaCaT cells exposed to UVB. Taken together, these data reveal that RhoA/ROCK signaling is one of the regulators contributing to oxidative damage and apoptosis in human keratinocytes, suggesting that RhoA/ROCK signaling has strong potential to be used as a useful therapeutic target in skin diseases including PV.

  18. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects, and tissue-specific enrichment of eQTLs

    PubMed Central

    Below, Jennifer E.; Parra, Esteban J.; Gamazon, Eric R.; Torres, Jason; Krithika, S.; Candille, Sophie; Lu, Yingchang; Manichakul, Ani; Peralta-Romero, Jesus; Duan, Qing; Li, Yun; Morris, Andrew P.; Gottesman, Omri; Bottinger, Erwin; Wang, Xin-Qun; Taylor, Kent D.; Ida Chen, Y.-D.; Rotter, Jerome I.; Rich, Stephen S.; Loos, Ruth J. F.; Tang, Hua; Cox, Nancy J.; Cruz, Miguel; Hanis, Craig L.; Valladares-Salgado, Adan

    2016-01-01

    We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci. PMID:26780889

  19. [Current options of insulin resistence correction in patients with metabolic syndrome].

    PubMed

    Demidova, T Iu; Ametov, A S; Titova, O I

    2006-01-01

    To study thiasolidindion drug pioglitazone for efficacy in metabolic syndrome (MS). Twenty patients with MS were examined at baseline and after 12 week therapy with pioglitazone. The examination included estimation of fasting and postprandial glycemia, insulin resistance index, HOMA-IR index, HbAlc, lipid profile, microalbuminuria (MAU), blood pressure, endothelium-related vasodilation. Pioglitazone therapy for 12 weeks significantly reduced HbAlc, fasting and postprandial glycemia, insulinemia, HOMA-IR, improved blood lipid spectrum, reduced visceral obesity. Positive effects were also achieved on blood pressure, MAU and endothelium-related vasodilation.

  20. Construction of the descriptive system for the Assessment of Quality of Life AQoL-6D utility instrument.

    PubMed

    Richardson, Jeffrey R J; Peacock, Stuart J; Hawthorne, Graeme; Iezzi, Angelo; Elsworth, Gerald; Day, Neil A

    2012-04-17

    Multi attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument. The AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements. The resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model. The AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs.

  1. Current conservation status of Germain's langur (Trachypithecus germaini) in Vietnam.

    PubMed

    Van Tran, Bang; Nguyen, Minh Anh; Nguyen, Dat Quoc; Truong, Quan Bich Thi; Ang, Andie; Covert, Herbert H; Hoang, Duc Minh

    2017-07-01

    Following the split of the silvered langurs of Indochina into two species based on molecular and phenotypic data, there is a need to reevaluate their distribution and update their conservation status. Here, we report the distribution and assess the population size of Germain's langur (Trachypithecus germaini) within its known range across Vietnam. We confirmed this species at six of seven survey sites in different habitats within three provinces in the Mekong Delta Region, including semi-evergreen forest at the Seven Mountains of An Giang Province, mangrove forest in Ngoc Hien and Nam Can Districts and Melaleuca forest in U Minh Ha National Park of Ca Mau Province, and limestone forest at Kien Luong Karst Area and semi-evergreen and evergreen forests at Phu Quoc National Park of Kien Giang Province. We found no evidence of this species in Mui Ca Mau National Park, Ca Mau Province where it was previously reported. We conservatively estimate that the total population of Germain's langurs in Vietnam consists of 362-406 individuals, with the largest population found in the Kien Luong Karst Area. Hunting and habitat loss are severely impacting Germain's langur, resulting in the extirpation of the population in Mui Ca Mau National Park and small, isolated populations in the Seven Mountains and Ngoc Hien and Nam Can Districts. However, the ability of this species to inhabit a wide range of forest types, and its increasing population sizes in Phu Quoc National Park and Kien Luong Karst Area, provide signs of hope that continued conservation actions may help in its long-term survival.

  2. Poor Linkage to Care Despite Significant Improvement in Access to Early cART in Central Poland - Data from Test and Keep in Care (TAK) Project.

    PubMed

    Kowalska, Justyna D; Shepherd, Leah; Ankiersztejn-Bartczak, Magdalena; Cybula, Aneta; Czeszko-Paprocka, Hanna; Firląg-Burkacka, Ewa; Mocroft, Amanda; Horban, Andrzej

    2016-01-01

    The main objective of the TAK project is investigating barriers in accessing HIV care after HIV-diagnosis at the CBVCTs of central Poland. Here we describe factors associated with and changes over time in linkage to care and access to cART. Data collected in 2010-2013 in CBVCTs were linked with HIV clinics records using unique identifiers. Individuals were followed from the day of CBVCTs visit until first clinical visit or 4/06/2014. Cox-proportional hazard models were used to identify factors associated with being linked to care and starting cART. In total 232 persons were diagnosed HIV-positive and 144 (62.1% 95%CI: 55.5-68.3) persons were linked to care. There was no change over time in linkage to care (p = 0.48), while time to starting cART decreased (p = 0.02). Multivariate factors associated with a lower rate of linkage to care were hetero/bisexual sexual orientation, lower education, not having an HIV-positive partner and not using condoms in a stable relationship. Multivariate factors associated with starting cART were lower education, recent year of linked to care, and first HIV RNA and CD4 cell count. Benefits of linkage to care, measured by access to early treatment, steadily improved in recent years. However at least 1 in 3 persons aware of their HIV status in central Poland remained outside professional healthcare. Persons at higher risk of remaining outside care, thus target population for future interventions, are bi/heterosexuals and those with lower levels of education.

  3. Multi-decadal shoreline changes on Takú Atoll, Papua New Guinea: Observational evidence of early reef island recovery after the impact of storm waves

    NASA Astrophysics Data System (ADS)

    Mann, Thomas; Westphal, Hildegard

    2016-03-01

    Hurricanes, tropical cyclones and other high-magnitude events are important steering mechanisms in the geomorphic development of coral reef islands. Sandy reef islands located outside the storm belts are strongly sensitive to the impact of occasional high-magnitude events and show abrupt, commonly erosive geomorphic change in response to such events. Based on the interpretation of remote sensing data, it is well known that the process of landform recovery might take several decades or even longer. However, despite the increasing amount of scientific attention towards short- and long-term island dynamics, the lack of data and models often prevent a robust analysis of the timing and nature of recovery initiation. Here we show how natural island recovery starts immediately after the impact of a high-magnitude event. We analyze multi-temporal shoreline changes on Takú Atoll, Papua New Guinea and combine our findings with a unique set of published field observations (Smithers and Hoeke, 2014). Trends of shoreline change since 1943 and changes in planform island area indicate a long-term accretionary mode for most islands. Apparent shoreline instability is detected for the last decade of analysis, however this can be explained by the impact of storm waves in December 2008 that (temporarily?) masked the long-term trend. The transition from negative to positive rates of change in the aftermath of this storm event is indicative of inherent negative feedback processes that counteract short-term changes in energy input and represent the initiation of island recovery. Collectively, our results support the concept of dynamic rather than static reef islands and clearly demonstrate how short-term processes can influence interpretations of medium-term change.

  4. Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population.

    PubMed

    Terao, Chikashi; Yoshifuji, Hajime; Kimura, Akinori; Matsumura, Takayoshi; Ohmura, Koichiro; Takahashi, Meiko; Shimizu, Masakazu; Kawaguchi, Takahisa; Chen, Zhiyong; Naruse, Taeko K; Sato-Otsubo, Aiko; Ebana, Yusuke; Maejima, Yasuhiro; Kinoshita, Hideyuki; Murakami, Kosaku; Kawabata, Daisuke; Wada, Yoko; Narita, Ichiei; Tazaki, Junichi; Kawaguchi, Yasushi; Yamanaka, Hisashi; Yurugi, Kimiko; Miura, Yasuo; Maekawa, Taira; Ogawa, Seishi; Komuro, Issei; Nagai, Ryozo; Yamada, Ryo; Tabara, Yasuharu; Isobe, Mitsuaki; Mimori, Tsuneyo; Matsuda, Fumihiko

    2013-08-08

    Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. Prescription n-3 fatty acids, but not eicosapentaenoic acid alone, improve reference memory-related learning ability by increasing brain-derived neurotrophic factor levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.

    PubMed

    Hashimoto, Michio; Inoue, Takayuki; Katakura, Masanori; Tanabe, Yoko; Hossain, Shahdat; Tsuchikura, Satoru; Shido, Osamu

    2013-10-01

    Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr(cp)/NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline.

  6. Tethyan evolution of central Asia

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sengor, A.M.C.

    1990-05-01

    The study area extends from the eastern shores of the Caspian Sea in the west to the Helan Shan and Longmen Shan in the east and from about 40{degree}N parallel in the north to the neo-Tethyan sutures in the south, thus including what is called Middle Asia in the Soviet literature. In the region thus delineated lies the boundary between the largely late Paleozoic core of Asia (Altaids) and the Tethyside superorogenic complex. This boundary passes through continental objects that collided with nuclear Asia in the late Paleozoic to terminate its Altaid evolution. Subduction to the south of some ofmore » these had commenced before they collided (e.g., Tarim in the Kuen-Lun), in others later (e.g., South Ghissar area west of Pamirs). This subduction 1ed, in the late Paleozoic, to the opening of marginal basins, at least one of which may be partly extant (Tarim). Giant subduction accretion complexes of Paleozoic to earliest Triassic age dominate farther south in the basement of Turan (mainly in Turkmenian SSR) and in the Kuen-Lun/Nan Shan ranges. No discrete continental collisions or any continental basement in these regions could be unequivocally recognized contrary to most current interpretations. Magmatic arcs that developed along the southern margin of Asia in the late Paleozoic to early Mesozoic grew atop these subduction-accretion complexes and record a gradual southerly migration of magmatism through time. Subduction also dominated the northern margin of Gondwanaland between Iran and China in late Paleozoic time, although the record in Afghanistan and northwest Tibet is scrappy. It led to back-arc basin formation, which in Iran and Oman became neo-Tethys and, in at least parts of central Asia, the Waser-Mushan-Pshart/Banggong Co-Nu Jiang ocean. This ocean was probably connected with the Omani part of the neo-Tethys via the Sistan region.« less

  7. Vitamin D Levels in Takayasu's Arteritis and a Review of the Literature on Vasculitides.

    PubMed

    Alibaz-Oner, Fatma; Asmaz-Haliloglu, Özlem; Gogas-Yavuz, Dilek; Can, Meryem; Haklar, Goncagul; Direskeneli, Haner

    2016-09-01

    Takayasu's arteritis (TAK) is a chronic, large-vessel vasculitis. Vitamin D, as a steroidal hormone, has recently been shown to have immunoregulatory and immunosuppressive effects. Low vitamin D levels are demonstrated in various autoimmune disorders. The aim of this study is to investigate vitamin D levels in patients with TAK. A comprehensive review of vitamin D levels in systemic vasculitides (SVs) is also performed. The study included 36 patients with TAK, 28 patients with Behçet's disease (BD) as disease control and 30 sex-matched healthy controls. Plasma 25-hydroxy vitamin D (25(OH) vit D) levels were measured with high-performance liquid chromatography. "Deficiency" was defined as 25(OH) vit D levels below 25 nmol/l and "insufficiency" as below 50 nmol/l. Plasma 25(OH) vit D levels were significantly lower in TAK patients (16.93 ± 10.62 nmol/l) than healthy controls (64.63 ± 21.82 nmol/l). Vitamin D level in BD patients (38.8 ± 20.9 nmol/l) is lower than healthy controls but higher than TAK patients. The frequency of vitamin D deficiency was 83.3% in patients with TAK compared to 3.3% in healthy controls. Plasma 25(OH) vit D levels were same between clinically active and inactive patients. In literature review, very few studies were found to investigate vitamin D in SVs. We observed a high prevalence of vitamin D deficiency in patients with TAK. As various immune effects of vitamin D on mononuclear cells and arterial endothelium is shown, vitamin D deficiency can be a predisposing factor for immune activation in SV. We therefore suggest monitorization and replacement of vitamin D status in all TAK and other SV patients. © 2015 Wiley Periodicals, Inc.

  8. Subclinical Kidney Damage in Hypertensive Patients: A Renal Window Opened on the Cardiovascular System. Focus on Microalbuminuria.

    PubMed

    Mulè, Giuseppe; Castiglia, Antonella; Cusumano, Claudia; Scaduto, Emilia; Geraci, Giulio; Altieri, Dario; Di Natale, Epifanio; Cacciatore, Onofrio; Cerasola, Giovanni; Cottone, Santina

    2017-01-01

    presence of microalbuminuria (MAU), that is an amount of albumin in the urine of 30-300 mg/day or an albumin/creatinine ratio, preferentially on morning spot urine, of 30-300 mg/g.There is clear evidence that urinary albumin excretion levels, even below the cut-off values used to define MAU, are associated with an increased risk of CV events. The relationships of MAU with a variety of risk factors, such as blood pressure, diabetes and metabolic syndrome and with several indices of subclinical organ damage, may contribute, at least in part, to explain the enhanced CV risk conferred by MAU. Nonetheless, several studies showed that the association between MAU and CV disease remains when all these risk factors are taken into account in multivariate analyses. Therefore, the exact pathophysiological mechanisms explaining the association between MAU and CV risk remain to be elucidated. The simple search for MAU and in general of subclinical renal involvement in hypertensive patients may enable the clinician to better assess absolute CV risk, and its identification may induce physicians to encourage patients to make healthy lifestyle changes and perhaps would prompt to more aggressive modification of standard CV risk factors.

  9. Construction of the descriptive system for the assessment of quality of life AQoL-6D utility instrument

    PubMed Central

    2012-01-01

    Background Multi attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument. Methods The AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements. Results and Discussion The resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model. Conclusions The AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs. PMID:22507254

  10. Cascade of care and factors associated with virological suppression among HIV-positive persons linked to care in the Test and Keep in Care (TAK) project.

    PubMed

    Kowalska, Justyna D; Ankiersztejn-Bartczak, Magdalena; Shepherd, Leah; Mocroft, Amanda

    2018-05-21

    Early treatment remains the most effective HIV prevention strategy; poor linkage to care after HIV diagnosis may compromise this benefit. We sought to better understand patient characteristics and their association with virological suppression (VS) following cART initiation. The TAK project collects pre-linkage to care and clinical data on patients diagnosed with HIV in voluntary testing facilities in central Poland. Data collected for persons diagnosed in 2010-2013 were linked with HIV clinic records. Individuals linked to care who commenced cART were followed from until the earliest of first VS (HIV RNA < 50 copies/ml), last visit, death or 6 January 2016. Cox-proportional hazard models were used to identify factors associated with first viral suppression. 232 persons were HIV positive, 144 (62%, 95% CI 55, 68%) linked to care, 116 (81% of those linked to care, 95% CI 73, 87%) started cART during follow up, of which 113 (97%, 95% CI 93, 99%) achieved VS. Non-PI based regimen (for integrase inhibitors aHR: 5.03: 1.90, 13.32) and HLA B5701-positive (aHR: 3.97: 1.33, 11.85) were associated with higher chance of VS. Unknown syphilis status (aHR: 0.27: 0.13, 0.57) and higher HIV RNA (aHR a tenfold increase: 0.56: 0.42, 0.75) remained associated with lower chance of VS. Although a low proportion of persons were linked to care, almost all those linked to care started cART and achieved rapid VS. The high rates of VS were irrespective of prior HIV-associated risk behaviours. Linkage to care remains the highest priority in prevention strategies in central Poland.

  11. Surface-sediment grain-size distribution and sediment transport in the subaqueous Mekong Delta, Vietnam

    NASA Astrophysics Data System (ADS)

    Nguyen, T. T.; Stattegger, K.; Nittrouer, C.; Phung, P. V.; Liu, P.; DeMaster, D. J.; Bui, D. V.; Le, A. D.; Nguyen, T. N.

    2016-02-01

    Collected surface-sediment samples in coastal water around Mekong Delta (from distributary channels to Ca Mau Peninsula) were analyzed to determine surface-sediment grain-size distribution and sediment-transport trend in the subaqueous Mekong Delta. The grain-size data set of 238 samples was obtained by using the laser instrument Mastersizer 2000 and LS Particle Size Analyzer. Fourteen samples were selected for geochemical analysis (total-organic and carbonate content). These geochemical results were used to assist in interpreting variations of granulometricparamenters along the cross-shore transects. Nine transects were examined from CungHau river mouth to Ca Mau Peninsula and six thematic maps on the whole study area were made. The research results indicate that: (1) generally, the sediment becomes finer from the delta front downwards to prodelta and becomes coarser again and poorer sorted on the adjacent inner shelf due to different sources of sediment; (2) sediment-granulometry parameters vary among sedimentary sub-environments of the underwater part of Mekong Delta, the distance from sediment source and hydrodynamic regime controlling each region; (3) the net sediment transport is southwest toward the Ca Mau Peninsula.

  12. Decision making for Pap testing among Pacific Islander women.

    PubMed

    Weiss, Jie W; Mouttapa, Michele; Sablan-Santos, Lola; DeGuzman Lacsamana, Jasmine; Quitugua, Lourdes; Park Tanjasiri, Sora

    2016-12-01

    This study employed a Multi-Attribute Utility (MAU) model to examine the Pap test decision-making process among Pacific Islanders (PI) residing in Southern California. A total of 585 PI women were recruited through social networks from Samoan and Tongan churches, and Chamorro family clans. A questionnaire assessed Pap test knowledge, beliefs and past behaviour. The three MAU parameters of subjective value, subjective probability and momentary salience were measured for eight anticipated consequences of having a Pap test (e.g., feeling embarrassed, spending money). Logistic regression indicated that women who had a Pap test (Pap women) had higher total MAU utility scores compared to women who had not had a Pap test within the past three years (No Pap women) (adjusted Odds Ratio = 1.10). In particular, Pap women had higher utilities for the positive consequences 'Detecting cervical cancer early, Peace of mind, and Protecting my family', compared to No Pap women. It is concluded that the connection between utility and behaviour offers a promising pathway toward a better understanding of the decision to undergo Pap testing. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  13. Collaborative Model for Acceleration of Individualized Therapy of Colon Cancer

    DTIC Science & Technology

    2013-10-01

    Methods: The anti-proliferative effects of TAK-960 as a single agent and in combination with irinotecan (SN38) or cetuximab were assessed using an assay...following treatment with TAK-960 alone or in combination with standard agents (irinotecan or cetuximab ). Results: CRC cell lines were quite...sensitive to TAK-960 with IC50 values ranging from 0.007 to 1 umol/L. While no synergy was observed in the KRAS WT CRC cell lines in the cetuximab

  14. Inhibition of autophagy by TAB2 and TAB3

    PubMed Central

    Criollo, Alfredo; Niso-Santano, Mireia; Malik, Shoaib Ahmad; Michaud, Mickael; Morselli, Eugenia; Mariño, Guillermo; Lachkar, Sylvie; Arkhipenko, Alexander V; Harper, Francis; Pierron, Gérard; Rain, Jean-Christophe; Ninomiya-Tsuji, Jun; Fuentes, José M; Lavandero, Sergio; Galluzzi, Lorenzo; Maiuri, Maria Chiara; Kroemer, Guido

    2011-01-01

    Autophagic responses are coupled to the activation of the inhibitor of NF-κB kinase (IKK). Here, we report that the essential autophagy mediator Beclin 1 and TGFβ-activated kinase 1 (TAK1)-binding proteins 2 and 3 (TAB2 and TAB3), two upstream activators of the TAK1-IKK signalling axis, constitutively interact with each other via their coiled-coil domains (CCDs). Upon autophagy induction, TAB2 and TAB3 dissociate from Beclin 1 and bind TAK1. Moreover, overexpression of TAB2 and TAB3 suppresses, while their depletion triggers, autophagy. The expression of the C-terminal domain of TAB2 or TAB3 or that of the CCD of Beclin 1 competitively disrupts the interaction between endogenous Beclin 1, TAB2 and TAB3, hence stimulating autophagy through a pathway that requires endogenous Beclin 1, TAK1 and IKK to be optimally efficient. These results point to the existence of an autophagy-stimulatory ‘switch' whereby TAB2 and TAB3 abandon inhibitory interactions with Beclin 1 to engage in a stimulatory liaison with TAK1. PMID:22081109

  15. Inhibition of autophagy by TAB2 and TAB3.

    PubMed

    Criollo, Alfredo; Niso-Santano, Mireia; Malik, Shoaib Ahmad; Michaud, Mickael; Morselli, Eugenia; Mariño, Guillermo; Lachkar, Sylvie; Arkhipenko, Alexander V; Harper, Francis; Pierron, Gérard; Rain, Jean-Christophe; Ninomiya-Tsuji, Jun; Fuentes, José M; Lavandero, Sergio; Galluzzi, Lorenzo; Maiuri, Maria Chiara; Kroemer, Guido

    2011-11-11

    Autophagic responses are coupled to the activation of the inhibitor of NF-κB kinase (IKK). Here, we report that the essential autophagy mediator Beclin 1 and TGFβ-activated kinase 1 (TAK1)-binding proteins 2 and 3 (TAB2 and TAB3), two upstream activators of the TAK1-IKK signalling axis, constitutively interact with each other via their coiled-coil domains (CCDs). Upon autophagy induction, TAB2 and TAB3 dissociate from Beclin 1 and bind TAK1. Moreover, overexpression of TAB2 and TAB3 suppresses, while their depletion triggers, autophagy. The expression of the C-terminal domain of TAB2 or TAB3 or that of the CCD of Beclin 1 competitively disrupts the interaction between endogenous Beclin 1, TAB2 and TAB3, hence stimulating autophagy through a pathway that requires endogenous Beclin 1, TAK1 and IKK to be optimally efficient. These results point to the existence of an autophagy-stimulatory 'switch' whereby TAB2 and TAB3 abandon inhibitory interactions with Beclin 1 to engage in a stimulatory liaison with TAK1.

  16. Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats.

    PubMed

    Zhang, Ning; Liang, Hanyu; Farese, Robert V; Li, Ji; Musi, Nicolas; Hussey, Sophie E

    2015-01-01

    To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo.

  17. The genetics of Takayasu arteritis.

    PubMed

    Renauer, Paul; Sawalha, Amr H

    Takayasu arteritis (TAK) is a rare systemic vasculitis that is characterized by granulomatous inflammation of the aorta and its major branches. The cellular and biochemical processes involved in the pathogenesis of TAK are beginning to be elucidated, and implicate both cell and antibody-mediated autoimmune mechanisms. In addition, the underlying etiology to TAK may be explained, at least in part, by a complex genetic contribution. The most well-recognized genetic susceptibility locus for the disease is the classical HLA allele, HLA-B*52, which has been confirmed in several ethnicities. The genetic susceptibility with HLA-B*52, as well as additional classical alleles and loci, implicate both HLA class I and class II involvement in TAK. Furthermore, genetic associations with genes encoding immune response regulators, pro-inflammatory cytokines and mediators of humoral immunity may directly relate to disease mechanisms. Non-HLA susceptibility loci that have been recently established for TAK with a genome-wide level of significance include FCGR2A/FCGR3A, IL12B, IL6, RPS9/LILRB3, and a locus on chromosome 21 near PSMG1. In this review, we present the complex genetic predisposition to TAK and discuss how recent findings identified potential targets in the pathogenesis and treatment of the disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, Bin; Li, Wei; Zheng, Qichang

    Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negativemore » effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.« less

  19. LYATK1 potently inhibits LPS-mediated pro-inflammatory response

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xi, Feng; Liu, Yuan; Wang, Xiujuan

    Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine productionmore » was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.« less

  20. Island of Hawaii, State of Hawaii seen from Skylab

    NASA Technical Reports Server (NTRS)

    1974-01-01

    A vertical view of the Island of Hawaii, State of Hawaii (19.5N, 155.5W), as photographed from the Skylab space station in Earth orbit by a Skylab 4 crewman. This photograph, taken on January 8, 1974, is very useful in studies of volcanic areas. Prominent volcanic features such as the summit caldera on Mauna Loa, the extinct volcano Mauna Kea, the Kilauea caldera, and the pit crater at Halo Mau Mau within the caldera are easily identified. Kilauea was undergoing frequent eruption during the mission. Detailed features such as the extent and delineation of historic lava flows on Mauna Loa can be determined and are important parameters in volcanic studies.

  1. Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats

    PubMed Central

    Zhang, Ning; Liang, Hanyu; Farese, Robert V.; Li, Ji

    2015-01-01

    Aims To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. PMID:26196892

  2. Direct molecular interactions between Beclin 1 and the canonical NFκB activation pathway.

    PubMed

    Niso-Santano, Mireia; Criollo, Alfredo; Malik, Shoaib Ahmad; Michaud, Michael; Morselli, Eugenia; Mariño, Guillermo; Lachkar, Sylvie; Galluzzi, Lorenzo; Maiuri, Maria Chaira; Kroemer, Guido

    2012-02-01

    General (macro)autophagy and the activation of NFκB constitute prominent responses to a large array of intracellular and extracellular stress conditions. The depletion of any of the three subunits of the inhibitor of NFκB (IκB) kinase (IKKα, IKKβ, IKKγ/NEMO), each of which is essential for the canonical NFκB activation pathway, limits autophagy induction by physiological or pharmacological triggers, while constitutive active IKK subunits suffice to stimulate autophagy. The activation of IKK usually relies on TGFβ-activated kinase 1 (TAK1), which is also necessary for the optimal induction of autophagy in multiple settings. TAK1 interacts with two structurally similar co-activators, TAK1-binding proteins 2 and 3 (TAB2 and TAB3). Importantly, in resting conditions both TAB2 and TAB3 bind the essential autophagic factor Beclin 1, but not TAK1. In response to pro-autophagic stimuli, TAB2 and TAB3 dissociate from Beclin 1 and engage in stimulatory interactions with TAK1. The inhibitory interaction between TABs and Beclin 1 is mediated by their coiled-coil domains (CCDs). Accordingly, the overexpression of either TAB2 or TAB3 CCD stimulates Beclin 1- and TAK1-dependent autophagy. These results point to the existence of a direct molecular crosstalk between the canonical NFκB activation pathway and the autophagic core machinery that guarantees the coordinated induction of these processes in response to stress.

  3. A novel susceptibility locus for Takayasu arteritis in the IL12B region can be a genetic marker of disease severity.

    PubMed

    Matsumura, Takayoshi; Amiya, Eisuke; Tamura, Natsuko; Maejima, Yasuhiro; Komuro, Issei; Isobe, Mitsuaki

    2016-06-01

    Takayasu arteritis (TAK) is an acute and chronic vasculitis of unknown etiology. Recently, our group reported that SNP rs6871626 in the IL12B region had significant association with disease susceptibility to TAK. However, association of the SNP with clinical characteristics of TAK has yet to be determined. Therefore, we assessed whether this SNP was associated with TAK disease severity as represented by early onset and/or refractoriness to medical therapy. A total of 90 patients were genotyped for rs6871626 and their clinical charts were reviewed retrospectively. By examining the relationship between genotype and clinical profiles of patients, we found a strong association between the number of risk alleles and the frequency of severe cases as defined by (1) age at onset <20 years old, (2) steroid resistance, and/or (3) a relapse of disease [p = 0.03; odds ratio 3.75 (95 % confidence interval 1.13-13.5)]. Thus, our study points to potential diagnostic use of SNP rs6871626 for predicting disease severity of TAK, with the goal of genotyping-oriented therapy in the near future.

  4. A Novel c-Jun N-terminal Kinase (JNK) Signaling Complex Involved in Neuronal Migration during Brain Development.

    PubMed

    Zhang, Feng; Yu, Jingwen; Yang, Tao; Xu, Dan; Chi, Zhixia; Xia, Yanheng; Xu, Zhiheng

    2016-05-27

    Disturbance of neuronal migration may cause various neurological disorders. Both the transforming growth factor-β (TGF-β) signaling and microcephaly-associated protein WDR62 are important for neuronal migration during brain development; however, the underlying molecular mechanisms involved remain unclear. We show here that knock-out or knockdown of Tak1 (TGFβ-activated kinase 1) and Jnk2 (c-Jun N-terminal kinase 2) perturbs neuronal migration during cortical development and that the migration defects incurred by knock-out and/or knockdown of Tβr2 (type II TGF-β receptor) or Tak1 can be partially rescued by expression of TAK1 and JNK2, respectively. Furthermore, TAK1 forms a protein complex with RAC1 and two scaffold proteins of the JNK pathway, the microcephaly-associated protein WDR62 and the RAC1-interacting protein POSH (plenty of Src homology). Components of the complex coordinate with each other in the regulation of TAK1 as well as JNK activities. We suggest that unique JNK protein complexes are involved in the diversified biological and pathological functions during brain development and pathogenesis of diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Evaluation of Deterministic Models for Near Surface Soil Moisture Prediction

    DTIC Science & Technology

    1988-05-01

    soil hydrological properties (max of 3) ’ . 30. mean length of segment (hWen) 31. cmax of each layer ( cmax I (k,j), k= kno, j=1,jno) 32. porosity of...kelvin Variable name: tac Subroutines: ’bevapor’ Description: air temperature in celsius • * Variable name: tak Subroutines: ’bevapor’ Description: air...3 C - 1 *’ C GET-TABLE-VALUES assign 9865 to i9930 goto 9930 9865 cloud-yn takc-ta tac-( tak -273.15) ea-6. 108*rh*exp( (ac*tac)/ ( tak -bc)) alphi

  6. Anatomy of a physics test: Validation of the physics items on the Texas Assessment of Knowledge and Skills

    NASA Astrophysics Data System (ADS)

    Marshall, Jill A.; Hagedorn, Eric A.; O'Connor, Jerry

    2009-06-01

    We report the results of an analysis of the Texas Assessment of Knowledge and Skills (TAKS) designed to determine whether the TAKS is a valid indicator of whether students know and can do physics at the level necessary for success in future coursework, STEM careers, and life in a technological society. We categorized science items from the 2003 and 2004 10th and 11th grade TAKS by content area(s) covered, knowledge and skills required to select the correct answer, and overall quality. We also analyzed a 5000 student sample of item-level results from the 2004 11th grade exam, performing full-information factor analysis, calculating classical test indices, and determining each item's response curve using item response theory. Triangulation of our results revealed strengths and weaknesses of the different methods of analysis. The TAKS was found to be only weakly indicative of physics preparation and we make recommendations for increasing the validity of standardized physics testing.

  7. Takayasu's arteritis is associated with HLA-B*52, but not with HLA-B*51, in Turkey.

    PubMed

    Sahin, Ziver; Bıcakcıgil, Muge; Aksu, Kenan; Kamali, Sevil; Akar, Servet; Onen, Fatos; Karadag, Omer; Ozbalkan, Zeynep; Ates, Askin; Ozer, Huseyin Te; Yilmaz, Vuslat; Seyahi, Emire; Ozturk, Mehmet A; Cefle, Ayse; Cobankara, Veli; Onat, A Mesut; Tunc, Ercan; Düzgün, Nursen; Aydin, Sibel Z; Yilmaz, Neslihan; Fresko, İzzet; Karaaslan, Yasar; Kiraz, Sedat; Akkoc, Nurullah; Inanc, Murat; Keser, Gokhan; Uyar, F Aytul; Direskeneli, Haner; Saruhan-Direskeneli, Güher

    2012-02-06

    HLA-B*51 and HLA-B*52 are two close human leukocyte antigen (HLA) allele groups with minor amino acid differences. However, they are associated with two different vasculitides (HLA-B*51 in Behçet's disease and HLA-B*52 in Takayasu's arteritis (TAK)) and with major clinical and immunological differences. In this study, we aimed to screen a large cohort of TAK patients from Turkey for the presence of HLA-B*51 and HLA-B*52 as susceptibility and severity factors. TAK patients (n = 330) followed at a total of 15 centers were included in the study. The mean age of the patients was 37.8 years, and 86% were women. DNA samples from the patients and healthy controls (HC; n = 210) were isolated, and the presence of HLA-B*51 or HLA-B*52 was screened for by using PCR with sequence-specific primers. We found a significant association of HLA-B*52 with TAK (20.9% vs HC = 6.7%, P = 0.000, OR = 3.7, 95% CI = 2.02 to 6.77). The distribution of HLA-B*51 did not differ between TAK patients and HCs (22.7% vs 24.8%, OR = 0.9, 95% CI = 0.60 to 1.34). The presence of HLA-B*52 decreased in late-onset patients (> 40 years of age; 12.0%, P = 0.024, OR = 0.43, 95% CI = 0.20 to 0.91). Patients with angiographic type I disease with limited aortic involvement also had a lower presence of HLA-B*52 compared to those with all other disease subtypes (13.1% vs 26%, P = 0.005, OR = 0.43, 95% CI = 0.23 to 0.78). In this study, the previously reported association of TAK with HLA-B*52 in other populations was confirmed in patients from Turkey. The functional relevance of HLA-B*52 in TAK pathogenesis needs to be explored further.

  8. 50 CFR 665.13 - Permits and fees.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... service incurred in processing the permit. The fee may not exceed such costs and is specified with each.... (ii) Mau Zone limited access permit. (iii) Coral reef ecosystem special permit. (iv) American Samoa...

  9. 50 CFR 665.13 - Permits and fees.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... service incurred in processing the permit. The fee may not exceed such costs and is specified with each.... (ii) Mau Zone limited access permit. (iii) Coral reef ecosystem special permit. (iv) American Samoa...

  10. 50 CFR 665.13 - Permits and fees.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... service incurred in processing the permit. The fee may not exceed such costs and is specified with each.... (ii) Mau Zone limited access permit. (iii) Coral reef ecosystem special permit. (iv) American Samoa...

  11. Converting Parkinson-Specific Scores into Health State Utilities to Assess Cost-Utility Analysis.

    PubMed

    Chen, Gang; Garcia-Gordillo, Miguel A; Collado-Mateo, Daniel; Del Pozo-Cruz, Borja; Adsuar, José C; Cordero-Ferrera, José Manuel; Abellán-Perpiñán, José María; Sánchez-Martínez, Fernando Ignacio

    2018-06-07

    The aim of this study was to compare the Parkinson's Disease Questionnaire-8 (PDQ-8) with three multi-attribute utility (MAU) instruments (EQ-5D-3L, EQ-5D-5L, and 15D) and to develop mapping algorithms that could be used to transform PDQ-8 scores into MAU scores. A cross-sectional study was conducted. A final sample of 228 evaluable patients was included in the analyses. Sociodemographic and clinical data were also collected. Two EQ-5D questionnaires were scored using Spanish tariffs. Two models and three statistical techniques were used to estimate each model in the direct mapping framework for all three MAU instruments, including the most widely used ordinary least squares (OLS), the robust MM-estimator, and the generalized linear model (GLM). For both EQ-5D-3L and EQ-5D-5L, indirect response mapping based on an ordered logit model was also conducted. Three goodness-of-fit tests were employed to compare the models: the mean absolute error (MAE), the root-mean-square error (RMSE), and the intra-class correlation coefficient (ICC) between the predicted and observed utilities. Health state utility scores ranged from 0.61 (EQ-5D-3L) to 0.74 (15D). The mean PDQ-8 score was 27.51. The correlation between overall PDQ-8 score and each MAU instrument ranged from - 0.729 (EQ-5D-5L) to - 0.752 (EQ-5D-3L). A mapping algorithm based on PDQ-8 items had better performance than using the overall score. For the two EQ-5D questionnaires, in general, the indirect mapping approach had comparable or even better performance than direct mapping based on MAE. Mapping algorithms developed in this study enable the estimation of utility values from the PDQ-8. The indirect mapping equations reported for two EQ-5D questionnaires will further facilitate the calculation of EQ-5D utility scores using other country-specific tariffs.

  12. Island of Hawaii, State of Hawaii seen from Skylab

    NASA Image and Video Library

    1974-01-08

    SL4-139-3997 (8 Jan. 1974) --- A vertical view of the Island of Hawaii, State of Hawaii, as photographed from the Skylab space station in Earth orbit by a Skylab 4 crewman. The camera used was a hand-held Hasselblad camera, with SO-368 medium-speed Ektachrome film. This photograph, taken on Jan. 8, 1974, is very useful in studies of volcanic areas. Prominent volcanic features such as the summit caldera on Mauna Loa, the extinct volcano Mauna Kea, the Kilauea caldera, and the pit crater at Halo mau mau within the caldera are easily identified. (Kilauea was undergoing frequent eruption during the mission). Detailed features such as the extent and delineation of historic lava flows on Mauna Loa can be determined and are important parameters in volcanic studies. Photo credit: NASA

  13. Role of TLR4 signaling in the nephrotoxicity of heme and heme proteins.

    PubMed

    Nath, Karl A; Belcher, John D; Nath, Meryl C; Grande, Joseph P; Croatt, Anthony J; Ackerman, Allan W; Katusic, Zvonimir S; Vercellotti, Gregory M

    2018-05-01

    Destabilized heme proteins release heme, and free heme is toxic. Heme is now recognized as an agonist for the Toll-like receptor-4 (TLR4) receptor. This study examined whether the TLR4 receptor mediates the nephrotoxicity of heme, specifically, the effects of heme on renal blood flow and inflammatory responses. We blocked TLR4 signaling by the specific antagonist TAK-242. Intravenous administration of heme to mice promptly reduced renal blood flow, an effect attenuated by TAK-242. In vitro, TAK-242 reduced heme-elicited activation of NF-κB and its downstream gene monocyte chemoattractant protein-1(MCP-1); in contrast, TAK-242 failed to reduce heme-induced activation of the anti-inflammatory transcription factor Nrf2 and its downstream gene heme oxygenase-1 (HO-1). TAK-242 did not reduce heme-induced renal MCP-1 upregulation in vivo. TAK-242 did not reduce dysfunction and histological injury in the glycerol model of heme protein-induced acute kidney injury (AKI), findings corroborated by studies in TLR4 +/+ and TLR4 -/- mice. We conclude that 1) acute heme-mediated renal vasoconstriction occurs through TLR4 signaling; 2) proinflammatory effects of heme in renal epithelial cells involve TLR4 signaling, whereas the anti-inflammatory effects of heme do not; 3) TLR4 signaling does not mediate the proinflammatory effects of heme in the kidney; and 4) major mechanisms underlying glycerol-induced, heme protein-mediated AKI do not involve TLR4 signaling. These findings in the glycerol model are in stark contrast with findings in virtually all other AKI models studied to date and emphasize the importance of TLR4-independent pathways of heme protein-mediated injury in this model. Finally, these studies urge caution when using observations derived in vitro to predict what occurs in vivo.

  14. Effect of dietary n-3 fatty acids supplementation on fatty acid metabolism in atorvastatin-administered SHR.Cg-Leprcp/NDmcr rats, a metabolic syndrome model.

    PubMed

    Al Mamun, Abdullah; Hashimoto, Michio; Katakura, Masanori; Tanabe, Yoko; Tsuchikura, Satoru; Hossain, Shahdat; Shido, Osamu

    2017-01-01

    The effects of cholesterol-lowering statins, which substantially benefit future cardiovascular events, on fatty acid metabolism have remained largely obscured. In this study, we investigated the effects of atorvastatin on fatty acid metabolism together with the effects of TAK-085 containing highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl ester on atorvastatin-induced n-3 polyunsaturated fatty acid lowering in SHR.Cg-Lepr cp /NDmcr (SHRcp) rats, as a metabolic syndrome model. Supplementation with 10mg/kg body weight/day of atorvastatin for 17 weeks significantly decreased plasma total cholesterol and very low density lipoprotein cholesterol. Atorvastatin alone caused a subtle change in fatty acid composition particularly of EPA and DHA in the plasma, liver or erythrocyte membranes. However, the TAK-085 consistently increased both the levels of EPA and DHA in the plasma, liver and erythrocyte membranes. After confirming the reduction of plasma total cholesterol, 300mg/kg body weight/day of TAK-085 was continuously administered for another 6 weeks. Supplementation with TAK-085 did not decrease plasma total cholesterol but significantly increased the EPA and DHA levels in both the plasma and liver compared with rats administered atorvastatin only. Supplementation with atorvastatin alone significantly decreased sterol regulatory element-binding protein-1c, Δ5- and Δ6-desaturases, elongase-5, and stearoyl-coenzyme A (CoA) desaturase-2 levels and increased 3-hydroxy-3-methylglutaryl-CoA reductase mRNA expression in the liver compared with control rats. TAK-085 supplementation significantly increased stearoyl-CoA desaturase-2 mRNA expression. These results suggest that long-term supplementation with atorvastatin decreases the EPA and DHA levels by inhibiting the desaturation and elongation of n-3 fatty acid metabolism, while TAK-085 supplementation effectively replenishes this effect in SHRcp rat liver. Copyright © 2016 Elsevier Masson

  15. Takayasu Arteritis in Major Rheumatology Centers in Malaysia.

    PubMed

    Khor, Chiew Gek; Tan, Bee Eng; Kan, Sow Lai; Tsang, Esther Ee Ling; Lim, Ai Lee; Chong, Eleen Yun Yin; Rachel, Thundyil; Teh, Cheng Lay; Loh, Yet Lin; Chʼng, Shereen Suyin; dʼSouza, Beryl Agnes; Mohd Mokhtar, Ainon; Ong, Swee Gaik; Mohd Isa, Liza

    2016-06-01

    There is paucity of data for Takayasu arteritis (TAK) among South Asians. We aimed to evaluate the clinical features, angiographic findings, as well as treatment and outcome of TAK among Malaysian multiethnic groups. This is a retrospective review of 40 patients with TAK seen in major rheumatology centres in Malaysia between April 2006 and September 2013. Majority were female patients (92.5%), with a female-to-male ratio of 12:1. Median duration of disease from diagnosis was 66 months (interquartile range, 33-177 months). Fifteen (37.5%) were Malays, 9 (22.5%) each were Indians and indigenous from East Malaysia and 7 (17.5%) were Chinese. Indian and indigenous from East Malaysia were overrepresented in this disease. The mean (SD) age of symptom onset and diagnosis were 25.5 (8.1) and 27.4 (8.4), respectively. The 3 most common clinical presentations at diagnosis were diminished or absent pulse, which occurred in 80% of the patients, followed by blood pressure discrepancy (60%) and arterial bruit (52.5%). There was no difference in clinical presentation among ethnic groups. The subclavian artery was the commonest vessel involved (72.5%), followed by the carotid artery (65%) and renal artery (47.5%). Eight patients had coronary artery involvement, and 2 patients had pulmonary artery involvement. Type I arterial involvement was the commonest (80.0%), followed by type IV (35%), present in isolation or mixed type. Glucocorticoid was the main medical treatment (90.0%). Nineteen patients (47.5%) underwent revascularization procedures. Five patients died during the follow-up period. The Malaysian TAK cohort had similarities with and differences from other published TAK cohort. A nationwide TAK registry is needed to determine the prevalence of the disease among different ethnic groups.

  16. The Relationship between Grade Configuration and Standardized Science Test Scores of Fifth-Grade Students: What School Administrators Should Know

    ERIC Educational Resources Information Center

    Johnson, Delonda; Jones, Lisa; Simieou, Felix; Matthew, Kathryn; Morgan, Bryan

    2013-01-01

    This study utilized a causal comparative (ex post facto) design to determine if a consistent relationship existed between fifth-grade students' success on the Science Texas Assessment of Knowledge and Skills (TAKS) at the elementary (K-5) level in comparison to fifth-grade students' success on the science TAKS at the intermediate (5-6) level. The…

  17. Analysis of Texas Achievement Data for Elementary African American and Latino Females

    ERIC Educational Resources Information Center

    Larke, Patricia J.; Webb-Hasan, Gwendolyn; Jimarez, Teresa; Li, Yeping

    2014-01-01

    This study provides a critical look at achievement of African American (AA), and Latino (L) females in third and fifth grades on the Texas Assessment of Knowledge and Skills (TAKS) in reading, mathematics and science. Descriptive statistics were used to analyze the 2007 and 2011 TAKS raw data. Data analyses indicate that AAL females had the lowest…

  18. Stabilization of golden cages by encapsulation of a single transition metal atom

    PubMed Central

    Li, Hui-Fang

    2018-01-01

    Golden cage-doped nanoclusters have attracted great attention in the past decade due to their remarkable electronic, optical and catalytic properties. However, the structures of large golden cage doped with Mo and Tc are still not well known because of the challenges in global structural searches. Here, we report anionic and neutral golden cage doped with a transition metal atom MAu16 (M = Mo and Tc) using Saunders ‘Kick' stochastic automation search method associated with density-functional theory (DFT) calculation (SK-DFT). The geometric structures and electronic properties of the doped clusters, MAu16q (M = Mo and Tc; q = 0 and −1), are investigated by means of DFT theoretical calculations. Our calculations confirm that the 4d transition metals Mo and Tc can be stably encapsulated in the Au16− cage, forming three different configurations, i.e. endohedral cages, planar structures and exohedral derivatives. The ground-state structures of endohedral cages C2v Mo@Au16−-(a) and C1 Tc@Au16−-(b) exhibit a marked stability, as judged by their high binding energy per atom (greater than 2.46 eV), doping energy (0.29 eV) as well as a large HOMO–LUMO gap (greater than 0.40 eV). The predicted photoelectron spectra should aid in future experimental characterization of MAu16− (M = Mo and Tc). PMID:29410813

  19. An examination of the association between demographic and educational factors and African American achievement in science

    NASA Astrophysics Data System (ADS)

    Cottledge, Michael Christopher

    Objective of the Study: The objective of this research study was to investigate whether an association exists between teacher demographic factors (years of teaching experience and gender), 2 educational factors (certification type and certification pathway) and the percent passing rate of tenth grade African American male students on the 2010 science TAKS. Answers to the following questions were sought: 1. Is there an association between teacher demographic factors and the percent passing rate of their tenth grade African American male students on the 2010 science TAKS? 2. Is there an association between teacher educational factors and the percent passing rate of their tenth grade African American male students on the 2010 science TAKS? 3. Is there an association between teacher demographic factors, educational factors and the percent passing rate of their tenth grade African American male students on the 2010 science TAKS? Status of the Question: According to the Bureau of Labor Statistics (BLS), science and engineering jobs in the U.S. have increased steadily over recent years and by the year 2016 the number of STEM (Science, Technology, Engineering and Math) jobs will have grown by more than 21 percent. This increase in science and engineering jobs will double the growth rate of all other workforce sectors combined. The BLS also reports that qualified minority applicants needed to fill these positions will be few and far between. African Americans, Latinos, and other minorities constitute 24 percent of the U.S. population but only 13 percent of college graduates and just 10 percent of people with college degrees who work in science and engineering (Education Trust, 2009). Drawing on the above information, I proposed the following hypotheses to the research questions: H01: There will be no significant statistical association between the demographic factors teacher gender and years of teaching experience and the percent passing rate of their tenth grade African

  20. Computer-Aided Process and Tools for Mobile Software Acquisition

    DTIC Science & Technology

    2013-04-01

    Software Acquisition Christopher Bonine , Man-Tak Shing, and Thomas W. Otani Naval Postgraduate School Published April 1, 2013 Approved for public...ManTech International Corporation Computer-Aided Process and Tools for Mobile Software Acquisition Christopher Bonine , Man-Tak Shing, and Thomas W. Otani...Mobile Software Acquisition Christopher Bonine — Bonine is a lieutenant in the United States Navy. He is currently assigned to the Navy Cyber Defense

  1. The relationship between vertical teaming in science and student achievement as reported in the Academic Excellence Indicator System (AEIS) at selected public schools in Bexar County, Texas

    NASA Astrophysics Data System (ADS)

    Arteaga, Veronica Hernandez

    The purpose of this study was to examine the relationship between vertical teaming in science and student achievement. This study compared student achievement of campuses implementing vertical teaming with schools that do not practice vertical teaming. In addition, this study explored the relationship between selected demographic variables and vertical teaming using Grade 5 Science TAKS results in the Academic Excellence Indicator System (AEIS). Campus demographic variables such as economically disadvantaged, minority students, English language learners, student mobility, and experienced teachers were researched. A call-out yielded 168 responses. With the exclusion of the 12 campuses, a total of 156 participating campuses from 18 traditional school districts remained. Campuses employing vertical teaming were self-identified on the basis of having implemented the process for two or more years. The gain in percent mastered for Science TAKS scores from 2004 to 2007 was used as the Science TAKS score variable. Results indicated that there was no significant difference in student achievement in science for campuses practicing vertical teaming and campuses that did not. The two-way ANOVA was used to measure the relationship between the independent variables (vertical teaming and campus demographic variables) on the dependent variable (student achievement on Science TAKS). The results suggested that campuses having low percentages of economically disadvantaged students statistically gained more on the Science TAKS than campuses that have high percentages of economically disadvantaged students irrespective of vertical teaming practices. In addition, campuses that have low percentages of minority students statistically gained more on the Science TAKS than campuses that have high percentages of minority students despite vertical teaming participation. Recommendations include districts, state, and federal agencies providing campuses with a high percent of economically

  2. Computed tomography scan to detect traumatic arthrotomies and identify periarticular wounds not requiring surgical intervention: an improvement over the saline load test.

    PubMed

    Konda, Sanjit R; Davidovitch, Roy I; Egol, Kenneth A

    2013-09-01

    To report our experience with computed tomography (CT) scans to detect traumatic arthrotomies of the knee (TAK) joint based on the presence of intra-articular air. Retrospective review. Level I trauma center. Sixty-two consecutive patients (63 knees) underwent a CT scan of the knee in the emergency department and had a minimum of 14 days follow-up. Cohort of 37 patients (37 knees) from the original 62 patients who underwent a saline load test (SLT). CT scan and SLT. Positive traumatic arthrotomy of the knee (+TAK) was defined as operating room (OR) confirmation of an arthrotomy or no intra-articular air on CT scan (-iaCT) (and -SLT if performed) with follow-up revealing a septic knee. Periarticular wound equivalent to no traumatic arthrotomy (pw = (-TAK)) was defined as OR evaluation revealing no arthrotomy or -iaCT (and -SLT if performed) with follow-up revealing no septic knee. All 32 knees with intra-articular air on CT scan (+iaCT) had OR confirmation of a TAK and none of these patients had a knee infection at a mean follow-up of 140.0 ± 279.6 days. None of the 31 patients with -iaCT had a knee infection at a mean follow-up of 291.0 ± 548.1 days. Based on these results, the sensitivity and specificity of the CT scan to detect +TAK and pw = (-TAK) was 100%. In a subgroup of 37 patients that received both a CT scan and the conventional SLT, the sensitivity and specificity of the CT scan was 100% compared with 92% for the SLT (P < 0.001). CT scan performs better than the conventional SLT to detect traumatic knee arthrotomies and identify periarticular knee wounds that do not require surgical intervention and should be considered a valid diagnostic test in the appropriate clinical setting. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

  3. Supercritical Wing Preliminary Design Study

    DTIC Science & Technology

    1975-12-01

    SHIN «" NOME« <i./t. TAK t«/C» Ttff MA. TAft 4P) JON*« SO M »<• n y »■« • ii n VT«t 4il rtt-Tin J.l.. .S • T» 4...UPM At 1 54 ;t’ -"fi Vitll TI|K EMS IQH A4 ZEE TAff i>^ /tr TAfE <!•/£► TAK KOMUl CUJT« ■no pl TfJK A« *>1» FT J’ T<»£ 511...N« AMT* Oa/tr I» MB »AIM NO. NO. MATEWAL n «ttr ASSY Ott».!. -1 fio.if 5»»« J («It» TAK , I 1 ftf»6 Sf»* »" Cit/t»T««l

  4. Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.

    PubMed

    Marcinak, John F; Munsaka, Melvin S; Watkins, Paul B; Ohira, Takashi; Smith, Neila

    2018-06-01

    Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3

  5. EXPERIMENTING WITH MULTI-ATTRIBUTE UTILITY SURVEY METHODS IN A MULTI-DIMENSIONAL VALUATION PROBLEM. (R824699)

    EPA Science Inventory

    Abstract

    The use of willingness-to-pay (WTP) survey techniques based on multi-attribute utility (MAU) approaches has been recommended by some authors as a way to deal simultaneously with two difficulties that increasingly plague environmental valuation. The first of th...

  6. Utilizing a Web-Based Career Development Workshop to Address Career Decision-Making Difficulty among Community College Distance Learners

    ERIC Educational Resources Information Center

    Brown, Johanna Michele

    2011-01-01

    Career decision making difficulty, as it relates to undecided college students and career indecision, has been a concern for counselors and academic advisors for decades (Gordon, 2006; Mau, 2004). Individuals struggling with career indecision often seek assistance via career counseling, self-help tools, and/or computer-assisted career guidance…

  7. Topics in Culture Learning, Volume 5.

    ERIC Educational Resources Information Center

    Brislin, Richard W., Ed.; Hamnett, Michael P., Ed.

    The first section of this volume includes articles on cross-cultural teaching: "Mau Piailug's Navigation of Hokule'a from Hawaii to Tahiti," by David Lewis; "The New World Order and the Globalization of Social Science: Some Implications for Teaching Cross-Culturally," by Amarjit Singh; "Ponape: Cross-Cultural Contact,…

  8. Characterization of the free energy dependence of an interprotein electron transfer reaction by variation of pH and site-directed mutagenesis.

    PubMed

    Dow, Brian A; Davidson, Victor L

    2015-10-01

    The interprotein electron transfer (ET) reactions of the cupredoxin amicyanin, which mediates ET from the tryptophan tryptophylquinone (TTQ) cofactor of methylamine dehydrogenase to cytochrome c-551i have been extensively studied. However, it was not possible to perform certain key experiments in that native system. This study examines the ET reaction from reduced amicyanin to an alternative electron acceptor, the diheme protein MauG. It was possible to vary the ΔG° for this ET reaction by simply changing pH to determine the dependence of kET on ΔG°. A P94A mutation of amicyanin significantly altered its oxidation-reduction midpoint potential value. It was not possible to study the ET from reduced P94A amicyanin to cytochrome c-551i in the native system because that reaction was kinetically coupled. However, the reaction from reduced P94A amicyanin to MauG was a true ET reaction and it was possible to determine values of reorganization energy (λ) and electronic coupling for the reactions of this variant as well as native amicyanin. Comparison of the λ values associated with the ET reactions between amicyanin and the TTQ of methylamine dehydrogenase, the diheme center of MauG and the single heme of cytochrome c-551i, provides insight into the factors that dictate the λ values for the respective reactions. These results demonstrate how study of ET reactions with alternative redox partner proteins can complement and enhance our understanding of the reactions with the natural redox partners, and further our understanding of mechanisms of protein ET reactions. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. A quantitative comparative analysis of Advancement via Independent Determination (AVID) in Texas middle schools

    NASA Astrophysics Data System (ADS)

    Reed, Krystal Astra

    The "Advancement via Individual Determination (AVID) program was designed to provide resources and strategies that enable underrepresented minority students to attend 4-year colleges" (AVID Center, 2013, p. 2). These students are characterized as the forgotten middle in that they have high test scores, average-to-low grades, minority or low socioeconomic status, and will be first-generation college students (AVID, 2011). Research indicates (Huerta, Watt, & Butcher, 2013) that strict adherence to 11 program components supports success of students enrolled in AVID, and AVID certification depends on districts following those components. Several studies (AVID Center, 2013) have investigated claims about the AVID program through qualitative analyses; however, very few have addressed this program quantitatively. This researcher sought to determine whether differences existed between student achievement and attendance rates between AVID and non-AVID middle schools. To achieve this goal, the researcher compared eighth-grade science and seventh- and eighth-grade mathematics scores from the 2007 to 2011 Texas Assessment of Knowledge and Skills (TAKS) and overall attendance rates in demographically equivalent AVID and non-AVID middle schools. Academic Excellence Indicator System (AEIS) reports from the Texas Education Agency (TEA) were used to obtain 2007 to 2011 TAKS results and attendance information for the selected schools. The results indicated a statistically significant difference between AVID demonstration students and non-AVID students in schools with similar CI. No statistically significant differences were found on any component of the TAKS for AVID economically disadvantaged students. The mean scores indicated an achievement gap between non-AVID and AVID demonstration middle schools. The findings from the other three research questions indicated no statistically significant differences between AVID and non-AVID student passing rates on the seventh- and eighth

  10. Systematic Analysis of Quantitative Logic Model Ensembles Predicts Drug Combination Effects on Cell Signaling Networks

    DTIC Science & Technology

    2016-08-27

    acted to inhibit both TAK1 and MEK. Experimental data for these prediction tests are shown in Figure 4, and comparison between predictions and valida...would decrease did not contain this interaction. The fact that phospho-cJun did decrease in the experimental test of this prediction (Figure 4...pathways primarily through TAK1. Does IL-1 signal through MEKK1 in HepG2 cells? Given the potential importance of MEKK1, we experimentally tested whether IL

  11. Indoor air pollution and its association with poor lung function, microalbuminuria and variations in blood pressure among kitchen workers in India: a cross-sectional study.

    PubMed

    Singh, Amarnath; Kesavachandran, Chandrasekharan Nair; Kamal, Ritul; Bihari, Vipin; Ansari, Afzal; Azeez, Parappurath Abdul; Saxena, Prem Narain; Ks, Anil Kumar; Khan, Altaf Hussain

    2017-04-04

    The present study is an attempt to explore the association between kitchen indoor air pollutants and physiological profiles in kitchen workers with microalbuminuria (MAU) in north India (Lucknow) and south India (Coimbatore). The subjects comprised 145 control subjects, 233 kitchen workers from north India and 186 kitchen workers from south India. Information related to the personal and occupational history and health of the subjects at both locations were collected using a custom-made questionnaire. Worker lung function was measured using a spirometer. Blood pressure was monitored using a sphygmomanometer. Urinary MAU was measured using a urine analyzer. Indoor air monitoring in kitchens for particulate matter (PM), total volatile organic compounds (TVOC), carbon dioxide (CO 2 ) and carbon monoxide (CO) was conducted using indoor air quality monitors. The size and shape of PM in indoor air was assessed using a scanning electron microscope (SEM). Fourier transform infrared (FTIR) spectroscopy was used to detect organic or inorganic compounds in the air samples. Particulate matter concentrations (PM 2.5 and PM 1 ) were significantly higher in both north and south Indian kitchens than in non-kitchen areas. The concentrations of TVOC, CO and CO 2 were higher in the kitchens of north and south India than in the control locations (non-kitchen areas). Coarse, fine and ultrafine particles and several elements were also detected in kitchens in both locations by SEM and elemental analysis. The FTIR spectra of kitchen indoor air at both locations show the presence of organic chemicals. Significant declines in systolic blood pressure and lung function were observed in the kitchen workers with MAU at both locations compared to those of the control subjects. A higher prevalence of obstruction cases with MAU was observed among the workers in the southern region than in the controls (p < 0.01). Kitchen workers in south India have lower lung capacities and a greater risk of

  12. Investigation of the Binding Interaction of Fatty Acids with Human G Protein-Coupled Receptor 40 Using a Site-Specific Fluorescence Probe by Flow Cytometry.

    PubMed

    Ren, Xiao-Min; Cao, Lin-Ying; Zhang, Jing; Qin, Wei-Ping; Yang, Yu; Wan, Bin; Guo, Liang-Hong

    2016-04-05

    Human G protein-coupled receptor 40 (hGPR40), with medium- and long-chain free fatty acids (FFAs) as its natural ligands, plays an important role in the enhancement of glucose-dependent insulin secretion. To date, information about the direct binding of FFAs to hGPR40 is very limited, and how carbon-chain length affects the activities of FFAs on hGPR40 is not yet understood. In this study, a fluorescein-fasiglifam analogue (F-TAK-875A) conjugate was designed and synthesized as a site-specific fluorescence probe to study the interaction of FFAs with hGPR40. hGPR40 was expressed in human embryonic kidney 293 cells and labeled with F-TAK-875A. By using flow cytometry, competitive binding of FFA and F-TAK-875A to hGPR40-expressed cells was measured. Binding affinities of 18 saturated FFAs, with carbon-chain lengths ranging from C6 to C23, were analyzed. The results showed that the binding potencies of FFAs to hGPR40 were dependent on carbon length. There was a positive correlation between length and binding potency for seven FFAs (C9-C15), with myristic acid (C15) showing the highest potency, 0.2% relative to TAK-875. For FFAs with a length of fewer than C9 or more than C15, they had very weak or no binding. Molecular docking results showed that the binding pocket of TAK-875 in hGPR40 could enclose FFAs with lengths of C15 or fewer. However, for FFAs with lengths longer than C15, part of the alkyl chain extended out of the binding pocket. This study provided insights into the structural dependence of FFAs binding to and activation of hGPR40.

  13. Docosahexaenoic acid, G protein-coupled receptors, and melanoma: is G protein-coupled receptor 40 a potential therapeutic target?

    PubMed

    Nehra, Deepika; Pan, Amy H; Le, Hau D; Fallon, Erica M; Carlson, Sarah J; Kalish, Brian T; Puder, Mark

    2014-05-15

    To determine the effect of docosahexaenoic acid (DHA) on the growth of human melanoma in vitro and in vivo and to better understand the potential role of the G protein-coupled receptors (GPRs) in mediating this effect. For in vitro studies, human melanoma and control fibroblast cells were treated with DHA and TAK-875 (selective GPR40 agonist) and a cell viability assay was performed to determine cell counts. A murine subcutaneous xenograft model of human melanoma was used to test the effect of dietary treatment with an omega-3 fatty acid (FA) rich diet compared with an omega-6 FA rich diet on the growth of human melanoma in vivo. A similar animal model was used to test the effect of oral TAK-875 on the growth of established melanoma tumors in vivo. DHA has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals on the omega-3 FA rich diet were 69% smaller in weight (P = 0.005) and 76% smaller in volume compared with tumors from animals on the omega-6 FA rich diet. TAK-875 has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals treated with TAK-875 were 46% smaller in weight (P = 0.07), 62% smaller in volume (P = 0.03), and grew 77% slower (P = 0.04) compared with the placebo group. DHA and TAK-875 have a profound and selective inhibitory effect on the growth of human melanoma both in vitro and in vivo. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Optimization of T-cell Reactivity by Exploiting TCR Chain Centricity for the Purpose of Safe and Effective Antitumor TCR Gene Therapy.

    PubMed

    Ochi, Toshiki; Nakatsugawa, Munehide; Chamoto, Kenji; Tanaka, Shinya; Yamashita, Yuki; Guo, Tingxi; Fujiwara, Hiroshi; Yasukawa, Masaki; Butler, Marcus O; Hirano, Naoto

    2015-09-01

    Adoptive transfer of T cells redirected by a high-affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains. In this study, we comprehensively studied how TCR chain centricity affects reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1(235-243) (A24/WT1(235)) and cross-reactive with B*57:01 (B57). The TAK1β, but not the TAK1α, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCRα counter-chains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1β-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1(235) and/or to B57. T cells reconstituted with these TCRα genes along with TAK1β possessed a very broad range (>3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically unselected TCRs. ©2015 American Association for Cancer Research.

  15. Arjunolic acid, a peroxisome proliferator-activated receptor α agonist, regresses cardiac fibrosis by inhibiting non-canonical TGF-β signaling.

    PubMed

    Bansal, Trisha; Chatterjee, Emeli; Singh, Jasdeep; Ray, Arjun; Kundu, Bishwajit; Thankamani, V; Sengupta, Shantanu; Sarkar, Sagartirtha

    2017-10-06

    Cardiac hypertrophy and associated heart fibrosis remain a major cause of death worldwide. Phytochemicals have gained attention as alternative therapeutics for managing cardiovascular diseases. These include the extract from the plant Terminalia arjuna, which is a popular cardioprotectant and may prevent or slow progression of pathological hypertrophy to heart failure. Here, we investigated the mode of action of a principal bioactive T. arjuna compound, arjunolic acid (AA), in ameliorating hemodynamic load-induced cardiac fibrosis and identified its intracellular target. Our data revealed that AA significantly represses collagen expression and improves cardiac function during hypertrophy. We found that AA binds to and stabilizes the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) and increases its expression during cardiac hypertrophy. PPARα knockdown during AA treatment in hypertrophy samples, including angiotensin II-treated adult cardiac fibroblasts and renal artery-ligated rat heart, suggests that AA-driven cardioprotection primarily arises from PPARα agonism. Moreover, AA-induced PPARα up-regulation leads to repression of TGF-β signaling, specifically by inhibiting TGF-β-activated kinase1 (TAK1) phosphorylation. We observed that PPARα directly interacts with TAK1, predominantly via PPARα N-terminal transactivation domain (AF-1) thereby masking the TAK1 kinase domain. The AA-induced PPARα-bound TAK1 level thereby shows inverse correlation with the phosphorylation level of TAK1 and subsequent reduction in p38 MAPK and NF-κBp65 activation, ultimately culminating in amelioration of excess collagen synthesis in cardiac hypertrophy. In conclusion, our findings unravel the mechanism of AA action in regressing hypertrophy-associated cardiac fibrosis by assigning a role of AA as a PPARα agonist that inactivates non-canonical TGF-β signaling. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Transdermal Nitroglycerin Delivery Using Acrylic Matrices: Design, Formulation, and In Vitro Characterization

    PubMed Central

    Ramazani Saadat Abadi, Ahmad

    2014-01-01

    Nitroglycerin (TNG) transdermal drug delivery systems (TDDSs) with different acrylic pressure-sensitive adhesives (PSAs) and chemical permeation enhancers (CPEs) were prepared. The effects of PSAs and CPEs types and concentrations on skin permeation and in vitro drug release from devices were evaluated using the dissolution method as well as the modified-jacketed Franz diffusion cells fitted with excised rat abdominal skin. It was demonstrated that the permeation rate or steady state flux (J ss) of the drug through the excised rat skin was dependent on the viscosity and type of acrylic PSA as well as the type of CPE. Among different acrylic PSAs, Duro-Tak 2516 and Duro-Tak 2054 showed the highest and Duro-Tak 2051 showed the lowest J ss. Among the various CPEs, propylene glycol and cetyl alcohol showed the highest and the lowest enhancement of the skin permeation of TNG, respectively. The adhesion properties of devices such as 180° peel strength and probe tack values were obtained. It was shown that increasing the concentration of CPE led to reduction in the adhesion property of PSA. Moreover, after optimization of the formulation, it was found that the use of 10% PG as a CPE and 25% nitroglycerin loading in Duro-Tak 2054 is an effective monolithic DIAP for the development of a transdermal therapeutic system for nitroglycerin. PMID:24511396

  17. Inhibition of HIV Fusion with Multivalent Gold Nanoparticles

    PubMed Central

    Bowman, Mary-Catherine; Ballard, T. Eric; Ackerson, Christopher J.; Feldheim, Daniel L.; Margolis, David M.; Melander, Christian

    2010-01-01

    The design and synthesis of a multivalent gold nanoparticle therapeutic is presented. SDC-1721, a fragment of the potent HIV inhibitor TAK-779, was synthesized and conjugated to 2.0 nm diameter gold nanoparticles. Free SDC-1721 had no inhibitory effect on HIV infection; however, the (SDC-1721)-gold nanoparticle conjugates displayed activity comparable to that of TAK-779. This result suggests that multivalent presentation of small molecules on gold nanoparticle surfaces can convert inactive drugs into potent therapeutics. PMID:18473457

  18. Organic Coasts? Regulatory Challenges of Certifying Integrated Shrimp-Mangrove Production Systems in Vietnam

    ERIC Educational Resources Information Center

    Ha, Tran Thi Thu; Bush, Simon R.; Mol, Arthur P. J.; van Dijk, Han

    2012-01-01

    The Vietnamese government aims to expand the scale of Naturland certified organic production in integrated shrimp-mangrove farming systems across the coast of Ca Mau province by 2015. In doing so the division between public and private regulation has become blurred. We analyze the government's goal by examining the regulatory challenges of using…

  19. Decision Making for Pap Testing among Pacific Islander Women

    ERIC Educational Resources Information Center

    Weiss, Jie W.; Mouttapa, Michele; Sablan-Santos, Lola; DeGuzman Lacsamana, Jasmine; Quitugua, Lourdes; Park Tanjasiri, Sora

    2016-01-01

    This study employed a Multi-Attribute Utility (MAU) model to examine the Pap test decision-making process among Pacific Islanders (PI) residing in Southern California. A total of 585 PI women were recruited through social networks from Samoan and Tongan churches, and Chamorro family clans. A questionnaire assessed Pap test knowledge, beliefs and…

  20. Validation of Physics Standardized Test Items

    NASA Astrophysics Data System (ADS)

    Marshall, Jill

    2008-10-01

    The Texas Physics Assessment Team (TPAT) examined the Texas Assessment of Knowledge and Skills (TAKS) to determine whether it is a valid indicator of physics preparation for future course work and employment, and of the knowledge and skills needed to act as an informed citizen in a technological society. We categorized science items from the 2003 and 2004 10th and 11th grade TAKS by content area(s) covered, knowledge and skills required to select the correct answer, and overall quality. We also analyzed a 5000 student sample of item-level results from the 2004 11th grade exam using standard statistical methods employed by test developers (factor analysis and Item Response Theory). Triangulation of our results revealed strengths and weaknesses of the different methods of analysis. The TAKS was found to be only weakly indicative of physics preparation and we make recommendations for increasing the validity of standardized physics testing..

  1. Biodistribution of radiomercury in rabbits and efficacy of dimercaptopropanesulfonic acid (DMPS) and dimercaprol (BAL) to reduce tracer-level kidney (kid) burden of radiomercury in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Coveney, J.R.; Robbins, M.S.

    There is clinical interest in /sup 195m/Hg//sup 195m/Au generators for radionuclide angiocardiography. Generators are /sup 195m/Hg-impregnated columns through which S/sub 2/O/sub 3//sup 2 -//NO/sub 3//sup -/ eluant is passed to recover /sup 195m/Au daughter (t/sub 1/2p/ approx. 30s) permitting repeated patient study at short intervals, but co-elution of some /sup 195m/Hg (t/sub 1/2p approx. 40h) limits per-study dose: eluate was injected i.v. to male and female New Zealand White rabbits (1.4-2.4 kg, 12 ml eluate ea.); approx. 40% of injected dose (ID) of /sup 195m/Hg was in kids by 3d and approx. 20% ID remained after 14d; only 37% IDmore » was excreted (2/3 in feces) at 7d. To evaluate DMPS action upon kid /sup 195m/Hg burden, male Sprague-Dawley rats (187-240 g) were injected i.v. with 2ml eluate containing 0.02 mg DMPS/ml or eluate alone. DMPS slightly reduced % ID /sup 195m/Hg in kids 22h later: 12.2 +/- 0.3 to 8.5 +/- 0.3 (mean +/- s.e.m., n = 4). Additional rats were given 5 mg BAL/kg, i.p., or 2ml propylene glycol vehicle/kg 3-4' before 2ml eluate, i.v.; % ID of Hg was again only slightly reduced (14.4 +/- 0.2 to 10.7 +/- 0.1). Neither BAL nor DMPS, useful in repeat-dose regimens in heavy metal poisoning, are suitable in single doses for reducing absorbed radiation dose in /sup 195m/Au angiocardiography.« less

  2. Development of outcome measures for large-vessel vasculitis for use in clinical trials: opportunities, challenges, and research agenda.

    PubMed

    Direskeneli, Haner; Aydin, Sibel Z; Kermani, Tanaz A; Matteson, Eric L; Boers, Maarten; Herlyn, Karen; Luqmani, Raashid A; Neogi, Tuhina; Seo, Philip; Suppiah, Ravi; Tomasson, Gunnar; Merkel, Peter A

    2011-07-01

    Giant cell (GCA) and Takayasu's arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.

  3. Development of Outcome Measures for Large-vessel Vasculitis for Use in Clinical Trials: Opportunities, Challenges, and Research Agenda

    PubMed Central

    DIRESKENELI, HANER; AYDIN, SIBEL Z.; KERMANI, TANAZ A.; MATTESON, ERIC L.; BOERS, MAARTEN; HERLYN, KAREN; LUQMANI, RAASHID A.; NEOGI, TUHINA; SEO, PHILIP; SUPPIAH, RAVI; TOMASSON, GUNNAR; MERKEL, PETER A.

    2013-01-01

    Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development. PMID:21724719

  4. Inhibition of endogenous heat shock protein 70 attenuates inducible nitric oxide synthase induction via disruption of heat shock protein 70/Na(+) /H(+) exchanger 1-Ca(2+) -calcium-calmodulin-dependent protein kinase II/transforming growth factor β-activated kinase 1-nuclear factor-κB signals in BV-2 microglia.

    PubMed

    Huang, Chao; Lu, Xu; Wang, Jia; Tong, Lijuan; Jiang, Bo; Zhang, Wei

    2015-08-01

    Inducible nitric oxide synthase (iNOS) critically contributes to inflammation and host defense. The inhibition of heat shock protein 70 (Hsp70) prevents iNOS induction in lipopolysaccharide (LPS)-stimulated macrophages. However, the role and mechanism of endogenous Hsp70 in iNOS induction in microglia remains unclear. This study addresses this issue in BV-2 microglia, showing that Hsp70 inhibition or knockdown prevents LPS-induced iNOS protein expression and nitric oxide production. Real-time PCR experiments showed that LPS-induced iNOS mRNA transcription was blocked by Hsp70 inhibition. Further studies revealed that the inhibition of Hsp70 attenuated LPS-stimulated nuclear translocation and phosphorylation of nuclear factor (NF)-κB as well as the degradation of inhibitor of κB (IκB)-α and phosphorylation of IκB kinase β (IKKβ). This prevention effect of Hsp70 inhibition on IKKβ-NF-κB activation was found to be dependent on the Ca(2+) /calcium-calmodulin-dependent protein kinase II (CaMKII)/transforming growth factor β-activated kinase 1 (TAK1) signals based on the following observations: 1) chelation of intracellular Ca(2+) or inhibition of CaMKII reduced LPS-induced increases in TAK1 phosphorylation and 2) Hsp70 inhibition reduced LPS-induced increases in CaMKII/TAK1 phosphorylation, intracellular pH value, [Ca(2+) ]i , and CaMKII/TAK1 association. Mechanistic studies showed that Hsp70 inhibition disrupted the association between Hsp70 and Na(+) /H(+) exchanger 1 (NHE1), which is an important exchanger responsible for Ca(2+) influx in LPS-stimulated cells. These studies demonstrate that the inhibition of endogenous Hsp70 attenuates the induction of iNOS, which likely occurs through the disruption of NHE1/Hsp70-Ca(2+) -CaMKII/TAK1-NF-κB signals in BV-2 microglia, providing further insight into the functions of Hsp70 in the CNS. © 2015 Wiley Periodicals, Inc.

  5. Transforming Growth Factor-β-Activated Kinase 1 Is Required for Human FcγRIIIb-Induced Neutrophil Extracellular Trap Formation.

    PubMed

    Alemán, Omar Rafael; Mora, Nancy; Cortes-Vieyra, Ricarda; Uribe-Querol, Eileen; Rosales, Carlos

    2016-01-01

    Neutrophils (PMNs) are the most abundant leukocytes in the blood. PMN migrates from the circulation to sites of infection where they are responsible for antimicrobial functions. PMN uses phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. Several stimuli, including bacteria, fungi, and parasites, and some pharmacological compounds, such as Phorbol 12-myristate 13-acetate (PMA), are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. Recently, it was reported that FcγRIIIb cross-linking induced NET formation similarly to PMA stimulation. Direct cross-linking of FcγRIIA or integrins did not promote NET formation. FcγRIIIb-induced NET formation presented different kinetics from PMA-induced NET formation, suggesting differences in signaling. Because FcγRIIIb also induces a strong activation of extracellular signal-regulated kinase (ERK) and nuclear factor Elk-1, and the transforming growth factor-β-activated kinase 1 (TAK1) has recently been implicated in ERK signaling, in the present report, we explored the role of TAK1 in the signaling pathway activated by FcγRIIIb leading to NET formation. FcγRIIIb was stimulated by specific monoclonal antibodies, and NET formation was evaluated in the presence or absence of pharmacological inhibitors. The antibiotic LL Z1640-2, a selective inhibitor of TAK1 prevented FcγRIIIb-induced, but not PMA-induced NET formation. Both PMA and FcγRIIIb cross-linking induced phosphorylation of ERK. But, LL Z1640-2 only inhibited the FcγRIIIb-mediated activation of ERK. Also, only FcγRIIIb, similarly to transforming growth factor-β-induced TAK1 phosphorylation. A MEK (ERK kinase)-specific inhibitor was able to prevent ERK phosphorylation induced by both PMA and FcγRIIIb. These data show for the first time that FcγRIIIb cross-linking activates TAK1, and that this kinase is required for triggering the MEK/ERK signaling pathway to NETosis.

  6. Impact of Texas high school science teacher credentials on student performance in high school science

    NASA Astrophysics Data System (ADS)

    George, Anna Ray Bayless

    A study was conducted to determine the relationship between the credentials held by science teachers who taught at a school that administered the Science Texas Assessment on Knowledge and Skills (Science TAKS), the state standardized exam in science, at grade 11 and student performance on a state standardized exam in science administered in grade 11. Years of teaching experience, teacher certification type(s), highest degree level held, teacher and school demographic information, and the percentage of students who met the passing standard on the Science TAKS were obtained through a public records request to the Texas Education Agency (TEA) and the State Board for Educator Certification (SBEC). Analysis was performed through the use of canonical correlation analysis and multiple linear regression analysis. The results of the multiple linear regression analysis indicate that a larger percentage of students met the passing standard on the Science TAKS state attended schools in which a large portion of the high school science teachers held post baccalaureate degrees, elementary and physical science certifications, and had 11-20 years of teaching experience.

  7. A role for NRAGE in NF-κB activation through the non-canonical BMP pathway

    PubMed Central

    2010-01-01

    Background Previous studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab1 complex. Its effect on NF-κB has yet to be explored. Results Herein we report that NRAGE, via the same XIAP-Tak1-Tab1 complex, is required for the phosphorylation of IKK -α/β and subsequent transcriptional activation of the p65 subunit of NF-κB. Ablation of endogenous NRAGE by siRNA inhibited NF-κB pathway activation, while ablation of Tak1 and Tab1 by morpholino inhibited overexpression of NRAGE from activating NF-κB. Finally, cytokine profiling of an NRAGE over-expressing stable line revealed the expression of macrophage migration inhibitory factor. Conclusion Modulation of NRAGE expression revealed novel roles in regulating NF-κB activity in the non-canonical bone morphogenic protein signaling pathway. The expression of macrophage migration inhibitory factor by bone morphogenic protein -4 reveals novel crosstalk between an immune cytokine and a developmental pathway. PMID:20100315

  8. Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway.

    PubMed

    Chen, Zhengxu; Zhang, Dan; Li, Man; Wang, Baolong

    2018-06-12

    Lipoteichoic acid (LTA)-induced acute lung injury (ALI) is an experimental model for mimicking Gram-positive bacteria-induced pneumonia that is a refractory disease with lack of effective medicines. Here, we reported that costunolide, a sesquiterpene lactone, ameliorated LTA-induced ALI. Costunolide treatment reduced LTA-induced neutrophil lung infiltration, cytokine and chemokine production (TNF-α, IL-6 and KC), and pulmonary edema. In response to LTA challenge, treatment with costunolide resulted less iNOS expression and produced less inflammatory cytokines in bone marrow derived macrophages (BMDMs). Pretreatment with costunolide also attenuated the LTA-induced the phosphorylation of p38 MAPK and ERK in BMDMs. Furthermore, costunolide treatment reduced the phosphorylation of TAK1 and inhibited the interaction of TAK1 with Tab1. In conclusion, we have demonstrated that costunolide protects against LTA-induced ALI via inhibiting TAK1-mediated MAPK signaling pathway, and our studies suggest that costunolide is a promising agent for treatment of Gram-positive bacteria-mediated pneumonia. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Dynamic one-dimensional modeling of secondary settling tanks and design impacts of sizing decisions.

    PubMed

    Li, Ben; Stenstrom, Michael K

    2014-03-01

    As one of the most significant components in the activated sludge process (ASP), secondary settling tanks (SSTs) can be investigated with mathematical models to optimize design and operation. This paper takes a new look at the one-dimensional (1-D) SST model by analyzing and considering the impacts of numerical problems, especially the process robustness. An improved SST model with Yee-Roe-Davis technique as the PDE solver is proposed and compared with the widely used Takács model to show its improvement in numerical solution quality. The improved and Takács models are coupled with a bioreactor model to reevaluate ASP design basis and several popular control strategies for economic plausibility, contaminant removal efficiency and system robustness. The time-to-failure due to rising sludge blanket during overloading, as a key robustness indicator, is analyzed to demonstrate the differences caused by numerical issues in SST models. The calculated results indicate that the Takács model significantly underestimates time to failure, thus leading to a conservative design. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Microevolution and History of the Plague Bacillus, Yersinia pestis

    DTIC Science & Technology

    2004-12-21

    Nichols, R. A., Oyston, P. C., Hinds, J., Titball, R. W. & Wren, B. W. (2003) Genome Res. 13, 2018 –2029. 7. Zhou, D., Han, Y., Song, Y., Tong, Z., Wang...Res. 11, 179–197. 29. Deng, W., Burland, V., Plunkett, G., III, Boutin , A., Mayhew, G. F., Liss, P., Perna, N. T., Rose, D. J., Mau, B., Zhou, S., et

  11. U. S. Naval Forces, Vietnam Monthly Historical Supplement for September 1969

    DTIC Science & Technology

    1969-12-01

    A. SEAI.O)RDS - lISEP B. 5A,•f lORDS - 22 SEP,.". I *A "’\\4 5.: SCALl , CA MAU POINT _ __0 NAUTICAL MILES CG 41 POULO77.BASE 08I -I ".-il - v-CC...Cambodia. (See discussion of Border Interdiction Capaign within Operation SIA LOIDS Suwzary and discussion of SEA FLOAT in Coastal Surreillanoe 4 Tore

  12. EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.

    PubMed

    Kamata, Ryo; Bumdelger, Batmunkh; Kokubo, Hiroki; Fujii, Masayuki; Yoshimura, Koichi; Ishida, Takafumi; Ishida, Mari; Yoshizumi, Masao

    2016-01-01

    Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta-activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg-KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar-4, which results in the attenuation of AAA development.

  13. Association of vascular physical examination findings and arteriographic lesions in large vessel vasculitis.

    PubMed

    Grayson, Peter C; Tomasson, Gunnar; Cuthbertson, David; Carette, Simon; Hoffman, Gary S; Khalidi, Nader A; Langford, Carol A; McAlear, Carol A; Monach, Paul A; Seo, Philip; Warrington, Kenneth J; Ytterberg, Steven R; Merkel, Peter A

    2012-02-01

    To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu's arteritis (TAK) and giant cell arteritis (GCA). In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm. We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%-50%) and good-excellent specificity (range 71%-98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%-100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined. In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV.

  14. Molecular insights into the differences in anti-inflammatory activities of green tea catechins on IL-1β signaling in rheumatoid arthritis synovial fibroblasts.

    PubMed

    Fechtner, Sabrina; Singh, Anil; Chourasia, Mukesh; Ahmed, Salahuddin

    2017-08-15

    In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectiveness could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea. Copyright © 2017. Published by Elsevier Inc.

  15. Migrant and Refugee Patient Perspectives on Travel and Tuberculosis along the Thailand-Myanmar Border: A Qualitative Study.

    PubMed

    Tschirhart, Naomi; Sein, Tabitha; Nosten, Francois; Foster, Angel M

    2016-01-01

    The Thailand-Myanmar border separates two very different health systems. The healthcare system in eastern Myanmar remains underdeveloped as a result of decades of instability. Comparatively, Tak province, Thailand has more healthcare resources. In this Thai border province government hospitals and non-governmental organizations provide tuberculosis (TB) treatment to migrants and refugees. Our overall study aimed to explore accessibility of TB treatment, TB surveillance and health system responsiveness specific to migrant and refugee populations in Tak province. In this paper, we focus on the perspectives of migrant and refugee TB patients with respect to travel and treatment in Tak province. In 2014 we conducted focus group discussions with 61 TB, Tuberculosis and Human Immunodeficiency Virus co-infection, and multidrug-resistant TB patients in Tak province. We analyzed the data for content and themes and documented individual travel trajectories. Migrants are travelling with active TB within the country and between Thailand and Myanmar. Migrants primarily travelled to obtain treatment but two participants reported travelling home to seek family care in Myanmar before returning to Thailand for treatment. Travel, while expensive and arduous, is an adaptive strategy that migrants use to access healthcare. Migrant's need for travel points to larger difficulties associated with healthcare access in the border region. Long distance travel with an infectious disease can be seen as an indicator that local healthcare is not available or affordable. These findings suggest that public health officials from both sides of the border should discuss the factors that contribute to travel with active TB and explore potential solutions to mitigate disease transmission in migrant populations.

  16. Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5

    PubMed Central

    Fizazi, Karim; Jones, Robert; Oudard, Stephane; Efstathiou, Eleni; Saad, Fred; de Wit, Ronald; De Bono, Johann; Cruz, Felipe Melo; Fountzilas, George; Ulys, Albertas; Carcano, Flavio; Agarwal, Neeraj; Agus, David; Bellmunt, Joaquim; Petrylak, Daniel P.; Lee, Shih-Yuan; Webb, Iain J.; Tejura, Bindu; Borgstein, Niels; Dreicer, Robert

    2015-01-01

    Purpose Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory–Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. Results The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). Conclusion Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity. PMID:25624429

  17. Quantifying the Effectiveness of Crowd-Sourced Serious Games

    DTIC Science & Technology

    2014-09-01

    of All Metrics Used in the Thesis . . . . . . . . . . . . . . 37 Table 5.1 Average DAU and MAU for Selected Mobile , Social, and Online Games...of Sample VeriGames . . . . . . . . . . . . . . . . . . . . 41 Table 5.4 ER of Some Mobile , Social and Online Games and Developers . . 41 Table 5.5 ER...a code segment. A backend verification engine then combines the assertions produced from all related game instances and tries to obtain conditions

  18. Renal functional reserve and renal hemodynamics in hypertensive patients.

    PubMed

    Gaipov, Abduzhappar; Solak, Yalcin; Zhampeissov, Nurlan; Dzholdasbekova, Aliya; Popova, Nadezhda; Molnar, Miklos Z; Tuganbekova, Saltanat; Iskandirova, Elmira

    2016-10-01

    The renal functional reserve (RFR) is the ability of the kidneys to increase renal plasma flow and glomerular filtration rate (GFR) in response to protein intake. It is a measure of functional and anatomic integrity of nephrons. It is not known what relation between RFR and kidney Doppler parameters. We aimed to study the relation between the RFR and renal hemodynamic parameters in hypertensive patients with and without nephropathy who had normal kidney function. Twenty-four hypertensive subjects with nephropathy (HTN-n, n = 10) and hypertension without nephropathy (HTN, n = 14) were included in the study. Control group included 11 healthy subjects. Baseline GFR (GFR1) and GFR after intake of egg protein 1 mg/kg of body weight were determined (GFR2). RFR was calculated by the following formula: (GFR2-GFR1)/GFR1 × 100%. Doppler ultrasonography was performed. Arterial blood pressure (BP), body mass index (BMI), and estimated GFR were also recorded. HTN and HTN-n groups had impaired levels of RFR compared with controls (p < 0.05), significantly decreased value of flow velocity parameters (Vmax, Vmin), and increased RRI compared with controls. There was significant negative correlation of RFR with blood pressure levels (sBP, r = -0.435, p = 0.009; dBP, r = -0.504, p = 0.002), RRI (r = -0.456, p = 0.008), micro albuminuria (MAU, r = -0.366, p = 0.031) and positive correlation with Vmax and Vmin (r = 0.556, p = 0.001 and r = 0.643, respectively, p < 0.001). Linear regression showed that RRI and MAU were independent predictors of decreased RFR. RFR is lower in hypertensive patients despite near-normal level of kidney function and is related to particular level of BP. RRI and MAU were independent predictors of decreased RFR.

  19. [An experience of the use of angiotensin II receptor blocker losartan in patients with metabolic syndrome and chronic kidney disease].

    PubMed

    Beloborodova, A V; Morozova, T E; Shilov, E M

    2010-01-01

    Aim of the study--to assess efficacy and safety of one of angiotensin II receptor blockers in patients with metabolic syndrome (MS) and I-V stage chronic kidney disease. We studied cardiodynamic and renal effects of losartan in average daily dose 50 +/- 13.06 mg in 20 patients (9 men and 11 women aged 32-79 years) with MS and I-V stage chronic kidney disease. Cardiodynamic effects of losartan were assessed by office blood pressure (BP) measurements, 24-hour BP monitoring (24-HBPM), echocardiography. Laboratory investigations included biochemical analysis of the blood with measurement of creatinine levels, lipid blood composition, fasting glucose, and glucose under conditions of oral glucose tolerance test. Renal function was assessed by glomerular filtration rate and microalbuminuria (MAU). Parameters of quality of life were analyzed with the use of questionnaires "Quality of life of patients with hypertensive disease" and EuroQol EQ-5D VAS thermometer. Duration of follow up was 12 weeks. 24-HBPM revealed significant lowering of systolic and diastolic BP in all temporal intervals, significant decrease of elevated diurnal systolic and diastolic BP burden, tendency to lowering of variability and normalization of 24-hour BP profile. We also noted tendency to lowering of MAU from 5.60 mg/dl (median) (3.50; 9.20 [25th and 75th percentile]) to 3.25 mg/dl (0.40; 7.83); significant lowering of levels of triglycerides and glucose under conditions of glucose tolerance test; improvement of parameters characterizing quality of life namely reduction of integral assessment by the "Quality of life of patients with hypertensive disease" questionnaire and improvement of EQ-5D VAS (thermometer) score related to arterial hypertension. We conclude that losartan in patients with MS and early signs of impairment of kidney function in addition to antihypertensive action exerts favorable effect on parameters of 24-hour BP profile, has good safety profile, causes favorable metabolic

  20. Methylobacterium genome sequences: a reference blueprint to investigate microbial metabolism of C1 compounds from natural and industrial sources.

    PubMed

    Vuilleumier, Stéphane; Chistoserdova, Ludmila; Lee, Ming-Chun; Bringel, Françoise; Lajus, Aurélie; Zhou, Yang; Gourion, Benjamin; Barbe, Valérie; Chang, Jean; Cruveiller, Stéphane; Dossat, Carole; Gillett, Will; Gruffaz, Christelle; Haugen, Eric; Hourcade, Edith; Levy, Ruth; Mangenot, Sophie; Muller, Emilie; Nadalig, Thierry; Pagni, Marco; Penny, Christian; Peyraud, Rémi; Robinson, David G; Roche, David; Rouy, Zoé; Saenampechek, Channakhone; Salvignol, Grégory; Vallenet, David; Wu, Zaining; Marx, Christopher J; Vorholt, Julia A; Olson, Maynard V; Kaul, Rajinder; Weissenbach, Jean; Médigue, Claudine; Lidstrom, Mary E

    2009-01-01

    Methylotrophy describes the ability of organisms to grow on reduced organic compounds without carbon-carbon bonds. The genomes of two pink-pigmented facultative methylotrophic bacteria of the Alpha-proteobacterial genus Methylobacterium, the reference species Methylobacterium extorquens strain AM1 and the dichloromethane-degrading strain DM4, were compared. The 6.88 Mb genome of strain AM1 comprises a 5.51 Mb chromosome, a 1.26 Mb megaplasmid and three plasmids, while the 6.12 Mb genome of strain DM4 features a 5.94 Mb chromosome and two plasmids. The chromosomes are highly syntenic and share a large majority of genes, while plasmids are mostly strain-specific, with the exception of a 130 kb region of the strain AM1 megaplasmid which is syntenic to a chromosomal region of strain DM4. Both genomes contain large sets of insertion elements, many of them strain-specific, suggesting an important potential for genomic plasticity. Most of the genomic determinants associated with methylotrophy are nearly identical, with two exceptions that illustrate the metabolic and genomic versatility of Methylobacterium. A 126 kb dichloromethane utilization (dcm) gene cluster is essential for the ability of strain DM4 to use DCM as the sole carbon and energy source for growth and is unique to strain DM4. The methylamine utilization (mau) gene cluster is only found in strain AM1, indicating that strain DM4 employs an alternative system for growth with methylamine. The dcm and mau clusters represent two of the chromosomal genomic islands (AM1: 28; DM4: 17) that were defined. The mau cluster is flanked by mobile elements, but the dcm cluster disrupts a gene annotated as chelatase and for which we propose the name "island integration determinant" (iid). These two genome sequences provide a platform for intra- and interspecies genomic comparisons in the genus Methylobacterium, and for investigations of the adaptive mechanisms which allow bacterial lineages to acquire methylotrophic

  1. Methylobacterium Genome Sequences: A Reference Blueprint to Investigate Microbial Metabolism of C1 Compounds from Natural and Industrial Sources

    PubMed Central

    Lee, Ming-Chun; Bringel, Françoise; Lajus, Aurélie; Zhou, Yang; Gourion, Benjamin; Barbe, Valérie; Chang, Jean; Cruveiller, Stéphane; Dossat, Carole; Gillett, Will; Gruffaz, Christelle; Haugen, Eric; Hourcade, Edith; Levy, Ruth; Mangenot, Sophie; Muller, Emilie; Nadalig, Thierry; Pagni, Marco; Penny, Christian; Peyraud, Rémi; Robinson, David G.; Roche, David; Rouy, Zoé; Saenampechek, Channakhone; Salvignol, Grégory; Vallenet, David; Wu, Zaining; Marx, Christopher J.; Vorholt, Julia A.; Olson, Maynard V.; Kaul, Rajinder; Weissenbach, Jean; Médigue, Claudine; Lidstrom, Mary E.

    2009-01-01

    Background Methylotrophy describes the ability of organisms to grow on reduced organic compounds without carbon-carbon bonds. The genomes of two pink-pigmented facultative methylotrophic bacteria of the Alpha-proteobacterial genus Methylobacterium, the reference species Methylobacterium extorquens strain AM1 and the dichloromethane-degrading strain DM4, were compared. Methodology/Principal Findings The 6.88 Mb genome of strain AM1 comprises a 5.51 Mb chromosome, a 1.26 Mb megaplasmid and three plasmids, while the 6.12 Mb genome of strain DM4 features a 5.94 Mb chromosome and two plasmids. The chromosomes are highly syntenic and share a large majority of genes, while plasmids are mostly strain-specific, with the exception of a 130 kb region of the strain AM1 megaplasmid which is syntenic to a chromosomal region of strain DM4. Both genomes contain large sets of insertion elements, many of them strain-specific, suggesting an important potential for genomic plasticity. Most of the genomic determinants associated with methylotrophy are nearly identical, with two exceptions that illustrate the metabolic and genomic versatility of Methylobacterium. A 126 kb dichloromethane utilization (dcm) gene cluster is essential for the ability of strain DM4 to use DCM as the sole carbon and energy source for growth and is unique to strain DM4. The methylamine utilization (mau) gene cluster is only found in strain AM1, indicating that strain DM4 employs an alternative system for growth with methylamine. The dcm and mau clusters represent two of the chromosomal genomic islands (AM1: 28; DM4: 17) that were defined. The mau cluster is flanked by mobile elements, but the dcm cluster disrupts a gene annotated as chelatase and for which we propose the name “island integration determinant” (iid). Conclusion/Significance These two genome sequences provide a platform for intra- and interspecies genomic comparisons in the genus Methylobacterium, and for investigations of the adaptive

  2. EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4

    PubMed Central

    Kamata, Ryo; Bumdelger, Batmunkh; Kokubo, Hiroki; Fujii, Masayuki; Yoshimura, Koichi; Ishida, Takafumi; Ishida, Mari; Yoshizumi, Masao

    2016-01-01

    Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta-activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg-KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar-4, which results in the attenuation of AAA development. PMID:27764222

  3. Association of Vascular Physical Examination Findings and Arteriographic Lesions in Large Vessel Vasculitis

    PubMed Central

    GRAYSON, PETER C.; TOMASSON, GUNNAR; CUTHBERTSON, DAVID; CARETTE, SIMON; HOFFMAN, GARY S.; KHALIDI, NADER A.; LANGFORD, CAROL A.; McALEAR, CAROL A.; MONACH, PAUL A.; SEO, PHILIP; WARRINGTON, KENNETH J.; YTTERBERG, STEVEN R.; MERKEL, PETER A.

    2013-01-01

    Objective To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu’s arteritis (TAK) and giant cell arteritis (GCA). Methods In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm. Results We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%–50%) and good-excellent specificity (range 71%–98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%–100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined. Conclusion In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV. PMID:22174204

  4. Migrant and Refugee Patient Perspectives on Travel and Tuberculosis along the Thailand-Myanmar Border: A Qualitative Study

    PubMed Central

    Sein, Tabitha; Nosten, Francois; Foster, Angel M.

    2016-01-01

    Background The Thailand-Myanmar border separates two very different health systems. The healthcare system in eastern Myanmar remains underdeveloped as a result of decades of instability. Comparatively, Tak province, Thailand has more healthcare resources. In this Thai border province government hospitals and non-governmental organizations provide tuberculosis (TB) treatment to migrants and refugees. Objectives Our overall study aimed to explore accessibility of TB treatment, TB surveillance and health system responsiveness specific to migrant and refugee populations in Tak province. In this paper, we focus on the perspectives of migrant and refugee TB patients with respect to travel and treatment in Tak province. Methods In 2014 we conducted focus group discussions with 61 TB, Tuberculosis and Human Immunodeficiency Virus co-infection, and multidrug-resistant TB patients in Tak province. We analyzed the data for content and themes and documented individual travel trajectories. Results and Discussion Migrants are travelling with active TB within the country and between Thailand and Myanmar. Migrants primarily travelled to obtain treatment but two participants reported travelling home to seek family care in Myanmar before returning to Thailand for treatment. Travel, while expensive and arduous, is an adaptive strategy that migrants use to access healthcare. Conclusions Migrant’s need for travel points to larger difficulties associated with healthcare access in the border region. Long distance travel with an infectious disease can be seen as an indicator that local healthcare is not available or affordable. These findings suggest that public health officials from both sides of the border should discuss the factors that contribute to travel with active TB and explore potential solutions to mitigate disease transmission in migrant populations. PMID:27509036

  5. A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations.

    PubMed

    Ritelli, M; Morlino, S; Giacopuzzi, E; Bernardini, L; Torres, B; Santoro, G; Ravasio, V; Chiarelli, N; D'Angelantonio, D; Novelli, A; Grammatico, P; Colombi, M; Castori, M

    2018-01-01

    Deletions encompassing TAK1-binding protein 2 (TAB2) associated with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole-exome sequencing (WES) disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C-terminal zinc finger domain essential for activation of TAK1 (TGFβ-activated kinase 1)-dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers-Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. JPRS Report, East Asia Southeast Asia People’s Republic of Kampuchea: Biographic Information on Officials

    DTIC Science & Technology

    1989-03-30

    Revolutionary Committee; see KIM SANGKUM; candidate in May 81 general elections; secretary of Kompong Som municipal provisional party committee (SPK... UNG SAMI (Mar 87); deputy defense minister & chief of KPRAF General Staff replacing KOY BUNTHA (Dec 86); member of KPRP CC, deputy defense...Phnom Penh Military Command (SPK Mar 86); see VEN KAROM. KIM HAK Chairman of Phnom Penh District People’s Revolutionary Committee (Oct 80); see MAU

  7. Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

    PubMed

    Noujima-Harada, Mai; Takata, Katsuyoshi; Miyata-Takata, Tomoko; Sakurai, Hiroaki; Igarashi, Kazuhiko; Ito, Etsuro; Nagakita, Keina; Taniguchi, Kohei; Ohnishi, Nobuhiko; Omote, Shizuma; Tabata, Tetsuya; Sato, Yasuharu; Yoshino, Tadashi

    2017-05-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-β-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  8. Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis in Mice via a Toll-Like Receptor 4/p21-Activated Kinase 1 Cascade.

    PubMed

    Wu, Yaxin; Wu, Jiao; Chen, Ting; Li, Qing; Peng, Wei; Li, Huan; Tang, Xiaowei; Fu, Xiangsheng

    2018-05-01

    The underlying pathogenic mechanism of Fusobacterium nucleatum in the carcinogenesis of colorectal cancer has been poorly understood. Using C57BL/6-Apc Min/+ mice, we investigated gut microbial structures with F. nucleatum, antibiotics, and Toll-like receptor 4 (TLR4) antagonist TAK-242 treatment. In addition, we measured intestinal tumor formation and the expression of TLR4, p21-activated kinase 1 (PAK1), phosphorylated-PAK1 (p-PAK1), phosphorylated-β-catenin S675 (p-β-catenin S675), and cyclin D1 in mice with different treatments. Fusobacterium nucleatum and antibiotics treatment altered gut microbial structures in mice. In addition, F. nucleatum invaded into the intestinal mucosa in large amounts but were less abundant in the feces of F. nucleatum-fed mice. The average number and size of intestinal tumors in F. nucleatum groups was significantly increased compared to control groups in Apc Min/+ mice (P < 0.05). The expression of TLR4, PAK1, p-PAK1, p-β-catenin S675, and cyclin D1 was significantly increased in F. nucleatum groups compared to the control groups (P < 0.05). Moreover, TAK-242 significantly decreased the average number and size of intestinal tumors compared to F. nucleatum groups (P < 0.05). The expression of p-PAK1, p-β-catenin S675, and cyclin D1 was also significantly decreased in the TAK-242-treated group compared to F. nucleatum groups (P < 0.05). Fusobacterium nucleatum potentiates intestinal tumorigenesis in Apc Min/+ mice via a TLR4/p-PAK1/p-β-catenin S675 cascade. Fusobacterium nucleatum-induced intestinal tumorigenesis can be inhibited by TAK-242, implicating TLR4 as a potential target for the prevention and therapy of F. nucleatum-related colorectal cancer.

  9. A Geothermochronologic Investigation of the Coyote Mountains Metamorphic Core Complex (AZ)

    NASA Astrophysics Data System (ADS)

    Borel, M.; Gottardi, R.; Casale, G.

    2017-12-01

    The Coyote Mountains metamorphic core complex (CM-MCC) makes up the northern end of the Baboquivari Mountain complex, which is composed of Mesozoic rocks, Tertiary granites, pegmatites, and metasediments. The CM-MCC expose the Pan Tak granite, a 58 Ma intrusive muscovite-biotite-garnet peraluminous granite. The Pan Tak and other intrusions within the Baboquivari Mountains have been interpreted as anatectic melts representing the culmination of a Laramide crustal shortening orogenic event started in the Late Cretaceous ( 70 Ma). Evidence of this magmatic episode includes polysynthetic twinning in plagioclase, myrmekitic texture in alkali feldspars, and garnet, mica and feldspar assemblages. The magmatic fabric is overprinted by a Tertiary tectonic fabric, associated with the exhumation of the CM-MCC along the Ajo road décollement and associated shear zone. In the shear zone, the Pan Tak mylonite display N-dipping foliation defined by gneissic layering and aligned muscovite, and N-trending mineral stretching lineation. Various shear sense indicators are all consistent with a top-to the-N shear sense. Preliminary argon geochronology results suggest that the shear zone was exhumed 29 Ma ago, an age similar to the onset of detachment faulting in other nearby MCCs (Catalina, Rincon, Pinaleño). In the Pan Tak mylonite, quartz grains display regime 2 to 3 microstructures and shows extensive recrystallization by subgrain rotation and grain boundary migration. The recrystallized grain size ranges between 20 and 50 µm in all samples. Quartz crystallographic preferred orientation measured using electron backscatter diffraction (EBSD) shows that recrystallization was accommodated by dominant prism and minor rhomb slip, suggesting deformation temperature ranging from 450°C to 550°C. These preliminary results constrain the timing of uplift and exhumation, and thermomechanical evolution of the CM-MCC, and improve our understanding of recycling of the continental crust in

  10. Genetic diversity of the msp-1, msp-2, and glurp genes of Plasmodium falciparum isolates along the Thai-Myanmar borders.

    PubMed

    Congpuong, Kanungnit; Sukaram, Rungniran; Prompan, Yuparat; Dornae, Aibteesam

    2014-08-01

    To study the genetic diversity at the msp-1, msp-2, and glurp genes of Plasmodium falciparum (P. falciparum) isolates from 3 endemic areas in Thailand: Tak, Kanchanaburi and Ranong provinces. A total of 144 P. falciparum isolates collected prior to treatment during January, 2012 to June, 2013 were genotyped. DNA was extracted; allele frequency and diversity of msp-1, msp-2, and glurp genes were investigated by nested polymerase chain reaction. P. falciparum isolates in this study had high rate of multiple genotypes infection (96.5%) with an overall mean multiplicity of infection of 3.21. The distribution of allelic families of msp-1 was significantly different among isolates from Tak, Kanchanaburi, and Ranong but not for the msp-2. K1 and MAD20 were the predominant allelic families at the msp-1 gene, whereas alleles belonging to 3D7 were more frequent at the msp-2 gene. The glurp gene had the least diverse alleles. Population structure of P. falciparum isolates from Tak and Ranong was quite similar as revealed by the presence of similar proportions of MAD20 and K1 alleles at msp-1 loci, 3D7 and FC27 alleles at msp-2 loci as well as comparable mean MOI. Isolates from Kanchanaburi had different structures; the most prevalent alleles were K1 and RO33. The present study shows that P. falciparum isolates from Tak and Ranong provinces had similar allelic pattern of msp-1 and msp-2 and diversity but different from Kanchanaburi isolates. These allelic variant profiles are valuable baseline data for future epidemiological study of malaria transmission and for continued monitoring of polymorphisms associated with antimalarial drug resistance in these areas.

  11. 75 FR 31329 - Airworthiness Directives; The Boeing Company Model 757 Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-03

    ... after receipt. FOR FURTHER INFORMATION CONTACT: Tak Kobayashi, Aerospace Engineer, Propulsion Branch..., Aerospace Engineer, Propulsion Branch, ANM- 140S, FAA, Seattle Aircraft Certification Office, 1601 Lind...

  12. Military Adjustment Units (MAU) Fort Bliss, Texas and Fort Jackson, South Carolina

    DTIC Science & Technology

    1981-12-08

    for those not prepared for training. It allows the trainer, given proper guidance about deficiencies, to help fill in the gaps in knowledge ...Why You’re Needed", discuss with students the importance of "the role they play in the US Army, and how their efforts, abilities and knowledge can be...34Weari ng. of the Uniform", "Mirror, Mirror." DAY II - "Correctional Treatment", "Heritage of the Soldier." DAY III - "Tale of Two Skiers ." 22 APPENDIX

  13. Structural and energetic basis for the molecular recognition of dual synthetic vs. natural inhibitors of EGFR/HER2.

    PubMed

    Bello, Martiniano; Saldaña-Rivero, Lucia; Correa-Basurto, José; García, Benjamín; Sánchez-Espinosa, Victor Armando

    2018-05-01

    Activation of EGFR starts by ligand binding at the extracellular domain which results in homo and heterodimerization, leading to phosphorylation, activation of downstream signaling pathways which upregulate expression of genes, proliferation and angiogenesis. Abnormalities in the expression of EGFR play a critical role in the development of different types of cancer. HER2 is the preferred heterodimerization partner for EGFR; this biological characteristic together with the high percentage of structural homology has been exploited in the design of dual synthetic inhibitors against EGFR/HER2. Herein we combined structural data and molecular dynamics (MD) simulations coupled to an MMGBSA approach to provide insight into the binding mechanism between two dual synthetics (lapatinib and TAK-285) and one dual natural inhibitor (EGCG) which target EGFR/HER2. In addition, we proposed some EGCG derivatives which were filtered through in silico screening. Structural analysis demonstrated that the coupling of synthetic, natural or newly designed compounds impacts the conformational space of EGFR and HER2 differently. Energetic analysis points out that lapatinib and TAK-285 have better affinity for inactive EGFR than the active EGFR state or HER2, whereas some EGCG derivatives seem to form binding affinities similar to those observed for lapatinib or TAK-285. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Assessing the Reliability and Validity of Multi-Attribute Utility Procedures: An Application of the Theory of Generalizability

    DTIC Science & Technology

    1975-07-01

    I WIWIHIHlipi pqpv<Hi^«^Rii.i ii mmw AD-A016 282 ASSESSING THE REALIBILITY AND VALIDITY OF MULTI-ATTRIBUTE UTILITY PROCEDURES: AN...more complicated and use data from actual experiments. Example 1: Analysis of raters making Importance judgments about attributes. In MAU studies...generaluablllty of JUDGE as contrasted to ÜASC. To do this, we win reanaIyze the data for each syste™ separately. This 1. valid since the initial

  15. National Program for Inspection of Non-Federal Dams. Houghton Pond Dam (MA 00444), Charles River Basin, Holliston, Massachusetts. Phase I Inspection Report.

    DTIC Science & Technology

    1979-07-01

    RD-A154 892 NATIONAL PROGRAM FOR INSPECTION OF NON-FEDERAL DAMS i/I HOUGHTON POND DAM (MA..(U) CORPS OF ENGINEERS WALTHAM UNCLASSIFIED N NEN ENGLAND...HOUGHTON POND DAM MA 00444 PHASE I INSPECTION REPORT _ NATIONAL DAM INSPECTION PROGRAM DTIC EECTE CD JUN4 985 -LJE DEPARTMENT OF THE ARMY NEW ENGLAND...16 SUPPLEMENTARY NOTES Co ver program reads: Phase I Inspection Report, National Dam Inspection Program ; however, the official title of the program

  16. Development of Techniques for Multiple Data Stream Analysis and Short- Term Forecasting. Volume I. Multiple Data Stream Analysis

    DTIC Science & Technology

    1975-11-15

    ir in» l.iit.ii-nlrl-i . i ifr .-Viii ^„,„^>,,,,,.,,.,„.,,,.,™„„,^^^^ I ’Ulis Cable shows great similarity between the NYT and TOL as follows; o...from which the data have been derived. The authors challenge the contention by other data collectors that variation in interaction data derived from...LIC Luxemburg LUX Malagasy MAG Malawi MAW Malaysia MAL Maldive MAD Mali MLI Malta MLT Mauritius MAR Mauritania MAU Mexico MEX Monaco MOC

  17. Shigella flexneri type III secreted effector OspF reveals new crosstalks of proinflammatory signaling pathways during bacterial infection.

    PubMed

    Reiterer, Veronika; Grossniklaus, Lars; Tschon, Therese; Kasper, Christoph Alexander; Sorg, Isabel; Arrieumerlou, Cécile

    2011-07-01

    Shigella flexneri type III secreted effector OspF harbors a phosphothreonine lyase activity that irreversibly dephosphorylates MAP kinases (MAPKs) p38 and ERK in infected epithelial cells and thereby, dampens innate immunity. Whereas this activity has been well characterized, the impact of OspF on other host signaling pathways that control inflammation was unknown. Here we report that OspF potentiates the activation of the MAPK JNK and the transcription factor NF-κB during S. flexneri infection. This unexpected effect of OspF was dependent on the phosphothreonine lyase activity of OspF on p38, and resulted from the disruption of a negative feedback loop regulation between p38 and TGF-beta activated kinase 1 (TAK1), mediated via the phosphorylation of TAK1-binding protein 1. Interestingly, potentiated JNK activation was not associated with enhanced c-Jun signaling as OspF also inhibits c-Jun expression at the transcriptional level. Altogether, our data reveal the impact of OspF on the activation of NF-κB, JNK and c-Jun, and demonstrate the existence of a negative feedback loop regulation between p38 and TAK1 during S. flexneri infection. Furthermore, this study validates the use of bacterial effectors as molecular tools to identify the crosstalks that connect important host signaling pathways induced upon bacterial infection. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Zirconia-based dental crown to support a removable partial denture: a three-dimensional finite element analysis using contact elements and micro-CT data.

    PubMed

    Rocha, Eduardo Passos; Anchieta, Rodolfo Bruniera; de Almeida, Erika Oliveira; Freitas, Amilcar Chagas; Martini, Ana Paula; Sotto-Maior, Bruno Sales; Luersen, Marco Antonio; Ko, Ching Chang

    2015-01-01

    Veneer fracture is the most common complication in zirconia-based restorations. The aim of this study was to evaluate the mechanical behavior of a zirconia-based crown in a lower canine tooth supporting removable partial denture (RPD) prosthesis, varying the bond quality of the veneer/coping interface. Microtomography (μCT) data of an extracted left lower canine were used to build the finite element model (M) varying the core material (gold core - MAu; zirconia core - MZi) and the quality of the veneer/core interface (complete bonded - MZi; incomplete bonded - MZi-NL). The incomplete bonding condition was only applied for zirconia coping by using contact elements (Target/Contact) with 0.3 frictional coefficients. Stress fields were obtained using Ansys Workbench 10.0. The loading condition (L = 1 N) was vertically applied at the base of the RPD prosthesis metallic support towards the dental apex. Maximum principal (σmax) and von Mises equivalent (σvM) stresses were obtained. The σmax (MPa) for the bonded condition was similar between gold and zirconia cores (MAu, 0.42; MZi, 0.40). The incomplete bonded condition (MZi-NL) raised σmax in the veneer up to 800% (3.23 MPa) in contrast to the bonded condition. The peak of σvM increased up to 270% in the MZi-NL. The incomplete bond condition increasing the stress in the veneer/zirconia interface.

  19. Inhibitory effects of omega-3 fatty acids on early brain injury after subarachnoid hemorrhage in rats: Possible involvement of G protein-coupled receptor 120/β-arrestin2/TGF-β activated kinase-1 binding protein-1 signaling pathway.

    PubMed

    Yin, Jia; Li, Haiying; Meng, Chengjie; Chen, Dongdong; Chen, Zhouqing; Wang, Yibin; Wang, Zhong; Chen, Gang

    2016-06-01

    Omega-3 fatty acids have been reported to improve neuron functions during aging and in patients affected by mild cognitive impairment, and mediate potent anti-inflammatory via G protein-coupled receptor 120 (GPR120) signal pathway. Neuron dysfunction and inflammatory response also contributed to the progression of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was to examine the effects of omega-3 fatty acids on SAH-induced EBI. Two weeks before SAH, 30% Omega-3 fatty acids was administered by oral gavage at 1g/kg body weight once every 24h. Specific siRNA for GPR120 was exploited. Terminal deoxynucleotidyl transferase dUTP nick end labeling, fluoro-Jade B staining, and neurobehavioral scores and brain water content test showed that omega-3 fatty acids effectively suppressed SAH-induced brain cell apoptosis and neuronal degradation, behavioral impairment, and brain edema. Western blot, immunoprecipitation, and electrophoretic mobility shift assays results showed that omega-3 fatty acids effectively suppressed SAH-induced elevation of inflammatory factors, including cyclooxygenase-2, monocyte chemoattractant protein-1, and inducible nitric oxide synthase. In addition, omega-3 fatty acids could inhibit phosphorylation of transforming growth factor β activated kinase-1 (TAK1), MEK4, c-Jun N-terminal kinase, and IkappaB kinase as well as activation of nuclear factor kappa B through regulating GPR120/β-arrestin2/TAK1 binding protein-1 pathway. Furthermore, siRNA-induced GPR120 silencing blocked the protective effects of omega-3 fatty acids. Here, we show that stimulation of GPR120 with omega-3 fatty acids pretreatment causes anti-apoptosis and anti-inflammatory effects via β-arrestin2/TAK1 binding protein-1/TAK1 pathway in the brains of SAH rats. Fish omega-3 fatty acids as part of a daily diet may reduce EBI in an experimental rat model of SAH. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. MicroRNA-146a suppresses rheumatoid arthritis fibroblast-like synoviocytes proliferation and inflammatory responses by inhibiting the TLR4/NF-kB signaling

    PubMed Central

    Liu, Wei; Wu, Yuan-Hao; Zhang, Lei; Xue, Bin; Wang, Yi; Liu, Bin; Liu, Xiao-Ya; Zuo, Fang; Yang, Xiao-Yan; Chen, Fu-Yu; Duan, Ran; Cai, Yue; Zhang, Bo; Ji, Yang

    2018-01-01

    This study investigated whether microRNA-146a (miR-146a) mediating TLR4/NF-κB pathway affected proliferation and inflammatory responses of rheumatoid arthritis fibroblast-like synoviocytes from 12 RA patients (RA-FLSs). FLSs in the logarithmic growth phase were assigned into the control, miR-146a mimic miR-146a inhibitor, Tak-242 (treated with TLR4/NF-κB pathway inhibitor) and mimic + lipopolysaccharide (LPS) groups. Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry. The expression of miR-146a, TLR4/NF-κB pathway-related proteins and cytokines were determined by RT-qPCR, western blotting and ELISA, and the release of NO by Greiss reaction. RA rat models were constructed and the primary cells were classified into the control, negative control (NC), miR-146a mimic, miR-146a inhibitor, Tak-242, mimic + LPS, and TLR4 groups. Immunohistochemistry was used to detect the expression of proliferating cell nuclear antigen (PCNA) and intercellular adhesion molecular-1 (ICAM-1). The results showed that miR-146a levels were lower in RA-FLSs than control fibroblasts. miR-146a mimic and Tak-242 decreased RA-FLS proliferation and increased RA-FLS apoptosis, while miR-146a inhibitor had an opposite trend. miR-146a mimic and Tak-242 also decreased expression of TLR4, NF-κB, IL-1β, IL-6, IL-8, IL-17, COX-2, MMP-3, Seprase, and iNOS, as well as reduced NO level in RA-FLSs while miR-146a inhibitor and TLR4 increased them. TLR4 and NF-κB levels and the positive rates of PCNA and ICAM-1 expressions were lower in RA-FLSs from RA rats given miR-146a mimic from control or miR-146a inhibitor-treated rats. These results suggest that miR-146a inhibits the proliferation and inflammatory response of RA-FLSs by down-regulating TLR4/NF-κB pathway.

  1. SASH1 is a scaffold molecule in endothelial TLR4 signaling.

    PubMed

    Dauphinee, Shauna M; Clayton, Ashley; Hussainkhel, Angela; Yang, Cindy; Park, Yoo-Jin; Fuller, Megan E; Blonder, Josip; Veenstra, Timothy D; Karsan, Aly

    2013-07-15

    Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.

  2. Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone.

    PubMed

    Ichikawa, T; Kitazaki, T; Matsushita, Y; Yamada, M; Hayashi, R; Yamaguchi, M; Kiyota, Y; Okonogi, K; Itoh, K

    2001-09-01

    1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.

  3. TAK228 With Carbo and Taxol in Advanced Malignancies

    ClinicalTrials.gov

    2018-03-12

    Malignant Neoplasm of Breast; Malignant Neoplasms of Bone and Articular Cartilage; Malignant Neoplasms of Digestive Organs; Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Respiratory and Intrathoracic Organs; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Malignant Neoplasms Stated as Primary Lymphoid Haematopoietic

  4. Project CHECO Southeast Asia Report. Ranch Hand: Herbicide Operations in SEA

    DTIC Science & Technology

    1971-07-13

    Fortunately, the value of collecting and documenting our SEA expe-Uriences was recognized at an early date. In 1962 , Hq USAF directed CINCPACAF to...January 1962 to carry out the specific operations plan published the previous month, code named Sillm bI I "Ranch Hand." The first Ranch Hand aircraft...flew missions from 12 January 1962 I through 20 March 1962 . These missions were conducted along Route 15 north- 7/ west of Saigon and in the Ca Mau

  5. U. S. Naval Forces, Vietnam Monthly Historical Summary for October 1971

    DTIC Science & Technology

    1971-12-01

    COUNTY (LST-1166) as the Third Coastal Zone LST. t NNIMCB-5 Detail Bronco completed assigned tasks at ACTOVRAD Site Nui Ta Kou and returned to Bien...The last two weeks in Ca Mau were spent building access roads with very wet conditions prevailing. Detail Bronco at Nui Ta Kou, ACTOVRAD Site Nine...completed all work on 20 October and redeployed all material and men to Bien Hoa on the same doty. During October, Detail Bronco had finished road and

  6. Spray and Combustion of Gelled Hypergolic Propellants

    DTIC Science & Technology

    2014-10-20

    Anderson Postdoc tlnu 2/09 Ast:I·ium Mau DeRidder Anderson Postdoc tlnu 5110 Spacex Chenzhou Lian Merkle Postdoc tlnu 8/10 IBM Watson Labs Changjin Yoon...Heister PhD, 1211 1 GE Global Research Center - 5 - - 6 - Erik Dambach Heister/Pourpoint PhD, 5/11 SpaceX Paulo Santos Campanella PhD, 8/11...Yair Solomon Anderson MS, 8/12 Technion Jordan Forness Heister/Pourpoint MS, 5/13 SpaceX Jennifer Mallory Sojka PhD, 5/12 Western New England

  7. Environment Behavior Models for Real-Time Reactive System Testing Automation

    DTIC Science & Technology

    2006-09-01

    by Muharrem Ugur Aksu September 2006 Co-Advisors: Mikhail Auguston Man-Tak Shing Approved for public release; distribution is......Muharrem Ugur Aksu Naval Postgraduate School Computer Science Department Date: 20 July 2006 File Name: Shuttle.cpp

  8. Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells.

    PubMed

    Benakanakere, Indira; Johnson, Tyler; Sleightholm, Richard; Villeda, Virgilio; Arya, Monika; Bobba, Ravi; Freter, Carl; Huang, Chunfa

    2014-01-01

    Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL). MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations. We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients. Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment.

  9. LESSONS-LEARNED AND SUCCESS STORIES FROM EPA'S REAL-TIME ENVIRONMENTAL MONITORING, DATA DELIVERY, AND PUBLIC OUTREACH PROGRAM

    EPA Science Inventory

    TTSD has completed a series of technology transfer and risk communication handbooks, case studies, and summary reports for community-based environmental monitoring projects under EPA's Real-Time Environmental Monitoring, Data Delivery, and Public Outreach Program. The Program tak...

  10. The Anxious and Ambivalent Partisan: The Effect of Incidental Anxiety on Partisan Motivated Recall and Ambivalence.

    PubMed

    Groenendyk, Eric

    2016-01-01

    Affective Intelligence Theory (AIT) asserts that anxiety reduces the effect of party identification on candidate preferences (Marcus, Neuman, and MacKuen 2000), but recent studies have raised doubts about this causal claim. Rather than functioning as a moderator of party identification, perhaps anxiety has a direct effect on preferences, or perhaps the relationship is reversed and preferences drive emotions (Ladd and Lenz 2008). Alternatively, Marcus et al.'s measure of anxiety may simply be capturing partisan ambivalence, so the posited relationship is spurious (Lavine, Johnston, and Steenbergen 2012). This paper addresses each of these questions by examining the effect of experimentally induced emotions on the types of considerations that came to mind when a national sample of adult Americans was asked what they liked and disliked about Barack Obama. By directly manipulating anxiety, this experiment avoids the causal ambiguity plaguing this debate and ascertains the true nature of the relationship between anxiety and ambivalence. Consistent with AIT, anxiety led respondents to recall more contemporary considerations, whereas enthusiasm brought to mind more long-standing considerations. Because the political context at the time of the study (fall 2013) was a very tumultuous time for the Obama administration, the increased accessibility of contemporary considerations led Democratic participants to experience more ambivalence in the anxiety condition. This effect was concentrated among those Democrats who were exposed to the most newspaper coverage.

  11. The Anxious and Ambivalent Partisan

    PubMed Central

    Groenendyk, Eric

    2016-01-01

    Affective Intelligence Theory (AIT) asserts that anxiety reduces the effect of party identification on candidate preferences (Marcus, Neuman, and MacKuen 2000), but recent studies have raised doubts about this causal claim. Rather than functioning as a moderator of party identification, perhaps anxiety has a direct effect on preferences, or perhaps the relationship is reversed and preferences drive emotions (Ladd and Lenz 2008). Alternatively, Marcus et al.’s measure of anxiety may simply be capturing partisan ambivalence, so the posited relationship is spurious (Lavine, Johnston, and Steenbergen 2012). This paper addresses each of these questions by examining the effect of experimentally induced emotions on the types of considerations that came to mind when a national sample of adult Americans was asked what they liked and disliked about Barack Obama. By directly manipulating anxiety, this experiment avoids the causal ambiguity plaguing this debate and ascertains the true nature of the relationship between anxiety and ambivalence. Consistent with AIT, anxiety led respondents to recall more contemporary considerations, whereas enthusiasm brought to mind more long-standing considerations. Because the political context at the time of the study (fall 2013) was a very tumultuous time for the Obama administration, the increased accessibility of contemporary considerations led Democratic participants to experience more ambivalence in the anxiety condition. This effect was concentrated among those Democrats who were exposed to the most newspaper coverage. PMID:27274573

  12. 76 FR 19710 - Airworthiness Directives; The Boeing Company Model 757 Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-08

    ...: No person may operate an aircraft for which a manufacturer's maintenance manual or instructions for... by latent failures, alterations, repairs, or maintenance actions, which, in combination with... CONTACT: Tak Kobayashi, Aerospace Engineer, Propulsion Branch, ANM-140S, FAA, Seattle Aircraft...

  13. Impact of functional determinants on 5.5-year mortality in Amazon riparian elderly.

    PubMed

    Antonini, Tiago C; de Paz, Jose A; Ribeiro, Euler E; Brito, Elorídes; Mota, Kennya S; Silva, Terezinha L; Cristi-Monteiro, Carlos; Jung, Pedro V C; da Cruz, Ivana B M

    2016-08-01

    Objective To ascertain whether modifiable physical performance-based measurements predicted 5.5-year mortality in a riparian elderly cohort in the Amazon rainforest region. Methods A longitudinal study evaluating the impact of functional determinants on 5.5-year mortality in a riparian elderly cohort from Maués City in the state of Amazonas, Brazil, was performed. The study was a follow-up of a previous observational investigation that evaluated various fitness tests in 630 Amazonian riparian elderly (291 males and 339 females) aged 72.3 ± 8.0 (60-99) years old. The cohort was selected for its adverse environmental conditions, which increased the risk of falls yet required maintenance of good physical condition for carrying out relatively rigorous daily activities, and restricted access to specialized health services. Official death records were obtained from the Maués Municipal Health Department. Results A total of 80 study participants (12.7%) died over the 5.5-year study period. Kaplan-Meier regression analysis showed significant association between Timed Up and Go (TUG) test scores ≥ 14 seconds and mortality risk, independent of sex, age, and other health variables. Conclusions The study results suggest that the TUG test can be used as an indicator for initiating therapeutic and preventive actions, including conducting exercises or physical activities adapted to the health and functional conditions of the elderly, by identifying elderly people with a higher relative risk of mortality.

  14. Systems modeling and analysis for Saudi Arabian electric power requirements

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Al-Mohawes, N.A.

    This thesis addresses the long-range generation planning problem in Saudi Arabia up to the year 2000. The first part presents various models for electric energy consumption in the residential and industrial sectors. These models can be used by the decision makers for the purposes of policy analysis, evaluation, and forecasting. Forecasts of energy in each sector are obtained from two different models for each sector. These models are based on two forecasting techniques: (1) Hybrid econometric/time series model. The idea of adaptive smoothing was utilized to produce forecasts under several scenarios. (2) Box-Jenkins time series technique. Box-Jenkins models and forecastsmore » are developed for the monthly number of electric consumers and the monthly energy consumption per consumer. The results obtained indicate that high energy consumption is expected during the coming two decades which necessitate serious energy assessment and optimization. Optimization of a mix of energy sources was considered using the group multiattribute utility (MAU) function. The results of MAU for three classes of decision makers (managerial, technical, and consumers) are developed through personal interactions. The computer package WASP was also used to develop a tentative optimum plan. According to this plan, four heavy-water nuclear power plants (800 MW) and four light-water nuclear power plants (1200 MW) have to be introduced by the year 2000 in addition to sixteen oil-fired power plants (400 MW) and nine gas turbines (100 MW).« less

  15. Process for introducing electrical conductivity into high-temperature polymeric materials

    DOEpatents

    Liepins, R.; Jorgensen, B.S.; Liepins, L.Z.

    1993-12-21

    High-temperature electrically conducting polymers are described. The in situ reactions: AgNO[sub 3] + RCHO [yields] Ag + RCOOH and R[sub 3]M [yields] M + 3R, where M=Au or Pt have been found to introduce either substantial bulk or surface conductivity in high-temperature polymers. The reactions involving the R[sub 3]M were caused to proceed thermally suggesting the possibility of using laser means for initiating such reactions in selected areas or volumes of the polymeric materials. The polymers successfully investigated to date are polyphenylquinoxaline, polytolylquinoxaline, polyquinoline, polythiazole, and pyrone.

  16. Interferometric Determinations of Asteroid Diameters

    DTIC Science & Technology

    1979-01-01

    shapes. In pi ifleiple. leICccol)Cs of 4-. meter diaritter nott limited by seeing could obtain amigimlar tesi )IutiOn of 0.02 aicsec. tran~slatinig into...ran 12S. 11. WORI) EN pi’.~ ~ct htsfonIK1itP&. isae n a t buarcscc in V~c~tciL (A) ( Oritini. a rtzmilvett -cupcfgiat slt. (It) y oii- a puinl-3oIrcc...designed by ILynds flynds ai ai IN.6 llrcckintigel -TELE59M GUIDE EAOJCVOCe DETECTO *-gZ 3 iranr iri\\.nltd iifeOWMAtOR. AM" __ -=---- ----- -- ~ MAU

  17. Process for introducing electrical conductivity into high-temperature polymeric materials

    DOEpatents

    Liepins, Raimond; Jorgensen, Betty S.; Liepins, Leila Z.

    1993-01-01

    High-temperature electrically conducting polymers. The in situ reactions: AgNO.sub.3 +RCHO.fwdarw.Ag.degree.+RCOOH and R.sub.3 M.fwdarw.M.degree.+3R, where M=Au or Pt have been found to introduce either substantial bulk or surface conductivity in high-temperature polymers. The reactions involving the R.sub.3 M were caused to proceed thermally suggesting the possibility of using laser means for initiating such reactions in selected areas or volumes of the polymeric materials. The polymers successfully investigated to date are polyphenylquinoxaline, polytolylquinoxaline, polyquinoline, polythiazole, and pyrrone.

  18. CUHK Papers in Linguistics, Number 4.

    ERIC Educational Resources Information Center

    Tang, Gladys, Ed.

    1993-01-01

    Papers in this issue include the following: "Code-Mixing in Hongkong Cantonese-English Bilinguals: Constraints and Processes" (Brian Chan Hok-shing); "Information on Quantifiers and Argument Structure in English Learner's Dictionaries" (Thomas Hun-tak Lee); "Systematic Variability: In Search of a Linguistic…

  19. Vasculitis Pregnancy Registry

    ClinicalTrials.gov

    2018-04-30

    Vasculitis; Behcet's Disease; CNS Vasculitis; Cryoglobulinemic Vasculitis; Eosinophilic Granulomatosis With Polyangiitis (EGPA); Churg-Strauss Syndrome (CSS); Granulomatosis With Polyangiitis (GPA); Wegener's Granulomatosis; IgA Vasculitis; Henoch-Schoenlein Purpura (HSP); Microscopic Polyangiitis (MPA); Polyarteritis Nodosa (PAN); Takayasu Arteritis (TAK); Urticarial Vasculitis; Systemic Vasculitis

  20. Recent advances in Takayasu’s arteritis

    PubMed Central

    Alibaz-Öner, Fatma; Aydın, Sibel Zehra; Direskeneli, Haner

    2015-01-01

    Takayasu’s arteritis (TAK) is a rare, chronic large-vessel vasculitis (LVV) that predominantly affects the aorta, its major branches, and the pulmonary arteries. Recent advances in the diagnosis, clinical course, disease assessment with biomarkers/imaging and new clinical tools, patient-reported outcomes, and new treatment options of TAK are discussed in this review. Conventional angiography, the gold standard method for initial diagnosis, appears to have been replaced with new imaging modalities such as magnetic resonance angiography (MRA) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in recent years. MRA and FDG-PET are also promising for the assessment of disease activity. New tools for disease assessment such as Indian Takayasu’s Arteritis Score 2010 (ITAS2010) and color Doppler ultrasound (CDUS) aim to better characterize and quantify disease activity; however, different imaging modalities in routine follow-up are not incorporated sufficiently in these approaches. Prognosis is possibly getting better, with lower mortality in recent years; however, it is difficult to assess the widely different vascular intervention rates among the clinical series. Leflunomide, tumor necrosis factor (TNF)-α antagonists, and tocilizumab are new options for patients resistant to conventional therapies. There is a clear need to develop a validated set of outcome measures for use in clinical trials of TAK. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group has taken on this task, finished a Delphi exercise with experts, and aims to develop a core set of outcomes for LVV in accordance with OMERACT Filter 2.0. PMID:27708916

  1. Regulatory role of tumor necrosis factor receptor-associated factor 6 in breast cancer by activating the protein kinase B/glycogen synthase kinase 3β signaling pathway.

    PubMed

    Shen, Hongyu; Li, Liangpeng; Yang, Sujin; Wang, Dandan; Zhou, Siying; Chen, Xiu; Tang, Jinhai

    2017-08-01

    Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll‑like/interleukin‑1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription‑quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki‑67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor β‑activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF‑7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3β phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6‑TAK1 axis and its corresponding downstream AKT/GSK3β signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer.

  2. Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells

    PubMed Central

    2014-01-01

    Background Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL). Methods MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations. Results We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients. Conclusion Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment. PMID:25401046

  3. In Oregon, the EPA calculates nature's worth now and in the future

    EPA Science Inventory

    Ecosystem services are the many life-sustaining benefits we receive from nature — clean air and water, food and fiber production, greenhouse gas regulation, maintenance of biodiversity, etc. These ecosystem services are vital to our well-being, yet they are limited and often tak...

  4. Nextgen Navy eLearning Tracking

    DTIC Science & Technology

    2014-12-01

    ELEARNING TRACKING by William E. Miller December 2014 Thesis Advisor: Man-Tak Shing Co-Advisor: Arijit Das THIS PAGE INTENTIONALLY LEFT......Navy’s eLearning (NeL) computer-based learning system relies on a Learning Management System (LMS) for content delivery and tracking learning

  5. The Role of Flushing Dental Waterlines for the Removal of Microbial Contaminants - MCEARD

    EPA Science Inventory

    Objectives. This study was designed to determine the role of flushing dental water lines for the removal of heterotrophic plate count bacteria, Legionella spp., and free-living protozoa. Methods. Forty dental offices were surveyed in the study. An initial sample and a sample tak...

  6. Chemical induced behavioral responses in anopheles minimus and Anopheles harrisoni in Thailand

    USDA-ARS?s Scientific Manuscript database

    Behavioral responses of female mosquitoes representing two species in the Minimus Complex exposed to an operational field dose of bifenthrin or DEET (N,N-diethyl-m-toluamide) were described using an excito-repellency test system. Two test populations of An. minimus, one from the field (Tak Provinc...

  7. Culex (Thaiomyia) Dispectus, A New Subgenus and Species from Thailand (Diptera: Culicidae)

    DTIC Science & Technology

    1966-06-01

    Province; and Doi Sutep, Chiang Mai Province. Biology. Larvae have been collected on four occasions from open bamboo internodes or bamboo stumps in a...primary rain forest en- vironment. The collection from Chiang Mai was from an artificial container. Collections from Tak Province were made at an

  8. Estimating QALY gains in applied studies: a review of cost-utility analyses published in 2010.

    PubMed

    Wisløff, Torbjørn; Hagen, Gunhild; Hamidi, Vida; Movik, Espen; Klemp, Marianne; Olsen, Jan Abel

    2014-04-01

    Reimbursement agencies in several countries now require health outcomes to be measured in terms of quality-adjusted life-years (QALYs), leading to an immense increase in publications reporting QALY gains. However, there is a growing concern that the various 'multi-attribute utility' (MAU) instruments designed to measure the Q in the QALY yield disparate values, implying that results from different instruments are incommensurable. By reviewing cost-utility analyses published in 2010, we aim to contribute to improved knowledge on how QALYs are currently calculated in applied analyses; how transparently QALY measurement is presented; and how large the expected incremental QALY gains are. We searched Embase, MEDLINE and NHS EED for all cost-utility analyses published in 2010. All analyses that had estimated QALYs gained from health interventions were included. Of the 370 studies included in this review, 48% were pharmacoeconomic evaluations. Active comparators were used in 71% of studies. The median incremental QALY gain was 0.06, which translates to 3 weeks in best imaginable health. The EQ-5D-3L is the dominant instrument used. However, reporting of how QALY gains are estimated is generally inadequate. In 55% of the studies there was no reference to which MAU instrument or direct valuation method QALY data came from. The methods used for estimating expected QALY gains are not transparently reported in published papers. Given the wide variation in utility scores that different methodologies may assign to an identical health state, it is important for journal editors to require a more transparent way of reporting the estimation of incremental QALY gains.

  9. "Fibromyalgia and quality of life: mapping the revised fibromyalgia impact questionnaire to the preference-based instruments".

    PubMed

    Collado-Mateo, Daniel; Chen, Gang; Garcia-Gordillo, Miguel A; Iezzi, Angelo; Adsuar, José C; Olivares, Pedro R; Gusi, Narcis

    2017-05-30

    The revised version of the Fibromyalgia Impact Questionnaire (FIQR) is one of the most widely used specific questionnaires in FM studies. However, this questionnaire does not allow calculation of QALYs as it is not a preference-based measure. The aim of this study was to develop mapping algorithm which enable FIQR scores to be transformed into utility scores that can be used in the cost utility analyses. A cross-sectional survey was conducted. One hundred and 92 Spanish women with Fibromyalgia were asked to complete four general quality of life questionnaires, i.e. EQ-5D-5 L, 15D, AQoL-8D and SF-12, and one specific disease instrument, the FIQR. A direct mapping approach was adopted to derive mapping algorithms between the FIQR and each of the four multi-attribute utility (MAU) instruments. Health state utility was treated as the dependent variable in the regression analysis, whilst the FIQR score and age were predictors. The mean utility scores ranged from 0.47 (AQoL-8D) to 0.69 (15D). All correlations between the FIQR total score and MAU instruments utility scores were highly significant (p < 0.0001) with magnitudes larger than 0.5. Although very slight differences in the mean absolute error were found between ordinary least squares (OLS) estimator and generalized linear model (GLM), models based on GLM were better for EQ-5D-5 L, AQoL-8D and 15D. Mapping algorithms developed in this study enable the estimation of utility values from scores in a fibromyalgia specific questionnaire.

  10. A Causal-Comparative Analysis of the Effects of a Student Support Team (SST) Intervention Model at a Secondary School

    ERIC Educational Resources Information Center

    Johnson, Mid D.

    2010-01-01

    The purpose of this research was to identify and examine the effectiveness of a "Student Support Team" (SST) intervention model designed to increase the performance of struggling secondary students and to help them achieve prescribed state standards on the mathematics "Texas Assessment of Knowledge and Skills (TAKS)"…

  11. 76 FR 12962 - Ocean Transportation Intermediary License Applicants

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-09

    ...), 17910 Ajax Circle, City of Industry, CA 91748. Officers: Jacky C. Chen, President (Qualifying Individual... Change. J.A. Logistics, Inc. (NVO & OFF), 3905 West Albany Street, McHenry, IL 60050. Officers: Joseph M... Harbour Road, Wanchai, Hong Kong. Officers: Tsang M. Tak, Director/CEO (Qualifying Individual), Joseph P...

  12. β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1*

    PubMed Central

    Mancini, Arturo D.; Bertrand, Gyslaine; Vivot, Kevin; Carpentier, Éric; Tremblay, Caroline; Ghislain, Julien; Bouvier, Michel; Poitout, Vincent

    2015-01-01

    FFAR1/GPR40 is a seven-transmembrane domain receptor (7TMR) expressed in pancreatic β cells and activated by FFAs. Pharmacological activation of GPR40 is a strategy under consideration to increase insulin secretion in type 2 diabetes. GPR40 is known to signal predominantly via the heterotrimeric G proteins Gq/11. However, 7TMRs can also activate functionally distinct G protein-independent signaling via β-arrestins. Further, G protein- and β-arrestin-based signaling can be differentially modulated by different ligands, thus eliciting ligand-specific responses (“biased agonism”). Whether GPR40 engages β-arrestin-dependent mechanisms and is subject to biased agonism is unknown. Using bioluminescence resonance energy transfer-based biosensors for real-time monitoring of cell signaling in living cells, we detected a ligand-induced GPR40-β-arrestin interaction, with the synthetic GPR40 agonist TAK-875 being more effective than palmitate or oleate in recruiting β-arrestins 1 and 2. Conversely, TAK-875 acted as a partial agonist of Gq/11-dependent GPR40 signaling relative to both FFAs. Pharmacological blockade of Gq activity decreased FFA-induced insulin secretion. In contrast, knockdown or genetic ablation of β-arrestin 2 in an insulin-secreting cell line and mouse pancreatic islets, respectively, uniquely attenuated the insulinotropic activity of TAK-875, thus providing functional validation of the biosensor data. Collectively, these data reveal that in addition to coupling to Gq/11, GPR40 is functionally linked to a β-arrestin 2-mediated insulinotropic signaling axis. These observations expose previously unrecognized complexity for GPR40 signal transduction and may guide the development of biased agonists showing improved clinical profile in type 2 diabetes. PMID:26157145

  13. Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway.

    PubMed

    Yamanaka, Yasuhiro; Karuppaiah, Kannan; Abu-Amer, Yousef

    2011-07-08

    The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor β-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.

  14. Peroxiredoxin 5 modulates immune response in Drosophila

    PubMed Central

    Radyuk, Svetlana N.; Michalak, Katarzyna; Klichko, Vladimir I.; Benes, Judith; Orr, William C.

    2010-01-01

    Background Peroxiredoxins are redox-sensing enzymes with multiple cellular functions. Previously, we reported on the potent antioxidant function of Drosophila peroxiredoxin 5 (dPrx5). Studies with mammalian and human cells suggest that peroxiredoxins can modulate immune-related signaling. Methods Survivorship studies and bacteriological analysis were used to determine resistance of flies to fungal and bacterial infections. RT-PCR and immunoblot analyses determined expression of dPrx5 and immunity factors in response to bacterial challenge. Double mutants for dprx5 gene and genes comprising the Imd/Relish and dTak1/Basket branches of the immune signaling pathways were used in epistatic analysis. Results The dprx5 mutant flies were more resistant to bacterial infection than controls, while flies overexpressing dPrx5 were more susceptible. The enhanced resistance to bacteria was accompanied by rapid induction of the Imd-dependent antimicrobial peptides, phosphorylation of the JNK kinase Basket and altered transcriptional profiling of the transient response genes, puckered, ets21C and relish, while the opposite effects were observed in flies over-expressing dPrx5. Epistatic analysis of double mutants, using attacin D and Puckered as read outs of activation of the Imd and JNK pathways, implicated dPrx5 function in the control of the dTak1-JNK arm of immune signaling. Conclusions Differential effects on fly survivorship suggested a trade-off between the antioxidant and immune functions of dPrx5. Molecular and epistatic analyses identified dPrx5 as a negative regulator in the dTak1-JNK arm of immune signaling. General significance Our findings suggest that peroxiredoxins play an important modulatory role in the Drosophila immune response. PMID:20600624

  15. Process for introducing electrical conductivity into high-temperature polymeric materials

    DOEpatents

    Liepins, Raimond; Jorgensen, Betty S.; Liepins, Leila Z.

    1989-01-01

    High-temperature electrically conducting polymers. The in situ reactions: AgNO.sub.3 +RCHO.fwdarw.AG.sup.0 +RCOOH and R.sub.3 M.fwdarw.M.sup.0 3R, where M=Au or Pt have been found to introduce either substantial bulk or surface conductivity in high-temperature polymers. The reactions involving the R.sub.3 M were caused to proceed thermally suggesting the possibility of using laser means for initiating such reactions in selected areas or volumes of the polymeric materials. The polymers successfully investigated to date are polyphenylquinoxaline, polytolylquinoxaline, polyquinoline, polythiazole, and pyrrone.

  16. A seismic study of the Mekong subaqueous delta: Proximal versus distal sediment accumulation

    NASA Astrophysics Data System (ADS)

    Liu, J. Paul; DeMaster, David J.; Nittrouer, Charles A.; Eidam, Emily F.; Nguyen, Thanh T.

    2017-09-01

    The Mekong River Delta is one of the largest in Asia. To understand its sediment distribution, thickness, mass budget, stratigraphic sequences and sediment-transport process, extensive geophysical and geochemical surveys were conducted on the inner portions of the adjacent continental shelf. Analyses of > 80 high-resolution Chirp-sonar profiles show the Mekong River has formed a classic sigmoidal cross-shelf clinoform in the proximal areas, up to 15 m thick, with topset, foreset and bottomset facies, but constrained to water depths of < 20 m. Beyond this depth, the East Sea/western South China Sea shelf is dominated by relict silt, sand and gravel with patches of early to middle Holocene mud deposits. Parallel to shore, the Mekong-derived sediment has extended > 250 > 300 km southwestward to the tip of the Ca Mau Peninsula, forming a distal mud depocenter up to 22 m thick, and extending into the Gulf of Thailand. A large erosional trough or channel (up to 8 m deeper than the surrounding seafloor and parallel to the shore) was found on the top of the clinoform, east of the Ca Mau Peninsula. Based on the thicknesses and distribution revealed by Chirp sonar profiles, the total estimated volume of the Mekong River subaqueous clinoform on the shelf is 120 km3, which is equivalent to 120-140 × 109 t of sediment using an average sediment dry-bulk density of 1.0-1.2 g/cm3. Assuming the subaqueous deltaic deposit has formed within 1000 yr, the calculated millennial-timescale average sediment discharge to the shelf could be 120-140 × 106 t per year. Spatially, the proximal subaqueous delta has accumulated 45 × 109 t ( 33%) of sediment; the distal part around the Ca Mau Peninsula has received 55 × 109 t ( 42%) of sediment; and the remaining 35 × 109 t ( 25%) has accumulated within the central transition area, although the coastline and shoreface in this area are presently eroding. The spatially averaged 1000-yr-scale accumulate rate is up to 2 cm/yr. Compared to other

  17. The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways.

    PubMed

    Cohen, Philip; Strickson, Sam

    2017-07-01

    The adaptor protein MyD88 is required for signal transmission by toll-like receptors and receptors of the interleukin-1 family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex. The M1-Ub chains, which are formed by the linear ubiquitin chain assembly complex (LUBAC), bind to the NEMO (NF-κB essential modulator) component of the IKK complex and are required for TAK1 to activate IKKs, but not MAP kinases. An essential E3 ligase-independent role of TRAF6 is to recruit LUBAC into the MyD88 signalling complex, where it recognises preformed K63-Ub chains attached to protein components of these complexes, such as IRAK1 (IL-1 receptor-associated kinase), producing ubiquitin chains containing both types of linkage, termed K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways, permits the co-recruitment of proteins that interact with either K63-Ub or M1-Ub chains. Two likely roles for K63/M1-Ub hybrids are to facilitate the TAK1-dependent activation of the IKK complex and to prevent the hyperactivation of these kinases by recruiting A20 and A20-binding inhibitor of NF-κB1 (ABIN1). These proteins restrict activation of the TAK1 and IKK complexes, probably by competing with them for binding to K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids may also regulate the rate at which the ubiquitin linkages in these chains are hydrolysed. The IKK-catalysed phosphorylation of some of its substrates permits their recognition by the E3 ligase SCF βTRCP , leading to their Lys48-linked ubiquitylation and proteasomal degradation. Innate immune signalling is therefore controlled

  18. The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways

    PubMed Central

    Cohen, Philip; Strickson, Sam

    2017-01-01

    The adaptor protein MyD88 is required for signal transmission by toll-like receptors and receptors of the interleukin-1 family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex. The M1-Ub chains, which are formed by the linear ubiquitin chain assembly complex (LUBAC), bind to the NEMO (NF-κB essential modulator) component of the IKK complex and are required for TAK1 to activate IKKs, but not MAP kinases. An essential E3 ligase-independent role of TRAF6 is to recruit LUBAC into the MyD88 signalling complex, where it recognises preformed K63-Ub chains attached to protein components of these complexes, such as IRAK1 (IL-1 receptor-associated kinase), producing ubiquitin chains containing both types of linkage, termed K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways, permits the co-recruitment of proteins that interact with either K63-Ub or M1-Ub chains. Two likely roles for K63/M1-Ub hybrids are to facilitate the TAK1-dependent activation of the IKK complex and to prevent the hyperactivation of these kinases by recruiting A20 and A20-binding inhibitor of NF-κB1 (ABIN1). These proteins restrict activation of the TAK1 and IKK complexes, probably by competing with them for binding to K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids may also regulate the rate at which the ubiquitin linkages in these chains are hydrolysed. The IKK-catalysed phosphorylation of some of its substrates permits their recognition by the E3 ligase SCFβTRCP, leading to their Lys48-linked ubiquitylation and proteasomal degradation. Innate immune signalling is therefore controlled by

  19. A Comparison of Career Technical Education--16 Career Pathway High School Participants with Non-Participants on Academic Achievement, School Engagement, and Development of Technical Skills

    ERIC Educational Resources Information Center

    Orozco, Edith Aimee

    2010-01-01

    The objective of this research was to compare Career Technical Education--16 Career Pathway high school participants with non-participants on academic achievement, development of technical skills and school engagement. Academic achievement was measured by Exit Level Math and English Language Arts Texas Assessment of Knowledge and Skills (TAKS)…

  20. The Effects of Elementary School Principals' Leadership Styles and the Preferred Managerial Styles of Teachers on Student Achievement

    ERIC Educational Resources Information Center

    Pichon, Christopher, Sr.

    2010-01-01

    The objective of this study is to identify principal leadership styles and teacher preferred principal leadership styles, as well as to examine the independent and combined effects of these variables on the TAKS Mathematics achievement scores of elementary students. School leadership affects every aspect of an institution. Studies reveal that the…

  1. The Effectiveness of Business Leadership Practices among Principals on Student Achievement on Public School Campuses in Texas

    ERIC Educational Resources Information Center

    Cooper, Kary M.

    2009-01-01

    The purpose of this descriptive study was to determine if business leadership practices by Texas public school principals have an impact on principals' campus student achievement in mathematics and reading, as measured by TAKS scores. The survey instrument was the Leadership Assessment Instrument (LAI), developed by Warren Bennis in 1989. The…

  2. Differences in Academic Achievement among Texas High School Students as a Function of Music Enrollment

    ERIC Educational Resources Information Center

    Horton, Robert Wayne

    2012-01-01

    Purpose: The purpose of this study was to examine the score differences on the Texas Academic Knowledge and Skills (TAKS) Reading and Mathematics measures among students in Grades 10 and 11 as a function of music enrollment. Specifically, gender, ethnicity, socioeconomic status, and enrollment in choir, band, or orchestra or no music enrollment…

  3. The Effect of a Constructivist-Based Approach on Fifth Grade Reading Achievement

    ERIC Educational Resources Information Center

    Harkness, Lori M.

    2016-01-01

    The problem investigated in this quantitative study was that schools in a small, rural East Texas town were falling below acceptable ratings in reading on the Texas Assessment of Knowledge and Skills (TAKS) and the State of Texas Assessment of Academic Readiness (STAAR). Researchers have found that constructive-based learning environments (CBLEs)…

  4. Utilizing the Six Realms of Meaning in Improving Campus Standardized Test Scores through Team Teaching and Strategic Planning

    ERIC Educational Resources Information Center

    Stevenson, Rosnisha D.; Kritsonis, William Allan

    2009-01-01

    This article will seek to utilize Dr. William Allan Kritsonis' book "Ways of Knowing Through the Realms of Meaning" (2007) as a framework to improve a campus's standardized test scores, more specifically, their TAKS (Texas Assessment of Knowledge and Skills) scores. Many campuses have an improvement plan, also known as a Campus…

  5. Genetics Home Reference: ocular albinism

    MedlinePlus

    ... Available from http://www.ncbi.nlm.nih.gov/books/NBK1343/ Citation on PubMed Oetting WS. New insights into ocular albinism type 1 (OA1): Mutations and polymorphisms of the OA1 gene. Hum Mutat. 2002 Feb;19(2):85-92. Review. Citation on PubMed Tak WJ, Kim MN, Hong ...

  6. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide.

    PubMed

    Ali, Irshad; Nanchal, Rahul; Husnain, Fouad; Audi, Said; Konduri, G Ganesh; Densmore, John C; Medhora, Meetha; Jacobs, Elizabeth R

    2013-09-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo.

  7. Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide

    PubMed Central

    Nanchal, Rahul; Audi, Said; Konduri, G. Ganesh; Medhora, Meetha

    2013-01-01

    Abstract Pulmonary or systemic infections and hypoxemic respiratory failure are among the leading causes of admission to intensive care units, and these conditions frequently exist in sequence or in tandem. Inflammatory responses to infections are reproduced by lipopolysaccharide (LPS) engaging Toll-like receptor 4 (TLR4). Apoptosis is a hallmark of lung injury in sepsis. This study was conducted to determine whether preexposure to LPS or hypoxia modulated the survival of pulmonary artery endothelial cells (PAECs). We also investigated the role TLR4 receptor expression plays in apoptosis due to these conditions. Bovine PAECs were cultured in hypoxic or normoxic environments and treated with LPS. TLR4 antagonist TAK-242 was used to probe the role played by TLR4 receptors in cell survival. Cell apoptosis and survival were measured by caspase 3 activity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) incorporation. TLR4 expression and tumor necrosis factor α (TNF-α) production were also determined. LPS increased caspase 3 activity in a TAK-242-sensitive manner and decreased MTT incorporation. Apoptosis was decreased in PAECs preconditioned with hypoxia prior to LPS exposure. LPS increased TNF-α production, and hypoxic preconditioning blunted it. Hypoxic preconditioning reduced LPS-induced TLR4 messenger RNA and TLR4 protein. TAK-242 decreased to baseline the LPS-stimulated expression of TLR4 messenger RNA regardless of environmental conditions. In contrast, LPS followed by hypoxia substantially increased apoptosis and cell death. In conclusion, protection from LPS-stimulated PAEC apoptosis by hypoxic preconditioning is attributable in part to reduction in TLR4 expression. If these signaling pathways apply to septic patients, they may account for differing sensitivities of individuals to acute lung injury depending on oxygen tensions in PAECs in vivo. PMID:24618542

  8. What goal is of most worth? The effects of the implementation of the Texas Assessment of Knowledge and Skills on elementary science teaching

    NASA Astrophysics Data System (ADS)

    Rodgers, Pamela England

    This qualitative, narrative study centered on the effects of the implementation of the science portion of the fifth grade Texas Assessment of Knowledge and Skills (TAKS) on the instruction of science at the elementary level, grades one through five. Fourteen teachers and five administrators were interviewed at two elementary schools (kindergarten through grade four) and one middle school (grades five and six). Classroom observations of each of the teachers were also conducted. The study focused on the effect of the implementation of the science TAKS on the amount of time spent on science as well as the instructional methods utilized in the elementary science classroom. Lower grade levels were found to have changed little in these areas unless strong administrative leadership---emphasizing curriculum alignment, providing adequate materials and facilities, and encouraging sustained, content-based professional development in science---was present in the school. At the fifth grade level, however, the amount of time spent on science had increased significantly, although the instructional methods utilized by the teachers were focused more often upon increasing ratings on the test rather than providing the research-based best practice methods of hands-on, inquiry-based science instruction. In addition, the study also explored the teachers' and administrators' perceptions of the state and local mandates concerning science instruction and preparation for the TAKS. Other topics that came to light during the course of the study included the teachers' views on accountability and the effects of the state assessments on children in their classrooms. It was found that most teachers readily accept accountability for themselves, but are opposed to one-shot high-stakes tests which they feel are damaging for their students emotionally and academically---adversely affecting their love of learning science.

  9. The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma

    PubMed Central

    Goleva, Elena; Jackson, Leisa P.; Harris, J. Kirk; Robertson, Charles E.; Sutherland, E. Rand; Hall, Clifton F.; Good, James T.; Gelfand, Erwin W.; Martin, Richard J.

    2013-01-01

    Rationale: The role of airway microbiome in corticosteroid response in asthma is unknown. Objectives: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. Methods: 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. Measurements and Main Results: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β–associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. Conclusions: A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce

  10. β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1.

    PubMed

    Mancini, Arturo D; Bertrand, Gyslaine; Vivot, Kevin; Carpentier, Éric; Tremblay, Caroline; Ghislain, Julien; Bouvier, Michel; Poitout, Vincent

    2015-08-21

    FFAR1/GPR40 is a seven-transmembrane domain receptor (7TMR) expressed in pancreatic β cells and activated by FFAs. Pharmacological activation of GPR40 is a strategy under consideration to increase insulin secretion in type 2 diabetes. GPR40 is known to signal predominantly via the heterotrimeric G proteins Gq/11. However, 7TMRs can also activate functionally distinct G protein-independent signaling via β-arrestins. Further, G protein- and β-arrestin-based signaling can be differentially modulated by different ligands, thus eliciting ligand-specific responses ("biased agonism"). Whether GPR40 engages β-arrestin-dependent mechanisms and is subject to biased agonism is unknown. Using bioluminescence resonance energy transfer-based biosensors for real-time monitoring of cell signaling in living cells, we detected a ligand-induced GPR40-β-arrestin interaction, with the synthetic GPR40 agonist TAK-875 being more effective than palmitate or oleate in recruiting β-arrestins 1 and 2. Conversely, TAK-875 acted as a partial agonist of Gq/11-dependent GPR40 signaling relative to both FFAs. Pharmacological blockade of Gq activity decreased FFA-induced insulin secretion. In contrast, knockdown or genetic ablation of β-arrestin 2 in an insulin-secreting cell line and mouse pancreatic islets, respectively, uniquely attenuated the insulinotropic activity of TAK-875, thus providing functional validation of the biosensor data. Collectively, these data reveal that in addition to coupling to Gq/11, GPR40 is functionally linked to a β-arrestin 2-mediated insulinotropic signaling axis. These observations expose previously unrecognized complexity for GPR40 signal transduction and may guide the development of biased agonists showing improved clinical profile in type 2 diabetes. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. The Relationship between Computer-Assisted Instruction and Alternative Programs to Enhance Fifth-Grade Mathematics Success on the Annual Texas Assessment of Knowledge and Skills

    ERIC Educational Resources Information Center

    Tucker, Tommy Howard

    2009-01-01

    The purpose of this study was to determine the relationship between using computer-assisted instruction (CAI) size and success on the Texas Assessment of Knowledge and Skills (TAKS) mathematics exam with fifth-grade students in Texas compared to the effect of alternative improvement approaches used by a control group. Research explored the use of…

  12. Impact of Texas High School Science Teacher Credentials on Student Performance in High School Science

    ERIC Educational Resources Information Center

    George, Anna Ray Bayless

    2012-01-01

    A study was conducted to determine the relationship between the credentials held by science teachers who taught at a school that administered the Science Texas Assessment on Knowledge and Skills (Science TAKS), the state standardized exam in science, at grade 11 and student performance on a state standardized exam in science administered in grade…

  13. Middle School Mathematics: A Study of Three Programs in South Texas

    ERIC Educational Resources Information Center

    Ellis, Joanetta Dowell

    2011-01-01

    In 2010, the Texas Assessment of Knowledge and Skills (TAKS) began its seventh year of testing (Texas Education Agency, 2009a). High stakes testing is a reality. This study considered the impact on mathematics achievement based on the mathematics program students were receiving during their middle school years. The purpose of this study was to…

  14. A Comparative Analysis of Texas Grade Five Student Achievement between Year-Round and Traditional School Calendars

    ERIC Educational Resources Information Center

    Wilmore-Dafonte, Christy N.

    2013-01-01

    Purpose: The purpose of this dissertation was to determine the extent to which school instructional calendar configuration (i.e., year-round or traditional) influenced Grade 5 student academic performance as reflected on the Texas Assessment of Knowledge and Skills (TAKS) test as a function of student ethnicity (i.e., Hispanic, White, and Black)…

  15. Unchained Melody: Revisiting the Estimation of SF-6D Values

    PubMed Central

    Craig, Benjamin M.

    2015-01-01

    Purpose In the original SF-6D valuation study, the analytical design inherited conventions that detrimentally affected its ability to predict values on a quality-adjusted life year (QALY) scale. Our objective is to estimate UK values for SF-6D states using the original data and multi-attribute utility (MAU) regression after addressing its limitations and to compare the revised SF-6D and EQ-5D value predictions. Methods Using the unaltered data (611 respondents, 3503 SG responses), the parameters of the original MAU model were re-estimated under 3 alternative error specifications, known as the instant, episodic, and angular random utility models. Value predictions on a QALY scale were compared to EQ-5D3L predictions using the 1996 Health Survey for England. Results Contrary to the original results, the revised SF-6D value predictions range below 0 QALYs (i.e., worse than death) and agree largely with EQ-5D predictions after adjusting for scale. Although a QALY is defined as a year in optimal health, the SF-6D sets a higher standard for optimal health than the EQ-5D-3L; therefore, it has larger units on a QALY scale by construction (20.9% more). Conclusions Much of the debate in health valuation has focused on differences between preference elicitation tasks, sampling, and instruments. After correcting errant econometric practices and adjusting for differences in QALY scale between the EQ-5D and SF-6D values, the revised predictions demonstrate convergent validity, making them more suitable for UK economic evaluations compared to original estimates. PMID:26359242

  16. TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling

    PubMed Central

    Sanjo, Hideki; Takeda, Kiyoshi; Tsujimura, Tohru; Ninomiya-Tsuji, Jun; Matsumoto, Kunihiro; Akira, Shizuo

    2003-01-01

    The proinflammatory cytokine interleukin-1 (IL-1) transmits a signal via several critical cytoplasmic proteins such as MyD88, IRAKs and TRAF6. Recently, serine/threonine kinase TAK1 and TAK1 binding protein 1 and 2 (TAB1/2) have been identified as molecules involved in IL-1-induced TRAF6-mediated activation of AP-1 and NF-κB via mitogen-activated protein (MAP) kinases and IκB kinases, respectively. However, their physiological functions remain to be clarified. To elucidate their roles in vivo, we generated TAB2-deficient mice. The TAB2 deficiency was embryonic lethal due to liver degeneration and apoptosis. This phenotype was similar to that of NF-κB p65-, IKKβ-, and NEMO/IKKγ-deficient mice. However, the IL-1-induced activation of NF-κB and MAP kinases was not impaired in TAB2-deficient embryonic fibroblasts. These findings demonstrate that TAB2 is essential for embryonic development through prevention of liver apoptosis but not for the IL-1 receptor-mediated signaling pathway. PMID:12556483

  17. Regulation of the nuclear factor (NF)-kappaB pathway by ISGylation.

    PubMed

    Minakawa, Miki; Sone, Takayuki; Takeuchi, Tomoharu; Yokosawa, Hideyoshi

    2008-12-01

    Post-translational modification with ISG15 (interferon-stimulated gene 15 kDa) (ISGylation) is mediated by a sequential reaction similar to ubiquitination, and various target proteins for ISGylation have been identified. We previously reported that ISGylation of the E2 ubiquitin-conjugating enzyme Ubc13 suppresses its E2 activity. Ubc13 forms a heterodimer with Uev1A, a ubiquitin-conjugating enzyme variant, and the Ubc13-Uev1A complex catalyzes the assembly of a Lys63-linked polyubiquitin chain, which plays a non-proteolytic role in the nuclear factor (NF)-kappaB pathway. In this study, we examined the effect of ISGylation on tumor necrosis factor receptor-associated factor (TRAF)-6/transforming growth factor beta-activated kinase (TAK)-1-dependent NF-kappaB activation. We found that expression of the ISGylation system suppresses NF-kappaB activation via TRAF6 and TAK1 and that the level of polyubiquitinated TRAF6 is reduced by expression of the ISGylation system. Taken together, the results suggest that the NF-kappaB pathway is negatively regulated by ISGylation.

  18. The E3 ubiquitin ligase mind bomb-2 (MIB2) protein controls B-cell CLL/lymphoma 10 (BCL10)-dependent NF-κB activation.

    PubMed

    Stempin, Cinthia C; Chi, Liying; Giraldo-Vela, Juan P; High, Anthony A; Häcker, Hans; Redecke, Vanessa

    2011-10-28

    B-cell CLL/lymphoma 10 (BCL10) is crucial for the activation of NF-κB in numerous immune receptor signaling pathways, including the T-cell receptor (TCR) and B-cell receptor signaling pathways. However, the molecular mechanisms that lead to signal transduction from BCL10 to downstream NF-κB effector kinases, such as TAK1 and components of the IKK complex, are not entirely understood. Here we used a proteomic approach and identified the E3 ligase MIB2 as a novel component of the activated BCL10 complex. In vitro translation and pulldown assays suggest direct interaction between BCL10 and MIB2. Overexpression experiments show that MIB2 controls BCL10-mediated activation of NF-κB by promoting autoubiquitination and ubiquitination of IKKγ/NEMO, as well as recruitment and activation of TAK1. Knockdown of MIB2 inhibited BCL10-dependent NF-κB activation. Together, our results identify MIB2 as a novel component of the activated BCL10 signaling complex and a missing link in the BCL10-dependent NF-κB signaling pathway.

  19. Simulators for Mariner Training and Licensing. Phase 1. The Role of Simulators in the Mariner Training and Licensing Process. Volume II.

    DTIC Science & Technology

    1980-07-01

    imidi NZN V) 0& TI ds003 LU- C- j Ito *AI~I om Qu N V V V V V CJ~ ~ ~~ INWOA~ illsVV VVV 2~SMUW~ d V V...WYIA N .3DC- 4 .*4N N SOMMIM C1 UW.!!0Ŗ N 141 A-4 AINI ’ SU W (4N ri N .., N 34M4 CD) ’T" J " D N f NdN Mau N 4 0-44 C~~~ d 2-NIINF LI AA-4 LL),~, rimi...SI-M L) J * Mcd d _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ I’d (A~~~~ ~~~ -IN svm~ d

  20. A Fluidic Voice Communication System and Data Link.

    DTIC Science & Technology

    1980-03-01

    AD-AO4 OfA NAVAL POSTGAATAE SCHOOL HOuTEfuY CA F/S mTa A FLUIDIC VOICE CGUUNI[CATION SYSTI AND DATA LINK.UI NM O T N P.SEuCKI UNCLASSCO M I’I mlii...1119 Q8 ""󈧚ii1 13"L. 11H 1IlIIo MICROCOPY RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS 196 A NAVAL POSTGRADUATE SCHOOL Monterey, California...Postgraduate School Ma 4Y Mechanical Engineering Department Is NuM41611off 4 iuCwTOlftG A49MCV mauIS 4ADOCSSS(to Uffint Imo Ctemiltsd 0111 cc IS. 59CUIRITY

  1. Coastal and Estuarine Mangrove Squeeze in the Mekong and Saigon Delta

    NASA Astrophysics Data System (ADS)

    Stive, M.

    2016-02-01

    Both in the Mekong and Saigon deltas coastal squeeze is a frequent and pregnant problem, which leads to amazingly alarmous coastal and estuarine erosion rates. From the landside the squeeze is due to encroaching dike relocations and agri- and aquacultures, from the sea side it is due to decreasing sediment sources and relative sea level rise. These multiple pressures at some locations, certainly away from the sediment sources (like Ca Mau) leads to unprecedentent erosion rates. Managed retreat may be a longer term solution, but this will require a new way of thinking. Sandy and silt nourishment strategies may be an innovative alternative, but will require underbuilding scientific and practical research.

  2. Strategies for Improving School Performance

    ERIC Educational Resources Information Center

    Johnson, William L.; Johnson, Annabel M.; Johnson, Jared W.

    2014-01-01

    The document is from a presentation at the Texas Region VII 2014 Curriculum Conference. The study examined the effects of a three-tiered high school program designed to increase student achievement and Texas end-of-course (EOC) TAKS and STAAR chemistry scores. The student sample (n = 625) consisted 75% high school sophomores and 25% high school…

  3. The Effectiveness of Inclusion in Texas High Schools

    ERIC Educational Resources Information Center

    Patterson, Steven T.

    2013-01-01

    The purpose of this study was to employ value-added methodology to determine which placement setting offered the ninth grade 2009 special education high school cohort the most academic growth as measured on the Texas Assessment of Knowledge and Skills (TAKS). This particular cohort was selected because it was the most recent cohort for which 3…

  4. Effects of Year-Round Education on Texas Middle School Student Performance

    ERIC Educational Resources Information Center

    Coopersmith, Michael

    2011-01-01

    This study was designed to investigate the effects of the year-round calendar on student performance in Texas middle schools as measured by achievement on the Texas Assessment of Knowledge and Skills (TAKS) test. In the State of Texas, 15 schools served students in grades six through eight using the year-round calendar in 2009-2010. The 15…

  5. Long-Term Implications of the 2013 Future Years Defense Program

    DTIC Science & Technology

    2012-07-01

    difficult for the department to manage because it would need to be achieved in only nine months (between the cut’s tak - ing effect in January 2013 and the...Estimate of DoD’s Funding Under the BCA Caps After Automatic Reductionse 469 472 475 477 480 483 485 487 489 493 d Nominal Dollars 2013 Dollars 2022

  6. The Prediction of Reading Levels between Second and Third Grade Limited English Proficient Students in a Bilingual Program

    ERIC Educational Resources Information Center

    Moses, Britani Creel

    2010-01-01

    The purpose of this study was to predict the third grade English reading TAKS scores while considering the same students' native language, Spanish, reading level as assessed by a state-approved reading assessment, the Evaluacion del desarrollo de la lectura (EDL), from the end of the second grade year. In addition, this study was been designed to…

  7. Strategies for Science Student Achievement & Productive School Management

    ERIC Educational Resources Information Center

    Johnson, William L.

    2010-01-01

    There is an increasing literature pertaining to student achievement and school productivity. This session will present school and classroom strategies used in high school science classes at Robert E. Lee High School (5A) in Tyler, Texas. This year, 84% of the students at Lee passed the science TAKS test. Lee is also ranked in the top 1500 high…

  8. Specification, Validation and Verification of Mobile Application Behavior

    DTIC Science & Technology

    2013-03-01

    VALIDATION AND VERIFICATION OF MOBILE APPLICATION BEHAVIOR by Christopher B. Bonine March 2013 Thesis Advisor: Man-Tak Shing Thesis Co...NUMBERS 6. AUTHOR(S) Christopher B. Bonine 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Naval Postgraduate School Monterey, CA 93943–5000 8...VALIDATION AND VERIFICATION OF MOBILE APPLICATION BEHAVIOR Christopher B. Bonine Lieutenant, United States Navy B.S. Southern Polytechnic State

  9. Organizing Chaos: The Tactical Assault Kit Collaborative Mission Planner

    DTIC Science & Technology

    2018-12-01

    choice. Case studies , such as the 2017 Presidential Inauguration Collective Security Event, Operation Flaming Sword 2017, and the counter-ISIS campaign...rallied around the Tactical Assault Kit (TAK) as their mission command tool of choice. Case studies , such as the 2017 Presidential Inauguration...authorities ADA Air Defense Artillery ADM Army Design Methodology ADAPT Advanced Digital Advisor Partner Technologies ATAK Android Tactical Assault Kit

  10. Academic Accountability in Texas Public Schools: 2003-2007

    ERIC Educational Resources Information Center

    Jaska, Patrick; Hogan, Patrick; Wen, Zhezhu

    2009-01-01

    This study examines factors affecting test scores in a sample of thirty-seven Texas public high schools from 2003 to 2007 since the implementation of the No Child Left Behind (NCLB) Act of 2001. The schools were chosen based upon similar tax rates and district sizes. The Texas Assessment of Knowledge and Skills (TAKS) test was implemented in 2003…

  11. Light quality influences the virulence and physiological responses of Colletotrichum acutatum causing anthracnose in pepper plants.

    PubMed

    Yu, S-M; Ramkumar, G; Lee, Y H

    2013-08-01

    To explore the effects of light quality on the physiology and pathogenicity of Colletotrichum acutatum, we analysed the morphological traits, melanin production and virulence of the pathogen under different light wavelengths. The influence of light wavelength on the mycelial growth and conidial germination of C. acutatum was investigated using red, green, blue and white light sources. Red and green light reduced the mycelial growth in comparison with blue and white light, and dark conditions. The least percentage of conidial germination was observed under blue light, while the germination rate among white, red and green light, as well as in the dark, was insignificant. In comparison with its influence on mycelial growth and conidial germination, light wavelength significantly affected the pathogen's virulence towards hot pepper fruits. The highest disease severity was observed under blue light, which was at least a twofold increase compared with the disease severity under other light conditions. To elucidate the effect of light on the disparity in virulence, scytalone was assayed by HPLC, and scd1 gene expression was examined with real-time PCR. The highest and lowest scytalone production was observed in the cultures incubated under blue (10.9 mAU) and green light (1.5 mAU), respectively. Higher scd1 gene expression (~ 40-fold increase) was observed in cultures incubated under blue and white light in comparison with those incubated in the dark. This study revealed that light affects the growth, colonial morphology and virulence of C. acutatum. The pathogen needs light for its active melanin production and also to attain higher virulence. This is the first report on the effect of light quality on the virulence of C. acutatum. The findings of this study will broaden our knowledge of the influence of light on physiological responses of fungal pathogens. © 2013 The Society for Applied Microbiology.

  12. Relevance to Home Blood Pressure Monitoring Protocol of Blood Pressure Measurements Taken Before First-Morning Micturition and in the Afternoon

    PubMed Central

    de Almeida, Antonio Eduardo Monteiro; Stein, Ricardo; Gus, Miguel; Nascimento, João Agnaldo; Belli, Karlyse Claudino; Arévalo, Jorge Rene Garcia; Fuchs, Flávio Dani

    2014-01-01

    Background The importance of measuring blood pressure before morning micturition and in the afternoon, while working, is yet to be established in relation to the accuracy of home blood pressure monitoring (HBPM). Objective: To compare two HBPM protocols, considering 24-hour ambulatory blood pressure monitoring (wakefulness ABPM) as gold-standard and measurements taken before morning micturition (BM) and in the afternoon (AM), for the best diagnosis of systemic arterial hypertension (SAH), and their association with prognostic markers. Methods After undergoing 24-hour wakefulness ABPM, 158 participants (84 women) were randomized for 3- or 5-day HBPM. Two variations of the 3-day protocol were considered: with measurements taken before morning micturition and in the afternoon (BM+AM); and with post-morning-micturition and evening measurements (PM+EM). All patients underwent echocardiography (for left ventricular hypertrophy - LVH) and urinary albumin measurement (for microalbuminuria - MAU). Result Kappa statistic for the diagnosis of SAH between wakefulness-ABPM and standard 3-day HBPM, 3-day HBPM (BM+AM) and (PM+EM), and 5-day HBPM were 0.660, 0.638, 0.348 and 0.387, respectively. The values of sensitivity of (BM+AM) versus (PM+EM) were 82.6% × 71%, respectively, and of specificity, 84.8% × 74%, respectively. The positive and negative predictive values were 69.1% × 40% and 92.2% × 91.2%, respectively. The comparisons of intraclass correlations for the diagnosis of LVH and MAU between (BM+AM) and (PM+EM) were 0.782 × 0.474 and 0.511 × 0.276, respectively. Conclusions The 3 day-HBPM protocol including measurements taken before morning micturition and during work in the afternoon showed the best agreement with SAH diagnosis and the best association with prognostic markers. PMID:25352508

  13. On Ensino de Astronomia: Desafios para Implantação

    NASA Astrophysics Data System (ADS)

    Faria, R. Z.; Voelzke, M. R.

    2008-09-01

    Em 2002 o ensino de Astronomia foi proposto como um dos temas estruturadores pelos Parâmetros Curriculares Nacionais e sugerido como facilitador para que o aluno compreendesse a Física como construção humana e parte do seu mundo vivencial, mas raramente seus conceitos foram ensinados. A presente pesquisa discute dois aspectos relacionados à abordagem de Astronomia. O primeiro aspecto é se ela está sendo abordada pelos professores do Ensino Médio e o segundo, aborda a maneira como ela está sendo ensinada. Optou-se pela aplicação de um questionário a partir do 2° semestre de 2006 e durante o ano de 2007 com professores que ministram a disciplina de Física, os quais trabalham em escolas estaduais em Rio Grande da Serra, Ribeirão Pires e Mauá no estado São Paulo. Dos 66,2% dos professores que responderam ao questionário nos municípios de Rio Grande da Serra, Ribeirão Pires e Mauá, 57,4% não aplicaram nenhum tópico de astronomia, 70,2% não utilizaram laboratório, 89,4% não utilizaram qualquer tipo de programa computacional, 83,0% nunca fizeram visitas com alunos a museus e planetários e 38,3% não indicaram qualquer tipo de livro ou revista referente à astronomia aos seus alunos. Mesmo considerando a Astronomia um conteúdo potencialmente significativo, esta não fez parte dos planejamentos escolares. Portanto são necessárias propostas que visem estratégias para a educação continuada dos professores como, por exemplo, cursos específicos sobre o ensino em Astronomia.

  14. Maui Optical Site, Mount Halekualia, Hawaii, Revised Uniform Summary of Surface Weather Observations (RUSSWO). Parts C, E and F

    DTIC Science & Technology

    1981-03-01

    printed frot a0silablg Peek .astI fow 060 V Newmtk, how,.? aW asterisk (*) to printed &a the data block It laoS tWa go$ ( or mre missift qbeewvatioms...SPEED (FROM HOURLY OBSERVATIONS) oflQ.nJ MAuI OPTICAL kT£ 11 NORTH TOWER __-I__ JAN__ _ _ ILL WEAlTHER 20- 3D UI ONI IO ( 1 1) I) •3 4.4 1.10 11. V...9- 14~.0 u A .2 .3.Z ). 13a sWC _ I t -: R - 1 -1 s . 3d . 1-9.. --.L .. 1..L ...L.%.L AAA..L (.L - ’~L a v~sw @g’ISVA’W. I’. ’Ii’w USAETAC

  15. Sealift and the U.S. Merchant Marine: Vulnerabilities and Implications For Defense

    DTIC Science & Technology

    1993-12-01

    ships with high endurance and enhanced cargo -carrying capacity. As a result of these...gasoline tankers (T-AOG), fleet oilers (T-AO), and multi- purpose cargo ships (T-AK/ AKR ). 2. Maritime Prepositioning Ships Over a decade has passed... cargo carried to Vietnam during this period, twenty-six percent 18 A "system" refers to the method of loading or unloading cargo for a particular ship

  16. Department of Defense Dictionary of Military and Associated Terms

    DTIC Science & Technology

    2008-05-30

    cargo on board a ship for the purpose of accomplishing en route maintenance and security. supersonic — Of or pertaining to speed ...information systems TAK cargo ship T- AKR fast logistics ship TALCE tanker airlift control element Appendix A As Amended Through 30 May 2008...priorities committee — (*) A committee set up to determine the priorities of passengers and cargo . air raid reporting control ship — (*) A

  17. Lagrangian Mixing in an Axisymmetric Hurricane Model

    DTIC Science & Technology

    2010-07-23

    The MMR r is found by tak - ing the log of the time-series 6ρ(t)−A1, where A1 is 90% of the minimum value of6ρ(t), and the slope of the linear func...Advective mixing in a nondivergent barotropic hurricane model, Atmos. Chem. Phys., 10, 475 –497, doi:10.5194/acp-10- 475 -2010, 2010. Salman, H., Ide, K

  18. Transforming growth factor-beta1 transcriptionally activates CD34 and prevents induced differentiation of TF-1 cells in the absence of any cell-cycle effects.

    PubMed

    Marone, M; Scambia, G; Bonanno, G; Rutella, S; de Ritis, D; Guidi, F; Leone, G; Pierelli, L

    2002-01-01

    A number of cytokines modulate self-renewal and differentiation of hematopoietic elements. Among these is transforming growth factor beta1 (TGF-beta1), which regulates cell cycle and differentiation of hematopoietic cells, but has pleiotropic activities depending on the state of responsiveness of the target cells. It has been previously shown by us and other authors that TGF-beta1 maintains human CD34(+) hematopoietic progenitors in an undifferentiated state, independently of any cell cycle effects, and that depletion of TGF-beta1 triggers differentiation accompanied by a decrease in CD34 antigen expression. In the present work, we show that exogenous TGF-beta1 upregulates the human CD34 antigen in the CD34(+) cell lines TF-1 and KG-1a, but not in the more differentiated CD34(-) cell lines HL-60 and K-562. We further studied this effect in the pluripotent erythroleukemia cell line TF-1. Here, TGF-beta1 did not effect cell growth, but induced transcriptional activation of full-length CD34 and prevented differentiation induced by differentiating agents. This effect was associated with nuclear translocation of Smad-2, activation of TAK-1, and with a dramatic decrease in p38 phosphorylation. In other systems TGF-beta1 has been shown to activate a TGF-beta-activated kinase 1 (TAK1), which in turn, activates p38. The specific inhibitor of p38 phosphorylation, SB202190, also increased CD34 RNA expression, indicating the existence of a link between p-38 inhibition by TGF-beta1 and CD34 overexpression. Our data demonstrate that TGF-beta1 transcriptionally activates CD34 and prevents differentiation of TF-1 cells by acting independently through the Smad, TAK1 and p38 pathways, and thus provide important clues for the understanding of hematopoietic development and a potential tool to modify response of hematopoietic cells to mitogens or differentiating agents.

  19. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gu, Jun; Liu, Xu, E-mail: xkliuxu@yahoo.cn; Wang, Quan-xing, E-mail: shmywqx@126.com

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated proteinmore » kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.« less

  20. A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia.

    PubMed

    Shanmugam, Rajasubramaniam; Gade, Padmaja; Wilson-Weekes, Annique; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A; Baghdadi, Tareq Al; Sargent, Katie J; Cripe, Larry D; Kalvakolanu, Dhananjaya V; Boswell, H Scott

    2012-01-15

    Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB-and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD(+) cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD(+) AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD(+) human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-κB. Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML. ©2011 AACR.

  1. A non-canonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia (AML)

    PubMed Central

    Shanmugam, Rajasubramaniam; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A.; Baghdadi, Tareq Al; Sargent, Katie J.; Cripe, Larry D.; Kalvakolanu, Dhananjaya V.; Boswell, H. Scott

    2014-01-01

    Purpose DAPK1, a tumor suppressor, is a rate-limiting effector in an ER stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of AML with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB- and c- jun-responsive genes, was studied. RNAi knockdown studies were performed in Flt3ITD+ve cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were performed to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results AMLs characterized by normal karyotype with Flt3ITD were found to have 10-100-fold lower DAPK1 transcripts normalized to the expression of c-jun, a transcriptional activator of DAPK1, as compared to a heterogeneous cytogenetic category. Meis1, a c-jun-responsive adverse AML prognostic gene signature was also measured as control. These Flt3ITD+ve AMLs over-express relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter along with HDAC2 and HDAC6 in the Flt3ITD+ve human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NIK, de-repressed DAPK1. DAPK1-repressed primary Flt3ITD+ve AMLs had selective nuclear activation of p52NF-κB. Conclusions Flt3ITD promotes a non-canonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD+ve AML. PMID:22096027

  2. Integration of Experience API Into CDET’s E-Learning

    DTIC Science & Technology

    2016-06-01

    based on customers ’ actual usage on a transaction basis. Value-based Penetration Pricing • Market segments where buyers have high price...they need to accomplish the course learning objectives (see Figure 6). This method allows each student to customize their own learning experiences ... EXPERIENCE API INTO CDET’S E- LEARNING by Clayton C. MacAloney June 2016 Thesis Advisor: Man-Tak Shing Co-Advisor: Arijit Das THIS PAGE

  3. Six New Species of the Culex (Lophoceraomyia) Mammilifer Group from Thailand (Diptera: Culicidae)

    DTIC Science & Technology

    1967-03-01

    Distribution. Known only from the following Provinces in Thai- land: Tak, Nakhon Nayok, and Chiang Mai . Eleven individual c Fig. 2, Culer...Distribution. The authors have seen specimens from the following Provinces in Thailand: Trang, Chiang Mai , Sara Buri, Narathiwat, Phatthalung...male with terminalia and antennae slide mounted from Doi Sutep, Chiang Mai Province, Thailand, 7. I. 53, D. C. and E. B. Thurman, deposited in the U

  4. A Virtual World for an Autonomous Underwater Vehicle

    DTIC Science & Technology

    1994-12-01

    LEGIBLY ON BLACK AND WHITE MICROFICHE. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704 Public reporting burden for this collection of information is...event simulation. He and Man-Tak Shing also gave v\\aluable advice on the Ph.D. process. Mike Macedonia’s unparalleled understanding of computer...networks helped make an entire field intelligible. Dave Pratt blazed the trail with NPSNET, still the best virtual world around and still gaining on all

  5. U.S. House of Representatives Committee on Armed Services Panel on Roles and Missions: Initial Perspectives

    DTIC Science & Technology

    2008-01-01

    opinions led Alexander Yakovlev, a principal architect of Mikhail Gorbachev’s perestroika, to bemoan his compatriots’ pen- chant for authoritarian rule...isn’t a communist country anymore. It’s got a different sys- tem: meritocratic paternalism . You joke: Imagine the Ivy League tak- ing over the shell of...long as the reforms never chal- lenge the political order). Most of all, you believe, edu- cated paternalism has delivered the goods. China is

  6. The Realistic Job Preview as a Persuasive Communication.

    DTIC Science & Technology

    1982-02-01

    10. PROGRAM ELEMENT, PROJECT. TAK AREA 6 WORK UNIT NUMBERS Michigan State Uiversity NR 170-894 Ii. CONTROLLING OFFICE NAME AND ADDRESS IS. REPORT...RJP research seems to show a stronger preview effect using more intelligent subjects. That is, studies of life insurance agents (Weitz, 1956; Youngberg...University Department of Psychological Sciences west Lafayette, INl 47907 1 Dr. Philip G. Zi±bardo*2 ~ Staniford Uiversity Department of Psychology Stanford, CA 94305 <El

  7. A Sampling of U.S. Naval Humanitarian Operations.

    DTIC Science & Technology

    1990-11-01

    from the evacuation services to survivors of a Naval Auxiliary Air Station, Fallon, volcano eruption on Miyako Island, Nevada, and from the San...February 1974 aircraft from Midway to Hawaii for treatment. On 13 February 1974, TAK-241 Private Francis X. McCraw rescued six Philippine Sea, September...Pacific, July 1989 Western Atlantic, January 1990 DD-965 Kinkaid and Coast Guard While on a training flight on 25 forces from Hawaii rescued a

  8. The Correlation of Students' Classroom-Assigned Time Social Networking with TAKS Literacy Scores

    ERIC Educational Resources Information Center

    Bicknell, Angela

    2012-01-01

    Education has continued to follow a traditional teaching model which may not prepare students with needed workforce skills. Social networking has been viewed as a technology tool useful for enhancing communication at both the business and educational level. The theory of connectivism underscores the need for social group interaction to provide…

  9. Organic Reactions in Aqueous Media (by Chao-Jun Li and Tak-Hang Chan)

    NASA Astrophysics Data System (ADS)

    Rosan, Reviewed Alan M.

    2000-06-01

    This concise book joins the series of Wiley Interscience special topic publications. In seven chapters it selectively reviews the burgeoning literature on organic reactions conducted in water or in aqueous media as a reaction cosolvent, nicely complementing another recent book on the subject by Grieco. Following a short introduction there are six chapters that vary in length from 10 to 50 pages; they cover pericyclic reactions, nucleophilic additions and substitutions, metal-mediated reactions, transition metal-catalyzed reactions, oxidation and reduction reactions, and industrial applications. These chapters, each of which is prefaced with a short provocative quotation, also vary in depth, containing from 11 to more than 180 references. The literature is complete through 1996 and commendably includes citations of original papers by Barbier, Faraday, Frankland, Grignard, Kolbe, Lapworth, and Reformatsky as well as references to selected U.S. and foreign patents and the Russian literature. There is a subject index but no author index. This book is timely and effective. From the title, one might expect a broad discussion of the unique properties of water and water-soluble components (salts, surfactants, etc.) that would be thought to bear on organic reactivity. The first chapter opens by noting that water is the most abundant volatile material in comets and briefly describes those properties that suggest its utility as a solvent or cosolvent, summarizing the potential technical, economic, and environmental advantages. Also described are the remarkable changes in density, conductance, heat capacity, dielectric constant, and ionization constant that accompany the transition to the critical point, but the emphasis here is on the effect of water under non-critical conditions. Discussion of the structure of liquid water and the role of hydrogen bonding in mediating molecular recognition events is abbreviated. In fact, the term "hydrogen bond" is surprisingly absent from the index. The text does not explicitly include a discussion of what has come to be broadly termed biphasic reaction conditions. Understandably, enzymatic reactions are beyond the scope of the presentation. This book has a decidedly applied character with an understated environmental theme, and the authors succinctly present the extraordinary effects of water on the kinetics, efficiency, and stereoselectivity of a large number of diverse reactions. In addition to their emphasis on the historically significant aqueous Diels-Alder reaction, discovered in 1980, and the literature regarding reactions of various nucleophilic organometals, the authors are to be commended for gathering together a wide and diverse body of information: it is clear that many of the examples shown are gems buried among larger bodies of work. Thus the book does an excellent job of culling and surveying a vast amount of data. There is, however, less emphasis on organizing the mechanistic bases underlying these often dramatic effects. For example, the apparent lack of generality of the effect of water on rate and selectivity in pericyclic reactions calls for some theoretical foundation. The singularly effective use of aqueous TlOH in the Suzuki reaction is cited without comment. On the other hand, the authors' concept of a mechanistic triad that incorporates to various degrees anion, radical, or covalent character in the carbon-carbon bond-forming step between various organometals and carbonyl substrates is appealing and suggests the need for future sophisticated experimental design. The most interesting sections are those dealing with synthesis and industrial applications. Unfortunately the latter is also the shortest chapter. The synthetic examples are timely and well chosen and include water-promoted Heck, Stille, Suzuki, and aldol reactions. There is an extensive, highly informative listing and survey of the use of water-soluble phosphines (both achiral and chiral) and an excellent discussion of the diastereoselectivity that often accompanies carbonyl attack by indium, tin, and zinc organometals (Barbier-Grignard reaction). The liberal use, on nearly every page, of clear, detailed drawings enhances the text, and substantive errors are few. Inexplicably, water is described as serving as a presumptive weak Lewis acid (pages 54-55) in the aqueous Mukaiyama reaction. Occasional slips of grammar, spelling, and syntax, including confusion over the difference between media and medium, are relatively minor. Some expressions, such as "olefinated", are unfortunate and there are several mysterious changes in font. This is not a textbook and no problems are offered. Many technical advances, some occurring since this book was published, have impacted the economic and environmental advantages of water. However, these more recent findings, involving the use of triphase aqueous-fluorous-organic systems, the discovery of living homogeneous ROMP catalysis in water, the utilization of supercritical water oxidation for toxic cleanup, and the utility of biphasic supercritical carbon dioxide-water emulsions, can be appreciated within the broad scope of reactivity described here. With the emerging wide interest, technical feasibility, and rapid innovative advances and an increasingly vast literature in this area, this book is most useful as a selected compendium rather than a definitive treatise. It is certainly suitable as a reference in a special topics or an advanced course. Rich with well-explicated examples and reactions, it is an invitingly readable and valuable survey of this fascinating area.

  10. Optical redox ratio using endogenous fluorescence to assess the metabolic changes associated with treatment response of bioconjugated gold nanoparticles in streptozotocin-induced diabetic rats

    NASA Astrophysics Data System (ADS)

    Adavallan, K.; Gurushankar, K.; Nazeer, Shaiju S.; Gohulkumar, M.; Jayasree, Ramapurath S.; Krishnakumar, N.

    2017-06-01

    Fluorescence spectroscopic techniques have the potential to assess the metabolic changes during disease development and evaluation of treatment response in a non-invasive and label-free manner. The present study aims to evaluate the effect of mulberry-mediated gold nanoparticles (MAuNPs) in comparison with mulberry leaf extract alone (MLE) for monitoring endogenous fluorophores and to quantify the metabolic changes associated with mitochondrial redox states during streptozotocin-induced diabetic liver tissues using fluorescence spectroscopy. Two mitochondrial metabolic coenzymes, reduced nicotinamide dinucleotide (NADH) and oxidized flavin adenine dinucleotide (FAD) are autofluorescent and are important optical biomarkers to estimate the redox state of a cell. Significant differences in the autofluorescence spectral signatures between the control and the experimental diabetic animals have been noticed under the excitation wavelength at 320 nm with emission ranging from 350-550 nm. A direct correlation between the progression of diabetes and the levels of collagen and optical redox ratio was observed. The results revealed that a significant increase in the emission of collagen in diabetic liver tissues as compared with the control liver tissues. Moreover, there was a significant decrease in the optical redox ratio (FAD/(FAD  +  NADH)) observed in diabetic control liver tissues, which indicates an increased oxidative stress compared to the liver tissues of control rats. Further, the extent of increased oxidative stress was confirmed by the reduced levels of reduced glutathione (GSH) in diabetic liver tissues. On a comparative basis, treatment with MAuNPs was found to be more effective than MLE for reducing the progression of diabetes and improving the optical redox ratio to a near normal range in streptozotocin-induced diabetic liver tissues. Furthermore, principal component analysis followed by linear discriminant analysis (PC-LDA) has been used to

  11. Global De Novo Protein-Protein Interactome Elucidates Interactions of Drought-Responsive Proteins in Horse Gram (Macrotyloma uniflorum).

    PubMed

    Bhardwaj, Jyoti; Gangwar, Indu; Panzade, Ganesh; Shankar, Ravi; Yadav, Sudesh Kumar

    2016-06-03

    Inspired by the availability of de novo transcriptome of horse gram (Macrotyloma uniflorum) and recent developments in systems biology studies, the first ever global protein-protein interactome (PPI) map was constructed for this highly drought-tolerant legume. Large-scale studies of PPIs and the constructed database would provide rationale behind the interplay at cascading translational levels for drought stress-adaptive mechanisms in horse gram. Using a bidirectional approach (interolog and domain-based), a high-confidence interactome map and database for horse gram was constructed. Available transcriptomic information for shoot and root tissues of a sensitive (M-191; genotype 1) and a drought-tolerant (M-249; genotype 2) genotype of horse gram was utilized to draw comparative PPI subnetworks under drought stress. High-confidence 6804 interactions were predicted among 1812 proteins covering about one-fourth of the horse gram proteome. The highest number of interactions (33.86%) in horse gram interactome matched with Arabidopsis PPI data. The top five hub nodes mostly included ubiquitin and heat-shock-related proteins. Higher numbers of PPIs were found to be responsive in shoot tissue (416) and root tissue (2228) of genotype 2 compared with shoot tissue (136) and root tissue (579) of genotype 1. Characterization of PPIs using gene ontology analysis revealed that kinase and transferase activities involved in signal transduction, cellular processes, nucleocytoplasmic transport, protein ubiquitination, and localization of molecules were most responsive to drought stress. Hence, these could be framed in stress adaptive mechanisms of horse gram. Being the first legume global PPI map, it would provide new insights into gene and protein regulatory networks for drought stress tolerance mechanisms in horse gram. Information compiled in the form of database (MauPIR) will provide the much needed high-confidence systems biology information for horse gram genes, proteins, and

  12. The impact of a science-based integrated instructional protocol on the motivation, reading comprehension, and science achievement of fourth and fifth graders

    NASA Astrophysics Data System (ADS)

    Stephens, Kathy E.

    The purpose of this study was to determine the impact of implementing an integrated instructional protocol of science-based informational texts as teacher read alouds, student independent reading, and written journal responses on motivation, reading comprehension, and science achievement of fourth- and fifth-grade students with attention to specific student groups, including gender and ethnicities. A mixed methods research design included a 12-week intervention conducted with 68 fourth and fifth graders and 30 nonintervention fourth and fifth graders. Participating fourth and fifth graders completed the comprehension subtest of the Gates-MacGinitie Reading Test ([GMRT] MacGinitie, MacGinitie, Maria, & Dreyer, 2000) and the Texas Assessment of Knowledge and Skills ([TAKS] Texas Education Agency [TEA], 2005a). The Reading Survey of the Motivation to Read Profile ([MRP], Gambrell, Palmer, Codling, & Mazzoni, 1996) served as another quantitative data source. Qualitative data sources included classroom observations, key informant interviews, and student journal entries. The GMRT results indicated that the intervention fourth graders demonstrated the largest growth in reading comprehension achievement. Significant differences were noted by GMRT results between the intervention and nonintervention fourth graders. A significant difference was found between fourth-grade males and females on the GMRT, with a larger gain posted by the females. No significant differences were found on the GMRT in fifth grade Reading TAKS results indicated a significant difference between intervention fourth-grade Hispanic and African American students, while fifth-grade Science TAKS results indicated no significant differences. The MRP Reading Survey results indicated no significant differences; however, fourth-grade Hispanic and fifth-grade male students demonstrated significant growth. Classroom observations documented the progress of the 12-week intervention; 9 primary instructional and

  13. A Survey of Data-Base Information Systems Relevant to Navy Requirements Planning

    DTIC Science & Technology

    1983-02-01

    SHIPS \\ AK (FEM) T-AK (FEM) AKD/T-AKO _" ’ AKL/T-AKL AKM MULTIPURPOSE CAR 0 SHI’’S AKR VEHICLE CARGO SHIPS . -■, AK3 ANL AO OILER AC • NEW...the most demanding condition of operation for which a ship must be manned. ( a ) At sea in wartime. (b) Capable of performing all offensive... ship , and aircraft) researchers and others could quickly obtain basic information. 3. The Navy currently maintains a number of related

  14. Sub-Saharan Africa Report, No. 2830

    DTIC Science & Technology

    1983-08-12

    proceeds abroad and earn in- come. This scheme would require suffi- cient forex reserves. It would provide a counter revenue which could be set...also as- sisted our credit rating. Forex controls Your Money: Is there a benchmark gold price for the lifting of foreign exchange controls? Dc...first and lest it before tak- ing the next step. Your Money: The lift- ing of forex controls could lead to a vola- tile exchange rate. De Loor

  15. The Nature of Expansion of Paget’s Disease of Bone

    DTIC Science & Technology

    2013-04-01

    SQSTM1 mutant PDB samples. Two exogenous stimulators of the TLR signaling pathway are shown: MV – measles virus and LPS – Lipopolysaccharide. A...stimulation by Interleukins (ILs), LPS or measles , leads to ubiquitination of TRAF6 and binding of the ubiquitinated TRAF6 to the TAB2/TAK1 complex, which... measles virus in the delay of onset of PDB. 11 Conclusion Our laboratory has shown that SQSTM1 mutations also occur in the affected bone of PDB

  16. Aerodynamic Characteristics of Airfoils. Volume 4.

    DTIC Science & Technology

    1927-01-01

    8-6-4 -2 02a46 a 10 12 14 16is 20 2Angie of Attack in Degrees. Angle of Attack in Deprese . I~r xi N . A rxi (𔃺\\I ) M ITTll IK’ FORi AERONAUT~ICS RFM...8217 ~ 86--20a2 46 a10 12 14 163826 D Aogle of Attack in Deprese . Angle of it tak in Deprese . A II~ il A CHC ARACTERIISTICS OF Al RFOILS-i V 205 nzmuRRCS

  17. Molecular ion yield enhancement induced by gold deposition in static secondary ion mass spectrometry

    NASA Astrophysics Data System (ADS)

    Wehbe, Nimer; Delcorte, Arnaud; Heile, Andreas; Arlinghaus, Heinrich F.; Bertrand, Patrick

    2008-12-01

    Static ToF-SIMS was used to evaluate the effect of gold condensation as a sample treatment prior to analysis. The experiments were carried out with a model molecular layer (Triacontane M = 422.4 Da), upon atomic (In +) and polyatomic (Bi 3+) projectile bombardment. The results indicate that the effect of molecular ion yield improvement using gold metallization exists only under atomic projectile impact. While the quasi-molecular ion (M+Au) + signal can become two orders of magnitude larger than that of the deprotonated molecular ion from the pristine sample under In + bombardment, it barely reaches the initial intensity of (M-H) + when Bi 3+ projectiles are used. The differences observed for mono- and polyatomic primary ion bombardment might be explained by differences in near-surface energy deposition, which influences the sputtering and ionization processes.

  18. Analysis of the astronomical concepts presented by teachers of some state schools

    NASA Astrophysics Data System (ADS)

    Gonzaga, E. P.; Voelzke, M. R.

    2011-06-01

    Many Basic Education's teachers (EB) don't deal concepts related to astronomy and when they do so, they just follow didactic books which contain many conceptual errors. Astronomy is one of the contents taught in the EB and is part of the curriculum proposed by the Education Department of the State of São Paulo. With the intention to minimise some deficiencies, a University Extension Course for teachers of the Diretoria de Ensino Regional (Mauá, Ribeirão Pires and Rio Grande da Serra) was conducted with the following objectives: to raise alternative conceptions, to subsidise teachers by means of lectures, discussions and workshops, and to check the learning after the course. Therefore, sixteen questions were applied before and after the course. The results were quite satisfactory.

  19. The arrival of high temperature superconductors

    NASA Astrophysics Data System (ADS)

    Chu, Paul C. W.

    2011-03-01

    The attainment of high temperature superconductivity has been considered a major advancement of modern science. It was the seminal discovery of the first cuprate high temperature superconductor, the Ba-doped La 2 Cu O4 , with a Tc of 35 K in 1986 by Alex Müller and George Bednorz of IBM Zurich Lab, who were awarded the Nobel Prize in 1987, that ushered in the era of cuprate high temperature superconductivity. It was the first liquid nitrogen high temperature superconductor, YBa 2 Cu 3 O7 with a Tc of 93 K discovered in 1987 by Paul C. W. Chu, Maw-Kuen Wu and colleagues in the respective groups at the University of Houston and the University of Alabama at Huntsville that heralded the new era of high temperature superconductivity, drastically changing the psyche of superconductivity research and bringing superconductivity applications a giant step closer to reality. In the ensuing years, many high temperature superconductors have been found, leading to the current record Tc of 134 K which was observed by A. Schilling et al. of ETH in 1993 in HgBa 2 Ca 2 Cu 3 O9 - δ at ambient and later raised to 164 K under 30 GPa by L. Gao et al. In the present talk, I shall briefly recall a few events leading to and during the arrival of high temperature superconductivity. The prospects for future superconductors with higher Tc will also be discussed. Supported in part by U.S. AFOSR, U.S. DoE through ORNL, U.S. AFRL CONTACT through Rice University, the T. L. L. Temple Foundation, the John J. and Rebecca Moores Endowment, and the State of Texas through TCSUH.

  20. The effect of curriculum changes and instructional techniques on science-reasoning skills among high school students

    NASA Astrophysics Data System (ADS)

    Newman, Joan T.

    Any change, particularly on a large scale like a sequence change in a district with 75,000 students, is difficult. However, with the advent of the new TAKS science test and the new requirements for high school graduation in the state of Texas, educators and students alike are engaged in innovative educational approaches to meet these requirements. This study investigated a different, non-traditional science sequence to investigate relationships among secondary core-science course sequencing, student science-reasoning performance, and classroom pedagogy. The methodology adopted in the study led to a deeper understanding of the successes and challenges faced by teachers in teaching conceptual physics and chemistry to 8 th and 9th grade students. The qualitative analysis suggested a difference in pedagogy employed by middle and high school science teachers and a need for secondary science teachers to enhance their content knowledge and pedagogical skills, as well as change their underlying attitudes and beliefs about the abilities of students. The study examined scores of 495 randomly chosen students following three different matriculation patterns within one large independent school district. The study indicated that students who follow a sequence with 9th grade IPC generally increase their science-reasoning skills as demonstrated on the 10th grade TAKS science test when these scores are compared with those of students who do not have 9th grade IPC in the science sequence.

  1. Perceptions of leadership and student performance in science from campus leaders in selected high schools

    NASA Astrophysics Data System (ADS)

    Wilder, Sharon Mae

    This naturalistic study focused on the perceptions of leadership and student performance in science from campus leaders in three purposefully selected secondary campuses of ninth through twelfth grades. Each school had experienced an improvement in student passing rates on the science TAKS test that exceeded the state's percent improvement in passing rates for the past three years and had a record of improving science TAKS scores for the period of 2003 to 2008 exceeding fifteen percentage points. The qualitative research technique of multi-case studies design was used. Data was collected through semi-structured, in-depth interviews with four campus leaders from each of the selected schools. These campus leaders included campus administrators, science department chairs, and grade-level team leaders. A framework of transformational leadership was utilized in the analysis of the data generated from the interviews. The perception from the campus leaders was that leadership has a positive impact on student success in science. The findings indicated perceptions of leadership from the campus leaders had certain leadership practices in common. These included (a) clear vision and goals from the campus principal, (b) high performance expectations for teachers and students from administrators and science department leaders, (c) encouragement and support from campus administrators and science department leaders to develop new programs to address problem areas, (d) emphasis on collaborative teams, and (e) open door policy from administrators.

  2. Effect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinEffect of isopropyl myristate on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserinretain-->.

    PubMed

    Zhao, Chunyi; Quan, Peng; Liu, Chao; Li, Qiaoyun; Fang, Liang

    2016-11-01

    The purpose of this study was to investigate the effect of isopropyl myristate (IPM), a penetration enhancer, on the viscoelasticity and drug release of a drug-in-adhesive transdermal patch containing blonanserin. The patches were prepared with DURO-TAK ® 87-2287 as a pressure-sensitive adhesive (PSA) containing 5% ( w / w ) of blonanserin and different concentrations of IPM. An in vitro release experiment was performed and the adhesive performance of the drug-in-adhesive patches with different concentrations of IPM was evaluated by a rolling ball tack test and a shear-adhesion test. The glass transition temperature ( T g ) and rheological parameters of the drug-in-adhesive layers were determined to study the effect of IPM on the mechanical properties of the PSA. The results of the in vitro release experiment showed that the release rate of blonanserin increased with an increasing concentration of IPM. The rolling ball tack test and shear-adhesion test showed decreasing values with increasing IPM concentration. The results were interpreted on the basis of the IPM-induced plasticization of the PSA, as evidenced by a depression of the glass transition temperature and a decrease in the elastic modulus. In conclusion, IPM acted as a plasticizer on DURO-TAK ® 87-2287, and it increased the release of blonanserin and affected the adhesive properties of the PSA.

  3. Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films.

    PubMed

    Wolff, Hans-Michael; Irsan; Dodou, Kalliopi

    2014-08-01

    We aimed to investigate the effect of solubility parameter and drug concentration on the rheological behaviour of drug-in-adhesive films intended for transdermal application. Films were prepared over a range of drug concentrations (5%, 10% and 20% w/w) using ibuprofen, benzoic acid, nicotinic acid and lidocaine as model drugs in acrylic (Duro-Tak 87-4287 and Duro-Tak 87900A) or silicone (Bio-PSA 7-4301 and Bio-PSA 7-4302) pressure sensitive adhesives (PSAs). Saturation status of films was determined using light microscopy. Viscoelastic parameters were measured in rheology tests at 32°C. Subsaturated films had lower viscoelastic moduli whereas saturated films had higher moduli than the placebo films and/or a concentration-dependent increase in their modulus. Saturation concentration of each drug in the films was reflected by decreasing/increasing viscoelastic patterns. The viscoelastic windows (VWs) of the adhesive and drug-in-adhesive films clearly depicted the effect of solubility parameter differences, molar concentration of drug in the adhesive film and differences in PSA chemistry. Drug solubility parameters and molar drug concentrations have an impact on rheological patterns and thus on the adhesive performance of tested pressure sensitive adhesives intended for use in transdermal drug delivery systems. Use of the Flory equation in its limiting form was appropriate to predict drug solubility in the tested formulations.

  4. Varicella Zoster Virus and Large Vessel Vasculitis, the Absence of an Association.

    PubMed

    Procop, Gary W; Eng, Charis; Clifford, Alison; Villa-Forte, Alexandra; Calabrese, Leonard H; Roselli, Eric; Svensson, Lars; Johnston, Douglas; Pettersson, Gosta; Soltesz, Edward; Lystad, Lisa; Perry, Julian D; Blandford, Alexander; Wilson, Deborah A; Hoffman, Gary S

    2017-01-01

    It is controversial whether microorganisms play a role in the pathogenesis of large and medium vessel vasculitides (eg, giant cell arteritis [GCA], Takayasu arteritis [TAK] and focal idiopathic aortitis [FIA]). Recent studies have reported the presence of Varicella Zoster Virus (VZV) within formalin-fixed, paraffin-embedded temporal arteries and aortas of about three-quarters or more of patients with these conditions, and in a minority of controls. In a prospective study, we sought to confirm these findings using DNA extracted from vessels that were harvested under surgically aseptic conditions and snap frozen. DNA samples extracted from 11 surgically sterile temporal arteries and 31 surgically sterile thoracic aortas were used in an attempt to identify the vessel-associated VZV genome. Two different validated PCR methods were used. Thirty-one thoracic aorta aneurysm specimens included biopsies from 8 patients with GCA, 2 from patients with TAK, 6 from patients with FIA, and 15 from patients without vasculitis, who had non-inflammatory aneurysms. Eleven temporal artery biopsies were collected from 5 patients with GCA and 6 controls. The presence of VZV was not identified in either the specimens from patients with large vessel vasculitis or from the controls. Using surgically sterile snap-frozen specimens, we were unable to confirm recent reports of the presence of VZV in either aortas or temporal arteries from patients with large vessel vasculitis or controls.

  5. Investigation of Biological Adhesives and Polyurea Crosslinked Silica-Based Aerogels

    NASA Astrophysics Data System (ADS)

    Lyons, Laura; Cauble, Meagan; Cole, Judith; Sabri, Firouzeh

    2009-11-01

    One of the key steps towards developing new technology for nerve repair is to look at the interaction mechanism and strength of biological components with the material under investigation. The existing technology for peripheral nerve repair relies on suturing techniques for attaching and immobilization of the implant. It is also limited to connecting two nerve components only, through a cylindrical-shaped unit which we will refer to as 1-D. The focus of our work is to develop an aerogel-based printed circuit board (PCB) system for precise guidance of multiple (n-D) neuronal components, simultaneously. Here we report on the adhesion strength of sciatic nerve segments removed from cadaver Sprague Dawley rats and the surface of treated and untreated polyurea cross-linked silica-based aerogels. The adhesion strength of the nerve to the aerogel surface was studied under varying environmental conditions as well as surface coating types. The coatings tested were basement membrane extract (BME), Cell Tak, and the combination. Since the mechanism of adhesion to cells and other surfaces is different and non-competing for BME and Cell Tak it is expected that a stronger adhesion should be accomplished by combining these two adhesives. The effect of temperature, nerve elasticity, and ionic concentration on the strength of adhesion was investigated also and will be reported.

  6. Mutagenicity and antimutagenicity of extracts of three spices and a medicinal plant in Thailand.

    PubMed

    Higashimoto, M; Purintrapiban, J; Kataoka, K; Kinouchi, T; Vinitketkumnuen, U; Akimoto, S; Matsumoto, H; Ohnishi, Y

    1993-11-01

    Three kinds of spices (caraway, coriander and black pepper seeds) and a medicinal plant called 'tong tak' in Thai (Baliospermum axillar, a species of the spurge family) were fractionated into hot water, methanol and hexane extracts. These extracts were not mutagenic for Salmonella typhimurium strains TA98 and TA100 by the Ames assay. However, when the extracts were treated with nitrite, samples of the water and methanol extracts were mutagenic for strain TA100 without metabolic activation. The mutagenicity of the nitrite-treated methanol and hot water extracts of black pepper was highest (8380 and 22,200 His+ per 0.1 g of spice powder, respectively), and that of the nitrite-treated hot water extracts of caraway and tong tak was moderate. The hot water extracts were examined for their antimutagenic activity against mutagenicity induced by various carcinogens by the Ames assay, using the preincubation technique. The tested samples (equivalent to 1-2 mg of spice powder) reduced the mutagenicity induced by 2.7 nmole (397 ng) of N-methyl-N'-nitro-N-nitrosoguanidine by more than 84%, and that induced by dimethylnitrosamine (1.48 mg) or ICR-170 (10 ng) by 30-60%. However, they did not inhibit the mutagenic activity of 1-nitropyrene, 3-nitrofluoranthene, AF-2, methyl methanesulfonate, N-ethyl-N'-nitro-N-nitrosoguanidine, 2-aminoanthracene, 2-acetylaminofluorene, benzo[a]pyrene or IQ.

  7. Two New Plant-Like Pathways Link Hemoglobin Degradation to Lipid Biogenesis in Falciparum Malaria: Novel Targets for Anti-Malarial Chemotherapy

    DTIC Science & Technology

    2005-03-01

    when the compound was added at 50/uM (Appendix VI, B). Furthermore, clofibric acid , an inhibitor of PtdEtn methylransferases (19), had no effect on Pfpmt...reduced when the compound was added at 50 AM (Fig. 5B). Furthermore, clofibric acid , an inhibitor of PtdEtn B 35 methyltransferases (34), had no...Fig. 5B). Furthermore, clofibric acid , an takDs .Shnmn .Jnsn .Coday n .U~a o inhibitor of PtdEtn methyltransferases, had no effect on Pfpmt helpful

  8. The Defence of Duffer’s Drift

    DTIC Science & Technology

    1905-01-01

    w.arned me that my colour -sergeant was waiting for orders. (See Map 2) After a moment’s consideration, I decided to pitch my small camp on a spot just...recognised as my unhappy camera. Here, I suppose, my mind must have slightly wandered, for I found myself re- peating some Latin lines, once my favourite ...patrols returned shortly with their bag of a few men, women and children . The women indulged in much useless abuse, and refused to obey orders, tak- ing

  9. Scoping review of medical assessment units and older people with complex health needs.

    PubMed

    Rushton, Carole; Crilly, Julia; Adeleye, Adeniyi; Grealish, Laurie; Beylacq, Mandy; Forbes, Mark

    2017-03-01

    To explore current knowledge of medical assessment units (MAUs) with specific reference to older people with complex needs and to stimulate new topics and questions for future policy, research and practice. A scoping review was conducted using an integrated-latent thematic approach. This review provides a unique perspective on MAUs and older people which is framed using four themes: efficiency, effectiveness, equity and time. Eighteen articles were reviewed. Most (14) articles reported on efficiency and effectiveness while none reported explicitly on equity. Time was identified as a fourth, latent theme within the literature. Findings from this review indicate that future policy, research and practice relating to MAUs should focus on older people with complex needs, patient-centred metrics and those MAU characteristics most likely to deliver positive health outcomes to this particular cohort of patients. © 2016 AJA Inc.

  10. On the effects of thermal wake from the optical pulsating discharge on the body aerodynamic drag

    NASA Astrophysics Data System (ADS)

    Kiseleva, T. A.; Golyshev, A. A.; Yakovlev, V. I.; Orishich, A. M.

    2018-03-01

    The effect of an optical pulsed discharge created by CO2-laser with an average power of 1.8 kW on the aerodynamic drag of a model in a supersonic air flow is experimentally investigated. Experiments were carried out in a supersonic wind tunnel MAU-M (diameter of the nozzle outlet dc = 50 mm) on the modes M = 1,36, Re1 = 1.4-3.8*107 1/m. To ensure a stable optical breakdown, a jet of argon gas was introduced into the focusing region of the laser beam. As a result, a decrease in the aerodynamic drag force was obtained. It is shown, that the increasing of the laser pulses repetition frequency leads to the decreasing in the aerodynamic drag force. The maximum decrease was 15% at a maximum frequency f = 90 kHz.

  11. Matrix infrared spectroscopy and quantum-chemical calculations for the coinage-metal fluorides: comparisons of Ar-AuF, Ne-AuF, and Molecules MF2 and MF3.

    PubMed

    Wang, Xuefeng; Andrews, Lester; Brosi, Felix; Riedel, Sebastian

    2013-01-21

    The reactions of laser-ablated Au, Ag, and Cu atoms with F(2) in excess argon and neon gave new absorptions in the M-F stretching region of their IR spectra, which were assigned to metal-fluoride species. For gold, a Ng-AuF bond was identified in mixed neon/argon samples. However, this bonding was much weaker with AgF and CuF. Molecules MF(2) and MF(3) (M=Au, Ag, Cu) were identified from the isotopic distribution of the Cu and Ag atoms, comparison of the frequencies for three metal fluorides, and theoretical frequency calculations. The AuF(5) molecule was characterized by its strongest stretching mode and theoretical frequency calculations. Additional evidence was observed for the formation of the Au(2) F(6) molecule. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Bilateral comparison on electric field measurements between TÜBİTAK UME and SASO NMCC

    NASA Astrophysics Data System (ADS)

    Aslan, Çağlar; Alrobaish, Abdullah M.; Şen, Osman

    2017-01-01

    Electromagnetic (EM) probes are widely utilized in the measurement of EM fields for non-ionizing radiation, electromagnetic compatibility (EMC) testing and other applications in the frequency range 5 Hz-60 GHz. They must be calibrated by National Metrology Institutes (NMIs) or accredited calibration laboratories in accordance with international standards such as IEEE 1309. The existing NMIs or emerging NMIs should refer to the international comparison measurements in order to assure the quality of their measurement results. Therefore, the electric field comparison measurements organized by TUBITAK UME were performed between TUBITAK UME and SASO NMCC at the 100 Hz, 1 kHz, 10 MHz, 100 MHz, 1 GHz, 10 GHz and 18 GHz frequencies in order to obtain the correction factors of the electric field probes. The comparison measurements were carried out in accordance with the Technical Protocol prepared by TUBITAK UME. The measurements started in October 2017 and were completed in January 2017. There was good agreement found for the correction factors. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

  13. The Effect of Rician Fading and Partial-Band Interference on Noise- Normalized Fast Frequency-Hopped MFSK Receivers

    DTIC Science & Technology

    1994-03-01

    FSK 16. PmCI coot 17. SECURITY CLASSWsAI1OW IL SICUURW CLA$SIICATION SECURITY CLASSIICATION 20. LIMIATION Of ABSTRACT CW REPOW ? OF TiNS PAU OF ...hop k of a symbol when partial-band interference is present is obtained from (11) and the linear transformation of random variables given by (3) as...from (13) and the transformation of random variables indicated by (9) as [16] fzwjm(zwik) = f cTak!X. (Xmk, = ZmkOkI17) f~(0,kdo . -- (,.U(zk’ )fE2

  14. M/V ELIAS Explosion and Fire at Fort Mifflin, PA., on 9 April 1974 with Loss of Life.

    DTIC Science & Technology

    1977-09-09

    above crude oilin acaro tak my beignted t alowr tepertur tha themeaure flash point of a sample of the same cargo. The reason for this anomaly is as...of 72 hours. William CALAFATY Security Guard 715 E. Allegheny Ave . Philadelphia, Pa. 4. The weather at the time of casualty was overcast with good...recess. Ladder steps on the inside of the Imer boundaries of the recesseswere seveiely wasted to a feather edqe at each sten. BEST AV A1ABIE COPY’ 25 g

  15. An Iterative Procedure for Obtaining I-Projections onto the Intersection of Convex Sets.

    DTIC Science & Technology

    1984-06-01

    Dykstra Department of Statistics and Actuarial Science The University of Iowa Iowa City, Iowa 52242 Technical Report #106 June 1984D I e ELECTE lSEP...t Theorem ~ ~ 2.. Asm i where the 4 are closed, convex sets of PD’s and R d 0 is a nonnegative vector such that there exists a T E 4 where I(TIR) < M...PERFOMING ORGANIZATION NAME AND ADDRESS 1. PROGIRA ILEMNT. PROJECT. TAK Department of Statistics and Actuarial Science AEAS a WORK UNIT Numaa The

  16. A Jupiter-mass planet around the K0 giant HD 208897

    NASA Astrophysics Data System (ADS)

    Yılmaz, M.; Sato, B.; Bikmaev, I.; Selam, S. O.; Izumiura, H.; Keskin, V.; Kambe, E.; Melnikov, S. S.; Galeev, A.; Özavcı, İ.; Irtuganov, E. N.; Zhuchkov, R. Ya.

    2017-11-01

    For over 10 years, we have carried out a precise radial velocity (RV) survey to find substellar companions around evolved G, K-type stars to extend our knowledge of planet formation and evolution. We performed high precision RV measurements for the giant star HD 208897 using an iodine (I2) absorption cell. The measurements were made at TÜBİTAK National Observatory (TUG; RTT150) and Okayama Astrophysical Observatory (OAO). For the origin of the periodic variation seen in the RV data of the star, we adopted a Keplerian motion caused by an unseen companion. We found that the star hosts a planet with a minimum mass of m2sini = 1.40 MJ, which is relatively low compared to those of known planets orbiting evolved intermediate-mass stars. The planet is in a nearly circular orbit with a period of P = 353 days at about 1 AU distance from the host star. The star is metal rich and located at the early phase of ascent along the red giant branch. The photometric observations of the star at Ankara University Kreiken Observatory (AUKR) and the Hipparcos photometry show no sign of variation with periods associated with the RV variation. Neither bisector velocity analysis nor analysis of the Ca II and Hα lines shows any correlation with the RV measurements. This work was supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK), the project number of 114F099.

  17. Benchmark experiment for the cross section of the 100Mo(p,2n)99mTc and 100Mo(p,pn)99Mo reactions

    NASA Astrophysics Data System (ADS)

    Takács, S.; Ditrói, F.; Aikawa, M.; Haba, H.; Otuka, N.

    2016-05-01

    As nuclear medicine community has shown an increasing interest in accelerator produced 99mTc radionuclide, the possible alternative direct production routes for producing 99mTc were investigated intensively. One of these accelerator production routes is based on the 100Mo(p,2n)99mTc reaction. The cross section of this nuclear reaction was studied by several laboratories earlier but the available data-sets are not in good agreement. For large scale accelerator production of 99mTc based on the 100Mo(p,2n)99mTc reaction, a well-defined excitation function is required to optimise the production process effectively. One of our recent publications pointed out that most of the available experimental excitation functions for the 100Mo(p,2n)99mTc reaction have the same general shape while their amplitudes are different. To confirm the proper amplitude of the excitation function, results of three independent experiments were presented (Takács et al., 2015). In this work we present results of a thick target count rate measurement of the Eγ = 140.5 keV gamma-line from molybdenum irradiated by Ep = 17.9 MeV proton beam, as an integral benchmark experiment, to prove the cross section data reported for the 100Mo(p,2n)99mTc and 100Mo(p,pn)99Mo reactions in Takács et al. (2015).

  18. Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes.

    PubMed

    Nishimoto, Tomoyuki; Tozawa, Ryuichi; Amano, Yuichiro; Wada, Takeo; Imura, Yoshimi; Sugiyama, Yasuo

    2003-12-01

    TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.

  19. Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome.

    PubMed

    Ackerman, Jaeger P; Smestad, John A; Tester, David J; Qureshi, Muhammad Y; Crabb, Beau A; Mendelsohn, Nancy J; Ackerman, Michael J

    2016-09-01

    To use whole exome sequencing (WES) of a family trio to identify a genetic cause for polyvalvular syndrome. A male child was born with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus that were closed surgically. Subsequently, the phenotype of polyvalvular syndrome with involvement of both semilunar and both atrioventricular valves emerged. His family history was negative for congenital heart disease. Because of hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism, either Noonan syndrome- or William syndrome-spectrum disorders were suspected clinically. However, chromosomal analysis was normal and commercially available Noonan syndrome and William syndrome genetic tests were negative. Whole exome sequencing of the patient and both parents was performed. Variants were analyzed by sporadic and autosomal recessive inheritance models. A sporadic mutation, annotated as c.1491 T > A, in TAB2, resulting in a nonsense mutation, p.Y497X, in the TAB2-encoded TGF-beta activated kinase 1 (TAK1) was identified as the most likely disease-susceptibility gene. This mutation results in elimination of the terminal 197 amino acids, including the C-terminal binding motif critical for interactions with TRAF6 and TAK1. The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome. © 2016 Wiley Periodicals, Inc.

  20. Varicella Zoster Virus and Large Vessel Vasculitis, the Absence of an Association

    PubMed Central

    Procop, Gary W.; Eng, Charis; Clifford, Alison; Villa-Forte, Alexandra; Calabrese, Leonard H.; Roselli, Eric; Svensson, Lars; Johnston, Douglas; Pettersson, Gosta; Soltesz, Edward; Lystad, Lisa; Perry, Julian D.; Blandford, Alexander; Wilson, Deborah A.; Hoffman, Gary S.

    2017-01-01

    Objective It is controversial whether microorganisms play a role in the pathogenesis of large and medium vessel vasculitides (eg, giant cell arteritis [GCA], Takayasu arteritis [TAK] and focal idiopathic aortitis [FIA]). Recent studies have reported the presence of Varicella Zoster Virus (VZV) within formalin-fixed, paraffin-embedded temporal arteries and aortas of about three-quarters or more of patients with these conditions, and in a minority of controls. In a prospective study, we sought to confirm these findings using DNA extracted from vessels that were harvested under surgically aseptic conditions and snap frozen. Methods and Results DNA samples extracted from 11 surgically sterile temporal arteries and 31 surgically sterile thoracic aortas were used in an attempt to identify the vessel-associated VZV genome. Two different validated PCR methods were used. Thirty-one thoracic aorta aneurysm specimens included biopsies from 8 patients with GCA, 2 from patients with TAK, 6 from patients with FIA, and 15 from patients without vasculitis, who had non-inflammatory aneurysms. Eleven temporal artery biopsies were collected from 5 patients with GCA and 6 controls. The presence of VZV was not identified in either the specimens from patients with large vessel vasculitis or from the controls. Conclusions Using surgically sterile snap-frozen specimens, we were unable to confirm recent reports of the presence of VZV in either aortas or temporal arteries from patients with large vessel vasculitis or controls. PMID:28758156

  1. Evaluation of Forged Helicopter Components Processed with Controlled Solidification and Thermal-Mechanical Treatments.

    DTIC Science & Technology

    1980-06-01

    PAGEREDISUCON E BEFOR COMPLEF)C TI NG FOMO 12. GOVLIENAN ACESOON.7VRTI EESAAOGNME . A U AC (nIn, on Deec . ai7e -I Jueaaee vd deey y lok um fouRMLMCAIL tak...2O 0Tf0 U02 00 1 it0 as a Sea Goo 0-0 c9 Sm . or.u9r09 04 dAA 0 0 0 𔄃 0 0 0 as gas .tstd a ass as 4.J -* N2 9: 01 1 1, 1 N1 , NN N N N _;I

  2. Synthesis of Si Nanowires for an Anode Material of Li Batteries

    DTIC Science & Technology

    2007-12-04

    Zhou, H. Li, H.P. Sun , D.P. Yu, Y.Q. Wang, X.J. Huang, L.Q. Chen, Z. Zhang, Appl. Phys. Lett. 75 (16) (1999) 2447 6. A.M. Wilson, B.M. Way, J.R. Dahn...Y. Liu, Electrochem. Commun. 5 (2003) 165 12. Tatsuo Umeno, Kenji Fukuda, Hongyu Wang, Nikolay Dimov, Takashi Iwao, Masaki Yoshio, Chem. Lett...Hansu Kim, Junghee Choi, Hun-Joon Sohn and Tak Kang, J. Electrochem. Soc. 146 (12) (1999) 4401 18. G.X. Wang, L. Sun , D.H. Bradhurst, S. Zhong, S.X. Dou

  3. Goddard Institute for Space Studies (GISS) 3-Dimensional (3-D) Global Tracer Transport Model (DB1006)

    DOE Data Explorer

    Fung, I.

    1993-01-01

    This directory contains the input files used in simulations of atmospheric CO2 using the GISS 3-D global tracer transport model. The directory contains 16 files including a help file (CO2FUNG.HLP), 12 files containing monthly exchanges with vegetation and soils (CO2VEG.JAN - DEC), 1 file containing releases of CO2 from fossil fuel burning (CO2FOS.MRL), 1 file containing releases of CO2 from land transformations (CO2DEF.HOU), and 1 file containing the patterns of CO2 exchange with the oceans (CO2OCN.TAK).

  4. Squalene synthase inhibition: a novel target for the management of dyslipidemia.

    PubMed

    Davidson, Michael H

    2007-01-01

    A new class of compounds, known as squalene synthase inhibitors, has recently reached phase III clinical trials and may provide another therapeutic option for clinicians to improve risk management of low-density lipoprotein cholesterol (LDL-C). The clinical need for another LDL-C-lowering therapy is evident by the inability to achieve an LDL-C target of less than 70 mg/dL in the majority of very high-risk patients on statin monotherapy. Human clinical trial data with TAK-475, a novel and potent inhibitor of squalene synthase, have not yet been published.

  5. Identification, Characterization and Clinical Development of the New Generation of Breast Cancer Susceptibility Alleles

    DTIC Science & Technology

    2011-03-01

    Neil M Walker2, Nicholas A Watkins8,9, Thilo Winzer8, John A Todd2, Willem H Ouwehand8,9 1958 Birth Cohort Controls: Richard W Jones18, Wendy L...Sarah Nutland2, Helen E Stevens2, Neil M Walker2, Barry Widmer2,41, John A Todd2 Type 2 Diabetes (Exeter): Timothy M Frayling42,43, Rachel M...Ravindrarajah5, Pamela Whittaker5, Claire Widden5, David Withers5, Panos Deloukas5; (Cambridge): Hin Tak Leung2, Sarah Nutland2, Helen E Stevens2, Neil M

  6. The Analytic Hierarchy Process: Enhancing Operational Level Decision Making

    DTIC Science & Technology

    1993-03-10

    USN 13 TPEOFWO713b. ?WE COVERED 4L. DAT! OF, RIM" ( fta *. NWkO Isi P*MA 001MFAMo to__ / izI 16. SUP"LE MNIARY NOTATION A p ibaikitted the Pl Faat o b...TakQrce The FaajdsWar,.9-82 (New York: Viking Penguin , Inc, Rev. ed., 1988). 26 1. MISSION. To seize the Falkland Islands and eject Argentinian...Falklands War4 1982 (New York: Viking Penguin , Inc, Rev. ed., 1988). Max Hastings and Simon Jenkins, The Battle for the Falklands (New York: W. W. Norton

  7. [The effect of Toll-like receptor 4 in nicotine suppressing the osteogenic potential of periodontal ligament stem cells].

    PubMed

    Luan, Yan; Deqin, Yang

    2017-08-01

    Objective To explore the impact of nicotine on proliferation and osteogenic capability of periodontal ligament stem cells (PDLSCs), and the role of Toll-like receptor 4 (TLR4) in nicotine, suppressing the osteogenic capability of PDLSCs. Methods PDLSCs were cultured in vitro, and the flow cytometer was used to identify the surface antigen markers of PDLSCs. WST-1 was used to detect the proliferation ability of PDLSCs, which were stimulated by different concentrations of nicotine. Alizarin red staining was used to observe the formation of mineralized nodules after PDLSCs stimulation with different concentrations of nicotine. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to detect the change in osteogenic potential of PDLSCs stimulated by nicotine, after TAK-242, and with the inhibitor of TLR4. Results PDLSCs expressed mesenchymal stem cell-associated markers CD90 and CD105. When the concentration of nicotine was 10⁻⁴ mol·L⁻¹, the PDLSC proliferation could be suppressed after 3 d compared with the control group (P<0.05). The amount of mineralized nodules reduced after osteogenic differentiation at 21 d by alizarin red staining. RT-PCR and Western blot showed the expression levels of alkaline phosphatase (ALP), and osteocalcin (OCN), and the Runt-related transcription factor-2 (Runx-2) were lower than in the control group when nicotine suppressed the PDLSCs (P<0.05). This effect was attenuated after TAK-242 was added. Conclusion Nicotine suppresses the proliferation and osteogenic capability of PDLSCs, which may be regulated by TLR4.

  8. Exploring relationships between the use of affect in science instruction and the pressures of a high-stakes testing environment

    NASA Astrophysics Data System (ADS)

    Jerome, Diane C.

    This study explored how science teachers and school administrators perceive the use of the affective domain during science instruction situated within a high-stakes testing environment. Through a multimethodological inquiry using phenomenology and critical ethnography, the researcher conducted semi-structured interviews with six fifth-grade science teachers and two administrators from two Texas school districts. Data reconstructions from interviews formed a bricolage of diagrams that trace the researcher's steps through a reflective exploration of these phenomena. This study addressed the following research questions: (a) What are the attitudes, interests, and values (affective domain) that fifth-grade science teachers integrate into science instruction? (b) How do fifth-grade science teachers attempt to integrate attitudes, interests and values (affective domain) in science instruction? and (c) How do fifth-grade science teachers manage to balance the tension from the seeming pressures caused by a high-stakes testing environment and the integration of attitudes, interests and values (affective domain) in science instruction? The findings from this study indicate that as teachers tried to integrate the affective domain during science instruction, (a) their work was set within a framework of institutional values, (b) teaching science for understanding looked different before and after the onset of the science Texas Assessment of Knowledge and Skills (TAKS), and (c) upon administration of the science TAKS---teachers broadened their aim, raised their expectations, and furthered their professional development. The integration of the affective domain fell into two distinct categories: 1) teachers targeted student affect and 2) teachers modeled affective behavior.

  9. Microstructured Titanium Regulates Interleukin Production by Osteoblasts, an Effect Modulated by Exogenous BMP-2

    PubMed Central

    Hyzy, Sharon; Olivares-Navarrete, Rene; Hutton, Daphne L.; Tan, Christian; Boyan, Barbara D.; Schwartz, Zvi

    2013-01-01

    Microtextured implant surfaces increase osteoblast differentiation in vitro and enhance bone-to-implant contact in vivo and clinically. These implants may be used in combination with recombinant human bone morphogenetic protein 2 (rhBMP-2) to enhance peri-implant bone formation. However, the effect of surface modifications alone or in combination with rhBMP-2 on osteoblast-produced inflammatory microenvironment is unknown. MG63 cells were cultured on tissue culture polystyrene or titanium substrates: smooth pretreated (PT, Ra=0.2μm), sandblasted/acid-etched (SLA, Ra=3.2μm), or hydrophilic-SLA (modSLA). Expression and protein production of pro-inflammatory interleukins (IL1b, IL6, IL8, IL17) and anti-inflammatory interleukins (IL10) were measured in cells with or without rhBMP-2. To determine which BMP signaling pathways were involved, cultures were incubated with BMP pathway inhibitors to blocking Smad (dorsomorphin), TAB/TAK1 ((5Z)-7-oxozeaenol), or PKA (H-8) signaling. Culture on rough SLA and modSLA surfaces decreased pro-inflammatory interleukins and increased anti-inflammatory IL10. This effect was negated in cells treated with rhBMP-2, which caused an increase in pro-inflammatory interleukins and a decrease in anti-inflammatory interleukins through TAB/TAK signaling. The results suggest that surface microtexture modulates the inflammatory process during osseointegration, an effect that may enhance healing. However, rhBMP-2 in combination with microtextured titanium implants can influence the effect of cells on these surfaces, and may adversely affect cells involved in osseointegration. PMID:23123301

  10. Coinheritance of Hb S [β6(A3)Glu→Val, GAG>GTG] with β0-thalassemia codon 17 (A>T) in a Thai patient.

    PubMed

    Pornprasert, Sakorn; Panyasai, Sitthichai; Kongthai, Kanyakan; Treesuwan, Kallayanee

    2012-01-01

    Hb S [β6(A3)Glu→Val, GAG>GTG] is a β-globin gene variant that has a very low incidence in the Thai population. Coinheritance of Hb S and β(0)-thalassemia (β-thal) can result in severe clinical conditions. This study reports the case of a Thai patient with a compound heterozygosity for Hb S and β(0)-thal codon 17 (A>T). His hemoglobin (Hb), hematocrit (packed cell volume, PCV), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) levels were all less than the lower limits, while red cell distribution width (RDW) was higher than the upper limit. Levels of Hbs S, F and A(2) detected by high performance liquid chromatography (HPLC) were comparable to those from capillary electrophoresis (CE). As Hb S has a similar electrophoretic mobility and the HPLC profile is also similar to those of Hb Tak [β147, Term→Thr (+AC)] and Hb D-Punjab [β121(GH4)Glu→Gln, GAA>CAA], DNA sequencing was then performed. This was to detect β(0)-thal, and to differentiate Hb S from the Hb Tak and Hb D-Punjab mutations. The β(0)-thal codon 17 and Hb S mutations were detected indicating that coinheritance of these two mutations can be found in the Thai population. Therefore, to provide proper clinical management and genetic counseling of this rare case, DNA analysis should be performed in all cases when a peak at the S-window is detected by HPLC or CE.

  11. Evidence of the presence of a Be circumstelar disk in the Be/X-ray binaries KS 1947+ 300 and Cep X-4

    NASA Astrophysics Data System (ADS)

    Ozbey-Arabaci, M.; Camero-Arranz, A.; Fabregat, J.; Ozcan, H. Bilal; Peris, V.

    2014-06-01

    We report on photometric and spectroscopic optical observations of the Be/X-ray binaries KS 1947+300 and Cep X-4, obtained with the TUG Faint Object Spectrograph and Camera (TFOSC) mounted on the focal plane of the 1.5-m Russian-Turkish Telescope (RTT150) at T & Uuml;B & #304TAK National Observatory (Antalya, Turkey) between 2014 June 18-20 (MJD 56826.933-56828.067), and with the spectrograph located at the 51-cm telescope of the Observatorio de Aras de los Olmos of the University of Valencia on 2014 June 3 (MJD 56811.097). ...

  12. Maintenance Task Data Base for Buildings: Architectural Systems

    DTIC Science & Technology

    1991-05-01

    EXTERIOR DOOR Task Descriptin REPLACE METAL WIRE MESH PAINTD EEIO DOOR Unit of Measure: CWNT~ Fr enc of ccrence: H: i.~UU A: 15U.UU L: 160.00 Persons...5R.ULA5S:REPL.3RD FL.WD.FR.PAIN.)DL.EX .WIND0WS Unit of Measure: COURT- Freq.. enc OfOcr ee : 0.Yu A: 1.UU L: 1AiI Persons per Team: 1 Task DuRation: 0...System: EXTERIOR WINDOWS Susystem: INOPERABLE WIND)OWS Tak ecrpRtVLACE 2ND FLOOR STEEL FRAME(PAIT ETWINDOWS Unit of Measure: - JN I Frequjeng orOc ence : N

  13. Real-Time Environmental Artic Monitoring (R-TEAM).

    DTIC Science & Technology

    1987-11-01

    critical points of the mooring. Tension, tilt, pressure and temperature data are recorded on solid state memory for the duration of the deployment. Two...To iUe Tna£ LA6aksIIorZ. Um DESCaiPTiow r oj.t.TAK 2ALUMINUM PIPE -ob.I’ -WALL. 5e1 . Sm IVI IlSdh7 Z BOT’TOM END CAPME G,15473 (5 2 R.OD 3__ MX 306 as...described in Reference 2. Each instrument, located at a critical point of the mooring, measures and records in solid state memory tension, tilt, temperature

  14. Apoptosis-Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction.

    PubMed

    Aonuma, Tatsuya; Takehara, Naofumi; Maruyama, Keisuke; Kabara, Maki; Matsuki, Motoki; Yamauchi, Atsushi; Kawabe, Jun-Ichi; Hasebe, Naoyuki

    2016-08-01

    : Overcoming the insufficient survival of cell grafts is an essential objective in cell-based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell-based therapy. CPCs isolated from 8- to 10-week-old C57BL/6 mouse hearts were infected with retrovirus harboring APE1-DsRed (APE1-CPC) or a DsRed control (control-CPC). Oxidative stress-induced apoptosis was then assessed in APE1-CPCs, control-CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor β-activated kinase 1 (TAK1) and nuclear factor (NF)-κB. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1-CPCs compared with control-CPCs. Moreover, the number of surviving DsRed-positive CPC grafts was significantly higher 7 days after the transplant of APE1-CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1-CPCs compared with control-CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac α-sarcomeric actinin-positive CPC-grafts were observed in mice injected with APE1-CPCs compared with control-CPCs after 7 days. In conclusion, antiapoptotic APE1-CPC graft, which increased TAK1-NF-κB pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy. Improving the survival of cell grafts is essential to maximize the efficacy of cell therapy. The authors investigated the role of APE1 in

  15. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hinshaw, Stephen M.; Makrantoni, Vasso; Kerr, Alastair

    The cohesin ring holds newly replicated sister chromatids together until their separation at anaphase. Initiation of sister chromatid cohesion depends on a separate complex, Scc2NIPBL/Scc4Mau2 (Scc2/4), which loads cohesin onto DNA and determines its localization across the genome. Proper cohesin loading is essential for cell division, and partial defects cause chromosome missegregation and aberrant transcriptional regulation, leading to severe developmental defects in multicellular organisms. We present here a crystal structure showing the interaction between Scc2 and Scc4. Scc4 is a TPR array that envelops an extended Scc2 peptide. Using budding yeast, we demonstrate that a conserved patch on the surfacemore » of Scc4 is required to recruit Scc2/4 to centromeres and to build pericentromeric cohesion. These findings reveal the role of Scc4 in determining the localization of cohesin loading and establish a molecular basis for Scc2/4 recruitment to centromeres.« less

  16. Constitutional self-organization of adenine-uracil-derived hybrid materials.

    PubMed

    Arnal-Hérault, Carole; Barboiu, Mihai; Pasc, Andreea; Michau, Mathieu; Perriat, Pascal; van der Lee, Arie

    2007-01-01

    The alkoxysilane nucleobase adenine (A) and uracil (U) precursors described in this paper generate in solution a complex library of hydrogen-bonded aggregates, which can be expressed in the solid state as discrete higher oligomers. The different interconverting outputs that nucleobases may form by oligomerization define a dynamic polyfunctional diversity that may be "extracted selectively" in solid state by sol-gel transcription, under the intrinsic stability of the system. After the sol-gel process, unique constitutional preference for specific geometries in hybrid materials is consistent with a preferential arrangement of nucleobase systems, favoring the self-assembly by the Hoogsteen geometry. FTIR and NMR spectroscopy and X-ray powder diffraction experiments demonstrate the formation of self-organized hybrid supramolecular materials. Electron microscopy reveals the micrometric platelike morphology of the hybrid materials. The M(A-U) hybrid material is nanostructured in ordered circular domains of 5 nm in diameter of alternative light and dark rows with an one-dimensional periodicity of 3.5 A.

  17. Evaluation of ilmenite serpentine concrete and ordinary concrete as nuclear reactor shielding

    NASA Astrophysics Data System (ADS)

    Abulfaraj, Waleed H.; Kamal, Salah M.

    1994-07-01

    The present study involves adapting a formal decision methodology to the selection of alternative nuclear reactor concretes shielding. Multiattribute utility theory is selected to accommodate decision makers' preferences. Multiattribute utility theory (MAU) is here employed to evaluate two appropriate nuclear reactor shielding concretes in terms of effectiveness to determine the optimal choice in order to meet the radiation protection regulations. These concretes are Ordinary concrete (O.C.) and Ilmenite Serpentile concrete (I.S.C.). These are normal weight concrete and heavy heat resistive concrete, respectively. The effectiveness objective of the nuclear reactor shielding is defined and structured into definite attributes and subattributes to evaluate the best alternative. Factors affecting the decision are dose received by reactor's workers, the material properties as well as cost of concrete shield. A computer program is employed to assist in performing utility analysis. Based upon data, the result shows the superiority of Ordinary concrete over Ilmenite Serpentine concrete.

  18. Studies on the antioxidant properties of Tualang honey of Malaysia.

    PubMed

    Mohamed, Mahaneem; Sirajudeen, Kns; Swamy, M; Yaacob, Nik Soriani; Sulaiman, Siti Amrah

    2009-10-15

    Honey has been used since ancient times for its nutritional as well as curative properties. Tualang honey is collected from wild honey bees' hives on Tualang trees found in the Malaysian rain forest. It has been used traditionally for the treatment of various diseases, where its therapeutic value has partly been related to its antioxidant properties. This study therefore assessed the colour intensity, total phenolic content, antioxidant activity and antiradical activity of gamma irradiated Tualang Honey. The colour intensity at ABS₄₅₀ was 489.5 ± 1.7 mAU, total phenolic content was 251.7 ± 7.9 mg (gallic acid) /Kg honey, total antioxidant activity by FRAP assay was 322.1 ± 9.7 (µM Fe(II)) and the antiradical activity by DPPH assay was 41.30 ± 0.78 (% inhibition). The data confirms that the antioxidant properties of gamma irradiated Tualang honey are similar to other types of honeys reported in the literature.

  19. Public Perceptions of Ethical, Legal and Social Implications of Pre-implantation Genetic Diagnosis (PGD) in Malaysia.

    PubMed

    Olesen, Angelina P; Mohd Nor, Siti Nurani; Amin, Latifah; Che Ngah, Anisah

    2017-12-01

    Pre-implantation genetic diagnosis (PGD) became well known in Malaysia after the birth of the first Malaysian 'designer baby', Yau Tak in 2004. Two years later, the Malaysian Medical Council implemented the first and only regulation on the use of Pre-implantation Genetic Diagnosis in this country. The birth of Yau Tak triggered a public outcry because PGD was used for non-medical sex selection thus, raising concerns about PGD and its implications for the society. This study aims to explore participants' perceptions of the future implications of PGD for the Malaysian society. We conducted in-depth interviews with 21 participants over a period of one year, using a semi-structured questionnaire. Findings reveal that responses varied substantially among the participants; there was a broad acceptance as well as rejection of PGD. Contentious ethical, legal and social issues of PGD were raised during the discussions, including intolerance to and discrimination against people with genetic disabilities; societal pressure and the 'slippery slope' of PGD were raised during the discussions. This study also highlights participants' legal standpoint, and major issues regarding PGD in relation to the accuracy of diagnosis. At the social policy level, considerations are given to access as well as the impact of this technology on families, women and physicians. Given these different perceptions of the use of PGD, and its implications and conflicts, policies and regulations of the use of PGD have to be dealt with on a case-by-case basis while taking into consideration of the risk-benefit balance, since its application will impact the lives of so many people in the society.

  20. Sources of granite magmatism in the Embu Terrane (Ribeira Belt, Brazil): Neoproterozoic crust recycling constrained by elemental and isotope (Sr-Nd-Pb) geochemistry

    NASA Astrophysics Data System (ADS)

    Alves, Adriana; Janasi, Valdecir de Assis; Campos Neto, Mario da Costa

    2016-07-01

    Whole rock elemental and Sr-Nd isotope geochemistry and in situ K-feldspar Pb isotope geochemistry were used to identify the sources involved in the genesis of Neoproterozoic granites from the Embu Terrane, Ribeira Belt, SE Brazil. Granite magmatism spanned over 200 Ma (810-580 Ma), and is dominated by crust-derived relatively low-T (850-750 °C, zircon saturation) biotite granites to biotite-muscovite granites. Two Cryogenian plutons show the least negative εNdt (-8 to -10) and highest mg# (30-40) of the whole set. Their compositions are strongly contrasted, implying distinct sources for the peraluminous (ASI ∼ 1.2) ∼660 Ma Serra do Quebra-Cangalha batholith (metasedimentary rocks from relatively young upper crust with high Rb/Sr and low Th/U) and the metaluminous (ASI = 0.96-1.00) ∼ 630 Ma Santa Catarina Granite. Although not typical, the geochemical signature of these granites may reflect a continental margin arc environment, and they could be products of a prolonged period of oceanic plate consumption started at ∼810 Ma. The predominant Ediacaran (595-580 Ma) plutons have a spread of compositions from biotite granites with SiO2 as low as ∼65% (e.g., Itapeti, Mauá, Sabaúna and Lagoinha granites) to fractionated muscovite granites (Mogi das Cruzes, Santa Branca and Guacuri granites; up to ∼75% SiO2). εNdT are characteristically negative (-12 to -18), with corresponding Nd TDM indicating sources with Paleoproterozoic mean crustal ages (2.0-2.5 Ga). The Guacuri and Santa Branca muscovite granites have the more negative εNdt, highest 87Sr/86Srt (0.714-0.717) and lowest 208Pb/206Pb and 207Pb/206Pb, consistent with an old metasedimentary source with low time-integrated Rb/Sr. However, a positive Nd-Sr isotope correlation is suggested by data from the other granites, and would be consistent with mixing between an older source predominant in the Mauá granite and a younger, high Rb/Sr source that is more abundant in the Lagoinha granite sample. The

  1. Inter-decadal variation of the Tropical Atlantic-Korea (TA-K) teleconnection pattern during boreal summer season

    NASA Astrophysics Data System (ADS)

    Ham, Yoo-Geun; Hwang, YeonJi; Lim, Young-Kwon; Kwon, Minho

    2017-12-01

    The inter-decadal variation of the positive relationship between the tropical Atlantic sea surface temperature (SST) and Korean precipitation during boreal summer season during 1900-2010 is examined. The 15-year moving correlation between the Tropical Atlantic SST (TAtlSST) index (SST anomalies from 30°S to 30°N and 60°W to 20°E) and Korean precipitation (precipitation anomalies from 35°-40°N to 120°-130°E) during June-July-August exhibits strong inter-decadal variation, which becomes positive at the 95% confidence level after the 1980s. Intensification of the linkage between the TAtlSST index and Korean precipitation after the 1980s is attributed to global warming via the increased background SST. The increase in the background SST over the Atlantic provides background conditions that enhance anomalous convective activity by anomalous Atlantic SST warming. Therefore, the overall atmospheric responses associated with the tropical Atlantic SST warming could intensify. The correlation between the TAtlSST index and Korean precipitation also exhibits strong inter-decadal variation within 1980-2010, which is over 0.8 during early 2000s, while it is relative low (i.e., around 0.6) during the early 1980s. The enhanced co-variability between the tropical and the mid-latitude Atlantic SST during the early 2000s indicates the intensification of TAtlSST-related Rossby wave source over the mid-latitude Atlantic, which excites stationary waves propagated from the Atlantic to the Korean peninsula across northern Europe and northeast Asia. This Rossby-wave train induces a cyclonic flow over the northern edge of the Korea, which intensifies southwesterly and results in precipitation over Korea. This observed decadal difference is well simulated by the stationary wave model experiments with a prescribed TAtlSST-related Rossby wave source over the mid-latitude Atlantic.

  2. High-resolution abundance analysis of the metallic-line star HR 7250

    NASA Astrophysics Data System (ADS)

    Elmaslı, Aslı; Ünal, Kübraözge; Çalışkan, Şeyma

    2018-07-01

    We estimated the stellar parameters and chemical abundances of the highly neglected A-type star HR 7250. The star's high resolution spectrum, spanning a wavelength range from 3900 to 7900 Å, was obtained at the TÜBİTAK National Observatory. We derived the abundances of 14 elements (O, Na, Mg, Si, S, Ca, Sc, Ti, Cr, Fe, Ni, Sr, Y, and Ba) for HR 7250 from the unblended lines of the star's spectrum. Our analysis shows that HR 7250 is a chemically peculiar Am star. We also estimated its age and mass as 400 ± 70 Myr and 3.25 ± 0.17 M⊙ from evolutionary tracks and isochrones.

  3. A new software on TUG-T60 autonomous telescope for astronomical transient events

    NASA Astrophysics Data System (ADS)

    Dindar, Murat; Helhel, Selçuk; Esenoğlu, Hasan; Parmaksızoğlu, Murat

    2015-03-01

    Robotic telescopes usually run under the control of a scheduler, which provides high-level control by selecting astronomical targets for observation. TÜBİTAK (Scientific and Technological Research Council of Turkey) National Observatory (TUG)-T60 Robotic Telescope is controlled by open-source OCAAS software, formally named Talon. This study introduces new software which was designed for Talon to catch GRB, GAIA and transient alerts. The new GRB software module (daemon process) alertd is running with all other modules of Talon such as telescoped; focus, dome; camerad and telrun. Maximum slew velocity and acceleration limits of the T60 telescope are enough fast for the GRB and transient observations.

  4. Carbon dynamics and CO2 and CH4 outgassing in the Mekong delta

    NASA Astrophysics Data System (ADS)

    Borges, Alberto V.; Abril, Gwenaël; Bouillon, Steven

    2018-02-01

    -POC variations also indicated intense phytoplankton growth in the side channels, presumably due to nutrient enrichment related to the shrimp farming ponds. A data set in the mangrove creeks of the Ca Mau province (part of the Mekong delta) was also acquired in April and October 2004. These data extended the range of variability in pCO2 and %O2 with more extreme values than in the Mekong delta (Bến Tre), with maxima and minima of 6912 ppm and 37 %, respectively. Similarly, the maximum CH4 concentration (686 nmol L-1) was higher in the Ca Mau province mangrove creeks than in the Mekong delta (Bến Tre, maximum 222 nmol L-1) during the October 2004 cruise (rainy season and high freshwater discharge period). In April 2004 (dry season and low freshwater discharge period), the CH4 values were much lower than in October 2004 (average 19 ± 13 and 210 ± 158 nmol L-1, respectively) in the Ca Mau province mangrove creeks, owing to the higher salinity (average 33.2 ± 0.6 and 14.1 ± 1.2, respectively) that probably led to higher sediment sulfate reduction, leading to inhibition of sediment methanogenesis and higher anaerobic CH4 oxidation. In the inner estuarine region (three branches of the Mekong delta), CO2 emissions to the atmosphere averaged 121 mmol m-2 d-1, and the CH4 emissions averaged 118 µmol m-2 d-1. The CO2 emission to the atmosphere from the Mekong inner estuary was higher than reported in the Yangtze and Pearl river inner estuaries. This was probably due to the lower salinity in the Mekong delta branches, possibly due to different morphology: relatively linear channels in the Mekong delta versus funnel-shaped estuaries for the Yangtze and Pearl river inner estuaries.

  5. In Vitro Studies on the Antimicrobial Peptide Human Beta-Defensin 9 (HBD9): Signalling Pathways and Pathogen-Related Response (An American Ophthalmological Society Thesis)

    PubMed Central

    Dua, Harminder S.; Otri, Ahmad Muneer; Hopkinson, Andrew; Mohammed, Imran

    2014-01-01

    Purpose: Human β-defensins (HBDs) are an important part of the innate immune host defense at the ocular surface. Unlike other defensins, expression of HBD9 at the ocular surface is reduced during microbial infection, but activation of toll-like receptor 2 (TLR2) in corneal epithelial cells has been shown to up-regulate HBD9. Our purpose was to test the hypothesis that TLR2 has a key role in the signalling pathway(s) involved in the overexpression or underexpression of HBD9, and accordingly, different pathogens would induce a different expression pattern of HBD9. Methods: The in vitro RNAi silencing method and response to dexamethasone were used to determine key molecules involved in signalling pathways of HBD9 in immortalized human corneal epithelial cells. The techniques included cell culture with exposure to specific transcription factor inhibitors and bacteria, RNA extraction and cDNA synthesis, quantitative real-time polymerase chain reaction, and immunohistology. Results: This study demonstrates that TLR2 induces HBD9 mRNA and protein expression in a time- and dose-dependent manner. Transforming growth factor-β–activated kinase 1 (TAK1) plays a central role in HBD9 induction by TLR2, and transcription factors c-JUN and activating transcription factor 2 are also involved. Dexamethasone reduces TLR2-mediated up-regulation of HBD9 mRNA and protein levels in mitogen-activated protein kinase phosphatase 1 (MKP1)-dependent and c-JUN-independent manner. HBD9 expression differs with gram-negative and gram-positive bacteria. Conclusions: TLR2-mediated MKPs and nuclear factor-κB signalling pathways are involved in HBD9 expression. TAK-1 is a key molecule. These molecules can be potentially targeted to modulate HBD9 expression. Differential expression of HBD9 with different bacteria could be related to differences in pathogen-associated molecular patterns of these organisms. PMID:25646028

  6. Polyphenols from Lonicera caerulea L. Berry Inhibit LPS-Induced Inflammation through Dual Modulation of Inflammatory and Antioxidant Mediators.

    PubMed

    Wu, Shusong; Yano, Satoshi; Chen, Jihua; Hisanaga, Ayami; Sakao, Kozue; He, Xi; He, Jianhua; Hou, De-Xing

    2017-06-28

    Lonicera caerulea L. berry polyphenols (LCBP) are considered as major components for bioactivity. This study aimed to clarify the molecular mechanisms by monitoring inflammatory and antioxidant mediator actions in lipopolysaccharide (LPS)-induced mouse paw edema and macrophage cell model. LCBP significantly attenuated LPS-induced paw edema (3.0 ± 0.1 to 2.8 ± 0.1 mm, P < 0.05) and reduced (P < 0.05) serum levels of monocyte chemotactic protein-1 (MCP-1, 100.9 ± 2.3 to 58.3 ± 14.5 ng/mL), interleukin (IL)-10 (1596.1 ± 424.3 to 709.7 ± 65.7 pg/mL), macrophage inflammatory protein (MIP)-1α (1761.9 ± 208.3 to 1369.1 ± 56.4 pg/mL), IL-6 (1262.8 ± 71.7 to 499.0 ± 67.1 pg/mL), IL-4 (93.3 ± 25.7 to 50.7 ± 12.5 pg/mL), IL-12(p-70) (580.4 ± 132.0 to 315.2 ± 35.1 pg/mL), and tumor necrosis factor-α (TNF-α, 2045.5 ± 264.9 to 1270.7 ± 158.6 pg/mL). Cell signaling analysis revealed that LCBP inhibited transforming growth factor β activated kinase-1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways, and enhanced the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and manganese-dependent superoxide dismutase (MnSOD) in earlier response. Moreover, cyanidin 3-glucoside (C3G) and (-)-epicatechin (EC), two major components of LCBP, directly bound to TAK1. These data demonstrated that LCBP might inhibit LPS-induced inflammation by modulating both inflammatory and antioxidant mediators.

  7. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling.

    PubMed

    Channavajhala, Padma L; Wu, Leeying; Cuozzo, John W; Hall, J Perry; Liu, Wei; Lin, Lih-Ling; Zhang, Yuhua

    2003-11-21

    Kinase suppressor of Ras (KSR) is an integral and conserved component of the Ras signaling pathway. Although KSR is a positive regulator of the Ras/mitogen-activated protein (MAP) kinase pathway, the role of KSR in Cot-mediated MAPK activation has not been identified. The serine/threonine kinase Cot (also known as Tpl2) is a member of the MAP kinase kinase kinase (MAP3K) family that is known to regulate oncogenic and inflammatory pathways; however, the mechanism(s) of its regulation are not precisely known. In this report, we identify an 830-amino acid novel human KSR, designated hKSR-2, using predictions from genomic data base mining based on the structural profile of the KSR kinase domain. We show that, similar to the known human KSR, hKSR-2 co-immunoprecipitates with many signaling components of the Ras/MAPK pathway, including Ras, Raf, MEK-1, and ERK-1/2. In addition, we demonstrate that hKSR-2 co-immunoprecipitates with Cot and that co-expression of hKSR-2 with Cot significantly reduces Cot-mediated MAPK and NF-kappaB activation. This inhibition is specific to Cot, because Ras-induced ERK and IkappaB kinase-induced NF-kappaB activation are not significantly affected by hKSR-2 co-expression. Moreover, Cot-induced interleukin-8 production in HeLa cells is almost completely inhibited by the concurrent expression of hKSR-2, whereas transforming growth factor beta-activated kinase 1 (TAK1)/TAK1-binding protein 1 (TAB1)-induced interleukin-8 production is not affected by hKSR-2 co-expression. Taken together, these results indicate that hKSR-2, a new member of the KSR family, negatively regulates Cot-mediated MAP kinase and NF-kappaB pathway signaling.

  8. GDF‑15 prevents LPS and D‑galactosamine‑induced inflammation and acute liver injury in mice.

    PubMed

    Li, Min; Song, Kui; Huang, Xiaowen; Fu, Simao; Zeng, Qiyi

    2018-06-27

    Growth differentiation factor‑15 (GDF‑15) is a transforming growth factor (TGF)‑β superfamily member with a poorly characterized biological activity, speculated to be implicated in several diseases. The present study aimed to determine whether GDF‑15 participates in sepsis‑induced acute liver injury in mice. Lipopolysaccharide (LPS) and D‑galactosamine (D‑GalN) were administered to mice to induce acute liver injury. Survival of mice, histological changes in liver tissue, and levels of inflammatory biomarkers in serum and liver tissue were evaluated following treatment with GDF‑15. The underlying mechanism was investigated by western blotting, ELISA, flow cytometry, and reverse transcription‑quantitative polymerase chain reaction using Kupffer cells. The results demonstrated that GDF‑15 prevented LPS/D‑GalN‑induced death, increase in inflammatory cell infiltration and serum alanine aminotransferase and aspartate aminotransferase activities. In addition, GDF‑15 treatment reduced the production of hepatic malondialdehyde and myeloperoxidase, and attenuated the increase of interleukin (IL)‑6, tumor necrosis factor (TNF)‑α, and IL‑1β expression in serum and liver tissue, accompanied by inducible nitric oxide synthase (iNOS) inactivation in the liver. Similar changes in the expression of inflammatory cytokines, IL‑6, TNF‑α and IL‑1β, and iNOS activation were observed in the Kupffer cells. Further mechanistic experiments revealed that GDF‑15 effectively protected against LPS‑induced nuclear factor (NF)‑κB pathway activation by regulating TGFβ‑activated kinase 1 (TAK1) phosphorylation in Kupffer cells. In conclusion, GDF‑15 reduced the activation of pro‑inflammatory factors, and prevented LPS‑induced liver injury, most likely by disrupting TAK1 phosphorylation, and consequently inhibiting the activation of the NF‑κB pathway in the liver.

  9. Mode of coreceptor use by R5 HIV type 1 correlates with disease stage: a study of paired plasma and cerebrospinal fluid isolates.

    PubMed

    Karlsson, Ulf; Antonsson, Liselotte; Repits, Johanna; Medstrand, Patrik; Owman, Christer; Kidd-Ljunggren, Karin; Hagberg, Lars; Svennerholm, Bo; Jansson, Marianne; Gisslén, Magnus; Ljungberg, Bengt

    2009-12-01

    Through the use of chimeric CXCR4/CCR5 receptors we have previously shown that CCR5-tropic (R5) HIV-1 isolates acquire a more flexible receptor use over time, and that this links to a reduced viral susceptibility to inhibition by the CCR5 ligand RANTES. These findings may have relevance with regards to the efficacy of antiretroviral compounds that target CCR5/virus interactions. Compartmentalized discrepancies in coreceptor use may occur, which could also affect the efficacy of these compounds at specific anatomical sites, such as within the CNS. In this cross-sectional study we have used wild-type CCR5 and CXCR4 as well as chimeric CXCR4/CCR5 receptors to characterize coreceptor use by paired plasma and cerebrospinal fluid (CSF) isolates from 28 HIV-1-infected individuals. Furthermore, selected R5 isolates, with varying chimeric receptor use, were tested for sensitivity to inhibition by the CCR5 antagonist TAK-779. Discordant CSF/plasma virus coreceptor use was found in 10/28 patients. Low CD4+ T cell counts correlated strongly with a more flexible mode of R5 virus CCR5 usage, as disclosed by an increased ability to utilize chimeric CXCR4/CCR5 receptors, specifically receptor FC-2. Importantly, an elevated ability to utilize chimeric receptors correlated with a reduced susceptibility to inhibition by TAK-779. Our findings show that a discordant CSF and plasma virus coreceptor use is not uncommon. Furthermore, we provide support for an emerging paradigm, where the acquisition of a more flexible mode of CCR5 usage is a key event in R5 virus pathogenesis. This may, in turn, negatively impact the efficacy of CCR5 antagonist treatment in late stage HIV-1 disease.

  10. Differences in TGF-β1 signaling and clinicopathologic characteristics of histologic subtypes of gastric cancer.

    PubMed

    Pak, Kyung Ho; Kim, Dong Hoon; Kim, Hyunki; Lee, Do Hyung; Cheong, Jae-Ho

    2016-02-04

    Aberrant TGF-β1 signaling is suggested to be involved in gastric carcinogenesis. However, the role of TGF-β1 in intestinal-type [i-GC] and diffuse-type [d-GC] gastric cancer remains largely unknown. In this study, we evaluated the expression of TGF-β1 signaling molecules and compared the clinicopathological features of i-GC and d-GC. Patients (n=365, consecutive) who underwent curative gastrectomy for gastric adenocarcinoma in 2005 were enrolled. We performed immunohistochemical staining of TGF-β1, TGF-β1 receptor-2 (TβR2), Smad4, p-ERK1/2, TGF-activated kinase (TAK)1, and p-Akt in 68 paraffin-embedded tumor blocks (33 i-GC and 35 d-GC), scored the expression according to the extent of staining, and evaluated differences between the histologic subtypes. Patients with d-GC differed from those with i-GC as follows: younger and more likely to be female; more aggressive stage; higher recurrence rate. The expression of TGF-β1 and TβR2 was higher in i-GC (P = 0.05 and P <0.001, respectively). The expression of Smad4, a representative molecule of the Smad-dependent pathway, was decreased in both subtypes. TAK1 and p-Akt, two major molecules involved in the Smad-independent pathway, were over-expressed (69 ~87% of cases stained), without a statistically significant difference between i-GC and d-GC. Of note, the expression of p-ERK1/2, a Smad-independent pathway, was significantly increased in i-GC (P = 0.008). The clinicopathological characteristics vary in different histologic gastric cancer subtypes. Although TGF-β1 signaling in gastric cancer cells appears hyper-activated in i-GC compared to d-GC, the Smad-dependent pathway seems down-regulated while the Smad-independent pathway seems up-regulated in both histologic subtypes.

  11. NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells.

    PubMed

    Kim, Ki-Hyung; Park, Seong-Hwan; Do, Kee Hun; Kim, Juil; Choi, Kyung Un; Moon, Yuseok

    2016-11-01

    Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.

  12. Azilsartan medoxomil: a new angiotensin II receptor antagonist for treatment of hypertension.

    PubMed

    Baker, William L; White, William B

    2011-12-01

    To evaluate the efficacy, safety, and clinical role of azilsartan medoxomil, an angiotensin II receptor blocker (ARB) that recently gained Food and Drug Administration approval for lowering of blood pressure (BP) in patients with hypertension. A systematic review of the literature was performed through August 2011 using MEDLINE, Web of Science, and International Pharmaceutical Abstracts and the key words and MeSH terms azilsartan, azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Abstracts presented in the last 2 years from the annual meetings of appropriate medical societies were reviewed in addition to a search of clinicaltrials.gov. Studies eligible for inclusion were in vitro or in vivo evaluations of azilsartan medoxomil, with no restrictions on patient population or indication. Data related to the patient populations and outcomes of interest were extracted from each publication. Three trials are available in full publication form with others available only as abstracts. Azilsartan medoxomil 40 mg and 80 mg daily significantly improves both systolic and diastolic BP from baseline compared with placebo, and the 80-mg dose has greater efficacy than other ARBs, including olmesartan 40 mg daily and valsartan 320 mg daily. Improvements in both 24-hour BP using ambulatory monitoring and clinic monitoring have been seen with azilsartan medoxomil as well as a higher proportion of patients reaching the goal level. Additional information shows added BP lowering when azilsartan medoxomil is combined with chlorthalidone. Adverse events are similar with azilsartan medoxomil versus other ARBs and include headache, dizziness, urinary tract infections, and fatigue. Azilsartan medoxomil is a safe and effective ARB with a unique pharmacologic profile versus other agents, including slowed angiotensin II type 1 receptor dissociation rates and improved receptor specificity. Studies have shown azilsartan medoxomil 80 mg once daily to reduce BP to a greater extent than valsartan

  13. Geopolymers in Construction / Zastosowanie Geopolimerów W Budownictwie

    NASA Astrophysics Data System (ADS)

    Błaszczyński, Tomasz Z.; Król, Maciej R.

    2015-03-01

    Within the framework of quests of supplementary and "healthier" binders to the production of concrete followed the development of geopolymers in construction. However the practical application of these materials is still very limited. The production of each ton of cement introduces one ton of CO2 into the atmosphere. According to various estimations, the synthesis of geopolymers absorbs 2-3 times less energy than the Portland cement and causes a generation of 4-8 times less of CO2. Geopolymeric concretes possess a high compressive strength, very small shrinkage and small creep, and they possess a high resistance to acid and sulphate corrosion. These concretes are also resistant to carbonate corrosion and possess a very high fire resistance and also a high resistance to UV radiation. W ramach poszukiwania zastępczych i "zdrowszych" spoiw do produkcji betonu nastąpił rozwój geopolimerów w budownictwie. Jednakże praktyczne zastosowanie tych materiałów jest jeszcze nadal bardzo ograniczone. Produkcja każdej tony cementu wprowadza do atmosfery tonę CO2. Według różnych szacunków, synteza geopolimerów pochłania 2-3 razy mniej energii, niż cementu portlandzkiego oraz powoduje wydzielenie 4-8 razy mniejszej ilości CO2. Do tego betony geopolimerowe posiadają wysoką wytrzymałość na ściskanie, bardzo mały skurcz i małe pełzanie oraz dają wysoką odporność na korozję kwasową i siarczanową. Betony te są także odporne na korozję węglanową i posiadają bardzo wysoką odporność ogniową, a także wysoką odporność na promieniowanie UV.

  14. IRAK4 kinase activity controls Toll-like receptor-induced inflammation through the transcription factor IRF5 in primary human monocytes.

    PubMed

    Cushing, Leah; Winkler, Aaron; Jelinsky, Scott A; Lee, Katherine; Korver, Wouter; Hawtin, Rachael; Rao, Vikram R; Fleming, Margaret; Lin, Lih-Ling

    2017-11-10

    Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate immune signaling by Toll-like receptors (TLRs), and loss of IRAK4 activity in mice and humans increases susceptibility to bacterial infections and causes defects in TLR and IL1 ligand sensing. However, the mechanism by which IRAK4 activity regulates the production of downstream inflammatory cytokines is unclear. Using transcriptomic and biochemical analyses of human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the activation of interferon regulatory factor 5 (IRF5), a transcription factor implicated in the pathogenesis of multiple autoimmune diseases. Following TLR7/8 stimulation by its agonist R848, chemical inhibition of IRAK4 abolished IRF5 translocation to the nucleus and thus prevented IRF5 binding to and activation of the promoters of inflammatory cytokines in human monocytes. We also found that IKKβ, an upstream IRF5 activator, is phosphorylated in response to the agonist-induced TLR signaling. Of note, IRAK4 inhibition blocked IKKβ phosphorylation but did not block the nuclear translocation of NFκB, which was surprising, given the canonical role of IKKβ in phosphorylating IκB to allow NFκB activation. Moreover, pharmacological inhibition of either IKKβ or the serine/threonine protein kinase TAK1 in monocytes blocked TLR-induced cytokine production and IRF5 translocation to the nucleus, but not nuclear translocation of NFκB. Taken together, our data suggest a mechanism by which IRAK4 activity regulates TAK1 and IKKβ activation, leading to the nuclear translocation of IRF5 and induction of inflammatory cytokines in human monocytes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Student achievement in science and mathematics on campuses that have implemented the CSCOPE curriculum model

    NASA Astrophysics Data System (ADS)

    Wilson, Emily R.

    The purpose of this study was to determine whether differences in student achievement exist between school campuses which followed a specific standards-based curriculum model (CSCOPE) and school campuses which followed a non-CSCOPE or traditional curriculum model. One-hundred and sixty CSCOPE curriculum campuses and 160 non-CSCOPE curriculum campuses were used in the study. Achievement data were collected on students in the fifth, eighth, and eleventh grades using the campuses percentage passing on the Texas Assessment of Knowledge and Skills (TAKS) for both science and mathematics. The TAKS is the state-mandated assessment system used to comply with federal testing guidelines. Data for the 2007-2008 school year were used for the elementary level while data from 2006-2007 and 2007-2008 were used for junior high (middle school) and high school levels. Data were analyzed by overall class as well as aggregated by ethnic classifications. Descriptive statistics were used to summarize achievement results and t-tests were utilized to analyze achievement differences between the two curriculum models. Overall fifth grade students in CSCOPE schools outperformed (p < .05) non-CSCOPE counterparts in science and mathematics. Also, fifth grade Hispanic students using CSCOPE curriculum scored higher (p < .05) than those in traditional curricula. Eighth grade students in CSCOPE schools performed better (p < .05) in science than students in non-CSCOPE schools. Finally, eighth grade Hispanic and White subgroups using CSCOPE curriculum outperformed ( p < .05) their ethnic counterparts using traditional curriculum models. The only statistically significant finding at the eleventh grade level was the African-American subgroup in science, but this subgroup had too small of a sample to infer the findings to the population. Thus, the results would tend to support use of the standardized curriculum model (CSCOPE) at lower levels whereas achievement in high school may not be differentially

  16. Feline urate urolithiasis.

    PubMed

    Appel, Sherry L; Houston, Doreen M; Moore, Andrew E P; Weese, J Scott

    2010-05-01

    This retrospective case control study describes associations between feline urate urolithiasis and breed, age, gender, and urine composition. Data from cases of feline uroliths submitted to the Canadian Veterinary Urolith Centre (CVUC) between February 2, 1998 and July 7, 2007 were reviewed. There were 10 083 feline uroliths examined, including 385 ammonium urate, 13 uric acid, and 21 mixed struvite/urate uroliths. The Egyptian Mau, Birman, and Siamese breeds were significantly predisposed to urate urolithiasis [odds ratio (OR) = 118, 95% confidence interval (CI) = 38.2 to 510, P < 0.001], (OR = 9.1, 95% CI = 2.0 to 32, P < 0.001) and (OR = 3.9, 95% CI = 2.5 to 5.9, P < 0.001), respectively. Urate urolithiasis was more frequent in younger cats (mean age 6.3 versus 7.1 y in cats with other uroliths, P < 0.0001) and in male cats (P = 0.024). The association between Egyptian Maus and urate urolithiasis was remarkable. The association in Siamese cats is consistent with prior reports, and the association with Birman cats requires further study.

  17. A Method for Exploring Program and Portfolio Affordability Tradeoffs Under Uncertainty Using Epoch-Era Analysis: A Case Application to Carrier Strike Group Design

    DTIC Science & Technology

    2015-04-30

    Portfolio C reaches an fNPT value of one at a K value of 10%. This means that Portfolio C is within 10% of the Pareto frontier in terms of MAU and...Åèìáëáíáçå=oÉëÉ~êÅÜ=mêçÖê~ã= dê~Çì~íÉ=pÅÜççä=çÑ=_ìëáåÉëë= C =mìÄäáÅ=mçäáÅó= k~î~ä=mçëíÖê~Çì~íÉ=pÅÜççä= SYM-AM-15-101 mêçÅÉÉÇáåÖë= çÑ=íÜÉ= qïÉäÑíÜ...b. ABSTRACT unclassified c . THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 ^Åèìáëáíáçå=oÉëÉ~êÅÜ=mêçÖê~ã

  18. Cross section of α-induced reactions on iridium isotopes obtained from thick target yield measurement for the astrophysical γ process

    NASA Astrophysics Data System (ADS)

    Szücs, T.; Kiss, G. G.; Gyürky, Gy.; Halász, Z.; Fülöp, Zs.; Rauscher, T.

    2018-01-01

    The stellar reaction rates of radiative α-capture reactions on heavy isotopes are of crucial importance for the γ process network calculations. These rates are usually derived from statistical model calculations, which need to be validated, but the experimental database is very scarce. This paper presents the results of α-induced reaction cross section measurements on iridium isotopes carried out at first close to the astrophysically relevant energy region. Thick target yields of 191Ir(α,γ)195Au, 191Ir(α,n)194Au, 193Ir(α,n)196mAu, 193Ir(α,n)196Au reactions have been measured with the activation technique between Eα = 13.4 MeV and 17 MeV. For the first time the thick target yield was determined with X-ray counting. This led to a previously unprecedented sensitivity. From the measured thick target yields, reaction cross sections are derived and compared with statistical model calculations. The recently suggested energy-dependent modification of the α + nucleus optical potential gives a good description of the experimental data.

  19. In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject.

    PubMed

    Tsibris, Athe M N; Sagar, Manish; Gulick, Roy M; Su, Zhaohui; Hughes, Michael; Greaves, Wayne; Subramanian, Mani; Flexner, Charles; Giguel, Françoise; Leopold, Kay E; Coakley, Eoin; Kuritzkes, Daniel R

    2008-08-01

    Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.

  20. Inhibition of Glycogen Synthase Kinase-3ß Enhances Cognitive Recovery after Stroke: The Role of TAK1

    ERIC Educational Resources Information Center

    Venna, Venugopal Reddy; Benashski, Sharon E.; Chauhan, Anjali; McCullough, Louise D.

    2015-01-01

    Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3ß (GSK-3ß) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3ß is active only when…

  1. Smoking, alcohol consumption and betal-quid chewing among young adult Myanmar laborers in Thailand.

    PubMed

    Htin, Kyaw; Howteerakull, Nopporn; Suwannapong, Nawarat; TipayamongkholgulI, Mathuros

    2014-07-01

    Health-risk behaviors among young adults are a serious public health problem. This cross sectional study aimed to estimate the prevalence of single and concurrent multiple health-risk behaviors: smoking tobacco, consuming alcohol, and chewing betel quid among young adult Myanmar laborers in Mae Sot District, Tak Province, Thailand. Three hundred Myanmar laborers, aged 18-24 years, were interviewed using a structured questionnaire. About 33.6% reported no risk behaviors, 24.7% had one, and 41.7% had two or three risk behaviors. Multinomial logistic regression analysis showed six variables were significantly associated with health-risk behaviors: male gender, high/moderate custom/traditional influences, friends who smoked/consumed alcohol/chewed betel quid, and exposure to betel-quid chewing by other family members.

  2. Proximal metatarsal osteotomies: a comparative geometric analysis conducted on sawbone models.

    PubMed

    Nyska, Meir; Trnka, Hans-Jörg; Parks, Brent G; Myerson, Mark S

    2002-10-01

    We evaluated the change in position of the first metatarsal head using a three-dimensional digitizer on sawbone models. Crescentic, closing wedge, oblique shaft (Ludloff 8 degrees and 16 degrees), reverse oblique shaft (Mau 8 degrees and 16 degrees), rotational "Z" (Scarf), and proximal chevron osteotomies were performed and secured using 3-mm screws. The 16 degrees Ludloff provided the most lateral shift (9.5 mm) and angular correction (14.5 degrees) but also produced the most elevation (1.4 mm) and shortening (2.9 mm). The 8 degrees Ludloff provided lateral and angular corrections similar to those of the crescentic and closing wedge osteotomies with less elevation and shortening. Because the displacement osteotomies (Scarf, proximal chevron) provided less angular correction, the same lateral displacement, and less shortening than the basilar angular osteotomies, based upon this model they can be more reliably used for a patient with a mild to moderate deformity, a short first metatarsal, or an intermediate deformity with a large distal metatarsal articular angle. These results can serve as recommendations for selecting the optimal osteotomy with which to correct a deformation.

  3. Visible-light promoted catalytic activity of dumbbell-like Au nanorods supported on graphene/TiO2 sheets towards hydrogenation reaction.

    PubMed

    Dai, Yunqian; Zhu, Mingyun; Wang, Xiaotian; Wu, Yanan; Huang, Chengqian; Fu, Wanlin; Meng, Xiangyu; Sun, Yueming

    2018-06-15

    In this work, the rationally-designed sharp corners on Au nanorods tremendously improved the catalytic activity, particularly in the presence of visible light irradiation, towards the hydrogenation of 4-nitrophenol to 4-aminophenol. A strikingly increased rate constant of 50.6 g -1 s -1 L was achieved in M-Au-3, which was 41.8 times higher than that of parent Au nanorods under dark conditions. The enhanced activities were proportional to the extent of the protruding sharp corners. Furthermore, remarkably enhanced activities were achieved in novel ternary Au/RGO/TiO 2 sheets, which were endowed with a 52.0 times higher rate constant than that of straight Au nanorods. These remarkably enhanced activities were even higher than those of previously reported 3-5 nm Au and 3 nm Pt nanoparticles. It was systematically observed that there are three aspects to the synergistic effects between Au and RGO sheets: (i) electron transfer from RGO to Au, (ii) a high concentration of p-nitrophenol close to dumbbell-like Au nanorods on RGO sheets, and (iii) increased local reaction temperature from the photothermal effect of both dumbbell-like Au nanorods and RGO sheets.

  4. Towards microalbuminuria determination on a disposable diagnostic microchip with integrated fluorescence detection based on thin-film organic light emitting diodes.

    PubMed

    Hofmann, Oliver; Wang, Xuhua; Demello, John C; Bradley, Donal D C; Demello, Andrew J

    2005-08-01

    As a first step towards a fully disposable stand-alone diagnostic microchip for determination of urinary human serum albumin (HSA), we report the use of a thin-film organic light emitting diode (OLED) as an excitation source for microscale fluorescence detection. The OLED has a peak emission wavelength of 540 nm, is simple to fabricate on flexible or rigid substrates, and operates at drive voltages below 10 V. In a fluorescence assay, HSA is reacted with Albumin Blue 580, generating a strong emission at 620 nm when excited with the OLED. Filter-less discrimination between excitation light and generated fluorescence is achieved through an orthogonal detection geometry. When the assay is performed in 800 microm deep and 800 microm wide microchannels on a poly(dimethylsiloxane)(PDMS) microchip at flow rates of 20 microL min(-1), HSA concentrations down to 10 mg L(-1) can be detected with a linear range from 10 to 100 mg L(-1). This sensitivity is sufficient for the determination of microalbuminuria (MAU), an increased urinary albumin excretion indicative of renal disease (clinical cut-off levels: 15-40 mg L(-1)).

  5. Design and Fabrication of the NASA Decoupler Pylon for the F-16 Aircraft

    NASA Technical Reports Server (NTRS)

    Clayton, J. D.; Haller, R. L.; Hassler, J. M., Jr.

    1985-01-01

    The NASA Decoupler Pylon is a passive means of suppressing wing-store flutter. The feasibility of demonstrating this concept on the F-16 aircraft was established through model wind tunnel tests and analyses. As a result of these tests and studies a ship set of Decoupler Pylons was designed and fabricated for a flight test demonstration on the F-16 aircraft. Basic design criteria were developed during the analysis study pertaining to pylon pitch stiffness, alignment system requirements, and damping requirements. A design was developed which utilized an electrical motor for the pylon alignment system. The design uses a four pin, two link pivot design which results in a remote pivot located at the center of gravity of the store when the store is in the aligned position. The pitch spring was fabricated from a tapered constant stress cantilevered beam. The pylon has the same external lines as the existing production pylon and is designed to use a MAU-12 ejection rack which is the same as the one used with the production pylon. The detailed design and fabrication was supported with a complete ground test of the pylon prior to shipment to NASA.

  6. Absorbance detector for high performance liquid chromatography based on a deep-UV light-emitting diode at 235nm.

    PubMed

    da Silveira Petruci, João Flavio; Liebetanz, Michael G; Cardoso, Arnaldo Alves; Hauser, Peter C

    2017-08-25

    In this communication, we describe a flow-through optical absorption detector for HPLC using for the first time a deep-UV light-emitting diode with an emission band at 235nm as light source. The detector is also comprised of a UV-sensitive photodiode positioned to enable measurement of radiation through a flow-through cuvette with round aperture of 1mm diameter and optical path length of 10mm, and a second one positioned as reference photodiode; a beam splitter and a power supply. The absorbance was measured and related to the analyte concentration by emulating the Lambert-Beer law with a log-ratio amplifier circuitry. This detector showed noise levels of 0.30mAU, which is comparable with our previous LED-based detectors employing LEDs at 280 and 255nm. The detector was coupled to a HPLC system and successfully evaluated for the determination of the anti-diabetic drugs pioglitazone and glimepiride in an isocratic separation and the benzodiazepines flurazepam, oxazepam and clobazam in a gradient elution. Good linearities (r>0.99), a precision better than 0.85% and limits of detection at sub-ppm levels were achieved. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Discovery and Mass Measurements of a Cold, Sub-Neptune Mass Planet and Its Host Star

    NASA Technical Reports Server (NTRS)

    Barry, Richard K., Jr.

    2011-01-01

    The gravitational microlensing exoplanet detection method is uniquely sensitive to cold, low-mass planets which orbit beyond the snow-line, where the most massive planets are thought to form. The early statistical results from microlensing indicate that Neptune-Saturn mass planets located beyond the snow-line are substantially more common than their counterparts in closer orbits that have found by the Doppler radial velocity method. We present the discovery of the planet MOA-2009-BLG-266Lb, which demonstrates that the gravitational microlensing method also has the capability to measure the masses of cold, low-mass planets. The mass measurements of the host star and the planet are made possible by the detection of the microlensing parallax signal due to the orbital motion or the Earth as well as observations from the EPOXI spacecraft in a Heliocentric orbit. The microlensing light curve indicates a planetary host star mass of M(sun) = 0.54 + / - 0.05M(sun) located at a distance of DL= 2.94 _ 0.21 kpc, orbited by a planet of mass mp= 9.8 +/-1.1M(Earth) with a semi-major axis of a = 3.1(+1.9-0.4)MAU.

  8. Visible-light promoted catalytic activity of dumbbell-like Au nanorods supported on graphene/TiO2 sheets towards hydrogenation reaction

    NASA Astrophysics Data System (ADS)

    Dai, Yunqian; Zhu, Mingyun; Wang, Xiaotian; Wu, Yanan; Huang, Chengqian; Fu, Wanlin; Meng, Xiangyu; Sun, Yueming

    2018-06-01

    In this work, the rationally-designed sharp corners on Au nanorods tremendously improved the catalytic activity, particularly in the presence of visible light irradiation, towards the hydrogenation of 4-nitrophenol to 4-aminophenol. A strikingly increased rate constant of 50.6 g‑1 s‑1 L was achieved in M-Au-3, which was 41.8 times higher than that of parent Au nanorods under dark conditions. The enhanced activities were proportional to the extent of the protruding sharp corners. Furthermore, remarkably enhanced activities were achieved in novel ternary Au/RGO/TiO2 sheets, which were endowed with a 52.0 times higher rate constant than that of straight Au nanorods. These remarkably enhanced activities were even higher than those of previously reported 3–5 nm Au and 3 nm Pt nanoparticles. It was systematically observed that there are three aspects to the synergistic effects between Au and RGO sheets: (i) electron transfer from RGO to Au, (ii) a high concentration of p-nitrophenol close to dumbbell-like Au nanorods on RGO sheets, and (iii) increased local reaction temperature from the photothermal effect of both dumbbell-like Au nanorods and RGO sheets.

  9. Study of spectral characteristics of radiation from a thermal wake of a pulsating optical discharge in a supersonic air flow

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Malov, A N; Orishich, A M; Terent'eva, Ya S

    The spectral characteristics of the thermal wake of a pulsating optical discharge (POD) in a supersonic air flow are studied. The POD is stimulated by radiation of a mechanically Q-switched, repetitively pulsed CO{sub 2} laser with a pulse repetition rate of 7 – 150 kHz and a power up to 4.5 kW. The flow is produced by means of the supersonic aerodynamic MAU-M setup having a conic nozzle with a critical cross-section size of 50 mm, the Mach number being 1.3 – 1.6. We describe in detail the system of optical diagnostics that allows the detection of the spectrum ofmore » the weak thermal wake glow against the background of high-power POD radiation. The glow of the thermal wake is due to the emission of light by atoms and ions of nitrogen and oxygen, carried by the flow in the form of hot low-density gas clouds (caverns). The wavelengths of the thermal wake emission and the data on the transitions, corresponding to the spectral lines are presented. (laser applications and other topics in quantum electronics)« less

  10. Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis.

    PubMed

    Li, Tian-Fang; Gao, Lin; Sheu, Tzong-Jen; Sampson, Erik R; Flick, Lisa M; Konttinen, Yrjö T; Chen, Di; Schwarz, Edward M; Zuscik, Michael J; Jonason, Jennifer H; O'Keefe, Regis J

    2010-08-01

    To investigate the biologic significance of Smad3 in the progression of osteoarthritis (OA), the crosstalk between Smad3 and activating transcription factor 2 (ATF-2) in the transforming growth factor beta (TGFbeta) signaling pathway, and the effects of ATF-2 overexpression and p38 activation in chondrocyte differentiation. Joint disease in Smad3-knockout (Smad3(-/-)) mice was examined by microfocal computed tomography and histologic analysis. Numerous in vitro methods including immunostaining, real-time polymerase chain reaction, Western blotting, an ATF-2 DNA-binding assay, and a p38 kinase activity assay were used to study the various signaling responses and protein interactions underlying the altered chondrocyte phenotype in Smad3(-/-) mice. In Smad3(-/-) mice, an end-stage OA phenotype gradually developed. TGFbeta-activated kinase 1 (TAK1)/ATF-2 signaling was disrupted in Smad3(-/-) mouse chondrocytes at the level of p38 MAP kinase (MAPK) activation, resulting in reduced ATF-2 phosphorylation and transcriptional activity. Reintroduction of Smad3 into Smad3(-/-) cells restored the normal p38 response to TGFbeta. Phosphorylated p38 formed a complex with Smad3 by binding to a portion of Smad3 containing both the MAD homology 1 and linker domains. Additionally, Smad3 inhibited the dephosphorylation of p38 by MAPK phosphatase 1 (MKP-1). Both ATF-2 overexpression and p38 activation repressed type X collagen expression in wild-type and Smad3(-/-) chondrocytes. P38 was detected in articular cartilage and perichondrium; articular and sternal chondrocytes expressed p38 isoforms alpha, beta, and gamma, but not delta. Smad3 is involved in both the onset and progression of OA. Loss of Smad3 abrogates TAK1/ATF-2 signaling, most likely by disrupting the Smad3-phosphorylated p38 complex, thereby promoting p38 dephosphorylation and inactivation by MKP-1. ATF-2 and p38 activation inhibit chondrocyte hypertrophy. Modulation of p38 isoform activity may provide a new therapeutic

  11. Mental health status among Burmese adolescent students living in boarding houses in Thailand: a cross-sectional study

    PubMed Central

    2013-01-01

    Background In Tak province of Thailand, a number of adolescent students who migrated from Burma have resided in the boarding houses of migrant schools. This study investigated mental health status and its relationship with perceived social support among such students. Methods This cross-sectional study surveyed 428 students, aged 12–18 years, who lived in boarding houses. The Hopkins Symptom Checklist (HSCL)-37 A, Stressful Life Events (SLE) and Reactions of Adolescents to Traumatic Stress (RATS) questionnaires were used to assess participants’ mental health status and experience of traumatic events. The Medical Outcome Study (MOS) Social Support Survey Scale was used to measure their perceived level of social support. Descriptive analysis was conducted to examine the distribution of sociodemographic characteristics, trauma experiences, and mental health status. Further, multivariate linear regression analysis was used to examine the association between such characteristics and participants’ mental health status. Results In total, 771 students were invited to participate in the study and 428 students chose to take part. Of these students, 304 completed the questionnaire. A large proportion (62.8%) indicated that both of their parents lived in Myanmar, while only 11.8% answered that both of their parents lived in Thailand. The mean total number of traumatic events experienced was 5.7 (standard deviation [SD] 2.9), mean total score on the HSCL-37A was 63.1 (SD 11.4), and mean total score on the RATS was 41.4 (SD 9.9). Multivariate linear regression analysis revealed that higher number of traumatic events was associated with more mental health problems. Conclusions Many students residing in boarding houses suffered from poor mental health in Thailand’s Tak province. The number of traumatic experiences reported was higher than expected. Furthermore, these traumatic experiences were associated with poorer mental health status. Rather than making a generalized

  12. HTLV-1 Tax-Induced Rapid Senescence Is Driven by the Transcriptional Activity of NF-κB and Depends on Chronically Activated IKKα and p65/RelA

    PubMed Central

    Ho, Yik-Khuan; Zhi, Huijun; DeBiaso, Dominic; Philip, Subha; Shih, Hsiu-Ming

    2012-01-01

    The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-κB pathways and is thought to promote cell proliferation and transformation via NF-κB activation. We showed recently that hyperactivation of NF-κB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-κB activation by expression of I-κBα superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-κB. Knockdown of IKKγ, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-κB pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKKα in the transcriptional activity of NF-κB, IKKα deficiency drastically decreased NF-κB trans-activation by Tax, although it only modestly reduced Tax-mediated I-κBα degradation and NF-κB nuclear localization. In contrast, although IKKβ knockdown attenuated Tax-induced NF-κB transcriptional activation, the residual NF-κB activation in IKKβ-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKKα and IKKβ knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKKγ, helps recruit NIK and TAK1 for IKKα and IKKβ activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-κB pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-κB, which depends on activated IKKα and p65/RelA. PMID:22740410

  13. Interleukin-1 Acts via the JNK-2 Signaling Pathway to Induce Aggrecan Degradation by Human Chondrocytes.

    PubMed

    Ismail, Heba M; Yamamoto, Kazuhiro; Vincent, Tonia L; Nagase, Hideaki; Troeberg, Linda; Saklatvala, Jeremy

    2015-07-01

    Aggrecan enables articular cartilage to bear load and resist compression. Aggrecan loss occurs early in osteoarthritis and rheumatoid arthritis and can be induced by inflammatory cytokines such as interleukin-1 (IL-1). IL-1 induces cleavage of specific aggrecans characteristic of the ADAMTS proteinases. The aim of this study was to identify the intracellular signaling pathways by which IL-1 causes aggrecan degradation by human chondrocytes and to investigate how aggrecanase activity is controlled by chondrocytes. We developed a cell-based assay combining small interfering RNA (siRNA)-induced knockdown with aggrecan degradation assays. Human articular chondrocytes were overlaid with bovine aggrecan after transfection with siRNAs against molecules of the IL-1 signaling pathway. After IL-1 stimulation, released aggrecan fragments were detected with AGEG and ARGS neoepitope antibodies. Aggrecanase activity and tissue inhibitor of metalloproteinases 3 levels were measured by enzyme-linked immunosorbent assay. Low-density lipoprotein receptor-related protein 1 (LRP-1) shedding was analyzed by Western blotting. ADAMTS-5 is a major aggrecanase in human chondrocytes, regulating aggrecan degradation in response to IL-1. The tumor necrosis factor receptor-associated 6 (TRAF-6)/transforming growth factor β-activated kinase 1 (TAK-1)/MKK-4 signaling axis is essential for IL-1-induced aggrecan degradation, while NF-κB is not. Of the 3 MAPKs (ERK, p38, and JNK), only JNK-2 showed a significant role in aggrecan degradation. Chondrocytes constitutively secreted aggrecanase, which was continuously endocytosed by LRP-1, keeping the extracellular level of aggrecanase low. IL-1 induced aggrecanase activity in the medium in a JNK-2-dependent manner, possibly by reducing aggrecanase endocytosis, because IL-1 caused JNK-2-dependent shedding of LRP-1. The signaling axis TRAF-6/TAK-1/MKK-4/JNK-2 mediates IL-1-induced aggrecanolysis. The level of aggrecanase is controlled by its

  14. SU-F-I-77: Radiation Dose in Cardiac Catheterization Procedures: Impact of a Systematic Reduction in Pulsed Fluoroscopy Frame Rate

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Schultz, C; Dixon, S

    Purpose: To evaluate whether one small systematic reduction in fluoroscopy frame rate has a significant effect on the total air kerma and/or dose area product for diagnostic and interventional cardiac catheterization procedures. Methods: The default fluoroscopy frame rate (FFR) was lowered from 15 to 10 fps in 5 Siemens™ Axiom Artis cardiac catheterization labs (CCL) on July 1, 2013. A total of 7212 consecutive diagnostic and interventional CCL procedures were divided into two study groups: 3602 procedures from 10/1/12 –6/30/13 with FFR of 15 fps; and 3610 procedures 7/1/13 – 3/31/14 at 10 fps. For each procedure, total air kermamore » (TAK), fluoroscopy skin dose (FSD), total/fluoroscopy dose area products (TAD, FAD), and total fluoroscopy time (FT) were recorded. Patient specific data collected for each procedure included: BSA, sex, height, weight, interventional versus diagnostic; and elective versus emergent. Results: For pre to post change in FFR, each categorical variable was compared using Pearson’s Chi-square test, Odds ratios and 95% confidence intervals. No statistically significant difference in BSA, height, weight, number of interventional versus diagnostic, elective versus emergent procedures was found between the two study groups. Decreasing the default FFR from 15 fps to 10 fps in the two study groups significantly reduced TAK from 1305 to 1061 mGy (p<0.0001), FSD from 627 to 454 mGy (p<0.0001), TAD from 8681 to 6991 uGy × m{sup 2}(p<0.0001), and FAD from 4493 to 3297 uGy × m{sup 2}(p<0.0001). No statistically significant difference in FT was noted. Clinical image quality was not analyzed, and reports of noticeable effects were minimal. From July 1, 2013 to date, the default FFR has remained 10 fps. Conclusion: Reducing the FFR from 15 to 10 fps significantly reduced total air kerma and dose area product which may decrease risk for potential radiation-induced skin injuries and improve patient outcomes.« less

  15. Pleiotrophin regulates microglia-mediated neuroinflammation.

    PubMed

    Fernández-Calle, Rosalía; Vicente-Rodríguez, Marta; Gramage, Esther; Pita, Jimena; Pérez-García, Carmen; Ferrer-Alcón, Marcel; Uribarri, María; Ramos, María P; Herradón, Gonzalo

    2017-03-04

    Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved. In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO). We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS. Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by

  16. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cuadrado, Irene; Cidre, Florencia; Herranz, Sandra

    Labdane derivatives obtained from the diterpenoid labdanediol suppressed NO and PGE{sub 2} production in LPS-stimulated RAW 264.7 macrophages. However, mechanisms involved in these inhibitory effects are not elucidated. In this study, we investigated the signaling pathways involved in the anti-inflammatory effects of labdanolic acid methyl ester (LAME) in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. LAME reduced the production of NO and PGE{sub 2} in LPS-activated macrophages. This effect involved the inhibition of NOS-2 and COX-2 gene expression, acting at the transcription level. Examination of the effects of the diterpene on NF-κB signaling showedmore » that LAME inhibits the phosphorylation of IκBα and IκBβ, preventing their degradation and the nuclear translocation of the NF-κB p65 subunit. Moreover, inhibition of MAPK signaling was also observed. A further experiment revealed that LAME inhibited the phosphorylation of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), an upstream signaling molecule required for IKK and mitogen-activated protein kinases (MAPKs) activation. Inflammatory cytokines such as IL-6, TNF-α and IP-10 were downregulated in the presence of this compound after stimulation with LPS. Additionally, LAME also improved survival in a mouse model of endotoxemia and reduced the circulatory levels of cytokines (IL-6, TNF-α). In conclusion, these results indicate that labdane diterpene LAME significantly attenuates the pro-inflammatory response induced by LPS both in vivo and in vitro. Highlights: ► LAME reduced the production of NO and PGE{sub 2} in LPS-activated macrophages. ► IL-6, TNF-α and IP-10 were also inhibited by LAME. ► Inhibition of TAK-1 activation is the mechanism involved in this process. ► LAME improved survival in a mouse model of endotoxemia. ► LAME reduced the circulatory levels of cytokines (IL-6, TNF-α).« less

  17. Directionally Efficient Robust Estimators of Location Via Exponential Embedding.

    DTIC Science & Technology

    1983-05-01

    20 25 25 40 40 45 47.5 JOH 40 20 20 22.5 TAK 20 10 15 17.5 JAE 20 20 25 25 HG1 20 30 35 37.5 HG2 40 30 35 37.5 largest j for which the estimator is...SK(50) ,FY(2,50) COMPLEX ZSM ,ZLG 0 LOGICAL GCASE COMMON DT1 .RN,DRS,DRK EXTERNAL F1,F2 DATA SQRT8/2.828427125D0/4 RN=DBLE(N) NHALF=N/2 NHP1-NHALF+l M...35j KO=KO-l 6O TO 30 35 IF((IFLAG .EQ. 0) .AND. (KO .EQ. NHALF)) THEN THETA-XDAR GO TO 700 END IF s1.0.0 DO 50 X=KO,1,-1 *50 S1=XDAR-X(I).Sl K-Ko

  18. Inactivating KISS1 mutation and hypogonadotropic hypogonadism.

    PubMed

    Topaloglu, A Kemal; Tello, Javier A; Kotan, L Damla; Ozbek, Mehmet N; Yilmaz, M Bertan; Erdogan, Seref; Gurbuz, Fatih; Temiz, Fatih; Millar, Robert P; Yuksel, Bilgin

    2012-02-16

    Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).

  19. Demonstration of a high speed hybrid electrical and optical sensing system for next generation launcher applications

    NASA Astrophysics Data System (ADS)

    Ibrahim, Selwan K.; O'Dowd, John A.; Honniball, Arthur; Bessler, Vivian; Farnan, Martin; O'Connor, Peter; Melicher, Milos; Gleeson, Danny

    2017-09-01

    The Future Launchers Preparatory Programme (FLPP) supported by the European Space Agency (ESA) has a goal of developing various launch vehicle system concepts and identifying the technologies required for the design of Europe's Next-Generation Launcher (NGL) while maintaining competitiveness on the commercial market. Avionics fiber optic sensing technology was investigated as part of the FLPP programme. Here we demonstrate and evaluate a high speed hybrid electrical/optical data acquisition system based on commercial off the shelf (COTS) technology capable of acquiring data from traditional electrical sensors and optical Fibre Bragg Grating (FBG) sensors. The proposed system consists of the KAM-500 data acquisition system developed by Curtis-Wright and the I4 tunable laser based fiber optic sensor interrogator developed by FAZ Technology. The key objective was to demonstrate the capability of the hybrid system to acquire data from traditional electrical sensors used in launcher applications e.g. strain, temperature and pressure in combination with optical FBG sensors, as well as data delivery to spacecraft avionics systems. The KAM-500 was configured as the main acquisition unit (MAU) and provided a 1 kHz sampling clock to the I4 interrogator that was configured as the secondary acquisition unit (SAU) to synchronize the data acquisition sample rate between both systems. The SAU acquired data from an array of optical FBG sensors, while the MAU data acquisition system acquired data from the electrical sensors. Data acquired from the optical sensors was processed by the FAZ I4 interrogation system and then encapsulated into UDP/IP packets and transferred to the KAM-500. The KAM-500 encapsulated the optical sensor data together with the data acquired from electrical sensors and transmitted the data over MIL-STD-1553 and Ethernet data interface. The temperature measurements resulted in the optical and electrical sensors performing on a par with each other, with all

  20. iTAK: A program for genome-wide prediction and classification of plant transcription factors, transcriptional regulators and protein kinases

    USDA-ARS?s Scientific Manuscript database

    Transcription factors (TFs) are proteins that regulate the expression of target genes by binding to specific elements in their regulatory regions. Transcriptional regulators (TRs) also regulate the expression of target genes; however, they operate indirectly via interaction with the basal transcript...

  1. Detection of a large increase of the size of the Be disk from the X-ray binary A 0535+262

    NASA Astrophysics Data System (ADS)

    Camero-Arranz, A.; Ozbey-Arabaci, M.; Fabregat, J.; Gutierrez-Soto, J.; Finger, Mark H.; Peris, V.; Brevia, O.

    2014-04-01

    We report on the evolution of the H & alpha; equivalent width (EW) of the Be/X-ray binary system A 0535+262/HD 245770, using observations performed with the spectrograph Albireo, at the 1.5 m telescope of the Observatorio de Sierra Nevada (Granada, Spain) on 2012-03-26 22:27:59.000 UTC (MJD 56012.936), and recently with the spectrograph located at the 51 cm telescope of the Observatorio de Aras de los Olmos of the University of Valencia on 2014-Mar-07 at 21:07:00.000 UTC (MJD 56723.879), and also with the TFOSC spectrometer at the 1.5 m telescope RTT150 of the T & Uuml;B & #304TAK National Observatory (Antalya, Turkey) on 2014-03-18 19:57:14.688 UTC (MJD 56734.831) and 2014-03-19 19:58:30.746 UTC (MJD 56735.832). ...

  2. Activation of macrophages by an exopolysaccharide isolated from Antarctic Psychrobacter sp. B-3

    NASA Astrophysics Data System (ADS)

    Yu, Leiye; Sun, Guojie; Wei, Jingfang; Wang, Yingze; Du, Chao; Li, Jiang

    2016-09-01

    An exopolysaccharide (EPS) was isolated and purified from an Antarctic psychrophilic bacterium B-3, identified as Psychrobacter sp., and the activation of RAW264.7 cells by B-3 EPS was investigated. The results show that B-3 EPS, over a certain concentration range, promoted cell viability, nitric oxide production, tumor necrosis factor (TNF)α secretion, and phagocytic ability. Furthermore, TAK-242, an inhibitor of the toll-like receptor 4 (TLR4) significantly reduced nitric oxide production by these cells after stimulation with B-3 EPS. Moreover, B-3 EPS induced p65 phosphorylation and IκBα degradation in these cells. In conclusion, B-3 EPS might have activated RAW264.7 cells by combining with TLR4 on cell surface and triggering activation of NF-κB signaling pathways, implying that this EPS could activate macrophages and regulate initial immune response.

  3. A Journey in Science: “Not Lost in Translation”

    PubMed Central

    Mak, Tak

    2016-01-01

    Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by Tak Mak, PhD, Professor, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre in Toronto. A visionary in the field of cancer, this is the story of Dr. Mak’s scientific journey. PMID:27819109

  4. GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit.

    PubMed

    Mancini, A D; Poitout, V

    2015-07-01

    The free fatty acid receptor GPR40 has been proposed as a potential target for type 2 diabetes (T2D) pharmacotherapy. This idea has been validated in both preclinical and clinical studies, in which activation of GPR40 was shown to improve glycaemic control by stimulating glucose-dependent insulin secretion; however, the recent termination of phase III clinical trials using the GPR40 agonist TAK-875 (fasiglifam) has raised important questions regarding the long-term safety and viability of targeting GPR40 and, more specifically, about our understanding of this receptor's basic biology. In the present review, we provide a summary of established and novel concepts related to GPR40's pharmacobiology and discuss the current status and future outlook for GPR40-based drug development for the treatment of T2D. © 2015 John Wiley & Sons Ltd.

  5. Python Radiative Transfer Emission code (PyRaTE): non-LTE spectral lines simulations

    NASA Astrophysics Data System (ADS)

    Tritsis, A.; Yorke, H.; Tassis, K.

    2018-05-01

    We describe PyRaTE, a new, non-local thermodynamic equilibrium (non-LTE) line radiative transfer code developed specifically for post-processing astrochemical simulations. Population densities are estimated using the escape probability method. When computing the escape probability, the optical depth is calculated towards all directions with density, molecular abundance, temperature and velocity variations all taken into account. A very easy-to-use interface, capable of importing data from simulations outputs performed with all major astrophysical codes, is also developed. The code is written in PYTHON using an "embarrassingly parallel" strategy and can handle all geometries and projection angles. We benchmark the code by comparing our results with those from RADEX (van der Tak et al. 2007) and against analytical solutions and present case studies using hydrochemical simulations. The code will be released for public use.

  6. Binding energy of the donor impurities in GaAs-Ga 1- x Al x As quantum well wires with Morse potential in the presence of electric and magnetic fields

    NASA Astrophysics Data System (ADS)

    Aciksoz, Esra; Bayrak, Orhan; Soylu, Asim

    2016-10-01

    The behavior of a donor in the GaAs-Ga1-x Al x As quantum well wire represented by the Morse potential is examined within the framework of the effective-mass approximation. The donor binding energies are numerically calculated for with and without the electric and magnetic fields in order to show their influence on the binding energies. Moreover, how the donor binding energies change for the constant potential parameters (D e, r e, and a) as well as with the different values of the electric and magnetic field strengths is determined. It is found that the donor binding energy is highly dependent on the external electric and magnetic fields as well as parameters of the Morse potential. Project supported by the Turkish Science Research Council (TÜBİTAK) and the Financial Supports from Akdeniz and Nigde Universities.

  7. Kathy Pan, sticks and pummelling: techniques used to induce abortion by Burmese women on the Thai border.

    PubMed

    Belton, Suzanne; Whittaker, Andrea

    2007-10-01

    Forced migrants face particular reproductive health problems. Migrant Burmese women in Thailand often need to work to support themselves and their families, and mistimed and unwanted pregnancies are a common problem. They have limited access to culturally appropriate reproductive health services and no access to safe elective abortion. They are at risk of deportation or at least harassment by Thai authorities if they travel. They use traditional methods such as herbal medicines, and employ lay midwives to provide pummelling and stick abortions to end their pregnancies. This ethnographic study used various methods to collect data over 10 months in Tak Province, Thailand. The authors describe the women's motives and means of ending their pregnancies and some of the difficulties in obtaining reliable modern methods of contraception. This study highlights the need for reproductive health care for displaced populations.

  8. Phylogenetic lineages in Pseudocercospora

    PubMed Central

    Crous, P.W.; Braun, U.; Hunter, G.C.; Wingfield, M.J.; Verkley, G.J.M.; Shin, H.-D.; Nakashima, C.; Groenewald, J.Z.

    2013-01-01

    .S. Salmon & Wormald) Crous, H.D. Shin & U. Braun, Pseudocercospora hakeae (U. Braun & Crous) U. Braun & Crous, Pseudocercospora leucadendri (Cooke) U. Braun & Crous, Pseudocercospora snelliana (Reichert) U. Braun, H.D. Shin, C. Nakash. & Crous, Pseudocercosporella chaenomelis (Y. Suto) C. Nakash., Crous, U. Braun & H.D. Shin; Typifications: Epitypifications - Pseudocercospora angolensis (T. Carvalho & O. Mendes) Crous & U. Braun, Pseudocercospora araliae (Henn.) Deighton, Pseudocercospora cercidis-chinensis H.D. Shin & U. Braun, Pseudocercospora corylopsidis (Togashi & Katsuki) C. Nakash. & Tak. Kobay., Pseudocercospora dovyalidis (Chupp & Doidge) Deighton, Pseudocercospora fukuokaensis (Chupp) X.J. Liu & Y.L. Guo, Pseudocercospora humuli (Hori) Y.L. Guo & X.J. Liu, Pseudocercospora kiggelariae (Syd.) Crous & U. Braun, Pseudocercospora lyoniae (Katsuki & Tak. Kobay.) Deighton, Pseudocercospora lythri H.D. Shin & U. Braun, Pseudocercospora sambucigena U. Braun, Crous & K. Schub., Pseudocercospora stephanandrae (Tak. Kobay. & H. Horie) C. Nakash. & Tak. Kobay., Pseudocercospora viburnigena U. Braun & Crous, Pseudocercosporella chaenomelis (Y. Suto) C. Nakash., Crous, U. Braun & H.D. Shin, Xenostigmina zilleri (A. Funk) Crous; Lectotypification - Pseudocercospora ocimicola (Petr. & Cif.) Deighton; Neotypifications - Pseudocercospora kiggelariae (Syd.) Crous & U. Braun, Pseudocercospora lonicericola (W. Yamam.) Deighton, Pseudocercospora zelkovae (Hori) X.J. Liu & Y.L. Guo. PMID:24014898

  9. Conference Committees: Conference Committees

    NASA Astrophysics Data System (ADS)

    2009-09-01

    International Programm Committee (IPC) Harald Ade NCSU Sadao Aoki University Tsukuba David Attwood Lawrence Berkeley National Laboratory/CXRO Christian David Paul Scherrer Institut Peter Fischer Lawrence Berkeley National Laboratory Adam Hitchcock McMaster University Chris Jacobsen SUNY, Stony Brook Denis Joyeux Lab Charles Fabry de l'Institut d'Optique Yasushi Kagoshima University of Hyogo Hiroshi Kihara Kansai Medical University Janos Kirz SUNY Stony Brook Maya Kiskinova ELETTRA Ian McNulty Argonne National Lab/APS Alan Michette Kings College London Graeme Morrison Kings College London Keith Nugent University of Melbourne Zhu Peiping BSRF Institute of High Energy Physics Francois Polack Soleil Christoph Quitmann Paul Scherrer Institut Günther Schmahl University Göttingen Gerd Schneider Bessy Hyun-Joon Shin Pohang Accelerator Lab Jean Susini ESRF Mau-Tsu Tang NSRRC Tony Warwick Lawrence Berkeley Lab/ALS Local Organizing Committee Christoph Quitmann Chair, Scientific Program Charlotte Heer Secretary Christian David Scientific Program Frithjof Nolting Scientific Program Franz Pfeiffer Scientific Program Marco Stampanoni Scientific Program Robert Rudolph Sponsoring, Financials Alfred Waser Industry Exhibition Robert Keller Public Relation Markus Knecht Computing and WWW Annick Cavedon Proceedings and Excursions and Accompanying Persons Program Margrit Eichler Excursions and Accompanying Persons Program Kathy Eikenberry Excursions and Accompanying Persons Program Marlies Locher Excursions and Accompanying Persons Program

  10. Magnetic susceptibilities of liquid Cr-Au, Mn-Au and Fe-Au alloys

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ohno, S.; Shimakura, H.; Tahara, S.

    The magnetic susceptibility of liquid Cr-Au, Mn-Au, Fe-Au and Cu-Au alloys was investigated as a function of temperature and composition. Liquid Cr{sub 1-c}Au{sub c} with 0.5 ≤ c and Mn{sub 1-c}Au{sub c} with 0.3≤c obeyed the Curie-Weiss law with regard to their dependence of χ on temperature. The magnetic susceptibilities of liquid Fe-Au alloys also exhibited Curie-Weiss behavior with a reasonable value for the effective number of Bohr magneton. On the Au-rich side, the composition dependence of χ for liquid TM-Au (TM=Cr, Mn, Fe) alloys increased rapidly with increasing TM content, respectively. Additionally, the composition dependences of χ for liquidmore » Cr-Au, Mn-Au, and Fe-Au alloys had maxima at compositions of 50 at% Cr, 70 at% Mn, and 85 at% Fe, respectively. We compared the composition dependences of χ{sub 3d} due to 3d electrons for liquid binary TM-M (M=Au, Al, Si, Sb), and investigated the relationship between χ{sub 3d} and E{sub F} in liquid binary TM-M alloys at a composition of 50 at% TM.« less

  11. Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4.

    PubMed

    Ma, Fei; Kouzoukas, Dimitrios E; Meyer-Siegler, Katherine L; Westlund, Karin N; Hunt, David E; Vera, Pedro L

    2017-05-25

    Bladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particularly when the pain is not accompanied by bladder pathology. Stimulation of protease activated receptor 4 (PAR4) in the urothelium results in bladder pain through release of urothelial high mobility group box-1 (HMGB1). HGMB1 has two functionally active redox states (disulfide and all-thiol) and it is not known which form elicits bladder pain. Therefore, we investigated whether intravesical administration of specific HMGB1 redox forms caused abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation in female C57BL/6 mice 24 hours post-administration. Moreover, we determined which of the specific HMGB1 receptors, Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE), mediate HMGB1-induced changes. Disulfide HMGB1 elicited abdominal mechanical hypersensitivity 24 hours after intravesical (5, 10, 20 μg/150 μl) instillation. In contrast, all-thiol HMGB1 did not produce abdominal mechanical hypersensitivity in any of the doses tested (1, 2, 5, 10, 20 μg/150 μl). Both HMGB1 redox forms caused micturition changes only at the highest dose tested (20 μg/150 μl) while eliciting mild bladder edema and reactive changes at all doses. We subsequently tested whether the effects of intravesical disulfide HMGB1 (10 μg/150 μl; a dose that did not produce inflammation) were prevented by systemic (i.p.) or local (intravesical) administration of either a TLR4 antagonist (TAK-242) or a RAGE antagonist (FPS-ZM1). Systemic administration of either TAK-242 (3 mg/kg) or FPS-ZM1 (10 mg/kg) prevented HMGB1 induced abdominal mechanical hypersensitivity while only intravesical TLR4 antagonist pretreatment (1.5 mg/ml; not RAGE) had this effect. The disulfide form of HMGB1 mediates bladder pain directly (not

  12. Challenges in tackling tuberculosis on the Thai-Myanmar border: findings from a qualitative study with health professionals.

    PubMed

    Kaji, Aiko; Thi, Sein Sein; Smith, Terrence; Charunwatthana, Prakaykaew; Nosten, Francois H

    2015-10-09

    Myanmar and Thailand belong to the top 22 high burden countries for tuberculosis (TB). Health care organizations play an essential role in addressing TB control in the two bridging border jurisdictions, Tak province, Thailand and Myawaddy district, Kayin state, Myanmar. However, health professionals face difficulties in TB control effort due to the nature of fluid population movements, resource constraints and ambiguous mechanisms to implement collaboration along the border. The purpose of this study is to identify the challenges to TB control among Myanmar migrants faced by stakeholders, focusing on the area of collaboration and interaction along the border. The study conducted in-depth interviews with health policy makers and health care providers responsible for developing and implementing policies and TB programs in Tak province, Thailand and Myawaddy district, Kayin state, Myanmar. The participants included members of government organizations, United Nations agencies, community based organizations, and international NGO. One or two key stakeholders from each organization were approached to participate in the study. We gathered baseline information to identify TB policies and programs available on websites, brochures, and publications. Observations including field notes were made on site. The data transcriptions were coded for qualitative data analysis. Coding also developed categories that led to key themes. A total of 31 respondents (18 in Thailand and 13 in Myanmar) participated in the study. The main theme reported by participants was challenges in limited corroboration and coordination among stakeholders. Unstructured information sharing and lack of communication hindered the stakeholders from engaging in TB control. The respondents stressed that referral mechanisms across the border need to be strengthened. Other challenges were associated with increasing loss to follow up and subsequent MDR cases, constraints of service delivery, shortage of human

  13. Organisational aspects of spatial information infrastructure in Poland

    NASA Astrophysics Data System (ADS)

    Bielecka, Elzbieta; Zwirowicz-Rutkowska, Agnieszka

    2013-06-01

    One of the more important elements of spatial information infrastructure is the organisational structure defining the obligations and dependencies between stakeholders that are responsible for the infrastructure. Many SDI practitioners and theoreticians emphasise that its influence on the success or failure of activities undertaken is significantly greater than that of technical aspects. Being aware of the role of the organisational structure in the creating, operating and maintenance of spatial information infrastructure (SII), Polish legislators placed appropriate regulations in the Spatial Information Infrastructure Act, being the transposition of the INSPIRE Directive into Polish Law. The principal spatial information infrastructure stakeholders are discussed in the article and also the scope of cooperation between them. The tasks and relationships between stakeholders are illustrated in UML, in both the use case and the class diagram. Mentioned also are the main problems and obstructions resulting from imprecise legal regulations. Jednym z istotniejszych komponentów infrastruktury informacji przestrzennej (IIP) jest struktura organizacyjna określająca m.in. zależności pomiędzy organizacjami tworzącymi infrastrukturę. Wielu praktyków i teoretyków SDI podkreśla, że wpływ aspektów organizacyjnych na sukces lub porażkę SDI jest dużo większy niż elementów technicznych. Mając świadomość znaczącej roli struktury organizacyjnej w tworzeniu, funkcjonowaniu i zarządzaniu infrastrukturą przestrzenną w Polsce, legislatorzy umieścili odpowiednie zapisy w ustawie z dnia 4 marca 2010 r. o infrastrukturze informacji przestrzennej, będącej transpozycją dyrektywy INSPIRE do prawa polskiego. W artykule omówiono strukturę organizacyjną IIP w Polsce, podając (m.in. w postaci diagramów UML) obowiązki poszczególnych organów administracji zaangażowanych w jej budowę i rozwój, a także omówiono zależności i zakres współpracy pomi

  14. Underground Lead-Zinc Mine Production Planning Using Fuzzy Stochastic Inventory Policy / Planowanie Wydobycia Cynku I Ołowiu W Kopalniach Podziemnych Z Wykorzystaniem Podejścia Stochastycznego Z Elementami Logiki Rozmytej Do Określania Niezbędnego Poziomu Zapasów

    NASA Astrophysics Data System (ADS)

    Gligoric, Zoran; Beljic, Cedomir; Gluscevic, Branko; Cvijovic, Cedomir

    2015-03-01

    Methodology for long-term underground lead-zinc mine planning based on fuzzy inventory theory is presented in this paper. We developed a fuzzy stochastic model of inventory control problem for planning lead-zinc ore production under uncertainty. The final purpose of this article is to find the optimal quantity of mined ore that should be stockpiled, in order to enable "feeding" of mineral processing plant in cases when the production in underground mine is interrupted, by using Possibilistic mean value of fuzzy number for defuzzing the fuzzy total annual inventory costs, and by using Extension of the Lagrangean method for solving inequality constrain problem. The different types of costs involved in mined ore inventory problems affect the efficiency of production scheduling. Dynamic nature of lead and zinc metal price is described by Ornstein-Uhlenbeck stochastic mean reverting process. The model is illustrated with a numerical example. W pracy przedstawiono metodologię długoterminowego wydobycia cynku i ołowiu w kopalniach podziemnych z wykorzystaniem podejścia stochastycznego z elementami logiki rozmytej do określania wymaganego poziomu zapasów. Opracowaliśmy model stochastyczny z wykorzystaniem elementów logiki rozmytej do kontroli zapasów w planowaniu wydobycia cynku i ołowiu w warunkach niepewności. Celem końcowym pracy jest określenie optymalnej ilości wydobywanej rudy, którą należy zachować jako zapas tak aby zapewnić odpowiednie jej dostawy do zakładu przeróbczego nawet w przypadku przerwania wydobycia w kopalni podziemnej, opierając się na posybilistycznej wartości średniej liczby rozmytej i wyostrzeniu całkowitych rocznych kosztów zapasów. Wykorzystano także rozszerzenie metody Lagrange'a do rozwiązywania problemu więzów w nierówności. Różnorakie koszty związane ze składowaniem zapasów wydobywanej rudy mają wpływ na wydajność planowanej produkcji. Dynamiczne zmiany cen cynku i o

  15. Water Management in the Klodnica Catchment in 2000-2010

    NASA Astrophysics Data System (ADS)

    Drąg, Magdalena

    2012-01-01

    The article takes up an attempt to present the changes that has occurred in the water management at the beginning of the 21st century in the area of Silesian Voivoideship. Communes situated within the boundaries of Klodnica catchment, closed by the section of Gliwice, were analysed as an example of water management in the area which undergoes a strong anthropopression. Klodnica catchment is an area where all the elements of the geographical environment were transformed, but it was the water environment that was changed most visibly. At the beginning of the 21st century, there were a lot of changes conducted in Poland, not only political, but also in the economic and legal sectors. Owing to these factors, the following changes appeared: water consumption, the structure of distribution of water among different branches of economy and the water and sewage system infrastructure. The effect of these changes is the decrease in water consumption and sewage discharge as well as upgrading the technologies of its treatment (Absalon 2007). W artykule podjęto próbę przedstawienia zmian jakie zaszły w gospodarowaniu wodą na początku XXI wieku na obszarze województwa śląskiego. Szczegółowej analizie poddano gminy znajdujące się w granicach zlewni Kłodnicy zamkniętej przekrojem Gliwice, jako przykład gospodarowania wodą na obszarze podlegającym silnej antropopresji. Zlewnia Kłodnicy jest to teren, gdzie wszystkie elementy środowiska geograficznego zostały przekształcone, lecz najbardziej widocznym zmianom uległo środowisko wodne. Wraz z początkiem XXI wieku w Polsce wprowadzono wiele zmian i to nie tylko politycznych, ale także w sektorze ekonomicznym i prawnym. Dzięki tym czynnikom pojawiły się zmiany: zużycia wody, struktury jej rozdziału na poszczególne gałęzie gospodarki oraz infrastruktury wodociągowej i kanalizacyjnej. Efektem tych zmian jest zmniejszenie zużycia wody oraz zrzutu ścieków, a także unowocześnianie technologii ich

  16. The Problem of Form in Objects under Redevelopment (On the Basis of Bytom Market Square Redevelopment Design) / Problem Formy W Obiektach Przebudowywanych (Na Przykładzie Projektu Realizacyjnego Przebudowy Bytomskiego Rynku)

    NASA Astrophysics Data System (ADS)

    Maryńczuk, Paweł

    2015-03-01

    The author believes that if a designer has performed many design or research works entailing solutions to various problems, it is recommendable to consider and become aware of previously used methods whose application might have been unwitting or instinctive. The outcome of such reflection can be worth describing and recording in order to formulate a set of guidelines useful in the future. Such methods, being intuitive in nature, are often tied to the designer's subconsciousness, thus are rarely expressed in a clear manner. By using own methods a designer can prove that space should be composed in a given way in order to address specific needs and defined objectives. All this is aimed at preventing accidental formation of space. An example of reasoning serving the aforementioned purpose can be found in a method referred to as CQC or Composition Quality Control, the application of which facilitates intentional shaping of an architectural piece of work. Autor uważa uważa, że jeśli projektant ma za sobą wiele prac projektowych lub też prac badawczych, które połączone były z rozwiązywaniem różnych problemów, to warto zastanowić się i uświadomić sobie sposoby, które dotychczas - może nieświadomie lub odruchowo - były stosowane. Wynik refleksji warto opisać i zapisać po to, żeby ująć go w układ wskazań na przyszłość. Metody te, mając charakter intuicyjny, często związane są z podświadomością projektanta, w związku z tym rzadko można spotkać je jako wyrażone w sposób wyraźny. Stosując metody własne można dowieść, że przestrzeń winna być komponowana tak, a nie inaczej dla określonych potrzeb i wytyczonych celów tak, aby jej forma nie była przypadkowa. Przykładem takiego rozumowania jest przyjeta metoda KJK, której zastosowanie pomaga w swiadomym kształtowaniu dzieła architektonicznego.

  17. Transcription factor specificity protein 1 modulates TGFβ1/Smad signaling to negatively regulate SIGIRR expression by human M1 macrophages stimulated with substance P.

    PubMed

    Yamaguchi, Rui; Sakamoto, Arisa; Yamaguchi, Reona; Haraguchi, Misa; Narahara, Shinji; Sugiuchi, Hiroyuki; Yamaguchi, Yasuo

    2018-08-01

    The stimuli inducing expression of single immunoglobulin IL-1-related receptor (SIGIRR) and the relevant regulatory mechanisms are not well defined. Transforming growth factor β1 (TGFβ1) delays internalization of neurokinin-1 receptor (NK1R) and subsequently enhances cellular signaling. This study investigated the effect of TGFβ1 on SIGIRR protein production by human M1 macrophages in response to stimulation with substance P (SP). SP caused upregulation of SIGIRR expression in a concentration-dependent manner, whereas aprepitant (an NK1R inhibitor) blunted this response. Silencing p38γMAPK or TAK-1 partially attenuated the response to SP stimulation, while TGFβ1/2/3 siRNA dramatically diminished it. SP induced much greater SIGIRR protein production than either lipopolysaccharide (a TLR4 agonist) or resiquimod (a TLR7/8 agonist). Unexpectedly, silencing of transcription factor specificity protein 1 (Sp1) led to significant upregulation of SIGIRR expression after SP stimulation, while KLF2 siRNA only partially enhanced it and Fli-1 siRNA reduced it. SP also upregulated TGFβ1 expression, along with a corresponding increase of SIGIRR protein, whereas silencing TGFβ1/2/3 blunted these responses. Sp1 siRNA or mithramycin (a gene-selective Sp1 inhibitor) significantly enhanced the expression of TGFβ1 and SIGIRR by macrophages after SP stimulation. Importantly, this effect of Sp1 siRNA on TGFβ1 and SIGIRR was blunted by siRNA for Smad2, Smad3, or Smad4, but not by TAK-1 siRNA. Next, we investigated the influence of transcription factor cross-talk on SIGIRR expression in response to SP. Co-transfection of macrophages with Sp1 siRNA and C/EBPβ or TIF1β siRNA attenuated the upregulation of SIGIRR by SP, while a combination of Sp1 siRNA and Fli-1 siRNA dramatically diminished it. In conclusion, TGFβ1 may be an intermediary between SP/NK1R activation and SIGIRR expression in Sp1 siRNA-transfected macrophages. In addition, Sp1 modulates TGFβ1/Smad signaling and

  18. Azilsartan medoxomil: a new Angiotensin receptor blocker.

    PubMed

    Zaiken, Kathy; Cheng, Judy W M

    2011-11-01

    Azilsartan medoxomil is an angiotensin receptor blocker, approved on February 25, 2011 by the US Food and Drug Administration (FDA) for hypertension management. The purpose of this study was to review the pharmacology, pharmacokinetics, efficacy, safety profile, and role of azilsartan for hypertension management. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Contents (both 1966 to August 31, 2011) using the search terms azilsartan, TAK-491, TAK-536, pharmacology, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. The FDA Web site and manufacturer prescribing information were also reviewed to identify other relevant information. Compared with olmesartan 40 mg daily, azilsartan 80 mg reduced mean systolic blood pressure (SBP) by an additional 2.1 mm Hg (P = 0.038), whereas azilsartan 40 mg was noninferior to olmesartan 40 mg. Azilsartan 40 mg or 80 mg added to chlorthalidone 25 mg daily significantly reduced SBP to a greater extent than did chlorthalidone alone (P < 0.05), but there was no difference between azilsartan 40 mg and 80 mg (40 mg: -31.72 mm Hg; 80 mg: -31.3 mm Hg [P > 0.05]). When coadministered with amlodipine 5 mg daily, both azilsartan 40 mg and 80 mg + amlodipine decreased SBP significantly more than amlodipine alone (amlodipine: -13.6 mm Hg; with azilsartan 40 mg: -24.79 mm Hg; with azilsartan 80 mg: -24.51 mm Hg [P < 0.05]). Compared with ramipril 10 mg daily, both azilsartan 40 mg and 80 mg resulted in significantly (P < 0.001) greater reductions in mean SBP (-20.63 and -21.24 mm Hg, respectively; ramipril: -12.22 mm Hg). The most common adverse events reported were dizziness (4%), dyslipidemia (3.3%), and diarrhea (2%). At the recommended dose of 80 mg once daily, azilsartan is reported to be an efficacious BP-lowering agent. With once-daily dosing and a favorable side-effect profile, azilsartan is an attractive option for the treatment of

  19. Urinary cadmium level in children between nine to fifteen years old in three Sub-districts of Tak Province in Thailand

    NASA Astrophysics Data System (ADS)

    Chaiwong, S.; Sthiannopkao, S.; Kim, K. W.; Chuenchoojit, S.; Poopatpiboon, K.; Poodendean, C.; Supanpaiboon, W.

    2009-07-01

    Urinary cadmium (UCd) is an indicator of the long term exposure of human health. The objective of this research was to study UCd of people aged between 9 to 12 and 13 to 15 years old in both sexes in Prathadpadeang, in Mae Tao and Mae Ku. 849 urines were collected, and determined by using the ICP-MS. The results revealed that 64.30% had UCd less than 1 μg/gCr. XUCd in 3 Sub-districts were 0.132 μg/gCr in Prathadpadeang, 0.141 μg/gCr in Mae Tao, and 0.105 μg/gCr in Mae Ku. The difference in the 3 Sub-districts was significant. XUCd were 0.125 μg/gCr and 0.129 μg/gCr in boys and girls, and 0.119 μg/gCr and 0.135 μg/gCr in age group 9-12 and 13-15 years old.

  20. Comparison of TAK-438 (Vonoprazan) to Lansoprazole in the Treatment of Gastric Ulcer Participants With or Without Helicobacter Pylori Infection

    ClinicalTrials.gov

    2017-05-24

    Gastric Ulcer; Peptic Ulcer; Gastrointestinal Diseases; Digestive System Diseases; Lansoprazole; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action

  1. Community engagement on the Thai–Burmese border: rationale, experience and lessons learnt

    PubMed Central

    Cheah, Phaik Yeong; Lwin, Khin Maung; Phaiphun, Lucy; Maelankiri, Ladda; Parker, Michael; Day, Nicholas P.; White, Nicholas J.; Nosten, François

    2012-01-01

    Community engagement is increasingly promoted in developing countries, especially in international health research, but there is little published experience. The Shoklo Malaria Research Unit (SMRU) conducts research with refugees, migrant workers, displaced people, and day migrants on the Thai-Burmese border, and has recently facilitated the set up of the Tak Province Border Community Ethics Advisory Board (T-CAB). Valuable lessons have been learnt from consultation with the T-CAB especially in the area of participant recruitment and the informed consent process. A lot of new research questions have emerged from consultation with the T-CAB. This paper describes our experience, lessons learnt and the unique challenges faced working with the T-CAB from its initial conception to date. We conclude that consultation with the T-CAB has made improvements in our research in particular operational and ethical aspects of our studies. PMID:22984375

  2. Zastosowanie oznaczeń nikotyny we włosach jako narzędzia do oceny narażenia na dym tytoniowy

    PubMed Central

    Koszowski, Bartosz; Czogała, Jan; Goniewicz, Maciej Łukasz; Sobczak, Andrzej; Kolasińska, Ewelina; Kośmider, Leon; Kuma, Tomasz

    2009-01-01

    Pierwsza praca dotycząca oznaczania nikotyny we włosach została opublikowana w 1983 roku przez Ishiyama i wsp. Od czasu tych pionierskich badań minęło już ponad 25 lat, a badanie zawartości nikotyny we włosach stało się cennym narzędziem służącym ocenie narażenia na liczne ksenobiotyki, w tym na dym tytoniowy. Niniejszy artykuł jest próbą zwięzłego przeglądu najważniejszych badań ostatnich lat, które wykorzystywały nikotynę we włosach jako biomarker. W artykule opisano także stosowane do oznaczeń nikotyny we włosach techniki laboratoryjne oraz przedstawiono wady i zalety włosów jako biomarkera narażenia na dym tytoniowy. PMID:19189581

  3. Evolution of genetic polymorphisms of Plasmodium falciparum merozoite surface protein (PfMSP) in Thailand.

    PubMed

    Kuesap, Jiraporn; Chaijaroenkul, Wanna; Ketprathum, Kanchanok; Tattiyapong, Puntanat; Na-Bangchang, Kesara

    2014-02-01

    Plasmodium falciparum malaria is a major public health problem in Thailand due to the emergence of multidrug resistance. The understanding of genetic diversity of malaria parasites is essential for developing effective drugs and vaccines. The genetic diversity of the merozoite surface protein-1 (PfMSP-1) and merozoite surface protein-2 (PfMSP-2) genes was investigated in a total of 145 P. falciparum isolates collected from Mae Sot District, Tak Province, Thailand during 3 different periods (1997-1999, 2005-2007, and 2009-2010). Analysis of genetic polymorphisms was performed to track the evolution of genetic change of P. falciparum using PCR. Both individual genes and their combination patterns showed marked genetic diversity during the 3 study periods. The results strongly support that P. falciparum isolates in Thailand are markedly diverse and patterns changed with time. These 2 polymorphic genes could be used as molecular markers to detect multiple clone infections and differentiate recrudescence from reinfection in P. falciparum isolates in Thailand.

  4. Design and synthesis of N-(4-aminopyridin-2-yl)amides as B-Raf(V600E) inhibitors.

    PubMed

    Li, Xiaokai; Shen, Jiayi; Tan, Li; Zhang, Zhang; Gao, Donglin; Luo, Jinfeng; Cheng, Huimin; Zhou, Xiaoping; Ma, Jie; Ding, Ke; Lu, Xiaoyun

    2016-06-15

    B-Raf(V600E) was an effective target for the treatment of human cancers. Based on a pan-Raf inhibitor TAK-632, a series of N-(4-aminopyridin-2-yl)amide derivatives were designed as novel B-Raf(V600E) inhibitors. Detailed structure-activity studies of the compounds revealed that most of the compounds displayed potent enzymatic activity against B-Raf(V600E), and good selectivity over B-Raf(WT). One of the most promising compound 4l exhibited potent inhibitory activity with an IC50 value of 38nM for B-raf(V600E), and displayed antiproliferative activities against colo205 and HT29 cells with IC50 values of 0.136 and 0.094μM, respectively. It also displayed good selectivity on both enzymatic and cellular assays over B-Raf(WT). These inhibitors may serve as lead compounds for further developing novel B-Raf(V600E) inhibitors as anticancer drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways.

    PubMed

    Shambharkar, Prashant B; Blonska, Marzenna; Pappu, Bhanu P; Li, Hongxiu; You, Yun; Sakurai, Hiroaki; Darnay, Bryant G; Hara, Hiromitsu; Penninger, Josef; Lin, Xin

    2007-04-04

    The IkappaB kinase (IKK) complex serves as the master regulator for the activation of NF-kappaB by various stimuli. It contains two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKalpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKKalpha/beta activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKalpha/beta phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKalpha/beta and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.

  6. The PP2C Alphabet is a negative regulator of stress-activated protein kinase signaling in Drosophila.

    PubMed

    Baril, Caroline; Sahmi, Malha; Ashton-Beaucage, Dariel; Stronach, Beth; Therrien, Marc

    2009-02-01

    The Jun N-terminal kinase and p38 pathways, also known as stress-activated protein kinase (SAPK) pathways, are signaling conduits reiteratively used throughout the development and adult life of metazoans where they play central roles in the control of apoptosis, immune function, and environmental stress responses. We recently identified a Drosophila Ser/Thr phosphatase of the PP2C family, named Alphabet (Alph), which acts as a negative regulator of the Ras/ERK pathway. Here we show that Alph also plays an inhibitory role with respect to Drosophila SAPK signaling during development as well as under stress conditions such as oxidative or genotoxic stresses. Epistasis experiments suggest that Alph acts at a step upstream of the MAPKKs Hep and Lic. Consistent with this interpretation, biochemical experiments identify the upstream MAPKKKs Slpr, Tak1, and Wnd as putative substrates. Together with previous findings, this work identifies Alph as a general attenuator of MAPK signaling in Drosophila.

  7. Dynamic one-dimensional modeling of secondary settling tanks and system robustness evaluation.

    PubMed

    Li, Ben; Stenstrom, M K

    2014-01-01

    One-dimensional secondary settling tank models are widely used in current engineering practice for design and optimization, and usually can be expressed as a nonlinear hyperbolic or nonlinear strongly degenerate parabolic partial differential equation (PDE). Reliable numerical methods are needed to produce approximate solutions that converge to the exact analytical solutions. In this study, we introduced a reliable numerical technique, the Yee-Roe-Davis (YRD) method as the governing PDE solver, and compared its reliability with the prevalent Stenstrom-Vitasovic-Takács (SVT) method by assessing their simulation results at various operating conditions. The YRD method also produced a similar solution to the previously developed Method G and Enquist-Osher method. The YRD and SVT methods were also used for a time-to-failure evaluation, and the results show that the choice of numerical method can greatly impact the solution. Reliable numerical methods, such as the YRD method, are strongly recommended.

  8. Preliminary study of urine metabolism in type two diabetic patients based on GC-MS

    PubMed Central

    Zhang, Ning; Geng, Fang; Hu, Zhong-Hua; Liu, Bin; Wang, Ye-Qiu; Liu, Jun-Cen; Qi, Yong-Hua; Li, Li-Jing

    2016-01-01

    Objective: Comparative study of type 2 diabetes and healthy controls by metabolomics methods to explore the pathogenesis of Type II diabetes. Methods: Gas chromatography - mass spectrometry (GC-MS) with a variety of multivariate statistical analysis methods to the healthy control group 58 cases, 68 cases of Type II diabetes group were analyzed. Chromatographic conditions: DB-5MS column; the carrier gas He; flow rate of 1 mL·min-1, the injection volume 1 uL; split ratio is 100: 1. MS conditions: electron impact (EI) ion source, an auxiliary temperature of 280°C, the ion source 230°C, quadrupole 150°C; mass scan range 30~600 mAu. Results: Established analytical method based on urine metabolomics GC-MS of Type II diabetes, determine the urine succinic acid, L-leucine, L-isoleucine, tyrosine, slanine, acetoace acid, mannose, L-isoleucine, L-threonine, Phenylalanine, fructose, D-glucose, palmi acid, oleic acid and arachidonic acid were significantly were significantly changed. Conclusion: Based on metabolomics of GC-MS detection and analysis metabolites can be found differences between type 2 diabetes and healthy control group, PCA diagram can effectively distinguish Type II diabetes and healthy control group, with load diagrams and PLS-DA VIP value metabolite screening, the resulting differences in metabolic pathways involved metabolites, including amino acid metabolism, lipid metabolism, glucose metabolism and energy metabolism. PMID:27508010

  9. Insertional Polymorphisms of Endogenous Feline Leukemia Viruses

    PubMed Central

    Roca, Alfred L.; Nash, William G.; Menninger, Joan C.; Murphy, William J.; O'Brien, Stephen J.

    2005-01-01

    The number, chromosomal distribution, and insertional polymorphisms of endogenous feline leukemia viruses (enFeLVs) were determined in four domestic cats (Burmese, Egyptian Mau, Persian, and nonbreed) using fluorescent in situ hybridization and radiation hybrid mapping. Twenty-nine distinct enFeLV loci were detected across 12 of the 18 autosomes. Each cat carried enFeLV at only 9 to 16 of the loci, and many loci were heterozygous for presence of the provirus. Thus, an average of 19 autosomal copies of enFeLV were present per cat diploid genome. Only five of the autosomal enFeLV sites were present in all four cats, and at only one autosomal locus, B4q15, was enFeLV present in both homologues of all four cats. A single enFeLV occurred in the X chromosome of the Burmese cat, while three to five enFeLV proviruses occurred in each Y chromosome. The X chromosome and nine autosomal enFeLV loci were telomeric, suggesting that ectopic recombination between nonhomologous subtelomeres may contribute to enFeLV distribution. Since endogenous FeLVs may affect the infectiousness or pathogenicity of exogenous FeLVs, genomic variation in enFeLVs represents a candidate for genetic influences on FeLV leukemogenesis in cats. PMID:15767400

  10. CURB-65 Score is Equal to NEWS for Identifying Mortality Risk of Pneumonia Patients: An Observational Study.

    PubMed

    Brabrand, Mikkel; Henriksen, Daniel Pilsgaard

    2018-06-01

    The CURB-65 score is widely implemented as a prediction tool for identifying patients with community-acquired pneumonia (cap) at increased risk of 30-day mortality. However, since most ingredients of CURB-65 are used as general prediction tools, it is likely that other prediction tools, e.g. the British National Early Warning Score (NEWS), could be as good as CURB-65 at predicting the fate of CAP patients. To determine whether NEWS is better than CURB-65 at predicting 30-day mortality of CAP patients. This was a single-centre, 6-month observational study using patients' vital signs and demographic information registered upon admission, survival status extracted from the Danish Civil Registration System after discharge and blood test results extracted from a local database. The study was conducted in the medical admission unit (MAU) at the Hospital of South West Jutland, a regional teaching hospital in Denmark. The participants consisted of 570 CAP patients, 291 female and 279 male, median age 74 (20-102) years. The CURB-65 score had a discriminatory power of 0.728 (0.667-0.789) and NEWS 0.710 (0.645-0.775), both with good calibration and no statistical significant difference. CURB-65 was not demonstrated to be significantly statistically better than NEWS at identifying CAP patients at risk of 30-day mortality.

  11. Relativistic DFT investigation of electronic structure effects arising from doping the Au25 nanocluster with transition metals.

    PubMed

    Alkan, Fahri; Muñoz-Castro, Alvaro; Aikens, Christine M

    2017-10-26

    We perform a theoretical investigation using density functional theory (DFT) and time-dependent DFT (TDDFT) on the doping of the Au 25 (SR) 18 -1 nanocluster with group IX transition metals (M = cobalt, rhodium and iridium). Different doping motifs, charge states and spin multiplicities were considered for the single-atom doped nanoclusters. Our results show that the interaction (or the lack of interaction) between the d-type energy levels that mainly originate from the dopant atom and the super-atomic levels plays an important role in the energetics, the electronic structure and the optical properties of the doped systems. The evaluated MAu 24 (SR) 18 q (q = -1, -3) systems favor an endohedral disposition of the doping atom typically in a singlet ground state, with either a 6- or 8-valence electron icosahedral core. For the sake of comparison, the role of the d energy levels in the electronic structure of a variety of doped Au 25 (SR) 18 -1 nanoclusters was investigated for dopant atoms from other families such as Cd, Ag and Pd. Finally, the effect of spin-orbit coupling (SOC) on the electronic structure and absorption spectra was determined. The information in this study regarding the relative energetics of the d-based and super-atom energy levels can be useful to extend our understanding of the preferred doping modes of different transition metals in protected gold nanoclusters.

  12. The Modernization of the Energy Sector in Poland vs. Poland's Energy Security / Modernizacja sektora energii w polsce a bezpieczeństwo energetyczne Polski

    NASA Astrophysics Data System (ADS)

    Frączek, Paweł; Kaliski, Maciej; Siemek, Paweł

    2013-06-01

    ększenia bezpieczeństwa energetycznego kraju konieczne jest także konsekwentne prowadzenie dalszych działań na rzecz rozwoju alternatywnych technologii energetycznych, co pozwoli na skorzystanie z ewentualnych pojawiających się szans dotyczących różnych opcji. Szczególne miejsce w tych działaniach powinna mieć budowa w Polsce pierwszej elektrowni atomowej. Realizacja tej inwestycji pozwoli na pozyskanie taniej i czystej ekologicznie energii elektrycznej. Istotne jest także odnotowywane znaczące poparcie społeczne dla realizacji tej inwestycji. Podkreślono, że ewentualna zwłoka w pracach służących budowie pierwszej elektrowni atomowej w kraju może przyczynić się do ograniczenia konkurencyjności gospodarki. Ponadto wskazano, że konieczne będą także działania o charakterze edukacyjnym, które uświadomią społeczeństwu skalę wyzwań, jakie stoją przed krajowym sektorem energii, oraz wskażą wpływ upowszechniania konkurencyjnych cenowo źródeł energii na sytuację krajowej gospodarki oraz na utrzymanie i tworzenie miejsc pracy. Działania te przyczynią się do uzyskania poparcia wszystkich uczestników rynku energii dla podejmowania działań na rzecz takiego kształtowania struktury źródeł energii pierwotnej, aby możliwe było uzyskiwanie jak najniższych kosztów wytwarzania energii elektrycznej oraz jednoczesne minimalizowanie konsekwencji ekologicznych prowadzenia gospodarki energetycznej.

  13. Effect of vegetated filter strips on transport and deposition rates of Escherichia coli in overland flow in the eastern escarpments of the Mau Forest, Njoro River Watershed, Kenya

    PubMed Central

    Onyando, J. O.; Moturi, W. N.; Muia, A. W.; Ombui, P.; Shivoga, W. A.; Roegner, A. F.

    2016-01-01

    The fate and transport of Escherichia coli (E. coli) in lotic waters through vegetated filter strips (VFSs) was evaluated in a field model pasture, utilizing VFSMOD Windows along with direct pathogen testing. This study assessed effects of VFS on transport and deposition rates of E. coli in lotic overland flow waters. The VFS measured 44 m long by 40 m wide, covering an area of 1584 m2 and land slope of 15 %. Cowpat was applied onto the model pasture and washed by overland flow into the VFS. The 4-methylumbelliferyl β-D-glucuronide substrate confirmed the identity of E. coli prior to cowpat application and after isolating them from soil using centrifugation and membrane filtration techniques. Napier grass root system recorded the highest recovery rates of E. coli at 99.9 % along the length of VFS III. This efficiency reduced significantly (p < 0.05; df = 29) to 95 % in Kikuyu grass and 75 % in Couch grass–Buffer grass. The data demonstrated similarity in transport of manure-borne E. coli and organic carbon (OC) through all the simulated VFS. These results indicated that OC could be used as a true natural tracer of manure-borne E. coli, a pollution indicator organism of lentic and lotic surface waters provided the OC release kinetics from cowpat were similar to that of E. coli kinetics. Thus, efficient filtering to reduce E. coli concentrations and load in overland flows requires managing combined grass species, agro-pastoral systems models and dispersed or preferential flows to enhance surface water quality standards. PMID:28393102

  14. CORRIGENDUM: Universal variational expansion for high-precision bound-state calculations in three-body systems. Applications to weakly bound, adiabatic and two-shell cluster systems

    NASA Astrophysics Data System (ADS)

    Bailey, David H.; Frolov, Alexei M.

    2003-12-01

    Since the above paper was published we have received a suggestion from T K Rebane that our variational energy, -402.261 928 652 266 220 998 au, for the 3S(L = 0) state from table 4 (right-hand column) is wrong in the fourth and fifth decimal digits. Our original variational energies were E(2000) = -402.192 865 226 622 099 583 au and E(3000) = -402.192 865 226 622 099 838 au. Unfortunately, table 4 contains a simple typographic error. The first two digits after the decimal point (26) in the published energies must be removed. Then the results exactly coincide with the original energies. These digits (26) were left in table 4 from the original version, which also included the 2S(L = 0) states of the helium-muonic atoms. A similar typographic error was found in table 4 of another paper by A M Frolov (2001 J. Phys. B: At. Mol. Opt. Phys. 34 3813). The computed ground state energy for the ppµ muonic molecular ion was -0.494 386 820 248 934 546 94 mau. In table 4 of that paper the first figure '8' (fifth digit after the decimal point) was lost from the energy value presented in this table. We wish to thank T K Rebane of the Fock Physical Institute in St Petersburg for pointing out the misprint related to the helium(4)-muonic atom.

  15. Physicochemical and Antioxidant Properties of Honeys from the Sundarbans Mangrove Forest of Bangladesh

    PubMed Central

    Islam, M Rabiul; Pervin, Tahmina; Hossain, Hemayet; Saha, Badhan; Hossain, Sheikh Julfikar

    2017-01-01

    This study evaluated the physicochemical, nutritional, antioxidant, and phenolic properties of ten honey samples from the Sundarbans mangrove forest, Bangladesh. The average pH, electrical conductivity, total dissolved solid, ash, moisture, hydroxymethyl furfural, titrable acidity, and absorbance were 4.3, 0.38 mS/cm, 187.5 ppm, 0.14%, 17.88%, 4.4 mg/kg, 37.7 meq/kg, and 483 mAU, respectively. In the honeys, the average contents of Ca, Cu, Fe, K, Mg, Mn, and Na were 95.5, 0.19, 6.4, 302, 39.9, 3.4, and 597 ppm, respectively, whereas Cd, Cr, Pb, and Ni were not found. The average contents of total sugar, protein, lipid, vitamin C, polyphenols, flavonoids, and anthocyanins in the honeys were 69.3%, 0.8%, 0.29%, 107.3 mg/kg, 757.2 mg gallic acid equivalent/kg, 43.1 mg chatechin equivalent/kg, and 5.4 mg/kg, respectively. The honeys had strong 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity, reducing power and total antioxidant capacity. High-performance liquid chromatography analysis of the honey fractions revealed the quantification of six polyphenols namely, (+)-catechin, (−)-epicatechin, p-caumeric acid, syringic acid, trans-cinnamic acid, and vanillic acid at 194.98, 330.34, 74.64, 218.97, 49.55, and 118.84 mg/kg, respectively. Therefore, the honeys in the Sundarbans are of excellent quality and a prospective source of polyphenols, and antioxidants. PMID:29333387

  16. Prevalence of tobacco use among power loom workers - a cross-sectional study.

    PubMed

    Ansari, Zaki Anwar; Bano, S Nafees; Zulkifle, M

    2010-01-01

    Tobacco use is a major public health problem globally. According to the World Health Organization (WHO), tobacco is the second most important cause of death in the world. It is currently estimated to be responsible for about 5 million deaths each year worldwide. In India, it is responsible for over 8 lakh deaths every year. To estimate the prevalence of tobacco use among power loom workers in Mau Aima Town, District Allahabad, UP. Five hundred power loom workers were randomly chosen. Out of them 448 workers were interviewed through a questionnaire survey during May-June 2007. Data on demographics, education, and type of work were collected along with details regarding tobacco use and smoking status, duration of the habit, and daily consumption. Prevalence of tobacco chewing and/or bidi and cigarette smoking, and their sociodemographic correlates, were examined. The overall prevalence of tobacco use was 85.9%; the prevalence of smoking and tobacco chewing were 62.28% and 66.07%, respectively. Statistical analysis showed that smoking is more common in the elderly, while chewing gutka (a type of chewing tobacco) is popular among the younger age-groups. The prevalence of tobacco use among power loom workers is very high compared to that in general population. Immediate intervention programs are warranted to reduce the future burden of tobacco-related morbidity among these workers who are already exposed to the highly polluted environment in power loom factories.

  17. Decreasing flood risk perception in Porto Alegre - Brazil and its influence on water resource management decisions

    NASA Astrophysics Data System (ADS)

    Allasia, D. G.; Tassi, R.; Bemfica, D.; Goldenfum, J. A.

    2015-06-01

    Porto Alegre is the capital and largest city in the Brazilian state of Rio Grande do Sul in Southern Brazil with approximately 1.5 million inhabitants. The city lies on the eastern bank of the Guaiba Lake, formed by the convergence of five rivers and leading to the Lagoa dos Patos, a giant freshwater lagoon navigable by even the largest of ships. This river junction has become an important alluvial port as well as a chief industrial and commercial centre. However, this strategic location resulted in severe damage because of its exposure to flooding from the river system, affecting the city in the years 1873, 1928, 1936, 1941 and 1967. In order to reduce flood risk, a complex system of levees and pump stations was implemented during 1960s and 1970s. Since its construction, not a single large flood event occurred. However, in recent years, the levees in the downtown region of Porto Alegre were severally criticized by city planners and population. Several projects have been proposed to demolish the Mauá Wall due to the false perception of lack of flood risk. Similar opinions and reactions against flood infrastructure have been observed in other cities in Brazil, such as Itajaí and Blumenau, with disastrous consequences. This paper illustrates how the perception of flood risk in Porto Alegre has changed over recent years as a result of flood infrastructure, and how such changes in perceptions can influence water management decisions.

  18. Storing of Extracts in Polypropylene Microcentrifuge Tubes Yields Contaminant Peak During Ultra-flow Liquid Chromatographic Analysis.

    PubMed

    Kshirsagar, Parthraj R; Hegde, Harsha; Pai, Sandeep R

    2016-05-01

    This study was designed to understand the effect of storage in polypropylene microcentrifuge tubes and glass vials during ultra-flow liquid chromatographic (UFLC) analysis. One ml of methanol was placed in polypropylene microcentrifuge tubes (PP material, Autoclavable) and glass vials (Borosilicate) separately for 1, 2, 4, 8, 10, 20, 40, and 80 days intervals stored at -4°C. Contaminant peak was detected in methanol stored in polypropylene microcentrifuge tubes using UFLC analysis. The contaminant peak detected was prominent, sharp detectable at 9.176 ± 0.138 min on a Waters 250-4.6 mm, 4 μ, Nova-Pak C18 column with mobile phase consisting of methanol:water (70:30). It was evident from the study that long-term storage of biological samples prepared using methanol in polypropylene microcentrifuge tubes produce contaminant peak. Further, this may mislead in future reporting an unnatural compound by researchers. Long-term storage of biological samples prepared using methanol in polypropylene microcentrifuge tubes produce contaminant peakContamination peak with higher area under the curve (609993) was obtained in ultra-flow liquid chromatographic run for methanol stored in PP microcentrifuge tubesContamination peak was detected at retention time 9.113 min with a lambda max of 220.38 nm and 300 mAU intensity on the given chromatographic conditionsGlass vials serve better option over PP microcentrifuge tubes for storing biological samples. Abbreviations used: UFLC: Ultra Flow Liquid Chromatography; LC: Liquid Chromatography; MS: Mass spectrometry; AUC: Area Under Curve.

  19. Arbitrary mangrove-to-water ratios imposed on shrimp farmers in Vietnam contradict with the aims of sustainable forest management.

    PubMed

    Baumgartner, Urs; Kell, Shelagh; Nguyen, Tuan Hoang

    2016-01-01

    Worldwide, an estimated 35 % of mangrove forests have been lost between 1980 and 2005-among other reasons due to expansion of aquaculture production systems. In Vietnam, where the total mangrove area decreased from 269,150 ha in 1980 to 157,500 ha in 2000, regulation of such systems in the form of 'mangrove-to-water surface ratio' has had limited success to halt these losses. In this study, a survey of 40 Vietnamese households was conducted in mangrove production forests in Rach Goc commune, Ngoc Hien district, Ca Mau province to understand whether fixed limits on minimal mangrove coverage influence farmers' decisions on mangrove protection. Results of the survey suggest that rural households greatly depend on the incomes generated from shrimp (and crab) farming but that they do not have a share in economic incentives from timber harvests due to lack of full ownership. A strong relationship between mangrove coverage and per pond area income was also revealed. Because farmers are not aware of applicable laws in terms of mangrove-to-water ratios, mangrove coverage tends to shift in favour of higher pond areas. Overall, the findings indicate that regulations in the form of universal mangrove-to-water ratios do not consider the realities of local households, nor are they economically or environmentally useful-rather, they appear to be arbitrary limitations that are not respected by affected communities. The findings question the efficiency of efforts put into stricter enforcement.

  20. Physicochemical and Antioxidant Properties of Honeys from the Sundarbans Mangrove Forest of Bangladesh.

    PubMed

    Islam, M Rabiul; Pervin, Tahmina; Hossain, Hemayet; Saha, Badhan; Hossain, Sheikh Julfikar

    2017-12-01

    This study evaluated the physicochemical, nutritional, antioxidant, and phenolic properties of ten honey samples from the Sundarbans mangrove forest, Bangladesh. The average pH, electrical conductivity, total dissolved solid, ash, moisture, hydroxymethyl furfural, titrable acidity, and absorbance were 4.3, 0.38 mS/cm, 187.5 ppm, 0.14%, 17.88%, 4.4 mg/kg, 37.7 meq/kg, and 483 mAU, respectively. In the honeys, the average contents of Ca, Cu, Fe, K, Mg, Mn, and Na were 95.5, 0.19, 6.4, 302, 39.9, 3.4, and 597 ppm, respectively, whereas Cd, Cr, Pb, and Ni were not found. The average contents of total sugar, protein, lipid, vitamin C, polyphenols, flavonoids, and anthocyanins in the honeys were 69.3%, 0.8%, 0.29%, 107.3 mg/kg, 757.2 mg gallic acid equivalent/kg, 43.1 mg chatechin equivalent/kg, and 5.4 mg/kg, respectively. The honeys had strong 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity, reducing power and total antioxidant capacity. High-performance liquid chromatography analysis of the honey fractions revealed the quantification of six polyphenols namely, (+)-catechin, (-)-epicatechin, p -caumeric acid, syringic acid, trans -cinnamic acid, and vanillic acid at 194.98, 330.34, 74.64, 218.97, 49.55, and 118.84 mg/kg, respectively. Therefore, the honeys in the Sundarbans are of excellent quality and a prospective source of polyphenols, and antioxidants.

  1. Molecular Diagnostics of the Internal Motions of Massive Cores

    NASA Astrophysics Data System (ADS)

    Pineda, Jorge; Velusamy, T.; Goldsmith, P.; Li, D.; Peng, R.; Langer, W.

    2009-12-01

    We present models of the internal kinematics of massive cores in the Orion molecular cloud. We use a sample of cores studied by Velusamy et al. (2008) that show red, blue, and no asymmetry in their HCO+ line profiles in equal proportion, and which therefore may represent a sample of cores in different kinematic states. We use the radiative transfer code RATRAN (Hogerheijde & van der Tak 2000) to model several transitions of HCO+ and H13CO+ as well as the dust continuum emission, of a spherical model cloud with radial density, temperature, and velocity gradients. We find that an excitation and velocity gradients are prerequisites to reproduce the observed line profiles. We use the dust continuum emission to constrain the density and temperature gradients. This allows us to narrow down the functional forms of the velocity gradient giving us the opportunity to test several theoretical predictions of velocity gradients produced by the effect of magnetic fields (e.g. Tassis et. al. 2007) and turbulence (e.g. Vasquez-Semanedi et al 2007).

  2. Astrometry with A-Track Using Gaia DR1 Catalogue

    NASA Astrophysics Data System (ADS)

    Kılıç, Yücel; Erece, Orhan; Kaplan, Murat

    2018-04-01

    In this work, we built all sky index files from Gaia DR1 catalogue for the high-precision astrometric field solution and the precise WCS coordinates of the moving objects. For this, we used build-astrometry-index program as a part of astrometry.net code suit. Additionally, we added astrometry.net's WCS solution tool to our previously developed software which is a fast and robust pipeline for detecting moving objects such as asteroids and comets in sequential FITS images, called A-Track. Moreover, MPC module was added to A-Track. This module is linked to an asteroid database to name the found objects and prepare the MPC file to report the results. After these innovations, we tested a new version of the A-Track code on photometrical data taken by the SI-1100 CCD with 1-meter telescope at TÜBİTAK National Observatory, Antalya. The pipeline can be used to analyse large data archives or daily sequential data. The code is hosted on GitHub under the GNU GPL v3 license.

  3. Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.

    PubMed

    Seiki, Stephanie; Frishman, William H

    2009-01-01

    Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.

  4. Structure-based design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors.

    PubMed

    Kaieda, Akira; Takahashi, Masashi; Takai, Takafumi; Goto, Masayuki; Miyazaki, Takahiro; Hori, Yuri; Unno, Satoko; Kawamoto, Tomohiro; Tanaka, Toshimasa; Itono, Sachiko; Takagi, Terufumi; Hamada, Teruki; Shirasaki, Mikio; Okada, Kengo; Snell, Gyorgy; Bragstad, Ken; Sang, Bi-Ching; Uchikawa, Osamu; Miwatashi, Seiji

    2018-02-01

    We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Using drugs to target necroptosis: dual roles in disease therapy.

    PubMed

    Wang, Zhen; Guo, Li-Min; Zhou, Hong-Kang; Qu, Hong-Ke; Wang, Shu-Chao; Liu, Feng-Xia; Chen, Dan; Huang, Ju-Fang; Xiong, Kun

    2018-02-01

    Necroptosis is programmed necrosis, a process which has been studied for over a decade. The most common accepted mechanism is through the RIP1-RIP3-MLKL axis to regulate necroptotic cell death. As a result of previous studies on necroptosis, positive regulation for promoting necroptosis such as HSP90 stabilization and hyperactivation of TAK1 on RIP1 is clear. Similarly, the negative regulation of necroptosis, such as through caspase 8, c-FLIP, CHIP, MK2, PELI1, ABIN-1, is also clear. Therefore, the promise of corresponding applications in treating diseases becomes hopeful. Studies have shown that necroptosis is involved in the development of many diseases, such as ischemic injury diseases in various organs, neurodegenerative diseases, infectious diseases, and cancer. Given these results, drugs that inhibit or trigger necroptosis can be discovered to treat diseases. In this review, we briefly introduce up to date concepts concerning the mechanism of necroptosis, the diseases that involve necroptosis, and the drugs that can be applied to treat such diseases.

  6. Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium.

    PubMed

    Ros, Uris; Peña-Blanco, Aida; Hänggi, Kay; Kunzendorf, Ulrich; Krautwald, Stefan; Wong, W Wei-Lynn; García-Sáez, Ana J

    2017-04-04

    Necroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

    PubMed Central

    Vargas-Rodríguez, Rosa del Carmen Miluska; da Silva Bastos, Melissa; Menezes, Maria José; Orjuela-Sánchez, Pamela; Ferreira, Marcelo U.

    2012-01-01

    Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 (pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally (< 4%), but became common (> 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria. PMID:22949516

  8. Single-nucleotide polymorphism and copy number variation of the multidrug resistance-1 locus of Plasmodium vivax: local and global patterns.

    PubMed

    Vargas-Rodríguez, Rosa del Carmen Miluska; da Silva Bastos, Melissa; Menezes, Maria José; Orjuela-Sánchez, Pamela; Ferreira, Marcelo U

    2012-11-01

    Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 (pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally (< 4%), but became common (> 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria.

  9. Local structure and defects in ion irradiated KTaO3

    NASA Astrophysics Data System (ADS)

    Zhang, F. X.; Xi, J.; Zhang, Y.; Tong, Yang; Xue, H.; Huang, R.; Trautmann, C.; Weber, W. J.

    2018-04-01

    The modification of the local structure in cubic perovskite KTaO3 irradiated with 3 MeV and 1.1 GeV Au ions is studied by Raman and x-ray absorption spectroscopy, complemented by density functional theory (DFT) calculations. In the case of irradiation with 3 MeV Au ions where displacement cascade processes are dominant, the Ta L3-edge x-ray absorption measurements suggest that a peak corresponding to the Ta-O bonds in the TaO6 octahedra splits, which is attributed to the formation of TaK antisite defects that are coupled with oxygen vacancies, V O. This finding is consistent with the DFT calculations. Under irradiation with 1.1 GeV ions, the intense ionization and electronic energy deposition lead to a blue shift and an intensity reduction of active Raman bands. In the case of sequential irradiations, extended x-ray absorption fine structure measurements reveal a decrease in concentration of coupled TaK-V O defects under subsequent irradiation with 1.1 GeV Au ions.

  10. Electrical properties of sub-100 nm SiGe nanowires

    NASA Astrophysics Data System (ADS)

    Hamawandi, B.; Noroozi, M.; Jayakumar, G.; Ergül, A.; Zahmatkesh, K.; Toprak, M. S.; Radamson, H. H.

    2016-10-01

    In this study, the electrical properties of SiGe nanowires in terms of process and fabrication integrity, measurement reliability, width scaling, and doping levels were investigated. Nanowires were fabricated on SiGe-on oxide (SGOI) wafers with thickness of 52 nm and Ge content of 47%. The first group of SiGe wires was initially formed by using conventional I-line lithography and then their size was longitudinally reduced by cutting with a focused ion beam (FIB) to any desired nanometer range down to 60 nm. The other nanowire group was manufactured directly to a chosen nanometer level by using sidewall transfer lithography (STL). It has been shown that the FIB fabrication process allows manipulation of the line width and doping level of nanowires using Ga atoms. The resistance of wires thinned by FIB was 10 times lower than STL wires which shows the possible dependency of electrical behavior on fabrication method. Project support by the Swedish Foundation for Strategic Research “SSF” (No. EM-011-0002) and the Scientific and Technological Research Council of Turkey (No. TÜBİTAK).

  11. MKK6 controls T3-mediated browning of white adipose tissue.

    PubMed

    Matesanz, Nuria; Bernardo, Edgar; Acín-Pérez, Rebeca; Manieri, Elisa; Pérez-Sieira, Sonia; Hernández-Cosido, Lourdes; Montalvo-Romeral, Valle; Mora, Alfonso; Rodríguez, Elena; Leiva-Vega, Luis; Lechuga-Vieco, Ana Victoria; Ruiz-Cabello, Jesús; Torres, Jorge L; Crespo-Ruiz, Maria; Centeno, Francisco; Álvarez, Clara V; Marcos, Miguel; Enríquez, Jose Antonio; Nogueiras, Ruben; Sabio, Guadalupe

    2017-10-11

    Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of the p38 MAPK activator MKK6 is elevated in white adipose tissue of obese individuals. Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically, we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB. Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure.

  12. Transmission-blocking activity of tafenoquine (WR-238605) and artelinic acid against naturally circulating strains of Plasmodium vivax in Thailand.

    PubMed

    Ponsa, Narong; Sattabongkot, Jetsumon; Kittayapong, Pattamaporn; Eikarat, Nantana; Coleman, Russell E

    2003-11-01

    The sporontocidal activity of tafenoquine (WR-238605) and artelinic acid was determined against naturally circulating isolates of Plasmodium vivax in western Thailand. Primaquine was used as a negative control and a dihydroacridine-dione (WR-250547) was used as a positive control. Laboratory-reared Anopheles dirus mosquitoes were infected with P. vivax by allowing mosquitoes to feed on blood (placed in an artificial-membrane feeding apparatus) collected from gametocytemic volunteers reporting to local malaria clinics in Tak province, Thailand. Four days post-infection, mosquitoes were refed on uninfected mice treated 90 minutes earlier with a given drug. Drug activity was determined by assessing oocyst and sporozoite development. Neither primaquine nor artelinic acid affected oocyst or sporozoite development at a dose of 100 mg of base drug/kg of mouse body weight. In contrast, tafenoquine and WR-250547 affected sporogonic development at doses as low as 25.0 and 0.39 mg/kg, respectively. The potential role of these compounds in the prevention of malaria transmission is discussed, as are alternative strategies for the use of transmission-blocking antimalarial drugs.

  13. Comparative Effect of an Addition of a Surface Term to Woods-Saxon Potential on Thermodynamics of a Nucleon

    NASA Astrophysics Data System (ADS)

    Lütfüoğlu, B. C.

    2018-01-01

    In this study, we reveal the difference between Woods-Saxon (WS) and Generalized Symmetric Woods-Saxon (GSWS) potentials in order to describe the physical properties of a nucleon, by means of solving Schrödinger equation for the two potentials. The additional term squeezes the WS potential well, which leads an upward shift in the spectrum, resulting in a more realistic picture. The resulting GSWS potential does not merely accommodate extra quasi bound states, but also has modified bound state spectrum. As an application, we apply the formalism to a real problem, an α particle confined in Bohrium-270 nucleus. The thermodynamic functions Helmholtz energy, entropy, internal energy, specific heat of the system are calculated and compared for both wells. The internal energy and the specific heat capacity increase as a result of upward shift in the spectrum. The shift of the Helmholtz free energy is a direct consequence of the shift of the spectrum. The entropy decreases because of a decrement in the number of available states. Supported by the Turkish Science and Research Council (TÜBİTAK) and Akdeniz University

  14. Tuneable reactivity with PPh3 and SnX2 of four- and five-coordinate Pd(II) and Pt(II) complexes containing polyphosphines.

    PubMed

    Fernández-Anca, Damián; García-Seijo, M Inés; García-Fernández, M Esther

    2013-07-28

    The reactivity of the unusual d(8) trigonal-bipyramidal systems [MX(PP3)]X (X = Cl: M = Pd(1a), Pt(2a); X = Br: M = Pd(3a), Pt(4a); X = I: M = Pd(5a), Pt(6a); PP3 = tris[2-(diphenylphosphino)ethyl]phosphine) in CHCl3-CH3OH, the square-pyramidal compounds [MCl(NP3)]Cl (M = Pd(7a); Pt(8a); NP3 = tris[2-(diphenylphosphino)ethyl]amine) in CD3OD-DMF and the distorted square-planar mononuclear [MX(PNP)]X (M = Pd: X = Cl(10a); M = Pt: X = I(10b); PNP = bis[2-(diphenylphosphino)ethyl]amine) and the heteronuclear [PdAu2X4(PP3)] [X = I(9a), Cl(14a), Br(15a)] and [MAuX2(PP3)]X [M = Pd: X = Cl(16a); M = Pt: X = Cl(17a), Br(18a)] species in CDCl3 with PPh3 + SnX2 has been explored to establish the factors that influence the nature of the products. With the mononuclear precursors the course of the reaction is strongly dependent on the tripodal or linear arrangement of the polydentate ligand and in the former case on the halogen. Thus, while for chlorides (1a-2a, 7a-8a) and bromides (3a-4a) the reaction led to the trigonal-bipyramidal compounds [M(SnCl3)(AP3)][SnCl3] [A = P: M = Pd(1), Pt(2); A = N: M = Pd(7), Pt(8)], [MBr(PP3)][SnBr3] [M = Pd(4), Pt(6)] containing M-Sn and M-Br bonds, respectively, for iodides (5a-6a) resulted in the unknown neutral square-planar compounds [MI2(PP(PO)2)(SnI2)2] [M = Pd(9) and Pt(10)] bearing two dangling P=O-SnI2 units and P2MI2 environments. However, complexes of the type [PtCl(PP2PO)X]X' [X = SnCl2, X' = [SnCl3](-)(11)] and [M(PP(PO)2)2X4]X'2 [X = SnCl2, X' = [SnCl3](-): M = Pd(12), Pt(13)] showing P=O-SnCl2 arms were obtained by direct reaction of [PtCl(PP2PO)]Cl (11a) and [M(PP(PO)2)2]Cl2 [M = Pd(12a), Pt(13a)] with SnCl2 in CH3OH. Although complex 9 was also prepared by interaction of the heteronuclear iodide 9a with PPh3 + SnI2 in CDCl3, the use of the neutral and ionic heteronuclear chlorides and bromides (14a-18a) as starting materials afforded the distorted square-planar ionic systems [MAuX'(PP3)(PPh3)][SnX3]2 [M = Pd: X = Cl, X' = Sn

  15. Conceptual Learning in Social Studies Classroom: An Analysis of Texas Assessment of Knowledge and Skills (TAKS) Social Studies Questions with and without Concept

    ERIC Educational Resources Information Center

    Kilinc, Emin

    2012-01-01

    We are living in a conceptual world which we build through both informal and systematic interaction. Concepts enable us to simplify and organize our environment and communicate efficiently with others. The learning of concepts is represented by a general idea, usually expressed by a word, which represent a class or group of things or actions…

  16. [Tri-phalā (Three Myrobalans) as Described in the Second Part of the Bower Manuscript, the Nāvanītaka].

    PubMed

    Natsume, Yohko

    2015-01-01

    In India, since ancient times Tri-phalā (meaning "three fruits" in Sanskrit) has been considered to be a combination of the following fruits: -Harītakī (Terminalia chebula, Retz.), Āmalaka (Embelica officinalis Gaertn), and Vibhītaka (Terminalia belerica Roxb.). These plants are also listed in the Ayurvedic Pharmacopoeia of India. Harītakī and Āmalaka have also been used for medicinal purposes since ancient times in Japan under the Japanese names of (see text) (Kariroku) and (see text) (Annmaroku), respectively. Both have been carefully preserved as treasured drugs in the nationally important Shosoin treasure storehouse. This study attempts to clarify the description of Tri-phalā in the Nāvanītaka, which is the second part of the Bower Manuscript (Bower Ms.), and examines the reasons why these plants were combined. This paper begins with a summary description of Tri-phalā in the context of traditional Asian medicine, followed by the delineation of drug selection principles in Ayurveda. Tri-phalā formulas in the Nāvanītaka are then examined. The Carakasamhitā (CS) treats Tri-phalā as a purifier and tonic (rasāyana), describing it as a formula for rejuvenation and longevity. On the other hand, the Susrutasamhitd (SS) regards Tri-phalā as having the efficacy of balancing kapha (phlegm) and pitta (bile), and also as being a medicine to promote excretion and enhance digestive functions for better nutritional intake. It is described to have an effect of curing diseases by keeping the tridhāu (theree element) valance. Tri-phalā is thus used as an ingredient of laxatives for diseases that result from kapha imbalance and tonic. The Aşţāngahŗdayasamhitā (AHS) considers Tri-phalā to have a particular superiority among cure-all medicines with the power to dispel illness. It controls kapha and overcomes blood diseases. Tri-phalā formulas found in the Nāvanītaka were prescribed for the treatment of abdominal tumors induced by vāyu (wind) disorder

  17. Modelling the cost-effectiveness of HIV care shows a clear benefit when transmission risk is considered in the calculations - A message for Central and Eastern Europe.

    PubMed

    Kowalska, Justyna D; Wójcik, Grzegorz; Rutkowski, Jakub; Ankiersztejn-Bartczak, Magdalena; Siewaszewicz, Ewa

    2017-01-01

    HIV epidemic remains a major global health issue. Data from cost-effectiveness analyses base on CD4+ count and morbidity in patients with symptomatic and asymptomatic HIV infection. The approach adopted in these analyses includes many other factors, previously not investigated. Additionally, we evaluate the impact of sexual HIV transmission due to delayed cART on the cost-effectiveness of care. A lifetime Markov model (1-month cycle) was developed to estimate the cost per quality adjusted life years (QALY) for a 1- and 3-year delay in starting cART (as compared to starting immediately at linkage to care) lifetime costs, clinical outcomes and cost-effectiveness. Patients were categorized into having asymptomatic HIV, AIDS, Hodgkin's Lymphoma, and non-AIDS defining condition. Mortality rates and utility values were obtained from published literature. The number of new infected persons was estimated on the basis of sexual orientation, the number of sexual partners per year, the number of sex acts per month, frequency of condom use and use of cART. For the input Test and Keep in Care (TAK) project cohort data were used. Costs of care, cART and potential life-years lost were based on estimated total costs and the difference in expected QALY gained between an HIV-positive and an average person in Polish population. Costs were based on real expenditures of the Ministry of Health, National Health Fund, available studies and experts' opinion. Costs and effects were discounted at rates of 5% and 3.5%, respectively. Input data were available for 141 patients form TAK cohort. The estimated number of new HIV infections in low, medium and high risk transmission groups were 0.28, 0.61, 2.07 with 1 and 0.82, 1.80, 6.11 with a 3-year delay, respectively. This reflected QALY loss due to cART delay of 0.52, 1.13, 3.84 and 2.02, 4.43, 15.03 for a 1- and 3-year delay, respectively. If additional costs of treatment and potential life-years lost due to new HIV infections were not taken

  18. Combustion of Coal-Mule Briquettes / Spalanie Brykietów Z Mułu Węglowego

    NASA Astrophysics Data System (ADS)

    Kijo-Kleczkowska, Agnieszka

    2013-09-01

    Combustion technologies coal-mule fuels create a number of new possibilities for organising combustion processes so that they fulfil contemporary requirements (e.g., in terms of the environment protection- related issues). The paper describes the problems of coal-mule fuel combustion that have acquired a wider significance as the quality requirements of coal combustion in power plants have been growing. Coal mines that want to fulfill expectations of power industry workers have been forced to develop and modernize plants of coal wet cleaning. It all results in the growing amount of waste arising in the process of coal wet cleaning which contains smaller and smaller coal undersizes. In this situation the concept of direct combustion of the above mentioned waste and their co-combustion with other fuels, coal and biomass, seems to be attractive. Biomass is one from the most promising sources of renewable energy. The main aim of the paper is to identify the mechanism and kinetics of combustion of coal-mule fuels and their co- -combustion with coal and biomass in the briquettes form based on extensive experimental research in air. Niekorzystny bilans paliwowy naszego kraju powoduje nadmierne obciążenie środowiska, wywołane emisją CO2, NOx, SO2 i pyłów, a także powiększeniem powierzchni koniecznych na składowanie wciąż narastających stałych odpadów paleniskowych. Górnictwo, od którego energetyka oczekuje coraz lepszego paliwa, musi stosować głębsze wzbogacanie węgla. Powoduje to ciągłą produkcję odpadów w postaci mułów poflotacyjnych. Najlepszą metodą utylizacji tych mułów jest ich spalanie w postaci zawiesin, a także ich współspalanie z innymi paliwami, węglem czy biomasą. Biomasa jest bowiem jednym z najbardziej obiecujących źródeł OZE, a jej współspalanie z paliwami węglowymi znajduje w ostatnich latach coraz szersze zastosowanie zarówno w kraju, jak i na świecie. W tej sytuacji istotne jest prowadzenie badań naukowych

  19. Vulnerability of climate change and its adaptation in the Mekong Delta: monitoring and resident's perception along the coast

    NASA Astrophysics Data System (ADS)

    Tamura, M.; Yasuhara, K.

    2014-12-01

    The Mekong Delta in Vietnam is expected to face challenges from various forms of climate-induced events. In addition, a growing population, which currently stands at 18.6 million people lives in the Mekong Delta, Vietnam. Therefore, the Mekong Delta is the focus of international action for adaptation. However, many climate sensitive regions and communities are unprepared for climate-induced natural disasters due to mismatch in perception with their respective risks. This study examines the vulnerability and appropriate adaptation in the Mekong Delta from both scientific and regional aspects. First, we show the change in coastal areas in Soc Trang province, comparing the past to the present images using Unmanned Aerial Vehicle (UAV) and satellite. We identify some vulnerable areas which derived from multiple factors due to coastal erosion, flooding, and sea level rise. Second, we present results of perception survey about climate change and the adaptation at community level in Ca Mau, Soc Trang, and An Giang Provinces, which were conducted in 2012 and 2014. While the findings suggest varying degrees of adaptation to seasonal flooding by raising the ground floors of their homes and repairing houses, their capacity to prepare for extreme flooding is limited in spite of the residents' awareness of the increasing frequency and intensity of natural disasters. Third, we propose an erosion-resistant dyke reinforcement technique by mixing natural palm tree fiber and cement, both of which are locally available materials in the Mekong Delta. It is expected that adaptation with multiple protections in accordance to regional feature can work well for such coastal disasters.

  20. Tailoring Enzyme-Like Activities of Gold Nanoclusters by Polymeric Tertiary Amines for Protecting Neurons Against Oxidative Stress.

    PubMed

    Liu, Ching-Ping; Wu, Te-Haw; Lin, Yu-Lung; Liu, Chia-Yeh; Wang, Sabrina; Lin, Shu-Yi

    2016-08-01

    The cytotoxicity of nanozymes has drawn much attention recently because their peroxidase-like activity can decompose hydrogen peroxide (H2 O2 ) to produce highly toxic hydroxyl radicals (•OH) under acidic conditions. Although catalytic activities of nanozymes are highly associated with their surface properties, little is known about the mechanism underlying the surface coating-mediated enzyme-like activities. Herein, it is reported for the first time that amine-terminated PAMAM dendrimer-entrapped gold nanoclusters (AuNCs-NH2 ) unexpectedly lose their peroxidase-like activity while still retaining their catalase-like activity in physiological conditions. Surprisingly, the methylated form of AuNCs-NH2 (i.e., MAuNCs-N(+) R3 , where R = H or CH3 ) results in a dramatic recovery of the intrinsic peroxidase-like activity while blocking most primary and tertiary amines (1°- and 3°-amines) of dendrimers to form quaternary ammonium ions (4°-amines). However, the hidden peroxidase-like activity is also found in hydroxyl-terminated dendrimer-encapsulated AuNCs (AuNCs-OH, inside backbone with 3°-amines), indicating that 3°-amines are dominant in mediating the peroxidase-like activity. The possible mechanism is further confirmed that the enrichment of polymeric 3°-amines on the surface of dendrimer-encapsulated AuNCs provides sufficient suppression of the critical mediator •OH for the peroxidase-like activity. Finally, it is demonstrated that AuNCs-NH2 with diminished cytotoxicity have great potential for use in primary neuronal protection against oxidative damage. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Genome-wide comparative chromosome maps of Arvicola amphibius, Dicrostonyx torquatus, and Myodes rutilus.

    PubMed

    Romanenko, Svetlana A; Lemskaya, Natalya A; Trifonov, Vladimir A; Serdyukova, Natalya A; O'Brien, Patricia C M; Bulatova, Nina Sh; Golenishchev, Feodor N; Ferguson-Smith, Malcolm A; Yang, Fengtang; Graphodatsky, Alexander S

    2016-05-01

    The subfamily Arvicolinae consists of a great number of species with highly diversified karyotypes. In spite of the wide use of arvicolines in biological and medicine studies, the data on their karyotype structures are limited. Here, we made a set of painting probes from flow-sorted chromosomes of a male Palearctic collared lemming (Dicrostonyx torquatus, DTO). Together with the sets of painting probes made previously from the field vole (Microtus agrestis, MAG) and golden hamster (Mesocricetus auratus, MAU), we carried out a reciprocal chromosome painting between these three species. The three sets of probes were further hybridized onto the chromosomes of the Eurasian water vole (Arvicola amphibius) and northern red-backed vole (Myodes rutilus). We defined the diploid chromosome number in D. torquatus karyotype as 2n = 45 + Bs and showed that the system of sex chromosomes is X1X2Y1. The probes developed here provide a genomic tool-kit, which will help to investigate the evolutionary biology of the Arvicolinae rodents. Our results show that the syntenic association MAG1/17 is present not only in Arvicolinae but also in some species of Cricetinae; and thus, should not be considered as a cytogenetic signature for Arvicolinae. Although cytogenetic signature markers for the genera have not yet been found, our data provides insight into the likely ancestral karyotype of Arvicolinae. We conclude that the karyotypes of modern voles could have evolved from a common ancestral arvicoline karyotype (AAK) with 2n = 56 mainly by centric fusions and fissions.

  2. Cognitive ability of preschool, primary and secondary school children in Costa Rica.

    PubMed

    Rindermann, Heiner; Stiegmaier, Eva-Maria; Meisenberg, Gerhard

    2015-05-01

    Cognitive abilities of children in Costa Rica and Austria were compared using three age groups (N = 385/366). Cognitive ability tests (mental speed, culture reduced/fluid intelligence, literacy/crystallized intelligence) were applied that differed in the extent to which they refer to school-related knowledge. Preschool children (kindergarten, 5-6 years old, N(CR) = 80, N(Au) = 51) were assessed with the Coloured Progressive Matrices (CPM), primary school children (4th grade, 9-11 years old, N(CR) = 71, N(Au) = 71) with ZVT (a trail-making test), Standard Progressive Matrices (SPM) and items from PIRLS-Reading and TIMSS-Mathematics, and secondary school students (15-16 years old, N(CR) = 48, N(Au) = 48) with ZVT, Advanced Progressive Matrices (APM) and items from PISA-Reading and PISA-Mathematics. Additionally, parents and pupils were given questionnaires covering family characteristics and instruction. Average cognitive abilities were higher in Austria (Greenwich-IQ M(CR) = 87 and M(Au) = 99, d(IQ) = 12 points) and differences were smaller in preschool than in secondary school (d(IQ) = 7 vs 20 points). Differences in crystallized intelligence were larger than in fluid intelligence (mental speed: d(IQ) = 12, Raven: d(IQ) = 10, student achievement tests: d(IQ) = 17 IQ points). Differences were larger in comparisons at the level of g-factors. Austrian children were also taller (6.80 cm, d = 1.07 SD), but had lower body mass index (BMI(CR) = 19.35 vs BMI(Au) = 17.59, d = -0.89 SD). Different causal hypotheses explaining these differences are compared.

  3. Genetic and Phenotypic Comparison of Facultative Methylotrophy between Methylobacterium extorquens Strains PA1 and AM1

    PubMed Central

    Nayak, Dipti D.; Marx, Christopher J.

    2014-01-01

    Methylobacterium extorquens AM1, a strain serendipitously isolated half a century ago, has become the best-characterized model system for the study of aerobic methylotrophy (the ability to grow on reduced single-carbon compounds). However, with 5 replicons and 174 insertion sequence (IS) elements in the genome as well as a long history of domestication in the laboratory, genetic and genomic analysis of M. extorquens AM1 face several challenges. On the contrary, a recently isolated strain - M. extorquens PA1- is closely related to M. extorquens AM1 (100% 16S rRNA identity) and contains a streamlined genome with a single replicon and only 20 IS elements. With the exception of the methylamine dehydrogenase encoding gene cluster (mau), genes known to be involved in methylotrophy are well conserved between M. extorquens AM1 and M. extorquens PA1. In this paper we report four primary findings regarding methylotrophy in PA1. First, with a few notable exceptions, the repertoire of methylotrophy genes between PA1 and AM1 is extremely similar. Second, PA1 grows faster with higher yields compared to AM1 on C1 and multi-C substrates in minimal media, but AM1 grows faster in rich medium. Third, deletion mutants in PA1 throughout methylotrophy modules have the same C1 growth phenotypes observed in AM1. Finally, the precision of our growth assays revealed several unexpected growth phenotypes for various knockout mutants that serve as leads for future work in understanding their basis and generality across Methylobacterium strains. PMID:25232997

  4. Stability Assessment of the High Safety Pillars in Slovenian Natural Stone Mines / Ocena Stabilności Wysokich Filarów Bezpieczeństwa W Kopalniach Kamieni Naturalnych W Słowenii

    NASA Astrophysics Data System (ADS)

    Kortnik, Jože

    2015-03-01

    (wapień), w 2008 kamieniołom Lipica I (wapień), w roku 2009 wapień pozyskiwać także zaczęto z kamieniołomu w Dolinie. Działo się to głównie z uwagi na strukturę geologiczną w tych miejscach, warunki geologiczne kamieniołomów, potencjalnie grube warstwy nadkładu w przypadku rozszerzania działalności w części odkrywkowej kamieniołomu, a także rosnący popyt na te surowce (kamień naturalny). Podziemne wydobycie kamieni naturalnych we wszystkich tych lokalizacjach odbywa się za pomocą zmodyfikowanej metody filarowo- komorowej, dostosowanej do uwarunkowań poszczególnych lokalizacji, z wykorzystaniem układu mniej lub bardziej regularnie rozmieszczonych filarów zabezpieczających. Ponieważ podziemne wydobycie naturalnych bloków skalnych odbywa się stosunkowo płytko pod powierzchnią, (na głębokościach rzędu 10-40 m), to wartości pierwotnego naprężenia pionowego są stosunkowo niewielkie (poniżej 1.0 MPa). Wskutek tego powstaje poważne ryzyko odrywania się od stropu bloków skalnych w kształcie klinów, zwłaszcza w dużych, otwartych komorach podziemnych. W latach ubiegłych instalowano układy monitorujące stan naprężeń i odkształceń, wykorzystywane przy planowaniu wymiarów (szerokości i wysokości) dużych, otwartych, przestrzennych komór podziemnych oraz wymiarów filarów zabezpieczających, a także układy zapewniające stałą kontrolę i wykrywanie niestabilności w obrębie stropu oraz w ścianach bocznych komór. Niniejsza praca zawiera przegląd metod i urządzeń wykorzystywanych do optymalizacji i bezpieczeństwa monitorowania stanu filarów zabezpieczających w podziemnych kopalniach kamieni naturalnych w Słowenii.

  5. [Behaviour therapy and child welfare - results of an approach to improve mental health care of aggressive children].

    PubMed

    Nitkowski, Dennis; Petermann, Franz; Büttner, Peter; Krause-Leipoldt, Carsten; Petermann, Ulrike

    2009-09-01

    The Training with Aggressive Children (Petermann & Petermann, 2008) was integrated into the setting of a child welfare service. This study examined, if mental health care of aggressive children in child welfare settings can be improved, compared the effectiveness of a combination of the training and child welfare intervention after six months with effects of the TAK. 25 Children with conduct problems (24 boys, one girl) aged 7;6 to 13;0 years participated in the study. A pretest-follow up comparison of parent ratings on the Child Behavior Checklist (CBCL) documented a large reduction of aggressive-delinquent behaviour and social problems in the training and child welfare group. Furthermore, conduct and peer relationship problems decreased essentially on the Strengths and Difficulties Questionnaire (SDQ). By reducing conduct, attention and social problems, and delinquent behaviour, the therapeutic outcome of the training and child welfare group was clearly superior to training group. In comparison to the training, the combination of child welfare and training seemed to reduce a wider range of behavioural problems more effectively. This indicates that combined intervention programs can optimize mental health care of aggressive children.

  6. Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation.

    PubMed

    Marwick, John A; Mills, Ross; Kay, Oliver; Michail, Kyriakos; Stephen, Jillian; Rossi, Adriano G; Dransfield, Ian; Hirani, Nikhil

    2018-06-04

    Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-κB signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-κB activation occurs through a blockade in transforming growth factor β-activated kinase 1 (TAK1) and IKKβ activation. As a consequence, NF-κB (p65) phosphorylation is reduced, its translocation to the nucleus is inhibited and NF-κB-mediated inflammatory cytokine transcription is suppressed. Gene Set Enrichment Analysis reveals that this suppression of NF-κB activation is not restricted to post-translational modifications of the canonical NF-κB pathway, but is also imprinted at the transcriptional level. Thus neutrophils exert a sustained anti-inflammatory phenotypic reprogramming of the macrophage, which is reflected by the sustained reduction in the release of pro- but not anti- inflammatory cytokines from the macrophage. Together, our findings identify a novel apoptosis-independent mechanism by which neutrophils regulate the mediator profile and reprogramming of monocytes/macrophages, representing an important nodal point for inflammatory control.

  7. CYP17 inhibitors for prostate cancer therapy

    PubMed Central

    Vasaitis, Tadas S.; Bruno, Robert D.; Njar, Vincent C. O.

    2010-01-01

    Prostate cancer (PC) is now the second most prevalent cause of death in men in the USA and Europe. At present, the major treatment options include surgical or medical castration. These strategies cause ablation of the production of testosterone (T), dihydrotestosterone (DHT) and related androgens by the testes. However, because these procedures do not affect adrenal, prostate and other tissues androgen production, they are often combined with androgen receptor antagonists to block their action. Indeed, recent studies have unequivocally established that in castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. Clearly, inhibition of the key enzyme which catalyzes the biosynthesis of androgens from pregnane precursors, 17α-hydroxy/17,20-lyase (hereafter referred to as CYP17) could prevent androgen production from all sources. Thus, total ablation of androgen production by potent CYP17 inhibitors may provide effective treatment of prostate cancer patients. This review highlights the role of androgen biosynthesis in the progression of prostate cancer and the impact of CYP17 inhibitors, such as ketoconazole, abiraterone acetate, VN/124-1 (TOK-001) and TAK-700 in the clinic and in clinical development. PMID:21092758

  8. Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

    PubMed Central

    Patel, Jesal C.; Maughan, Benjamin L.; Agarwal, Archana M.; Batten, Julia A.; Zhang, Tian Y.; Agarwal, Neeraj

    2013-01-01

    Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials. PMID:23819055

  9. A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways

    PubMed Central

    Huang, Tianzhi; Alvarez, Angel A.; Pangeni, Rajendra P.; M. Horbinski, Craig; Lu, Songjian; Kim, Sung-Hak; James, C. David; J. Raizer, Jeffery; A. Kessler, John; Brenann, Cameron W.; Sulman, Erik P.; Finocchiaro, Gaetano; Tan, Ming; Nishikawa, Ryo; Lu, Xinghua; Nakano, Ichiro; Hu, Bo; Cheng, Shi-Yuan

    2016-01-01

    Molecularly defined subclassification is associated with phenotypic malignancy of glioblastoma (GBM). However, current understanding of the molecular basis of subclass conversion that is often involved in GBM recurrence remain rudimentary at best. Here we report that canonical Wnt signalling that is active in proneural (PN) but inactive in mesenchymal (MES) GBM, along with miR-125b and miR-20b that are expressed at high levels in PN compared with MES GBM, comprise a regulatory circuit involving TCF4-miR-125b/miR-20b-FZD6. FZD6 acts as a negative regulator of this circuit by activating CaMKII–TAK1–NLK signalling, which, in turn, attenuates Wnt pathway activity while promoting STAT3 and NF-κB signalling that are important regulators of the MES-associated phenotype. These findings are confirmed by targeting differentially enriched pathways in PN versus MES GBM that results in inhibition of distinct GBM subtypes. Correlative expressions of the components of this circuit are prognostic relevant for clinical GBM. Our findings provide insights for understanding GBM pathogenesis and for improving treatment of GBM. PMID:27698350

  10. Dynamic modelling of solids in a full-scale activated sludge plant preceded by CEPT as a preliminary step for micropollutant removal modelling.

    PubMed

    Baalbaki, Zeina; Torfs, Elena; Maere, Thomas; Yargeau, Viviane; Vanrolleghem, Peter A

    2017-04-01

    The presence of micropollutants in the environment has triggered research on quantifying and predicting their fate in wastewater treatment plants (WWTPs). Since the removal of micropollutants is highly related to conventional pollutant removal and affected by hydraulics, aeration, biomass composition and solids concentration, the fate of these conventional pollutants and characteristics must be well predicted before tackling models to predict the fate of micropollutants. In light of this, the current paper presents the dynamic modelling of conventional pollutants undergoing activated sludge treatment using a limited set of additional daily composite data besides the routine data collected at a WWTP over one year. Results showed that as a basis for modelling, the removal of micropollutants, the Bürger-Diehl settler model was found to capture the actual effluent total suspended solids (TSS) concentrations more efficiently than the Takács model by explicitly modelling the overflow boundary. Results also demonstrated that particular attention must be given to characterizing incoming TSS to obtain a representative solids balance in the presence of a chemically enhanced primary treatment, which is key to predict the fate of micropollutants.

  11. Substantial population structure of Plasmodium vivax in Thailand facilitates identification of the sources of residual transmission.

    PubMed

    Kittichai, Veerayuth; Koepfli, Cristian; Nguitragool, Wang; Sattabongkot, Jetsumon; Cui, Liwang

    2017-10-01

    Plasmodium vivax transmission in Thailand has been substantially reduced over the past 10 years, yet it remains highly endemic along international borders. Understanding the genetic relationship of residual parasite populations can help track the origins of the parasites that are reintroduced into malaria-free regions within the country. A total of 127 P. vivax isolates were genotyped from two western provinces (Tak and Kanchanaburi) and one eastern province (Ubon Ratchathani) of Thailand using 10 microsatellite markers. Genetic diversity was high, but recent clonal expansion was detected in all three provinces. Substantial population structure and genetic differentiation of parasites among provinces suggest limited gene flow among these sites. There was no haplotype sharing among the three sites, and a reduced panel of four microsatellite markers was sufficient to assign the parasites to their provincial origins. Significant parasite genetic differentiation between provinces shows successful interruption of parasite spread within Thailand, but high diversity along international borders implies a substantial parasite population size in these regions. The provincial origin of P. vivax cases can be reliably determined by genotyping four microsatellite markers, which should be useful for monitoring parasite reintroduction after malaria elimination.

  12. Modelling the cost-effectiveness of HIV care shows a clear benefit when transmission risk is considered in the calculations – A message for Central and Eastern Europe

    PubMed Central

    Wójcik, Grzegorz; Rutkowski, Jakub; Ankiersztejn-Bartczak, Magdalena; Siewaszewicz, Ewa

    2017-01-01

    Background HIV epidemic remains a major global health issue. Data from cost-effectiveness analyses base on CD4+ count and morbidity in patients with symptomatic and asymptomatic HIV infection. The approach adopted in these analyses includes many other factors, previously not investigated. Additionally, we evaluate the impact of sexual HIV transmission due to delayed cART on the cost-effectiveness of care. Methods A lifetime Markov model (1-month cycle) was developed to estimate the cost per quality adjusted life years (QALY) for a 1- and 3-year delay in starting cART (as compared to starting immediately at linkage to care) lifetime costs, clinical outcomes and cost-effectiveness. Patients were categorized into having asymptomatic HIV, AIDS, Hodgkin’s Lymphoma, and non-AIDS defining condition. Mortality rates and utility values were obtained from published literature. The number of new infected persons was estimated on the basis of sexual orientation, the number of sexual partners per year, the number of sex acts per month, frequency of condom use and use of cART. For the input Test and Keep in Care (TAK) project cohort data were used. Costs of care, cART and potential life-years lost were based on estimated total costs and the difference in expected QALY gained between an HIV-positive and an average person in Polish population. Costs were based on real expenditures of the Ministry of Health, National Health Fund, available studies and experts’ opinion. Costs and effects were discounted at rates of 5% and 3.5%, respectively. Results Input data were available for 141 patients form TAK cohort. The estimated number of new HIV infections in low, medium and high risk transmission groups were 0.28, 0.61, 2.07 with 1 and 0.82, 1.80, 6.11 with a 3-year delay, respectively. This reflected QALY loss due to cART delay of 0.52, 1.13, 3.84 and 2.02, 4.43, 15.03 for a 1- and 3-year delay, respectively. If additional costs of treatment and potential life-years lost due to new

  13. Geochemical Transformation of Cadmium (Cd) from Creek to Paddy Fields in W Thailand

    NASA Astrophysics Data System (ADS)

    Kosolsaksakul, Peerapat; Graham, Margaret; Farmer, John

    2013-04-01

    Extensive Cd contamination of paddy soils in Tak Province, western Thailand, a consequence of Zn mining activities, was first established in 2005 and medical studies showed that the health of local communities was being impaired. Mae Tao, Tak Province, comprising many paddy fields and irrigation canals, has been selected for this study of the geochemical transformation of Cd from the contamination source in the mountainous region to the east of the study site through the community irrigation system to the paddy soils. The aim of this research is to (i) investigate the geochemical transformation of Cd as it is transported from the main irrigation creek through the canals and to the paddy fields, (ii) assess the availability of Cd to rice plants, which may be affected by both chemical and physical factors, and (iii) trial some practical treatments to minimise Cd concentrations in rice grains. Soils, irrigation canal sediments and water samples were collected during the dry season and at the onset of the rainy season. Rice samples were collected at harvesting time and samples of soil fertiliser were also obtained. Water samples were filtered, ultrafiltered and analysed by ICP-MS whilst sub-samples of dried, ground soils and sediments were first subjected to micro-wave assisted acid digestion (modified US EPA method 3052). XRD and SEM-EDX methods were used for mineralogical characterisation and selective chemical extractions have assisted in the characterisation of solid phase Cd associations. Soil Cd concentrations were in the range 2.5-87.6 µg g-1, with higher values being obtained for fields furthest from the main creek. Although current irrigation water Cd inputs are low (mean 1.9 μg L-1; flood period), high loads of suspended particles still contribute additional Cd (4.2-9.8 µg L-1) to the paddy fields. For bioavailability assessment by a 3-step BCR sequential extraction, 70-90% Cd was in the exchangeable; HOAc-extractable fraction. That indicated that most of

  14. Deriving health utilities from the MacNew Heart Disease Quality of Life Questionnaire.

    PubMed

    Chen, Gang; McKie, John; Khan, Munir A; Richardson, Jeff R

    2015-10-01

    Quality of life is included in the economic evaluation of health services by measuring the preference for health states, i.e. health state utilities. However, most intervention studies include a disease-specific, not a utility, instrument. Consequently, there has been increasing use of statistical mapping algorithms which permit utilities to be estimated from a disease-specific instrument. The present paper provides such algorithms between the MacNew Heart Disease Quality of Life Questionnaire (MacNew) instrument and six multi-attribute utility (MAU) instruments, the Euroqol (EQ-5D), the Short Form 6D (SF-6D), the Health Utilities Index (HUI) 3, the Quality of Wellbeing (QWB), the 15D (15 Dimension) and the Assessment of Quality of Life (AQoL-8D). Heart disease patients and members of the healthy public were recruited from six countries. Non-parametric rank tests were used to compare subgroup utilities and MacNew scores. Mapping algorithms were estimated using three separate statistical techniques. Mapping algorithms achieved a high degree of precision. Based on the mean absolute error and the intra class correlation the preferred mapping is MacNew into SF-6D or 15D. Using the R squared statistic the preferred mapping is MacNew into AQoL-8D. The algorithms reported in this paper enable MacNew data to be mapped into utilities predicted from any of six instruments. This permits studies which have included the MacNew to be used in cost utility analyses which, in turn, allows the comparison of services with interventions across the health system. © The European Society of Cardiology 2014.

  15. Analysis of the astronomical concepts presented by teachers of some Brazilian state schools

    NASA Astrophysics Data System (ADS)

    Voelzke, Marcos Rincon; Pereira Gonzaga, Edwon

    2013-01-01

    The reason for the development of this work is based on the fact that many teachers of the basic education level (EL) don't deal with concepts related to astronomy, but when they do so they just follow didactic books, which contain many conceptual errors. Astronomy is one of the subjects being taught in the EL and it is part of the proposals of the Education Ministry and the Education Department of the State of São Paulo; but it is a fact that several researchers point out many mistakes in teaching Astronomy. Their purpose is to minimize some deficiencies, and this aim was worked out in an Academical Extension Course for Teachers from the Directorate of Regional (DR) Teaching (Mauá, Ribeirão Pires and Rio Grande da Serra) with the following objectives: to raise alternative conceptions; to provide supplemental instruction of teachers by means of lectures, discussions and workshops, and to check the learning success after the course. Therefore, sixteen questions were applied before and after the course, so that quite satisfactory results could be established afterwards: 100.0% of the teachers knew the names of the phases of the moon, 97.0% understood that the Solar System is composed by eight planets, 78.1% were able to explain how a "Lunar Eclipse" occurs, a "Solar Eclipse" and a "Solstice", 72.7% knew how to explain the occurrence of the seasons of the year; 64.5% explained the occurrence of the equinox correctly, 89.7% were able to define properly the term "comet"; 63.6% defined "Asteroid", 54.5% "meteor"; 58.1% "galaxy", and 42.4% "planet".

  16. [Features of metabolic syndrome in patients with depressive disorder].

    PubMed

    Zeman, M; Jirák, R; Zák, A; Jáchymová, M; Vecka, M; Tvrzická, E; Vávrová, L; Kodydková, J; Stanková, B

    2009-01-01

    Depressive disorder is a serious illness with a high incidence, proxime accessit after anxiety disorders among the psychiatric diseases. It is accompanied by an increased risk of development of type 2 diabetes mellitus, cardiovascular disease, and by increased all-cause mortality. Recently published data have suggested that factors connected with the insulin resistance are at the background of this association. In this pilot study we have investigated parameters of lipid metabolism and glucose homeostasis in consecutively admitted patients suffering from depressive disorder (DD) (group of 42 people), in 57 patients with the metabolic syndrome (MetS) and in a control group of 49 apparently healthy persons (CON). Depressive patients did not differ from the control group by age or body mass index (BMI) value, but they had statistically significantly higher concentrations of serum insulin, C-peptide, glucose, triglycerides (TG), conjugated dienes in LDL particles (CD-LDL), higher value of microalbuminuria and of insulin resistance (HOMA-IR) index. They simultaneously had significantly lower value of the insulin sensitivity (QUICKI) index. In comparison with the MetS group the depressive patients were characterized by significantly lower both systolic and diastolic blood pressure, BMI , serum TG, apolipoprotein B, uric acid, C-peptide and by higher concentrations of apolipoprotein A-I and HDL-cholesterol. On the contrary, we have not found statistically significant differences between the DD and MetS groups in the concentrations of serum insulin, glucose, HOMA and QUICKI indices, in CD-LDL and MAU. In this pilot study, we have found in patients with depressive disorder certain features of metabolic syndrome, especially insulin resistance and oxidative stress.

  17. Trends in Stroke-Related Mortality in the ABC Region, São Paulo, Brazil: An Ecological Study Between 1997 and 2012.

    PubMed

    Sousa, Luiz Vinicius de Alcantara; Paiva, Laércio da Silva; Figueiredo, Francisco Winter Dos Santos; Almeida, Tabata Cristina do Carmo; Oliveira, Fernando Rocha; Adami, Fernando

    2017-01-01

    Stroke is the second leading cause of death and the third leading cause of physical disability in the world, with a high burden of morbidity and mortality, but it has been shown a reduction in mortality worldwide over the past two decades, especially in regions with higher income. The study analyzed the temporal trend and the factors associated with stroke-related mortality in the cities that make up the ABC region of São Paulo (Santo André, São Bernardo do Campo, São Caetano do Sul, Diadema, Mauá, Ribeirão Pires, and Rio Grande da Serra), in comparison to data from the capital city of São Paulo, in the state of São Paulo, Brazil. This was an ecological study conducted in 2017 using data from 1997 to 2012. Data were collected in 2017 from the Department of Informatics of the Brazilian Unified National Health System (DATASUS), where the Mortality Information System (SIM/SUS) was accessed. Linear regression analysis was used to estimate the temporal trend of stroke-related mortality according to sex, stroke subtypes, and regions. The confidence level adopted was 95%. There was a reduction in the mortality rates stratified according to sex, age groups above 15 years, and subtypes of stroke. Mortality from hemorrhagic and non-specified stroke decreased in all regions. However, a significant reduction in ischemic stroke-related mortality was observed only in the ABC region and in Brazil. The ABC region showed greater mortality due to stroke in males, the age group above 49 years, and non-specified stroke between 1997 and 2012.

  18. Abscisic acid induces a transient shift in signaling that enhances NF-κB-mediated parasite killing in the midgut of Anopheles stephensi without reducing lifespan or fecundity.

    PubMed

    Glennon, Elizabeth K K; Torrevillas, Brandi K; Morrissey, Shannon F; Ejercito, Jadrian M; Luckhart, Shirley

    2017-07-13

    Abscisic acid (ABA) is naturally present in mammalian blood and circulating levels can be increased by oral supplementation. We showed previously that oral ABA supplementation in a mouse model of Plasmodium yoelii 17XNL infection reduced parasitemia and gametocytemia, spleen and liver pathology, and parasite transmission to the mosquito Anopheles stephensi fed on these mice. Treatment of cultured Plasmodium falciparum with ABA at levels detected in our model had no effects on asexual growth or gametocyte formation in vitro. However, ABA treatment of cultured P. falciparum immediately prior to mosquito feeding significantly reduced oocyst development in A. stephensi via ABA-dependent synthesis of nitric oxide (NO) in the mosquito midgut. Here we describe the mechanisms of effects of ABA on mosquito physiology, which are dependent on phosphorylation of TGF-β-activated kinase 1 (TAK1) and associated with changes in homeostatic gene expression and activity of kinases that are central to metabolic regulation in the midgut epithelium. Collectively, the timing of these effects suggests a transient physiological shift that enhances NF-κB-dependent innate immunity without significantly altering mosquito lifespan or fecundity. ABA is a highly conserved regulator of immune and metabolic homeostasis within the malaria vector A. stephensi with potential as a transmission-blocking supplemental treatment.

  19. Seismic hazards in Thailand: a compilation and updated probabilistic analysis

    NASA Astrophysics Data System (ADS)

    Pailoplee, Santi; Charusiri, Punya

    2016-06-01

    A probabilistic seismic hazard analysis (PSHA) for Thailand was performed and compared to those of previous works. This PSHA was based upon (1) the most up-to-date paleoseismological data (slip rates), (2) the seismic source zones, (3) the seismicity parameters ( a and b values), and (4) the strong ground-motion attenuation models suggested as being suitable models for Thailand. For the PSHA mapping, both the ground shaking and probability of exceedance (POE) were analyzed and mapped using various methods of presentation. In addition, site-specific PSHAs were demonstrated for ten major provinces within Thailand. For instance, a 2 and 10 % POE in the next 50 years of a 0.1-0.4 g and 0.1-0.2 g ground shaking, respectively, was found for western Thailand, defining this area as the most earthquake-prone region evaluated in Thailand. In a comparison between the ten selected specific provinces within Thailand, the Kanchanaburi and Tak provinces had comparatively high seismic hazards, and therefore, effective mitigation plans for these areas should be made. Although Bangkok was defined as being within a low seismic hazard in this PSHA, a further study of seismic wave amplification due to the soft soil beneath Bangkok is required.

  20. Geometric and Radiometric Evaluation of Rasat Images

    NASA Astrophysics Data System (ADS)

    Cam, Ali; Topan, Hüseyin; Oruç, Murat; Özendi, Mustafa; Bayık, Çağlar

    2016-06-01

    RASAT, the second remote sensing satellite of Turkey, was designed and assembled, and also is being operated by TÜBİTAK Uzay (Space) Technologies Research Institute (Ankara). RASAT images in various levels are available free-of-charge via Gezgin portal for Turkish citizens. In this paper, the images in panchromatic (7.5 m GSD) and RGB (15 m GSD) bands in various levels were investigated with respect to its geometric and radiometric characteristics. The first geometric analysis is the estimation of the effective GSD as less than 1 pixel for radiometrically processed level (L1R) of both panchromatic and RGB images. Secondly, 2D georeferencing accuracy is estimated by various non-physical transformation models (similarity, 2D affine, polynomial, affine projection, projective, DLT and GCP based RFM) reaching sub-pixel accuracy using minimum 39 and maximum 52 GCPs. The radiometric characteristics are also investigated for 8 bits, estimating SNR between 21.8-42.2, and noise 0.0-3.5 for panchromatic and MS images for L1R when the sea is masked to obtain the results for land areas. The analysis show that RASAT images satisfies requirements for various applications. The research is carried out in Zonguldak test site which is mountainous and partly covered by dense forest and urban areas.