Sample records for ja taks tutvustavad

  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. 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

  3. 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

  4. 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.

  5. 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).

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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…

  5. 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

  6. 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

  7. 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…

  8. 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.

  9. 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

  10. 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…

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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…

  2. 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…

  3. Effects of MeJA on Arabidopsis metabolome under endogenous JA deficiency

    NASA Astrophysics Data System (ADS)

    Cao, Jingjing; Li, Mengya; Chen, Jian; Liu, Pei; Li, Zhen

    2016-11-01

    Jasmonates (JAs) play important roles in plant growth, development and defense. Comprehensive metabolomics profiling of plants under JA treatment provides insights into the interaction and regulation network of plant hormones. Here we applied high resolution mass spectrometry based metabolomics approach on Arabidopsis wild type and JA synthesis deficiency mutant opr3. The effects of exogenous MeJA treatment on the metabolites of opr3 were investigated. More than 10000 ion signals were detected and more than 2000 signals showed significant variation in different genotypes and treatment groups. Multivariate statistic analyses (PCA and PLS-DA) were performed and a differential compound library containing 174 metabolites with high resolution precursor ion-product ions pairs was obtained. Classification and pathway analysis of 109 identified compounds in this library showed that glucosinolates and tryptophan metabolism, amino acids and small peptides metabolism, lipid metabolism, especially fatty acyls metabolism, were impacted by endogenous JA deficiency and exogenous MeJA treatment. These results were further verified by quantitative reverse transcription PCR (RT-qPCR) analysis of 21 related genes involved in the metabolism of glucosinolates, tryptophan and α-linolenic acid pathways. The results would greatly enhance our understanding of the biological functions of JA.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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).

  12. 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.

  13. 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...

  14. 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.

  15. 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.

  16. 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.

  17. Coordinate expression of AOS genes and JA accumulation: JA is not required for initiation of closing layer in wound healing tubers

    USDA-ARS?s Scientific Manuscript database

    Wounding induces a series of coordinated physiological responses essential for protection and healing of the damaged tissue. Wound-induced formation of jasmonic acid (JA) is important in defense responses in leaves, but comparatively little is known about the induction of JA biosynthesis and its ro...

  18. Synthesis, structural characterization and biological activity of two diastereomeric JA-Ile macrolactones.

    PubMed

    Jimenez-Aleman, Guillermo H; Machado, Ricardo A R; Görls, Helmar; Baldwin, Ian T; Boland, Wilhelm

    2015-06-07

    Jasmonates are phytohormones involved in a wide range of plant processes, including growth, development, senescence, and defense. Jasmonoyl-L-isoleucine (JA-Ile, 2), an amino acid conjugate of jasmonic acid (JA, 1), has been identified as a bioactive endogenous jasmonate. However, JA-Ile (2) analogues trigger different responses in the plant. ω-Hydroxylation of the pentenyl side chain leads to the inactive 12-OH-JA-Ile (3) acting as a “stop” signal. On the other hand, a lactone derivative of 12-OH-JA (5) (jasmine ketolactone, JKL) occurs in nature, although with no known biological function. Inspired by the chemical structure of JKL (6) and in order to further explore the potential biological activities of 12-modified JA-Ile derivatives, we synthesized two macrolactones (JA-Ile-lactones (4a) and (4b)) derived from 12-OH-JA-Ile (3). The biological activity of (4a) and (4b) was tested for their ability to elicit nicotine production, a well-known jasmonate dependent secondary metabolite. Both macrolactones showed strong biological activity, inducing nicotine accumulation to a similar extent as methyl jasmonate does in Nicotiana attenuata leaves. Surprisingly, the highest nicotine contents were found in plants treated with the JA-Ile-lactone (4b), which has (3S,7S) configuration at the cyclopentanone not known from natural jasmonates. Macrolactone (4a) is a valuable standard to explore for its occurrence in nature.

  19. Endogenous Bioactive Jasmonate Is Composed of a Set of (+)-7-iso-JA-Amino Acid Conjugates1

    PubMed Central

    Li, Suhua; Li, Yuwen; Chen, Juan; Yang, Mai; Tong, Jianhua; Xiao, Langtao; Nan, Fajun; Xie, Daoxin

    2016-01-01

    Jasmonates (JAs) regulate a wide range of plant defense and development processes. The bioactive JA is perceived by its receptor COI1 to trigger the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins and subsequently derepress the JAZ-repressed transcription factors for activation of expression of JA-responsive genes. So far, (+)-7-iso-JA-l-Ile has been the only identified endogenous bioactive JA molecule. Here, we designed coronafacic acid (CFA) conjugates with all the amino acids (CFA-AA) to mimic the JA amino acid conjugates, and revealed that (+)-7-iso-JA-Leu, (+)-7-iso-JA-Val, (+)-7-iso-JA-Met, and (+)-7-iso-JA-Ala are new endogenous bioactive JA molecules. Furthermore, our studies uncover the general characteristics for all the bioactive JA molecules, and provide a new strategy to synthetically generate novel active JA molecules. PMID:27756820

  20. 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.

  1. 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.

  2. Effect of MeJA treatment on polyamine, energy status and anthracnose rot of loquat fruit.

    PubMed

    Cao, Shifeng; Cai, Yuting; Yang, Zhenfeng; Joyce, Daryl C; Zheng, Yonghua

    2014-02-15

    The effect of methyl jasmonate (MeJA) on changes in polyamines content and energy status and their relation to disease resistance was investigated. Freshly harvested loquat fruit were treated with 10 μmol l(-1) MeJA and wound inoculated with Colletotrichum acutatum spore suspension (1.0 × 10(5) spores ml(-1)) after 24h, and then stored at 20 °C for 6 days. MeJA treatment significantly reduced decay incidence. MeJA treated fruit manifested higher contents of polyamines (putrescine, spermidine and spermine) compared with the control fruit, during storage. MeJA treatment also maintained higher levels of adenosine triphosphate, and suppressed an increase in adenosine monophosphate content in loquat fruit. These results suggest that MeJA treatment may inhibit anthracnose rot by increasing polyamine content and maintaining the energy status. Copyright © 2013. Published by Elsevier Ltd.

  3. 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

  4. 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.

  5. JaSTA-2: Second version of the Java Superposition T-matrix Application

    NASA Astrophysics Data System (ADS)

    Halder, Prithish; Das, Himadri Sekhar

    2017-12-01

    In this article, we announce the development of a new version of the Java Superposition T-matrix App (JaSTA-2), to study the light scattering properties of porous aggregate particles. It has been developed using Netbeans 7.1.2, which is a java integrated development environment (IDE). The JaSTA uses double precision superposition T-matrix codes for multi-sphere clusters in random orientation, developed by Mackowski and Mischenko (1996). The new version consists of two options as part of the input parameters: (i) single wavelength and (ii) multiple wavelengths. The first option (which retains the applicability of older version of JaSTA) calculates the light scattering properties of aggregates of spheres for a single wavelength at a given instant of time whereas the second option can execute the code for a multiple numbers of wavelengths in a single run. JaSTA-2 provides convenient and quicker data analysis which can be used in diverse fields like Planetary Science, Atmospheric Physics, Nanoscience, etc. This version of the software is developed for Linux platform only, and it can be operated over all the cores of a processor using the multi-threading option.

  6. 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

  7. High-Rate Mechanical Properties of JA2 Propellant at Temperatures from -50 to 80 deg C

    DTIC Science & Technology

    2015-07-01

    panorama of postcompression JA2 grain sample (uniaxially compressed at a rate of ~100 s–1, 80 °C, and strain greater than 40%), 50× magnification...19 Fig. 36 SEM panorama of postcompression JA2 grain sample...19 Fig. 37 SEM panorama of postcompression JA2 grain sample (uniaxially compressed at a rate of ~100 s–1, 60 °C, and strain

  8. 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

  9. 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

  10. 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.

  11. Arabidopsis GOLDEN2-LIKE (GLK) transcription factors activate jasmonic acid (JA)-dependent disease susceptibility to the biotrophic pathogen Hyaloperonospora arabidopsidis, as well as JA-independent plant immunity against the necrotrophic pathogen Botrytis cinerea.

    PubMed

    Murmu, Jhadeswar; Wilton, Michael; Allard, Ghislaine; Pandeya, Radhey; Desveaux, Darrell; Singh, Jas; Subramaniam, Rajagopal

    2014-02-01

    Arabidopsis thaliana GOLDEN2-LIKE (GLK1 and 2) transcription factors regulate chloroplast development in a redundant manner. Overexpression of AtGLK1 (35S:AtGLK1) in Arabidopsis also confers resistance to the cereal pathogen Fusarium graminearum. To further elucidate the role of GLK transcription factors in plant defence, the Arabidopsis glk1 glk2 double-mutant and 35S:AtGLK1 plants were challenged with the virulent oomycete pathogen Hyaloperonospora arabidopsidis (Hpa) Noco2. Compared with Col-0, glk1 glk2 plants were highly resistant to Hpa Noco2, whereas 35S:AtGLK1 plants showed enhanced susceptibility to this pathogen. Genetic studies suggested that AtGLK-mediated plant defence to Hpa Noco2 was partially dependent on salicylic acid (SA) accumulation, but independent of the SA signalling protein NONEXPRESSOR OF PATHOGENESIS-RELATED 1 (NPR1). Pretreatment with jasmonic acid (JA) dramatically reversed Hpa Noco2 resistance in the glk1 glk2 double mutant, but only marginally affected the 35S:AtGLK1 plants. In addition, overexpression of AtGLK1 in the JA signalling mutant coi1-16 did not increase susceptibility to Hpa Noco2. Together, our GLK gain-of-function and loss-of-function experiments suggest that GLK acts upstream of JA signalling in disease susceptibility to Hpa Noco2. In contrast, glk1 glk2 plants were more susceptible to the necrotrophic fungal pathogen Botrytis cinerea, whereas 35S:AtGLK1 plants exhibited heightened resistance which could be maintained in the absence of JA signalling. Together, the data reveal that AtGLK1 is involved in JA-dependent susceptibility to the biotrophic pathogen Hpa Noco2 and in JA-independent resistance to the necrotrophic pathogen B. cinerea. © 2013 HER MAJESTY THE QUEEN IN RIGHT OF CANADA. MOLECULAR PLANT PATHOLOGY © 2013 BSPP. REPRODUCED WITH THE PERMISSION OF THE MINISTER OF AGRICULTURE AND AGRI-FOOD CANADA.

  12. Parasitism by Cuscuta pentagona sequentially induces JA and SA defence pathways in tomato.

    PubMed

    Runyon, Justin B; Mescher, Mark C; Felton, Gary W; De Moraes, Consuelo M

    2010-02-01

    While plant responses to herbivores and pathogens are well characterized, responses to attack by other plants remain largely unexplored. We measured phytohormones and C(18) fatty acids in tomato attacked by the parasitic plant Cuscuta pentagona, and used transgenic and mutant plants to explore the roles of the defence-related phytohormones salicylic acid (SA) and jasmonic acid (JA). Parasite attachment to 10-day-old tomato plants elicited few biochemical changes, but a second attachment 10 d later elicited a 60-fold increase in JA, a 30-fold increase in SA and a hypersensitive-like response (HLR). Host age also influenced the response: neither Cuscuta seedlings nor established vines elicited a HLR in 10-day-old hosts, but both did in 20-day-old hosts. Parasites grew larger on hosts deficient in SA (NahG) or insensitive to JA [jasmonic acid-insensitive1 (jai1)], suggesting that both phytohormones mediate effective defences. Moreover, amounts of JA peaked 12 h before SA, indicating that defences may be coordinated via sequential induction of these hormones. Parasitism also induced increases in free linolenic and linoleic acids and abscisic acid. These findings provide the first documentation of plant hormonal signalling induced by a parasitic plant and show that tomato responses to C. pentagona display characteristics similar to both herbivore- and pathogen-induced responses.

  13. Transcriptome Analysis in Haematococcus pluvialis: Astaxanthin Induction by Salicylic Acid (SA) and Jasmonic Acid (JA).

    PubMed

    Gao, Zhengquan; Li, Yan; Wu, Guanxun; Li, Guoqiang; Sun, Haifeng; Deng, Suzhen; Shen, Yicheng; Chen, Guoqiang; Zhang, Ruihao; Meng, Chunxiao; Zhang, Xiaowen

    2015-01-01

    Haematococcus pluvialis is an astaxanthin-rich microalga that can increase its astaxanthin production by salicylic acid (SA) or jasmonic acid (JA) induction. The genetic transcriptome details of astaxanthin biosynthesis were analyzed by exposing the algal cells to 25 mg/L of SA and JA for 1, 6 and 24 hours, plus to the control (no stress). Based on the RNA-seq analysis, 56,077 unigenes (51.7%) were identified with functions in response to the hormone stress. The top five identified subcategories were cell, cellular process, intracellular, catalytic activity and cytoplasm, which possessed 5600 (~9.99%), 5302 (~9.45%), 5242 (~9.35%), 4407 (~7.86%) and 4195 (~7.48%) unigenes, respectively. Furthermore, 59 unigenes were identified and assigned to 26 putative transcription factors (TFs), including 12 plant-specific TFs. They were likely associated with astaxanthin biosynthesis in Haematococcus upon SA and JA stress. In comparison, the up-regulation of differential expressed genes occurred much earlier, with higher transcript levels in the JA treatment (about 6 h later) than in the SA treatment (beyond 24 h). These results provide valuable information for directing metabolic engineering efforts to improve astaxanthin biosynthesis in H. pluvialis.

  14. Transcriptome sequencing and de novo analysis of cytoplasmic male sterility and maintenance in JA-CMS cotton.

    PubMed

    Yang, Peng; Han, Jinfeng; Huang, Jinling

    2014-01-01

    Cytoplasmic male sterility (CMS) is the failure to produce functional pollen, which is inherited maternally. And it is known that anther development is modulated through complicated interactions between nuclear and mitochondrial genes in sporophytic and gametophytic tissues. However, an unbiased transcriptome sequencing analysis of CMS in cotton is currently lacking in the literature. This study compared differentially expressed (DE) genes of floral buds at the sporogenous cells stage (SS) and microsporocyte stage (MS) (the two most important stages for pollen abortion in JA-CMS) between JA-CMS and its fertile maintainer line JB cotton plants, using the Illumina HiSeq 2000 sequencing platform. A total of 709 (1.8%) DE genes including 293 up-regulated and 416 down-regulated genes were identified in JA-CMS line comparing with its maintainer line at the SS stage, and 644 (1.6%) DE genes with 263 up-regulated and 381 down-regulated genes were detected at the MS stage. By comparing the two stages in the same material, there were 8 up-regulated and 9 down-regulated DE genes in JA-CMS line and 29 up-regulated and 9 down-regulated DE genes in JB maintainer line at the MS stage. Quantitative RT-PCR was used to validate 7 randomly selected DE genes. Bioinformatics analysis revealed that genes involved in reduction-oxidation reactions and alpha-linolenic acid metabolism were down-regulated, while genes pertaining to photosynthesis and flavonoid biosynthesis were up-regulated in JA-CMS floral buds compared with their JB counterparts at the SS and/or MS stages. All these four biological processes play important roles in reactive oxygen species (ROS) homeostasis, which may be an important factor contributing to the sterile trait of JA-CMS. Further experiments are warranted to elucidate molecular mechanisms of these genes that lead to CMS.

  15. Transcriptome Sequencing and De Novo Analysis of Cytoplasmic Male Sterility and Maintenance in JA-CMS Cotton

    PubMed Central

    Yang, Peng; Han, Jinfeng; Huang, Jinling

    2014-01-01

    Cytoplasmic male sterility (CMS) is the failure to produce functional pollen, which is inherited maternally. And it is known that anther development is modulated through complicated interactions between nuclear and mitochondrial genes in sporophytic and gametophytic tissues. However, an unbiased transcriptome sequencing analysis of CMS in cotton is currently lacking in the literature. This study compared differentially expressed (DE) genes of floral buds at the sporogenous cells stage (SS) and microsporocyte stage (MS) (the two most important stages for pollen abortion in JA-CMS) between JA-CMS and its fertile maintainer line JB cotton plants, using the Illumina HiSeq 2000 sequencing platform. A total of 709 (1.8%) DE genes including 293 up-regulated and 416 down-regulated genes were identified in JA-CMS line comparing with its maintainer line at the SS stage, and 644 (1.6%) DE genes with 263 up-regulated and 381 down-regulated genes were detected at the MS stage. By comparing the two stages in the same material, there were 8 up-regulated and 9 down-regulated DE genes in JA-CMS line and 29 up-regulated and 9 down-regulated DE genes in JB maintainer line at the MS stage. Quantitative RT-PCR was used to validate 7 randomly selected DE genes. Bioinformatics analysis revealed that genes involved in reduction-oxidation reactions and alpha-linolenic acid metabolism were down-regulated, while genes pertaining to photosynthesis and flavonoid biosynthesis were up-regulated in JA-CMS floral buds compared with their JB counterparts at the SS and/or MS stages. All these four biological processes play important roles in reactive oxygen species (ROS) homeostasis, which may be an important factor contributing to the sterile trait of JA-CMS. Further experiments are warranted to elucidate molecular mechanisms of these genes that lead to CMS. PMID:25372034

  16. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction.

    PubMed

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de Los Santos, Berta; Arroyo, Francisco T; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen.

  17. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction

    PubMed Central

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de los Santos, Berta; Arroyo, Francisco T.; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L.

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

  18. MAPK-dependent JA and SA signalling in Nicotiana attenuata affects plant growth and fitness during competition with conspecifics

    PubMed Central

    2012-01-01

    Background Induced defense responses to herbivores are generally believed to have evolved as cost-saving strategies that defer the fitness costs of defense metabolism until these defenses are needed. The fitness costs of jasmonate (JA)-mediated defenses have been well documented. Those of the early signaling units mediating induced resistance to herbivores have yet to be examined. Early signaling components that mediate herbivore-induced defense responses in Nicotiana attenuata, have been well characterized and here we examine their growth and fitness costs during competition with conspecifics. Two mitogen-activated protein kinases (MAPKs), salicylic acid (SA)-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK) are rapidly activated after perception of herbivory and both kinases regulate herbivory-induced JA levels and JA-mediated defense metabolite accumulations. Since JA-induced defenses result in resource-based trade-offs that compromise plant productivity, we evaluated if silencing SIPK (irSIPK) and WIPK (irWIPK) benefits the growth and fitness of plants competiting with wild type (WT) plants, as has been shown for plants silenced in JA-signaling by the reduction of Lipoxygenase 3 (LOX3) levels. Results As expected, irWIPK and LOX3-silenced plants out-performed their competing WT plants. Surprisingly, irSIPK plants, which have the largest reductions in JA signaling, did not. Phytohormone profiling of leaves revealed that irSIPK plants accumulated higher levels of SA compared to WT. To test the hypothesis that these high levels of SA, and their presumed associated fitness costs of pathogen associated defenses in irSIPK plants had nullified the JA-deficiency-mediated growth benefits in these plants, we genetically reduced SA levels in irSIPK plants. Reducing SA levels partially recovered the biomass and fitness deficits of irSIPK plants. We also evaluated whether the increased fitness of plants with reduced SA or JA levels resulted from

  19. Two bHLH-type transcription factors, JA-ASSOCIATED MYC2-LIKE2 and JAM3, are transcriptional repressors and affect male fertility

    PubMed Central

    Nakata, Masaru; Ohme-Takagi, Masaru

    2013-01-01

    The jasmonate (JA) plant hormones regulate responses to biotic and abiotic stress and aspects of plant development, including male fertility in Arabidopsis thaliana. The bHLH-type transcription factor JA-ASSOCIATED MYC2-LIKE1 (JAM1) negatively regulates JA signaling and gain-of-function JAM1 transgenic plants have impaired JA-mediated male fertility. Here we report that JAM2 and JAM3, 2 bHLHs closely related to JAM1, also act as transcriptional repressors. Moreover, overexpression of JAM2 and JAM3 also results in reduced male fertility. These results suggest that JAM1, JAM2, and JAM3 act redundantly as negative regulators of JA-mediated male fertility. PMID:24056034

  20. Physiological Characteristics and Production of Folic Acid of Lactobacillus plantarum JA71 Isolated from Jeotgal, a Traditional Korean Fermented Seafood

    PubMed Central

    Lim, Sang-Dong

    2014-01-01

    Folic acid, one of the B group of vitamins, is an essential substance for maintaining the functions of the nervous system, and is also known to decrease the level of homocysteine in plasma. Homocysteine influences the lowering of the cognitive function in humans, and especially in elderly people. In order to determine the strains with a strong capacity to produce folic acid, 190 bacteria were isolated from various kinds of jeotgal and chungkuk-jang. In our test experiment, JA71 was found to contain 9.03μg/mL of folic acid after 24 h of incubation in an MRS broth. This showed that JA71 has the highest folic acid production ability compared to the other lactic acid bacteria that were isolated. JA71 was identified as Lactobacillus plantarum by the result of API carbohydrate fermentation pattern and 16s rDNA sequence. JA71 was investigated for its physiological characteristics. The optimum growth temperature of JA71 was 37℃, and the cultures took 12 h to reach pH 4.4. JA71 proved more sensitive to bacitracin when compared with fifteen different antibiotics, and showed most resistance to neomycin and vancomycin. Moreover, it was comparatively tolerant of bile juice and acid, and displayed resistance to Escherichia coli, Salmonella Typhimurium, and Staphylococcus aureus with restraint rates of 60.4%, 96.7%, and 76.2%, respectively. These results demonstrate that JA71 could be an excellent strain for application to functional products. PMID:26760752

  1. Application of a JA-Ile Biosynthesis Inhibitor to Methyl Jasmonate-Treated Strawberry Fruit Induces Upregulation of Specific MBW Complex-Related Genes and Accumulation of Proanthocyanidins.

    PubMed

    Delgado, Laura D; Zúñiga, Paz E; Figueroa, Nicolás E; Pastene, Edgar; Escobar-Sepúlveda, Hugo F; Figueroa, Pablo M; Garrido-Bigotes, Adrián; Figueroa, Carlos R

    2018-06-13

    Fleshy fruits are an important source of anthocyanins and proanthocyanidins (PAs), which protect plants against stress, and their consumption provides beneficial effects for human health. In strawberry fruit, the application of exogenous methyl jasmonate (MeJA) upregulates anthocyanin accumulation, although the relationship between the jasmonate pathway and anthocyanin and PA biosynthesis in fruits remains to be understood. Anthocyanin and PA accumulation is mainly regulated at the transcriptional level through R2R3-MYB and bHLH transcription factors in different plant species and organs. Here, the effect of jarin-1, a specific inhibitor of bioactive JA (jasmonoyl-isoleucine, JA-Ile) biosynthesis, on anthocyanin and PA accumulation was evaluated during strawberry ( Fragaria × ananassa ) fruit development using an in vitro ripening system for 48 h. Also, we observed the effects of MeJA and the application of jarin-1 to MeJA-treated fruits (MeJA + jarin-1 treatment). We assessed changes of expression levels for the JA-Ile and MeJA biosynthetic ( FaJAR1.2 and FaJMT ), JA signaling-related ( FaMYC2 and FaJAZ1 ), MYB-bHLH-WD40 (MBW) complex-related ( FabHLH3/33 , FaMYB9/10/11 , and repressor FaMYB1 ), and anthocyanin and PA biosynthetic (FaANS , FaUFGT , FaANR , and FaLAR ) genes. In addition, the promoter region of MBW complex-related MYB genes was isolated and sequenced. We found a higher redness of strawberry fruit skin and anthocyanin content in MeJA-treated fruits with respect to jarin-1-treated ones concomitant with an upregulation of FaANS and FaUFGT genes. Inversely, the PA content was higher in jarin-1- and MeJA + jarin-1-treated than in MeJA-treated fruits. MeJA + jarin-1 treatment resulted in an upregulation of FaANR and associated transcription factors such as FabHLH33 and FaMYB9/11 along with FaJMT and FaJAR1.2 . Finally, we found JA-responsive elements in the promoter regions of FaMYB1/9/10/11 genes. It is proposed that PA biosynthesis-related genes

  2. JA, a new type of polyunsaturated fatty acid isolated from Juglans mandshurica Maxim, limits the survival and induces apoptosis of heptocarcinoma cells.

    PubMed

    Gao, Xiu-Li; Lin, Hua; Zhao, Wei; Hou, Ya-Qin; Bao, Yong-Li; Song, Zhen-Bo; Sun, Lu-Guo; Tian, Shang-Yi; Liu, Biao; Li, Yu-Xin

    2016-03-01

    Juglans mandshurica Maxim (Juglandaceae) is a famous folk medicine for cancer treatment and some natural compounds isolated from it have been studied extensively. Previously we isolated a type of ω-9 polyunsaturated fatty acid (JA) from the bark of J. mandshurica, however little is known about its activity and the underlying mechanisms. In this study, we studied anti-tumor activity of JA on several human cancer cell lines. Results showed that JA is cytotoxic to HepG2, MDA-MB-231, SGC-7901, A549 and Huh7 cells at a concentration exerting minimal toxic effects on L02 cells. The selective toxicity of JA was better than other classical anti-cancer drugs. Further investigation indicated that JA could induce cell apoptosis, characterized by chromatin condensation, DNA fragmentation and activation of the apoptosis-associated proteins such as Caspase-3 and PARP-1. Moreover, we investigated the cellular apoptosis pathway involved in the apoptosis process in HepG2 cells. We found that proteins involved in mitochondrion (cleaved-Caspase-9, Apaf-1, HtrA2/Omi, Bax, and Mitochondrial Bax) and endocytoplasmic reticulum (XBP-1s, GRP78, cleaved-Caspase-7 and cleaved-Caspase-12) apoptotic pathways were up-regulated when cells were treated by JA. In addition, a morphological change in the mitochondrion was detected. Furthermore, we found that JA could inhibit DNA synthesis and induce G2/M cell cycle arrest. The expression of G2-to-M transition related proteins, such as CyclinB1 and phosphorylated-CDK1, were reduced. In contrast, the G2-to-M inhibitor p21 was increased in JA-treated cells. Overall, our results suggest that JA can induce mitochondrion- and endocytoplasmic reticulum-mediated apoptosis, and G2/M phase arrest in HepG2 cells, making it a promising therapeutic agent against hepatoma.

  3. The tomato res mutant which accumulates JA in roots in non-stressed conditions restores cell structure alterations under salinity.

    PubMed

    Garcia-Abellan, José O; Fernandez-Garcia, Nieves; Lopez-Berenguer, Carmen; Egea, Isabel; Flores, Francisco B; Angosto, Trinidad; Capel, Juan; Lozano, Rafael; Pineda, Benito; Moreno, Vicente; Olmos, Enrique; Bolarin, Maria C

    2015-11-01

    Jasmonic acid (JA) regulates a wide spectrum of plant biological processes, from plant development to stress defense responses. The role of JA in plant response to salt stress is scarcely known, and even less known is the specific response in root, the main plant organ responsible for ionic uptake and transport to the shoot. Here we report the characterization of the first tomato (Solanum lycopersicum) mutant, named res (restored cell structure by salinity), that accumulates JA in roots prior to exposure to stress. The res tomato mutant presented remarkable growth inhibition and displayed important morphological alterations and cellular disorganization in roots and leaves under control conditions, while these alterations disappeared when the res mutant plants were grown under salt stress. Reciprocal grafting between res and wild type (WT) (tomato cv. Moneymaker) indicated that the main organ responsible for the development of alterations was the root. The JA-signaling pathway is activated in res roots prior to stress, with transcripts levels being even higher in control condition than in salinity. Future studies on this mutant will provide significant advances in the knowledge of JA role in root in salt-stress tolerance response, as well as in the energy trade-off between plant growth and response to stress. © 2015 Scandinavian Plant Physiology Society.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. NtWRKY-R1, a Novel Transcription Factor, Integrates IAA and JA Signal Pathway under Topping Damage Stress in Nicotiana tabacum

    PubMed Central

    Jin, Weihuan; Zhou, Qi; Wei, Yuanfang; Yang, Jinmiao; Hao, Fengsheng; Cheng, Zhipeng; Guo, Hongxiang; Liu, Weiqun

    2018-01-01

    Topping damage can induce the nicotine synthesis in tobacco roots, which involves the activation of JA and auxin signal transduction. It remains unclear how these hormone signals are integrated to regulate nicotine synthesis. Here we isolated a transcription factor NtWRKY-R1 from the group IIe of WRKY family and it had strong negative correlation with the expression of putrescine N-methyltransferase, the key enzyme of nicotine synthesis pathway. NtWRKY-R1 was specifically and highly expressed in tobacco roots, and it contains two transcriptional activity domains in the N- and C-terminal. The promoter region of NtWRKY-R1 contains two cis-elements which are responding to JA and auxin signals, respectively. Deletion of NtWRKY-R1 promoter showed that JA and auxin signals were subdued by NtWRKY-R1, and the expression of NtWRKY-R1 was more sensitive to auxin than JA. Furthermore, Yeast two-hybrid experiment demonstrated that NtWRKY-R1 can interact with the actin-binding protein. Our data showed that the intensity of JA and auxin signals can be translated into the expression of NtWRKY-R1, which regulates the balance of actin polymerization and depolymerization through binding actin-binding protein, and then regulates the expression of genes related to nicotine synthesis. The results will help us better understand the function of the WRKY-IIe family in the signaling crosstalk of JA and auxin under damage stress. PMID:29379516

  10. Transcriptome Analysis of ABA/JA-Dual Responsive Genes in Rice Shoot and Root.

    PubMed

    Kim, Jin-Ae; Bhatnagar, Nikita; Kwon, Soon Jae; Min, Myung Ki; Moon, Seok-Jun; Yoon, In Sun; Kwon, Taek-Ryoun; Kim, Sun Tae; Kim, Beom-Gi

    2018-01-01

    The phytohormone abscisic acid (ABA) enables plants to adapt to adverse environmental conditions through the modulation of metabolic pathways and of growth and developmental programs. We used comparative microarray analysis to identify genes exhibiting ABA-dependent expression and other hormone-dependent expression among them in Oryza sativa shoot and root. We identified 854 genes as significantly up- or down-regulated in root or shoot under ABA treatment condition. Most of these genes had similar expression profiles in root and shoot under ABA treatment condition, whereas 86 genes displayed opposite expression responses in root and shoot. To examine the crosstalk between ABA and other hormones, we compared the expression profiles of the ABA-dependently regulated genes under several different hormone treatment conditions. Interestingly, around half of the ABA-dependently expressed genes were also regulated by jasmonic acid based on microarray data analysis. We searched the promoter regions of these genes for cis-elements that could be responsible for their responsiveness to both hormones, and found that ABRE and MYC2 elements, among others, were common to the promoters of genes that were regulated by both ABA and JA. These results show that ABA and JA might have common gene expression regulation system and might explain why the JA could function for both abiotic and biotic stress tolerance.

  11. Integrated metabolomic and proteomic analysis reveals systemic responses of Rubrivivax benzoatilyticus JA2 to aniline stress.

    PubMed

    Mujahid, Md; Prasuna, M Lakshmi; Sasikala, Ch; Ramana, Ch Venkata

    2015-02-06

    Aromatic amines are widely distributed in the environment and are major environmental pollutants. Although degradation of aromatic amines is well studied in bacteria, physiological adaptations and stress response to these toxic compounds is not yet fully understood. In the present study, systemic responses of Rubrivivax benzoatilyticus JA2 to aniline stress were deciphered using metabolite and iTRAQ-labeled protein profiling. Strain JA2 tolerated high concentrations of aniline (30 mM) with trace amounts of aniline being transformed to acetanilide. GC-MS metabolite profiling revealed aniline stress phenotype wherein amino acid, carbohydrate, fatty acid, nitrogen metabolisms, and TCA (tricarboxylic acid cycle) were modulated. Strain JA2 responded to aniline by remodeling the proteome, and cellular functions, such as signaling, transcription, translation, stress tolerance, transport and carbohydrate metabolism, were highly modulated. Key adaptive responses, such as transcription/translational changes, molecular chaperones to control protein folding, and efflux pumps implicated in solvent extrusion, were induced in response to aniline stress. Proteo-metabolomics indicated extensive rewiring of metabolism to aniline. TCA cycle and amino acid catabolism were down-regulated while gluconeogenesis and pentose phosphate pathways were up-regulated, leading to the synthesis of extracellular polymeric substances. Furthermore, increased saturated fatty acid ratios in membranes due to aniline stress suggest membrane adaptation. The present study thus indicates that strain JA2 employs multilayered responses: stress response, toxic compound tolerance, energy conservation, and metabolic rearrangements to aniline.

  12. 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.

  13. 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

  14. JaK/STAT Inhibition to Prevent Post-Traumatic Epileptogenesis

    DTIC Science & Technology

    2013-07-31

    months 22-28) 2i. Assess mossy fiber sprouting, cell loss and glial proliferation 10 weeks post injury using Timm and Nissl staining (40 mice...1e. Assess protein levels and regional/cellular expression of JaK1 and 2, pSTAT1-5 using fluorescent immunohistochemistry with co- staining for cell...treated with CCI, 10 of which were treated with WP1066. Early post-injury experiments are underway; Timm staining has not revealed mossy fiber

  15. OsMPK3 positively regulates the JA signaling pathway and plant resistance to a chewing herbivore in rice.

    PubMed

    Wang, Qi; Li, Jiancai; Hu, Lingfei; Zhang, Tongfang; Zhang, Guren; Lou, Yonggen

    2013-07-01

    KEY MESSAGE : Silencing OsMPK3 decreased elicited JA levels, which subsequently reduced levels of herbivore-induced trypsin protease inhibitors (TrypPIs) and improved the performance of SSB larvae, but did not influence BPH. Mitogen-activated protein kinases (MPKs) are known to play an important role in plant defense by transferring biotic and abiotic signals into programmed cellular responses. However, their functions in the herbivore-induced defense response in rice remain largely unknown. Here, we identified a MPK3 gene from rice, OsMPK3, and found that its expression levels were up-regulated in response to infestation by the larvae of the striped stem borer (SSB) (Chilo suppressalis), to mechanical wounding and to treatment with jasmonic acid (JA), but not to infestation by the brown planthopper (BPH) Nilaparvata lugens or to treatment with salicylic acid. Moreover, mechanical wounding and SSB infestation induced the expression of OsMPK3 strongly and quickly, whereas JA treatment induced the gene more weakly and slowly. Silencing OsMPK3 (ir-mpk3) reduced the expression of the gene by 50-70 %, decreased elicited levels of JA and diminished the expression of a lipoxygenase gene OsHI-LOX and an allene oxide synthase gene OsAOS1. The reduced JA signaling in ir-mpk3 plants decreased the levels of herbivore-induced trypsin protease inhibitors (TrypPIs) and improved the performance of SSB larvae, but did not influence BPH. Our findings suggest that the gene OsMPK3 responds early in herbivore-induced defense and can be regulated by rice plants to activate a specific and appropriate defense response to different herbivores.

  16. 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.

  17. 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.

  18. 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.

  19. Stable Isotope-Assisted Metabolic Profiling Reveals Growth Mode Dependent Differential Metabolism and Multiple Catabolic Pathways of l-Phenylalanine in Rubrivivax benzoatilyticus JA2.

    PubMed

    Mekala, Lakshmi Prasuna; Mohammed, Mujahid; Chintalapati, Sasikala; Chintalapati, Venkata Ramana

    2018-01-05

    Anoxygenic phototrophic bacteria are metabolically versatile and survive under different growth modes using diverse organic compounds, yet their metabolic diversity is largely unexplored. In the present study, we employed stable-isotope-assisted metabolic profiling to unravel the l-phenylalanine catabolism in Rubrivivax benzoatilyticus JA2 under varying growth modes. Strain JA2 grows under anaerobic and aerobic conditions by utilizing l-phenylalanine as a nitrogen source. Furthermore, ring-labeled 13 C 6 -phenylalanine feeding followed by liquid chromatography-mass spectrometry exometabolite profiling revealed 60 labeled metabolic features (M + 6, M + 12, and M + 18) derived solely from l-phenylalanine, of which 11 were identified, 7 putatively identified, and 42 unidentified under anaerobic and aerobic conditions. However, labeled metabolites were significantly higher in aerobic compared to anaerobic conditions. Furthermore, detected metabolites and enzyme activities indicated multiple l-phenylalanine catabolic routes mainly Ehrlich, homogentisate-dependent melanin, benzenoid, and unidentified pathways operating under anaerobic and aerobic conditions in strain JA2. Interestingly, the study indicated l-phenylalanine-dependent and independent benzenoid biosynthesis in strain JA2 and a differential flux of l-phenylalanine to Ehrlich and benzenoid pathways under anaerobic and aerobic conditions. Additionally, unidentified labeled metabolites strongly suggest the presence of unknown phenylalanine catabolic routes in strain JA2. Overall, the study uncovered the l-phenylalanine catabolic diversity in strain JA2 and demonstrated the potential of stable isotope-assisted metabolomics in unraveling the hidden metabolic repertoire.

  20. 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.

  1. 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

  2. Aniline Is an Inducer, and Not a Precursor, for Indole Derivatives in Rubrivivax benzoatilyticus JA2

    PubMed Central

    Mohammed, Mujahid; Ch, Sasikala; Ch, Ramana V.

    2014-01-01

    Rubrivivax benzoatilyticus JA2 and other anoxygenic photosynthetic bacteria produce indole derivatives when exposed to aniline, a xenobiotic compound. Though this phenomenon has been reported previously, the role of aniline in the production of indoles is still a biochemical riddle. The present study aims at understanding the specific role of aniline (as precursor or stimulator) in the production of indoles and elucidating the biochemical pathway of indoles in aniline-exposed cells by using stable isotope approaches. Metabolic profiling revealed tryptophan accumulation only in aniline exposed cells along with indole 3-acetic acid (IAA) and indole 3-aldehyde (IAld), the two major catabolites of tryptophan. Deuterium labelled aniline feeding studies revealed that aniline is not a precursor of indoles in strain JA2. Further, production of indoles only in aniline-exposed cells suggests that aniline is an indoles stimulator. In addition, production of indoles depended on the presence of a carbon source, and production enhanced when carbon sources were added to the culture. Isotope labelled fumarate feeding identified, fumarate as the precursor of indole, indicating de novo synthesis of indoles. Glyphosate (shikimate pathway inhibitor) inhibited the indoles production, accumulation of tryptophan, IAA and IAld indicating that indoles synthesis in strain JA2 occurs via the de novo shikimate pathway. The up-regulation of anthranilate synthase gene and induction of anthranilate synthase activity correlated well with tryptophan production in strain JA2. Induction of tryptophan aminotransferase and tryptophan 2-monooxygenase activities corroborated well with IAA levels, suggesting that tryptophan catabolism occurs simultaneously in aniline exposed cells. Our study demonstrates that aniline (stress) stimulates tryptophan/indoles synthesis via the shikimate pathway by possibly modulating the metabolic pathway. PMID:24533057

  3. Aniline is an inducer, and not a precursor, for indole derivatives in Rubrivivax benzoatilyticus JA2.

    PubMed

    Mujahid, Mohammed; Sasikala, Ch; Ramana, Ch V

    2014-01-01

    Rubrivivax benzoatilyticus JA2 and other anoxygenic photosynthetic bacteria produce indole derivatives when exposed to aniline, a xenobiotic compound. Though this phenomenon has been reported previously, the role of aniline in the production of indoles is still a biochemical riddle. The present study aims at understanding the specific role of aniline (as precursor or stimulator) in the production of indoles and elucidating the biochemical pathway of indoles in aniline-exposed cells by using stable isotope approaches. Metabolic profiling revealed tryptophan accumulation only in aniline exposed cells along with indole 3-acetic acid (IAA) and indole 3-aldehyde (IAld), the two major catabolites of tryptophan. Deuterium labelled aniline feeding studies revealed that aniline is not a precursor of indoles in strain JA2. Further, production of indoles only in aniline-exposed cells suggests that aniline is an indoles stimulator. In addition, production of indoles depended on the presence of a carbon source, and production enhanced when carbon sources were added to the culture. Isotope labelled fumarate feeding identified, fumarate as the precursor of indole, indicating de novo synthesis of indoles. Glyphosate (shikimate pathway inhibitor) inhibited the indoles production, accumulation of tryptophan, IAA and IAld indicating that indoles synthesis in strain JA2 occurs via the de novo shikimate pathway. The up-regulation of anthranilate synthase gene and induction of anthranilate synthase activity correlated well with tryptophan production in strain JA2. Induction of tryptophan aminotransferase and tryptophan 2-monooxygenase activities corroborated well with IAA levels, suggesting that tryptophan catabolism occurs simultaneously in aniline exposed cells. Our study demonstrates that aniline (stress) stimulates tryptophan/indoles synthesis via the shikimate pathway by possibly modulating the metabolic pathway.

  4. 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.

  5. 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

  6. 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.

  7. Genome Analysis of the Biotechnologically Relevant Acidophilic Iron Oxidising Strain JA12 Indicates Phylogenetic and Metabolic Diversity within the Novel Genus “Ferrovum”

    PubMed Central

    Ullrich, Sophie R.; Poehlein, Anja; Tischler, Judith S.; González, Carolina; Ossandon, Francisco J.; Daniel, Rolf; Holmes, David S.; Schlömann, Michael; Mühling, Martin

    2016-01-01

    Background Members of the genus “Ferrovum” are ubiquitously distributed in acid mine drainage (AMD) waters which are characterised by their high metal and sulfate loads. So far isolation and microbiological characterisation have only been successful for the designated type strain “Ferrovum myxofaciens” P3G. Thus, knowledge about physiological characteristics and the phylogeny of the genus “Ferrovum” is extremely scarce. Objective In order to access the wider genetic pool of the genus “Ferrovum” we sequenced the genome of a “Ferrovum”-containing mixed culture and successfully assembled the almost complete genome sequence of the novel “Ferrovum” strain JA12. Phylogeny and Lifestyle The genome-based phylogenetic analysis indicates that strain JA12 and the type strain represent two distinct “Ferrovum” species. “Ferrovum” strain JA12 is characterised by an unusually small genome in comparison to the type strain and other iron oxidising bacteria. The prediction of nutrient assimilation pathways suggests that “Ferrovum” strain JA12 maintains a chemolithoautotrophic lifestyle utilising carbon dioxide and bicarbonate, ammonium and urea, sulfate, phosphate and ferrous iron as carbon, nitrogen, sulfur, phosphorous and energy sources, respectively. Unique Metabolic Features The potential utilisation of urea by “Ferrovum” strain JA12 is moreover remarkable since it may furthermore represent a strategy among extreme acidophiles to cope with the acidic environment. Unlike other acidophilic chemolithoautotrophs “Ferrovum” strain JA12 exhibits a complete tricarboxylic acid cycle, a metabolic feature shared with the closer related neutrophilic iron oxidisers among the Betaproteobacteria including Sideroxydans lithotrophicus and Thiobacillus denitrificans. Furthermore, the absence of characteristic redox proteins involved in iron oxidation in the well-studied acidophiles Acidithiobacillus ferrooxidans (rusticyanin) and Acidithiobacillus

  8. Early dust formation and a massive progenitor for SN 2011ja?

    NASA Astrophysics Data System (ADS)

    Andrews, J. E.; Krafton, Kelsie M.; Clayton, Geoffrey C.; Montiel, E.; Wesson, R.; Sugerman, Ben E. K.; Barlow, M. J.; Matsuura, M.; Drass, H.

    2016-04-01

    SN 2011ja was a bright (I = -18.3) Type II supernova occurring in the nearby edge on spiral galaxy NGC 4945. Flat-topped and multipeaked H α and H β spectral emission lines appear between 64 and 84 d post-explosion, indicating interaction with a disc-like circumstellar medium inclined ˜45° from edge-on. After day 84, an increase in the H- and K-band flux along with heavy attenuation of the red wing of the emission lines are strong indications of early dust formation, likely located in the cool dense shell created between the forward shock of the SN ejecta and the reverse shock created as the ejecta plows into the existing circumstellar material. Radiative transfer modelling reveals both ≈1 × 10-5 M⊙ of pre-existing dust located ˜1016.7 cm away and up to ≈6 × 10-4 M⊙ of newly formed dust. Spectral observations after 1.5 yr reveal the possibility that the fading SN is located within a young (3-6 Myr) massive stellar cluster, which when combined with tentative 56Ni mass estimates of 0.2 M⊙ may indicate a massive (≥25 M⊙) progenitor for SN 2011ja.

  9. 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.

  10. New Enhanced Artificial Bee Colony (JA-ABC5) Algorithm with Application for Reactive Power Optimization

    PubMed Central

    2015-01-01

    The standard artificial bee colony (ABC) algorithm involves exploration and exploitation processes which need to be balanced for enhanced performance. This paper proposes a new modified ABC algorithm named JA-ABC5 to enhance convergence speed and improve the ability to reach the global optimum by balancing exploration and exploitation processes. New stages have been proposed at the earlier stages of the algorithm to increase the exploitation process. Besides that, modified mutation equations have also been introduced in the employed and onlooker-bees phases to balance the two processes. The performance of JA-ABC5 has been analyzed on 27 commonly used benchmark functions and tested to optimize the reactive power optimization problem. The performance results have clearly shown that the newly proposed algorithm has outperformed other compared algorithms in terms of convergence speed and global optimum achievement. PMID:25879054

  11. New enhanced artificial bee colony (JA-ABC5) algorithm with application for reactive power optimization.

    PubMed

    Sulaiman, Noorazliza; Mohamad-Saleh, Junita; Abro, Abdul Ghani

    2015-01-01

    The standard artificial bee colony (ABC) algorithm involves exploration and exploitation processes which need to be balanced for enhanced performance. This paper proposes a new modified ABC algorithm named JA-ABC5 to enhance convergence speed and improve the ability to reach the global optimum by balancing exploration and exploitation processes. New stages have been proposed at the earlier stages of the algorithm to increase the exploitation process. Besides that, modified mutation equations have also been introduced in the employed and onlooker-bees phases to balance the two processes. The performance of JA-ABC5 has been analyzed on 27 commonly used benchmark functions and tested to optimize the reactive power optimization problem. The performance results have clearly shown that the newly proposed algorithm has outperformed other compared algorithms in terms of convergence speed and global optimum achievement.

  12. 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.

  13. [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.

  14. Biosynthesis of silver and zinc oxide nanoparticles using Pichia fermentans JA2 and their antimicrobial property

    NASA Astrophysics Data System (ADS)

    Chauhan, Ritika; Reddy, Arpita; Abraham, Jayanthi

    2015-01-01

    The development of eco-friendly alternative to chemical synthesis of metal nanoparticles is of great challenge among researchers. The present study aimed to investigate the biological synthesis, characterization, antimicrobial study and synergistic effect of silver and zinc oxide nanoparticles against clinical pathogens using Pichia fermentans JA2. The extracellular biosynthesis of silver and zinc oxide nanoparticles was investigated using Pichia fermentans JA2 isolated from spoiled fruit pulp bought in Vellore local market. The crystalline and stable metallic nanoparticles were characterized evolving several analytical techniques including UV-visible spectrophotometer, X-ray diffraction pattern analysis and FE-scanning electron microscope with EDX-analysis. The biosynthesized metallic nanoparticles were tested for their antimicrobial property against medically important Gram positive, Gram negative and fungal pathogenic microorganisms. Furthermore, the biosynthesized nanoparticles were also evaluated for their increased antimicrobial activities with various commercially available antibiotics against clinical pathogens. The biosynthesized silver nanoparticles inhibited most of the Gram negative clinical pathogens, whereas zinc oxide nanoparticles were able to inhibit only Pseudomonas aeruginosa. The combined effect of standard antibiotic disc and biosynthesized metallic nanoparticles enhanced the inhibitory effect against clinical pathogens. The biological synthesis of silver and zinc oxide nanoparticles is a novel and cost-effective approach over harmful chemical synthesis techniques. The metallic nanoparticles synthesized using Pichia fermentans JA2 possess potent inhibitory effect that offers valuable contribution to pharmaceutical associations.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. Cyclic lipopeptide iturin A structure-dependently induces defense response in Arabidopsis plants by activating SA and JA signaling pathways.

    PubMed

    Kawagoe, Yumi; Shiraishi, Soma; Kondo, Hiroko; Yamamoto, Shoko; Aoki, Yoshinao; Suzuki, Shunji

    2015-05-15

    Iturin A is the most well studied antifungal cyclic lipopeptide produced by Bacillus species that are frequently utilized as biological control agents. Iturin A not only shows strong antifungal activity against phytopathogens but also induces defense response in plants, thereby reducing plant disease severity. Here we report the defense signaling pathways triggered by iturin A in Arabidopsis salicylic acid (SA) or jasmonic acid (JA)-insensitive mutants. Iturin A activated the transcription of defense genes PR1 and PDF1.2 through the SA and JA signaling pathways, respectively. The role of iturin A as an elicitor was dependent on the cyclization of the seven amino acids and/or the β-hydroxy fatty acid chain. The iturin A derivative peptide, NH2-(L-Asn)-(D-Tyr)-(D-Asn)-(L-Gln)-(L-Pro)-(D-Asn)-(L-Ser)-COOH, completely suppressed PR1 and PDF1.2 gene expression in wild Arabidopsis plants. The identification of target molecules binding to iturin A and its derivative peptide is expected to shed new light on defense response in plants through the SA and JA signaling pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Deep Sequencing Reveals the Effect of MeJA on Scutellarin Biosynthesis in Erigeron breviscapus

    PubMed Central

    Xiao, Ying; Zhang, Feng; Chen, Jun-feng; Ji, Qian; Tan, He-Xin; Huang, Xin; Feng, Hao; Huang, Bao-Kang; Chen, Wan-Sheng; Zhang, Lei

    2015-01-01

    Background Erigeron breviscapus, a well-known traditional Chinese medicinal herb, is broadly used in the treatment of cerebrovascular disease. Scutellarin, a kind of flavonoids, is considered as the material base of the pharmaceutical activities in E. breviscapus. The stable and high content of scutellarin is critical for the quality and efficiency of E. breviscapus in the clinical use. Therefore, understanding the molecular mechanism of scutellarin biosynthesis is crucial for metabolic engineering to increase the content of the active compound. However, there is virtually no study available yet concerning the genetic research of scutellarin biosynthesis in E. breviscapus. Results Using Illumina sequencing technology, we obtained over three billion bases of high-quality sequence data and conducted de novo assembly and annotation without prior genome information. A total of 182,527 unigenes (mean length = 738 bp) were found. 63,059 unigenes were functionally annotated with a cut-off E-value of 10−5. Next, a total of 238 (200 up-regulated and 38 down-regulated genes) and 513 (375 up-regulated and 138 down-regulated genes) differentially expressed genes were identified at different time points after methyl jasmonate (MeJA) treatment, which fell into categories of ‘metabolic process’ and ‘cellular process’ using GO database, suggesting that MeJA-induced activities of signal pathway in plant mainly led to re-programming of metabolism and cell activity. In addition, 13 predicted genes that might participate in the metabolism of flavonoids were found by two co-expression analyses in E. breviscapus. Conclusions Our study is the first to provide a transcriptome sequence resource for E. breviscapus plants after MeJA treatment and it reveals transcriptome re-programming upon elicitation. As the result, several putative unknown genes involved in the metabolism of flavonoids were predicted. These data provide a valuable resource for the genetic and genomic studies of

  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. 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.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. The Combined Effects of Ethylene and MeJA on Metabolic Profiling of Phenolic Compounds in Catharanthus roseus Revealed by Metabolomics Analysis

    PubMed Central

    Liu, Jia; Liu, Yang; Wang, Yu; Zhang, Zhong-Hua; Zu, Yuan-Gang; Efferth, Thomas; Tang, Zhong-Hua

    2016-01-01

    Phenolic compounds belong to a class of secondary metabolites and are implicated in a wide range of responsive mechanisms in plants triggered by both biotic and abiotic elicitors. In this study, we approached the combinational effects of ethylene and MeJA (methyl jasmonate) on phenolic compounds profiles and gene expressions in the medicinal plant Catharanthus roseus. In virtue of a widely non-targeted metabolomics method, we identified a total of 34 kinds of phenolic compounds in the leaves, composed by 7 C6C1-, 11 C6C3-, and 16 C6C3C6 compounds. In addition, 7 kinds of intermediates critical for the biosynthesis of phenolic compounds and alkaloids were identified and discussed with phenolic metabolism. The combinational actions of ethylene and MeJA effectively promoted the total phenolic compounds, especially the C6C1 compounds (such as salicylic acid, benzoic acid) and C6C3 ones (such as cinnamic acid, sinapic acid). In contrast, the C6C3C6 compounds displayed a notably inhibitory trend in this case. Subsequently, the gene-to-metabolite networks were drawn up by searching for correlations between the expression profiles of 5 gene tags and the accumulation profiles of 41 metabolite peaks. Generally, we provide an insight into the controlling mode of ethylene-MeJA combination on phenolic metabolism in C. roseus leaves. PMID:27375495

  12. The Combined Effects of Ethylene and MeJA on Metabolic Profiling of Phenolic Compounds in Catharanthus roseus Revealed by Metabolomics Analysis.

    PubMed

    Liu, Jia; Liu, Yang; Wang, Yu; Zhang, Zhong-Hua; Zu, Yuan-Gang; Efferth, Thomas; Tang, Zhong-Hua

    2016-01-01

    Phenolic compounds belong to a class of secondary metabolites and are implicated in a wide range of responsive mechanisms in plants triggered by both biotic and abiotic elicitors. In this study, we approached the combinational effects of ethylene and MeJA (methyl jasmonate) on phenolic compounds profiles and gene expressions in the medicinal plant Catharanthus roseus. In virtue of a widely non-targeted metabolomics method, we identified a total of 34 kinds of phenolic compounds in the leaves, composed by 7 C6C1-, 11 C6C3-, and 16 C6C3C6 compounds. In addition, 7 kinds of intermediates critical for the biosynthesis of phenolic compounds and alkaloids were identified and discussed with phenolic metabolism. The combinational actions of ethylene and MeJA effectively promoted the total phenolic compounds, especially the C6C1 compounds (such as salicylic acid, benzoic acid) and C6C3 ones (such as cinnamic acid, sinapic acid). In contrast, the C6C3C6 compounds displayed a notably inhibitory trend in this case. Subsequently, the gene-to-metabolite networks were drawn up by searching for correlations between the expression profiles of 5 gene tags and the accumulation profiles of 41 metabolite peaks. Generally, we provide an insight into the controlling mode of ethylene-MeJA combination on phenolic metabolism in C. roseus leaves.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. Changes in ABA, IAA and JA levels during calyx, fruit and leaves development in cape gooseberry plants (Physalis peruviana L.).

    PubMed

    Álvarez-Flórez, F; López-Cristoffanini, C; Jáuregui, O; Melgarejo, L M; López-Carbonell, M

    2017-06-01

    Changes in abscisic acid (ABA), indole-3-acetic acid (IAA) and jasmonic acid (JA) content in developing calyx, fruits and leaves of Physalis peruviana L. plants were analysed. Plant hormones have been widely studied for their roles in the regulation of various aspects related to plant development and, in particular, into their action during development and ripening of fleshly fruits. The obtained evidences suggest that the functions of these hormones are no restricted to a particular development stage, and more than one hormone is involved in controlling various aspects of plant development. Our results will contribute to understand the role of these hormones during growth and development of calyx, fruits and leaves in cape gooseberry plants. This work offers a good, quickly and efficiently protocol to extract and quantify simultaneously ABA, IAA and JA in different tissues of cape gooseberry plants. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. European network for Health Technology Assessment Joint Action (EUnetHTA JA): a process evaluation performed by questionnaires and documentary analysis.

    PubMed

    Woodford Guegan, Eleanor; Cook, Andrew

    2014-06-01

    The European network for Health Technology Assessment Joint Action (EUnetHTA JA) project's overarching objective was to 'establish an effective and sustainable HTA [Health technology assessment] collaboration in Europe that brings added value at the regional, national and European level'. Specific objectives were to develop a strategy and business model for sustainable European collaboration on HTA, develop HTA tools and methods and promote good practice in HTA methods and processes. We describe activities performed on behalf of the National Institute for Health Research HTA programme; evaluating the project processes and developing a data set for a registry of planned clinical studies of relevance to public funders. Annual self-completion online questionnaires were sent to project participants and external stakeholders to identify their views about the project processes. Documentary review was undertaken at the project end on the final technical reports from the work packages to examine whether or not their deliverables had been achieved. The project's impact was assessed by whether or not the deliverables were produced, the objectives met and additional 'added value' generated. The project's effectiveness was evaluated by its processes, communication, administration, workings of individual work packages and involvement of external stakeholders. A two-stage Delphi exercise was undertaken to identify the data elements that should be included in a registry of planned clinical studies of relevance to public funders. The data set was validated by an efficacy testing exercise. High response rates were achieved for the questionnaires sent to project participants and this was attributed to the evidence-based strategy implemented. Response rates to questionnaires sent to external stakeholders were disappointingly lower. Most of the high-level objectives were achieved, although applying the developed tools in practice will be implemented in the European network for Health

  6. European network for Health Technology Assessment Joint Action (EUnetHTA JA): a process evaluation performed by questionnaires and documentary analysis.

    PubMed Central

    Woodford Guegan, Eleanor; Cook, Andrew

    2014-01-01

    BACKGROUND The European network for Health Technology Assessment Joint Action (EUnetHTA JA) project's overarching objective was to 'establish an effective and sustainable HTA [Health technology assessment] collaboration in Europe that brings added value at the regional, national and European level'. Specific objectives were to develop a strategy and business model for sustainable European collaboration on HTA, develop HTA tools and methods and promote good practice in HTA methods and processes. We describe activities performed on behalf of the National Institute for Health Research HTA programme; evaluating the project processes and developing a data set for a registry of planned clinical studies of relevance to public funders. METHODS Annual self-completion online questionnaires were sent to project participants and external stakeholders to identify their views about the project processes. Documentary review was undertaken at the project end on the final technical reports from the work packages to examine whether or not their deliverables had been achieved. The project's impact was assessed by whether or not the deliverables were produced, the objectives met and additional 'added value' generated. The project's effectiveness was evaluated by its processes, communication, administration, workings of individual work packages and involvement of external stakeholders. A two-stage Delphi exercise was undertaken to identify the data elements that should be included in a registry of planned clinical studies of relevance to public funders. The data set was validated by an efficacy testing exercise. RESULTS AND DISCUSSION High response rates were achieved for the questionnaires sent to project participants and this was attributed to the evidence-based strategy implemented. Response rates to questionnaires sent to external stakeholders were disappointingly lower. Most of the high-level objectives were achieved, although applying the developed tools in practice will be

  7. 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.

  8. 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

  9. 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.

  10. GA3 and other signal regulators (MeJA and IAA) improve xanthumin biosynthesis in different manners in Xanthium strumarium L.

    PubMed

    Li, Changfu; Chen, Fangfang; Zhang, Yansheng

    2014-08-25

    Xanthanolides from Xanthium strumarium L. exhibit various pharmacological activities and these compounds are mainly produced in the glandular trichomes of aerial plant parts. The regulation of xanthanolide biosynthesis has never been reported in the literature. In this study, the effects of phytohormonal stimulation on xanthumin (a xanthanolide compound) biosynthesis, glandular trichomes and germacrene A synthase (GAS) gene expression in X. strumarium L. young leaves were investigated. The exogenous applications of methyl jasmonate (MeJA), indole-3-acetic acid (IAA), and gibberrellin A3 (GA3) at appropriate concentrations were all found to improve xanthumin biosynthesis, but in different ways. It was suggested that a higher gland density stimulated by MeJA (400 µM) or IAA (200 µM) treatment caused at least in part an improvement in xanthumin production, whereas GA3 (10 µM) led to an improvement by up-regulating xanthumin biosynthetic genes within gland cells, not by forming more glandular trichomes. Compared to the plants before the flowering stage, plants that had initiated flowering showed enhanced xanthumin biosynthesis, but no higher gland density, an effect was similar to that caused by exogenous GA3 treatment.

  11. Assessment of iodine nutritional status in the general population in the province of Jaén.

    PubMed

    Olmedo Carrillo, Pablo; García Fuentes, Eduardo; Gutiérrez Alcántara, Carmen; Serrano Quero, Manuel; Moreno Martínez, Macarena; Ureña Fernández, Tomás; Santiago Fernández, Piedad

    2015-10-01

    Iodine deficiency affecting both pregnant women and schoolchildren has been reported in Jaén. Iodine deficiency is one of the leading causes of thyroid dysfunction and goiter, and adequate iodine prophylaxis with iodized salt, milk, and dairy products, or iodine supplementation have been shown to significantly improve iodine status in pregnancy. The purpose of this study was to assess iodine nutritional status in the general population of a iodine-deficient area with no previous institutional campaigns of iodine prophylaxis. A descriptive, cross-sectional study. Urinary iodine levels were measured in subjects from the Jaén healthcare district. The data were stratified by sex and age groups, and a survey was conducted on iodized salt consumption. Median and mean urinary iodine levels were 110.59 mcg/L and 130.11 mcg/L respectively. Urinary iodine levels were significantly higher in schoolchildren as compared to other age groups (161.52μg/L vs 109.33μg/L in subjects older than 65 years). Forty-three percent of the population had urinary iodine levels less than 100μg/L, and 68% of women of childbearing age had levels less than 150μg/L. Iodine nutritional status appears to be adequate, but the proportion of the population with urinary iodine levels less than 100μg/L is still very high, and iodized salt consumption is much less common than recommended by the WHO. Copyright © 2015 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  12. 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…

  13. 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…

  14. RNA sequencing on Amomum villosum Lour. induced by MeJA identifies the genes of WRKY and terpene synthases involved in terpene biosynthesis.

    PubMed

    He, Xueying; Wang, Huan; Yang, Jinfen; Deng, Ke; Wang, Teng

    2018-02-01

    Amomum villosum Lour. is an important Chinese medicinal plant that has diverse medicinal functions, and mainly contains volatile terpenes. This study aims to explore the WRKY transcription factors (TFs) and terpene synthase (TPS) unigenes that might be involved in terpene biosynthesis in A. villosum, and thus providing some new information on the regulation of terpenes in plants. RNA sequencing of A. villosum induced by methyl jasmonate (MeJA) revealed that the WRKY family was the second largest TF family in the transcriptome. Thirty-six complete WRKY domain sequences were expressed in response to MeJA. Further, six WRKY unigenes were highly correlated with eight deduced TPS unigenes. Ultimately, we combined the terpene abundance with the expression of candidate WRKY TFs and TPS unigenes to presume a possible model wherein AvWRKY61, AvWRKY28, and AvWRKY40 might coordinately trans-activate the AvNeoD promoter. We propose an approach to further investigate TF unigenes that might be involved in terpenoid biosynthesis, and identified four unigenes for further analyses.

  15. Pro Memoria. Professor Bolesław Jałowy (1906-1943): Mortui viventes obligant - the livings are obligated to the dead.

    PubMed

    Wincewicz, Andrzej

    2016-01-01

    Professor Bolesław Jałowy (1906-1943) was a chairman of Department of Histology and Embryology at Faculty of Medicine of King John Casimir University (Polish: Universytet Jana Kazimierza: UJK) in Lvov. He succeeded Professor Władysław Szymonowicz (1869-1939) who held this position for decades. As the most skillful followers of his tutor, Bolesław Jałowy was a great investigator of physiology of human tissue, embryogenesis, histological consequences of female sex hormones on blood clotting action as well as regeneration of nerves in addition to description of silver staining technique for reticulin fibers of skin. He was a hard working person with gentle attitude to such a subtle matter as microscopic structure of human body. However, he happened to live in brutal conditions of nationalistic struggles. His example shows how much a dedicated scientist could do in a very short time as his life was tragically ended with murdering him during World War Two. His story is a great lesson for generations of academic workers how to meet high moral standards with efficient and creative scientific work in evil and destructive, nationalistic climate that occurs usually in wartime.

  16. 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

  17. Integrated Performance of Next Generation High Data Rate Receiver and AR4JA LDPC Codec for Space Communications

    NASA Technical Reports Server (NTRS)

    Cheng, Michael K.; Lyubarev, Mark; Nakashima, Michael A.; Andrews, Kenneth S.; Lee, Dennis

    2008-01-01

    Low-density parity-check (LDPC) codes are the state-of-the-art in forward error correction (FEC) technology that exhibits capacity approaching performance. The Jet Propulsion Laboratory (JPL) has designed a family of LDPC codes that are similar in structure and therefore, leads to a single decoder implementation. The Accumulate-Repeat-by-4-Jagged- Accumulate (AR4JA) code design offers a family of codes with rates 1/2, 2/3, 4/5 and lengths 1024, 4096, 16384 information bits. Performance is less than one dB from capacity for all combinations.Integrating a stand-alone LDPC decoder with a commercial-off-the-shelf (COTS) receiver faces additional challenges than building a single receiver-decoder unit from scratch. In this work, we outline the issues and show that these additional challenges can be over-come by simple solutions. To demonstrate that an LDPC decoder can be made to work seamlessly with a COTS receiver, we interface an AR4JA LDPC decoder developed on a field-programmable gate array (FPGA) with a modern high data rate receiver and mea- sure the combined receiver-decoder performance. Through optimizations that include an improved frame synchronizer and different soft-symbol scaling algorithms, we show that a combined implementation loss of less than one dB is possible and therefore, most of the coding gain evidence in theory can also be obtained in practice. Our techniques can benefit any modem that utilizes an advanced FEC code.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Investigation of sodium arsenite, thioacetamide, and diethanolamine in the alkaline comet assay: Part of the JaCVAM comet validation exercise.

    PubMed

    Beevers, Carol; Henderson, Debbie; Lillford, Lucinda

    2015-07-01

    As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined sodium arsenite, thioacetamide, and diethanolamine. Using the JaCVAM approved study protocol version 14.2, each chemical was tested in male rats up to maximum tolerated dose levels and DNA damage in the liver and stomach was assessed approximately 3h after the final administration by gavage. Histopathology assessments of liver and stomach sections from the same animals were also examined for evidence of cytotoxicity or necrosis. No evidence of DNA damage was observed in the stomach of animals treated with sodium arsenite at 7.5, 15, or 30 mg/kg/day. However, equivocal findings were found in the liver, where increases in DNA migration were observed in two independent experiments, but not in all treated animals and not at the same dose levels. Thioacetamide caused an increase in DNA migration in the stomach of rats treated at 19, 38, and 75 mg/kg/day, but not in the liver, despite evidence of marked hepatotoxicity following histopathology assessments. No evidence of DNA damage was observed in the stomach or liver of animals treated with diethanolamine at 175, 350, or 700 mg/kg/day. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. 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

  4. ["The madhouse" by W. Kaulbach and the meaning of the picture interpreted by J.A. Schilling, 1863].

    PubMed

    Rothkopf, A

    1980-01-01

    This article deals with the picture "Das Narrenhaus" (the Madhouse) by W. Kaulbach and its interpretation by the psychiatrist J.A. Schilling, which he gave in his book "Psychiatrische Briefe" (psychiatric letters) in 1863. This picture is often used as a contemporary document for the situation in the treatment of the mentally ill at the beginning of the last century. The article points out doubts in this procedure. The interpretation by Schilling cannot be considered a document for psychiatric records; on the contrary, it is influenced by contemporary romantic medicine and utilises the picture to exemplify the theoretical concept of culpable human offence as the cause for mental illness.

  5. Risk of malnutrition (over and under-nutrition): validation of the JaNuS screening tool.

    PubMed

    Donini, Lorenzo M; Ricciardi, Laura Maria; Neri, Barbara; Lenzi, Andrea; Marchesini, Giulio

    2014-12-01

    Malnutrition (over and under-nutrition) is highly prevalent in patients admitted to hospital and it is a well-known risk factor for increased morbidity and mortality. Nutritional problems are often misdiagnosed, and especially the coexistence of over and undernutrition is not usually recognized. We aimed to develop and validate a screening tool for the easy detection and reporting of both undernutrition and overnutrition, specifically identifying the clinical conditions where the two types of malnutrition coexist. The study consisted of three phases: 1) selection of an appropriate study population (estimation sample) and of the hospital admission parameters to identify overnutrition and undernutrition; 2) combination of selected variables to create a screening tool to assess the nutritional risk in case of undernutrition, overnutrition, or the copresence of both the conditions, to be used by non-specialist health care professionals; 3) validation of the screening tool in a different patient sample (validation sample). Two groups of variables (12 for undernutrition, 7 for overnutrition) were identified in separate logistic models for their correlation with the outcome variables. Both models showed high efficacy, sensitivity and specificity (overnutrition, 97.7%, 99.6%, 66.6%, respectively; undernutrition, 84.4%, 83.6%, 84.8%). The logistic models were used to construct a two-faced test (named JaNuS - Just A Nutritional Screening) fitting into a two-dimension Cartesian coordinate graphic system. In the validation sample the JaNuS test confirmed its predictive value. Internal consistency and test-retest analysis provide evidence for the reliability of the test. The study provides a screening tool for the assessment of the nutritional risk, based on parameters easy-to-use by health care personnel lacking nutritional competence and characterized by excellent predictive validity. The test might be confidently applied in the clinical setting to determine the importance of

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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..

  15. Citrus leprosis virus C Infection Results in Hypersensitive-Like Response, Suppression of the JA/ET Plant Defense Pathway and Promotion of the Colonization of Its Mite Vector

    PubMed Central

    Arena, Gabriella D.; Ramos-González, Pedro L.; Nunes, Maria A.; Ribeiro-Alves, Marcelo; Camargo, Luis E. A.; Kitajima, Elliot W.; Machado, Marcos A.; Freitas-Astúa, Juliana

    2016-01-01

    Leprosis is a serious disease of citrus caused by Citrus leprosis virus C (CiLV-C, genus Cilevirus) whose transmission is mediated by false spider mites of the genus Brevipalpus. CiLV-C infection does not systemically spread in any of its known host plants, thus remaining restricted to local lesions around the feeding sites of viruliferous mites. To get insight into this unusual pathosystem, we evaluated the expression profiles of genes involved in defense mechanisms of Arabidopsis thaliana and Citrus sinensis upon infestation with non-viruliferous and viruliferous mites by using reverse-transcription qPCR. These results were analyzed together with the production of reactive oxygen species (ROS) and the appearance of dead cells as assessed by histochemical assays. After interaction with non-viruliferous mites, plants locally accumulated ROS and triggered the salicylic acid (SA) and jasmonate/ethylene (JA/ET) pathways. ERF branch of the JA/ET pathways was highly activated. In contrast, JA pathway genes were markedly suppressed upon the CiLV-C infection mediated by viruliferous mites. Viral infection also intensified the ROS burst and cell death, and enhanced the expression of genes involved in the RNA silencing mechanism and SA pathway. After 13 days of infestation of two sets of Arabidopsis plants with non-viruliferous and viruliferous mites, the number of mites in the CiLV-C infected Arabidopsis plants was significantly higher than in those infested with the non-viruliferous ones. Oviposition of the viruliferous mites occurred preferentially in the CiLV-C infected leaves. Based on these results, we postulated the first model of plant/Brevipalpus mite/cilevirus interaction in which cells surrounding the feeding sites of viruliferous mites typify the outcome of a hypersensitive-like response, whereas viral infection induces changes in the behavior of its vector. PMID:27933078

  16. 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.

  17. 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

  18. Buckwheat (Fagopyrum esculentum M.) Sprout Treated with Methyl Jasmonate (MeJA) Improved Anti-Adipogenic Activity Associated with the Oxidative Stress System in 3T3-L1 Adipocytes

    PubMed Central

    Lee, Young-Jun; Kim, Kui-Jin; Park, Kee-Jai; Yoon, Bo-Ra; Lim, Jeong-Ho; Lee, Ok-Hwan

    2013-01-01

    Buckwheat sprouts contain various bioactive compounds including rutin which have a number of biological activities. We have previously shown that buckwheat sprouts (TBWE) treated with methyl jasmonate (MeJA) significantly increased the amount of phenolics and the antioxidant activity. The aim of this study was to demonstrate the effect of TBWE on anti-adipogenesis and pro-oxidant enzyme in 3T3-L1 adipocytes. We also evaluated the anti-oxidative activity of TBWE in adipocytes by using the nitroblue tetrazolium assay. Our data showed that TBWE markedly inhibited adipocyte differentiation and ROS production in 3T3-L1 cells compared with control groups. Moreover, TBWE has strongly shown the inhibition of adipogenic transcription factor as well as pro-oxidant enzymes. Together, we demonstrate that the MeJA treatment significantly increased the amount of phenolic compound, resulting in the suppression of adipogenesis and ROS production in the 3T3-L1 cells. These findings indicate that TBWE has the potential for anti-adipogenesis activity with anti-oxidative properties. PMID:23344050

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. Mechanical Properties of Aerojet, Thiokol, and JA2 High-Energy Gun Propellants at 1.5 m/s Deformation Rate

    DTIC Science & Technology

    2002-01-01

    a2 6 n -32 4C La /C A> i c 4S Figure 5. Remains of specimens tested at 210, 630, and -32 0C. 5 I AUg 2001 "-1t AERQJET/"THIDKOL LOTS 0111W PM 4-40.00...10.00 +78.00 STRESS (Mra) -THIOKOL LOT LA -10T3--01 +5.C THIOKOL LOT JA-IEZ35--Z-02 JAZ LOT HCL03JO14-001 -28.00 AE J>:T? +0.00 4.00 0.0 .0 *20.0 O30 +40M0...WARREN MI 48397-5000 MATERIAL SCIENCE TEAM AMSSB RSS 14 BENET LABORATORIES J HERBERT AMSTA AR CCB M SENNETT R FISCELLA KANSAS ST M SOJA NATICK MA 01760

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. Condensed-Phase Processes during Solid Propellant Combustion. Part 2: Chemical and Microscopic Examination of Conductively Quenched Samples of RDX, XM39, JA2, M30, and HMX-Binder Compositions

    DTIC Science & Technology

    1992-05-01

    combustion of most of the propellants, with the possible exception of JA2; scanning electron microcope examination shows the existence of a liquid layer but... compounds are similar (Fifer et Sl. 1985; Hoffsommer, Glover, and Elban 1985), the relative Intensities In Table 2 should provide rough, order-of...top of the liquid layer. In addition, the HPLC chromatograms contained a number of very weak, unknown peaks apparently corresponding to compounds

  16. Extending MAM5 Meta-Model and JaCalIV E Framework to Integrate Smart Devices from Real Environments

    PubMed Central

    2016-01-01

    This paper presents the extension of a meta-model (MAM5) and a framework based on the model (JaCalIVE) for developing intelligent virtual environments. The goal of this extension is to develop augmented mirror worlds that represent a real and virtual world coupled, so that the virtual world not only reflects the real one, but also complements it. A new component called a smart resource artifact, that enables modelling and developing devices to access the real physical world, and a human in the loop agent to place a human in the system have been included in the meta-model and framework. The proposed extension of MAM5 has been tested by simulating a light control system where agents can access both virtual and real sensor/actuators through the smart resources developed. The results show that the use of real environment interactive elements (smart resource artifacts) in agent-based simulations allows to minimize the error between simulated and real system. PMID:26926691

  17. Extending MAM5 Meta-Model and JaCalIV E Framework to Integrate Smart Devices from Real Environments.

    PubMed

    Rincon, J A; Poza-Lujan, Jose-Luis; Julian, V; Posadas-Yagüe, Juan-Luis; Carrascosa, C

    2016-01-01

    This paper presents the extension of a meta-model (MAM5) and a framework based on the model (JaCalIVE) for developing intelligent virtual environments. The goal of this extension is to develop augmented mirror worlds that represent a real and virtual world coupled, so that the virtual world not only reflects the real one, but also complements it. A new component called a smart resource artifact, that enables modelling and developing devices to access the real physical world, and a human in the loop agent to place a human in the system have been included in the meta-model and framework. The proposed extension of MAM5 has been tested by simulating a light control system where agents can access both virtual and real sensor/actuators through the smart resources developed. The results show that the use of real environment interactive elements (smart resource artifacts) in agent-based simulations allows to minimize the error between simulated and real system.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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...

  3. 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.

  4. Seed germination ecology of feather lovegrass [Eragrostis tenella (L.) Beauv. Ex Roemer & J.A. Schultes].

    PubMed

    Chauhan, Bhagirath S

    2013-01-01

    Feather lovegrass [Eragrostis tenella (L.) Beauv. Ex Roemer & J.A. Schultes] is a C4 grass weed that has the ability to grow in both lowland and upland conditions. Experiments were conducted in the laboratory and screenhouse to evaluate the effect of environmental factors on germination, emergence, and growth of this weed species. Germination in the light/dark regime was higher at alternating day/night temperatures of 30/20 °C (98%) than at 35/25 °C (83%) or 25/15 °C (62%). Germination was completely inhibited by darkness. The osmotic potential and sodium chloride concentrations required for 50% inhibition of maximum germination were -0.7 MPa and 76 mM, respectively. The highest seedling emergence (69%) was observed from the seeds sown on the soil surface and no seedlings emerged from seeds buried at depths of 0.5 cm or more. The use of residue as mulches significantly reduced the emergence and biomass of feather lovegrass seedlings. A residue amount of 0.5 t ha(-1) was needed to suppress 50% of the maximum seedlings. Because germination was strongly stimulated by light and seedling emergence was the highest for the seeds sown on the soil surface, feather lovegrass is likely to become a problematic weed in zero-till systems. The knowledge gained from this study could help in developing effective and sustainable weed management strategies.

  5. The JaCVAM international validation study on the in vivo comet assay: Selection of test chemicals.

    PubMed

    Morita, Takeshi; Uno, Yoshifumi; Honma, Masamitsu; Kojima, Hajime; Hayashi, Makoto; Tice, Raymond R; Corvi, Raffaella; Schechtman, Leonard

    2015-07-01

    The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and genotoxic data, differences in chemical class or genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 genotoxic carcinogens, 6 genotoxic non-carcinogens, 7 non-genotoxic carcinogens and 8 non-genotoxic non-carcinogens. "Genotoxicity" was defined as positive in the Ames mutagenicity test or in one of the standard in vivo genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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...

  15. 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...

  16. Gene-to-metabolite network for biosynthesis of lignans in MeJA-elicited Isatis indigotica hairy root cultures

    PubMed Central

    Chen, Ruibing; Li, Qing; Tan, Hexin; Chen, Junfeng; Xiao, Ying; Ma, Ruifang; Gao, Shouhong; Zerbe, Philipp; Chen, Wansheng; Zhang, Lei

    2015-01-01

    Root and leaf tissue of Isatis indigotica shows notable anti-viral efficacy, and are widely used as “Banlangen” and “Daqingye” in traditional Chinese medicine. The plants' pharmacological activity is attributed to phenylpropanoids, especially a group of lignan metabolites. However, the biosynthesis of lignans in I. indigotica remains opaque. This study describes the discovery and analysis of biosynthetic genes and AP2/ERF-type transcription factors involved in lignan biosynthesis in I. indigotica. MeJA treatment revealed differential expression of three genes involved in phenylpropanoid backbone biosynthesis (IiPAL, IiC4H, Ii4CL), five genes involved in lignan biosynthesis (IiCAD, IiC3H, IiCCR, IiDIR, and IiPLR), and 112 putative AP2/ERF transcription factors. In addition, four intermediates of lariciresinol biosynthesis were found to be induced. Based on these results, a canonical correlation analysis using Pearson's correlation coefficient was performed to construct gene-to-metabolite networks and identify putative key genes and rate-limiting reactions in lignan biosynthesis. Over-expression of IiC3H, identified as a key pathway gene, was used for metabolic engineering of I. indigotica hairy roots, and resulted in an increase in lariciresinol production. These findings illustrate the utility of canonical correlation analysis for the discovery and metabolic engineering of key metabolic genes in plants. PMID:26579184

  17. Partial amino acid sequence of the branched chain amino acid aminotransferase (TmB) of E. coli JA199 pDU11

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

    Feild, M.J.; Armstrong, F.B.

    1987-05-01

    E. coli JA199 pDU11 harbors a multicopy plasmid containing the ilv GEDAY gene cluster of S. typhimurium. TmB, gene product of ilv E, was purified, crystallized, and subjected to Edman degradation using a gas phase sequencer. The intact protein yielded an amino terminal 31 residue sequence. Both carboxymethylated apoenzyme and (/sup 3/H)-NaBH-reduced holoenzyme were then subjected to digestion by trypsin. The digests were fractionated using reversed phase HPLC, and the peptides isolated were sequenced. The borohydride-treated holoenzyme was used to isolate the cofactor-binding peptide. The peptide is 27 residues long and a comparison with known sequences of other aminotransferases revealedmore » limited homology. Peptides accounting for 211 of 288 predicted residues have been sequenced, including 9 residues of the carboxyl terminus. Comparison of peptides with the inferred amino acid sequence of the E. coli K-12 enzyme has helped determine the sequence of the amino terminal 59 residues; only two differences between the sequences are noted in this region.« less

  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. Monitoring of selected priority and emerging contaminants in the Guadalquivir River and other related surface waters in the province of Jaén, South East Spain.

    PubMed

    Robles-Molina, José; Gilbert-López, Bienvenida; García-Reyes, Juan F; Molina-Díaz, Antonio

    2014-05-01

    The province of Jaén counts with four natural parks, numerous rivers, reservoirs and wetlands; moreover, it is probably the region with higher olive oil production in the world, which makes this zone a proper target to be studied based on the European Water Framework Directive 2000/60/CE. The aim of this survey is to monitor a total number of 373 compounds belonging to different families (pesticides, PAHs, nitrosamines, drugs of abuse, pharmaceuticals and life-style compounds) in surface waters located at different points of the province of Jaén. Among these compounds some priority organic substances (regulated by the EU Directive 2008/105/EC) and pollutants of emerging concern (not regulated yet) can be found. A liquid chromatography electrospray time-of-flight mass spectrometry (LC-TOFMS) method covering 340 compounds was developed and applied, together with a gas chromatography triple-quadrupole mass spectrometry (GC-MS/MS) method which enabled the analysis of 63 organic contaminants (30 of these compounds are analyzed by LC-TOFMS as well). From April 2009 to November 2010 a total of 83 surface water samples were collected (rivers, reservoirs and wetlands). In this period numerous organic contaminants were detected, most of them at the ng L(-1) level. The most frequently priority substances found were chlorpyrifos ethyl, diuron and hexachlorobenzene. Within the other groups, the most frequently detected compounds were: terbuthylazine, oxyfluorfen, desethyl terbuthylazine, diphenylamine (pesticide family); fluorene, phenanthrene, pyrene (PAHs group), codeine, paracetamol (pharmaceuticals compounds) and caffeine, nicotine (life-style compounds). As is could be expected, the total concentration of emerging contaminants is distinctly larger than that of priority pollutants, highlighting the importance of continuing with the study of their presence, fate and effects in aquatic environments. However, concentration levels (at the ng per liter level) are low in

  1. 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

  2. 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.

  3. 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

  4. 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...

  5. 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

  6. 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...

  7. Synthesis and mode of action studies of N-[(-)-jasmonyl]-S-tyrosin and ester seiridin jasmonate.

    PubMed

    Reveglia, Pierluigi; Chini, Andrea; Mandoli, Alessandro; Masi, Marco; Cimmino, Alessio; Pescitelli, Gennaro; Evidente, Antonio

    2018-03-01

    Recent analyses on fungal jasmonic acid (JA)-containing metabolites suggest a mode-of-action of these naturally occurring compounds as inactive storage pools of JA. Plants and/or fungi can catabolize JA into the bioactive jasmonyl-isoleucine (JA-Ile) that in turn activates the JA-Ile-pathway in planta. To extend our knowledge on JA-derivates related to natural occurring JA conjugates, N-[(-)-jasmonyl]-S-tyrosin (JA-Tyr) and the ester JA-Sei between JA and seiridin, a fungal disubstituted furanone, were synthesized. The classical procedures for ester synthesis were applied for compound JA-Sei, while N-[(-)-jasmonyl]-S-tyrosin was synthesized with an optimized procedure. JA-Tyr and JA-Sei were characterized by spectroscopic method (essentially 1D and 2D NMR spectroscopy and ESI-MS) and their stereochemical composition was determined by means of HPLC and circular dichroism analysis. Finally, the activity of these JA-derivates was analyzed in planta. JA-Tyr and JA-Sei trigger JA-regulated plant responses, such as protein degradation and growth inhibition. These effects require the conversion of JA into JA-Ile and its recognition by the plant JA-Ile perception complex COI1-JAZ. Overall, these data suggest a mode-of-action of JA-Tyr and JA-Sei as inactive pool of JA that can be transformed into the bioactive JA-Ile to induce the canonical JA-Ile-pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. 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...

  9. 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

  10. Unclassified Publications of Lincoln Laboratory, 1 January - 31 December 1991. Volume 17

    DTIC Science & Technology

    1991-12-31

    FIBER OPTIC ANALOG LINK MS-9183 MS-8873 FABRY - PEROT LASER FIBER OPTIC APPLICATIONS JA-6656 JA-6686 FABRY - PEROT SCANNING FIBER OPTIC LINK JA-6567 MS...8532, MS-9353 FABRY - PEROT SPECTRUM ANALYZER FIBER OPTICS TECHNOLOGY JA-6682 JA-6458 FAR-FIELD BEAM DIVERGENCE FIELD EFFECT TRANSISTORS JA-6505 JA-6662...8734 JA-6604, JA-6680 CRAMER-RAO LOWER BOUND DELAY LINES JA-6461 MS-8890 CROSS-CORRELATION DEMODULATION MS-8734 TR-91 0 CROSSLINK DEPOSITION METHODS JA

  11. Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine.

    PubMed

    McNamee, J P; Bellier, P V

    2015-07-01

    As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), our laboratory examined ampicillin trihydrate (AMP), 1,2-dimethylhydrazine dihydrochloride (DMH), and N-nitrosodimethylamine (NDA) using a standard comet assay validation protocol (v14.2) developed by the JaCVAM validation management team (VMT). Coded samples were received by our laboratory along with basic MSDS information. Solubility analysis and range-finding experiments of the coded test compounds were conducted for dose selection. Animal dosing schedules, the comet assay processing and analysis, and statistical analysis were conducted in accordance with the standard protocol. Based upon our blinded evaluation, AMP was not found to exhibit evidence of genotoxicity in either the rat liver or stomach. However, both NDA and DMH were observed to cause a significant increase in % tail DNA in the rat liver at all dose levels tested. While acute hepatoxicity was observed for these compounds in the high dose group, in the investigators opinion there were a sufficient number of consistently damaged/measurable cells at the medium and low dose groups to judge these compounds as genotoxic. There was no evidence of genotoxicity from either NDA or DMH in the rat stomach. In conclusion, our laboratory observed increased DNA damage from two blinded test compounds in rat liver (later identified as genotoxic carcinogens), while no evidence of genotoxicity was observed for the third blinded test compound (later identified as a non-genotoxic, non-carcinogen). This data supports the use of a standardized protocol of the in vivo comet assay as a cost-effective alternative genotoxicity assay for regulatory testing purposes. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  12. Unclassified Publications of Lincoln Laboratory, 1 January - 31 December 1989. Volume 15

    DTIC Science & Technology

    1989-12-01

    BOLTZMANN MACHINE JA-6051 JA-6290 BEAM PATH CONDITIONING BORON CONTAINING MOLECULES MS-8143 JA-6135 BEAM STEERING BORON TRICHLORIDE MS-8285 JA-6129...BERNZOMATIC TOTE TORCH BORON TRICHLORIDE -ARGON DISCHARGE JA-6260 JA-6129 BIAS CORRELATION BOUNDARY LAYER JA-6326 JA-6192, MS-8141 BINARY INTEGRATION BROADBAND...MS-8345 MODULATORS IRIDIUM MS-7998 JA-6192 67 Subject Index IRIDIUM SILICIDE SCHOTTKY-BARRIER KWAJALEIN DISCRIMINATION SYSTEM INFRARED DETECTORS JA

  13. 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)"…

  14. 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

  15. 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.

  16. 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

  17. Unclassified Publications of Lincoln Laboratory 1 January - 31 December 1994, Volume 20.

    DTIC Science & Technology

    1994-12-31

    J. Ehrlich, DJ. Hollis, M.A. Kosicki, B.B. Powdrill, T. Beattie, K. Smith, S. Varma, R. Gangadharan, R. Mallik , A. Burke, B.E. Wallace, D...JA-6972, JA-7028 Mallik , A., JA-7164 Manfra, M.J., JA-7027, MS-10604 Mankiewich, P.M., JA-7001 Maragos, P., JA-6764, JA-6888 Marcus, S., JA-6898

  18. 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

  19. 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

  20. 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)…

  1. 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…

  2. 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…

  3. Endoplasmic reticulum-associated inactivation of the hormone jasmonoyl-L-isoleucine by multiple members of the cytochrome P450 94 family in Arabidopsis.

    PubMed

    Koo, Abraham J; Thireault, Caitlin; Zemelis, Starla; Poudel, Arati N; Zhang, Tong; Kitaoka, Naoki; Brandizzi, Federica; Matsuura, Hideyuki; Howe, Gregg A

    2014-10-24

    The plant hormone jasmonate (JA) controls diverse aspects of plant immunity, growth, and development. The amplitude and duration of JA responses are controlled in large part by the intracellular level of jasmonoyl-L-isoleucine (JA-Ile). In contrast to detailed knowledge of the JA-Ile biosynthetic pathway, little is known about enzymes involved in JA-Ile metabolism and turnover. Cytochromes P450 (CYP) 94B3 and 94C1 were recently shown to sequentially oxidize JA-Ile to hydroxy (12OH-JA-Ile) and dicarboxy (12COOH-JA-Ile) derivatives. Here, we report that a third member (CYP94B1) of the CYP94 family also participates in oxidative turnover of JA-Ile in Arabidopsis. In vitro studies showed that recombinant CYP94B1 converts JA-Ile to 12OH-JA-Ile and lesser amounts of 12COOH-JA-Ile. Consistent with this finding, metabolic and physiological characterization of CYP94B1 loss-of-function and overexpressing plants demonstrated that CYP94B1 and CYP94B3 coordinately govern the majority (>95%) of 12-hydroxylation of JA-Ile in wounded leaves. Analysis of CYP94-promoter-GUS reporter lines indicated that CYP94B1 and CYP94B3 serve unique and overlapping spatio-temporal roles in JA-Ile homeostasis. Subcellular localization studies showed that CYP94s involved in conversion of JA-Ile to 12COOH-JA-Ile reside on endoplasmic reticulum (ER). In vitro studies further showed that 12COOH-JA-Ile, unlike JA-Ile, fails to promote assembly of COI1-JAZ co-receptor complexes. The double loss-of-function mutant of CYP94B3 and ILL6, a JA-Ile amidohydrolase, displayed a JA profile consistent with the collaborative action of the oxidative and the hydrolytic pathways in JA-Ile turnover. Collectively, our results provide an integrated view of how multiple ER-localized CYP94 and JA amidohydrolase enzymes attenuate JA signaling during stress responses. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Endoplasmic Reticulum-associated Inactivation of the Hormone Jasmonoyl-l-Isoleucine by Multiple Members of the Cytochrome P450 94 Family in Arabidopsis*

    PubMed Central

    Koo, Abraham J.; Thireault, Caitlin; Zemelis, Starla; Poudel, Arati N.; Zhang, Tong; Kitaoka, Naoki; Brandizzi, Federica; Matsuura, Hideyuki; Howe, Gregg A.

    2014-01-01

    The plant hormone jasmonate (JA) controls diverse aspects of plant immunity, growth, and development. The amplitude and duration of JA responses are controlled in large part by the intracellular level of jasmonoyl-l-isoleucine (JA-Ile). In contrast to detailed knowledge of the JA-Ile biosynthetic pathway, little is known about enzymes involved in JA-Ile metabolism and turnover. Cytochromes P450 (CYP) 94B3 and 94C1 were recently shown to sequentially oxidize JA-Ile to hydroxy (12OH-JA-Ile) and dicarboxy (12COOH-JA-Ile) derivatives. Here, we report that a third member (CYP94B1) of the CYP94 family also participates in oxidative turnover of JA-Ile in Arabidopsis. In vitro studies showed that recombinant CYP94B1 converts JA-Ile to 12OH-JA-Ile and lesser amounts of 12COOH-JA-Ile. Consistent with this finding, metabolic and physiological characterization of CYP94B1 loss-of-function and overexpressing plants demonstrated that CYP94B1 and CYP94B3 coordinately govern the majority (>95%) of 12-hydroxylation of JA-Ile in wounded leaves. Analysis of CYP94-promoter-GUS reporter lines indicated that CYP94B1 and CYP94B3 serve unique and overlapping spatio-temporal roles in JA-Ile homeostasis. Subcellular localization studies showed that CYP94s involved in conversion of JA-Ile to 12COOH-JA-Ile reside on endoplasmic reticulum (ER). In vitro studies further showed that 12COOH-JA-Ile, unlike JA-Ile, fails to promote assembly of COI1-JAZ co-receptor complexes. The double loss-of-function mutant of CYP94B3 and ILL6, a JA-Ile amidohydrolase, displayed a JA profile consistent with the collaborative action of the oxidative and the hydrolytic pathways in JA-Ile turnover. Collectively, our results provide an integrated view of how multiple ER-localized CYP94 and JA amidohydrolase enzymes attenuate JA signaling during stress responses. PMID:25210037

  5. 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…

  6. 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)…

  7. 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…

  8. 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 ...

  9. LOW-TEMPERATURE ION TRAP STUDIES OF N{sup +}({sup 3} P{sub ja} ) + H{sub 2}(j) {yields} NH{sup +} + H

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

    Zymak, I.; Hejduk, M.; Mulin, D.

    2013-05-01

    Using a low-temperature 22-pole ion trap apparatus, detailed measurements for the title reaction have been performed between 10 K and 100 K in order to get some state specific information about this fundamental hydrogen abstraction process. The relative population of the two lowest H{sub 2} rotational states, j = 0 and 1, has been varied systematically. NH{sup +} formation is nearly thermo-neutral; however, to date, the energetics are not known with the accuracy required for low-temperature astrochemistry. Additional complications arise from the fact that, so far, there is no reliable theoretical or experimental information on how the reactivity of themore » N{sup +} ion depends on its fine-structure (FS) state {sup 3} P{sub ja} . Since in the present trapping experiment, thermalization of the initially hot FS population competes with hydrogen abstraction, the evaluation of the decay of N{sup +} ions over long storage times and at various He and H{sub 2} gas densities provides information on these processes. First assuming strict adiabatic behavior, a set of state specific rate coefficients is derived from the measured thermal rate coefficients. In addition, by recording the disappearance of the N{sup +} ions over several orders of magnitude, information on nonadiabatic transitions is extracted including FS-changing collisions.« less

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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…

  16. 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…

  17. 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…

  18. 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)…

  19. 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

  20. 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.

  1. 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.

  2. Jasmonic acid/methyl jasmonate accumulate in wounded soybean hypocotyls and modulate wound gene expression.

    PubMed

    Creelman, R A; Tierney, M L; Mullet, J E

    1992-06-01

    Jasmonic acid (JA) and its methyl ester, methyl jasmonate (MeJA), are plant lipid derivatives that resemble mammalian eicosanoids in structure and biosynthesis. These compounds are proposed to play a role in plant wound and pathogen responses. Here we report the quantitative determination of JA/MeJA in planta by a procedure based on the use of [13C,2H3]MeJA as an internal standard. Wounded soybean (Glycine max [L] Merr. cv. Williams) stems rapidly accumulated MeJA and JA. Addition of MeJA to soybean suspension cultures also increased mRNA levels for three wound-responsive genes (chalcone synthase, vegetative storage protein, and proline-rich cell wall protein) suggesting a role for MeJA/JA in the mediation of several changes in gene expression associated with the plants' response to wounding.

  3. Gene Expression Profiling Confirms the Dosage-Dependent Additive Neuroprotective Effects of Jasminoidin in a Mouse Model of Ischemia-Reperfusion Injury.

    PubMed

    Li, Haixia; Wang, Jingtao; Wang, Pengqian; Zhang, Yingying; Liu, Jun; Yu, Yanan; Li, Bing; Wang, Zhong

    2018-01-01

    Recent evidence demonstrates that a double dose of Jasminoidin (2·JA) is more effective than Jasminoidin (JA) in cerebral ischemia therapy, but its dosage-effect mechanisms are unclear. In this study, the software GeneGo MetaCore was used to perform pathway analysis of the differentially expressed genes obtained in microarrays of mice belonging to four groups (Sham, Vehicle, JA, and 2·JA), aiming to elucidate differences in JA and 2·JA's dose-dependent pharmacological mechanism from a system's perspective. The top 10 enriched pathways in the 2·JA condition were mainly involved in neuroprotection (70% of the pathways), apoptosis and survival (40%), and anti-inflammation (20%), while JA induced pathways were mainly involved in apoptosis and survival (60%), anti-inflammation (20%), and lipid metabolism (20%). Regarding shared pathways and processes, 3, 1, and 3 pathways overlapped between the Vehicle and JA, Vehicle and 2·JA, and JA and 2·JA conditions, respectively; for the top ten overlapped processes these numbers were 3, 0, and 4, respectively. The common pathways and processes in the 2·JA condition included differentially expressed genes significantly different from those in JA. Seven representative pathways were only activated by 2·JA, such as Gamma-Secretase regulation of neuronal cell development. Process network comparison indicated that significant nodes, such as alpha-MSH , ACTH , PKR1 , and WNT , were involved in the pharmacological mechanism of 2·JA. Function distribution was different between JA and 2·JA groups, indicating a dosage additive mechanism in cerebral ischemia treatment. Such systemic approach based on whole-genome multiple pathways and networks may provide an effective and alternative approach to identify alterations underlining dosage-dependent therapeutic benefits of pharmacological compounds on complex disease processes.

  4. 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…

  5. 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…

  6. 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…

  7. 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

  8. 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…

  9. 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…

  10. Jasmonic acid/methyl jasmonate accumulate in wounded soybean hypocotyls and modulate wound gene expression.

    PubMed Central

    Creelman, R A; Tierney, M L; Mullet, J E

    1992-01-01

    Jasmonic acid (JA) and its methyl ester, methyl jasmonate (MeJA), are plant lipid derivatives that resemble mammalian eicosanoids in structure and biosynthesis. These compounds are proposed to play a role in plant wound and pathogen responses. Here we report the quantitative determination of JA/MeJA in planta by a procedure based on the use of [13C,2H3]MeJA as an internal standard. Wounded soybean (Glycine max [L] Merr. cv. Williams) stems rapidly accumulated MeJA and JA. Addition of MeJA to soybean suspension cultures also increased mRNA levels for three wound-responsive genes (chalcone synthase, vegetative storage protein, and proline-rich cell wall protein) suggesting a role for MeJA/JA in the mediation of several changes in gene expression associated with the plants' response to wounding. Images PMID:1594598

  11. 42 CFR 488.115 - Care guidelines.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Care guidelines. 488.115 Section 488.115 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... § 488.115 Care guidelines. EC01JA91.110 EC01JA91.111 EC01JA91.112 EC01JA91.113 EC01JA91.114 EC01JA91.115...

  12. Possible role of jasmonic acid in the regulation of floral induction, evocation and floral differentiation in Lemna minor L.

    PubMed

    Krajncic, B; Kristl, J; Janzekovic, I

    2006-01-01

    Jasmonic acid (JA) is implicated in a wide variety of developmental and physiological processes in plants. Here, we studied the effects of JA and the combination of JA and ethylenediamine-dio-hydroxyphenyl-acetic acid (EDDHA) on flowering in Lemna minor in axenical cultures. JA (0.475-47.5 nmol l(-1)) enhanced floral induction in L. minor under long-day (LD) conditions. Under the same conditions, at a concentration of 237.5 nmol l(-1), JA inhibited floral induction, and at a concentration of 475 nmol l(-1) it prevented floral induction. Under LD conditions with LD preculture, a combination of EDDHA (20,500 nmol l(-1)) and JA (47.5 nmol l(-1)) had a synergistic effect on the promotion of floral induction. Floral induction was enhanced to the greatest extent in experiments with LD precultures. Microscopic examination of microphotographs of histological sections showed that JA and, to an even greater extent, JA+EDDHA at optimal concentrations promote apical floral induction (evocation). Furthermore, JA, and to an even greater extent JA in combination with EDDHA in an optimal concentration, also promote flower differentiation, especially the development of stamens, as is evident from the microphotographs. The experimental results show that JA promotes floral induction in other species of Lemnaceae from various groups according to their photoperiodic response. The results support our hypothesis that, in addition to previously ascribed functions, JA may regulate floral induction, evocation and floral differentiation. Our hypothesis is supported also by the results obtained by quantitative determination of endogenous JA levels in L. minor at three growth stages. The levels of endogenous JA decreased from 389 ng JA g(-1) (fresh weight) of L. minor during the vegetative stage to 217 ng JA g(-1) during the evocation stage, and to 37.5 ng JA g(-1) during the flowering stage, which proves that JA is used for flowering.

  13. Jasmonic acid-isoleucine formation in grapevine (Vitis vinifera L.) by two enzymes with distinct transcription profiles.

    PubMed

    Böttcher, Christine; Burbidge, Crista A; di Rienzo, Valentina; Boss, Paul K; Davies, Christopher

    2015-07-01

    The plant hormone jasmonic acid (JA) is essential for stress responses and the formation of reproductive organs, but its role in fruit development and ripening is unclear. Conjugation of JA to isoleucine is a crucial step in the JA signaling pathway since only JA-Ile is recognized by the jasmonate receptor. The conjugation reaction is catalyzed by JA-amido synthetases, belonging to the family of Gretchen Hagen3 (GH3) proteins. Here, in vitro studies of two grapevine (Vitis vinifera L. cv Shiraz) GH3 enzymes, VvGH3-7 and VvGH3-9, demonstrated JA-conjugating activities with an overlapping range of amino acid substrates, including isoleucine. Expression studies of the corresponding genes in grape berries combined with JA and JA-Ile measurements suggested a primary role for JA signaling in fruit set and cell division and did not support an involvement of JA in the ripening process. In response to methyl JA (MeJA) treatment, and in wounded and unwounded (distal) leaves, VvGH3-9 transcripts accumulated, indicating a participation in the JA response. In contrast, VvGH3-7 was unresponsive to MeJA and local wounding, demonstrating a differential transcriptional regulation of VvGH3-7 and VvGH3-9. The transient induction of VvGH3-7 in unwounded, distal leaves was suggestive of the involvement of an unknown mobile wound signal. © 2014 Institute of Botany, Chinese Academy of Sciences.

  14. Disentangling the initiation from the response in joint attention: an eye-tracking study in toddlers with autism spectrum disorders.

    PubMed

    Billeci, L; Narzisi, A; Campatelli, G; Crifaci, G; Calderoni, S; Gagliano, A; Calzone, C; Colombi, C; Pioggia, G; Muratori, F

    2016-05-17

    Joint attention (JA), whose deficit is an early risk marker for autism spectrum disorder (ASD), has two dimensions: (1) responding to JA and (2) initiating JA. Eye-tracking technology has largely been used to investigate responding JA, but rarely to study initiating JA especially in young children with ASD. The aim of this study was to describe the differences in the visual patterns of toddlers with ASD and those with typical development (TD) during both responding JA and initiating JA tasks. Eye-tracking technology was used to monitor the gaze of 17 children with ASD and 15 age-matched children with TD during the presentation of short video sequences involving one responding JA and two initiating JA tasks (initiating JA-1 and initiating JA-2). Gaze accuracy, transitions and fixations were analyzed. No differences were found in the responding JA task between children with ASD and those with TD, whereas, in the initiating JA tasks, different patterns of fixation and transitions were shown between the groups. These results suggest that children with ASD and those with TD show different visual patterns when they are expected to initiate joint attention but not when they respond to joint attention. We hypothesized that differences in transitions and fixations are linked to ASD impairments in visual disengagement from face, in global scanning of the scene and in the ability to anticipate object's action.

  15. 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

  16. 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

  17. 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…

  18. Mapping methyl jasmonate-mediated transcriptional reprogramming of metabolism and cell cycle progression in cultured Arabidopsis cells

    PubMed Central

    Pauwels, Laurens; Morreel, Kris; De Witte, Emilie; Lammertyn, Freya; Van Montagu, Marc; Boerjan, Wout; Inzé, Dirk; Goossens, Alain

    2008-01-01

    Jasmonates (JAs) are plant-specific signaling molecules that steer a diverse set of physiological and developmental processes. Pathogen attack and wounding inflicted by herbivores induce the biosynthesis of these hormones, triggering defense responses both locally and systemically. We report on alterations in the transcriptome of a fast-dividing cell culture of the model plant Arabidopsis thaliana after exogenous application of methyl JA (MeJA). Early MeJA response genes encoded the JA biosynthesis pathway proteins and key regulators of MeJA responses, including most JA ZIM domain proteins and MYC2, together with transcriptional regulators with potential, but yet unknown, functions in MeJA signaling. In a second transcriptional wave, MeJA reprogrammed cellular metabolism and cell cycle progression. Up-regulation of the monolignol biosynthesis gene set resulted in an increased production of monolignols and oligolignols, the building blocks of lignin. Simultaneously, MeJA repressed activation of M-phase genes, arresting the cell cycle in G2. MeJA-responsive transcription factors were screened for their involvement in early signaling events, in particular the regulation of JA biosynthesis. Parallel screens based on yeast one-hybrid and transient transactivation assays identified both positive (MYC2 and the AP2/ERF factor ORA47) and negative (the C2H2 Zn finger proteins STZ/ZAT10 and AZF2) regulators, revealing a complex control of the JA autoregulatory loop and possibly other MeJA-mediated downstream processes. PMID:18216250

  19. Unclassified Publications of Lincoln Laboratory 1 January - 31 December 1997. Volume 23.

    DTIC Science & Technology

    1997-12-31

    ADA333490 7497 Nonconventional 3D Imaging Shirley, L.G. Line. Lab. J., Vol. 9, Using Wavelength-Dependent Hallerman , G.R. No. 2, 1996...11883 11905A 11941 A Comparison of Surface Contour Measurements Based on Speckle Pattern Sampling and Coordinate Measuring Machines Hallerman , G.R...Halbritter, J., MS-11729 Hall, K.L., JA-7354, JA-7367, JA-7462, JA-7477, MS-11776A, MS-12227, MS-12409 Haller, E.E., JA-7433 Hallerman , G.R., JA

  20. Induced plant-defenses suppress herbivore reproduction but also constrain predation of their offspring.

    PubMed

    Ataide, Livia M S; Pappas, Maria L; Schimmel, Bernardus C J; Lopez-Orenes, Antonio; Alba, Juan M; Duarte, Marcus V A; Pallini, Angelo; Schuurink, Robert C; Kant, Merijn R

    2016-11-01

    Inducible anti-herbivore defenses in plants are predominantly regulated by jasmonic acid (JA). On tomato plants, most genotypes of the herbivorous generalist spider mite Tetranychus urticae induce JA defenses and perform poorly on it, whereas the Solanaceae specialist Tetranychus evansi, who suppresses JA defenses, performs well on it. We asked to which extent these spider mites and the predatory mite Phytoseiulus longipes preying on these spider mites eggs are affected by induced JA-defenses. By artificially inducing the JA-response of the tomato JA-biosynthesis mutant def-1 using exogenous JA and isoleucine (Ile), we first established the relationship between endogenous JA-Ile-levels and the reproductive performance of spider mites. For both mite species we observed that they produced more eggs when levels of JA-Ile were low. Subsequently, we allowed predatory mites to prey on spider mite-eggs derived from wild-type tomato plants, def-1 and JA-Ile-treated def-1 and observed that they preferred, and consumed more, eggs produced on tomato plants with weak JA defenses. However, predatory mite oviposition was similar across treatments. Our results show that induced JA-responses negatively affect spider mite performance, but positively affect the survival of their offspring by constraining egg-predation. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  1. Complementary action of jasmonic acid on salicylic acid in mediating fungal elicitor-induced flavonol glycoside accumulation of Ginkgo biloba cells.

    PubMed

    Xu, Maojun; Dong, Jufang; Wang, Huizhong; Huang, Luqi

    2009-08-01

    The antagonistic action between jasmonic acid (JA) and salicylic acid (SA) in plant defence responses has been well documented. However, their relationship in secondary metabolite production is largely unknown. Here, we report that PB90, a protein elicitor from Phytophthora boehmeriae, triggers JA generation, SA accumulation and flavonol glycoside production of Ginkgo biloba cells. JA inhibitors suppress not only PB90-triggered JA generation, but also the elicitor-induced flavonol glycoside production. However, the elicitor can still enhance flavonol glycoside production even though the JA generation is totally inhibited. Over-expression of SA hydrolase gene NahG not only abolishes SA accumulation, but also suppresses the elicitor-induced flavonol glycoside production when JA signalling is inhibited. Interestingly, expression of NahG does not inhibit the elicitor-induced flavonol glycoside accumulation in the absence of JA inhibitors. Moreover, JA levels are significantly enhanced when SA accumulation is impaired in the transgenic cells. Together, the data suggest that both JA and SA are involved in PB90-induced flavonol glycoside production. Furthermore, we demonstrate that JA signalling might be enhanced to substitute for SA to mediate the elicitor-induced flavonol glycoside accumulation when SA signalling is impaired, which reveals an unusual complementary relationship between JA and SA in mediating plant secondary metabolite production.

  2. Role of jasmonic acid in improving tolerance of rapeseed (Brassica napus L.) to Cd toxicity*

    PubMed Central

    Ali, Essa; Hussain, Nazim; Shamsi, Imran Haider; Jabeen, Zahra; Siddiqui, Muzammil Hussain; Jiang, Li-xi

    2018-01-01

    The well-known detrimental effects of cadmium (Cd) on plants are chloroplast destruction, photosynthetic pigment inhibition, imbalance of essential plant nutrients, and membrane damage. Jasmonic acid (JA) is an alleviator against different stresses such as salinity and drought. However, the functional attributes of JA in plants such as the interactive effects of JA application and Cd on rapeseed in response to heavy metal stress remain unclear. JA at 50 μmol/L was observed in literature to have senescence effects in plants. In the present study, 25 μmol/L JA is observed to be a “stress ameliorating molecule” by improving the tolerance of rapeseed plants to Cd toxicity. JA reduces the Cd uptake in the leaves, thereby reducing membrane damage and malondialdehyde content and increasing the essential nutrient uptake. Furthermore, JA shields the chloroplast against the damaging effects of Cd, thereby increasing gas exchange and photosynthetic pigments. Moreover, JA modulates the antioxidant enzyme activity to strengthen the internal defense system. Our results demonstrate the function of JA in alleviating Cd toxicity and its underlying mechanism. Moreover, JA attenuates the damage of Cd to plants. This study enriches our knowledge regarding the use of and protection provided by JA in Cd stress. PMID:29405041

  3. Look into my eyes: Investigating joint attention using interactive eye-tracking and fMRI in a developmental sample.

    PubMed

    Oberwelland, E; Schilbach, L; Barisic, I; Krall, S C; Vogeley, K; Fink, G R; Herpertz-Dahlmann, B; Konrad, K; Schulte-Rüther, M

    2016-04-15

    Joint attention, the shared attentional focus of at least two people on a third significant object, is one of the earliest steps in social development and an essential aspect of reciprocal interaction. However, the neural basis of joint attention (JA) in the course of development is completely unknown. The present study made use of an interactive eye-tracking paradigm in order to examine the developmental trajectories of JA and the influence of a familiar interaction partner during the social encounter. Our results show that across children and adolescents JA elicits a similar network of "social brain" areas as well as attention and motor control associated areas as in adults. While other-initiated JA particularly recruited visual, attention and social processing areas, self-initiated JA specifically activated areas related to social cognition, decision-making, emotions and motivational/reward processes highlighting the rewarding character of self-initiated JA. Activation was further enhanced during self-initiated JA with a familiar interaction partner. With respect to developmental effects, activation of the precuneus declined from childhood to adolescence and additionally shifted from a general involvement in JA towards a more specific involvement for self-initiated JA. Similarly, the temporoparietal junction (TPJ) was broadly involved in JA in children and more specialized for self-initiated JA in adolescents. Taken together, this study provides first-time data on the developmental trajectories of JA and the effect of a familiar interaction partner incorporating the interactive character of JA, its reciprocity and motivational aspects. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Development of marker genes for jasmonic acid signaling in shoots and roots of wheat

    PubMed Central

    Liu, Hongwei; Carvalhais, Lilia Costa; Kazan, Kemal; Schenk, Peer M.

    2016-01-01

    ABSTRACT The jasmonic acid (JA) signaling pathway plays key roles in a diverse array of plant development, reproduction, and responses to biotic and abiotic stresses. Most of our understanding of the JA signaling pathway derives from the dicot model plant Arabidopsis thaliana, while corresponding knowledge in wheat is somewhat limited. In this study, the expression of 41 genes implicated in the JA signaling pathway has been assessed on 10 day-old bread wheat seedlings, 24 h, 48 h, and 72 h after methyl-jasmonate (MeJA) treatment using quantitative real-time PCR. The examined genes have been previously reported to be involved in JA biosynthesis and catabolism, JA perception and signaling, and pathogen defense in wheat shoots and roots. This study provides evidence to suggest that the effect of MeJA treatment is more prominent in shoots than roots of wheat seedlings, and substantial regulation of the JA pathway-dependent defense genes occurs at 72 h after MeJA treatment. Results show that the expression of 22 genes was significantly affected by MeJA treatment in wheat shoots. However, only PR1.1 and PR3 were significantly differentially expressed in wheat roots, both at 24 h post-MeJA treatment, with other genes showing large variation in their gene expression in roots. While providing marker genes on JA signaling in wheat, future work may focus on elucidating the regulatory function of JA-modulated transcription factors, some of which have well-studied potential orthologs in Arabidopsis. PMID:27115051

  5. Salicylic acid and jasmonic acid are essential for systemic resistance against tobacco mosaic virus in Nicotiana benthamiana.

    PubMed

    Zhu, Feng; Xi, De-Hui; Yuan, Shu; Xu, Fei; Zhang, Da-Wei; Lin, Hong-Hui

    2014-06-01

    Systemic resistance is induced by pathogens and confers protection against a broad range of pathogens. Recent studies have indicated that salicylic acid (SA) derivative methyl salicylate (MeSA) serves as a long-distance phloem-mobile systemic resistance signal in tobacco, Arabidopsis, and potato. However, other experiments indicate that jasmonic acid (JA) is a critical mobile signal. Here, we present evidence suggesting both MeSA and methyl jasmonate (MeJA) are essential for systemic resistance against Tobacco mosaic virus (TMV), possibly acting as the initiating signals for systemic resistance. Foliar application of JA followed by SA triggered the strongest systemic resistance against TMV. Furthermore, we use a virus-induced gene-silencing-based genetics approach to investigate the function of JA and SA biosynthesis or signaling genes in systemic response against TMV infection. Silencing of SA or JA biosynthetic and signaling genes in Nicotiana benthamiana plants increased susceptibility to TMV. Genetic experiments also proved the irreplaceable roles of MeSA and MeJA in systemic resistance response. Systemic resistance was compromised when SA methyl transferase or JA carboxyl methyltransferase, which are required for MeSA and MeJA formation, respectively, were silenced. Moreover, high-performance liquid chromatography-mass spectrometry analysis indicated that JA and MeJA accumulated in phloem exudates of leaves at early stages and SA and MeSA accumulated at later stages, after TMV infection. Our data also indicated that JA and MeJA could regulate MeSA and SA production. Taken together, our results demonstrate that (Me)JA and (Me)SA are required for systemic resistance response against TMV.

  6. 17 CFR Appendix 1 to Part 45 - Tables of Minimum Primary Economic Terms Data

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Tables of Minimum Primary Economic Terms Data 1 Appendix 1 to Part 45 Commodity and Securities Exchanges COMMODITY FUTURES TRADING... Minimum Primary Economic Terms Data ER13JA12.003 ER13JA12.004 ER13JA12.005 ER13JA12.006 ER13JA12.007...

  7. 17 CFR Appendix 1 to Part 45 - Tables of Minimum Primary Economic Terms Data

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 1 2013-04-01 2013-04-01 false Tables of Minimum Primary Economic Terms Data 1 Appendix 1 to Part 45 Commodity and Securities Exchanges COMMODITY FUTURES TRADING... Minimum Primary Economic Terms Data ER13JA12.003 ER13JA12.004 ER13JA12.005 ER13JA12.006 ER13JA12.007...

  8. Jasmonic acid carboxyl methyltransferase regulates development and herbivory-induced defense response in rice.

    PubMed

    Qi, Jinfeng; Li, Jiancai; Han, Xiu; Li, Ran; Wu, Jianqiang; Yu, Haixin; Hu, Lingfei; Xiao, Yutao; Lu, Jing; Lou, Yonggen

    2016-06-01

    Jasmonic acid (JA) and related metabolites play a key role in plant defense and growth. JA carboxyl methyltransferase (JMT) may be involved in plant defense and development by methylating JA to methyl jasmonate (MeJA) and thus influencing the concentrations of JA and related metabolites. However, no JMT gene has been well characterized in monocotyledon defense and development at the molecular level. After we cloned a rice JMT gene, OsJMT1, whose encoding protein was localized in the cytosol, we found that the recombinant OsJMT1 protein catalyzed JA to MeJA. OsJMT1 is up-regulated in response to infestation with the brown planthopper (BPH; Nilaparvata lugens). Plants in which OsJMT1 had been overexpressed (oe-JMT plants) showed reduced height and yield. These oe-JMT plants also exhibited increased MeJA levels but reduced levels of herbivore-induced JA and jasmonoyl-isoleucine (JA-Ile). The oe-JMT plants were more attractive to BPH female adults but showed increased resistance to BPH nymphs, probably owing to the different responses of BPH female adults and nymphs to the changes in levels of H2 O2 and MeJA in oe-JMT plants. These results indicate that OsJMT1, by altering levels of JA and related metabolites, plays a role in regulating plant development and herbivore-induced defense responses in rice. © 2015 Institute of Botany, Chinese Academy of Sciences.

  9. The relationship between joint attention and theory of mind in neurotypical adults.

    PubMed

    Shaw, Jordan A; Bryant, Lauren K; Malle, Bertram F; Povinelli, Daniel J; Pruett, John R

    2017-05-01

    Joint attention (JA) is hypothesized to have a close relationship with developing theory of mind (ToM) capabilities. We tested the co-occurrence of ToM and JA in social interactions between adults with no reported history of psychiatric illness or neurodevelopmental disorders. Participants engaged in an experimental task that encouraged nonverbal communication, including JA, and also ToM activity. We adapted an in-lab variant of experience sampling methods (Bryant et al., 2013) to measure ToM during JA based on participants' subjective reports of their thoughts while performing the task. This experiment successfully elicited instances of JA in 17/20 dyads. We compared participants' thought contents during episodes of JA and non-JA. Our results suggest that, in adults, JA and ToM may occur independently. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. Genome-wide association study reveals novel players in defense hormone crosstalk in Arabidopsis.

    PubMed

    Proietti, Silvia; Caarls, Lotte; Coolen, Silvia; Van Pelt, Johan A; Van Wees, Saskia C M; Pieterse, Corné M J

    2018-05-31

    Jasmonic acid (JA) regulates plant defenses against necrotrophic pathogens and insect herbivores. Salicylic acid (SA) and abscisic acid (ABA) can antagonize JA-regulated defenses, thereby modulating pathogen or insect resistance. We performed a genome-wide association (GWA) study on natural genetic variation in Arabidopsis thaliana for the effect of SA and ABA on the JA pathway. We treated 349 Arabidopsis accessions with methyl JA (MeJA), or a combination of MeJA and either SA or ABA, after which expression of the JA-responsive marker gene PDF1.2 was quantified as a readout for GWA analysis. Both hormones antagonized MeJA-induced PDF1.2 in the majority of the accessions, but with a large variation in magnitude. GWA mapping of the SA- and ABA-affected PDF1.2 expression data revealed loci associated with crosstalk. GLYI4 (encoding a glyoxalase) and ARR11 (encoding an Arabidopsis response regulator involved in cytokinin signaling) were confirmed by T-DNA insertion mutant analysis to affect SA-JA crosstalk and resistance against the necrotroph Botrytis cinerea. In addition, At1g16310 (encoding a cation efflux family protein) was confirmed to affect ABA-JA crosstalk and susceptibility to Mamestra brassicae herbivory. Collectively, this GWA study identified novel players in JA hormone crosstalk with potential roles in the regulation of pathogen or insect resistance. This article is protected by copyright. All rights reserved.

  18. Jasmonate and Phytochrome A Signaling in Arabidopsis Wound and Shade Responses Are Integrated through JAZ1 Stability[C][W

    PubMed Central

    Robson, Frances; Okamoto, Haruko; Patrick, Elaine; Harris, Sue-Ré; Wasternack, Claus; Brearley, Charles; Turner, John G.

    2010-01-01

    Jasmonate (JA) activates plant defense, promotes pollen maturation, and suppresses plant growth. An emerging theme in JA biology is its involvement in light responses; here, we examine the interdependence of the JA- and light-signaling pathways in Arabidopsis thaliana. We demonstrate that mutants deficient in JA biosynthesis and signaling are deficient in a subset of high irradiance responses in far-red (FR) light. These mutants display exaggerated shade responses to low, but not high, R/FR ratio light, suggesting a role for JA in phytochrome A (phyA) signaling. Additionally, we demonstrate that the FR light–induced expression of transcription factor genes is dependent on CORONATINE INSENSITIVE1 (COI1), a central component of JA signaling, and is suppressed by JA. phyA mutants had reduced JA-regulated growth inhibition and VSP expression and increased content of cis-(+)-12-oxophytodienoic acid, an intermediate in JA biosynthesis. Significantly, COI1-mediated degradation of JASMONATE ZIM DOMAIN1-β-glucuronidase (JAZ1-GUS) in response to mechanical wounding and JA treatment required phyA, and ectopic expression of JAZ1-GUS resulted in exaggerated shade responses. Together, these results indicate that JA and phyA signaling are integrated through degradation of the JAZ1 protein, and both are required for plant responses to light and stress. PMID:20435902

  19. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic Acid.

    PubMed

    Leon-Reyes, Antonio; Du, Yujuan; Koornneef, Annemart; Proietti, Silvia; Körbes, Ana P; Memelink, Johan; Pieterse, Corné M J; Ritsema, Tita

    2010-02-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitive to SA-mediated suppression of the JA-responsive marker genes PDF1.2 and VSP2. Accordingly, strong activation of JA and ET responses by the necrotrophic pathogens Botrytis cinerea and Alternaria brassicicola prior to SA treatment counteracted the ability of SA to suppress the JA response. Pharmacological assays, mutant analysis, and studies with the ET-signaling inhibitor 1-methylcyclopropene revealed that ET signaling renders the JA response insensitive to subsequent suppression by SA. The APETALA2/ETHYLENE RESPONSE FACTOR transcription factor ORA59, which regulates JA/ET-responsive genes such as PDF1.2, emerged as a potential mediator in this process. Collectively, our results point to a model in which simultaneous induction of the JA and ET pathway renders the plant insensitive to future SA-mediated suppression of JA-dependent defenses, which may prioritize the JA/ET pathway over the SA pathway during multi-attacker interactions.

  20. Identification of jasmonic acid and its methyl ester as gum-inducing factors in tulips.

    PubMed

    Skrzypek, Edyta; Miyamoto, Kensuke; Saniewski, Marian; Ueda, Junichi

    2005-02-01

    The purpose of this study was to identify endogenous factors that induce gummosis and to show their role in gummosis in tulip (Tulipa gesneriana L. cv. Apeldoorn) stems. Using procedures to detect endogenous factors that induce gum in the stem of tulips, jasmonic acid (JA) and methyl jasmonate (JA-Me) were successfully identified using gas-liquid chromatography-mass spectrometry. Total amounts of JA and JA-Me designated as jasmonates in tulip stems were also estimated at about 70-80 ng/g fresh weight, using deuterium-labeled jasmonates as internal standards. The application of JA and JA-Me as lanolin pastes substantially induced gums in tulip stems with ethylene production. The application of ethephon, an ethylene-generating compound, however, induced no gummosis although it slightly affected jasmonate content in tulip stems. These results strongly suggest that JA and JA-Me are endogenous factors that induce gummosis in tulip stems.

  1. Embryo-Specific Gene Expression in Microspore-Derived Embryos of Brassica napus. An Interaction between Abscisic Acid and Jasmonic Acid1, 2

    PubMed Central

    Hays, Dirk B.; Wilen, Ronald W.; Sheng, Chuxing; Moloney, Maurice M.; Pharis, Richard P.

    1999-01-01

    The induction of napin and oleosin gene expression in Brassica napus microspore-derived embryos (MDEs) was studied to assess the possible interaction between abscisic acid (ABA) and jasmonic acid (JA). Napin and oleosin transcripts were detected sooner following treatment with ABA than JA. Treatment of MDEs with ABA plus JA gave an additive accumulation of both napin and oleosin mRNA, the absolute amount being dependent on the concentration of each hormone. Endogenous ABA levels were reduced by 10-fold after treatment with JA, negating the possibility that the observed additive interaction was due to JA-induced ABA biosynthesis. Also, JA did not significantly increase the uptake of [3H-ABA] from the medium into MDEs. This suggests that the additive interaction was not due to an enhanced carrier-mediated ABA uptake by JA. Finally, when JA was added to MDEs that had been treated with the ABA biosynthesis inhibitor fluridone, napin mRNA did not increase. Based on these results with the MDE system, it is possible that embryos of B. napus use endogenous JA to modulate ABA effects on expression of both napin and oleosin. In addition, JA could play a causal role in the reduction of ABA that occurs during late stages of seed development. PMID:10069845

  2. CYP94-mediated jasmonoyl-isoleucine hormone oxidation shapes jasmonate profiles and attenuates defence responses to Botrytis cinerea infection

    PubMed Central

    Aubert, Yann; Widemann, Emilie; Miesch, Laurence; Pinot, Franck; Heitz, Thierry

    2015-01-01

    Induced resistance to the necrotrophic pathogen Botrytis cinerea depends on jasmonate metabolism and signalling in Arabidopsis. We have presented here extensive jasmonate profiling in this pathosystem and investigated the impact of the recently reported jasmonoyl-isoleucine (JA-Ile) catabolic pathway mediated by cytochrome P450 (CYP94) enzymes. Using a series of mutant and overexpressing (OE) plant lines, we showed that CYP94B3 and CYP94C1 are integral components of the fungus-induced jasmonate metabolic pathway and control the abundance of oxidized conjugated but also some unconjugated derivatives, such as sulfated 12-HSO4-JA. Despite causing JA-Ile overaccumulation due to impaired oxidation, CYP94 deficiency had negligible impacts on resistance, associated with enhanced JAZ repressor transcript levels. In contrast, plants overexpressing (OE) CYP94B3 or CYP94C1 were enriched in 12-OH-JA-Ile or 12-COOH-JA-Ile respectively. This shift towards oxidized JA-Ile derivatives was concomitant with strongly impaired defence gene induction and reduced disease resistance. CYP94B3-OE, but unexpectedly not CYP94C1-OE, plants displayed reduced JA-Ile levels compared with the wild type, suggesting that increased susceptibility in CYP94C1-OE plants may result from changes in the hormone oxidation ratio rather than absolute changes in JA-Ile levels. Consistently, while feeding JA-Ile to seedlings triggered strong induction of JA pathway genes, induction was largely reduced or abolished after feeding with the CYP94 products 12-OH-JA-Ile and 12-COOH-JA-Ile, respectively. This trend paralleled in vitro pull-down assays where 12-COOH-JA-Ile was unable to promote COI1–JAZ9 co-receptor assembly. Our results highlight the dual function of CYP94B3/C1 in antimicrobial defence: by controlling hormone oxidation status for signal attenuation, these enzymes also define JA-Ile as a metabolic hub directing jasmonate profile complexity. PMID:25903915

  3. Assessing the Role of ETHYLENE RESPONSE FACTOR Transcriptional Repressors in Salicylic Acid-Mediated Suppression of Jasmonic Acid-Responsive Genes.

    PubMed

    Caarls, Lotte; Van der Does, Dieuwertje; Hickman, Richard; Jansen, Wouter; Verk, Marcel C Van; Proietti, Silvia; Lorenzo, Oscar; Solano, Roberto; Pieterse, Corné M J; Van Wees, Saskia C M

    2017-02-01

    Salicylic acid (SA) and jasmonic acid (JA) cross-communicate in the plant immune signaling network to finely regulate induced defenses. In Arabidopsis, SA antagonizes many JA-responsive genes, partly by targeting the ETHYLENE RESPONSE FACTOR (ERF)-type transcriptional activator ORA59. Members of the ERF transcription factor family typically bind to GCC-box motifs in the promoters of JA- and ethylene-responsive genes, thereby positively or negatively regulating their expression. The GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Here, we investigated whether SA-induced ERF-type transcriptional repressors, which may compete with JA-induced ERF-type activators for binding at the GCC-box, play a role in SA/JA antagonism. We selected ERFs that are transcriptionally induced by SA and/or possess an EAR transcriptional repressor motif. Several of the 16 ERFs tested suppressed JA-dependent gene expression, as revealed by enhanced JA-induced PDF1.2 or VSP2 expression levels in the corresponding erf mutants, while others were involved in activation of these genes. However, SA could antagonize JA-induced PDF1.2 or VSP2 in all erf mutants, suggesting that the tested ERF transcriptional repressors are not required for SA/JA cross-talk. Moreover, a mutant in the co-repressor TOPLESS, that showed reduction in repression of JA signaling, still displayed SA-mediated antagonism of PDF1.2 and VSP2. Collectively, these results suggest that SA-regulated ERF transcriptional repressors are not essential for antagonism of JA-responsive gene expression by SA. We further show that de novo SA-induced protein synthesis is required for suppression of JA-induced PDF1.2, pointing to SA-stimulated production of an as yet unknown protein that suppresses JA-induced transcription. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Complete genome analysis of jasmine virus T from Jasminum sambac in China.

    PubMed

    Tang, Yajun; Gao, Fangluan; Yang, Zhen; Wu, Zujian; Yang, Liang

    2016-07-01

    The genome of a potyvirus (isolate JaVT_FZ) recovered from jasmine (Jasminum sambac L.) showing yellow ringspot symptoms in Fuzhou, China, was sequenced. JaVT_FZ is closely related to seven other potyviruses with completely sequenced genomes, with which it shares 66-70 % nucleotide and 52-56 % amino acid sequence identity. However, the coat protein (CP) gene shares 82-92 % nucleotide and 90-97 % amino acid sequence identity with those of two partially sequenced potyviruses, named jasmine potyvirus T (JaVT-jasmine) and jasmine yellow mosaic potyvirus (JaYMV-India), respectively. This suggests that JaVT_FZ, JaVT-jasmine and JaYMV-India should be regarded as members of a single potyvirus species, for which the name "Jasmine virus T" has priority.

  5. Unclassified Publications of Lincoln Laboratory, 1 January - 31 December 1990. Volume 16

    DTIC Science & Technology

    1990-12-31

    Apr. 1990 ADA223419 Hopped Communication Systems with Nonuniform Hopping Distributions 880 Bistatic Radar Cross Section of a Fenn, A.J. 2 May1990...EXPERIMENT JA-6241 MS-8424 LUNAR PERTURBATION MAXIMUM LIKELIHOOD ALGORITHM JA-6241 JA-6467 LWIR SPECTRAL BAND MAXIMUM LIKELIHOOD ESTIMATOR JA-6476 MS-8466

  6. Continuously Monocropped Jerusalem Artichoke Changed Soil Bacterial Community Composition and Ammonia-Oxidizing and Denitrifying Bacteria Abundances.

    PubMed

    Zhou, Xingang; Wang, Zhilin; Jia, Huiting; Li, Li; Wu, Fengzhi

    2018-01-01

    Soil microbial communities have profound effects on the growth, nutrition and health of plants in agroecosystems. Understanding soil microbial dynamics in cropping systems can assist in determining how agricultural practices influence soil processes mediated by microorganisms. In this study, soil bacterial communities were monitored in a continuously monocropped Jerusalem artichoke (JA) system, in which JA was successively monocropped for 3 years in a wheat field. Soil bacterial community compositions were estimated by amplicon sequencing of the 16S rRNA gene. Abundances of ammonia-oxidizing and denitrifying bacteria were estimated by quantitative PCR analysis of the amoA , nirS , and nirK genes. Results showed that 1-2 years of monocropping of JA did not significantly impact the microbial alpha diversity, and the third cropping of JA decreased the microbial alpha diversity ( P < 0.05). Principal coordinates analysis and permutational multivariate analysis of variance analyses revealed that continuous monocropping of JA changed soil bacterial community structure and function profile ( P < 0.001). At the phylum level, the wheat field was characterized with higher relative abundances of Latescibacteria , Planctomycetes , and Cyanobacteria , the first cropping of JA with Actinobacteria , the second cropping of JA with Acidobacteria , Armatimonadetes , Gemmatimonadetes , and Proteobacteria . At the genus level, the first cropping of JA was enriched with bacterial species with pathogen-antagonistic and/or plant growth promoting potentials, while members of genera that included potential denitrifiers increased in the second and third cropping of JA. The first cropping of JA had higher relative abundances of KO terms related to lignocellulose degradation and phosphorus cycling, the second cropping of JA had higher relative abundances of KO terms nitrous-oxide reductase and nitric-oxide reductase, and the third cropping of JA had higher relative abundances of KO terms

  7. The Recently Identified Isoleucine Conjugate of cis-12-Oxo-Phytodienoic Acid Is Partially Active in cis-12-Oxo-Phytodienoic Acid-Specific Gene Expression of Arabidopsis thaliana

    PubMed Central

    Floková, Kristýna; Miersch, Otto; Strnad, Miroslav; Novák, Ondřej; Wasternack, Claus; Hause, Bettina

    2016-01-01

    Oxylipins of the jasmonate family are active as signals in plant responses to biotic and abiotic stresses as well as in development. Jasmonic acid (JA), its precursor cis-12-oxo-phytodienoic acid (OPDA) and the isoleucine conjugate of JA (JA-Ile) are the most prominent members. OPDA and JA-Ile have individual signalling properties in several processes and differ in their pattern of gene expression. JA-Ile, but not OPDA, is perceived by the SCFCOI1-JAZ co-receptor complex. There are, however, numerous processes and genes specifically induced by OPDA. The recently identified OPDA-Ile suggests that OPDA specific responses might be mediated upon formation of OPDA-Ile. Here, we tested OPDA-Ile-induced gene expression in wild type and JA-deficient, JA-insensitive and JA-Ile-deficient mutant background. Tests on putative conversion of OPDA-Ile during treatments revealed only negligible conversion. Expression of two OPDA-inducible genes, GRX480 and ZAT10, by OPDA-Ile could be detected in a JA-independent manner in Arabidopsis seedlings but less in flowering plants. The data suggest a bioactivity in planta of OPDA-Ile. PMID:27611078

  8. Jasmonic acid and salicylic acid activate a common defense system in rice.

    PubMed

    Tamaoki, Daisuke; Seo, Shigemi; Yamada, Shoko; Kano, Akihito; Miyamoto, Ayumi; Shishido, Hodaka; Miyoshi, Seika; Taniguchi, Shiduku; Akimitsu, Kazuya; Gomi, Kenji

    2013-06-01

    Jasmonic acid (JA) and salicylic acid (SA) play important roles in plant defense systems. JA and SA signaling pathways interact antagonistically in dicotyledonous plants, but, the status of crosstalk between JA and SA signaling is unknown in monocots. Our rice microarray analysis showed that more than half of the genes upregulated by the SA analog BTH are also upregulated by JA, suggesting that a major portion of the SA-upregulated genes are regulated by JA-dependent signaling in rice. A common defense system that is activated by both JA and SA is thus proposed which plays an important role in pathogen defense responses in rice.

  9. 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

  10. 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

  11. Jasmonic acid distribution and action in plants: regulation during development and response to biotic and abiotic stress.

    PubMed Central

    Creelman, R A; Mullet, J E

    1995-01-01

    Jasmonic acid (JA) is a naturally occurring growth regulator found in higher plants. Several physiological roles have been described for this compound (or a related compound, methyl jasmonate) during plant development and in response to biotic and abiotic stress. To accurately determine JA levels in plant tissue, we have synthesized JA containing 13C for use as an internal standard with an isotopic composition of [225]:[224] 0.98:0.02 compared with [225]:[224] 0.15:0.85 for natural material. GC analysis (flame ionization detection and MS) indicate that the internal standard is composed of 92% 2-(+/-)-[13C]JA and 8% 2-(+/-)-7-iso-[13C]JA. In soybean plants, JA levels were highest in young leaves, flowers, and fruit (highest in the pericarp). In soybean seeds and seedlings, JA levels were highest in the youngest organs including the hypocotyl hook, plumule, and 12-h axis. In soybean leaves that had been dehydrated to cause a 15% decrease in fresh weight, JA levels increased approximately 5-fold within 2 h and declined to approximately control levels by 4 h. In contrast, a lag time of 1-2 h occurred before abscisic acid accumulation reached a maximum. These results will be discussed in the context of multiple pathways for JA biosynthesis and the role of JA in plant development and responses to environmental signals. PMID:11607536

  12. Jasmonic acid distribution and action in plants: regulation during development and response to biotic and abiotic stress.

    PubMed

    Creelman, R A; Mullet, J E

    1995-05-09

    Jasmonic acid (JA) is a naturally occurring growth regulator found in higher plants. Several physiological roles have been described for this compound (or a related compound, methyl jasmonate) during plant development and in response to biotic and abiotic stress. To accurately determine JA levels in plant tissue, we have synthesized JA containing 13C for use as an internal standard with an isotopic composition of [225]:[224] 0.98:0.02 compared with [225]:[224] 0.15:0.85 for natural material. GC analysis (flame ionization detection and MS) indicate that the internal standard is composed of 92% 2-(+/-)-[13C]JA and 8% 2-(+/-)-7-iso-[13C]JA. In soybean plants, JA levels were highest in young leaves, flowers, and fruit (highest in the pericarp). In soybean seeds and seedlings, JA levels were highest in the youngest organs including the hypocotyl hook, plumule, and 12-h axis. In soybean leaves that had been dehydrated to cause a 15% decrease in fresh weight, JA levels increased approximately 5-fold within 2 h and declined to approximately control levels by 4 h. In contrast, a lag time of 1-2 h occurred before abscisic acid accumulation reached a maximum. These results will be discussed in the context of multiple pathways for JA biosynthesis and the role of JA in plant development and responses to environmental signals.

  13. Costs of jasmonic acid induced defense in aboveground and belowground parts of corn (Zea mays L.).

    PubMed

    Feng, Yuanjiao; Wang, Jianwu; Luo, Shiming; Fan, Huizhi; Jin, Qiong

    2012-08-01

    Costs of jasmonic acid (JA) induced plant defense have gained increasing attention. In this study, JA was applied continuously to the aboveground (AG) or belowground (BG) parts, or AG plus BG parts of corn (Zea mays L.) to investigate whether JA exposure in one part of the plant would affect defense responses in another part, and whether or not JA induced defense would incur allocation costs. The results indicated that continuous JA application to AG parts systemically affected the quantities of defense chemicals in the roots, and vice versa. Quantities of DIMBOA and total amounts of phenolic compounds in leaves or roots generally increased 2 or 4 wk after the JA treatment to different plant parts. In the first 2 wk after application, the increase of defense chemicals in leaves and roots was accompanied by a significant decrease of root length, root surface area, and root biomass. Four weeks after the JA application, however, no such costs for the increase of defense chemicals in leaves and roots were detected. Instead, shoot biomass and root biomass increased. The results suggest that JA as a defense signal can be transferred from AG parts to BG parts of corn, and vice versa. Costs for induced defense elicited by continuous JA application were found in the early 2 wk, while distinct benefits were observed later, i.e., 4 wk after JA treatment.

  14. JaCVAM-organized international validation study of the in vivo rodent alkaline comet assay for the detection of genotoxic carcinogens: I. Summary of pre-validation study results.

    PubMed

    Uno, Yoshifumi; Kojima, Hajime; Omori, Takashi; Corvi, Raffaella; Honma, Masamistu; Schechtman, Leonard M; Tice, Raymond R; Burlinson, Brian; Escobar, Patricia A; Kraynak, Andrew R; Nakagawa, Yuzuki; Nakajima, Madoka; Pant, Kamala; Asano, Norihide; Lovell, David; Morita, Takeshi; Ohno, Yasuo; Hayashi, Makoto

    2015-07-01

    The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this validation effort was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The purpose of the pre-validation studies (i.e., Phase 1 through 3), conducted in four or five laboratories with extensive comet assay experience, was to optimize the protocol to be used during the definitive validation study. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Evaluation of methyl methanesulfonate, 2,6-diaminotoluene and 5-fluorouracil: Part of the Japanese center for the validation of alternative methods (JaCVAM) international validation study of the in vivo rat alkaline comet assay.

    PubMed

    Plappert-Helbig, Ulla; Junker-Walker, Ursula; Martus, Hans-Joerg

    2015-07-01

    As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined methyl methanesulfonate, 2,6-diaminotoluene, and 5-fluorouracil under coded test conditions. Rats were treated orally with the maximum tolerated dose (MTD) and two additional descending doses of the respective compounds. In the MMS treated groups liver and stomach showed significantly elevated DNA damage at each dose level and a significant dose-response relationship. 2,6-diaminotoluene induced significantly elevated DNA damage in the liver at each dose and a statistically significant dose-response relationship whereas no DNA damage was obtained in the stomach. 5-fluorouracil did not induce DNA damage in either liver or stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. In Silico Identification of Mimicking Molecules as Defense Inducers Triggering Jasmonic Acid Mediated Immunity against Alternaria Blight Disease in Brassica Species

    PubMed Central

    Pathak, Rajesh K.; Baunthiyal, Mamta; Shukla, Rohit; Pandey, Dinesh; Taj, Gohar; Kumar, Anil

    2017-01-01

    Alternaria brassicae and Alternaria brassicicola are two major phytopathogenic fungi which cause Alternaria blight, a recalcitrant disease on Brassica crops throughout the world, which is highly destructive and responsible for significant yield losses. Since no resistant source is available against Alternaria blight, therefore, efforts have been made in the present study to identify defense inducer molecules which can induce jasmonic acid (JA) mediated defense against the disease. It is believed that JA triggered defense response will prevent necrotrophic mode of colonization of Alternaria brassicae fungus. The JA receptor, COI1 is one of the potential targets for triggering JA mediated immunity through interaction with JA signal. In the present study, few mimicking compounds more efficient than naturally occurring JA in terms of interaction with COI1 were identified through virtual screening and molecular dynamics simulation studies. A high quality structural model of COI1 was developed using the protein sequence of Brassica rapa. This was followed by virtual screening of 767 analogs of JA from ZINC database for interaction with COI1. Two analogs viz. ZINC27640214 and ZINC43772052 showed more binding affinity with COI1 as compared to naturally occurring JA. Molecular dynamics simulation of COI1 and COI1-JA complex, as well as best screened interacting structural analogs of JA with COI1 was done for 50 ns to validate the stability of system. It was found that ZINC27640214 possesses efficient, stable, and good cell permeability properties. Based on the obtained results and its physicochemical properties, it is capable of mimicking JA signaling and may be used as defense inducers for triggering JA mediated resistance against Alternaria blight, only after further validation through field trials. PMID:28487711

  17. Methyl jasmonate-induced defense responses are associated with elevation of 1-aminocyclopropane-1-carboxylate oxidase in Lycopersicon esculentum fruit.

    PubMed

    Yu, Mengmeng; Shen, Lin; Zhang, Aijun; Sheng, Jiping

    2011-10-15

    It has been known that methyl jasmonate (MeJA) interacts with ethylene to elicit resistance. In green mature tomato fruits (Lycopersicon esculentum cv. Lichun), 0.02mM MeJA increased the activity of 1-aminocyclopropane-1-carboxylate oxidase (ACO), and consequently influenced the last step of ethylene biosynthesis. Fruits treated with a combination of 0.02 MeJA and 0.02 α-aminoisobutyric acid (AIB, a competitive inhibitor of ACO) exhibited a lower ethylene production comparing to that by 0.02mM MeJA alone. The increased activities of defense enzymes and subsequent control of disease incidence caused by Botrytis cinerea with 0.2mM MeJA treatment was impaired by AIB as well. A close relationship (P<0.05) was found between the activity alterations of ACO and that of chitinase (CHI) and β-1,3-glucanase (GLU). In addition, this study further detected the changes of gene expressions and enzyme kinetics of ACO to different concentrations of MeJA. LeACO1 was found the principal member from the ACO gene family to respond to MeJA. Accumulation of LeACO1/3/4 transcripts followed the concentration pattern of MeJA treatments, where the largest elevations were reached by 0.2mM. For kinetic analysis, K(m) values of ACO stepped up during the experiment and reached the maximums at 0.2mM MeJA with ascending concentrations of treatments. V(max) exhibited a gradual increase from 3h to 24h, and the largest induction appeared with 1.0mM MeJA. The results suggested that ACO is involved in MeJA-induced resistance in tomato, and the concentration influence of MeJA on ACO was attributable to the variation of gene transcripts and enzymatic properties. Copyright © 2011 Elsevier GmbH. All rights reserved.

  18. Transcriptome Analysis of Genes Associated with the Artemisinin Biosynthesis by Jasmonic Acid Treatment under the Light in Artemisia annua

    PubMed Central

    Hao, Xiaolong; Zhong, Yijun; Fu, Xueqing; Lv, Zongyou; Shen, Qian; Yan, Tingxiang; Shi, Pu; Ma, Yanan; Chen, Minghui; Lv, Xueying; Wu, Zhangkuanyu; Zhao, Jingya; Sun, Xiaofen; Li, Ling; Tang, Kexuan

    2017-01-01

    Artemisinin is a sesquiterpene lactone endoperoxide extracted from a traditional Chinese medicinal plant Artemisia annua. Artemisinin-based combination therapies (ACTs) are recommended as the best treatment of malaria by the World Health Organization (WHO). Both the phytohormone jasmonic acid (JA) and light promote artemisinin biosynthesis in A. annua. Interestingly, we found that the increase of artemisinin biosynthesis by JA was dependent on light. However, the relationship between the two signal pathways mediated by JA and light remains unclear. Here, we collected the A. annua seedlings of 24 h continuous light (Light), 24 h dark treatment (Dark), 4 h MeJA treatment under the continuous light conditions (Light-MeJA-4h) and 4 h MeJA treatment under the dark conditions (Dark-MeJA-4h) and performed the transcriptome sequencing using Illumina HiSeq 4000 System. A total of 266.7 million clean data were produced and assembled into 185,653 unigenes, with an average length of 537 bp. Among them, 59,490 unigenes were annotated and classified based on the public information. Differential expression analyses were performed between Light and Dark, Light and Light-MeJA-4h, Dark and Dark-MeJA-4h, Light-MeJA-4h, and Dark-MeJA-4h, respectively. Furthermore, transcription factor (TF) analysis revealed that 1588 TFs were identified and divided into 55 TF families, with 284 TFs down-regulated in the Dark relative to Light and 96 TFs up-regulated in the Light-MeJA-4h relative to Light. 8 TFs were selected as candidates for regulating the artemisinin biosynthesis and one of them was validated to be involved in artemisinin transcriptional regulation by Dual-Luciferase (Dual-LUC) assay. The transcriptome data shown in our study offered a comprehensive transcriptional expression pattern influenced by the MeJA and light in A. annua seedling, which will serve as a valuable resource for further studies on transcriptional regulation mechanisms underlying artemisinin biosynthesis. PMID

  19. Unclassified Publications of Lincoln Laboratory 1 January-31 December 1993. Volume 19

    DTIC Science & Technology

    1993-12-31

    Netishen, CM. Rothschild, M. Blundell, R Papa, D.C. Brown, E.R. Parker, CD. Shirley, L.G. Ariel, E.D. Hallerman , G.R. Payson, H.C Vivilecchia...Gustafson, T.K., JA-6838 Hallerman , G.R., JA-6932 Hallowell, R.G., MS-10253 Halversen, S.D., JA-6948, MS-10057, MS-10114 Hanes, A.S., JA-6924

  20. Defense Priming and Jasmonates: A Role for Free Fatty Acids in Insect Elicitor-Induced Long Distance Signaling

    PubMed Central

    Li, Ting; Cofer, Tristan; Engelberth, Marie; Engelberth, Jurgen

    2016-01-01

    Green leaf volatiles (GLV) prime plants against insect herbivore attack resulting in stronger and faster signaling by jasmonic acid (JA). In maize this response is specifically linked to insect elicitor (IE)-induced signaling processes, which cause JA accumulation not only around the damage site, but also in distant tissues, presumably through the activation of electrical signals. Here, we present additional data further characterizing these distal signaling events in maize. Also, we describe how exposure to GLV increases free fatty acid (fFA) levels in maize seedlings, but also in other plants, and how increased fFA levels affect IE-induced JA accumulation. Increased fFA, in particular α-linolenic acid (LnA), caused a significant increase in JA accumulation after IE treatment, while JA induced by mechanical wounding (MW) alone was not affected. We also identified treatments that significantly decreased certain fFA level including simulated wind and rain. In such treated plants, IE-induced JA accumulation was significantly reduced when compared to un-moved control plants, while MW-induced JA accumulation was not significantly affected. Since only IE-induced JA accumulation was altered by changes in the fFA composition, we conclude that changing levels of fFA affect primarily IE-induced signaling processes rather than serving as a substrate for JA. PMID:27135225

  1. Jasmonate induction of the monoterpene linalool confers resistance to rice bacterial blight and its biosynthesis is regulated by JAZ protein in rice.

    PubMed

    Taniguchi, Shiduku; Hosokawa-Shinonaga, Yumi; Tamaoki, Daisuke; Yamada, Shoko; Akimitsu, Kazuya; Gomi, Kenji

    2014-02-01

    Jasmonic acid (JA) is involved in the regulation of host immunity in plants. Recently, we demonstrated that JA signalling has an important role in resistance to rice bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) in rice. Here, we report that many volatile compounds accumulate in response to exogenous application of JA, including the monoterpene linalool. Expression of linalool synthase was up-regulated by JA. Vapour treatment with linalool induced resistance to Xoo, and transgenic rice plants overexpressing linalool synthase were more resistance to Xoo, presumably due to the up-regulation of defence-related genes in the absence of any treatment. JA-induced accumulation of linalool was regulated by OsJAZ8, a rice jasmonate ZIM-domain protein involving the JA signalling pathway at the transcriptional level, suggesting that linalool plays an important role in JA-induced resistance to Xoo in rice. © 2013 John Wiley & Sons Ltd.

  2. Cognitive and adaptive correlates of an ADOS-derived joint attention composite

    PubMed Central

    Harrison, Ashley Johnson; Lu, Zhenqiu (Laura); McLean, Rebecca L.; Sheinkopf, Stephen J.

    2016-01-01

    Joint attention skills have been shown to predict language outcomes in children with autism spectrum disorder (ASD). Less is known about the relationship between joint attention (JA) abilities in children with ASD and cognitive and adaptive abilities. In the current study, a subset of items from the Autism Diagnostic Observation Schedule (ADOS), designed to quantify JA abilities, were used to investigate social attention among an unusually large cross-sectional sample of children with ASD (n = 1061). An examination of the association between JA and a range of functional correlates (cognitive and adaptive) revealed JA was significantly related to verbal (VIQ) and non-verbal (NVIQ) cognitive ability as well as all domains of adaptive functioning (socialization, communication, and daily living skills). Additional analyses examined the degree to which the relation between adaptive abilities (socialization, communication, and daily living skills) and JA was maintained after taking into account the potentially mediating role of verbal and nonverbal cognitive ability. Results revealed that VIQ fully mediated the relation between JA and adaptive functioning, whereas the relation between these adaptive variables and JA was only partially mediated by NVIQ. Moderation analyses were also conducted to examine how verbal and non-verbal cognitive ability and gender impacted the relation between JA and adaptive functioning. In line with research showing a relation between language and JA, this indicates that while JA is significantly related to functional outcomes, this appears to be mediated specifically through a verbal cognitive pathway. PMID:28168003

  3. Jasmonoyl-l-Isoleucine Coordinates Metabolic Networks Required for Anthesis and Floral Attractant Emission in Wild Tobacco (Nicotiana attenuata)[C][W][OPEN

    PubMed Central

    Stitz, Michael; Hartl, Markus; Baldwin, Ian T.; Gaquerel, Emmanuel

    2014-01-01

    Jasmonic acid and its derivatives (jasmonates [JAs]) play central roles in floral development and maturation. The binding of jasmonoyl-l-isoleucine (JA-Ile) to the F-box of CORONATINE INSENSITIVE1 (COI1) is required for many JA-dependent physiological responses, but its role in anthesis and pollinator attraction traits remains largely unexplored. Here, we used the wild tobacco Nicotiana attenuata, which develops sympetalous flowers with complex pollination biology, to examine the coordinating function of JA homeostasis in the distinct metabolic processes that underlie flower maturation, opening, and advertisement to pollinators. From combined transcriptomic, targeted metabolic, and allometric analyses of transgenic N. attenuata plants for which signaling deficiencies were complemented with methyl jasmonate, JA-Ile, and its functional homolog, coronatine (COR), we demonstrate that (1) JA-Ile/COR-based signaling regulates corolla limb opening and a JA-negative feedback loop; (2) production of floral volatiles (night emissions of benzylacetone) and nectar requires JA-Ile/COR perception through COI1; and (3) limb expansion involves JA-Ile-induced changes in limb fresh mass and carbohydrate metabolism. These findings demonstrate a master regulatory function of the JA-Ile/COI1 duet for the main function of a sympetalous corolla, that of advertising for and rewarding pollinator services. Flower opening, by contrast, requires JA-Ile signaling-dependent changes in primary metabolism, which are not compromised in the COI1-silenced RNA interference line used in this study. PMID:25326292

  4. Insect-Induced Conifer Defense. White Pine Weevil and Methyl Jasmonate Induce Traumatic Resinosis, de Novo Formed Volatile Emissions, and Accumulation of Terpenoid Synthase and Putative Octadecanoid Pathway Transcripts in Sitka Spruce1[w

    PubMed Central

    Miller, Barbara; Madilao, Lufiani L.; Ralph, Steven; Bohlmann, Jörg

    2005-01-01

    Stem-boring insects and methyl jasmonate (MeJA) are thought to induce similar complex chemical and anatomical defenses in conifers. To compare insect- and MeJA-induced terpenoid responses, we analyzed traumatic oleoresin mixtures, emissions of terpenoid volatiles, and expression of terpenoid synthase (TPS) genes in Sitka spruce (Picea sitchensis) following attack by white pine weevils (Pissodes strobi) or application of MeJA. Both insects and MeJA caused traumatic resin accumulation in stems, with more accumulation induced by the weevils. Weevil-induced terpenoid emission profiles were also more complex than emissions induced by MeJA. Weevil feeding caused a rapid release of a blend of monoterpene olefins, presumably by passive evaporation of resin compounds from stem feeding sites. These compounds were not found in MeJA-induced emissions. Both weevils and MeJA caused delayed, diurnal emissions of (−)-linalool, indicating induced de novo biosynthesis of this compound. TPS transcripts strongly increased in stems upon insect attack or MeJA treatment. Time courses and intensity of induced TPS transcripts were different for monoterpene synthases, sesquiterpene synthases, and diterpene synthases. Increased levels of weevil- and MeJA-induced TPS transcripts accompanied major changes in terpenoid accumulation in stems. Induced TPS expression profiles in needles were less complex than those in stems and matched induced de novo emissions of (−)-linalool. Overall, weevils and MeJA induced similar, but not identical, terpenoid defense responses in Sitka spruce. Findings of insect- and MeJA-induced accumulation of allene oxide synthase-like and allene oxide cyclase-like transcripts are discussed in the context of traumatic resinosis and induced volatile emissions in this gymnosperm system. PMID:15618433

  5. Methyl jasmonate as an allelopathic agent: sagebrush inhibits germination of a neighboring tobacco, Nicotiana attenuata.

    PubMed

    Preston, Catherine A; Betts, Hazel; Baldwi, Ian T

    2002-11-01

    Artemisia tridentata ssp. tridentata is the dominant and defining shrub in the Great Basin Desert, with well-documented allelopathic tendencies that have generally been ascribed to its most abundantly released secondary metabolites. However, as a minor component, sagebrush releases a highly biologically active substance, methyljasmonate (MeJA), which is known to function as both a germination inhibitor and promoter in laboratory studies. Nicotiana attenuata is a tobacco species native to the Great Basin Desert and grows in newly burned juniper-sagebrush habitats for 2-3 yr following a fire. With a combination of field and laboratory studies, we examined the role of MeJA release from sagebrush by both air and water transport in inhibiting N. attenuata seed germination. We demonstrated that sagebrush interacts allelopathically with the seed bank of N. attenuata through its release of MeJA. In the field, seeds buried 0-40 cm from sagebrush plants for 4 months in net bags had significantly reduced germination compared to seeds buried similarly but protected in plastic bags. Moreover, germination on soils collected from underneath sagebrush plants was reduced by 60% compared to seeds placed on soils collected between sagebrush plants or outside of the sagebrush population. Exposure to A. tridentata seeds and seedlings did not affect N. attenuata germination, suggesting that established sagebrush plants only influence the tobacco's seed bank. In the laboratory, exposure of seeds to sagebrush emissions resulted in germination delays of up to 6 d. Exposure to volatile and aqueous MeJA also inhibited germination of N. attenuata seeds at quantities that are released naturally by sagebrush: 3.5 microg/hr and 1.12 microg/seed cup (56 ng/seed), respectively. A. tridentata seeds were significantly more resistant to MeJA, being inhibited at 336 microg MeJA (16.8 microg/seed), 300 times greater than the level of aqueous MeJA required to inhibit N. attenuata seeds. MeJA inhibited N

  6. 17 CFR Appendix 1 to Part 45 - Tables of Minimum Primary Economic Terms Data

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 2 2014-04-01 2014-04-01 false Tables of Minimum Primary Economic Terms Data 1 Appendix 1 to Part 45 Commodity and Securities Exchanges COMMODITY FUTURES TRADING... 45—Tables of Minimum Primary Economic Terms Data ER13JA12.003 ER13JA12.004 ER13JA12.005 ER13JA12.006...

  7. 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

  8. 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

  9. 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

  10. 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

  11. Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

    PubMed

    Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

    2013-05-01

    Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

  12. TIME FOR COFFEE Represses Accumulation of the MYC2 Transcription Factor to Provide Time-of-Day Regulation of Jasmonate Signaling in Arabidopsis[C][W][OA

    PubMed Central

    Shin, Jieun; Heidrich, Katharina; Sanchez-Villarreal, Alfredo; Parker, Jane E.; Davis, Seth J.

    2012-01-01

    Plants are confronted with predictable daily biotic and abiotic stresses that result from the day–night cycle. The circadian clock provides an anticipation mechanism to respond to these daily stress signals to increase fitness. Jasmonate (JA) is a phytohormone that mediates various growth and stress responses. Here, we found that the circadian-clock component TIME FOR COFFEE (TIC) acts as a negative factor in the JA-signaling pathway. We showed that the tic mutant is hypersensitive to growth-repressive effects of JA and displays altered JA-regulated gene expression. TIC was found to interact with MYC2, a key transcription factor of JA signaling. From this, we discovered that the circadian clock rhythmically regulates JA signaling. TIC is a key determinant in this circadian-gated process, and as a result, the tic mutant is defective in rhythmic JA responses to pathogen infection. TIC acts here by inhibiting MYC2 protein accumulation and by controlling the transcriptional repression of CORONATINE INSENSITIVE1 in an evening-phase–specific manner. Taken together, we propose that TIC acts as an output component of the circadian oscillator to influence JA signaling directly. PMID:22693280

  13. Involvement of nitric oxide in the jasmonate-dependent basal defense against root-knot nematode in tomato plants.

    PubMed

    Zhou, Jie; Jia, Feifei; Shao, Shujun; Zhang, Huan; Li, Guiping; Xia, Xiaojian; Zhou, Yanhong; Yu, Jingquan; Shi, Kai

    2015-01-01

    Jasmonic acid (JA) and nitric oxide (NO) are well-characterized signaling molecules in plant defense responses. However, their roles in plant defense against root-knot nematode (RKN, Meloidogyne incognita) infection are largely unknown. In this study, we found that the transcript levels of the JA- and NO-related biosynthetic and signaling component genes were induced after RKN infection. Application of exogenous JA and sodium nitroprusside (SNP; a NO donor) significantly decreased the number of egg masses in tomato roots after RKN infection and partially alleviated RKN-induced decreases in plant fresh weight and net photosynthetic rate. These molecules also alleviated RKN-induced increases in root electrolyte leakage and membrane peroxidation. Importantly, NO scavenger partially inhibited JA-induced RKN defense. The pharmacological inhibition of JA biosynthesis significantly increased the plants' susceptibility to RKNs, which was effectively alleviated by SNP application, showing that NO may be involved in the JA-dependent RKN defense pathway. Furthermore, both JA and SNP induced increases in protease inhibitor 2 (PI2) gene expression after RKN infestation. Silencing of PI2 compromised both JA- and SNP-induced RKN defense responses, suggesting that the PI2 gene mediates JA- and NO-induced defense against RKNs. This work will be important for deepening the understanding of the mechanisms involved in basal defense against RKN attack in plants.

  14. Contrasting nutrient-disease relationships: Potassium gradients in barley leaves have opposite effects on two fungal pathogens with different sensitivities to jasmonic acid.

    PubMed

    Davis, Jayne L; Armengaud, Patrick; Larson, Tony R; Graham, Ian A; White, Philip J; Newton, Adrian C; Amtmann, Anna

    2018-05-31

    Understanding the interactions between mineral nutrition and disease is essential for crop management. Our previous studies with Arabidopsis thaliana demonstrated that potassium (K) deprivation induced the biosynthesis of jasmonate (JA) and increased the plant's resistance to herbivorous insects. Here we addressed the question how tissue K affects the development of fungal pathogens and whether sensitivity of the pathogens to JA could play a role for the K-disease relationship in barley (Hordeum vulgare cv. Optic). We report that K-deprived barley plants showed increased leaf concentrations of JA and other oxylipins. Furthermore, a natural tip-to base K-concentrations gradient within leaves of K-sufficient plants was quantitatively mirrored by the transcript levels of JA-responsive genes. The local leaf tissue K concentrations affected the development of two economically important fungi in opposite ways, showing a positive correlation with powdery mildew (Blumeria graminis) and a negative correlation with leaf scald (Rhynchosporium commune) disease symptoms. B. graminis induced a JA-response in the plant and was sensitive to methyl-JA treatment while R. commune initiated no JA-response and was JA-insensitive. Our study challenges the view that high K generally improves plant health and suggests that JA-sensitivity of pathogens could be an important factor determining the exact K-disease relationship. This article is protected by copyright. All rights reserved.

  15. MYC2 Orchestrates a Hierarchical Transcriptional Cascade That Regulates Jasmonate-Mediated Plant Immunity in Tomato.

    PubMed

    Du, Minmin; Zhao, Jiuhai; Tzeng, David T W; Liu, Yuanyuan; Deng, Lei; Yang, Tianxia; Zhai, Qingzhe; Wu, Fangming; Huang, Zhuo; Zhou, Ming; Wang, Qiaomei; Chen, Qian; Zhong, Silin; Li, Chang-Bao; Li, Chuanyou

    2017-08-01

    The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato ( Solanum lycopersicum ) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA-responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA-induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA-mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea , MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes. © 2017 American Society of Plant Biologists. All rights reserved.

  16. MYC2 Orchestrates a Hierarchical Transcriptional Cascade That Regulates Jasmonate-Mediated Plant Immunity in Tomato[OPEN

    PubMed Central

    Liu, Yuanyuan; Deng, Lei; Wu, Fangming; Huang, Zhuo; Zhou, Ming; Chen, Qian; Zhong, Silin

    2017-01-01

    The hormone jasmonate (JA), which functions in plant immunity, regulates resistance to pathogen infection and insect attack through triggering genome-wide transcriptional reprogramming in plants. We show that the basic helix-loop-helix transcription factor (TF) MYC2 in tomato (Solanum lycopersicum) acts downstream of the JA receptor to orchestrate JA-mediated activation of both the wounding and pathogen responses. Using chromatin immunoprecipitation sequencing (ChIP-seq) coupled with RNA sequencing (RNA-seq) assays, we identified 655 MYC2-targeted JA-responsive genes. These genes are highly enriched in Gene Ontology categories related to TFs and the early response to JA, indicating that MYC2 functions at a high hierarchical level to regulate JA-mediated gene transcription. We also identified a group of MYC2-targeted TFs (MTFs) that may directly regulate the JA-induced transcription of late defense genes. Our findings suggest that MYC2 and its downstream MTFs form a hierarchical transcriptional cascade during JA-mediated plant immunity that initiates and amplifies transcriptional output. As proof of concept, we showed that during plant resistance to the necrotrophic pathogen Botrytis cinerea, MYC2 and the MTF JA2-Like form a transcription module that preferentially regulates wounding-responsive genes, whereas MYC2 and the MTF ETHYLENE RESPONSE FACTOR.C3 form a transcription module that preferentially regulates pathogen-responsive genes. PMID:28733419

  17. Involvement of nitric oxide in the jasmonate-dependent basal defense against root-knot nematode in tomato plants

    PubMed Central

    Zhou, Jie; Jia, Feifei; Shao, Shujun; Zhang, Huan; Li, Guiping; Xia, Xiaojian; Zhou, Yanhong; Yu, Jingquan; Shi, Kai

    2015-01-01

    Jasmonic acid (JA) and nitric oxide (NO) are well-characterized signaling molecules in plant defense responses. However, their roles in plant defense against root-knot nematode (RKN, Meloidogyne incognita) infection are largely unknown. In this study, we found that the transcript levels of the JA- and NO-related biosynthetic and signaling component genes were induced after RKN infection. Application of exogenous JA and sodium nitroprusside (SNP; a NO donor) significantly decreased the number of egg masses in tomato roots after RKN infection and partially alleviated RKN-induced decreases in plant fresh weight and net photosynthetic rate. These molecules also alleviated RKN-induced increases in root electrolyte leakage and membrane peroxidation. Importantly, NO scavenger partially inhibited JA-induced RKN defense. The pharmacological inhibition of JA biosynthesis significantly increased the plants’ susceptibility to RKNs, which was effectively alleviated by SNP application, showing that NO may be involved in the JA-dependent RKN defense pathway. Furthermore, both JA and SNP induced increases in protease inhibitor 2 (PI2) gene expression after RKN infestation. Silencing of PI2 compromised both JA- and SNP-induced RKN defense responses, suggesting that the PI2 gene mediates JA- and NO-induced defense against RKNs. This work will be important for deepening the understanding of the mechanisms involved in basal defense against RKN attack in plants. PMID:25914698

  18. The Calcium-Dependent Protein Kinase CPK28 Regulates Development by Inducing Growth Phase-Specific, Spatially Restricted Alterations in Jasmonic Acid Levels Independent of Defense Responses in Arabidopsis[OPEN

    PubMed Central

    Matschi, Susanne; Hake, Katharina; Herde, Marco; Hause, Bettina; Romeis, Tina

    2015-01-01

    Phytohormones play an important role in development and stress adaptations in plants, and several interacting hormonal pathways have been suggested to accomplish fine-tuning of stress responses at the expense of growth. This work describes the role played by the CALCIUM-DEPENDENT PROTEIN KINASE CPK28 in balancing phytohormone-mediated development in Arabidopsis thaliana, specifically during generative growth. cpk28 mutants exhibit growth reduction solely as adult plants, coinciding with altered balance of the phytohormones jasmonic acid (JA) and gibberellic acid (GA). JA-dependent gene expression and the levels of several JA metabolites were elevated in a growth phase-dependent manner in cpk28, and accumulation of JA metabolites was confined locally to the central rosette tissue. No elevated resistance toward herbivores or necrotrophic pathogens was detected for cpk28 plants, either on the whole-plant level or specifically within the tissue displaying elevated JA levels. Abolishment of JA biosynthesis or JA signaling led to a full reversion of the cpk28 growth phenotype, while modification of GA signaling did not. Our data identify CPK28 as a growth phase-dependent key negative regulator of distinct processes: While in seedlings, CPK28 regulates reactive oxygen species-mediated defense signaling; in adult plants, CPK28 confers developmental processes by the tissue-specific balance of JA and GA without affecting JA-mediated defense responses. PMID:25736059

  19. Characterization of a JAZ7 activation-tagged Arabidopsis mutant with increased susceptibility to the fungal pathogen Fusarium oxysporum

    PubMed Central

    Thatcher, Louise F.; Cevik, Volkan; Grant, Murray; Zhai, Bing; Jones, Jonathan D.G.; Manners, John M.; Kazan, Kemal

    2016-01-01

    In Arabidopsis, jasmonate (JA)-signaling plays a key role in mediating Fusarium oxysporum disease outcome. However, the roles of JASMONATE ZIM-domain (JAZ) proteins that repress JA-signaling have not been characterized in host resistance or susceptibility to this pathogen. Here, we found most JAZ genes are induced following F. oxysporum challenge, and screening T-DNA insertion lines in Arabidopsis JAZ family members identified a highly disease-susceptible JAZ7 mutant (jaz7-1D). This mutant exhibited constitutive JAZ7 expression and conferred increased JA-sensitivity, suggesting activation of JA-signaling. Unlike jaz7 loss-of-function alleles, jaz7-1D also had enhanced JA-responsive gene expression, altered development and increased susceptibility to the bacterial pathogen Pst DC3000 that also disrupts host JA-responses. We also demonstrate that JAZ7 interacts with transcription factors functioning as activators (MYC3, MYC4) or repressors (JAM1) of JA-signaling and contains a functional EAR repressor motif mediating transcriptional repression via the co-repressor TOPLESS (TPL). We propose through direct TPL recruitment, in wild-type plants JAZ7 functions as a repressor within the JA-response network and that in jaz7-1D plants, misregulated ectopic JAZ7 expression hyper-activates JA-signaling in part by disturbing finely-tuned COI1-JAZ-TPL-TF complexes. PMID:26896849

  20. Multimorbidity care model: Recommendations from the consensus meeting of the Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS).

    PubMed

    Palmer, Katie; Marengoni, Alessandra; Forjaz, Maria João; Jureviciene, Elena; Laatikainen, Tiina; Mammarella, Federica; Muth, Christiane; Navickas, Rokas; Prados-Torres, Alexandra; Rijken, Mieke; Rothe, Ulrike; Souchet, Laurène; Valderas, Jose; Vontetsianos, Theodore; Zaletel, Jelka; Onder, Graziano

    2018-01-01

    Patients with multimorbidity have complex health needs but, due to the current traditional disease-oriented approach, they face a highly fragmented form of care that leads to inefficient, ineffective, and possibly harmful clinical interventions. There is limited evidence on available integrated and multidimensional care pathways for multimorbid patients. An expert consensus meeting was held to develop a framework for care of multimorbid patients that can be applied across Europe, within a project funded by the European Union; the Joint Action on Chronic Diseases and Promoting Healthy Ageing across the Life Cycle (JA-CHRODIS). The experts included a diverse group representing care providers and patients, and included general practitioners, family medicine physicians, neurologists, geriatricians, internists, cardiologists, endocrinologists, diabetologists, epidemiologists, psychologists, and representatives from patient organizations. Sixteen components across five domains were identified (Delivery of Care; Decision Support; Self Management Support; Information Systems and Technology; and Social and Community Resources). The description and aim of each component are described in these guidelines, along with a summary of key characteristics and relevance to multimorbid patients. Due to the lack of evidence-based recommendations specific to multimorbid patients, this care model needs to be assessed and validated in different European settings to examine specifically how multimorbid patients will benefit from this care model, and whether certain components have more importance than others. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. The endoscopic endonasal approach for the treatment of juvenile angiofibromas.

    PubMed

    Llorente, José Luis; López, Fernando

    2018-05-12

    Juvenile angiofibroma (JA) is a benign tumour, for which the treatment of choice is surgery. It may be associated with significant morbidity because of its anatomical location and its locally destructive growth pattern. Severe haemorrhage constitutes a high risk in JA and its surgical management can be complex. The management of JA remains a challenge. The objective of this study was to review a series of patients with JA treated via the endonasal/endoscopic approach. Medical records of patients operated for JA were reviewed. tumour stage, intraoperative blood loss, complications and persistence/recurrence rates. A total of 30 male patients and one female were included. The mean age was 17 years. Using the Radkowski classification, one JA was classified as stage I, 5 stage IIA, 9 stage IIB, 4 stage IIC, 10 stage IIIA and 2 stage IIIB. Thirty-nine percent of the JA was classified as advanced stage JA (IIIA and IIIB). The mean blood loss was 1.156mL Except in one case, no significant complications were observed. Tumour persistence/recurrence was observed in 2 JA (6%), at the end of the follow-up. Mean postoperative follow-up time was 86 months. This retrospective study supports the notion that endonasal endoscopic approaches for a JA are a feasible option associated with good long-term results. Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Both the Jasmonic Acid and the Salicylic Acid Pathways Contribute to Resistance to the Biotrophic Clubroot Agent Plasmodiophora brassicae in Arabidopsis.

    PubMed

    Lemarié, Séverine; Robert-Seilaniantz, Alexandre; Lariagon, Christine; Lemoine, Jocelyne; Marnet, Nathalie; Jubault, Mélanie; Manzanares-Dauleux, Maria J; Gravot, Antoine

    2015-11-01

    The role of salicylic acid (SA) and jasmonic acid (JA) signaling in resistance to root pathogens has been poorly documented. We assessed the contribution of SA and JA to basal and partial resistance of Arabidopsis to the biotrophic clubroot agent Plasmodiophora brassicae. SA and JA levels as well as the expression of the SA-responsive genes PR2 and PR5 and the JA-responsive genes ARGAH2 and THI2.1 were monitored in infected roots of the accessions Col-0 (susceptible) and Bur-0 (partially resistant). SA signaling was activated in Bur-0 but not in Col-0. The JA pathway was weakly activated in Bur-0 but was strongly induced in Col-0. The contribution of both pathways to clubroot resistance was then assessed using exogenous phytohormone application and mutants affected in SA or JA signaling. Exogenous SA treatment decreased clubroot symptoms in the two Arabidopsis accessions, whereas JA treatment reduced clubroot symptoms only in Col-0. The cpr5-2 mutant, in which SA responses are constitutively induced, was more resistant to clubroot than the corresponding wild type, and the JA signaling-deficient mutant jar1 was more susceptible. Finally, we showed that the JA-mediated induction of NATA1 drove N(δ)-acetylornithine biosynthesis in infected Col-0 roots. The 35S::NATA1 and nata1 lines displayed reduced or enhanced clubroot symptoms, respectively, thus suggesting that in Col-0 this pathway was involved in the JA-mediated basal clubroot resistance. Overall, our data support the idea that, depending on the Arabidopsis accession, both SA and JA signaling can play a role in partial inhibition of clubroot development in compatible interactions with P. brassicae. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Multilayered Organization of Jasmonate Signalling in the Regulation of Root Growth

    PubMed Central

    Gasperini, Debora; Chételat, Aurore; Acosta, Ivan F.; Goossens, Jonas; Pauwels, Laurens; Goossens, Alain; Dreos, René; Alfonso, Esteban; Farmer, Edward E.

    2015-01-01

    Physical damage can strongly affect plant growth, reducing the biomass of developing organs situated at a distance from wounds. These effects, previously studied in leaves, require the activation of jasmonate (JA) signalling. Using a novel assay involving repetitive cotyledon wounding in Arabidopsis seedlings, we uncovered a function of JA in suppressing cell division and elongation in roots. Regulatory JA signalling components were then manipulated to delineate their relative impacts on root growth. The new transcription factor mutant myc2-322B was isolated. In vitro transcription assays and whole-plant approaches revealed that myc2-322B is a dosage-dependent gain-of-function mutant that can amplify JA growth responses. Moreover, myc2-322B displayed extreme hypersensitivity to JA that totally suppressed root elongation. The mutation weakly reduced root growth in undamaged plants but, when the upstream negative regulator NINJA was genetically removed, myc2-322B powerfully repressed root growth through its effects on cell division and cell elongation. Furthermore, in a JA-deficient mutant background, ninja1 myc2-322B still repressed root elongation, indicating that it is possible to generate JA-responses in the absence of JA. We show that NINJA forms a broadly expressed regulatory layer that is required to inhibit JA signalling in the apex of roots grown under basal conditions. By contrast, MYC2, MYC3 and MYC4 displayed cell layer-specific localisations and MYC3 and MYC4 were expressed in mutually exclusive regions. In nature, growing roots are likely subjected to constant mechanical stress during soil penetration that could lead to JA production and subsequent detrimental effects on growth. Our data reveal how distinct negative regulatory layers, including both NINJA-dependent and -independent mechanisms, restrain JA responses to allow normal root growth. Mechanistic insights from this work underline the importance of mapping JA signalling components to specific

  4. Safety and quality parameters of ready-to-cook minced pork meat products supplemented with Helianthus tuberosus L. tubers fermented by BLIS producing lactic acid bacteria.

    PubMed

    Stimbirys, Arturas; Bartkiene, Elena; Siugzdaite, Jurate; Augeniene, Dovile; Vidmantiene, Daiva; Juodeikiene, Grazina; Maruska, Audrius; Stankevicius, Mantas; Cizeikiene, Dalia

    2015-07-01

    The aim of this study was to evaluate the influence of additives of Jerusalem artichoke (JA), fermented with P. acidilactici KTU05-7, P. pentosaceus KTU05-9, L. sakei KTU05-6, on the quality and safety parameters of ready - to cook - minced pork (RCMP). Fermented JA additives reduced pH of the meat products and decreased water holding capacity (WHC) from 2.01 till 2.93 %. Concentrations of biogenic amines in RCMP with additives of the lactic acid bacteria (LAB) - fermented JA were significantly lower comparing with control sample. The number of pathogenic bacteria in artificially contaminated meat samples was significantly reduced in case of LAB-fermented JA additives. The highest antimicrobial activity was obtained using P. acidilactici fermented JA additives. The amounts of microbial pathogens E. coli and Ent. faecalis, S. aureus and Streptococcus spp. were determined 3.41, 3.38, 3,96 and 4.74 log CFU/g correspondingly, whereas without LAB-fermented JA additives were 8.94, 7.75, 8.82 and 8.58 log CFU/g, correspondingly. A possibility to improve sensory properties (flavor) of RCMP using LAB fermented JA additives was investigated. The composition of volatile compounds of RCMP without additive and with LAB-fermented JA additives was analyzed using gas chromatography-mass spectrometry (GC-MS). The results of sensory evaluation of meat products supplemented with fermented JA additives revealed specific odor, which is pleasant and acceptable for consumers might be explainable that LAB-fermented JA additives have shown considerable differences mainly due to the accumulation of volatiles such as toluene, ethylbenzene, decane, undecane, 2 methyl undecane. N-morpholinomethyl-isopropyl-sulfide, 6-undecilamine and N,N-dimethyl-1-pentadecanamine were not determined in RCMP with LAB-fermented JA additives. The results obtained show, that P. acidilactici fermented JA 5 % additive is most suitable for the RCMP processing in order to prevent microbiological spoilage, increase

  5. Japanese apricot improves symptoms of gastrointestinal dysmotility associated with gastroesophageal reflux disease.

    PubMed

    Maekita, Takao; Kato, Jun; Enomoto, Shotaro; Yoshida, Takeichi; Utsunomiya, Hirotoshi; Hayashi, Hideyuki; Hanamitsu, Toshiko; Inoue, Izumi; Maeda, Yoshimasa; Moribata, Kosaku; Muraki, Yosuke; Shingaki, Naoki; Deguchi, Hisanobu; Ueda, Kazuki; Iguchi, Mikitaka; Tamai, Hideyuki; Ichinose, Masao

    2015-07-14

    To investigate the effects of Japanese apricot (JA) consumption on gastroesophageal reflux disease (GERD)-related symptoms. Participants included individuals living in Minabe-cho, a well-known JA-growing region, who received specific medical check-ups by the local community health service in 2010. GERD-related symptoms were examined in 1303 Japanese individuals using a validated questionnaire, the Frequency Scale for Symptoms of GERD (FSSG), which consists of 7 questions associated with acid reflux symptoms and 5 questions asking about gastrointestinal dysmotility symptoms. Each question was answered using a 4-point scale, with higher scores indicating more severe GERD-related symptoms. Subjects were divided into two groups according to their intake of dried and pickled JA: daily intake (≥ 1 JA daily) (392 subjects) and none or occasional intake (< 1 JA daily) (911 subjects). FSSG scores were compared between subjects who consumed JA daily and those who did not. Next, subjects were stratified by age, gender and Helicobacter pylori (H. pylori) status for subanalyses. Those who ate JA daily were significantly older than those who did not (60.6 ± 10.5 years vs 56.0 ± 11.0 years, P < 0.001). Total FSSG scores were significantly lower in subjects with daily JA intake than in those with none or only occasional intake (2.13 ± 3.14 vs 2.70 ± 3.82, P = 0.005). In particular, subjects who consumed JA daily showed significantly improved FSSG dysmotility scores compared with subjects who did not (1.05 ± 1.58 vs 1.46 ± 2.11, P < 0.001). In contrast, the FSSG reflux score did not differ between subjects with and without daily intake of JA (1.08 ± 1.90 vs 1.24 ± 2.11, P = 0.177). Subanalysis indicated that improvement in dysmotility by JA intake was specifically observed in non-elderly (1.24 ± 1.68 vs 1.62 ± 2.22, P = 0.005) and H. pylori-negative subjects (0.99 ± 1.58 vs 1.57 ± 2.06, P < 0.001). GERD patients (total FSSG score ≥ 8) were less frequently observed

  6. Measurement of polar stratospheric NO2 from the 23rd and 24th Japanese Antarctic Research Expedition (JARE) balloon experiments

    NASA Technical Reports Server (NTRS)

    Shibasaki, K.; Iwagami, N.; Ogawa, T.

    1985-01-01

    As a part of the Japanese activities of MAP in the Antarctica, balloon-borne measurements of the stratospheric NO2 profile were planned and carried out by the JARE 23rd and 24th wintering parties. Few results have been reported so far as the stratospheric NO2 profile at high latitude. There were no reported balloon measurements carried out in the Southern Hemisphere. Profiles are presented for the first balloon-borne measurement of the stratospheric NO2 in the Antarctica. Three balloons named JA21, JA25 and JA26 were launched from Syowa Station (69 deg S, 35.6 deg E) using 5000 cu. cm plastic balloons. JA21 balloon was launched on November 24, 1982, and JA25 and JA26 balloons on November 12 and 20, 1983, respectively.

  7. 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…

  8. 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.

  9. 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

  10. Jasmonic Acid Enhances Al-Induced Root Growth Inhibition1[OPEN

    PubMed Central

    Yang, Zhong-Bao; Ma, Yanqi

    2017-01-01

    Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. PMID:27932419

  11. Disarming the jasmonate-dependent plant defense makes nonhost Arabidopsis plants accessible to the American serpentine leafminer.

    PubMed

    Abe, Hiroshi; Tateishi, Ken; Seo, Shigemi; Kugimiya, Soichi; Hirai, Masami Yokota; Sawada, Yuji; Murata, Yoshiyuki; Yara, Kaori; Shimoda, Takeshi; Kobayashi, Masatomo

    2013-11-01

    Here, we analyzed the interaction between Arabidopsis (Arabidopsis thaliana) and the American serpentine leafminer (Liriomyza trifolii), an important and intractable herbivore of many cultivated plants. We examined the role of the immunity-related plant hormone jasmonate (JA) in the plant response and resistance to leafminer feeding to determine whether JA affects host suitability for leafminers. The expression of marker genes for the JA-dependent plant defense was induced by leafminer feeding on Arabidopsis wild-type plants. Analyses of JA-insensitive coi1-1 mutants suggested the importance of JA in the plant response to leafminer feeding. The JA content of wild-type plants significantly increased after leafminer feeding. Moreover, coi1-1 mutants showed lower feeding resistance against leafminer attack than did wild-type plants. The number of feeding scars caused by inoculated adult leafminers in JA-insensitive coi1-1 mutants was higher than that in wild-type plants. In addition, adults of the following generation appeared only from coi1-1 mutants and not from wild-type plants, suggesting that the loss of the JA-dependent plant defense converted nonhost plants to accessible host plants. Interestingly, the glucosinolate-myrosinase defense system may play at most a minor role in this conversion, indicating that this major antiherbivore defense of Brassica species plants probably does not have a major function in plant resistance to leafminer. Application of JA to wild-type plants before leafminer feeding enhanced feeding resistance in Chinese cabbage (Brassica rapa), tomato (Solanum lycopersicum), and garland chrysanthemum (Chrysanthemum coronarium). Our results indicate that JA plays an important role in the plant response and resistance to leafminers and, in so doing, affects host plant suitability for leafminers.

  12. Exogenous polyamines elicit herbivore-induced volatiles in lima bean leaves: involvement of calcium, H2O2 and Jasmonic acid.

    PubMed

    Ozawa, Rika; Bertea, Cinzia M; Foti, Maria; Narayana, Ravishankar; Arimura, Gen-Ichiro; Muroi, Atsushi; Horiuchi, Jun-Ichiro; Nishioka, Takaaki; Maffei, Massimo E; Takabayashi, Junji

    2009-12-01

    We investigated the role of polyamines (PAs) in lima bean (Phaseolus lunatus) leaves on the production of herbivorous mite (Tetranychus urticae)-induced plant volatiles that attract carnivorous natural enemies of the herbivores. To do this, we focused on the effects of the exogenous PAs [cadaverine, putrescine, spermidine and spermine (Spm)] on the production of volatiles, H(2)O(2) and jasmonic acid (JA) and the levels of defensive genes, cytosolic calcium and reactive oxygen species (ROS). Among the tested PAs, Spm was the most active in inducing the production of volatile terpenoids known to be induced by T. urticae. An increase in JA levels was also found after Spm treatment, indicating that Spm induces the biosynthesis of JA, which has been shown elsewhere to regulate the production of some volatile terpenoids. Further, treatment with JA and Spm together resulted in greater volatile emission than that with JA alone. In a Y-tube olfactometer, leaves treated with Spm + JA attracted more predatory mites (Phytoseiulus persimilis) than those treated with JA alone. After treatment with Spm + JA, no effects were found on the enzyme activity of polyamine oxidase and copper amine oxidase. However, induction of calcium influx and ROS production, and increased enzyme activities and gene expression for NADPH oxidase complex, superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and glutathione peroxidase were found after treatment with Spm + JA. These results indicate that Spm plays an important role in the production of T. urticae-induced lima bean leaf volatiles.

  13. Transcriptome-wide analysis of jasmonate-treated BY-2 cells reveals new transcriptional regulators associated with alkaloid formation in tobacco.

    PubMed

    Yang, Yuping; Yan, Pengcheng; Yi, Che; Li, Wenzheng; Chai, Yuhui; Fei, Lingling; Gao, Ping; Zhao, Heping; Wang, Yingdian; Timko, Michael P; Wang, Bingwu; Han, Shengcheng

    2017-08-01

    Jasmonates (JAs) are well-known regulators of stress, defence, and secondary metabolism in plants, with JA perception triggering extensive transcriptional reprogramming, including both activation and/or repression of entire metabolic pathways. We performed RNA sequencing based transcriptomic profiling of tobacco BY-2 cells before and after treatment with methyl jasmonate (MeJA) to identify novel transcriptional regulators associated with alkaloid formation. A total of 107,140 unigenes were obtained through de novo assembly, and at least 33,213 transcripts (31%) encode proteins, in which 3419 transcription factors (TFs) were identified, representing 72 gene families, as well as 840 transcriptional regulators (TRs) distributed among 19 gene families. After MeJA treatment BY-2 cells, 7260 differentially expressed transcripts were characterised, which include 4443 MeJA-upregulated and 2817 MeJA-downregulated genes. Of these, 227 TFs/TRs in 36 families were specifically upregulated, and 102 TFs/TRs in 38 families were downregulated in MeJA-treated BY-2 cells. We further showed that the expression of 12 ethylene response factors and four basic helix-loop-helix factors increased at the transcriptional level after MeJA treatment in BY-2 cells and displayed specific expression patterns in nic mutants with or without MeJA treatments. Our data provide a catalogue of transcripts of tobacco BY-2 cells and benefit future study of JA-modulated regulation of secondary metabolism in tobacco. Copyright © 2017 Elsevier GmbH. All rights reserved.

  14. Prebiotic potential of Jerusalem artichoke (Helianthus tuberosus L.) in Wistar rats: effects of levels of supplementation on hindgut fermentation, intestinal morphology, blood metabolites and immune response.

    PubMed

    Samal, Lipismita; Chaturvedi, Vishwa Bandhu; Saikumar, Guttula; Somvanshi, Ramesh; Pattanaik, Ashok Kumar

    2015-06-01

    Many studies have been conducted using purified prebiotics such as inulin or fructooligosaccharides (FOS) as nutraceuticals, but there is very little information available on the prebiotic potential of raw products rich in inulin and FOS, such as Jerusalem artichoke (JA; Helianthus tuberosus L.). The present experiment aimed to evaluate the prebiotic effects of JA tubers in rats. Seventy-two Wistar weanling rats divided into four groups were fed for 12 weeks on a basal diet fortified with pulverized JA tubers at 0 (control), 20, 40 and 60 g kg(-1) levels. Enhanced cell-mediated immunity in terms of skin indurations (P = 0.082) and CD4+ T-lymphocyte population (P = 0.002) was observed in the JA-supplemented groups compared with the control group. Blood haemoglobin (P = 0.017), glucose (P = 0.001), urea (P = 0.004) and calcium (P = 0.048) varied favourably upon inclusion of JA. An increasing trend (P = 0.059) in the length of large intestine was apparent in the JA-fed groups. The tissue mass of caecum (P = 0.069) and colon (P = 0.003) was increased in the JA-supplemented groups, accompanied by higher (P = 0.007) caecal crypt depth. The pH and ammonia concentrations of intestinal digesta decreased and those of lactate and total volatile fatty acids increased in the JA-fed groups. The results suggest that JA had beneficial effects on immunity, blood metabolites, intestinal morphometry and hindgut fermentation of rats. © 2014 Society of Chemical Industry.

  15. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    PubMed Central

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  16. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59.

    PubMed

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C M; Pieterse, Corné M J

    2013-02-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCF(COI1), which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59.

  17. A role for jasmonates in the release of dormancy by cold stratification in wheat

    PubMed Central

    Xu, Qian; Truong, Thy T.; Barrero, Jose M.; Jacobsen, John V.; Hocart, Charles H.; Gubler, Frank

    2016-01-01

    Hydration at low temperatures, commonly referred to as cold stratification, is widely used for releasing dormancy and triggering germination in a wide range of species including wheat. However, the molecular mechanism that underlies its effect on germination has largely remained unknown. Our previous studies showed that methyl-jasmonate, a derivative of jasmonic acid (JA), promotes dormancy release in wheat. In this study, we found that cold-stimulated germination of dormant grains correlated with a transient increase in JA content and expression of JA biosynthesis genes in the dormant embryos after transfer to 20 oC. The induction of JA production was dependent on the extent of cold imbibition and precedes germination. Blocking JA biosynthesis with acetylsalicylic acid (ASA) inhibited the cold-stimulated germination in a dose-dependent manner. In addition, we have explored the relationship between JA and abscisic acid (ABA), a well-known dormancy promoter, in cold regulation of dormancy. We found an inverse relationship between JA and ABA content in dormant wheat embryos following stratification. ABA content decreased rapidly in response to stratification, and the decrease was reversed by addition of ASA. Our results indicate that the action of JA on cold-stratified grains is mediated by suppression of two key ABA biosynthesis genes, TaNCED1 and TaNCED2. PMID:27140440

  18. Aroma changes of black tea prepared from methyl jasmonate treated tea plants*

    PubMed Central

    Shi, Jiang; Wang, Li; Ma, Cheng-ying; Lv, Hai-peng; Chen, Zong-mao; Lin, Zhi

    2014-01-01

    Methyl jasmonate (MeJA) was widely applied in promoting food quality. Aroma is one of the key indicators in judging the quality of tea. This study examined the effect of exogenous MeJA treatment on tea aroma. The aroma components in black tea prepared from MeJA-treated fresh tea leaves were extracted using headspace solid-phase microextraction (HS-SPME) and were analyzed using gas chromatography-mass spectrometry (GC-MS) and GC-olfactometry (GC-O). Forty-five volatile compounds were identified. The results revealed that the MeJA-treated black tea had higher levels of terpene alcohols and hexenyl esters than the untreated tea. Moreover, several newly components, including copaene, cubenol, and indole, were induced by the MeJA treatment. The activities of polyphenol oxidase and β-glucosidase in fresh tea leaves changed after the MeJA treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that the gene expression levels of polyphenol oxidase and β-primeverosidase were upregulated by two and three folds, respectively, by the MeJA treatment (P<0.01); however, the gene expression of β-glucosidase was downregulated to a half level. In general, the aroma quality of the MeJA-treated black tea was clearly improved. PMID:24711352

  19. Joint aperture detection for speckle reduction and increased collection efficiency in ophthalmic MHz OCT

    PubMed Central

    Klein, Thomas; André, Raphael; Wieser, Wolfgang; Pfeiffer, Tom; Huber, Robert

    2013-01-01

    Joint-aperture optical coherence tomography (JA-OCT) is an angle-resolved OCT method, in which illumination from an active channel is simultaneously probed by several passive channels. JA-OCT increases the collection efficiency and effective sensitivity of the OCT system without increasing the power on the sample. Additionally, JA-OCT provides angular scattering information about the sample in a single acquisition, so the OCT imaging speed is not reduced. Thus, JA-OCT is especially suitable for ultra high speed in-vivo imaging. JA-OCT is compared to other angle-resolved techniques, and the relation between joint aperture imaging, adaptive optics, coherent and incoherent compounding is discussed. We present angle-resolved imaging of the human retina at an axial scan rate of 1.68 MHz, and demonstrate the benefits of JA-OCT: Speckle reduction, signal increase and suppression of specular and parasitic reflections. Moreover, in the future JA-OCT may allow for the reconstruction of the full Doppler vector and tissue discrimination by analysis of the angular scattering dependence. PMID:23577296

  20. Ligand-receptor co-evolution shaped the jasmonate pathway in land plants.

    PubMed

    Monte, Isabel; Ishida, Sakiko; Zamarreño, Angel M; Hamberg, Mats; Franco-Zorrilla, José M; García-Casado, Gloria; Gouhier-Darimont, Caroline; Reymond, Philippe; Takahashi, Kosaku; García-Mina, José M; Nishihama, Ryuichi; Kohchi, Takayuki; Solano, Roberto

    2018-05-01

    The phytohormone jasmonoyl-isoleucine (JA-Ile) regulates defense, growth and developmental responses in vascular plants. Bryophytes have conserved sequences for all JA-Ile signaling pathway components but lack JA-Ile. We show that, in spite of 450 million years of independent evolution, the JA-Ile receptor COI1 is functionally conserved between the bryophyte Marchantia polymorpha and the eudicot Arabidopsis thaliana but COI1 responds to different ligands in each species. We identified the ligand of Marchantia MpCOI1 as two isomeric forms of the JA-Ile precursor dinor-OPDA (dinor-cis-OPDA and dinor-iso-OPDA). We demonstrate that AtCOI1 functionally complements Mpcoi1 mutation and confers JA-Ile responsiveness and that a single-residue substitution in MpCOI1 is responsible for the evolutionary switch in ligand specificity. Our results identify the ancestral bioactive jasmonate and clarify its biosynthetic pathway, demonstrate the functional conservation of its signaling pathway, and show that JA-Ile and COI1 emergence in vascular plants required co-evolution of hormone biosynthetic complexity and receptor specificity.

  1. Jasmonic acid signaling modulates ozone-induced hypersensitive cell death.

    PubMed

    Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R

    2000-09-01

    Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

  2. Salicylic acid receptors activate jasmonic acid signalling through a non-canonical pathway to promote effector-triggered immunity.

    PubMed

    Liu, Lijing; Sonbol, Fathi-Mohamed; Huot, Bethany; Gu, Yangnan; Withers, John; Mwimba, Musoki; Yao, Jian; He, Sheng Yang; Dong, Xinnian

    2016-10-11

    It is an apparent conundrum how plants evolved effector-triggered immunity (ETI), involving programmed cell death (PCD), as a major defence mechanism against biotrophic pathogens, because ETI-associated PCD could leave them vulnerable to necrotrophic pathogens that thrive on dead host cells. Interestingly, during ETI, the normally antagonistic defence hormones, salicylic acid (SA) and jasmonic acid (JA) associated with defence against biotrophs and necrotrophs respectively, both accumulate to high levels. In this study, we made the surprising finding that JA is a positive regulator of RPS2-mediated ETI. Early induction of JA-responsive genes and de novo JA synthesis following SA accumulation is activated through the SA receptors NPR3 and NPR4, instead of the JA receptor COI1. We provide evidence that NPR3 and NPR4 may mediate this effect by promoting degradation of the JA transcriptional repressor JAZs. This unique interplay between SA and JA offers a possible explanation of how plants can mount defence against a biotrophic pathogen without becoming vulnerable to necrotrophic pathogens.

  3. Polarization properties of long-lived stimulated photon echo

    NASA Astrophysics Data System (ADS)

    Reshetov, V. A.; Popov, E. N.

    2015-01-01

    The polarization properties of the long-lived stimulated photon echo formed on the transition ja → jb with the atomic levels degenerate in the projections of the angular momenta are studied theoretically. The two particular transitions ja = 1 → jb = 0 and ja = 1 → jb = 1 with degenerate ground state ja = 1 are discussed. For the transitions ja = 1 → jb = 1 the polarizations and areas of the first (‘write’) and the third (‘read’) excitation pulses are found when the echo polarization faithfully reproduces the arbitrary polarization of the weak (single-photon) second (‘information’) pulse, so that this echo scheme may implement the quantum memory for a single-photon polarization qubit, while for the transitions ja = 1 → jb = 0 it is shown, that the echo polarization differs from that of the second pulse at any conditions.

  4. Top hits in contemporary JAZ: New information on jasmonate signaling

    PubMed Central

    Chung, Hoo Sun; Niu, Yajie; Browse, John; Howe, Gregg A.

    2012-01-01

    The phytohormone jasmonate (JA) regulates a wide range of growth, developmental, and defense-related processes during the plant life cycle. Identification of the JAZ family of proteins that repress JA responses has facilitated rapid progress in understanding how this lipid-derived hormone controls gene expression. Recent analysis of JAZ proteins has provided new insight into the nature of the JA receptor, the chemical specificity of signal perception, and cross-talk between JA and other hormone response pathways. Functional diversification of JAZ proteins by alternative splicing, together with the ability of JAZ proteins to homo- and heterodimerize, provide mechanisms to enhance combinatorial diversity and versatility in gene regulation by JA. PMID:19800644

  5. Selective enhancement of scopadulcic acid B production in the cultured tissues of Scoparia dulcis by methyl jasmonate.

    PubMed

    Nkembo, Kasidimoko Marguerite; Lee, Jung-Bum; Hayashi, Toshimitsu

    2005-07-01

    The effects of methyl jasmonate (MeJA) on isoprenoid production were evaluated in cultured tissues of Scoparia dulcis. It was found that MeJA suppressed the accumulation of chlorophylls, carotenoids, phytol and beta-sitosterol in the tissues. MeJA, however, remarkably enhanced the production of scopadulcic acid B (SDB), with 10 microM being optimal observed concentration for stimulation of SDB production. The maximum concentration of SDB was observed 6 d after MeJA treatment.

  6. 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

  7. 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

  8. 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

  9. 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

  10. Jasmonic Acid Enhances Al-Induced Root Growth Inhibition.

    PubMed

    Yang, Zhong-Bao; He, Chunmei; Ma, Yanqi; Herde, Marco; Ding, Zhaojun

    2017-02-01

    Phytohormones such as ethylene and auxin are involved in the regulation of the aluminum (Al)-induced root growth inhibition. Although jasmonate (JA) has been reported to play a crucial role in the regulation of root growth and development in response to environmental stresses through interplay with ethylene and auxin, its role in the regulation of root growth response to Al stress is not yet known. In an attempt to elucidate the role of JA, we found that exogenous application of JA enhanced the Al-induced root growth inhibition. Furthermore, phenotype analysis with mutants defective in either JA biosynthesis or signaling suggests that JA is involved in the regulation of Al-induced root growth inhibition. The expression of the JA receptor CORONATINE INSENSITIVE1 (COI1) and the key JA signaling regulator MYC2 was up-regulated in response to Al stress in the root tips. This process together with COI1-mediated Al-induced root growth inhibition under Al stress was controlled by ethylene but not auxin. Transcriptomic analysis revealed that many responsive genes under Al stress were regulated by JA signaling. The differential responsive of microtubule organization-related genes between the wild-type and coi1-2 mutant is consistent with the changed depolymerization of cortical microtubules in coi1 under Al stress. In addition, ALMT-mediated malate exudation and thus Al exclusion from roots in response to Al stress was also regulated by COI1-mediated JA signaling. Together, this study suggests that root growth inhibition is regulated by COI1-mediated JA signaling independent from auxin signaling and provides novel insights into the phytohormone-mediated root growth inhibition in response to Al stress. © 2017 American Society of Plant Biologists. All Rights Reserved.

  11. Disarming the Jasmonate-Dependent Plant Defense Makes Nonhost Arabidopsis Plants Accessible to the American Serpentine Leafminer1

    PubMed Central

    Abe, Hiroshi; Tateishi, Ken; Seo, Shigemi; Kugimiya, Soichi; Hirai, Masami Yokota; Sawada, Yuji; Murata, Yoshiyuki; Yara, Kaori; Shimoda, Takeshi; Kobayashi, Masatomo

    2013-01-01

    Here, we analyzed the interaction between Arabidopsis (Arabidopsis thaliana) and the American serpentine leafminer (Liriomyza trifolii), an important and intractable herbivore of many cultivated plants. We examined the role of the immunity-related plant hormone jasmonate (JA) in the plant response and resistance to leafminer feeding to determine whether JA affects host suitability for leafminers. The expression of marker genes for the JA-dependent plant defense was induced by leafminer feeding on Arabidopsis wild-type plants. Analyses of JA-insensitive coi1-1 mutants suggested the importance of JA in the plant response to leafminer feeding. The JA content of wild-type plants significantly increased after leafminer feeding. Moreover, coi1-1 mutants showed lower feeding resistance against leafminer attack than did wild-type plants. The number of feeding scars caused by inoculated adult leafminers in JA-insensitive coi1-1 mutants was higher than that in wild-type plants. In addition, adults of the following generation appeared only from coi1-1 mutants and not from wild-type plants, suggesting that the loss of the JA-dependent plant defense converted nonhost plants to accessible host plants. Interestingly, the glucosinolate-myrosinase defense system may play at most a minor role in this conversion, indicating that this major antiherbivore defense of Brassica species plants probably does not have a major function in plant resistance to leafminer. Application of JA to wild-type plants before leafminer feeding enhanced feeding resistance in Chinese cabbage (Brassica rapa), tomato (Solanum lycopersicum), and garland chrysanthemum (Chrysanthemum coronarium). Our results indicate that JA plays an important role in the plant response and resistance to leafminers and, in so doing, affects host plant suitability for leafminers. PMID:24022267

  12. Deep sequencing reveals transcriptome re-programming of Taxus × media cells to the elicitation with methyl jasmonate.

    PubMed

    Sun, Guiling; Yang, Yanfang; Xie, Fuliang; Wen, Jian-Fan; Wu, Jianqiang; Wilson, Iain W; Tang, Qi; Liu, Hongwei; Qiu, Deyou

    2013-01-01

    Plant cell culture represents an alternative source for producing high-value secondary metabolites including paclitaxel (Taxol®), which is mainly produced in Taxus and has been widely used in cancer chemotherapy. The phytohormone methyl jasmonate (MeJA) can significantly increase the production of paclitaxel, which is induced in plants as a secondary metabolite possibly in defense against herbivores and pathogens. In cell culture, MeJA also elicits the accumulation of paclitaxel; however, the mechanism is still largely unknown. To obtain insight into the global regulation mechanism of MeJA in the steady state of paclitaxel production (7 days after MeJA addition), especially on paclitaxel biosynthesis, we sequenced the transcriptomes of MeJA-treated and untreated Taxus × media cells and obtained ∼ 32.5 M high quality reads, from which 40,348 unique sequences were obtained by de novo assembly. Expression level analysis indicated that a large number of genes were associated with transcriptional regulation, DNA and histone modification, and MeJA signaling network. All the 29 known genes involved in the biosynthesis of terpenoid backbone and paclitaxel were found with 18 genes showing increased transcript abundance following elicitation of MeJA. The significantly up-regulated changes of 9 genes in paclitaxel biosynthesis were validated by qRT-PCR assays. According to the expression changes and the previously proposed enzyme functions, multiple candidates for the unknown steps in paclitaxel biosynthesis were identified. We also found some genes putatively involved in the transport and degradation of paclitaxel. Potential target prediction of miRNAs indicated that miRNAs may play an important role in the gene expression regulation following the elicitation of MeJA. Our results shed new light on the global regulation mechanism by which MeJA regulates the physiology of Taxus cells and is helpful to understand how MeJA elicits other plant species besides Taxus.

  13. Expression profiles of genes involved in jasmonic acid biosynthesis and signaling during growth and development of carrot.

    PubMed

    Wang, Guanglong; Huang, Wei; Li, Mengyao; Xu, Zhisheng; Wang, Feng; Xiong, Aisheng

    2016-09-01

    Jasmonates (JAs) are recognized as essential regulators in response to environmental stimuli and plant development. Carrot is an Apiaceae vegetable with great value and undergoes significant size changes over the course of plant growth. However, JA accumulation and its potential roles in carrot growth remain unclear. Here, methyl JA (MeJA) levels and expression profiles of JA-related genes were analyzed in carrot roots and leaves at five developmental stages. MeJA levels in the roots and leaves were the highest at the first stage and decreased as carrot growth proceeded. Transcript levels of several JA-related genes (Dc13-LOX1, Dc13-LOX2, DcAOS, DcAOC, DcOPR2, DcOPR3, DcOPCL1, DcJAR1, DcJMT, DcCOI1, DcJAZ1, DcJAZ2, DcMYC2, DcCHIB/PR3, DcLEC, and DcVSP2) were not well correlated with MeJA accumulation during carrot root and leaf development. In addition, some JA-related genes (DcJAR1, DcJMT, DcCOI1, DcMYC2, and DcVSP2) showed differential expression between roots and leaves. These results suggest that JAs may regulate carrot plant growth in stage-dependent and organ-specific manners. Our work provides novel insights into JA accumulation and its potential roles during carrot growth and development. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Transcriptional Profiling of Sorghum Induced by Methyl Jasmonate, Salicylic Acid, and Aminocyclopropane Carboxylic Acid Reveals Cooperative Regulation and Novel Gene Responses1[w

    PubMed Central

    Salzman, Ron A.; Brady, Jeff A.; Finlayson, Scott A.; Buchanan, Christina D.; Summer, Elizabeth J.; Sun, Feng; Klein, Patricia E.; Klein, Robert R.; Pratt, Lee H.; Cordonnier-Pratt, Marie-Michèle; Mullet, John E.

    2005-01-01

    We have conducted a large-scale study of gene expression in the C4 monocot sorghum (Sorghum bicolor) L. Moench cv BTx623 in response to the signaling compounds salicylic acid (SA), methyl jasmonate (MeJA), and the ethylene precursor aminocyclopropane carboxylic acid. Expression profiles were generated from seedling root and shoot tissue at 3 and 27 h, using a microarray containing 12,982 nonredundant elements. Data from 102 slides and quantitative reverse transcription-PCR data on mRNA abundance from 171 genes were collected and analyzed and are here made publicly available. Numerous gene clusters were identified in which expression was correlated with particular signaling compound and tissue combinations. Many genes previously implicated in defense responded to the treatments, including numerous pathogenesis-related genes and most members of the phenylpropanoid pathway, and several other genes that may represent novel activities or pathways. Genes of the octadecanoic acid pathway of jasmonic acid (JA) synthesis were induced by SA as well as by MeJA. The resulting hypothesis that increased SA could lead to increased endogenous JA production was confirmed by measurement of JA content. Comparison of responses to SA, MeJA, and combined SA+MeJA revealed patterns of one-way and mutual antagonisms, as well as synergistic effects on regulation of some genes. These experiments thus help further define the transcriptional results of cross talk between the SA and JA pathways and suggest that a subset of genes coregulated by SA and JA may comprise a uniquely evolved sector of plant signaling responsive cascades. PMID:15863699

  15. Questionnaire survey on pediatric hypertension in Japan and Korea.

    PubMed

    Yim, Hyung Eun; Lee, Eun Hee; Jang, Gi Young; Yoo, Kee Hwan; Son, Chang Sung; Hong, Young Sook; Lee, Joo Won; Ito, Yuhei; Ikezumi, Yohei; Uchiyama, Makoto

    2010-02-01

    Hypertension (HTN) is no longer viewed as an adult disease. The purpose of the present study was to understand how hypertensive children are evaluated and managed, by surveying pediatricians in Japan and South Korea. A questionnaire was mailed to 109 Japanese (JA) and 159 Korean (KO) pediatric cardiologists, pediatric nephrologists, and other pediatricians. A total of 127 replies were received (response rate 47%). Most of respondents did not check blood pressure (BP) routinely in outpatient clinics (JA 77%, KO 88%). A mercury sphygmomanometer was the most commonly used method for BP measurements (JA 72%, KO 62%). BP treatment goals were usually set at the 95th percentile for age, gender, and height (JA 47%, KO 54%). More KO used a lower goal in children with primary HTN than JA. KO respondents preferred angiotensin-converting enzyme inhibitors (ACEI) as initial agents regardless of underlying diseases whereas JA respondents chose various medications, that is, calcium channel blockers, diuretics, and ACEI. For BP monitoring, self-monitoring was found to be most frequent in both countries (JA 80%, KO 57%). Ambulatory BP monitoring was not frequently utilized in both countries (JA 33% KO 34%). The current assessment, management and differing trends in pediatric HTN in Japan and Korea have been identified in the present study. Pediatricians should be aware of the growing implications of HTN in children.

  16. Arabidopsis MYC Transcription Factors Are the Target of Hormonal Salicylic Acid/Jasmonic Acid Cross Talk in Response to Pieris brassicae Egg Extract1[OPEN

    PubMed Central

    Schmiesing, André; Gouhier-Darimont, Caroline

    2016-01-01

    Arabidopsis (Arabidopsis thaliana) plants recognize insect eggs and activate the salicylic acid (SA) pathway. As a consequence, expression of defense genes regulated by the jasmonic acid (JA) pathway is suppressed and larval performance is enhanced. Cross talk between defense signaling pathways is common in plant-pathogen interactions, but the molecular mechanism mediating this phenomenon is poorly understood. Here, we demonstrate that egg-induced SA/JA antagonism works independently of the APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factor ORA59, which controls the ERF branch of the JA pathway. In addition, treatment with egg extract did not enhance expression or stability of JASMONATE ZIM-domain transcriptional repressors, and SA/JA cross talk did not involve JASMONATE ASSOCIATED MYC2-LIKEs, which are negative regulators of the JA pathway. Investigating the stability of MYC2, MYC3, and MYC4, three basic helix-loop-helix transcription factors that additively control jasmonate-related defense responses, we found that egg extract treatment strongly diminished MYC protein levels in an SA-dependent manner. Furthermore, we identified WRKY75 as a novel and essential factor controlling SA/JA cross talk. These data indicate that insect eggs target the MYC branch of the JA pathway and uncover an unexpected modulation of SA/JA antagonism depending on the biological context in which the SA pathway is activated. PMID:26884488

  17. MYC2 Differentially Modulates Diverse Jasmonate-Dependent Functions in Arabidopsis[W

    PubMed Central

    Dombrecht, Bruno; Xue, Gang Ping; Sprague, Susan J.; Kirkegaard, John A.; Ross, John J.; Reid, James B.; Fitt, Gary P.; Sewelam, Nasser; Schenk, Peer M.; Manners, John M.; Kazan, Kemal

    2007-01-01

    The Arabidopsis thaliana basic helix-loop-helix Leu zipper transcription factor (TF) MYC2/JIN1 differentially regulates jasmonate (JA)-responsive pathogen defense (e.g., PDF1.2) and wound response (e.g., VSP) genes. In this study, genome-wide transcriptional profiling of wild type and mutant myc2/jin1 plants followed by functional analyses has revealed new roles for MYC2 in the modulation of diverse JA functions. We found that MYC2 negatively regulates Trp and Trp-derived secondary metabolism such as indole glucosinolate biosynthesis during JA signaling. Furthermore, MYC2 positively regulates JA-mediated resistance to insect pests, such as Helicoverpa armigera, and tolerance to oxidative stress, possibly via enhanced ascorbate redox cycling and flavonoid biosynthesis. Analyses of MYC2 cis binding elements and expression of MYC2-regulated genes in T-DNA insertion lines of a subset of MYC2–regulated TFs suggested that MYC2 might modulate JA responses via differential regulation of an intermediate spectrum of TFs with activating or repressing roles in JA signaling. MYC2 also negatively regulates its own expression, and this may be one of the mechanisms used in fine-tuning JA signaling. Overall, these results provide new insights into the function of MYC2 and the transcriptional coordination of the JA signaling pathway. PMID:17616737

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Control of Carbon Assimilation and Partitioning by Jasmonate: An Accounting of Growth-Defense Tradeoffs.

    PubMed

    Havko, Nathan E; Major, Ian T; Jewell, Jeremy B; Attaran, Elham; Browse, John; Howe, Gregg A

    2016-01-15

    Plant growth is often constrained by the limited availability of resources in the microenvironment. Despite the continuous threat of attack from insect herbivores and pathogens, investment in defense represents a lost opportunity to expand photosynthetic capacity in leaves and absorption of nutrients and water by roots. To mitigate the metabolic expenditure on defense, plants have evolved inducible defense strategies. The plant hormone jasmonate (JA) is a key regulator of many inducible defenses. Synthesis of JA in response to perceived danger leads to the deployment of a variety of defensive structures and compounds, along with a potent inhibition of growth. Genetic studies have established an important role for JA in mediating tradeoffs between growth and defense. However, several gaps remain in understanding of how JA signaling inhibits growth, either through direct transcriptional control of JA-response genes or crosstalk with other signaling pathways. Here, we highlight recent progress in uncovering the role of JA in controlling growth-defense balance and its relationship to resource acquisition and allocation. We also discuss tradeoffs in the context of the ability of JA to promote increased leaf mass per area (LMA), which is a key indicator of leaf construction costs and leaf life span.

  6. Jasmonic Acid Signaling Modulates Ozone-Induced Hypersensitive Cell Death

    PubMed Central

    Rao, Mulpuri V.; Lee, Hyung-il; Creelman, Robert A.; Mullet, John E.; Davis, Keith R.

    2000-01-01

    Recent studies suggest that cross-talk between salicylic acid (SA)–, jasmonic acid (JA)–, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O3) exposure activates a hypersensitive response (HR)–like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O3-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O3-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O3-induced H2O2 content and SA concentrations and completely abolished O3-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O3 exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O3 of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O3-induced HR-like cell death. PMID:11006337

  7. Jasmonate response decay and defense metabolite accumulation contributes to age-regulated dynamics of plant insect resistance

    PubMed Central

    Mao, Ying-Bo; Liu, Yao-Qian; Chen, Dian-Yang; Chen, Fang-Yan; Fang, Xin; Hong, Gao-Jie; Wang, Ling-Jian; Wang, Jia-Wei; Chen, Xiao-Ya

    2017-01-01

    Immunity deteriorates with age in animals but comparatively little is known about the temporal regulation of plant resistance to herbivores. The phytohormone jasmonate (JA) is a key regulator of plant insect defense. Here, we show that the JA response decays progressively in Arabidopsis. We show that this decay is regulated by the miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE9 (SPL9) group of proteins, which can interact with JA ZIM-domain (JAZ) proteins, including JAZ3. As SPL9 levels gradually increase, JAZ3 accumulates and the JA response is attenuated. We provide evidence that this pathway contributes to insect resistance in young plants. Interestingly however, despite the decay in JA response, older plants are still comparatively more resistant to both the lepidopteran generalist Helicoverpa armigera and the specialist Plutella xylostella, along with increased accumulation of glucosinolates. We propose a model whereby constitutive accumulation of defense compounds plays a role in compensating for age-related JA-response attenuation during plant maturation. PMID:28067238

  8. Effect of jasmonic acid elicitation on the yield, chemical composition, and antioxidant and anti-inflammatory properties of essential oil of lettuce leaf basil (Ocimum basilicum L.).

    PubMed

    Złotek, Urszula; Michalak-Majewska, Monika; Szymanowska, Urszula

    2016-12-15

    The effect of elicitation with jasmonic acid (JA) on the plant yield, the production and composition of essential oils of lettuce leaf basil was evaluated. JA-elicitation slightly affected the yield of plants and significantly increased the amount of essential oils produced by basil - the highest oil yield (0.78±0.005mL/100gdw) was achieved in plants elicited with 100μM JA. The application of the tested elicitor also influenced the chemical composition of basil essential oils - 100μM JA increased the linalool, eugenol, and limonene levels, while 1μM JA caused the highest increase in the methyl eugenol content. Essential oils from JA-elicited basil (especially 1μM and 100μM) exhibited more effective antioxidant and anti-inflammatory potential; therefore, this inducer may be a very useful biochemical tool for improving production and composition of herbal essential oils. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Jasmonate signaling in plant stress responses and development - active and inactive compounds.

    PubMed

    Wasternack, Claus; Strnad, Miroslav

    2016-09-25

    Jasmonates (JAs) are lipid-derived signals mediating plant responses to biotic and abiotic stresses and in plant development. Following the elucidation of each step in their biosynthesis and the important components of perception and signaling, several activators, repressors and co-repressors have been identified which contribute to fine-tuning the regulation of JA-induced gene expression. Many of the metabolic reactions in which JA participates, such as conjugation with amino acids, glucosylation, hydroxylation, carboxylation, sulfation and methylation, lead to numerous compounds with different biological activities. These metabolites may be highly active, partially active in specific processes or inactive. Hydroxylation, carboxylation and sulfation inactivate JA signaling. The precursor of JA biosynthesis, 12-oxo-phytodienoic acid (OPDA), has been identified as a JA-independent signaling compound. An increasing number of OPDA-specific processes is being identified. To conclude, the numerous JA compounds and their different modes of action allow plants to respond specifically and flexibly to alterations in the environment. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. 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

  11. 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

  12. Jasmonate Hormone: Regulating Synthesis of Reduced Carbon Compounds in Plants

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

    Browse, John

    Our original interest in understanding the role of jasmonate (JA) in regulating the final stages of stamen and pollen development led to our discovery of the JAZ repressors, and the molecular mechanism of JA action is now a second important focus of our research. The specific goals for this grant period are to: 1. Investigate the generation and clearance of the hormone with emphasis on the regulation of the OPR3 enzyme and the hydrolysis of JA-Ile. 2. Use dominant-negative and overexpression constructs to explore the role of the MYC5 transcription factor in initiating and regulating JA responses. 3. Investigate specificmore » JAZ protein interactions that will help us to recognize and understand the extended network of processes, such as sulfur nutrition, that interface with JA signaling. The COI1 F-Box protein is a JA-Ile coreceptor and coi1 mutant plants lack JA responses. We have tested the possibility that sites of JA action can be probed by using tissue-specific promoters to drive expression of a COI1-YFP fusion protein in coi1 mutant plants deficient in stamen and pollen function. When we expressed COI1 behind a filament-specific promoter (from the DAD1 gene), filament elongation was restored but not anther dehiscence or pollen function. Three tapetum specific promoters, all failed to restore any of these three functions but, unexpectedly, a promoter active in the stomium and epidermal cells, restored both pollen function and anther dehiscence. Most importantly, our results demonstrate the power of promoter::COI1-YFP constructs in revealing the primary sites of JA-regulated gene expression that control developmental and other responses in neighboring tissues. We now plan to use this new tool to test current hypotheses about JA action in other organs of the plant. The MYC2, MYC3, and MYC4 proteins are the primary transcription factors initiating defense and root growth responses to JA signaling. However, transgenic plants overexpressing these proteins do not

  13. Thiorhodococcus fuscus sp. nov., isolated from a lagoon.

    PubMed

    Lakshmi, K V N S; Divyasree, B; Sucharita, K; Sasikala, Ch; Ramana, Ch V

    2015-11-01

    A brown, moderately halophilic, photoautotrophic bacterium designated strain JA363T was purified from a photoheterotrophic enrichment obtained from sediment from Chilika lagoon, Odisha, India. Cells of the isolate were coccoid, motile by means of single polar flagellum and Gram-stain-negative. Strain JA363T had an obligate requirement for NaCl and could tolerate up to 7 % (w/v) NaCl. Strain JA363T had complex growth factor requirements. Internal photosynthetic membranes were present as vesicles. Strain JA363T contained bacteriochlorophyll a and spirilloxanthin series carotenoids with rhodopin as a major (>85 %) component. C16 : 1ω7c/C16 : 1ω6c, C18 : 1ω7c and C16 : 0 were the major fatty acids and phosphatidylglycerol and phosphatidylethanolamine were the major polar lipids. Q8 was the predominant quinone system of strain JA363T. The DNA G+C content was 64 mol%. The highest 16S rRNA gene sequence similarity of strain JA363T was found with the type strains of Thiorhodococcus kakinadensis (98.7 %), Thiohalobacter thiocyanaticus (98.2 %), Thiophaeococcus fuscus (97.4 %) and Thiorhodococcus bheemlicus (96.3 %). However, the phylogenetic trees generated firmly placed strain JA363T in the genus Thiorhodococcus, which was further supported by phenotypic and chemotaxonomic evidence. Consequently, strain JA363T is described as representing a novel species of the genus Thiorhodococcus as Thiorhodococcus fuscus sp. nov. The type strain is JA363T ( = KCTC 5701T = NBRC 104959T).

  14. Cloning of genes related to aliphatic glucosinolate metabolism and the mechanism of sulforaphane accumulation in broccoli sprouts under jasmonic acid treatment.

    PubMed

    Guo, Liping; Yang, Runqiang; Gu, Zhenxin

    2016-10-01

    Cytochrome P450 79F1 (CYP79F1), cytochrome P450 83A1 (CYP83A1), UDP-glucosyltransferase 74B1 (UGT74B1), sulfotransferase 18 (ST5b) and flavin-containing monooxygenase GS-OX1 (FMOGS - OX1 ) are important enzymes in aliphatic glucosinolate biosynthesis. In this study, their full-length cDNA in broccoli was firstly cloned, then the mechanism of sulforaphane accumulation under jasmonic acid (JA) treatment was investigated. The full-length cDNA of CYP79F1, CYP83A1, UGT74B1, ST5b and FMOGS - OX1 comprised 1980, 1652, 1592, 1378 and 1623 bp respectively. The increase in aliphatic glucosinolate accumulation in broccoli sprouts treated with JA was associated with elevated expression of genes in the aliphatic glucosinolate biosynthetic pathway. Application of 100 µmol L(-1) JA increased myrosinase (MYR) activity but did not affect epithiospecifier protein (ESP) activity in broccoli sprouts, which was supported by the expression of MYR and ESP. Sulforaphane formation in 7-day-old sprouts treated with 100 µmol L(-1) JA was 3.36 and 1.30 times that in the control and 300 µmol L(-1) JA treatment respectively. JA enhanced the accumulation of aliphatic glucosinolates in broccoli sprouts via up-regulation of related gene expression. Broccoli sprouts treated with 100 µmol L(-1) JA showed higher sulforphane formation than those treated with 300 µmol L(-1) JA owing to the higher glucoraphanin content and myrosinase activity under 100 µmol L(-1) JA treatment. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  15. Effect of methyl jasmonate on secondary metabolites of sweet basil (Ocimum basilicum L.).

    PubMed

    Kim, Hyun-Jin; Chen, Feng; Wang, Xi; Rajapakse, Nihal C

    2006-03-22

    The effect of methyl jasmonate (MeJA) in terms of its induction of inherent bioactive chemicals in sweet basil (Ocimum basilicum L.) was evaluated after MeJA was sprayed on healthy basil plants. The total phenolic content of the sweet basil significantly increased after 0.1 and 0.5 mM MeJA treatments compared with the control not subjected to MeJA. Two phenolic compounds, rosmarinic acid (RA) and caffeic acid (CA), were identified as strong antioxidant constituents of the sweet basil. Their amounts also significantly increased after the MeJA treatment. In addition, eugenol and linalool increased 56 and 43%, respectively, by the 0.5 mM MeJA treatment. Due to the accumulation of RA, CA, and eugenol, which possess strong 2,2-diphenyl-1-picrylhydrazyl (DPPH*) free radical scavenging activities, the antioxidant activity of the sweet basil extract was 2.3-fold greater than that of the control after the 0.5 mM MeJA treatment. In the DPPH* assay, the EC50 values of RA, CA, and eugenol were determined as 23, 46, and 59 microM, respectively, which indicated they were 6-, 3-, and 2.4-fold more efficient than BHT (140 microM). Besides, an unidentified HPLC peak in the methanolic extract of the sweet basil was 4.3-fold higher than that of the control after the 0.5 mM MeJA treatment.

  16. Plant hormone jasmonate prioritizes defense over growth by interfering with gibberellin signaling cascade.

    PubMed

    Yang, Dong-Lei; Yao, Jian; Mei, Chuan-Sheng; Tong, Xiao-Hong; Zeng, Long-Jun; Li, Qun; Xiao, Lang-Tao; Sun, Tai-ping; Li, Jigang; Deng, Xing-Wang; Lee, Chin Mei; Thomashow, Michael F; Yang, Yinong; He, Zuhua; He, Sheng Yang

    2012-05-08

    Plants must effectively defend against biotic and abiotic stresses to survive in nature. However, this defense is costly and is often accompanied by significant growth inhibition. How plants coordinate the fluctuating growth-defense dynamics is not well understood and remains a fundamental question. Jasmonate (JA) and gibberellic acid (GA) are important plant hormones that mediate defense and growth, respectively. Binding of bioactive JA or GA ligands to cognate receptors leads to proteasome-dependent degradation of specific transcriptional repressors (the JAZ or DELLA family of proteins), which, at the resting state, represses cognate transcription factors involved in defense (e.g., MYCs) or growth [e.g. phytochrome interacting factors (PIFs)]. In this study, we found that the coi1 JA receptor mutants of rice (a domesticated monocot crop) and Arabidopsis (a model dicot plant) both exhibit hallmark phenotypes of GA-hypersensitive mutants. JA delays GA-mediated DELLA protein degradation, and the della mutant is less sensitive to JA for growth inhibition. Overexpression of a selected group of JAZ repressors in Arabidopsis plants partially phenocopies GA-associated phenotypes of the coi1 mutant, and JAZ9 inhibits RGA (a DELLA protein) interaction with transcription factor PIF3. Importantly, the pif quadruple (pifq) mutant no longer responds to JA-induced growth inhibition, and overexpression of PIF3 could partially overcome JA-induced growth inhibition. Thus, a molecular cascade involving the COI1-JAZ-DELLA-PIF signaling module, by which angiosperm plants prioritize JA-mediated defense over growth, has been elucidated.

  17. Arabidopsis MYC Transcription Factors Are the Target of Hormonal Salicylic Acid/Jasmonic Acid Cross Talk in Response to Pieris brassicae Egg Extract.

    PubMed

    Schmiesing, André; Emonet, Aurélia; Gouhier-Darimont, Caroline; Reymond, Philippe

    2016-04-01

    Arabidopsis (Arabidopsis thaliana) plants recognize insect eggs and activate the salicylic acid (SA) pathway. As a consequence, expression of defense genes regulated by the jasmonic acid (JA) pathway is suppressed and larval performance is enhanced. Cross talk between defense signaling pathways is common in plant-pathogen interactions, but the molecular mechanism mediating this phenomenon is poorly understood. Here, we demonstrate that egg-induced SA/JA antagonism works independently of the APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factor ORA59, which controls the ERF branch of the JA pathway. In addition, treatment with egg extract did not enhance expression or stability of JASMONATE ZIM-domain transcriptional repressors, and SA/JA cross talk did not involve JASMONATE ASSOCIATED MYC2-LIKEs, which are negative regulators of the JA pathway. Investigating the stability of MYC2, MYC3, and MYC4, three basic helix-loop-helix transcription factors that additively control jasmonate-related defense responses, we found that egg extract treatment strongly diminished MYC protein levels in an SA-dependent manner. Furthermore, we identified WRKY75 as a novel and essential factor controlling SA/JA cross talk. These data indicate that insect eggs target the MYC branch of the JA pathway and uncover an unexpected modulation of SA/JA antagonism depending on the biological context in which the SA pathway is activated. © 2016 American Society of Plant Biologists. All Rights Reserved.

  18. Silencing brassinosteroid receptor BRI1 impairs herbivory-elicited accumulation of jasmonic acid-isoleucine and diterpene glycosides, but not jasmonic acid and trypsin proteinase inhibitors in Nicotiana attenuata.

    PubMed

    Yang, Da-Hai; Baldwin, Ian T; Wu, Jianqiang

    2013-06-01

    The brassinosteroid (BR) receptor, BR insensitive 1 (BRI1), plays a critical role in plant development, but whether BRI1-mediated BR signaling is involved in plant defense responses to herbivores was largely unknown. Here, we examined the function of BRI1 in the resistance of Nicotiana attenuata (Solanaceae) to its specialist insect herbivore Manduca sexta. Jasmonic acid (JA) and JA-isoleucine conjugate (JA-Ile) are important hormones that mediate resistance to herbivores and we found that after wounding or simulated herbivory NaBRI1 had little effect on JA levels, but was important for the induction of JA-Ile. Further experiments revealed that decreased JAR (the enzyme for JA-Ile production) activity and availability of Ile in NaBRI1-silenced plants were likely responsible for the low JA-Ile levels. Consistently, M. sexta larvae gained more weight on NaBRI1-silenced plants than on the control plants. Quantification of insect feeding-induced secondary metabolites revealed that silencing NaBRI1 resulted in decreased levels of carbon-rich defensive secondary metabolites (hydroxygeranyllinalool diterpene glycosides, chlorogenic acid, and rutin), but had little effect on the nitrogen-rich ones (nicotine and trypsin proteinase inhibitors). Thus, NaBRI1-mediated BR signaling is likely involved in plant defense responses to M. sexta, including maintaining JA-Ile levels and the accumulation of several carbon-rich defensive secondary metabolites. © 2013 Institute of Botany, Chinese Academy of Sciences.

  19. De novo characterization of Larix gmelinii (Rupr.) Rupr. transcriptome and analysis of its gene expression induced by jasmonates.

    PubMed

    Men, Lina; Yan, Shanchun; Liu, Guanjun

    2013-08-13

    Larix gmelinii is a dominant tree species in China's boreal forests and plays an important role in the coniferous ecosystem. It is also one of the most economically important tree species in the Chinese timber industry due to excellent water resistance and anti-corrosion of its wood products. Unfortunately, in Northeast China, L. gmelinii often suffers from serious attacks by diseases and insects. The application of exogenous volatile semiochemicals may induce and enhance its resistance against insect or disease attacks; however, little is known regarding the genes and molecular mechanisms related to induced resistance. We performed de novo sequencing and assembly of the L. gmelinii transcriptome using a short read sequencing technology (Illumina). Chemical defenses of L. gmelinii seedlings were induced with jasmonic acid (JA) or methyl jasmonate (MeJA) for 6 hours. Transcriptomes were compared between seedlings induced by JA, MeJA and untreated controls using a tag-based digital gene expression profiling system. In a single run, 25,977,782 short reads were produced and 51,157 unigenes were obtained with a mean length of 517 nt. We sequenced 3 digital gene expression libraries and generated between 3.5 and 5.9 million raw tags, and obtained 52,040 reliable reference genes after removing redundancy. The expression of disease/insect-resistance genes (e.g., phenylalanine ammonialyase, coumarate 3-hydroxylase, lipoxygenase, allene oxide synthase and allene oxide cyclase) was up-regulated. The expression profiles of some abundant genes under different elicitor treatment were studied by using real-time qRT-PCR.The results showed that the expression levels of disease/insect-resistance genes in the seedling samples induced by JA and MeJA were higher than those in the control group. The seedlings induced with MeJA elicited the strongest increases in disease/insect-resistance genes. Both JA and MeJA induced seedlings of L. gmelinii showed significantly increased expression

  20. Influence of (9Z)-12-hydroxy-9-dodecenoic acid and methyl jasmonate on plant protein phosphorylation.

    PubMed

    Tarchevsky, I A; Karimova, F G; Grechkin, A N; Moukhametchina, N U

    2000-12-01

    The products of the lipoxygenase pathway, methyl jasmonic acid (MeJA) and (9Z)-12-hydroxy-9-dodecenoic acid (HDA), hardly changed the relative level of phosphorylated polypeptides (RLPPs) during 2 h of incubation: 15 and 17 kDa RLPPs were enhanced by HDA, but decreased by MeJA. RLPPs of 73 and 82 kDa were increased by both compounds. MeJA and HDA treatment induced specific and unspecific effects in some RLPPs. It was shown that HDA and MeJA increased protein kinase activity in the presence of 1 microM cAMP.

  1. Control of Carbon Assimilation and Partitioning by Jasmonate: An Accounting of Growth–Defense Tradeoffs

    PubMed Central

    Havko, Nathan E.; Major, Ian T.; Jewell, Jeremy B.; Attaran, Elham; Browse, John; Howe, Gregg A.

    2016-01-01

    Plant growth is often constrained by the limited availability of resources in the microenvironment. Despite the continuous threat of attack from insect herbivores and pathogens, investment in defense represents a lost opportunity to expand photosynthetic capacity in leaves and absorption of nutrients and water by roots. To mitigate the metabolic expenditure on defense, plants have evolved inducible defense strategies. The plant hormone jasmonate (JA) is a key regulator of many inducible defenses. Synthesis of JA in response to perceived danger leads to the deployment of a variety of defensive structures and compounds, along with a potent inhibition of growth. Genetic studies have established an important role for JA in mediating tradeoffs between growth and defense. However, several gaps remain in understanding of how JA signaling inhibits growth, either through direct transcriptional control of JA-response genes or crosstalk with other signaling pathways. Here, we highlight recent progress in uncovering the role of JA in controlling growth-defense balance and its relationship to resource acquisition and allocation. We also discuss tradeoffs in the context of the ability of JA to promote increased leaf mass per area (LMA), which is a key indicator of leaf construction costs and leaf life span. PMID:27135227

  2. Intraspecific variation in a generalist herbivore accounts for differential induction and impact of host plant defences

    PubMed Central

    Kant, Merijn R; Sabelis, Maurice W; Haring, Michel A; Schuurink, Robert C

    2007-01-01

    Plants and herbivores are thought to be engaged in a coevolutionary arms race: rising frequencies of plants with anti-herbivore defences exert pressure on herbivores to resist or circumvent these defences and vice versa. Owing to its frequency-dependent character, the arms race hypothesis predicts that herbivores exhibit genetic variation for traits that determine how they deal with the defences of a given host plant phenotype. Here, we show the existence of distinct variation within a single herbivore species, the spider mite Tetranychus urticae, in traits that lead to resistance or susceptibility to jasmonate (JA)-dependent defences of a host plant but also in traits responsible for induction or repression of JA defences. We characterized three distinct lines of T. urticae that differentially induced JA-related defence genes and metabolites while feeding on tomato plants (Solanum lycopersicum). These lines were also differently affected by induced JA defences. The first line, which induced JA-dependent tomato defences, was susceptible to those defences; the second line also induced JA defences but was resistant to them; and the third, although susceptible to JA defences, repressed induction. We hypothesize that such intraspecific variation is common among herbivores living in environments with a diversity of plants that impose diverse selection pressure. PMID:18055390

  3. Jasmonic acid-mediated defense suppresses brassinosteroid-mediated susceptibility to Rice black streaked dwarf virus infection in rice.

    PubMed

    He, Yuqing; Zhang, Hehong; Sun, Zongtao; Li, Junmin; Hong, Gaojie; Zhu, Qisong; Zhou, Xuebiao; MacFarlane, Stuart; Yan, Fei; Chen, Jianping

    2017-04-01

    Plant hormones play a vital role in plant immune responses. However, in contrast to the relative wealth of information on hormone-mediated immunity in dicot plants, little information is available on monocot-virus defense systems. We used a high-throughput-sequencing approach to compare the global gene expression of Rice black-streaked dwarf virus (RBSDV)-infected rice plants with that of healthy plants. Exogenous hormone applications and transgenic rice were used to test RBSDV infectivity and pathogenicity. Our results revealed that the jasmonic acid (JA) pathway was induced while the brassinosteroid (BR) pathway was suppressed in infected plants. Foliar application of methyl jasmonate (MeJA) or brassinazole (BRZ) resulted in a significant reduction in RBSDV incidence, while epibrassinolide (BL) treatment increased RBSDV infection. Infection studies using coi1-13 and Go mutants demonstrated JA-mediated resistance and BR-mediated susceptibility to RBSDV infection. A mixture of MeJA and BL treatment resulted in a significant reduction in RBSDV infection compared with a single BL treatment. MeJA application efficiently suppressed the expression of BR pathway genes, and this inhibition depended on the JA coreceptor OsCOI1. Collectively, our results reveal that JA-mediated defense can suppress the BR-mediated susceptibility to RBSDV infection. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  4. Constitutive activation of jasmonate signaling in an Arabidopsis mutant correlates with enhanced resistance to Erysiphe cichoracearum, Pseudomonas syringae, and Myzus persicae.

    PubMed

    Ellis, Christine; Karafyllidis, Ioannis; Turner, John G

    2002-10-01

    In Arabidopsis spp., the jasmonate (JA) response pathway generally is required for defenses against necrotrophic pathogens and chewing insects, while the salicylic acid (SA) response pathway is generally required for specific, resistance (R) gene-mediated defenses against both biotrophic and necrotrophic pathogens. For example, SA-dependent defenses are required for resistance to the biotrophic fungal pathogen Erysiphe cichoracearum UCSC1 and the bacterial pathogen Pseudomonas syringae pv. maculicola, and also are expressed during response to the green peach aphid Myzus persicae. However, recent evidence indicates that the expression of JA-dependent defenses also may confer resistance to E. cichoracearum. To confirm and to extend this observation, we have compared the disease and pest resistance of wild-type Arabidopsis plants with that of the mutants coil, which is insensitive to JA, and cev1, which has constitutive JA signaling. Measurements of the colonization of these plants by E. cichoracearum, P. syringae pv. maculicola, and M. persicae indicated that activation of the JA signal pathway enhanced resistance, and was associated with the activation of JA-dependent defense genes and the suppression of SA-dependent defense genes. We conclude that JA and SA induce alternative defense pathways that can confer resistance to the same pathogens and pests.

  5. Arbuscular mycorrhizal symbiosis and methyl jasmonate avoid the inhibition of root hydraulic conductivity caused by drought.

    PubMed

    Sánchez-Romera, Beatriz; Ruiz-Lozano, Juan Manuel; Zamarreño, Ángel María; García-Mina, José María; Aroca, Ricardo

    2016-02-01

    Hormonal regulation and symbiotic relationships provide benefits for plants to overcome stress conditions. The aim of this study was to elucidate the effects of exogenous methyl jasmonate (MeJA) application on root hydraulic conductivity (L) of Phaseolus vulgaris plants which established arbuscular mycorrhizal (AM) symbiosis under two water regimes (well-watered and drought conditions). The variation in endogenous contents of several hormones (MeJA, JA, abscisic acid (ABA), indol-3-acetic acid (IAA), salicylic acid (SA)) and the changes in aquaporin gene expression, protein abundance and phosphorylation state were analyzed. AM symbiosis decreased L under well-watered conditions, which was partially reverted by the MeJA treatment, apparently by a drop in root IAA contents. Also, AM symbiosis and MeJA prevented inhibition of L under drought conditions, most probably by a reduction in root SA contents. Additionally, the gene expression of two fungal aquaporins was upregulated under drought conditions, independently of the MeJA treatment. Plant aquaporin gene expression could not explain the behaviour of L. Conversely, evidence was found for the control of L by phosphorylation of aquaporins. Hence, MeJA addition modified the response of L to both AM symbiosis and drought, presumably by regulating the root contents of IAA and SA and the phosphorylation state of aquaporins.

  6. A stable JAZ protein from peach mediates the transition from outcrossing to self-pollination.

    PubMed

    Sherif, Sherif; El-Sharkawy, Islam; Mathur, Jaideep; Ravindran, Pratibha; Kumar, Prakash; Paliyath, Gopinadhan; Jayasankar, Subramanian

    2015-02-13

    Variations in floral display represent one of the core features associated with the transition from allogamy to autogamy in angiosperms. The promotion of autogamy under stress conditions suggests the potential involvement of a signaling pathway with a dual role in both flower development and stress response. The jasmonic acid (JA) pathway is a plausible candidate to play such a role because of its involvement in many plant responses to environmental and developmental cues. In the present study, we used peach (Prunus persica L.) varieties with showy and non-showy flowers to investigate the role of JA (and JA signaling suppressors) in floral display. Our results show that PpJAZ1, a component of the JA signaling pathway in peach, regulates petal expansion during anthesis and promotes self-pollination. PpJAZ1 transcript levels were higher in petals of the non-showy flowers than those of showy flowers at anthesis. Moreover, the ectopic expression of PpJAZ1 in tobacco (Nicotiana tabacum L.) converted the showy, chasmogamous tobacco flowers into non-showy, cleistogamous flowers. Stability of PpJAZ1 was confirmed in vivo using PpJAZ1-GFP chimeric protein. PpJAZ1 inhibited JA-dependent processes in roots and leaves of transgenic plants, including induction of JA-response genes to mechanical wounding. However, the inhibitory effect of PpJAZ1 on JA-dependent fertility functions was weaker, indicating that PpJAZ1 regulates the spatial localization of JA signaling in different plant organs. Indeed, JA-related genes showed differential expression patterns in leaves and flowers of transgenic plants. Our results reveal that under stress conditions – for example, herbivore attacks – stable JAZ proteins such as PpJAZ1 may alter JA signaling in different plant organs, resulting in autogamy as a reproductive assurance mechanism. This represents an additional mechanism by which plant hormone signaling can modulate a vital developmental process in response to stress.

  7. The Jasmonate Pathway Is a Key Player in Systemically Induced Defense against Root Knot Nematodes in Rice1[C

    PubMed Central

    Nahar, Kamrun; Kyndt, Tina; De Vleesschauwer, David; Höfte, Monica; Gheysen, Godelieve

    2011-01-01

    Complex defense signaling pathways, controlled by different hormones, are involved in the reaction of plants to a wide range of biotic and abiotic stress factors. We studied the ability of salicylic acid, jasmonate (JA), and ethylene (ET) to induce systemic defense in rice (Oryza sativa) against the root knot nematode Meloidogyne graminicola. Exogenous ET (ethephon) and JA (methyl jasmonate) supply on the shoots induced a strong systemic defense response in the roots, exemplified by a major up-regulation of pathogenesis-related genes OsPR1a and OsPR1b, while the salicylic acid analog BTH (benzo-1,2,3-thiadiazole-7-carbothioic acid S-methyl ester) was a less potent systemic defense inducer from shoot to root. Experiments with JA biosynthesis mutants and ET-insensitive transgenics showed that ET-induced defense requires an intact JA pathway, while JA-induced defense was still functional when ET signaling was impaired. Pharmacological inhibition of JA and ET biosynthesis confirmed that JA biosynthesis is needed for ET-induced systemic defense, and quantitative real-time reverse transcription-polymerase chain reaction data revealed that ET application onto the shoots strongly activates JA biosynthesis and signaling genes in the roots. All data provided in this study point to the JA pathway to play a pivotal role in rice defense against root knot nematodes. The expression of defense-related genes was monitored in root galls caused by M. graminicola. Different analyzed defense genes were attenuated in root galls caused by the nematode at early time points after infection. However, when the exogenous defense inducers ethephon and methyl jasmonate were supplied to the plant, the nematode was less effective in counteracting root defense pathways, hence making the plant more resistant to nematode infection. PMID:21715672

  8. Jasmonate Controls Leaf Growth by Repressing Cell Proliferation and the Onset of Endoreduplication while Maintaining a Potential Stand-By Mode1[W][OA

    PubMed Central

    Noir, Sandra; Bömer, Moritz; Takahashi, Naoki; Ishida, Takashi; Tsui, Tjir-Li; Balbi, Virginia; Shanahan, Hugh; Sugimoto, Keiko; Devoto, Alessandra

    2013-01-01

    Phytohormones regulate plant growth from cell division to organ development. Jasmonates (JAs) are signaling molecules that have been implicated in stress-induced responses. However, they have also been shown to inhibit plant growth, but the mechanisms are not well understood. The effects of methyl jasmonate (MeJA) on leaf growth regulation were investigated in Arabidopsis (Arabidopsis thaliana) mutants altered in JA synthesis and perception, allene oxide synthase and coi1-16B (for coronatine insensitive1), respectively. We show that MeJA inhibits leaf growth through the JA receptor COI1 by reducing both cell number and size. Further investigations using flow cytometry analyses allowed us to evaluate ploidy levels and to monitor cell cycle progression in leaves and cotyledons of Arabidopsis and/or Nicotiana benthamiana at different stages of development. Additionally, a novel global transcription profiling analysis involving continuous treatment with MeJA was carried out to identify the molecular players whose expression is regulated during leaf development by this hormone and COI1. The results of these studies revealed that MeJA delays the switch from the mitotic cell cycle to the endoreduplication cycle, which accompanies cell expansion, in a COI1-dependent manner and inhibits the mitotic cycle itself, arresting cells in G1 phase prior to the S-phase transition. Significantly, we show that MeJA activates critical regulators of endoreduplication and affects the expression of key determinants of DNA replication. Our discoveries also suggest that MeJA may contribute to the maintenance of a cellular “stand-by mode” by keeping the expression of ribosomal genes at an elevated level. Finally, we propose a novel model for MeJA-regulated COI1-dependent leaf growth inhibition. PMID:23439917

  9. Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

    PubMed Central

    Guo, Yan-xia; Lin, Zhao-min; Wang, Mei-juan; Dong, Yi-wen; Niu, Huan-min; Young, Charles YF; Lou, Hong-xiang; Yuan, Hui-qing

    2016-01-01

    Aim: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. Methods: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Results: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. Conclusion: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest. PMID:27133304

  10. Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro.

    PubMed

    Guo, Yan-Xia; Lin, Zhao-Min; Wang, Mei-Juan; Dong, Yi-Wen; Niu, Huan-Min; Young, Charles Yf; Lou, Hong-Xiang; Yuan, Hui-Qing

    2016-06-01

    Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest.

  11. Structural insights into alternative splicing-mediated desensitization of jasmonate signaling.

    PubMed

    Zhang, Feng; Ke, Jiyuan; Zhang, Li; Chen, Rongzhi; Sugimoto, Koichi; Howe, Gregg A; Xu, H Eric; Zhou, Mingguo; He, Sheng Yang; Melcher, Karsten

    2017-02-14

    Jasmonate ZIM-domain (JAZ) transcriptional repressors play a key role in regulating jasmonate (JA) signaling in plants. Below a threshold concentration of jasmonoyl isoleucine (JA-Ile), the active form of JA, the C-terminal Jas motif of JAZ proteins binds MYC transcription factors to repress JA signaling. With increasing JA-Ile concentration, the Jas motif binds to JA-Ile and the COI1 subunit of the SCF COI1 E3 ligase, which mediates ubiquitination and proteasomal degradation of JAZ repressors, resulting in derepression of MYC transcription factors. JA signaling subsequently becomes desensitized, in part by feedback induction of JAZ splice variants that lack the C-terminal Jas motif but include an N-terminal cryptic MYC-interaction domain (CMID). The CMID sequence is dissimilar to the Jas motif and is incapable of recruiting SCF COI1 , allowing CMID-containing JAZ splice variants to accumulate in the presence of JA and to re-repress MYC transcription factors as an integral part of reestablishing signal homeostasis. The mechanism by which the CMID represses MYC transcription factors remains elusive. Here we describe the crystal structure of the MYC3-CMID JAZ10 complex. In contrast to the Jas motif, which forms a single continuous helix when bound to MYC3, the CMID adopts a loop-helix-loop-helix architecture with modular interactions with both the Jas-binding groove and the backside of the Jas-interaction domain of MYC3. This clamp-like interaction allows the CMID to bind MYC3 tightly and block access of MED25 (a subunit of the Mediator coactivator complex) to the MYC3 transcriptional activation domain, shedding light on the enigmatic mechanism by which JAZ splice variants desensitize JA signaling.

  12. Endogenous jasmonic and salicylic acids levels in the Cd-hyperaccumulator Noccaea (Thlaspi) praecox exposed to fungal infection and/or mechanical stress.

    PubMed

    Llugany, M; Martin, S R; Barceló, J; Poschenrieder, C

    2013-08-01

    Sensitivity to Erysiphe in Noccaea praecox with low metal supply is related to the failure in enhancing SA. Cadmium protects against fungal-infection by direct toxicity and/or enhanced fungal-induced JA signaling. Metal-based defense against biotic stress is an attractive hypothesis on evolutionary advantages of plant metal hyperaccumulation. Metals may compensate for a defect in biotic stress signaling in hyperaccumulators (metal-therapy) by either or both direct toxicity to pathogens and by metal-induced alternative signaling pathways. Jasmonic acid (JA) and salicylic acid (SA) are well-established components of stress signaling pathways. However, few studies evaluate the influence of metals on endogenous concentrations of these defense-related hormones. Even less data are available for metal hyperaccumulators. To further test the metal-therapy hypothesis we analyzed endogenous SA and JA concentrations in Noccaea praecox, a cadmium (Cd) hyperaccumulator. Plants treated or not with Cd, were exposed to mechanical wounding, expected to enhance JA signaling, and/or to infection by biotrophic fungus Erysiphe cruciferarum for triggering SA. JA and SA were analyzed in leaf extracts using LC-ESI(-)-MS/MS. Plants without Cd were more susceptible to fungal attack than plants receiving Cd. Cadmium alone tended to increase leaf SA but not JA. Either or both fungal attack and mechanical wounding decreased SA levels and enhanced JA in the Cd-rich leaves of plants exposed to Cd. High leaf Cd in N. praecox seems to hamper biotic-stress-induced SA, while triggering JA signaling in response to fungal attack and wounding. To the best of our knowledge, this is the first report on the endogenous JA and SA levels in a Cd-hyperaccumulator exposed to different biotic and abiotic stresses. Our results support the view of a defect in SA stress signaling in Cd hyperaccumulating N. praecox.

  13. Leaf and root glucosinolate profiles of Chinese cabbage (Brassica rapa ssp. pekinensis) as a systemic response to methyl jasmonate and salicylic acid elicitation.

    PubMed

    Zang, Yun-xiang; Ge, Jia-li; Huang, Ling-hui; Gao, Fei; Lv, Xi-shan; Zheng, Wei-wei; Hong, Seung-beom; Zhu, Zhu-jun

    2015-08-01

    Glucosinolates (GSs) are an important group of defensive phytochemicals mainly found in Brassicaceae. Plant hormones jasmonic acid (JA) and salicylic acid (SA) are major regulators of plant response to pathogen attack. However, there is little information about the interactive effect of both elicitors on inducing GS biosynthesis in Chinese cabbage (Brassica rapa ssp. pekinensis). In this study, we applied different concentrations of methyl jasmonate (MeJA) and/or SA onto the leaf and root of Chinese cabbage to investigate the time-course interactive profiles of GSs. Regardless of the site of the elicitation and the concentrations of the elicitors, the roots accumulated much more GSs and were more sensitive and more rapidly responsive to the elicitors than leaves. Irrespective of the elicitation site, MeJA had a greater inducing and longer lasting effect on GS accumulation than SA. All three components of indole GS (IGS) were detected along with aliphatic and aromatic GSs. However, IGS was a major component of total GSs that accumulated rapidly in both root and leaf tissues in response to MeJA and SA elicitation. Neoglucobrassicin (neoGBC) did not respond to SA but to MeJA in leaf tissue, while it responded to both SA and MeJA in root tissue. Conversion of glucobrassicin (GBC) to neoGBC occurred at a steady rate over 3 d of elicitation. Increased accumulation of 4-methoxy glucobrassicin (4-MGBC) occurred only in the root irrespective of the type of elicitors and the site of elicitation. Thus, accumulation of IGS is a major metabolic hallmark of SA- and MeJA-mediated systemic response systems. SA exerted an antagonistic effect on the MeJA-induced root GSs irrespective of the site of elicitation. However, SA showed synergistic and antagonistic effects on the MeJA-induced leaf GSs when roots and leaves are elicitated for 3 d, respectively.

  14. Ethylene independent induction of lycopene biosynthesis in tomato fruits by jasmonates

    PubMed Central

    Wei, Jia; Wang, Qiaomei

    2012-01-01

    One of the main characteristics of tomato (Solanum lycopersicum) fruit ripening is a massive accumulation of carotenoids (mainly lycopene), which may contribute to the nutrient quality of tomato fruit and its role in chemoprevention. Previous studies have shown that ethylene (ET) plays a central role in promoting fruit ripening. In this study, the role of jasmonic acid (JA) in controlling lycopene accumulation in tomato fruits was analysed by measuring fruit lycopene content and the expression levels of lycopene biosynthetic genes in JA-deficient mutants (spr2 and def1) and a 35S::prosystemin transgenic line (35S::prosys) with increased JA levels and constitutive JA signalling. The lycopene content was significantly decreased in the fruits of spr2 and def1, but was enhanced in 35S::prosys fruits. Simultaneously, the expression of lycopene biosynthetic genes followed a similar trend. Lycopene synthesis in methyl jasmonate (MeJA) vapour-treated fruits showed an inverted U-shaped dose response, which significantly enhanced the fruit lycopene content and restored lycopene accumulation in spr2 and def1 at a concentration of 0.5 µM. The results indicated that JA plays a positive role in lycopene biosynthesis. In addition, the role of ET in JA-induced lycopene accumulation was also examined. Ethylene production in tomato fruits was depressed in spr2 and def1 while it increased in 35S::prosys. However, the exogenous application of MeJA to Never ripe (Nr), the ET-insensitive mutant, significantly promoted lycopene accumulation, as well as the expression of lycopene biosynthetic genes. Based on these results, it is proposed that JA might function independently of ethylene to promote lycopene biosynthesis in tomato fruits. PMID:22945939

  15. Interacting signal pathways control defense gene expression in Arabidopsis in response to cell wall-degrading enzymes from Erwinia carotovora.

    PubMed

    Norman-Setterblad, C; Vidal, S; Palva, E T

    2000-04-01

    We have characterized the role of salicylic acid (SA)-independent defense signaling in Arabidopsis thaliana in response to the plant pathogen Erwinia carotovora subsp. carotovora. Use of pathway-specific target genes as well as signal mutants allowed us to elucidate the role and interactions of ethylene, jasmonic acid (JA), and SA signal pathways in this response. Gene expression studies suggest a central role for both ethylene and JA pathways in the regulation of defense gene expression triggered by the pathogen or by plant cell wall-degrading enzymes (CF) secreted by the pathogen. Our results suggest that ethylene and JA act in concert in this regulation. In addition, CF triggers another, strictly JA-mediated response inhibited by ethylene and SA. SA does not appear to have a major role in activating defense gene expression in response to CF. However, SA may have a dual role in controlling CF-induced gene expression, by enhancing the expression of genes synergistically induced by ethylene and JA and repressing genes induced by JA alone.

  16. Influence of the extent of westernization of lifestyle on the progression of preclinical atherosclerosis in Japanese subjects.

    PubMed

    Egusa, Genshi; Watanabe, Hiroshi; Ohshita, Kayo; Fujikawa, Rumi; Yamane, Kiminori; Okubo, Masamichi; Kohno, Nobuoki

    2002-01-01

    To clarify the influence of a westernized lifestyle on the risk factors for atherosclerosis and preclinical atherosclerosis in Japanese subjects, we surveyed a Japanese population and Japanese immigrants in the United States. Based on the extent of westernization of their lifestyle, the subjects were classified as Japanese (J), first generation Japanese-Americans (JA-I), and second or later generation Japanese-Americans (JA-II). The consumption of animal fat and simple carbohydrates increased in the order of J, JA-I, and JA-II, while the subjects with strenuous physical activity decreased in the same order. The waist-hip ratio, fasting insulin level, serum cholesterol and triglyceride levels, and prevalence of hypertension increased in the same order as the dietary changes. The carotid intima-media wall thickness and the plaque size, which are indices of preclinical atherosclerosis, also increased in the order of J, JA-I, and JA-II. These data indicate that a westernized lifestyle aggravates the risk factors for atherosclerosis and influences the progression of preclinical atherosclerosis, in correspondence with the extent of westernization.

  17. Methyl Jasmonate Alleviates Cadmium-Induced Photosynthetic Damages through Increased S-Assimilation and Glutathione Production in Mustard

    PubMed Central

    Per, Tasir S.; Khan, Nafees A.; Masood, Asim; Fatma, Mehar

    2016-01-01

    The effect of methyl jasmonate (MeJA) in mitigation of 50 μM cadmium (Cd) toxicity on structure and function of photosynthetic apparatus in presence or absence of 1.0 mM SO42– was investigated in mustard (Brassica juncea L. cv. Ro Agro 4001) at 30 days after sowing. Plants exhibited increased oxidative stress, impaired photosynthetic function when grown with Cd, but MeJA in presence of sulfur (S) more prominently ameliorated Cd effects through increased S-assimilation and production of reduced glutathione (GSH) and promoted photosynthetic functions. The transmission electron microscopy showed that MeJA protected chloroplast structure against Cd-toxicity. The use of GSH biosynthetic inhibitor, buthionine sulfoximine (BSO) substantiated the findings that ameliorating effect of MeJA was through GSH production. MeJA could not alleviate Cd effects when BSO was used due to unavailability of GSH even with the input of S. The study shows that MeJA regulates S-assimilation and GSH production for protection of structure and function of photosynthetic apparatus in mustard plants under Cd stress. PMID:28066485

  18. Determination of proteins induced in response to jasmonic acid and salicylic acid in resistant and susceptible cultivars of tomato.

    PubMed

    Afroz, Amber; Khan, Muhammad Rashid; Komatsu, Setsuko

    2010-07-01

    Jasmonic acid (JA) and salicylic acid (SA) are signaling molecules that play key roles in the regulation of metabolic processes, reproduction, and defense against pathogens. The proteomics approach was used to identify proteins that are induced by JA and SA in the tomato cultivars Roma and Pant Bahr, which are susceptible and resistant to bacterial wilt, respectively. Threonine deaminase and leucine amino peptidase were upregulated, and ribulose-1,5-bisphosphate carboxylase/oxygenase small chain was downregulated by time-course application of JA. Translationally controlled tumor protein was upregulated by time-course application of SA. Protein disulfide isomerase was upregulated by application of either JA or SA. Proteins related to defense, energy, and protein destination/storage are suspected to be responsible for the susceptibility or resistance of the cultivars. Furthermore, in Roma, iron ABC transporter was upregulated by JA and down-regulated by SA. Iron ABC transporter plays a part in the signal transduction of both JA and SA in cultivars of tomato that are resistant to bacterial wilt.

  19. 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).

  20. 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

  1. 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

  2. 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

  3. Jasmonates: Multifunctional Roles in Stress Tolerance

    PubMed Central

    Ahmad, Parvaiz; Rasool, Saiema; Gul, Alvina; Sheikh, Subzar A.; Akram, Nudrat A.; Ashraf, Muhammad; Kazi, A. M.; Gucel, Salih

    2016-01-01

    Jasmonates (JAs) [Jasmonic acid (JA) and methyl jasmonates (MeJAs)] are known to take part in various physiological processes. Exogenous application of JAs so far tested on different plants under abiotic stresses particularly salinity, drought, and temperature (low/high) conditions have proved effective in improving plant stress tolerance. However, its extent of effectiveness entirely depends on the type of plant species tested or its concentration. The effects of introgression or silencing of different JA- and Me-JA-related genes have been summarized in this review, which have shown a substantial role in improving crop yield and quality in different plants under stress or non-stress conditions. Regulation of JAs synthesis is impaired in stressed as well as unstressed plant cells/tissues, which is believed to be associated with a variety of metabolic events including signal transduction. Although, mitogen activated protein kinases (MAPKs) are important components of JA signaling and biosynthesis pathways, nitric oxide, ROS, calcium, ABA, ethylene, and salicylic acid are also important mediators of plant growth and development during JA signal transduction and synthesis. The exploration of other signaling molecules can be beneficial to examine the details of underlying molecular mechanisms of JA signal transduction. Much work is to be done in near future to find the proper answers of the questions like action of JA related metabolites, and identification of universal JA receptors etc. Complete signaling pathways involving MAPKs, CDPK, TGA, SIPK, WIPK, and WRKY transcription factors are yet to be investigated to understand the complete mechanism of action of JAs. PMID:27379115

  4. Jasmonate-triggered plant immunity.

    PubMed

    Campos, Marcelo L; Kang, Jin-Ho; Howe, Gregg A

    2014-07-01

    The plant hormone jasmonate (JA) exerts direct control over the production of chemical defense compounds that confer resistance to a remarkable spectrum of plant-associated organisms, ranging from microbial pathogens to vertebrate herbivores. The underlying mechanism of JA-triggered immunity (JATI) can be conceptualized as a multi-stage signal transduction cascade involving: i) pattern recognition receptors (PRRs) that couple the perception of danger signals to rapid synthesis of bioactive JA; ii) an evolutionarily conserved JA signaling module that links fluctuating JA levels to changes in the abundance of transcriptional repressor proteins; and iii) activation (de-repression) of transcription factors that orchestrate the expression of myriad chemical and morphological defense traits. Multiple negative feedback loops act in concert to restrain the duration and amplitude of defense responses, presumably to mitigate potential fitness costs of JATI. The convergence of diverse plant- and non-plant-derived signals on the core JA module indicates that JATI is a general response to perceived danger. However, the modular structure of JATI may accommodate attacker-specific defense responses through evolutionary innovation of PRRs (inputs) and defense traits (outputs). The efficacy of JATI as a defense strategy is highlighted by its capacity to shape natural populations of plant attackers, as well as the propensity of plant-associated organisms to subvert or otherwise manipulate JA signaling. As both a cellular hub for integrating informational cues from the environment and a common target of pathogen effectors, the core JA module provides a focal point for understanding immune system networks and the evolution of chemical diversity in the plant kingdom.

  5. Differential expression of jasmonate biosynthesis genes in cacao genotypes contrasting for resistance against Moniliophthora perniciosa.

    PubMed

    Litholdo, Celso G; Leal, Gildemberg A; Albuquerque, Paulo S B; Figueira, Antonio

    2015-10-01

    The resistance mechanism of cacao against M. perniciosa is likely to be mediated by JA/ET-signaling pathways due to the preferential TcAOS and TcSAM induction in a resistant genotype. The basidiomycete Moniliophthora perniciosa causes a serious disease in cacao (Theobroma cacao L.), and the use of resistant varieties is the only sustainable long-term solution. Cacao resistance against M. perniciosa is characterized by pathogen growth inhibition with reduced colonization and an attenuation of disease symptoms, suggesting a regulation by jasmonate (JA)/ethylene (ET) signaling pathways. The hypothesis that genes involved in JA biosynthesis would be active in the interaction of T. cacao and M. perniciosa was tested here. The cacao JA-related genes were evaluated for their relative quantitative expression in susceptible and resistant genotypes upon the exogenous application of ET, methyl-jasmonate (MJ), and salicylic acid (SA), or after M. perniciosa inoculation. MJ treatment triggered changes in the expression of genes involved in JA biosynthesis, indicating that the mechanism of positive regulation by exogenous MJ application occurs in cacao. However, a higher induction of these genes was observed in the susceptible genotype. Further, a contrast in JA-related transcriptional expression was detected between susceptible and resistant plants under M. perniciosa infection, with the induction of the allene oxide synthase gene (TcAOS), which encodes a key enzyme in the JA biosynthesis pathway in the resistant genotype. Altogether, this work provides additional evidences that the JA-dependent signaling pathway is modulating the defense response against M. perniciosa in a cacao-resistant genotype.

  6. PAMP-induced defense responses in potato require both salicylic acid and jasmonic acid.

    PubMed

    Halim, Vincentius A; Altmann, Simone; Ellinger, Dorothea; Eschen-Lippold, Lennart; Miersch, Otto; Scheel, Dierk; Rosahl, Sabine

    2009-01-01

    To elucidate the molecular mechanisms underlying pathogen-associated molecular pattern (PAMP)-induced defense responses in potato (Solanum tuberosum), the role of the signaling compounds salicylic acid (SA) and jasmonic acid (JA) was analyzed. Pep-13, a PAMP from Phytophthora, induces the accumulation of SA, JA and hydrogen peroxide, as well as the activation of defense genes and hypersensitive-like cell death. We have previously shown that SA is required for Pep-13-induced defense responses. To assess the importance of JA, RNA interference constructs targeted at the JA biosynthetic genes, allene oxide cyclase and 12-oxophytodienoic acid reductase, were expressed in transgenic potato plants. In addition, expression of the F-box protein COI1 was reduced by RNA interference. Plants expressing the RNA interference constructs failed to accumulate the respective transcripts in response to wounding or Pep-13 treatment, neither did they contain significant amounts of JA after elicitation. In response to infiltration of Pep-13, the transgenic plants exhibited a highly reduced accumulation of reactive oxygen species as well as reduced hypersensitive cell death. The ability of the JA-deficient plants to accumulate SA suggests that SA accumulation is independent or upstream of JA accumulation. These data show that PAMP responses in potato require both SA and JA and that, in contrast to Arabidopsis, these compounds act in the same signal transduction pathway. Despite their inability to fully respond to PAMP treatment, the transgenic RNA interference plants are not altered in their basal defense against Phytophthora infestans.

  7. Modulation of ethylene- and heat-controlled hyponastic leaf movement in Arabidopsis thaliana by the plant defence hormones jasmonate and salicylate.

    PubMed

    van Zanten, Martijn; Ritsema, Tita; Polko, Joanna K; Leon-Reyes, Antonio; Voesenek, Laurentius A C J; Millenaar, Frank F; Pieterse, Corné M J; Peeters, Anton J M

    2012-04-01

    Upward leaf movement (hyponastic growth) is adopted by several plant species including Arabidopsis thaliana, as a mechanism to escape adverse growth conditions. Among the signals that trigger hyponastic growth are, the gaseous hormone ethylene, low light intensities, and supra-optimal temperatures (heat). Recent studies indicated that the defence-related phytohormones jasmonic acid (JA) and salicylic acid (SA) synthesized by the plant upon biotic infestation repress low light-induced hyponastic growth. The hyponastic growth response induced by high temperature (heat) treatment and upon application of the gaseous hormone ethylene is highly similar to the response induced by low light. To test if these environmental signals induce hyponastic growth via parallel pathways or converge downstream, we studied here the roles of Methyl-JA (MeJA) and SA on ethylene- and heat-induced hyponastic growth. For this, we used a time-lapse camera setup. Our study includes pharmacological application of MeJA and SA and biological infestation using the JA-inducing caterpillar Pieris rapae as well as mutants lacking JA or SA signalling components. The data demonstrate that MeJA is a positive, and SA, a negative regulator of ethylene-induced hyponastic growth and that both hormones repress the response to heat. Taking previous studies into account, we conclude that SA is the first among many tested components which is repressing hyponastic growth under all tested inductive environmental stimuli. However, since MeJA is a positive regulator of ethylene-induced hyponastic growth and is inhibiting low light- and heat-induced leaf movement, we conclude that defence hormones control hyponastic growth by affecting stimulus-specific signalling pathways.

  8. Epidermal jasmonate perception is sufficient for all aspects of jasmonate-mediated male fertility in Arabidopsis.

    PubMed

    Jewell, Jeremy B; Browse, John

    2016-03-01

    Jasmonate (JA) signaling is essential for several environmental responses and reproductive development in many plant species. In Arabidopsis thaliana, the most obvious phenotype of JA biosynthetic and perception mutants is profound sporophytic male sterility characterized by failure of stamen filament elongation, severe delay of anther dehiscence and pollen inviability. The site of action of JA in the context of reproductive development has been discussed, but the ideas have not been tested experimentally. To this end we used targeted expression of a COI1-YFP transgene in the coi1-1 mutant background. As COI1 is an essential component of the JA co-receptor complex, the null coi1-1 mutant is male sterile due to lack of JA perception. We show that expression of COI1-YFP in the epidermis of the stamen filament and anther in coi1 mutant plants is sufficient to rescue filament elongation, anther dehiscence and pollen viability. In contrast, filament expression alone or expression in the tapetum do not restore dehiscence and pollen viability. These results demonstrate that epidermal JA perception is sufficient for anther function and pollen viability, and suggest the presence of a JA-dependent non-autonomous signal produced in the anther epidermis to synchronize both anther dehiscence and pollen maturation. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  9. Memory responses of jasmonic acid-associated Arabidopsis genes to a repeated dehydration stress.

    PubMed

    Liu, Ning; Staswick, Paul E; Avramova, Zoya

    2016-11-01

    Dehydration stress activates numerous genes co-regulated by diverse signaling pathways. Upon repeated exposures, however, a subset of these genes does not respond maintaining instead transcription at their initial pre-stressed levels ('revised-response' genes). Most of these genes are involved in jasmonic acid (JA) biosynthesis, JA-signaling and JA-mediated stress responses. How these JA-associated genes are regulated to provide different responses to similar dehydration stresses is an enigma. Here, we investigate molecular mechanisms that contribute to this transcriptional behavior. The memory-mechanism is stress-specific: one exposure to dehydration stress or to abscisic acid (ABA) is required to prevent transcription in the second. Both ABA-mediated and JA-mediated pathways are critical for the activation of these genes, but the two signaling pathways interact differently during a single or multiple encounters with dehydration stress. Synthesis of JA during the first (S1) but not the second dehydration stress (S2) accounts for the altered transcriptional responses. We propose a model for these memory responses, wherein lack of MYC2 and of JA synthesis in S2 is responsible for the lack of expression of downstream genes. The similar length of the memory displayed by different memory-type genes suggests biological relevance for transcriptional memory as a gene-regulating mechanism during recurring bouts of drought. © 2016 John Wiley & Sons Ltd.

  10. Repressor- and Activator-Type Ethylene Response Factors Functioning in Jasmonate Signaling and Disease Resistance Identified via a Genome-Wide Screen of Arabidopsis Transcription Factor Gene Expression[w

    PubMed Central

    McGrath, Ken C.; Dombrecht, Bruno; Manners, John M.; Schenk, Peer M.; Edgar, Cameron I.; Maclean, Donald J.; Scheible, Wolf-Rüdiger; Udvardi, Michael K.; Kazan, Kemal

    2005-01-01

    To identify transcription factors (TFs) involved in jasmonate (JA) signaling and plant defense, we screened 1,534 Arabidopsis (Arabidopsis thaliana) TFs by real-time quantitative reverse transcription-PCR for their altered transcript at 6 h following either methyl JA treatment or inoculation with the incompatible pathogen Alternaria brassicicola. We identified 134 TFs that showed a significant change in expression, including many APETALA2/ethylene response factor (AP2/ERF), MYB, WRKY, and NAC TF genes with unknown functions. Twenty TF genes were induced by both the pathogen and methyl JA and these included 10 members of the AP2/ERF TF family, primarily from the B1a and B3 subclusters. Functional analysis of the B1a TF AtERF4 revealed that AtERF4 acts as a novel negative regulator of JA-responsive defense gene expression and resistance to the necrotrophic fungal pathogen Fusarium oxysporum and antagonizes JA inhibition of root elongation. In contrast, functional analysis of the B3 TF AtERF2 showed that AtERF2 is a positive regulator of JA-responsive defense genes and resistance to F. oxysporum and enhances JA inhibition of root elongation. Our results suggest that plants coordinately express multiple repressor- and activator-type AP2/ERFs during pathogen challenge to modulate defense gene expression and disease resistance. PMID:16183832

  11. Herbivore- and Elicitor- Induced Resistance in Groundnut to Asian armyworm, Spodoptera litura (Fab.) (Lepidoptera: Noctuidae)

    PubMed Central

    War, Abdul Rashid; Paulraj, Michael Gabriel; War, Mohd Yousf; Ignacimuthu, Savarimuthu

    2011-01-01

    Induced defense was studied in three groundnut genotypes ICGV 86699 (resistant), NCAc 343 (resistant) and TMV 2 (susceptible) in response to Spodoptera litura infestation and jasmonic acid (JA) application. The activity of the oxidative enzymes [peroxidase (POD) and polyphenol oxidase (PPO)] and the amounts other host plant defense components [total phenols, hydrogen peroxide (H2O2), malondialdehyde (MDA), and protein content] were recorded at 24, 48, 72 and 96 h in JA pretreated (one day before) plants and infested with S. litura, and JA application and simultaneous infestation with S. litura to understand the defense response of groundnut genotypes against S. litura damage. Data on plant damage, larval survival and larval weights were also recorded. There was a rapid increase in the activities of POD and PPO and in the quantities of total phenols, H2O2, MDA and protein content in the JA pretreated + S. litura infested plants. All the three genotypes showed quick response to JA application and S. litura infestation by increasing the defensive compounds. Among all the genotypes, higher induction was recorded in ICGV 86699 in most of the parameters. Reduced plant damage, low larval survival and larval weights were observed in JA pretreated plants. It suggests that pretreatment with elicitors, such as JA could provide more opportunity for plant defense against herbivores. PMID:22042128

  12. Extrafloral nectar production of the ant-associated plant, Macaranga tanarius, is an induced, indirect, defensive response elicited by jasmonic acid

    PubMed Central

    Heil, Martin; Koch, Thomas; Hilpert, Andrea; Fiala, Brigitte; Boland, Wilhelm; Linsenmair, K. Eduard

    2001-01-01

    Plant species in at least 66 families produce extrafloral nectar (EFN) on their leaves or shoots and therewith attract predators and parasitoids, such as ants and wasps, which in turn defend them against herbivores. We investigated whether EFN secretion is induced by herbivory and/or artificial damage, and thus can be regarded as an induced defensive response. In addition, we studied the underlying signaling pathway. EFN secretion by field-grown Macaranga tanarius increased after herbivory, artificial leaf damage, and exogenous jasmonic acid (JA) application. Artificial damage strongly enhanced endogenous JA concentrations. The response in EFN production to artificial damage was much less pronounced in those leaves that were treated with phenidone to inhibit endogenous JA synthesis. Quantitative dose–response relations were found between the increase in nectar production and both the intensity of leaf damage and the amounts of exogenously applied JA. The amount of endogenously produced JA was positively correlated with the intensity of leaf damage. Increased numbers of defending insects and decreased numbers of herbivores were observed on leaves after inducing EFN production by exogenous JA treatment. Over 6 weeks, repeatedly applied JA or artificial damage resulted in a ten-fold reduction in herbivory. These results demonstrate that EFN production represents an alternative mechanism for induced, indirect defensive plant responses that are mediated via the octadecanoid signal transduction cascade. PMID:11158598

  13. Differential Effects of Methyl Jasmonate on the Expression of the Early Light-Inducible Proteins and Other Light-Regulated Genes in Barley1

    PubMed Central

    Wierstra, Inken; Kloppstech, Klaus

    2000-01-01

    The effects of methyl jasmonate (JA-Me) on early light-inducible protein (ELIP) expression in barley (Hordeum vulgare L. cv Apex) have been studied. Treatment of leaf segments with JA-Me induces the same symptoms as those exhibited by norflurazon bleaching, including a loss of pigments and enhanced light stress that results in increased ELIP expression under both high- and low-light conditions. The expression of both low- and high-molecular-mass ELIP families is considerably down-regulated by JA-Me at the transcript and protein levels. This repression occurs despite increased photoinhibition measurable as a massive degradation of D1 protein and a delayed recovery of photosystem II activity. In JA-Me-treated leaf segments, the decrease of the photochemical efficiency of photosystem II under high light is substantially more pronounced as compared to controls in water. The repression of ELIP expression by JA-Me is superimposed on the effect of the increased light stress that leads to enhanced ELIP expression. The fact that the reduction of ELIP transcript levels is less pronounced than those of light-harvesting complex II and small subunit of Rubisco transcripts indicates that light stress is still affecting gene expression in the presence of JA-Me. The jasmonate-induced protein transcript levels that are induced by JA-Me decline under light stress conditions. PMID:11027731

  14. Jasmonic acid-induced volatiles of Brassica oleracea attract parasitoids: effects of time and dose, and comparison with induction by herbivores

    PubMed Central

    Bruinsma, Maaike; Posthumus, Maarten A.; Mumm, Roland; Mueller, Martin J.; van Loon, Joop J. A.; Dicke, Marcel

    2009-01-01

    Caterpillar feeding induces direct and indirect defences in brassicaceous plants. This study focused on the role of the octadecanoid pathway in induced indirect defence in Brassica oleracea. The effect of induction by exogenous application of jasmonic acid (JA) on the responses of Brussels sprouts plants and on host-location behaviour of associated parasitoid wasps was studied. Feeding by the biting–chewing herbivores Pieris rapae and Plutella xylostella resulted in significantly increased endogenous levels of JA, a central component in the octadecanoid signalling pathway that mediates induced plant defence. The levels of the intermediate 12-oxophyto-dienoic acid (OPDA) were significantly induced only after P. rapae feeding. Three species of parasitoid wasps, Cotesia glomerata, C. rubecula, and Diadegma semiclausum, differing in host range and host specificity, were tested for their behavioural responses to volatiles from herbivore-induced, JA-induced, and non-induced plants. All three species were attracted to volatiles from JA-induced plants compared with control plants; however, they preferred volatiles from herbivore-induced plants over volatiles from JA-induced plants. Attraction of C. glomerata depended on both timing and dose of JA application. JA-induced plants produced larger quantities of volatiles than herbivore-induced and control plants, indicating that not only quantity, but also quality of the volatile blend is important in the host-location behaviour of the wasps. PMID:19451186

  15. Physicochemical and thermodynamic characterization of the encapsulation of methyl jasmonate by natural and modified cyclodextrins using reversed-phase high-pressure liquid chromatography.

    PubMed

    López-Nicolás, José Manuel; Escorial Camps, Marta; Pérez-Sánchez, Horacio; García-Carmona, Francisco

    2013-11-27

    Although the combinations of methyl jasmonate (MeJA) and cyclodextrins (CDs) have been used by different authors to stimulate the production of several metabolites, no study has been published about the possible formation of MeJA-CD complexes when these two molecules are added together to the reaction medium as elicitors. For this reason and because knowledge of the possible complexation process of MeJA with CD under different physicochemical conditions is essential if these two molecules are to be used in cell cultures, this paper looks at the complexation of MeJA with natural and modified CDs using a reversed-phase high-pressure liquid chromatography (RP-HPLC) system. The interaction of MeJA with β-CD was more efficient than with α- and γ-CDs. However, a modified CD, HP-β-CD, was the most effective of all of the CDs tested. Moreover, MeJA formed complexes with CD with a 1:1 stoichiometry, and the formation constants of these complexes were strongly dependent upon the temperature of the mobile phase used but not the pH. To obtain information about the mechanism of the affinity of MeJA for CD, the thermodynamic parameters ΔG°, ΔH°, and ΔS° were calculated. Finally, molecular modeling studies were carried out to propose which molecular interactions are established in the complexation process.

  16. 45 CFR Appendix B to Part 1158 - Disclosure Form to Report Lobbying

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 3 2014-10-01 2014-10-01 false Disclosure Form to Report Lobbying B Appendix B to... ARTS AND THE HUMANITIES NATIONAL ENDOWMENT FOR THE ARTS NEW RESTRICTIONS ON LOBBYING Pt. 1158, App. B Appendix B to Part 1158—Disclosure Form to Report Lobbying EC01JA91.010 EC01JA91.011 EC01JA91.012 ...

  17. 45 CFR Appendix B to Part 1168 - Disclosure Form To Report Lobbying

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 45 Public Welfare 3 2014-10-01 2014-10-01 false Disclosure Form To Report Lobbying B Appendix B to Part 1168 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL FOUNDATION ON THE..., App. B Appendix B to Part 1168—Disclosure Form To Report Lobbying EC01JA91.013 EC01JA91.014 EC01JA91...

  18. 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.

  19. 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).

  20. 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.

  1. 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.

  2. 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

  3. Temporal transcriptome changes induced by methyl jasmonate in Salvia sclarea.

    PubMed

    Hao, Da Cheng; Chen, Shi Lin; Osbourn, Anne; Kontogianni, Vassiliki G; Liu, Li Wei; Jordán, Maria J

    2015-03-01

    Salvia sclarea is a traditional medicinal and aromatic plant that grows in Europe and produces various economically important compounds, including phenylpropanoid derivatives and terpenoids. Methyl jasmonate (MeJA) is commonly used to elicit plant stress responses. However, how MeJA enhances production of secondary metabolites in S. sclarea is not well understood. We performed a genome-wide analysis of temporal gene expression in S. sclarea leaves and roots. The transcriptome profiles 0, 10 and 26 h after MeJA treatment were analyzed by Illumina RNA-Seq. A total of 16,142 isogenes (average length 866bp; N50 1035bp) were obtained by de novo assembly of 35,757,567 raw sequencing reads. When these sequencing reads were mapped onto the assembled Unigenes, 3236, 2792 and 798 Unigenes were found to be expressed differentially between 0 and 10h, 0 and 26 h, and 10 and 26h, respectively. These included many secondary metabolite biosynthesis, stress and defense-related genes. A qRT-PCR analysis confirmed the expression profiles of selected differentially expressed genes (DEGs) revealed by RNA-Seq data, and also extended our analysis of differential gene expression to 73 h. Our investigations revealed temporal differences in the responses of S. sclarea to MeJA treatment. MeJA treatment induced the expression of a large number of genes involved in phenylpropanoid biosynthesis, especially between 0 and 10h, and 0 and 26 h. Additionally, many genes encoding transcription factors, cytochrome P450s, glycosyltransferases, methyltransferases and transporters were shown to respond to MeJA elicitation. DEGs related to structural molecule activity and cell death showed a significant temporal variation. A chromatographic analysis of metabolites at 26h, 73h and six days after MeJA treatment indicated that these transcriptomic changes precede MeJA-induced changes in secondary metabolite content. This study sheds light on the molecular mechanisms of MeJA elicitation and is helpful in

  4. Pathogen exploitation of an abscisic acid- and jasmonate-inducible MAPK phosphatase and its interception by Arabidopsis immunity.

    PubMed

    Mine, Akira; Berens, Matthias L; Nobori, Tatsuya; Anver, Shajahan; Fukumoto, Kaori; Winkelmüller, Thomas M; Takeda, Atsushi; Becker, Dieter; Tsuda, Kenichi

    2017-07-11

    Phytopathogens promote virulence by, for example, exploiting signaling pathways mediated by phytohormones such as abscisic acid (ABA) and jasmonate (JA). Some plants can counteract pathogen virulence by invoking a potent form of immunity called effector-triggered immunity (ETI). Here, we report that ABA and JA mediate inactivation of the immune-associated MAP kinases (MAPKs), MPK3 and MPK6, in Arabidopsis thaliana ABA induced expression of genes encoding the protein phosphatases 2C (PP2Cs), HAI1 , HAI2 , and HAI3 through ABF/AREB transcription factors. These three HAI PP2Cs interacted with MPK3 and MPK6 and were required for ABA-mediated MPK3/MPK6 inactivation and immune suppression. The bacterial pathogen Pseudomonas syringae pv. tomato ( Pto ) DC3000 activates ABA signaling and produces a JA-mimicking phytotoxin, coronatine (COR), that promotes virulence. We found that Pto DC3000 induces HAI1 through COR-mediated activation of MYC2, a master transcription factor in JA signaling. HAI1 dephosphorylated MPK3 and MPK6 in vitro and was necessary for COR-mediated suppression of MPK3/MPK6 activation and immunity. Intriguingly, upon ETI activation, A. thaliana plants overcame the HAI1-dependent virulence of COR by blocking JA signaling. Finally, we showed conservation of induction of HAI PP2Cs by ABA and JA in other Brassicaceae species. Taken together, these results suggest that ABA and JA signaling pathways, which are hijacked by the bacterial pathogen, converge on the HAI PP2Cs that suppress activation of the immune-associated MAPKs. Also, our data unveil interception of JA-signaling activation as a host counterstrategy against the bacterial suppression of MAPKs during ETI.

  5. The Arabidopsis KH-Domain RNA-Binding Protein ESR1 Functions in Components of Jasmonate Signalling, Unlinking Growth Restraint and Resistance to Stress

    PubMed Central

    Thatcher, Louise F.; Kamphuis, Lars G.; Hane, James K.; Oñate-Sánchez, Luis; Singh, Karam B.

    2015-01-01

    Glutathione S-transferases (GSTs) play important roles in the protection of cells against toxins and oxidative damage where one Arabidopsis member, GSTF8, has become a commonly used marker gene for early stress and defense responses. A GSTF8 promoter fragment fused to the luciferase reporter gene was used in a forward genetic screen for Arabidopsis mutants with up-regulated GSTF8 promoter activity. This identified the esr1-1 (enhanced stress response 1) mutant which also conferred increased resistance to the fungal pathogen Fusarium oxysporum. Through positional cloning, the ESR1 gene was found to encode a KH-domain containing RNA-binding protein (At5g53060). Whole transcriptome sequencing of esr1-1 identified altered expression of genes involved in responses to biotic and abiotic stimuli, hormone signaling pathways and developmental processes. In particular was an overall significant enrichment for jasmonic acid (JA) mediated processes in the esr1-1 down-regulated dataset. A subset of these genes were tested for MeJA inducibility and we found the expression of some but not all were reduced in esr1-1. The esr1-1 mutant was not impaired in other aspects of JA-signalling such as JA- sensitivity or development, suggesting ESR1 functions in specific components of the JA-signaling pathway. Examination of salicylic acid (SA) regulated marker genes in esr1-1 showed no increase in basal or SA induced expression suggesting repression of JA-regulated genes is not due to antagonistic SA-JA crosstalk. These results define new roles for KH-domain containing proteins with ESR1 unlinking JA-mediated growth and defense responses. PMID:25985302

  6. The Arabidopsis KH-Domain RNA-Binding Protein ESR1 Functions in Components of Jasmonate Signalling, Unlinking Growth Restraint and Resistance to Stress.

    PubMed

    Thatcher, Louise F; Kamphuis, Lars G; Hane, James K; Oñate-Sánchez, Luis; Singh, Karam B

    2015-01-01

    Glutathione S-transferases (GSTs) play important roles in the protection of cells against toxins and oxidative damage where one Arabidopsis member, GSTF8, has become a commonly used marker gene for early stress and defense responses. A GSTF8 promoter fragment fused to the luciferase reporter gene was used in a forward genetic screen for Arabidopsis mutants with up-regulated GSTF8 promoter activity. This identified the esr1-1 (enhanced stress response 1) mutant which also conferred increased resistance to the fungal pathogen Fusarium oxysporum. Through positional cloning, the ESR1 gene was found to encode a KH-domain containing RNA-binding protein (At5g53060). Whole transcriptome sequencing of esr1-1 identified altered expression of genes involved in responses to biotic and abiotic stimuli, hormone signaling pathways and developmental processes. In particular was an overall significant enrichment for jasmonic acid (JA) mediated processes in the esr1-1 down-regulated dataset. A subset of these genes were tested for MeJA inducibility and we found the expression of some but not all were reduced in esr1-1. The esr1-1 mutant was not impaired in other aspects of JA-signalling such as JA- sensitivity or development, suggesting ESR1 functions in specific components of the JA-signaling pathway. Examination of salicylic acid (SA) regulated marker genes in esr1-1 showed no increase in basal or SA induced expression suggesting repression of JA-regulated genes is not due to antagonistic SA-JA crosstalk. These results define new roles for KH-domain containing proteins with ESR1 unlinking JA-mediated growth and defense responses.

  7. Induction of direct and indirect plant responses by jasmonic acid, low spider mite densities, or a combination of jasmonic acid treatment and spider mite infestation.

    PubMed

    Gols, Rieta; Roosjen, Mara; Dijkman, Herman; Dicke, Marcel

    2003-12-01

    Jasmonic acid (JA) and the octadecanoid pathway are involved in both induced direct and induced indirect plant responses. In this study, the herbivorous mite, Tetranychus urticae, and its predator, Phytoseiulus persimilis, were given a choice between Lima bean plants induced by JA or spider mites and uninduced control plants. Infestation densities resulting in the induction of predator attractants were much lower than thus far assumed, i.e., predatory mites were significantly attracted to plants that were infested for 2 days with only one or four spider mites per plant. Phytoseiulus persimilis showed a density-dependent response to volatiles from plants that were infested with different numbers of spider mites. Similarly, treating plants with increasing concentrations of JA also led to increased attraction of P. persimilis. Moreover, the duration of spider mite infestation was positively correlated with the proportion of predators that were attracted to mite-infested plants. A pretreatment of the plants with JA followed by a spider mite infestation enhanced the attraction of P. persimilis to plant volatiles compared to attraction to volatiles from plants that were only infested with spider mites and did not receive a pretreatment with JA. The herbivore, T. urticae preferred leaf tissue that previously had been infested with conspecifics to uninfested leaf tissue. In the case of choice tests with JA-induced and control leaf tissue, spider mites slightly preferred control leaf tissue. When spider mites were given a choice between leaf discs induced by JA and leaf discs damaged by spider mite feeding, they preferred the latter. The presence of herbivore induced chemicals and/or spider mite products enhanced settlement of the mites, whereas treatment with JA seemed to impede settlement.

  8. Parasitism by Cuscuta pentagona Attenuates Host Plant Defenses against Insect Herbivores1

    PubMed Central

    Runyon, Justin B.; Mescher, Mark C.; De Moraes, Consuelo M.

    2008-01-01

    Considerable research has examined plant responses to concurrent attack by herbivores and pathogens, but the effects of attack by parasitic plants, another important class of plant-feeding organisms, on plant defenses against other enemies has not been explored. We investigated how attack by the parasitic plant Cuscuta pentagona impacted tomato (Solanum lycopersicum) defenses against the chewing insect beet armyworm (Spodoptera exigua; BAW). In response to insect feeding, C. pentagona-infested (parasitized) tomato plants produced only one-third of the antiherbivore phytohormone jasmonic acid (JA) produced by unparasitized plants. Similarly, parasitized tomato, in contrast to unparasitized plants, failed to emit herbivore-induced volatiles after 3 d of BAW feeding. Although parasitism impaired antiherbivore defenses, BAW growth was slower on parasitized tomato leaves. Vines of C. pentagona did not translocate JA from BAW-infested plants: amounts of JA in parasite vines grown on caterpillar-fed and control plants were similar. Parasitized plants generally contained more salicylic acid (SA), which can inhibit JA in some systems. Parasitized mutant (NahG) tomato plants deficient in SA produced more JA in response to insect feeding than parasitized wild-type plants, further suggesting cross talk between the SA and JA defense signaling pathways. However, JA induction by BAW was still reduced in parasitized compared to unparasitized NahG, implying that other factors must be involved. We found that parasitized plants were capable of producing induced volatiles when experimentally treated with JA, indicating that resource depletion by the parasite does not fully explain the observed attenuation of volatile response to herbivore feeding. Collectively, these findings show that parasitic plants can have important consequences for host plant defense against herbivores. PMID:18165323

  9. Parasitism by Cuscuta pentagona attenuates host plant defenses against insect herbivores.

    PubMed

    Runyon, Justin B; Mescher, Mark C; De Moraes, Consuelo M

    2008-03-01

    Considerable research has examined plant responses to concurrent attack by herbivores and pathogens, but the effects of attack by parasitic plants, another important class of plant-feeding organisms, on plant defenses against other enemies has not been explored. We investigated how attack by the parasitic plant Cuscuta pentagona impacted tomato (Solanum lycopersicum) defenses against the chewing insect beet armyworm (Spodoptera exigua; BAW). In response to insect feeding, C. pentagona-infested (parasitized) tomato plants produced only one-third of the antiherbivore phytohormone jasmonic acid (JA) produced by unparasitized plants. Similarly, parasitized tomato, in contrast to unparasitized plants, failed to emit herbivore-induced volatiles after 3 d of BAW feeding. Although parasitism impaired antiherbivore defenses, BAW growth was slower on parasitized tomato leaves. Vines of C. pentagona did not translocate JA from BAW-infested plants: amounts of JA in parasite vines grown on caterpillar-fed and control plants were similar. Parasitized plants generally contained more salicylic acid (SA), which can inhibit JA in some systems. Parasitized mutant (NahG) tomato plants deficient in SA produced more JA in response to insect feeding than parasitized wild-type plants, further suggesting cross talk between the SA and JA defense signaling pathways. However, JA induction by BAW was still reduced in parasitized compared to unparasitized NahG, implying that other factors must be involved. We found that parasitized plants were capable of producing induced volatiles when experimentally treated with JA, indicating that resource depletion by the parasite does not fully explain the observed attenuation of volatile response to herbivore feeding. Collectively, these findings show that parasitic plants can have important consequences for host plant defense against herbivores.

  10. Bioassays for assessing jasmonate-dependent defenses triggered by pathogens, herbivorous insects, or beneficial rhizobacteria.

    PubMed

    Van Wees, Saskia C M; Van Pelt, Johan A; Bakker, Peter A H M; Pieterse, Corné M J

    2013-01-01

    Jasmonates, together with other plant hormones, are important orchestrators of the plant immune system. The different hormone-controlled signaling pathways cross-communicate in an antagonistic or a synergistic manner, providing the plant with a powerful capacity to finely regulate its immune response. Jasmonic acid (JA) signaling is required for plant resistance to harmful organisms, such as necrotrophic pathogens and herbivorous insects. Furthermore, JA signaling is essential in interactions of plants with beneficial microbes that induce systemic resistance to pathogens and insects. The role of JA signaling components in plant immunity can be studied by performing bioassays with different interacting organisms. Determination of the level of resistance and the induction of defense responses in plants with altered JA components, through mutation or ectopic expression, will unveil novel mechanisms of JA signaling. We provide detailed protocols of bioassays with the model plant Arabidopsis thaliana challenged with the pathogens Botrytis cinerea and Pseudomonas syringae, the insect herbivore Pieris rapae, and the beneficial microbe Pseudomonas fluorescens. In addition, we describe pharmacological assays to study the modulation of JA-regulated responses by exogenous application of combinations of hormones, because a simultaneous rise in hormone levels occurs during interaction of plants with other organisms.

  11. Multiple phytohormone signalling pathways modulate susceptibility of tomato plants to Alternaria alternata f. sp. lycopersici

    PubMed Central

    Jia, Chengguo; Zhang, Liping; Wang, Qiaomei

    2013-01-01

    Three phytohormone molecules – ethylene (ET), jasmonic acid (JA) and salicylic acid (SA) – play key roles in mediating disease response to necrotrophic fungal pathogens. This study investigated the roles of the ET, JA, and SA pathways as well as their crosstalk during the interaction between tomato (Solanum lycopersicum) plants and a necrotrophic fungal pathogen Alternaria alternata f. sp. lycopersici (AAL). Both the ET and JASMONIC ACID INSENSITIVE1 (JAI1) receptor-dependent JA signalling pathways are necessary for susceptibility, while SA response promotes resistance to AAL infection. In addition, the role of JA in susceptibility to AAL is partly dependent on ET biosynthesis and perception, while the SA pathway enhances resistance to AAL and antagonizes the ET response. Based on these results, it is proposed that ET, JA, and SA each on their own can influence the susceptibility of tomato to AAL. Furthermore, the functions of JA and SA in susceptibility to the pathogen are correlated with the enhanced or decreased action of ET, respectively. This study has revealed the functional relationship among the three key hormone pathways in tomato defence against AAL. PMID:23264518

  12. Defense to Sclerotinia sclerotiorum in oilseed rape is associated with the sequential activations of salicylic acid signaling and jasmonic acid signaling.

    PubMed

    Wang, Zheng; Tan, Xiaoli; Zhang, Zhiyan; Gu, Shoulai; Li, Guanying; Shi, Haifeng

    2012-03-01

    Signaling pathways mediated by salicylic acid (SA) and jasmonic acid (JA) are widely studied in various host-pathogen interactions. For oilseed rape (Brassica napus)-Sclerotinia sclerotiorum interaction, little information of the two signaling molecules has been described in detail. In this study, we showed that the level of SA and JA in B. napus leaves was increased with a distinct temporal profile, respectively, after S. sclerotiorum infection. The application of SA or methyl jasmonate enhanced the resistance to the pathogen. Furthermore, a set of SA and JA signaling marker genes were identified from B. napus and were used to monitor the signaling responses to S. sclerotiorum infection by examining the temporal expression profiles of these marker genes. The SA signaling was activated within 12h post inoculation (hpi) followed by the JA signaling which was activated around 24 hpi. In addition, SA-JA crosstalk genes were activated during this process. These results suggested that defense against S. sclerotiorum in oilseed rape is associated with a sequential activation of SA signaling and JA signaling, which provide important clues for designing strategies to curb diseases caused by S. sclerotioru. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. JaCVAM-organized international validation study of the in vivo rodent alkaline comet assay for detection of genotoxic carcinogens: II. Summary of definitive validation study results.

    PubMed

    Uno, Yoshifumi; Kojima, Hajime; Omori, Takashi; Corvi, Raffaella; Honma, Masamistu; Schechtman, Leonard M; Tice, Raymond R; Beevers, Carol; De Boeck, Marlies; Burlinson, Brian; Hobbs, Cheryl A; Kitamoto, Sachiko; Kraynak, Andrew R; McNamee, James; Nakagawa, Yuzuki; Pant, Kamala; Plappert-Helbig, Ulla; Priestley, Catherine; Takasawa, Hironao; Wada, Kunio; Wirnitzer, Uta; Asano, Norihide; Escobar, Patricia A; Lovell, David; Morita, Takeshi; Nakajima, Madoka; Ohno, Yasuo; Hayashi, Makoto

    2015-07-01

    The in vivo rodent alkaline comet assay (comet assay) is used internationally to investigate the in vivo genotoxic potential of test chemicals. This assay, however, has not previously been formally validated. The Japanese Center for the Validation of Alternative Methods (JaCVAM), with the cooperation of the U.S. NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)/the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Japanese Environmental Mutagen Society/Mammalian Mutagenesis Study Group (JEMS/MMS), organized an international validation study to evaluate the reliability and relevance of the assay for identifying genotoxic carcinogens, using liver and stomach as target organs. The ultimate goal of this exercise was to establish an Organisation for Economic Co-operation and Development (OECD) test guideline. The study protocol was optimized in the pre-validation studies, and then the definitive (4th phase) validation study was conducted in two steps. In the 1st step, assay reproducibility was confirmed among laboratories using four coded reference chemicals and the positive control ethyl methanesulfonate. In the 2nd step, the predictive capability was investigated using 40 coded chemicals with known genotoxic and carcinogenic activity (i.e., genotoxic carcinogens, genotoxic non-carcinogens, non-genotoxic carcinogens, and non-genotoxic non-carcinogens). Based on the results obtained, the in vivo comet assay is concluded to be highly capable of identifying genotoxic chemicals and therefore can serve as a reliable predictor of rodent carcinogenicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. 45 CFR Appendix B to Part 93 - Disclosure Form To Report Lobbying

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Disclosure Form To Report Lobbying B Appendix B to Part 93 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION NEW RESTRICTIONS ON LOBBYING Pt. 93, App. B Appendix B to Part 93—Disclosure Form To Report Lobbying EC01JA91.003 EC01JA91.004 EC01JA91.00...

  15. 45 CFR Appendix B to Part 604 - Disclosure Form To Report Lobbying

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 3 2012-10-01 2012-10-01 false Disclosure Form To Report Lobbying B Appendix B to Part 604 Public Welfare Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION NEW RESTRICTIONS ON LOBBYING Pt. 604, App. B Appendix B to Part 604—Disclosure Form To Report Lobbying EC01JA91.007 EC01JA91.008 EC01JA91.00...

  16. Mesenteric angiography

    MedlinePlus

    ... Arteriogram - abdomen; Mesenteric angiogram Images Mesenteric arteriography References Kaufman JA. Fundamentals of angiography. In: Kaufman JA, Lee MJ, eds. Vascular and Interventional Radiology: ...

  17. 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

  18. 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

  19. 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).

  20. 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.

  1. 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

  2. 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

  3. The plastidial retrograde signal methyl erythritol cyclopyrophosphate is a regulator of salicylic acid and jasmonic acid crosstalk

    PubMed Central

    Lemos, Mark; Xiao, Yanmei; Bjornson, Marta; Wang, Jin-zheng; Hicks, Derrick; de Souza, Amancio; Wang, Chang-Quan; Yang, Panyu; Ma, Shisong; Dinesh-Kumar, Savithramma; Dehesh, Katayoon

    2016-01-01

    The exquisite harmony between hormones and their corresponding signaling pathways is central to prioritizing plant responses to simultaneous and/or successive environmental trepidations. The crosstalk between jasmonic acid (JA) and salicylic acid (SA) is an established effective mechanism that optimizes and tailors plant adaptive responses. However, the underlying regulatory modules of this crosstalk are largely unknown. Global transcriptomic analyses of mutant plants (ceh1) with elevated levels of the stress-induced plastidial retrograde signaling metabolite 2-C-methyl-D-erythritol cyclopyrophosphate (MEcPP) revealed robustly induced JA marker genes, expected to be suppressed by the presence of constitutively high SA levels in the mutant background. Analyses of a range of genotypes with varying SA and MEcPP levels established the selective role of MEcPP-mediated signal(s) in induction of JA-responsive genes in the presence of elevated SA. Metabolic profiling revealed the presence of high levels of the JA precursor 12-oxo-phytodienoic acid (OPDA), but near wild type levels of JA in the ceh1 mutant plants. Analyses of coronatine-insensitive 1 (coi1)/ceh1 double mutant plants confirmed that the MEcPP-mediated induction is JA receptor COI1 dependent, potentially through elevated OPDA. These findings identify MEcPP as a previously unrecognized central regulatory module that induces JA-responsive genes in the presence of high SA, thereby staging a multifaceted plant response within the environmental context. PMID:26733689

  4. Low concentrations of salicylic acid delay methyl jasmonate-induced leaf senescence by up-regulating nitric oxide synthase activity.

    PubMed

    Ji, Yingbin; Liu, Jian; Xing, Da

    2016-09-01

    In plants, extensive efforts have been devoted to understanding the crosstalk between salicylic acid (SA) and jasmonic acid (JA) signaling in pathogen defenses, but this crosstalk has scarcely been addressed during senescence. In this study, the effect of SA application on methyl jasmonate (MeJA)-induced leaf senescence was assessed. We found that low concentrations of SA (1-50 μM) played a delayed role against the senescence promoted by MeJA. Furthermore, low concentrations of SA enhanced plant antioxidant defenses and restricted reactive oxygen species (ROS) accumulation in MeJA-treated leaves. When applied simultaneously with MeJA, low concentrations of SA triggered a nitric oxide (NO) burst, and the elevated NO levels were linked to the nitric oxide associated 1 (NOA1)-dependent pathway via nitric oxide synthase (NOS) activity. The ability of SA to up-regulate plant antioxidant defenses, reduce ROS accumulation, and suppress leaf senescence was lost in NO-deficient Atnoa1 plants. In a converse manner, exogenous addition of NO donors increased the plant antioxidant capacity and lowered the ROS levels in MeJA-treated leaves. Taken together, the results indicate that SA at low concentrations counteracts MeJA-induced leaf senescence through NOA1-dependent NO signaling and strengthening of the antioxidant defense. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  5. Effect of Exogenous Abscisic Acid and Methyl Jasmonate on Anthocyanin Composition, Fatty Acids, and Volatile Compounds of Cabernet Sauvignon (Vitis vinifera L.) Grape Berries.

    PubMed

    Ju, Yan-Lun; Liu, Min; Zhao, Hui; Meng, Jiang-Fei; Fang, Yu-Lin

    2016-10-12

    The anthocyanin composition, fatty acids, and volatile aromas are important for Cabernet Sauvignon grape quality. This study evaluated the effect of exogenous abscisic acid (ABA) and methyl jasmonate (MeJA) on the anthocyanin composition, fatty acids, lipoxygenase activity, and the volatile compounds of Cabernet Sauvignon grape berries. Exogenous ABA and MeJA improved the content of total anthocyanins (TAC) and individual anthocyanins. Lipoxygenase (LOX) activity also increased after treatment. Furthermore, 16 fatty acids were detected. The linoleic acid concentration gradually increased with ABA concentration. The fatty acid content decreased with increasing MeJA concentration and then increased again, with the exception of linoleic acid. After exogenous ABA and MeJA treatment, the C6 aroma content increased significantly. Interestingly, the exogenous ABA and MeJA treatments improved mainly the content of 1-hexanol, hexanal, and 2-heptanol. These results provide insight into the effect of plant hormones on wine grapes, which is useful for grape quality improvement.

  6. Pre-harvest methyl jasmonate treatment enhances cauliflower chemoprotective attributes without a loss in postharvest quality.

    PubMed

    Ku, Kang Mo; Choi, Jeong-Hee; Kushad, Mosbah M; Jeffery, Elizabeth H; Juvik, John A

    2013-06-01

    Methyl jasmonate (MeJA) treatment can significantly increase glucosinolate (GS) concentrations in Brassica vegetables and potentially enhance anticancer bioactivity. Although MeJA treatment may promote ethylene biosynthesis, which can be detrimental to postharvest quality, there are no previous reports of its effect on cauliflower postharvest quality. To address this, cauliflower curds in field plots were sprayed with either 0.1 % Triton X-100 (control) or 500 μM MeJA solutions four days prior to harvest, then stored at 4 °C. Tissue subsamples were collected after 0, 10, 20, and 30 days of postharvest storage and assayed for visual color change, ethylene production, GS concentrations, and extract quinone reductase inductive activity. MeJA treatment increased curd GS concentrations of glucoraphanin, glucobrassicin, and neoglucobrassicin by 1.5, 2.4, and 4.6-fold over controls, respectively. MeJA treated cauliflower showed significantly higher quinone reductase activity, a biomarker for anticancer bioactivity, without reducing visual color and postharvest quality for 10 days at 4 °C storage.

  7. Elicitation of Diosgenin Production in Trigonella foenum-graecum (Fenugreek) Seedlings by Methyl Jasmonate

    PubMed Central

    Chaudhary, Spandan; Chikara, Surendra K.; Sharma, Mahesh C.; Chaudhary, Abhinav; Alam Syed, Bakhtiyar; Chaudhary, Pooja S.; Mehta, Aditya; Patel, Maulik; Ghosh, Arpita; Iriti, Marcello

    2015-01-01

    The effects of methyl jasmonate (MeJA), an elicitor of plant defense mechanisms, on the biosynthesis of diosgenin, a steroidal saponin, were investigated in six fenugreek (Trigonella foenum-graecum) varieties (Gujarat Methi-2, Kasuri-1, Kasuri-2, Pusa Early Branching, Rajasthan Methi and Maharashtra Methi-5). Treatment with 0.01% MeJA increased diosgenin levels, in 12 days old seedlings, from 0.5%–0.9% to 1.1%–1.8%. In addition, MeJA upregulated the expression of two pivotal genes of the mevalonate pathway, the metabolic route leading to diosgenin: 3-hydroxy-3-methylglutaryl-CoA reductase (HMG) and sterol-3-β-glucosyl transferase (STRL). In particular, MeJA increased the expression of HMG and STRL genes by 3.2- and 22.2-fold, respectively, in the Gujarat Methi-2 variety, and by 25.4- and 28.4-fold, respectively, in the Kasuri-2 variety. Therefore, MeJA may be considered a promising elicitor for diosgenin production by fenugreek plants. PMID:26694357

  8. Jasmonic acid protects etiolated seedlings of Arabidopsis thaliana against herbivorous arthropods

    PubMed Central

    Boex-Fontvieille, Edouard; Rustgi, Sachin; Von Wettstein, Diter; Pollmann, Stephan; Reinbothe, Steffen; Reinbothe, Christiane

    2016-01-01

    ABSTRACT Seed predators can cause mass ingestion of larger seed populations. As well, herbivorous arthropods attempt to attack etiolated seedlings and chose the apical hook for ingestion, aimed at dropping the cotyledons for later consumption. Etiolated seedlings, as we show here, have established an efficient mechanism of protecting their Achilles' heel against these predators, however. Evidence is provided for a role of jasmonic acid (JA) in this largely uncharacterized plant-herbivore interaction during skotomorphogenesis and that this comprises the temporally and spatially tightly controlled synthesis of a cysteine protease inhibitors of the Kunitz family. Interestingly, the same Kunitz protease inhibitor was found to be expressed in flowers of Arabidopsis where endogenous JA levels are high for fertility. Because both the apical hook and inflorescences were preferred isopod targets in JA-deficient plants that could be rescued by exogenously administered JA, our data identify a JA-dependent mechanism of plant arthropod deterrence that is recalled in different organs and at quite different times of plant development. PMID:27485473

  9. The Treatment of BRCA1/2 Hereditary Breast Cancer and Sporadic Breast Cancer with Poly(ADP-ribose) PARP-1 Inhibitors and Chemotherapy

    DTIC Science & Technology

    2008-09-01

    American population d) D) Obesity, and breast cancer J. of Nursing and Bariatric Surgery . 2008 submitting. This paper uses in part mechanisms worked...National Med. Society. 2008 submitting D) Obesity, and breast cancer J. of Nursing and Bariatric Surgery . 2008 submitting Abstracts: A) De Soto JA...submitting De Soto JA. Obesity, breast cancer and bariatric surgery . J. of Nursing and Bariatric Surgery . 2008 submitting Davis JH, De Soto JA

  10. Cumulative and Synergistic Effects of Physical, Biological, and Acoustic Signals on Marine Mammal Habitat Use

    DTIC Science & Technology

    2011-09-30

    Science 59, 1326-1336. PUBLICATIONS Nystuen, JA, Miksis-Olds, JL, Stabeno, PJ (in prep). Soundscapes under sea ice. Journal of the Acoustical...International Conference:The Effects of Noise on Aquatic Life. Cork, Ireland. August 16-20. Nystuen, JA, Miksis-Olds, JL (2010). Soundscapes under sea... Soundscapes under sea ice:Can we listen for open water? Acoustical Society of America, Baltimore, MD. April 19-23. Miksis-Olds, JL, Nystuen, JA

  11. Cumulative and Synergistic Effects of Physical, Biological, and Acoustic Signals on Marine Mammal Habitat Use

    DTIC Science & Technology

    2010-09-30

    Science, Special Issue on Ocean Observatories. 7 Nystuen, JA, Miksis-Olds, JL, Stabeno, PJ (in prep). Soundscapes under sea ice. Journal of the...Conference:The Effects of Noise on Aquatic Life. Cork, Ireland. August 16-20. Nystuen, JA, Miksis-Olds, JL (2010). Soundscapes under sea ice:Can we...listen for open water? European Conference on Underwater Acoustics. Istanbul, Turkey. July 5-9. Nystuen, JA, Miksis-Olds, JL (2010). Soundscapes

  12. Extracellular ATP Acts on Jasmonate Signaling to Reinforce Plant Defense.

    PubMed

    Tripathi, Diwaker; Zhang, Tong; Koo, Abraham J; Stacey, Gary; Tanaka, Kiwamu

    2018-01-01

    Damaged cells send various signals to stimulate defense responses. Recent identification and genetic studies of the plant purinoceptor, P2K1 (also known as DORN1), have demonstrated that extracellular ATP is a signal involved in plant stress responses, including wounding, perhaps to evoke plant defense. However, it remains largely unknown how extracellular ATP induces plant defense responses. Here, we demonstrate that extracellular ATP induces plant defense mediated through activation of the intracellular signaling of jasmonate (JA), a well-characterized defense hormone. In Arabidopsis ( Arabidopsis thaliana ) leaves, ATP pretreatment induced resistance against the necrotrophic fungus, Botrytis cinerea The induced resistance was enhanced in the P2K1 receptor overexpression line, but reduced in the receptor mutant, dorn1 - 3 Mining the transcriptome data revealed that ATP induces a set of JA-induced genes. In addition, the P2K1-associated coexpression network contains defense-related genes, including those encoding jasmonate ZIM-domain (JAZ) proteins, which play key roles as repressors of JA signaling. We examined whether extracellular ATP impacts the stability of JAZ1 in Arabidopsis. The results showed that the JAZ1 stability decreased in response to ATP addition in a proteasome-dependent manner. This reduction required intracellular signaling via second messengers-cytosolic calcium, reactive oxygen species, and nitric oxide. Interestingly, the ATP-induced JAZ1 degradation was attenuated in the JA receptor mutant, coi1 , but not in the JA biosynthesis mutant, aos , or upon addition of JA biosynthesis inhibitors. Immunoprecipitation analysis demonstrated that ATP increases the interaction between COI1 and JAZ1, suggesting direct cross talk between extracellular ATP and JA in intracellular signaling events. Taken together, these results suggest that extracellular ATP signaling directly impacts the JA signaling pathway to maximize plant defense responses. © 2018

  13. Occurrence of jasmonates during cystocarp development in the red alga Grateloupia imbricata.

    PubMed

    Pilar, Garcia-Jimenez; Olegario, Brito-Romano; Rafael, Robaina R

    2016-12-01

    In this study, we highlight the effects of methyl jasmonate (MeJa) on cystocarp development in the red macroscopic alga Grateloupia imbricata. In G. imbricata, jasmonate release is related to the reproductive state, as fertile thalli (i.e., those that have cystocarps) released significant amounts of this volatile compound (1.27 ± 0.20 mM · mg fw -1  · h -1 ) compared with infertile thalli (0.95 ± 0.12 mM · mg fw -1  · h -1 ). Treating G. imbricata thalli with MeJa revealed a significant increase in cystocarp number (1.5 ± 0.27 cystocarps · mm -2 ), which was ~7.5-fold greater than in untreated thalli (0.2 ± 0.07 cystocarps · mm -2 ). Maturation was completed within 48 h with MeJa treatment, a shortening of the typical >3-week maturation period, and included the opening of cystocarps and the presence of dehiscent cavities. Release rates of jasmonates after exogenous MeJa treatment were also modified based on the cystocarp maturation level. All of these effects were reduced in the presence of phenidone, which blocks MeJa production, indicating that the MeJa action is genuine. The effects of MeJa during cystocarp maturation were not replicated by derivatives of reactive oxygen species from the same jasmonic acid biosynthetic pathway, as the activities of scavenger enzymes and lipid peroxidation were unchanged between infertile and fertile thalli. Therefore, a reactive oxygen species-based mechanism is not involved during cystocarp development. We conclude that MeJa has an independent function as a growth regulator during G. imbricata reproduction. © 2016 Phycological Society of America.

  14. Determination of the rate of photoreduction of O2 in the water-water cycle in watermelon leaves and enhancement of the rate by limitation of photosynthesis.

    PubMed

    Miyake, C; Yokota, A

    2000-03-01

    A study was performed to determine how the electron fluxes for the photosynthetic carbon reduction (PCR) and the photorespiratory carbon oxidation (PCO) cycles affect the photoreduction of O2 at PSI, which is the limiting step in the water-water cycle. Simultaneous measurements were made of CO2-gas exchange, transpiration and quantum yield of PSII [phi(PSII)] using leaves of watermelon (Citrullus lanatus). The total electron flux in PSII[Je(PSII)], as estimated from phi(PSII), was always larger than the total electron flux required for the PCR and PCO cycles at various partial pressures of CO2 and O2 and 1,100 micromol photons m(-2)s(-1). This observation suggested the existence of an alternative electron flux (Ja). Ja was divided into O2-dependent [Ja(O2-depend)] and O2-independent [Ja(O2-independ)] components. The magnitude of half Ja(O2-depend), 7.5 to 9.5 micromol e- m(-2)s(-1), and its apparent Km for O2, about 8.0 kPa, could be accounted for by the photoreduction of O2 at PSI either mediated by ferredoxin or catalyzed by monodehydroascorbate reductase. The results indicated that Ja(O2-depend) was driven by the water-water cycle. A decrease in the intercellular partial pressure of CO2 from 23 to 5.0 Pa at 21 kPa O2 enhanced Ja(O2-depend) by a factor of 1.3. Saturation of the activities of both the PCR and PCO cycles by increasing the photon flux density induced Ja. These results indicate the electron flux in PSII that exceeds the flux required for the PCR and PCO cycles induces the photoreduction of O2 in the water-water cycle.

  15. Jasmonate-Mediated Induced Volatiles in the American Cranberry, Vaccinium macrocarpon: From Gene Expression to Organismal Interactions

    PubMed Central

    Rodriguez-Saona, Cesar R.; Polashock, James; Malo, Edi A.

    2013-01-01

    Jasmonates, i.e., jasmonic acid (JA) and methyl jasmonate (MeJA), are signaling hormones that regulate a large number of defense responses in plants which in turn affect the plants’ interactions with herbivores and their natural enemies. Here, we investigated the effect of jasmonates on the emission of volatiles in the American cranberry, Vaccinium macrocarpon, at different levels of biological organization from gene expression to organismal interactions. At the molecular level, four genes (BCS, LLS, NER1, and TPS21) responded significantly to gypsy moth larval feeding, MeJA, and mechanical wounding, but to different degrees. The most dramatic changes in expression of BCS and TPS21 (genes in the sesquiterpenoid pathway) were when treated with MeJA. Gypsy moth-damaged and MeJA-treated plants also had significantly elevated expression of LLS and NER1 (genes in the monoterpene and homoterpene biosynthesis pathways, respectively). At the biochemical level, MeJA induced a complex blend of monoterpene and sesquiterpene compounds that differed from gypsy moth and mechanical damage, and followed a diurnal pattern of emission. At the organismal level, numbers of Sparganothis sulfureana moths were lower while numbers of parasitic wasps were higher on sticky traps near MeJA-treated cranberry plants than those near untreated plants. Out of 11 leaf volatiles tested, (Z)-3-hexenyl acetate, linalool, and linalool oxide elicited strong antennal (EAG) responses from S. sulfureana, whereas sesquiterpenes elicited weak EAG responses. In addition, mortality of S. sulfureana larvae increased by about 43% in JA treated cranberry plants as compared with untreated plants, indicating a relationship among adult preference, antennal sensitivity to plant odors, and offspring performance. This study highlights the role of the jasmonate-dependent defensive pathway in the emissions of herbivore-induced volatiles in cranberries and its importance in multi-trophic level interactions. PMID

  16. PgLOX6 encoding a lipoxygenase contributes to jasmonic acid biosynthesis and ginsenoside production in Panax ginseng

    PubMed Central

    Rahimi, Shadi; Kim, Yu-Jin; Sukweenadhi, Johan; Zhang, Dabing; Yang, Deok-Chun

    2016-01-01

    Ginsenosides, the valuable pharmaceutical compounds in Panax ginseng, are triterpene saponins that occur mainly in ginseng plants. It was shown that in vitro treatment with the phytohormone jasmonic acid (JA) is able to increase ginsenoside production in ginseng plants. To understand the molecular link between JA biosynthesis and ginsenoside biosynthesis, we identified a JA biosynthetic 13-lipoxygenase gene (PgLOX6) in P. ginseng that promotes ginsenoside production. The expression of PgLOX6 was high in vascular bundles, which corresponds with expression of ginsenoside biosynthetic genes. Consistent with the role of PgLOX6 in synthesizing JA and promoting ginsenoside synthesis, transgenic plants overexpressing PgLOX6 in Arabidopsis had increased amounts of JA and methyl jasmonate (MJ), increased expression of triterpene biosynthetic genes such as squalene synthase (AtSS1) and squalene epoxidase (AtSE1), and increased squalene content. Moreover, transgenic ginseng roots overexpressing PgLOX6 had around 1.4-fold increased ginsenoside content and upregulation of ginsenoside biosynthesis-related genes including PgSS1, PgSE1, and dammarenediol synthase (PgDDS), which is similar to that of treatment with MJ. However, MJ treatment of transgenic ginseng significantly enhanced JA and MJ, associated with a 2.8-fold increase of ginsenoside content compared with the non-treated, non-transgenic control plant, which was 1.4 times higher than the MJ treatment effect on non-transgenic plants. These results demonstrate that PgLOX6 is responsible for the biosynthesis of JA and promotion of the production of triterpenoid saponin through up-regulating the expression of ginsenoside biosynthetic genes. This work provides insight into the role of JA in biosynthesizing secondary metabolites and provides a molecular tool for increasing ginsenoside production. PMID:27811076

  17. PgLOX6 encoding a lipoxygenase contributes to jasmonic acid biosynthesis and ginsenoside production in Panax ginseng.

    PubMed

    Rahimi, Shadi; Kim, Yu-Jin; Sukweenadhi, Johan; Zhang, Dabing; Yang, Deok-Chun

    2016-11-01

    Ginsenosides, the valuable pharmaceutical compounds in Panax ginseng, are triterpene saponins that occur mainly in ginseng plants. It was shown that in vitro treatment with the phytohormone jasmonic acid (JA) is able to increase ginsenoside production in ginseng plants. To understand the molecular link between JA biosynthesis and ginsenoside biosynthesis, we identified a JA biosynthetic 13-lipoxygenase gene (PgLOX6) in P. ginseng that promotes ginsenoside production. The expression of PgLOX6 was high in vascular bundles, which corresponds with expression of ginsenoside biosynthetic genes. Consistent with the role of PgLOX6 in synthesizing JA and promoting ginsenoside synthesis, transgenic plants overexpressing PgLOX6 in Arabidopsis had increased amounts of JA and methyl jasmonate (MJ), increased expression of triterpene biosynthetic genes such as squalene synthase (AtSS1) and squalene epoxidase (AtSE1), and increased squalene content. Moreover, transgenic ginseng roots overexpressing PgLOX6 had around 1.4-fold increased ginsenoside content and upregulation of ginsenoside biosynthesis-related genes including PgSS1, PgSE1, and dammarenediol synthase (PgDDS), which is similar to that of treatment with MJ. However, MJ treatment of transgenic ginseng significantly enhanced JA and MJ, associated with a 2.8-fold increase of ginsenoside content compared with the non-treated, non-transgenic control plant, which was 1.4 times higher than the MJ treatment effect on non-transgenic plants. These results demonstrate that PgLOX6 is responsible for the biosynthesis of JA and promotion of the production of triterpenoid saponin through up-regulating the expression of ginsenoside biosynthetic genes. This work provides insight into the role of JA in biosynthesizing secondary metabolites and provides a molecular tool for increasing ginsenoside production. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  18. Jasmonate-Mediated Induced Volatiles in the American Cranberry, Vaccinium macrocarpon: From Gene Expression to Organismal Interactions.

    PubMed

    Rodriguez-Saona, Cesar R; Polashock, James; Malo, Edi A

    2013-01-01

    Jasmonates, i.e., jasmonic acid (JA) and methyl jasmonate (MeJA), are signaling hormones that regulate a large number of defense responses in plants which in turn affect the plants' interactions with herbivores and their natural enemies. Here, we investigated the effect of jasmonates on the emission of volatiles in the American cranberry, Vaccinium macrocarpon, at different levels of biological organization from gene expression to organismal interactions. At the molecular level, four genes (BCS, LLS, NER1, and TPS21) responded significantly to gypsy moth larval feeding, MeJA, and mechanical wounding, but to different degrees. The most dramatic changes in expression of BCS and TPS21 (genes in the sesquiterpenoid pathway) were when treated with MeJA. Gypsy moth-damaged and MeJA-treated plants also had significantly elevated expression of LLS and NER1 (genes in the monoterpene and homoterpene biosynthesis pathways, respectively). At the biochemical level, MeJA induced a complex blend of monoterpene and sesquiterpene compounds that differed from gypsy moth and mechanical damage, and followed a diurnal pattern of emission. At the organismal level, numbers of Sparganothis sulfureana moths were lower while numbers of parasitic wasps were higher on sticky traps near MeJA-treated cranberry plants than those near untreated plants. Out of 11 leaf volatiles tested, (Z)-3-hexenyl acetate, linalool, and linalool oxide elicited strong antennal (EAG) responses from S. sulfureana, whereas sesquiterpenes elicited weak EAG responses. In addition, mortality of S. sulfureana larvae increased by about 43% in JA treated cranberry plants as compared with untreated plants, indicating a relationship among adult preference, antennal sensitivity to plant odors, and offspring performance. This study highlights the role of the jasmonate-dependent defensive pathway in the emissions of herbivore-induced volatiles in cranberries and its importance in multi-trophic level interactions.

  19. Pure mechanistic analysis of additive neuroprotective effects between baicalin and jasminoidin in ischemic stroke mice.

    PubMed

    Wang, Peng-Qian; Liu, Qiong; Xu, Wen-Juan; Yu, Ya-Nan; Zhang, Ying-Ying; Li, Bing; Liu, Jun; Wang, Zhong

    2018-06-01

    Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action in ischemic stroke models. In this study we used transcriptome analysis to explore the pure therapeutic mechanisms of BA, JA and their combination (BJ) contributing to phenotype variation and reversal of pathological processes. Mice with middle cerebral artery obstruction were treated with BA, JA, their combination (BJ), or concha margaritifera (CM). Cerebral infarct volume was examined to determine the effect of these compounds on phenotype. Using the hippocampus microarray and ingenuity pathway analysis (IPA) software, we exacted the differentially expressed genes, networks, pathways, and functions in positive-phenotype groups (BA, JA and BJ) by comparing with the negative-phenotype group (CM). In the BA, JA, and BJ groups, a total of 7, 4, and 11 specific target molecules, 1, 1, and 4 networks, 51, 59, and 18 canonical pathways and 70, 53, and 64 biological functions, respectively, were identified. Pure therapeutic mechanisms of BA and JA were mainly overlapped in specific target molecules, functions and pathways, which were related to the nervous system, inflammation and immune response. The specific mechanisms of BA and JA were associated with apoptosis and cancer-related signaling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from mono-therapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. This pure mechanistic analysis may provide a clearer outline of the target profiles of multi-target compounds and combination therapies.

  20. Jolkinolide A and Jolkinolide B Inhibit Proliferation of A549 Cells and Activity of Human Umbilical Vein Endothelial Cells.

    PubMed

    Shen, Lei; Zhang, Shan-Qiang; Liu, Lei; Sun, Yu; Wu, Yu-Xuan; Xie, Li-Ping; Liu, Ji-Cheng

    2017-01-14

    BACKGROUND Jolkinolide A (JA) and Jolkinolide B (JB) are diterpenoids extracted from the roots of Euphorbia fischeriana Steud and have been shown to have anti-tumor activity. However, their effects on the ability of tumor cells to invade blood vessels and metastasize remain largely unknown. Investigations into the effects of JA and JB on the angiogenesis of tumor tissues may facilitate the identification of new natural drugs with anti-tumor growth and metastasis activities. MATERIAL AND METHODS We used different concentrations of JA and JB (20 μg/ml, 40 μg/ml, 60 μg/ml, 80 μg/ml, and 100 μg/ml) to stimulate A549 cells and then studied the effects on the growth and metastasis of lung cancers. In addition, we used conditional media from A549 cells (A549-CM) stimulated by either JA or JB in different concentrations to culture human umbilical vein endothelial cells (HUVECs). RESULTS We found that both JA and JB significantly inhibited the Akt-STAT3-mTOR signaling pathway and reduced the expression of VEGF in A549 cells, but JB exhibited more significant inhibitory effects than JA. The JB-stimulated A549 cell conditional media had a greater inhibitory effect on the proliferation and migration of HUVECs than did the conditional media of JA-stimulated A549 cells. This effect gradually increased with increasing concentrations of either type of Jolkinolide. CONCLUSIONS Our results suggest that JA and JB inhibited VEGF expression in A549 cells through the inhibition of the Akt-STAT3-mTOR signaling pathway, and directly inhibited the proliferation and migration of HUVECs. These findings are of great significance for the development of new plant-derived chemotherapy agents for the treatment of cancer.