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Sample records for receptor-dependent signaling response

  1. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior

    PubMed Central

    Al-Hasani, Ream; Bruchas, Michael R.

    2013-01-01

    Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years, and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled, and activate inhibitory G-proteins. These receptors form homo- and hetereodimeric complexes, signal to kinase cascades, and scaffold a variety of proteins. In this review, we discuss classical mechanisms and developments in understanding opioid tolerance, opioid receptor signaling, and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. We put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, we conclude that there is a continued need for more translational work on opioid receptors in vivo. PMID:22020140

  2. Sphingosine-1-Phosphate Elicits Receptor-Dependent Calcium Signaling in Retinal Amacrine Cells

    PubMed Central

    Crousillac, Scott; Colonna, Jeremy; McMains, Emily; Dewey, Jill Sayes

    2009-01-01

    Evidence is emerging indicating that sphingosine-1-phosphate (S1P) participates in signaling in the retina. To determine whether S1P might be involved in signaling in the inner retina specifically, we examine the effects of this sphingolipid on cultured retinal amacrine cells. Whole cell voltage-clamp recordings reveal that S1P activates a cation current that is dependent on signaling through Gi and phospholipase C. These observations are consistent with the involvement of members of the S1P receptor family of G-protein-coupled receptors in the production of the current. Immunocytochemistry and PCR amplification provide evidence for the expression of S1P1R and S1P3R in amacrine cells. The receptor-mediated channel activity is shown to be highly sensitive to blockade by lanthanides consistent with the behavior of transient receptor potential canonical (TRPC) channels. PCR products amplified from amacrine cells reveal that TRPCs 1 and 3–7 channel subunits have the potential to be expressed. Because TRPC channels provide a Ca2+ entry pathway, we asked whether S1P caused cytosolic Ca2+ elevations in amacrine cells. We show that S1P-dependent Ca2+ elevations do occur in these cells and that they might be mediated by S1P1R and S1P3R. The Ca2+ elevations are partially due to release from internal stores, but the largest contribution is from influx across the plasma membrane. The effect of inhibition of sphingosine kinase suggests that the production of cytosolic S1P underlies the sustained nature of the Ca2+ elevations. Elucidation of the downstream effects of these signals will provide clues to the role of S1P in regulating inner retinal function. PMID:19776367

  3. P2Y₁ receptor-dependent diacylglycerol signaling microdomains in β cells promote insulin secretion.

    PubMed

    Wuttke, Anne; Idevall-Hagren, Olof; Tengholm, Anders

    2013-04-01

    Diacylglycerol (DAG) controls numerous cell functions by regulating the localization of C1-domain-containing proteins, including protein kinase C (PKC), but little is known about the spatiotemporal dynamics of the lipid. Here, we explored plasma membrane DAG dynamics in pancreatic β cells and determined whether DAG signaling is involved in secretagogue-induced pulsatile release of insulin. Single MIN6 cells, primary mouse β cells, and human β cells within intact islets were transfected with translocation biosensors for DAG, PKC activity, or insulin secretion and imaged with total internal reflection fluorescence microscopy. Muscarinic receptor stimulation triggered stable, homogenous DAG elevations, whereas glucose induced short-lived (7.1 ± 0.4 s) but high-amplitude elevations (up to 109 ± 10% fluorescence increase) in spatially confined membrane regions. The spiking was mimicked by membrane depolarization and suppressed after inhibition of exocytosis or of purinergic P2Y₁, but not P2X receptors, reflecting involvement of autocrine purinoceptor activation after exocytotic release of ATP. Each DAG spike caused local PKC activation with resulting dissociation of its substrate protein MARCKS from the plasma membrane. Inhibition of spiking reduced glucose-induced pulsatile insulin secretion. Thus, stimulus-specific DAG signaling patterns appear in the plasma membrane, including distinct microdomains, which have implications for the kinetic control of exocytosis and other membrane-associated processes.

  4. Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity

    PubMed Central

    Ruest, Louis-Bruno; Xiang, Xilin; Lim, Kim-Chew; Levi, Giovanni; Clouthier, David E.

    2009-01-01

    Summary The lower jaw skeleton is derived from cephalic neural crest (CNC) cells that reside in the mandibular region of the first pharyngeal arch. Endothelin-A receptor (Ednra) signaling in crest cells is crucial for their development, as Ednra−/− mice are born with severe craniofacial defects resulting in neonatal lethality. In this study, we undertook a more detailed analysis of mandibular arch development in Ednra−/− embryos to better understand the cellular and molecular basis for these defects. We show that most lower jaw structures in Ednra−/− embryos undergo a homeotic transformation into maxillary-like structures similar to those observed in Dlx5/Dlx6−/− embryos, though lower incisors are still present in both mutant embryos. These structural changes are preceded by aberrant expansion of proximal first arch gene expression into the distal arch, in addition to the previously described loss of a Dlx6/Hand2 expression network. However, a small distal Hand2 expression domain remains. Although this distal expression is not dependent on either Ednra or Dlx5/Dlx6 function, it may require one or more GATA factors. Using fate analysis, we show that these distal Hand2-positive cells probably contribute to lower incisor formation. Together, our results suggest that the establishment of a ‘mandibular identity’ during lower jaw development requires both Ednra-dependent and -independent signaling pathways. PMID:15306564

  5. Tributyltin and triphenyltin inhibit osteoclast differentiation through a retinoic acid receptor-dependent signaling pathway

    SciTech Connect

    Yonezawa, Takayuki; Hasegawa, Shin-ichi; Ahn, Jae-Yong; Cha, Byung-Yoon; Teruya, Toshiaki; Hagiwara, Hiromi; Nagai, Kazuo; Woo, Je-Tae; E-mail: jwoo@isc.chubu.ac.jp

    2007-03-30

    Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), have been widely used in agriculture and industry. Although these compounds are known to have many toxic effects, including endocrine-disrupting effects, their effects on bone resorption are unknown. In this study, we investigated the effects of organotin compounds, such as monobutyltin (MBT), dibutyltin (DBT), TBT, and TPT, on osteoclast differentiation using mouse monocytic RAW264.7 cells. MBT and DBT had no effects, whereas TBT and TPT dose-dependently inhibited osteoclast differentiation at concentrations of 3-30 nM. Treatment with a retinoic acid receptor (RAR)-specific antagonist, Ro41-5253, restored the inhibition of osteoclastogenesis by TBT and TPT. TBT and TPT reduced receptor activator of nuclear factor-{kappa}B ligand (RANKL) induced nuclear factor of activated T cells (NFAT) c1 expression, and the reduction in NFATc1 expression was recovered by Ro41-5253. Our results suggest that TBT and TPT suppress osteoclastogenesis by inhibiting RANKL-induced NFATc1 expression via an RAR-dependent signaling pathway.

  6. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2

    PubMed Central

    Anyatonwu, Georgia I.; Estrada, Manuel; Tian, Xin; Somlo, Stefan; Ehrlich, Barbara E.

    2007-01-01

    Mutations in polycystin-2 (PC2) cause autosomal dominant polycystic kidney disease. A function for PC2 in the heart has not been described. Here, we show that PC2 coimmunoprecipitates with the cardiac ryanodine receptor (RyR2) from mouse heart. Biochemical assays showed that the N terminus of PC2 binds the RyR2, whereas the C terminus only binds to RyR2 in its open state. Lipid bilayer electrophysiological experiments indicated that the C terminus of PC2 functionally inhibited RyR2 channel activity in the presence of calcium (Ca2+). Pkd2−/− cardiomyocytes had a higher frequency of spontaneous Ca2+ oscillations, reduced Ca2+ release from the sarcoplasmic reticulum stores, and reduced Ca2+ content compared with Pkd2+/+ cardiomyocytes. In the presence of caffeine, Pkd2−/− cardiomyocytes exhibited decreased peak fluorescence, a slower rate of rise, and a longer duration of Ca2+ transients compared with Pkd2+/+. These data suggest that PC2 is important for regulation of RyR2 function and that loss of this regulation of RyR2, as occurs when PC2 is mutated, results in altered Ca2+ signaling in the heart. PMID:17404231

  7. Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex.

    PubMed

    Sidorov, Michael S; Kaplan, Eitan S; Osterweil, Emily K; Lindemann, Lothar; Bear, Mark F

    2015-10-13

    A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.

  8. Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex.

    PubMed

    Sidorov, Michael S; Kaplan, Eitan S; Osterweil, Emily K; Lindemann, Lothar; Bear, Mark F

    2015-10-13

    A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD. PMID:26417096

  9. Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms.

    PubMed

    Ahmad, Tasha; Lauzon, Nicole M; de Jaeger, Xavier; Laviolette, Steven R

    2013-09-25

    Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways. PMID:24068830

  10. Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes.

    PubMed

    Cai, Kai; Sewer, Marion B

    2013-09-01

    DGKs (diacylglycerol kinases) catalyse the conversion of diacylglycerol into PA (phosphatidic acid), a positive modulator of mTOR (mammalian target of rapamycin). We have found that chenodeoxycholic acid and the synthetic FXR (farnesoid X receptor) ligand GW4064 induce the mRNA and protein expression of DGKθ in the HepG2 cell line and in primary human hepatocytes. Reporter gene studies using 1.5 kB of the DGKθ promoter fused to the luciferase gene revealed that bile acids increase DGKθ transcriptional activity. Mutation of putative FXR-binding sites attenuated the ability of GW4046 to increase DGKθ luciferase activity. Consistent with this finding, ChIP (chromatin immunoprecipitation) assays demonstrated that bile acid signalling increased the recruitment of FXR to the DGKθ promoter. Furthermore, GW4064 evoked a time-dependent increase in the cellular concentration of PA. We also found that GW4064 and PA promote the phosphorylation of mTOR, Akt and FoxO1 (forkhead box O1), and that silencing DGKθ expression significantly abrogated the ability of GW4046 to promote the phosphorylation of these PA-regulated targets. DGKθ was also required for bile-acid-dependent decreased glucose production. Taken together, our results establish DGKθ as a key mediator of bile-acid-stimulated modulation of mTORC2 (mTOR complex 2), the Akt pathway and glucose homoeostasis.

  11. Receptor-dependent and Receptor-independent Endocannabinoid Signaling: A Therapeutic Target for Regulation of Cancer Growth

    PubMed Central

    Van Dross, Rukiyah; Soliman, Eman; Jha, Shalini; Johnson, Travious; Mukhopadhyay, Somnath

    2012-01-01

    The endocannabinoid system comprises the G-protein coupled CB1 cannabinoid receptor (CB1R) and CB2 cannabinoid receptor (CB2R), their endogenous ligands (endocannabinoids), and the enzymes responsible for their synthesis and catabolism. Recent works have revealed several important interactions between the endocannabinoid system and cancer. Moreover, it is now well established that synthetic small molecule cannabinoid receptor agonist acting on either CB1R or CB2R or both exert anti-cancer effects on a variety of tumor cells. Recent results from many laboratories reported that the expression of CB1R and CB2R in prostate cancer, breast cancer, and many other cancer cells are higher than corresponding non-malignant tissues. The mechanisms by which cannabinoids acting on CB1R or CB2R exert their effects on cancer cells are quite diverse and complex. Further, several studies demonstrated that some of the anti-proliferative and apoptotic effects of cannabinoids are mediated by receptor-independent mechanisms. In this minreview we provide an overview of the major findings on the effects of endogenous and/or synthetic cannabinoids on breast and prostate cancer. We also provide insight into receptor independent mechanisms of the anti-cancer effects of cannabinoids under in vitro and in vivo conditions. PMID:23069587

  12. The amino acid exchange R28E in ciliary neurotrophic factor (CNTF) abrogates interleukin-6 receptor-dependent but retains CNTF receptor-dependent signaling via glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR).

    PubMed

    Wagener, Eva-Maria; Aurich, Matthias; Aparicio-Siegmund, Samadhi; Floss, Doreen M; Garbers, Christoph; Breusing, Kati; Rabe, Björn; Schwanbeck, Ralf; Grötzinger, Joachim; Rose-John, Stefan; Scheller, Jürgen

    2014-06-27

    Ciliary neurotrophic factor (CNTF) is a neurotrophic factor with therapeutic potential for neurodegenerative diseases. Moreover, therapeutic application of CNTF reduced body weight in mice and humans. CNTF binds to high or low affinity receptor complexes consisting of CNTFR·gp130·LIFR or IL-6R·gp130·LIFR, respectively. Clinical studies of the CNTF derivative Axokine revealed intolerance at higher concentrations, which may rely on the low-affinity binding of CNTF to the IL-6R. Here, we aimed to generate a CNTFR-selective CNTF variant (CV). CV-1 contained the single amino acid exchange R28E. Arg(28) is in close proximity to the CNTFR binding site. Using molecular modeling, we hypothesized that Arg(28) might contribute to IL-6R/CNTFR plasticity of CNTF. CV-2 to CV-5 were generated by transferring parts of the CNTFR-binding site from cardiotrophin-like cytokine to CNTF. Cardiotrophin-like cytokine selectively signals via the CNTFR·gp130·LIFR complex, albeit with a much lower affinity compared with CNTF. As shown by immunoprecipitation, all CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2, and CV-5, however, lost the ability to bind to IL-6R. Although all variants induced cytokine-dependent cellular proliferation and STAT3 phosphorylation via CNTFR·gp130·LIFR, only CV-3 induced STAT3 phosphorylation via IL-6R·gp130·LIFR. Quantification of CNTF-dependent proliferation of CNTFR·gp130·LIFR expressing cells indicated that only CV-1 was as biologically active as CNTF. Thus, the CNTFR-selective CV-1 will allow discriminating between CNTFR- and IL-6R-mediated effects in vivo.

  13. TRPP2 modulates ryanodine- and inositol-1,4,5-trisphosphate receptors-dependent Ca2+ signals in opposite ways in cerebral arteries.

    PubMed

    Abdi, Azzedine; Mazzocco, Claire; Légeron, François-Pierre; Yvert, Blaise; Macrez, Nathalie; Morel, Jean-Luc

    2015-11-01

    TRPP2 is a cationic channel expressed in plasma membrane and in sarcoplasmic reticulum. In several cell lines, TRPP2 is described as a reticulum Ca(2+) leak channel but it also interacts with ryanodine and inositol 1,4,5-trisphosphate (InsP3) receptors to inhibit and increase the release of Ca(2+) stores, respectively. TRPP2 is known to be expressed in vascular smooth muscle cells, however its function in Ca(2+) signals remains poorly described in native cells, principally because the pharmacology is not developed. TRPP2 was expressed in cerebral arteries. Triptolide evoked Ca(2+) responses in a Ca(2+)-free solution as well as permeabilized arteries. This Ca(2+) signal was inhibited in presence of antisense oligonucleotide and siRNA directed against TRPP2 and antibody directed against the first loop of TRPP2. The partial inhibition of TRPP2 expression increased both the caffeine-evoked Ca(2+) responses and in vivo contraction. It also decreased the InsP3-evoked Ca(2+) responses. Finally, aging affected the regulations in which TRPP2 is engaged, whereas the triptolide-evoked Ca(2+) response was not modified. Taken together, our results have shown that TRPP2 is implicated in triptolide-induced Ca(2+) release from intracellular Ca(2+) stores. TRPP2 functionally interacts with both ryanodine and InsP3 receptors. These interactions were not similar in adult and old mice. PMID:26254047

  14. Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area.

    PubMed

    Arora, Devinder; Hearing, Matthew; Haluk, Desirae M; Mirkovic, Kelsey; Fajardo-Serrano, Ana; Wessendorf, Martin W; Watanabe, Masahiko; Luján, Rafael; Wickman, Kevin

    2011-08-24

    Enhanced glutamatergic neurotransmission in dopamine (DA) neurons of the ventral tegmental area (VTA), triggered by a single cocaine injection, represents an early adaptation linked to the more enduring effects of abused drugs that characterize addiction. Here, we examined the impact of in vivo cocaine exposure on metabotropic inhibitory signaling involving G-protein-gated inwardly rectifying K(+) (Girk) channels in VTA DA neurons. Somatodendritic Girk currents evoked by the GABA(B) receptor (GABA(B)R) agonist baclofen were diminished in a dose-dependent manner in mice given a single cocaine injection. This adaptation persisted for 3-4 d, was specific for DA neurons of the VTA, and occurred in parallel with an increase in spontaneous glutamatergic neurotransmission. No additional suppression of GABA(B)R-Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABA(B)R1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABA(B)R-Girk signaling correlated with a reduction in Girk2-containing channels at the plasma membrane in VTA DA neurons. Systemic pretreatment with sulpiride, but not SCH23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), prevented the cocaine-induced suppression of GABA(B)R-Girk signaling, implicating D(2/3) DA receptor activation in this adaptation. The acute cocaine-induced weakening of somatodendritic Girk signaling complements the previously demonstrated cocaine-induced strengthening of glutamatergic neurotransmission, likely contributing to enhanced output of VTA DA neurons during the early stages of addiction. PMID:21865468

  15. Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase- and thromboxane A2 receptor-dependent signaling pathways.

    PubMed

    Rodrigues, S; Nguyen, Q D; Faivre, S; Bruyneel, E; Thim, L; Westley, B; May, F; Flatau, G; Mareel, M; Gespach, C; Emami, S

    2001-07-01

    We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors (TFFs), src, and the cyclooxygenases COX-1 and COX-2. Pharmacological inhibitors of the Rho small GTPase (C3 exoenzyme), phospholipase C (U-73122), cyclooxygenases (SC-560, NS-398), and the thromboxane A2 receptor (TXA2-R) antagonist SQ-295 completely abolished invasion induced by intestinal trefoil factor, pS2, and src in kidney and colonic epithelial cells MDCKts.src and PCmsrc. In contrast, invasion was induced by the TXA2-R mimetic U-46619, constitutively activated forms of the heterotrimeric G-proteins Galphaq (AGalphaq), Galpha12, Galpha13 (AGalpha12/13), which are signaling elements downstream of TXA2-R. Ectopic overexpression of pS2 cDNA and protein in MDCKts.src-pS2 cells and human colorectal cancer cells HCT8/S11-pS2 initiate distinct invasion signals that are Rho independent and COX and TXA2-R dependent. We detected a marked induction of COX-2 protein and accumulation of the stable PGH2/TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src. This led to activation of the TXA2-R-dependent invasion pathway, which is monitored via a Rho- and Galpha12/Galpha13-independent mechanism using the Galphaq/PKC signaling cascade. These findings identify a new intracrine/paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers.

  16. Piceatannol, Natural Polyphenolic Stilbene, Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation*

    PubMed Central

    Kwon, Jung Yeon; Seo, Sang Gwon; Heo, Yong-Seok; Yue, Shuhua; Cheng, Ji-Xin; Lee, Ki Won; Kim, Kee-Hong

    2012-01-01

    Piceatannol, a natural stilbene, is an analog and a metabolite of resveratrol. Despite a well documented health benefit of resveratrol in intervention of the development of obesity, the role of piceatannol in the development of adipose tissue and related diseases is unknown. Here, we sought to determine the function of piceatannol in adipogenesis and elucidate the underlying mechanism. We show that piceatannol inhibits adipogenesis of 3T3-L1 preadipocytes in a dose-dependent manner at noncytotoxic concentrations. This anti-adipogenic property of piceatannol was largely limited to the early event of adipogenesis. In the early phase of adipogenesis, piceatannol-treated preadipocytes displayed a delayed cell cycle entry into G2/M phase at 24 h after initiation of adipogenesis. Furthermore, the piceatannol-suppressed mitotic clonal expansion was accompanied by reduced activation of the insulin-signaling pathway. Piceatannol dose-dependently inhibited differentiation mixture-induced phosphorylation of insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/Akt pathway in the early phase of adipogenesis. Moreover, we showed that piceatannol is an inhibitor of IR kinase activity and phosphatidylinositol 3-kinase (PI3K). Our kinetics study of IR further identified a Km value for ATP of 57.8 μm and a Ki value for piceatannol of 28.9 μm. We also showed that piceatannol directly binds to IR and inhibits IR kinase activity in a mixed noncompetitive manner to ATP, through which piceatannol appears to inhibit adipogenesis. Taken together, our study reveals an anti-adipogenic function of piceatannol and highlights IR and its downstream insulin signaling as novel targets for piceatannol in the early phase of adipogenesis. PMID:22298784

  17. CB1 Cannabinoid Receptor-Dependent Activation of mTORC1/Pax6 Signaling Drives Tbr2 Expression and Basal Progenitor Expansion in the Developing Mouse Cortex.

    PubMed

    Díaz-Alonso, Javier; Aguado, Tania; de Salas-Quiroga, Adán; Ortega, Zaira; Guzmán, Manuel; Galve-Roperh, Ismael

    2015-09-01

    The CB1 cannabinoid receptor regulates cortical progenitor proliferation during embryonic development, but the molecular mechanism of this action remains unknown. Here, we report that CB1-deficient mouse embryos show premature cell cycle exit, decreased Pax6- and Tbr2-positive cell number, and reduced mammalian target of rapamycin complex 1 (mTORC1) activation in the ventricular and subventricular cortical zones. Pharmacological stimulation of the CB1 receptor in cortical slices and progenitor cell cultures activated the mTORC1 pathway and increased the number of Pax6- and Tbr2-expressing cells. Likewise, acute CB1 knockdown in utero reduced mTORC1 activation and cannabinoid-induced Tbr2-positive cell generation. Luciferase reporter and chromatin immunoprecipitation assays revealed that the CB1 receptor drives Tbr2 expression downstream of Pax6 induction in an mTORC1-dependent manner. Altogether, our results demonstrate that the CB1 receptor tunes dorsal telencephalic progenitor proliferation by sustaining the transcriptional activity of the Pax6-Tbr2 axis via the mTORC1 pathway, and suggest that alterations of CB1 receptor signaling, by producing the missexpression of progenitor identity determinants may contribute to neurodevelopmental alterations.

  18. Estrogen modulates in vitro T cell responses in a concentration- and receptor-dependent manner: effects on intracellular molecular targets and antioxidant enzymes.

    PubMed

    Priyanka, Hannah P; Krishnan, Harini C; Singh, Ran Vijay; Hima, Lalgi; Thyagarajan, Srinivasan

    2013-12-01

    . Coincubation with 17β-estradiol and ERα- and β-agonists augmented p-ERK 1/2, p-CREB, and p-Akt expression in the lymphocytes and tamoxifen reversed the ER agonist-induced effects on these molecular targets. Estrogen increased the activities of SOD, CAT, and GPx in both non-stimulated and Con A-stimulated splenocytes in a concentration-dependent manner. Both ERα- and β-agonists enhanced CAT and GPx activity while ERα-agonist decreased SOD activity and ERβ-agonist increased SOD activity. The effects of ER agonists on the antioxidant enzymes were reversed by ICI(182,780). Coincubation of lower doses of 17β-estradiol with Con A and both ER agonists enhanced NO production while higher dose of estrogen with Con A and ERα agonist suppressed its production and these effects were reversed by tamoxifen. Taken together, these results suggest that the effects of estrogen on the cell-mediated immune responses are dependent upon its concentrations and mediated through specific estrogen receptors involving intracellular signaling pathways and antioxidant enzymes.

  19. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

    PubMed Central

    Safari, Tahereh; Nematbakhsh, Mehdi; Evans, Roger G.; Denton, Kate M.

    2015-01-01

    Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7 ± 1.9% in estradiol-treated rats but only by 27.3 ± 5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen. PMID:26681937

  20. Receptor-Dependent Coronavirus Infection of Dendritic Cells

    PubMed Central

    Turner, Brian C.; Hemmila, Erin M.; Beauchemin, Nicole; Holmes, Kathryn V.

    2004-01-01

    In several mammalian species, including humans, coronavirus infection can modulate the host immune response. We show a potential role of dendritic cells (DC) in murine coronavirus-induced immune modulation and pathogenesis by demonstrating that the JAW SII DC line and primary DC from BALB/c mice and p/p mice with reduced expression of the murine coronavirus receptor, murine CEACAM1a, are susceptible to murine coronavirus infection by a receptor-dependent pathway. PMID:15113927

  1. Ubiquitin signaling in immune responses

    PubMed Central

    Hu, Hongbo; Sun, Shao-Cong

    2016-01-01

    Ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes, including different aspects of immune functions. Ubiquitination regulates pattern-recognition receptor signaling that mediates both innate immune responses and dendritic cell maturation required for initiation of adaptive immune responses. Ubiquitination also regulates the development, activation, and differentiation of T cells, thereby maintaining efficient adaptive immune responses to pathogens and immunological tolerance to self-tissues. Like phosphorylation, ubiquitination is a reversible reaction tightly controlled by the opposing actions of ubiquitin ligases and deubiquitinases. Deregulated ubiquitination events are associated with immunological disorders, including autoimmune and inflammatory diseases. PMID:27012466

  2. Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway.

    PubMed

    Lee, Hye-Rim; Hwang, Kyung-A; Park, Min-Ah; Yi, Bo-Rim; Jeung, Eui-Bae; Choi, Kyung-Chul

    2012-05-01

    Various endocrine disrupting chemicals (EDCs) are exogenous compounds found in the environment and have the potential to interfere with the endocrine system and hormonal regulation. Among EDCs, bisphenol A (BPA) and 1,1,1-trichloro-2,2-bis(4-methoxyphenol)-ethane [methoxychlor (MXC)] have estrogenic activity resulting in a variety of dysfunctions in the E2-mediated response by binding to estrogen receptors (ERs), causing human health problems such as abnormal reproduction and carcinogenesis. In this study, we investigated the effects of BPA and MXC on cell proliferation facilitated by ER signaling in human breast cancer cells. MCF-7 cells are known to be ERα-positive and to be a highly E2-responsive cancer cell line; these cells are, therefore, a useful in vitro model for detecting estrogenic activity in response to EDCs. We evaluated cancer cell proliferation following BPA and MXC treatment using an MTT assay. We analyzed alterations in the expression of genes associated with the cell cycle in MCF-7 cells by semi-quantitative reverse-transcription PCR following treatment with BPA or MXC compared to EtOH. To determine whether BPA and MXC stimulate cancer cell growth though ER signaling, we co-treated the cells with agonists (propyl pyrazoletriol, PPT; and diarylpropionitrile, DPN) or an antagonist (ICI 182,780) of ER signaling and reduced ERα gene expression via siRNA in MCF-7 cells before treatment with EDCs. These studies confirmed the carcinogenicity of EDCs in vitro. As a result, BPA and MXC induced the cancer cell proliferation by the upregulation of genes that promote the cell cycle and the downregulation of anti-proliferative genes, especially ones affecting the G1/S transition via ERα signaling. These collective results confirm the carcinogenicity of these EDCs in vitro. Further studies are required to determine whether EDCs promote carcinogenesis in vivo.

  3. [The state of receptor-dependent signal pathways in the agranulocytes from the peripheral blood of the reconvalescent patients following community-acquired pneumonia under the influence of microwave radiation].

    PubMed

    Terekhov, I V; Bondar', S S; Khadartsev, A A

    2016-01-01

    The present article reports the study of the influence of low-intensity microwave radiation on the state of the JAK/STAT-signaling pathways in the mononuclear cells and the intercellular levels of the molecules maintaining the functioning of this pathway. The experiments on the model of intercellular interactions in the whole blood cell culture obtained during the convalescence phase of community-acquired bacterial pneumonia were designed to elucidate the effects of the cell-cell interactions in the culture exposed to electromagnetic radiation with a frequency of 1000 MHz and power flux density 0.1 mcW/cm2 on the intracellular levels of total and phosphorylated species of JAK-kinases, STAT-factors and SOCS-proteins. It is concluded that sensitivity of intracellular signaling systems to the effects of low-intensity microwave radiation manifests itself in the form of increased intracellular concentrations of Janus kinases and SOCS proteins with a simultaneous decrease in the level of STAT factors.

  4. [The state of receptor-dependent signal pathways in the agranulocytes from the peripheral blood of the reconvalescent patients following community-acquired pneumonia under the influence of microwave radiation].

    PubMed

    Terekhov, I V; Bondar', S S; Khadartsev, A A

    2016-01-01

    The present article reports the study of the influence of low-intensity microwave radiation on the state of the JAK/STAT-signaling pathways in the mononuclear cells and the intercellular levels of the molecules maintaining the functioning of this pathway. The experiments on the model of intercellular interactions in the whole blood cell culture obtained during the convalescence phase of community-acquired bacterial pneumonia were designed to elucidate the effects of the cell-cell interactions in the culture exposed to electromagnetic radiation with a frequency of 1000 MHz and power flux density 0.1 mcW/cm2 on the intracellular levels of total and phosphorylated species of JAK-kinases, STAT-factors and SOCS-proteins. It is concluded that sensitivity of intracellular signaling systems to the effects of low-intensity microwave radiation manifests itself in the form of increased intracellular concentrations of Janus kinases and SOCS proteins with a simultaneous decrease in the level of STAT factors. PMID:27271829

  5. Optically isolated signal coupler with linear response

    DOEpatents

    Kronberg, James W.

    1994-01-01

    An optocoupler for isolating electrical signals that translates an electrical input signal linearly to an electrical output signal. The optocoupler comprises a light emitter, a light receiver, and a light transmitting medium. The light emitter, preferably a blue, silicon carbide LED, is of the type that provides linear, electro-optical conversion of electrical signals within a narrow wavelength range. Correspondingly, the light receiver, which converts light signals to electrical signals and is preferably a cadmium sulfide photoconductor, is linearly responsive to light signals within substantially the same wavelength range as the blue LED.

  6. Albumin-stimulated DNA synthesis is mediated by Ca2+/PKC as well as EGF receptor-dependent p44/42 MAPK and NF-kappaB signal pathways in renal proximal tubule cells.

    PubMed

    Lee, Yu Jin; Han, Ho Jae

    2008-03-01

    It is now recognized that significant tubular reabsorption of albumin occurs under physiological conditions that may play an important role in maintaining proximal tubular integrity and function. Therefore, this study examined the effect of bovine serum albumin (BSA) on DNA synthesis and its related signal molecules in primary cultured rabbit renal proximal tubule cells (PTCs). BSA increased the level of [(3)H]thymidine incorporation in a dose (> or =3 mg/ml)- and time (> or =3 h)-dependent manner, intracellular Ca(2+) concentration, and the level of protein kinase C (PKC) phosphorylation and stimulated the phosphorylation of the epidermal growth factor receptor (EGFR), which was inhibited by EGTA (extracellular Ca(2+) chelator), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM, intracellular Ca(2+) chelator), or PKC inhibitors (staurosporine or bisindolylmaleimide I). In addition, the PKC inhibitors or an EGFR inhibitor (AG-1478) blocked the BSA-induced phosphorylation of p44/42 mitogen-activated protein kinases (MAPKs). BSA also increased the level of nuclear factor-kappaB (NF-kappaB) and inhibitor of NF-kappaB (IkappaB) phosphorylation, which was blocked by staurosporine, AG-1478, or PD-98059 (p44/42 MAPK inhibitor). Inhibition of Ca(2+), PKC, EGFR, p44/42 MAPK, or NF-kappaB signal pathways blocked the BSA-induced incorporation of [(3)H]thymidine. Consequently, the inhibition of Ca(2+), PKC, EGFR, p44/42 MAPKs, or NF-kappaB blocked the BSA-induced increases in cyclin D1, cyclin-dependent kinase (CDK)4, cyclin E, or CDK2 and restored the BSA-induced inhibition of p21(WAF/Cip1) and p27(Kip1) expression. In conclusion, BSA stimulates DNA synthesis that is mediated by Ca(2+)/PKC as well as the EGFR-dependent p44/42 MAPK and NF-kappaB signal pathways in PTCs.

  7. α-Lipoic acid interaction with dopamine D2 receptor-dependent activation of the Akt/GSK-3β signaling pathway induced by antipsychotics: potential relevance for the treatment of schizophrenia.

    PubMed

    Deslauriers, Jessica; Desmarais, Christian; Sarret, Philippe; Grignon, Sylvain

    2013-05-01

    Chronic administration of antipsychotics has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We have previously shown that haloperidol, a first-generation antipsychotic (FGA), exerted an increase in D2R expression and oxidative stress and that (±)-α-lipoic acid reversed its effect. Previous studies have implicated the Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway in antipsychotic action. These findings led us to examine whether the Akt/GSK-3β pathway was involved in D2R upregulation and oxidative stress elicited by antipsychotics and, in (±)-α-lipoic acid-induced reversal of these phenomena, in SH-SY5Y cells. Antipsychotics increased phosphorylation of Akt and GSK-3β, and additive effects were observed with (±)-α-lipoic acid. GSK-3β inhibitors reversed haloperidol-induced overexpression of D2R mRNA levels but did not affect haloperidol-induced oxidative stress. Sustained antipsychotic treatment increased β-arrestin-2 and D2R receptor interaction. Regarding Akt/GSK-3β downstream targets, antipsychotics increased β-catenin levels, whereas (±)-α-lipoic acid induced an elevation of mTOR activation. These results suggest (1) that the effect of antipsychotics on the Akt/GSK-3β pathway in SH-SY5Y cells is reminiscent of their in vivo action, (2) that (±)-α-lipoic acid partially synergizes with antipsychotic drugs (APDs) on the same pathway, and (3) that the Akt/GSK-3β signaling cascade is not involved in the preventive effect of (±)-α-lipoic acid on antipsychotics-induced D2R upregulation.

  8. A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization.

    PubMed

    Jung, Kwang-Mook; Astarita, Giuseppe; Zhu, Chenggang; Wallace, Matthew; Mackie, Ken; Piomelli, Daniele

    2007-09-01

    Activation of group I metabotropic glutamate (mGlu) receptors recruits the endocannabinoid system to produce both short- and long-term changes in synaptic strength in many regions of the brain. Although there is evidence that the endocannabinoid 2-arachidonoylglycerol (2-AG) mediates this process, the molecular mechanism underlying 2-AG mobilization remains unclear. In the present study, we used a combination of genetic and targeted lipidomic approaches to investigate the role of the postsynaptic membrane-associated lipase, diacylglycerol lipase type-alpha (DGL-alpha), in mGlu receptor-dependent 2-AG mobilization. DGL-alpha overexpression in mouse neuroblastoma Neuro-2a cells increased baseline 2-AG levels. This effect was accompanied by enhanced utilization of the 2-AG precursor 1-stearoyl,2-arachidonoyl-sn-glycerol and increased accumulation of the 2-AG breakdown product arachidonic acid. A similar, albeit less marked response was observed with other unsaturated and polyunsaturated monoacylglycerols, 1,2-diacylglycerols, and fatty acids. Silencing of DGL-alpha by RNA interference elicited lipidomic changes opposite those of DGL-alpha overexpression and abolished group I mGlu receptor-dependent 2-AG mobilization. Coimmunoprecipitation and site-directed mutagenesis experiments revealed that DGL-alpha interacts, via a PPxxF domain, with the coiled-coil (CC)-Homer proteins Homer-1b and Homer-2, two components of the molecular scaffold that enables group I mGlu signaling. DGL-alpha mutants that do not bind Homer maintained their ability to generate 2-AG in intact cells but failed to associate with the plasma membrane. The findings indicate that DGL-alpha mediates group I mGlu receptor-induced 2-AG mobilization. They further suggest that the interaction of CC-Homer with DGL-alpha is necessary for appropriate function of this lipase.

  9. The flavonoid baicalein promotes NMDA receptor-dependent long-term potentiation and enhances memory

    PubMed Central

    Wang, Wei; Wang, Fang; Yang, Yuan-Jian; Hu, Zhuang-Li; Long, Li-Hong; Fu, Hui; Xie, Na; Chen, Jian-Guo

    2011-01-01

    BACKGROUND AND PURPOSE There is growing interest in the physiological functions of flavonoids, especially in their effects on cognitive function and on neurodegenerative diseases. The aim of the current investigation was to evaluate the role of the flavonoid baicalein in long-term potentiation (LTP) in the hippocampal CA1 region and cognitive behavioural performance. EXPERIMENTAL APPROACH Effects of baicalein on LTP in rat hippocampal slices were investigated by electrophysiological methods. Phosphorylation of Akt (at Ser473), the extracellular signal-regulated kinase (ERK1/2) and the transcription factor cAMP response element-binding protein (CREB) (at Ser133) were analysed by Western blot. Fear conditioning was used to determine whether baicalein could improve learning and memory in rats. KEY RESULTS Baicalein enhanced the N-methyl-d-aspartate glutamate receptor-dependent LTP in a bell-shaped concentration-dependent manner. Addition of the lipoxygenase metabolites 12(S)-HETE and 12(S)-HPETE did not reverse these effects of baicalein. Baicalein treatment enhanced phosphorylation of Akt during induction of LTP with the same bell-shaped dose–response curve. LTP potentiation induced by baicalein was blocked by inhibitors of phosphoinositide 3-kinase. CREB phosphorylation was also increased in the CA1 region of baicalein-treated slices. Baicalein-treated rats performed significantly better than controls in a hippocampus-dependent contextual fear conditioning task. Furthermore, baicalein treatment selectively increased the phosphorylation of Akt and CREB in the CA1 region of hippocampus, but not in the prefrontal cortex, after fear conditioning training. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that the flavonoid baicalein can facilitate memory, and therefore it might be useful in the treatment of patients with memory disorders. PMID:21133890

  10. Ultrasensitive Responses and Specificity in Cell Signaling

    PubMed Central

    2010-01-01

    Background Interconnected cell signaling pathways are able to efficiently and accurately transmit a multitude of different signals, despite an inherent potential for undesirable levels of cross-talk. To ensure that an appropriate response is produced, biological systems have evolved network-level mechanisms that insulate pathways from crosstalk and prevent 'leaking' or 'spillover' between pathways. Many signaling pathways have been shown to respond in an ultrasensitive (switch-like) fashion to graded input, and this behavior may influence specificity. The relationship of ultrasensitivity to signaling specificity has not been extensively explored. Results We studied the behavior of simple mathematical models of signaling networks composed of two interconnected pathways that share an intermediate component, asking if the two pathways in the network could exhibit both output specificity (preferentially activate their own output) and input fidelity (preferentially respond to their own input). Previous results with weakly-activated pathways indicated that neither mutual specificity nor mutual fidelity were obtainable in the absence of an insulating mechanism, such as cross-pathway inhibition, combinatorial signaling or scaffolding/compartmentalization. Here we found that mutual specificity is obtainable for hyperbolic or ultrasensitive pathways, even in the absence of an insulating mechanism. However, mutual fidelity is impossible at steady-state, even if pathways are hyperbolic or ultrasensitive. Nevertheless, ultrasensitivity does provide advantages in attaining specificity and fidelity to networks that contain an insulating mechanism. For networks featuring cross-pathway inhibition or combinatorial signaling, ultrasensitive activation can increase specificity in a limited way, and can only be utilized by one of the two pathways. In contrast, for networks featuring scaffolding/compartmentalization, ultrasensitive activation of both pathways can dramatically improve

  11. Linear ubiquitination signals in adaptive immune responses

    PubMed Central

    Ikeda, Fumiyo

    2015-01-01

    Summary Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage-type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized Tumor Necrosis Factor (TNF) -induced canonical nuclear factor-kappa B (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways. PMID:26085218

  12. Phosphatidylcholine signaling in response to CSF-1.

    PubMed

    Jackowski, S; Xu, X X; Rock, C O

    1997-01-01

    The formation of cell membrane following CSF-1 stimulation of a macrophage cell line is coordinated with cell cycle progression. The majority of membrane phospholipid accumulates during the S phase and results from cell-cycle dependent oscillations in the rates of phosphatidylcholine biosynthesis and degradation. Both synthesis and degradation are enhanced during the G1 phase, resulting in a high rate of phosphatidylcholine turnover. Degradation of phosphatidylcholine after CSF-1 stimulation is mediated by a phospholipase C, and the release of diacylglycerol during G1 phase is biphasic. The degradation essentially stops during the S phase, thus allowing biosynthesis to supply the necessary membrane for cell division and doubling. The degradation of phosphatidylcholine during G1 signals the downstream activation of c-fos and junB transcription and can be mimicked by incubation of the macrophage cells with exogenous bacterial phospholipase C. In contrast, the expression of c-myc transcripts normally associated with CSF-1 stimulation is severely compromised in phospholipase C-treated cells, indicating that the diacylglycerol signals a pathway distinct from the pathway that governs c-myc activation. Constitutive expression of c-myc complements phospholipase C activity and permits the growth of cells in the presence of exogenous bacterial enzyme and the absence of CSF-1. Protein kinase C is not required to mediate the diacylglycerol signal that supports cell growth. GTP exchange on Ras is not enhanced, and MAP kinase activity is not stimulated in response to phosphatidylcholine degradation by exogenous phospholipase C. The 85 kDa cytoplasmic phospholipase A2 is activated, however, as well as a novel protein we have called p96. Rapid serine phosphorylation of p96 follows stimulation of cells with either CSF-1 or exogenous phospholipase C. Analysis of the murine cDNA encoding p96 reveals an amino-terminal domain with significant similarity to the amino-terminal domain of

  13. Early cellular signaling responses to axonal injury

    PubMed Central

    Lukas, Thomas J; Wang, Ai Ling; Yuan, Ming; Neufeld, Arthur H

    2009-01-01

    Background We have used optic nerve injury as a model to study early signaling events in neuronal tissue following axonal injury. Optic nerve injury results in the selective death of retinal ganglion cells (RGCs). The time course of cell death takes place over a period of days with the earliest detection of RGC death at about 48 hr post injury. We hypothesized that in the period immediately following axonal injury, there are changes in the soma that signal surrounding glia and neurons and that start programmed cell death. In the current study, we investigated early changes in cellular signaling and gene expression that occur within the first 6 hrs post optic nerve injury. Results We found evidence of cell to cell signaling within 30 min of axonal injury. We detected differences in phosphoproteins and gene expression within the 6 hrs time period. Activation of TNFα and glutamate receptors, two pathways that can initiate cell death, begins in RGCs within 6 hrs following axonal injury. Differential gene expression at 6 hrs post injury included genes involved in cytokine, neurotrophic factor signaling (Socs3) and apoptosis (Bax). Conclusion We interpret our studies to indicate that both neurons and glia in the retina have been signaled within 30 min after optic nerve injury. The signals are probably initiated by the RGC soma. In addition, signals activating cellular death pathways occur within 6 hrs of injury, which likely lead to RGC degeneration. PMID:19284657

  14. System proportions fluid-flow in response to demand signals

    NASA Technical Reports Server (NTRS)

    1966-01-01

    Control system provides proportioned fluid flow rates in response to demand signals. It compares a digital signal, representing a flow demand, with a reference signal to yield a control voltage to one or more solenoid valves connected to orifices of a predetermined size.

  15. Localization of a breathing crack using nonlinear subharmonic response signals

    NASA Astrophysics Data System (ADS)

    Semperlotti, F.; Wang, K. W.; Smith, E. C.

    2009-12-01

    The experimental validation of a structural health monitoring system based on the peculiar nonlinear dynamic response of cracked structures is proposed in this letter. The higher order harmonic response signal is a technique which allows detecting the location of a breathing crack taking advantage of the nonlinear dynamic response proper of a cracked structure. The experimental results show that information carried by the nonlinear harmonics allow detecting the structural damage without requiring a baseline signal of the healthy structure.

  16. Green light signaling and adaptive response

    PubMed Central

    Zhang, Tingting; Folta, Kevin M.

    2012-01-01

    To a plant, the sun’s light is not exclusively energy for photosynthesis, it also provides a package of data about time and prevailing conditions. The plant’s surroundings may dampen or filter solar energies, altering spectral profiles of their light environment. Plants use this information to adjust form and physiology, tailoring gene expression to best match ambient conditions. Extensive literature exists on how blue, red and far-red light contribute to plant adaptive responses. A growing body of work identifies discrete effects of green light (500–565 nm) that also shape plant biology. Green light responses are known to be either mediated through, or independent of, the cryptochrome blue light receptors. Responses to green light share a general tendency to oppose blue- or red-light-induced responses, including stem growth rate inhibition, anthocyanin accumulation or chloroplast gene expression. Recent evidence demonstrates a role for green light in sensing a shaded environment, independent from far-red shade responses. PMID:22301972

  17. Are responses in avoidance procedures "safety" signals?

    PubMed

    Branch, M N

    2001-05-01

    Dinsmoor's (2001) position has the advantage of parsimony in that it relies on well-established principles rather than a separate process--shock-frequency reduction--to account for avoidance. Other advantages are that it blends well with what is known about the effectiveness of momentary contiguities in the study of positive reinforcement and that it might provide an account of why different response forms seem to condition at different rates. Despite these advantages, the view needs elaboration about the temporal characteristics of response-associated stimuli, the functions that "warning'' stimuli may have, and especially about how ''safety" is established.

  18. Ultrasensitive response motifs: basic amplifiers in molecular signalling networks

    PubMed Central

    Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E.

    2013-01-01

    Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm. PMID:23615029

  19. Ionic signaling in plant gravity and touch responses

    NASA Technical Reports Server (NTRS)

    Massa, Gioia D.; Fasano, Jeremiah M.; Gilroy, Simon

    2003-01-01

    Plant roots are optimized to exploit resources from the soil and as each root explores this environment it will encounter a range of biotic and abiotic stimuli to which it must respond. Therefore, each root must possess a sensory array capable of monitoring and integrating these diverse stimuli to direct the appropriate growth response. Touch and gravity represent two of the biophysical stimuli that plants must integrate. As sensing both of these signals requires mechano-transduction of biophysical forces to biochemical signaling events, it is likely that they share signal transduction elements. These common signaling components may allow for cross-talk and so integration of thigmotropic and gravitropic responses. Indeed, signal transduction events in both plant touch and gravity sensing are thought to include Ca(2+)- and pH-dependent events. Additionally, it seems clear that the systems responsible for root touch and gravity response interact to generate an integrated growth response. Thus, primary and lateral roots of Arabidopsis respond to mechanical stimuli by eliciting tropic growth that is likely part of a growth strategy employed by the root to circumvent obstacles in the soil. Also, the mechano-signaling induced by encountering an obstacle apparently down-regulates the graviperception machinery to allow this kind of avoidance response. The challenge for future research will be to define how the cellular signaling events in the root cap facilitate this signal integration and growth regulation. In addition, whether other stimuli are likewise integrated with the graviresponse via signal transduction system cross-talk is an important question that remains to be answered.

  20. Changing the light environment: chloroplast signalling and response mechanisms.

    PubMed

    Spetea, Cornelia; Rintamäki, Eevi; Schoefs, Benoît

    2014-04-19

    Light is an essential environmental factor required for photosynthesis, but it also mediates signals to control plant development and growth and induces stress tolerance. The photosynthetic organelle (chloroplast) is a key component in the signalling and response network in plants. This theme issue of Philosophical Transactions of the Royal Society of London B: Biology provides updates, highlights and summaries of the most recent findings on chloroplast-initiated signalling cascades and responses to environmental changes, including light and biotic stress. Besides plant molecular cell biology and physiology, the theme issue includes aspects from the cross-disciplinary fields of environmental adaptation, ecology and agronomy.

  1. Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.

    PubMed

    Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T

    2016-02-01

    Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.

  2. Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons

    PubMed Central

    Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T.

    2016-01-01

    Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. PMID:26901880

  3. Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.

    PubMed

    Chay, Andrew; Zamparo, Ilaria; Koschinski, Andreas; Zaccolo, Manuela; Blackwell, Kim T

    2016-02-01

    Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory. PMID:26901880

  4. Effects of age, signal level, and signal rate on the auditory middle latency response.

    PubMed

    Tucker, D A; Ruth, R A

    1996-04-01

    The effects of age, signal rate, and signal level on the maturing auditory middle latency response (AMLR) were evaluated in 50 normal-hearing subjects ranging in age from 2 days to 35 years. Ipsilateral and contralateral AMLR waveforms were recorded in newborns (n = 10), children (n = 10), preteens (n = 10), teens (n = 10), and adults (n = 10). The AMLR Pa waveform was obtained in 70 to 100 percent of all subjects. The variables of age, signal level, and site of recording significantly affected Pa peak amplitude and absolute latency. However, stimulus rate did not significantly affect the response.

  5. Effects of age, signal level, and signal rate on the auditory middle latency response.

    PubMed

    Tucker, D A; Ruth, R A

    1996-04-01

    The effects of age, signal rate, and signal level on the maturing auditory middle latency response (AMLR) were evaluated in 50 normal-hearing subjects ranging in age from 2 days to 35 years. Ipsilateral and contralateral AMLR waveforms were recorded in newborns (n = 10), children (n = 10), preteens (n = 10), teens (n = 10), and adults (n = 10). The AMLR Pa waveform was obtained in 70 to 100 percent of all subjects. The variables of age, signal level, and site of recording significantly affected Pa peak amplitude and absolute latency. However, stimulus rate did not significantly affect the response. PMID:8652873

  6. Agrobacterium tumefaciens responses to plant-derived signaling molecules

    PubMed Central

    Subramoni, Sujatha; Nathoo, Naeem; Klimov, Eugene; Yuan, Ze-Chun

    2014-01-01

    As a special phytopathogen, Agrobacterium tumefaciens infects a wide range of plant hosts and causes plant tumors also known as crown galls. The complexity of Agrobacterium–plant interaction has been studied for several decades. Agrobacterium pathogenicity is largely attributed to its evolved capabilities of precise recognition and response to plant-derived chemical signals. Agrobacterium perceives plant-derived signals to activate its virulence genes, which are responsible for transferring and integrating its Transferred DNA (T-DNA) from its Tumor-inducing (Ti) plasmid into the plant nucleus. The expression of T-DNA in plant hosts leads to the production of a large amount of indole-3-acetic acid (IAA), cytokinin (CK), and opines. IAA and CK stimulate plant growth, resulting in tumor formation. Agrobacterium utilizes opines as nutrient sources as well as signals in order to activate its quorum sensing (QS) to further promote virulence and opine metabolism. Intriguingly, Agrobacterium also recognizes plant-derived signals including γ-amino butyric acid and salicylic acid (SA) to activate quorum quenching that reduces the level of QS signals, thereby avoiding the elicitation of plant defense and preserving energy. In addition, Agrobacterium hijacks plant-derived signals including SA, IAA, and ethylene to down-regulate its virulence genes located on the Ti plasmid. Moreover, certain metabolites from corn (Zea mays) also inhibit the expression of Agrobacterium virulence genes. Here we outline the responses of Agrobacterium to major plant-derived signals that impact Agrobacterium–plant interactions. PMID:25071805

  7. Signal transduction in responses to UV-B radiation.

    PubMed

    Jenkins, Gareth I

    2009-01-01

    UV-B radiation is a key environmental signal that initiates diverse responses in plants that affect metabolism, development, and viability. Many effects of UV-B involve the differential regulation of gene expression. The response to UV-B depends on the nature of the UV-B treatment, the extent of adaptation and acclimation to UV-B, and interaction with other environmental factors. Responses to UV-B are mediated by both nonspecific signaling pathways, involving DNA damage, reactive oxygen species, and wound/defense signaling molecules, and UV-B-specific pathways that mediate photomorphogenic responses to low levels of UV-B. Importantly, photomorphogenic signaling stimulates the expression of genes involved in UV-protection and hence promotes plant survival in UV-B. Photomorphogenic UV-B signaling is mediated by the UV-B-specific component UV RESISTANCE LOCUS8 (UVR8). Both UVR8 and CONSTITUTIVE PHOTOMORPHOGENESIS1 (COP1) are required for UV-B-induced expression of the ELONGATED HYPOCOTYL5 (HY5) transcription factor, which plays a central role in the regulation of genes involved in photomorphogenic UV-B responses.

  8. Evolutionarily labile responses to a signal of aggressive intent.

    PubMed Central

    Moretz, Jason A; Morris, Molly R

    2003-01-01

    Males of many swordtail species possess vertical bar pigment patterns that are used both in courtship and agonistic interactions. Expression of the bars may function as a conventional threat signal during conflicts with rival males; bars intensify at the onset of aggression and fade in the subordinate male at contest's end. We used mirror image stimulation and bar manipulations to compare the aggressive responses of the males of four swordtail species to their barred and barless images. We found that having a response to the bars is tightly linked to having genes for bars, while the nature of the response the bars evoked varied across species. Specifically, we report the first known instance where closely related species exhibited differing and contradictory responses to a signal of aggressive motivation. Demonstrating that a signal conveys the same information across species (aggressive intent) while the response to that information has changed among species suggests that the nature of the responses are more evolutionarily labile than the signal. PMID:14613614

  9. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  10. Large-signal transient response of a switching regulator

    NASA Astrophysics Data System (ADS)

    Harada, K.; Nabeshima, T.

    Analytical and experimental considerations on the large-signal transient-responses of the buck-type switching regulator are described. The behaviour under the large-signal operation is different from the case of small signal because of the saturation characteristics of the PWM feedback controller. The effect of this nonlinearity is analyzed by dividing its operation into three modes. As a result, the maximum peak values of the inrush current and output voltage are obtained analytically both for the start-up and for the step change of the load current.

  11. Ionic signaling in plant responses to gravity and touch

    NASA Technical Reports Server (NTRS)

    Fasano, Jeremiah M.; Massa, Gioia D.; Gilroy, Simon

    2002-01-01

    Touch and gravity are two of the many stimuli that plants must integrate to generate an appropriate growth response. Due to the mechanical nature of both of these signals, shared signal transduction elements could well form the basis of the cross-talk between these two sensory systems. However, touch stimulation must elicit signaling events across the plasma membrane whereas gravity sensing is thought to represent transformation of an internal force, amyloplast sedimentation, to signal transduction events. In addition, factors such as turgor pressure and presence of the cell wall may also place unique constraints on these plant mechanosensory systems. Even so, the candidate signal transduction elements in both plant touch and gravity sensing, changes in Ca2+, pH and membrane potential, do mirror the known ionic basis of signaling in animal mechanosensory cells. Distinct spatial and temporal signatures of Ca2+ ions may encode information about the different mechanosignaling stimuli. Signals such as Ca2+ waves or action potentials may also rapidly transfer information perceived in one cell throughout a tissue or organ leading to the systemic reactions characteristic of plant touch and gravity responses. Longer-term growth responses are likely sustained via changes in gene expression and asymmetries in compounds such as inositol-1,4,5-triphosphate (IP3) and calmodulin. Thus, it seems likely that plant mechanoperception involves both spatial and temporal encoding of information at all levels, from the cell to the whole plant. Defining this patterning will be a critical step towards understanding how plants integrate information from multiple mechanical stimuli to an appropriate growth response.

  12. Ionic signaling in plant responses to gravity and touch.

    PubMed

    Fasano, Jeremiah M; Massa, Gioia D; Gilroy, Simon

    2002-06-01

    Touch and gravity are two of the many stimuli that plants must integrate to generate an appropriate growth response. Due to the mechanical nature of both of these signals, shared signal transduction elements could well form the basis of the cross-talk between these two sensory systems. However, touch stimulation must elicit signaling events across the plasma membrane whereas gravity sensing is thought to represent transformation of an internal force, amyloplast sedimentation, to signal transduction events. In addition, factors such as turgor pressure and presence of the cell wall may also place unique constraints on these plant mechanosensory systems. Even so, the candidate signal transduction elements in both plant touch and gravity sensing, changes in Ca2+, pH and membrane potential, do mirror the known ionic basis of signaling in animal mechanosensory cells. Distinct spatial and temporal signatures of Ca2+ ions may encode information about the different mechanosignaling stimuli. Signals such as Ca2+ waves or action potentials may also rapidly transfer information perceived in one cell throughout a tissue or organ leading to the systemic reactions characteristic of plant touch and gravity responses. Longer-term growth responses are likely sustained via changes in gene expression and asymmetries in compounds such as inositol-1,4,5-triphosphate (IP3) and calmodulin. Thus, it seems likely that plant mechanoperception involves both spatial and temporal encoding of information at all levels, from the cell to the whole plant. Defining this patterning will be a critical step towards understanding how plants integrate information from multiple mechanical stimuli to an appropriate growth response.

  13. Dopamine signaling promotes the xenobiotic stress response and protein homeostasis.

    PubMed

    Joshi, Kishore K; Matlack, Tarmie L; Rongo, Christopher

    2016-09-01

    Multicellular organisms encounter environmental conditions that adversely affect protein homeostasis (proteostasis), including extreme temperatures, toxins, and pathogens. It is unclear how they use sensory signaling to detect adverse conditions and then activate stress response pathways so as to offset potential damage. Here, we show that dopaminergic mechanosensory neurons in C. elegans release the neurohormone dopamine to promote proteostasis in epithelia. Signaling through the DA receptor DOP-1 activates the expression of xenobiotic stress response genes involved in pathogenic resistance and toxin removal, and these genes are required for the removal of unstable proteins in epithelia. Exposure to a bacterial pathogen (Pseudomonas aeruginosa) results in elevated removal of unstable proteins in epithelia, and this enhancement requires DA signaling. In the absence of DA signaling, nematodes show increased sensitivity to pathogenic bacteria and heat-shock stress. Our results suggest that dopaminergic sensory neurons, in addition to slowing down locomotion upon sensing a potential bacterial feeding source, also signal to frontline epithelia to activate the xenobiotic stress response so as to maintain proteostasis and prepare for possible infection. PMID:27261197

  14. IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing.

    PubMed

    Braun, Matthias; Ress, Marie L; Yoo, Young-Eun; Scholz, Claus J; Eyrich, Matthias; Schlegel, Paul G; Wölfl, Matthias

    2016-07-01

    Interleukin 12 (IL12) is a key inflammatory cytokine critically influencing Th1/Tc1-T-cell responses at the time of initial antigen encounter. Therefore, it may be exploited for cancer immunotherapy. Here, we investigated how IL12, and other inflammatory cytokines, shape effector functions of human T-cells. Using a defined culture system, we followed the gradual differentiation and function of antigen-specific CD8(+) T cells from their initial activation as naïve T cells through their expansion phase as early memory cells to full differentiation as clonally expanded effector T cells. The addition of IL12 8 days after the initial priming event initiated two mechanistically separate events: First, IL12 sensitized the T-cell receptor (TCR) for antigen-specific activation, leading to an approximately 10-fold increase in peptide sensitivity and, in consequence, enhanced tumor cell killing. Secondly, IL12 enabled TCR/HLA-independent activation and cytotoxicity: this "non-specific" effect was mediated by the NK cell receptor DNAM1 (CD226) and dependent on ligand expression of the target cells. This IL12 regulated, DNAM1-mediated killing is dependent on src-kinases as well as on PTPRC (CD45) activity. Thus, besides enhancing TCR-mediated activation, we here identified for the first time a second IL12 mediated mechanism leading to activation of a receptor-dependent killing pathway via DNAM1. PMID:27622043

  15. β-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner

    PubMed Central

    Horváth, Béla; Mukhopadhyay, Partha; Kechrid, Malek; Patel, Vivek; Tanashian, Galin; Wink, David A.; Gertsch, Jürg; Pacher, Pál

    2012-01-01

    (E)-β-caryophyllene (BCP) is a natural sequiterpene found in many essential oils of spice (best known for contributing to the spiciness of black pepper) and food plants with recognized anti-inflammatory properties. Recently it was shown that BCP is a natural agonist of endogenous cannabinoid 2 (CB2) receptors, which are expressed in immune cells and mediate anti-inflammatory effects. In this study we aimed to test the effects of BCP in a clinically relevant murine model of nephropathy (induced by the widely used antineoplastic drug cisplatin) in which the tubular injury is largely dependent on inflammation and oxidative/nitrative stress. β-caryophyllene dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response (chemokines MCP-1 and MIP-2, cytokines TNF-α and IL-1β, adhesion molecule ICAM-1, and neutrophil and macrophage infiltration). It also markedly mitigated oxidative/nitrative stress (NOX-2, NOX-4 expression, 4-HNE and 3-NT content) and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB2 knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB2 receptor dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in multitude of diseases associated with inflammation and oxidative stress. PMID:22326488

  16. Cytokinin responses counterpoint auxin signaling during rhizobial infection.

    PubMed

    Liu, Cheng-Wu; Breakspear, Andrew; Roy, Sonali; Murray, Jeremy D

    2015-01-01

    The transcriptomics approach to study gene expression in root hairs from M. truncatula has shed light on the developmental events during rhizobial infection and the underlying hormone responses. This approach revealed the induction of several cyclins and an aurora kinase which suggests that the cell-division machinery plays a role in rhizobial infection. Changes in the cell cycle in plants are governed by hormones, in particular auxin and cytokinin. Through gene expression and genetic analyses, we have shown auxin plays a role during rhizobial infection. Here we provide further analysis of the data showing the induction of a set of cytokinin signaling components. These include genes encoding 2 cytokinin-activating enzymes, the cytokinin receptor CRE1, and 5 type-A cytokinin response regulators. We discuss the possible interactions between auxin and cytokinin signaling during the infection process. We also consider a potential role for cytokinin signaling in rhizobial attachment. PMID:26176899

  17. The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast

    PubMed Central

    Henry, Susan A.; Gaspar, Maria L.; Jesch, Stephen A.

    2014-01-01

    This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed. PMID:24418527

  18. The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast.

    PubMed

    Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A

    2014-05-01

    This article focuses on discoveries of the mechanisms governing the regulation of glycerolipid metabolism and stress response signaling in response to the phospholipid precursor, inositol. The regulation of glycerolipid lipid metabolism in yeast in response to inositol is highly complex, but increasingly well understood, and the roles of individual lipids in stress response are also increasingly well characterized. Discoveries that have emerged over several decades of genetic, molecular and biochemical analyses of metabolic, regulatory and signaling responses of yeast cells, both mutant and wild type, to the availability of the phospholipid precursor, inositol are discussed.

  19. Response inhibition in the stop-signal paradigm

    PubMed Central

    Logan, Gordon D.

    2009-01-01

    Response inhibition is a hallmark of executive control. The concept refers to the suppression of no-longer required or inappropriate actions, which supports flexible and goal-directed behavior in ever-changing environments. The stop-signal paradigm is most suitable for the study of response inhibition in a laboratory setting. The paradigm has become increasingly popular in cognitive psychology, cognitive neuroscience and psychopathology. We review recent findings in the stop-signal literature with the specific aim of demonstrating how each of these different fields contributes to better understanding of the processes involved in inhibiting a response and monitoring stopping performance, and more generally, discovering how behavior is controlled. PMID:18799345

  20. Paracrine communication maximizes cellular response fidelity in wound signaling

    PubMed Central

    Handly, L Naomi; Pilko, Anna; Wollman, Roy

    2015-01-01

    Population averaging due to paracrine communication can arbitrarily reduce cellular response variability. Yet, variability is ubiquitously observed, suggesting limits to paracrine averaging. It remains unclear whether and how biological systems may be affected by such limits of paracrine signaling. To address this question, we quantify the signal and noise of Ca2+ and ERK spatial gradients in response to an in vitro wound within a novel microfluidics-based device. We find that while paracrine communication reduces gradient noise, it also reduces the gradient magnitude. Accordingly we predict the existence of a maximum gradient signal to noise ratio. Direct in vitro measurement of paracrine communication verifies these predictions and reveals that cells utilize optimal levels of paracrine signaling to maximize the accuracy of gradient-based positional information. Our results demonstrate the limits of population averaging and show the inherent tradeoff in utilizing paracrine communication to regulate cellular response fidelity. DOI: http://dx.doi.org/10.7554/eLife.09652.001 PMID:26448485

  1. New Modeling Approaches to Investigate Cell Signaling in Radiation Response

    NASA Technical Reports Server (NTRS)

    Plante, Ianik; Cucinotta, Francis A.; Ponomarev, Artem L.

    2011-01-01

    Ionizing radiation damages individual cells and tissues leading to harmful biological effects. Among many radiation-induced lesions, DNA double-strand breaks (DSB) are considered the key precursors of most early and late effects [1] leading to direct mutation or aberrant signal transduction processes. In response to damage, a flow of information is communicated to cells not directly hit by the radiation through signal transduction pathways [2]. Non-targeted effects (NTE), which includes bystander effects and genomic instability in the progeny of irradiated cells and tissues, may be particularly important for space radiation risk assessment [1], because astronauts are exposed to a low fluence of heavy ions and only a small fraction of cells are traversed by an ion. NTE may also have important consequences clinical radiotherapy [3]. In the recent years, new simulation tools and modeling approaches have become available to study the tissue response to radiation. The simulation of signal transduction pathways require many elements such as detailed track structure calculations, a tissue or cell culture model, knowledge of biochemical pathways and Brownian Dynamics (BD) propagators of the signaling molecules in their micro-environment. Recently, the Monte-Carlo simulation code of radiation track structure RITRACKS was used for micro and nano-dosimetry calculations [4]. RITRACKS will be used to calculate the fraction of cells traversed by an ion and delta-rays and the energy deposited in cells in a tissue model. RITRACKS also simulates the formation of chemical species by the radiolysis of water [5], notably the .OH radical. This molecule is implicated in DNA damage and in the activation of the transforming growth factor beta (TGF), a signaling molecule involved in NTE. BD algorithms for a particle near a membrane comprising receptors were also developed and will be used to simulate trajectories of signaling molecules in the micro-environment and characterize autocrine

  2. GABAergic mechanisms contributing to categorical amygdala responses to chemosensory signals.

    PubMed

    Westberry, Jenne M; Meredith, Michael

    2016-09-01

    Chemosensory stimuli from conspecific and heterospecific animals, elicit categorically different immediate-early gene response-patterns in medial amygdala in male hamsters and mice. We previously showed that conspecific signals activate posterior (MeP) as well as anterior medial amygdala (MeA), and especially relevant heterospecific signals such as chemosensory stimuli from potential predators also activate MeP in mice. Other heterospecific chemosignals activate MeA, but not MeP. Here we show that male hamster amygdala responds significantly differentially to different conspecific signals, by activating different proportions of cells of different phenotype, possibly leading to differential activation of downstream circuits. Heterospecific signals that fail to activate MeP do activate GABA-immunoreactive cells in the adjacent caudal main intercalated nucleus (mICNc) and elicit selective suppression of MeP cells bearing GABA-Receptors, suggesting GABA inhibition in MeP by GABAergic cells in mICNc. Overall, work presented here suggests that medial amygdala may discriminate between important conspecific social signals, distinguish them from the social signals of other species and convey that information to brain circuits eliciting appropriate social behavior. PMID:27329335

  3. Melatonin as a Signaling Molecule for Metabolism Regulation in Response to Hypoxia in the Crab Neohelice granulata

    PubMed Central

    Maciel, Fábio Everton; Geihs, Márcio Alberto; Cruz, Bruno Pinto; Vargas, Marcelo Alves; Allodi, Silvana; Marins, Luis Fernando; Nery, Luiz Eduardo Maia

    2014-01-01

    Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) and circulating glucose and lactate levels, in response to different dissolved-oxygen concentrations, in the crab Neohelice granulata, as well as whether these possible effects are eyestalk- or receptor-dependent. Melatonin decreased CHH expression in crabs exposed for 45 min to 6 (2, 200 or 20,000 pmol·crab−1) or 2 mgO2·L−1 (200 pmol·crab−1). Since luzindole (200 nmol·crab−1) did not significantly (p > 0.05) alter the melatonin effect, its action does not seem to be mediated by vertebrate-typical MT1 and MT2 receptors. Melatonin (200 pmol·crab−1) increased the levels of glucose and lactate in crabs exposed to 6 mgO2·L−1, and luzindole (200 nmol·crab−1) decreased this effect, indicating that melatonin receptors are involved in hyperglycemia and lactemia. Melatonin showed no effect on VO2. Interestingly, in vitro incubation of eyestalk ganglia for 45 min at 0.7 mgO2·L−1 significantly (p < 0.05) increased melatonin production in this organ. In addition, injections of melatonin significantly increased the levels of circulating melatonin in crabs exposed for 45 min to 6 (200 or 20,000 pmol·crab−1), 2 (200 and 20,000 pmol·crab−1) and 0.7 (200 or 20,000 pmol·crab−1) mgO2·L−1. Therefore, melatonin seems to have an effect on the metabolism of N. granulata. This molecule inhibited the gene expression of CHH and caused an eyestalk- and receptor-dependent hyperglycemia, which suggests that melatonin may have a signaling role in metabolic regulation in this crab. PMID:25486055

  4. Melatonin as a signaling molecule for metabolism regulation in response to hypoxia in the crab Neohelice granulata.

    PubMed

    Maciel, Fábio Everton; Geihs, Márcio Alberto; Cruz, Bruno Pinto; Vargas, Marcelo Alves; Allodi, Silvana; Marins, Luis Fernando; Nery, Luiz Eduardo Maia

    2014-12-04

    Melatonin has been identified in a variety of crustacean species, but its function is not as well understood as in vertebrates. The present study investigates whether melatonin has an effect on crustacean hyperglycemic hormone (CHH) gene expression, oxygen consumption (VO2) and circulating glucose and lactate levels, in response to different dissolved-oxygen concentrations, in the crab Neohelice granulata, as well as whether these possible effects are eyestalk- or receptor-dependent. Melatonin decreased CHH expression in crabs exposed for 45 min to 6 (2, 200 or 20,000 pmol·crab-1) or 2 mgO2·L-1 (200 pmol·crab-1). Since luzindole (200 nmol·crab-1) did not significantly (p > 0.05) alter the melatonin effect, its action does not seem to be mediated by vertebrate-typical MT1 and MT2 receptors. Melatonin (200 pmol·crab-1) increased the levels of glucose and lactate in crabs exposed to 6 mgO2·L-1, and luzindole (200 nmol·crab-1) decreased this effect, indicating that melatonin receptors are involved in hyperglycemia and lactemia. Melatonin showed no effect on VO2. Interestingly, in vitro incubation of eyestalk ganglia for 45 min at 0.7 mgO2·L-1 significantly (p < 0.05) increased melatonin production in this organ. In addition, injections of melatonin significantly increased the levels of circulating melatonin in crabs exposed for 45 min to 6 (200 or 20,000 pmol·crab-1), 2 (200 and 20,000 pmol·crab-1) and 0.7 (200 or 20,000 pmol·crab-1) mgO2·L-1. Therefore, melatonin seems to have an effect on the metabolism of N. granulata. This molecule inhibited the gene expression of CHH and caused an eyestalk- and receptor-dependent hyperglycemia, which suggests that melatonin may have a signaling role in metabolic regulation in this crab.

  5. Constitutive IFNα/β signaling maintains expression of signaling intermediaries for efficient cytokine responses.

    PubMed

    Messina, Nicole L; Clarke, Christopher J P; Johnstone, Ricky W

    2016-01-01

    Interferons (IFNs) are a family of immunoregulatory cytokines with important roles in anti-viral and anti-tumor responses. Type I and II IFNs bind distinct receptors and are associated with different stages of the immune response. There is however, considerable crosstalk between these two cytokines with enhancement of IFNγ responses following IFNα/β priming and loss of IFNα/β receptor (IFNAR) resulting in diminished IFNγ responses. In this study, we sought to define the mechanism of crosstalk between the type I and II IFNs. Our previous reports demonstrated reduced expression of the canonically activated transcription factor signal transducer and activator of transcription (STAT)1, in cells lacking the IFNAR α chain (IFNAR1). Therefore, we used microarray analysis to determine whether reconstitution of STAT1 in IFNAR1-deficient cells was sufficient to restore IFNγ responses. We identified several biological pathways, including the MHC class I antigen presentation pathway, in which STAT1 reconstitution was able to significantly rescue IFNγ-mediated gene regulation in Ifnar1 (-/-) cells. Notably, we also found that in addition to low basal expression of STAT1, cells lacking the IFNAR1 also had aberrant expression of multiple other transcription factors and signaling intermediaries. The studies described herein demonstrate that basal and regulated expression of signaling intermediaries is a mechanism for crosstalk between cytokines including type I and II IFNs. PMID:27512617

  6. Phylogenetic signals and ecotoxicological responses: potential implications for aquatic biomonitoring.

    PubMed

    Carew, Melissa E; Miller, Adam D; Hoffmann, Ary A

    2011-05-01

    Macroinvertebrates can be successfully used as biomonitors of pollutants and environmental health because some groups are sensitive whereas, others are relatively tolerant to pollutants. An issue of ongoing debate is what constitutes an appropriate group for biomonitoring; should the group represent species, genera or higher taxonomic levels? A phylogenetic framework can provide new insights into this issue. By developing phylogenies for chironomids and mayflies, this investigation shows that there is strong phylogenetic signal for pollution responses, and that phylogenetic nodes are common to tolerant and sensitive groups of species. A phylogenetic analysis of biotic indices developed for mayflies based on their response to organic pollution shows that mayfly families varied in pollution tolerance. In contrast, based on sediment zinc concentrations as an indicator of pollution tolerance, Australian chironomids tend to vary in tolerance at lower taxonomic levels. Published data on North American chironomids shows much of the signal for pollution responses is contained within genera rather than sub-families. Tools are now available to distinguish whether this signal reflects historical evolutionary constraints or environmental effects leading to common evolved responses. This suggests that ideally higher taxonomic levels should be used for biomonitoring when there are strong phylogenetic constraints at higher levels. Evolutionary considerations can therefore help to guide the development of macroinvertebrate biomonitors and provide insights into processes that produce sensitive and tolerant taxa.

  7. Stress response signaling and virulence: insights from entomopathogenic fungi.

    PubMed

    Ortiz-Urquiza, Almudena; Keyhani, Nemat O

    2015-08-01

    The Ascomycete fungal insect pathogens, Beauveria and Metarhizium spp. have emerged as model systems with which to probe diverse aspects of fungal growth, stress response, and pathogenesis. Due to the availability of genomic resources and the development of robust methods for genetic manipulation, the last 5 years have witnessed a rapid increase in the molecular characterization of genes and their pathways involved in stress response and signal transduction in these fungi. These studies have been performed mainly via characterization of gene deletion/knockout mutants and have included the targeting of general proteins involved in stress response and/or virulence, e.g. catalases, superoxide dismutases, and osmolyte balance maintenance enzymes, membrane proteins and signaling pathways including GPI anchored proteins and G-protein coupled membrane receptors, MAPK pathways, e.g. (i) the pheromone/nutrient sensing, Fus3/Kss1, (ii) the cell wall integrity, Mpk1, and (iii) the high osmolarity, Hog1, the PKA/adenyl cyclase pathway, and various downstream transcription factors, e.g. Msn2, CreA and Pac1. Here, we will discuss current research that strongly suggests extensive underlying contributions of these biochemical and signaling pathways to both abiotic stress response and virulence. PMID:25113413

  8. Response inhibition signals and miscoding of direction in dorsomedial striatum

    PubMed Central

    Bryden, Daniel W.; Burton, Amanda C.; Kashtelyan, Vadim; Barnett, Brian R.; Roesch, Matthew R.

    2012-01-01

    The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS) in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO). On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP). Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons (MSNs) tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. PMID:22973206

  9. Response Selection and Response Execution in Task Switching: Evidence from a Go-Signal Paradigm

    ERIC Educational Resources Information Center

    Philipp, Andrea M.; Jolicoeur, Pierre; Falkenstein, Michael; Koch, Iring

    2007-01-01

    The present study used a go/no-go signal delay (GSD) to explore the role of response-related processes in task switching. A go/no-go signal was presented at either 100 ms or 1,500 ms after the stimulus. Participants were encouraged to use the GSD for response selection and preparation. The data indicate that the opportunity to select and prepare a…

  10. Scenarios for Consuming Standardized Automated Demand Response Signals

    SciTech Connect

    Koch, Ed; Piette, Mary Ann

    2008-10-03

    Automated Demand Response (DR) programs require that Utility/ISO's deliver DR signals to participants via a machine to machine communications channel. Typically these DR signals constitute business logic information (e.g. prices and reliability/shed levels) as opposed to commands to control specific loads in the facility. At some point in the chain from the Utility/ISO to the loads in a facility, the business level information sent by the Utility/ISO must be processed and used to execute a DR strategy for the facility. This paper explores the various scenarios and types of participants that may utilize DR signals from the Utility/ISO. Specifically it explores scenarios ranging from single end user facility, to third party facility managers and DR Aggregators. In each of these scenarios it is pointed out where the DR signal sent from the Utility/ISO is processed and turned into the specific load control commands that are part of a DR strategy for a facility. The information in these signals is discussed. In some cases the DR strategy will be completely embedded in the facility while in others it may be centralized at a third party (e.g. Aggregator) and part of an aggregated set of facilities. This paper also discusses the pros and cons of the various scenarios and discusses how the Utility/ISO can use an open standardized method (e.g. Open Automated Demand Response Communication Standards) for delivering DR signals that will promote interoperability and insure that the widest range of end user facilities can participate in DR programs regardless of which scenario they belong to.

  11. Subjective diffuseness of music signals convolved with binaural impulse responses

    NASA Astrophysics Data System (ADS)

    Shimokura, Ryota; Tronchin, Lamberto; Cocchi, Alessandro; Soeta, Yoshiharu

    2011-07-01

    The spatial impression of sound in a hall can be quantified using sound field factors such as the interaural cross-correlation coefficient (IACC) calculated from binaural impulse response (BIR), henceforth denoted by IACC IR. The subjective diffuseness for the listener is a spatial attribute which depends on factors associated both with the source signal and with the actual sound field, and is quantified using the IACC of the signal received by the listener, henceforth denoted by IACC SR. Therefore, the subjective diffuseness in a given hall may change with the music. The aims of this study are to estimate the IACC SR from the IACC IR and the factors, which is obtained from autocorrelation function (ACF) of music signal, and to evaluate the subjective diffuseness by these factors. First, the relationship between the IACC IR and IACC SR was investigated. Second, subjective diffuseness was measured by a psycho-acoustical experiment. As a result, the IACC SR could be estimated from the IACC IR of the BIR and the effective duration ( τe) from the ACF of music signal. It was found that the effects of BIRs on subjective diffuseness could be evaluated by IACC IR for almost all subjects, while the effects of music signals could be evaluated by the τe and the width of the peak at τ=0 ( Wϕ(0) ) of the ACF.

  12. Optoelectronic signal processing using finite impulse response neural networks

    NASA Astrophysics Data System (ADS)

    H. B. Xavier da Silveira, Paulo Eduardo

    2001-08-01

    This thesis investigates the use of finite impulse response neural network as the computational algorithm for efficient optoelectronic signal processing. The study begins with the analysis and development of different suitable algorithms, followed by the optoelectronic design of single-layer and multi-layer architectures, and it is concluded with the presentation of the results of a successful experimental implementation. First, finite impulse response adaptive filters and neural networks-the algorithmic building blocks-are introduced, followed by a description of finite impulse response neural networks. This introduction is followed by a historical background, describing early optoelectronic implementations of these algorithms. Next, different algorithms capable of temporal back-propagation are derived in detail, including a novel modification to the conventional algorithm, called delayed-feedback back- propagation. Based on these algorithms, different optoelectronic processors making use of adaptive volume holograms and three-dimensional optical processing are developed. Two single-layer architectures are presented: the input delay plane architecture and the output delay plane architecture. By combining them it is possible to implement both forward and backward propagation in two complementary multi-layer architectures: the first making use of the conventional temporal back-propagation and the second making use of delayed feedback back-propagation. Next, emphasis is given to a specific application: the processing of signals from adaptive antenna arrays. This research is initiated by computer simulations of different scenarios with multiple broadband signals and jammers, in planar and circular arrays, studying issues such as the effect of modulator non-linearities to the performance of the array, and the relation between the number of jammers and the final nulling depth. Two sets of simulations are presented: the first set applied to RF antenna arrays and the

  13. Chromium stress response effect on signal transduction and expression of signaling genes in rice.

    PubMed

    Trinh, Ngoc-Nam; Huang, Tsai-Lien; Chi, Wen-Chang; Fu, Shih-Feng; Chen, Chi-Chien; Huang, Hao-Jen

    2014-02-01

    Hexavalent chromium [Cr(VI)] is a non-essential metal for normal plants and is toxic to plants at high concentrations. However, signaling pathways and molecular mechanisms of its action on cell function and gene expression remain elusive. In this study, we found that Cr(VI) induced endogenous reactive oxygen species (ROS) generation and Ca(2+) accumulation and activated NADPH oxidase and calcium-dependent protein kinase. We investigated global transcriptional changes in rice roots by microarray analysis. Gene expression profiling indicated activation of abscisic acid-, ethylene- and jasmonic acid-mediated signaling and inactivation of gibberellic acid-related pathways in Cr(VI) stress-treated rice roots. Genes encoding signaling components such as the protein kinases domain of unknown function 26, receptor-like cytoplasmic kinase, LRK10-like kinase type 2 and protein phosphatase 2C, as well as transcription factors WRKY and apetala2/ethylene response factor were predominant during Cr(VI) stress. Genes involved in vesicle trafficking were subjected to functional characterization. Pretreating rice roots with a vesicle trafficking inhibitor, brefeldin A, effectively reduced Cr(VI)-induced ROS production. Suppression of the vesicle trafficking gene, Exo70, by virus-induced gene silencing strategies revealed that vesicle trafficking is required for mediation of Cr(VI)-induced ROS production. Taken together, these findings shed light on the molecular mechanisms in signaling pathways and transcriptional regulation in response to Cr stress in plants. PMID:24033343

  14. Seismo-electromagnetic thin-bed responses: Natural signal enhancements?

    NASA Astrophysics Data System (ADS)

    Grobbe, N.; Slob, E. C.

    2016-04-01

    We study if nature can help us overcome the very low signal-to-noise ratio of seismo-electromagnetic converted fields by investigating the effects of thin-bed geological structures on the seismo-electromagnetic signal. To investigate the effects of bed thinning on the seismo-electromagnetic interference patterns, we numerically simulate seismo-electromagnetic wave propagation through horizontally layered media with different amounts and thicknesses of thin beds. We distinguish two limits of bed thickness. Below the upper limit, the package of thin beds starts acting like an "effective" medium. Below the lower limit, further thinning does not affect the seismo-electromagnetic interface response signal strength anymore. We demonstrate seismo-electromagnetic sensitivity to changes in medium parameters on a spatial scale much smaller than the seismic resolution. Increasing amounts of thin beds can cause the interface response signal strength to increase or decrease. Whether constructive or destructive interference occurs seems to be dependent on the seismo-electromagnetic coupling coefficient contrasts. When the combined result of the contrast, between upper half-space and package of thin beds and the internal thin-bed contrast, is positive, constructive interference occurs. Destructive interference occurs when the combined contrast is negative. Maximum amplitude tuning occurs for thicknesses of thin-bed packages similar to the dominant pressure and shear wavelengths. Artifacts due to model periodicity are excluded by comparing periodic media with random models. By simulating moving oil/water contacts during production, where the oil layer is gradually being thinned, seismo-electromagnetic signals are proven very sensitive to oil/water contacts. An oil layer with a thickness of <1% of the dominant shear wavelength is still recognized.

  15. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide

    PubMed Central

    2013-01-01

    A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity. PMID:23339575

  16. Photoreceptor signaling networks in plant responses to shade.

    PubMed

    Casal, Jorge J

    2013-01-01

    The dynamic light environment of vegetation canopies is perceived by phytochromes, cryptochromes, phototropins, and UV RESISTANCE LOCUS 8 (UVR8). These receptors control avoidance responses to preclude exposure to limiting or excessive light and acclimation responses to cope with conditions that cannot be avoided. The low red/far-red ratios of shade light reduce phytochrome B activity, which allows PHYTOCHROME INTERACTING FACTORS (PIFs) to directly activate the transcription of auxin-synthesis genes, leading to shade-avoidance responses. Direct PIF interaction with DELLA proteins links gibberellin and brassinosteroid signaling to shade avoidance. Shade avoidance also requires CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1), a target of cryptochromes, phytochromes, and UVR8. Multiple regulatory loops and the input of the circadian clock create a complex network able to respond even to subtle threats of competition with neighbors while still compensating for major environmental fluctuations such as the day-night cycles.

  17. Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response.

    PubMed

    Shahin, Mohamed H; Johnson, Julie A

    2016-04-01

    Thiazide (TZD) diuretics are among the most commonly prescribed antihypertensives globally; however their chronic blood pressure (BP) lowering mechanism remains unclear. Herein we discuss the current evidence regarding specific mechanisms regulating the antihypertensive effects of TZDs, suggesting that TZDs act via multiple complex and interacting mechanisms, including natriuresis with short term use and direct vasodilatory effects chronically. Additionally, we review pharmacogenomics signals that have been associated with TZDs BP-response in several cohorts (i.e. NEDD4L, PRKCA, EDNRA-GNAS, and YEATS4) and discuss how these genes might be related to TZD BP-response mechanism. Understanding the association between these genes and TZD BP mechanism might facilitate the development of new drugs and therapeutic approaches based on a deeper understanding of the determinants of BP-response.

  18. DNA damage response and sphingolipid signaling in liver diseases

    PubMed Central

    Matsuda, Yasunobu; Moro, Kazuki; Tsuchida, Junko; Soma, Daiki; Hirose, Yuki; Kobayashi, Takashi; Kosugi, Shin-ichi; Takabe, Kazuaki; Komatsu, Masaaki; Wakai, Toshifumi

    2016-01-01

    Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC. PMID:26514817

  19. Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

    SciTech Connect

    L'Hote, Corine G.M. . E-mail: Corine.LHote@cancer.org.uk; Knowles, Margaret A.

    2005-04-01

    FGFR3 is a receptor tyrosine kinase (RTK) of the FGF receptor family, known to have a negative regulatory effect on long bone growth. Fgfr3 knockout mice display longer bones and, accordingly, most germline-activating mutations in man are associated with dwarfism. Somatically, some of the same activating mutations are associated with the human cancers multiple myeloma, cervical carcinoma and carcinoma of the bladder. How signalling through FGFR3 can lead to either chondrocyte apoptosis or cancer cell proliferation is not fully understood. Although FGFR3 can be expressed as two main splice isoforms (IIIb or IIIc), there is no apparent link with specific cell responses, which may rather be associated with the cell type or its differentiation status. Depending on cell type, differential activation of STAT proteins has been observed. STAT1 phosphorylation seems to be involved in inhibition of chondrocyte proliferation while activation of the ERK pathway inhibits chondrocyte differentiation and B-cell proliferation (as in multiple myeloma). The role of FGFR3 in epithelial cancers (bladder and cervix) is not known. Some of the cell specificity may arise via modulation of signalling by crosstalk with other signalling pathways. Recently, inhibition of the ERK pathway in achondroplastic mice has provided hope for an approach to the treatment of dwarfism. Further understanding of the ability of FGFR3 to trigger different responses depending on cell type and cellular context may lead to treatments for both skeletal dysplasias and cancer.

  20. From perception to attenuation: auxin signalling and responses.

    PubMed

    Peer, Wendy Ann

    2013-10-01

    The plant hormone auxin is essential for growth, development, and responses to environmental factors. Recently, Auxin Binding Protein 1 was shown to mediate non-transcriptional auxin signalling at the cell periphery. This has provoked reexamination of the paradigm that all auxin perception is intracellular and is mediated by the TIR1/AFB-Aux/IAA co-receptors for which auxin functions as a concentration-dependent molecular glue. Further, another F-box protein, SKP2a, was shown to bind auxin in the same way as TIR1/AFB, which provides a link to the role of auxin in the cell cycle. New work on auxin signalling and homeostasis include D6 PROTEIN KINASE activation of PINFORMED (PIN) auxin carriers, ROP-GTPase mediation of PIN localization, endoplasmic reticulum localization PIN and PIN-LIKES auxin carriers, and auxin biosynthesis and metabolism. PMID:24004572

  1. Endometrial responses to embryonic signals in the primate

    PubMed Central

    Banerjee, Prajna; Fazleabas, Asgerally T.

    2016-01-01

    The delicate interaction between an embryo and the uterus to initiate implantation and maintain pregnancy is one of the most elegant and fascinating interactions in human biology. Understanding the molecular events of embryo-maternal interaction is of interest to reproductive biologists, clinicians and couples affected by infertility. We have established the baboon as the non-human primate model for studying embryo implantation. Infusion of chorionic gonadotropin (CG), the major embryonic signal of primates, into the uterine cavity of normal cycling baboons during the window of receptivity induces a myriad of morphological, biochemical and molecular changes in the estrogen and progesterone primed endometrium. The luminal epithelium responds by forming plaques, the overall secretory function of the glandular epithelium increases and the stromal response is characterized by induction of α-smooth muscle actin (αSMA). Cross talk between ovarian and embryonic hormones is evidenced by the fact that these responses are inhibited upon treatment with a progesterone receptor antagonist. CG signals principally through the seven transmembrane LH/CG G-protein coupled receptor, and activates a mitogen activated protein kinase pathway in the endometrial epithelium that is unique and independent of all the classical signaling pathways. In the stromal compartment, CG both rescues stromal fibroblasts from their apoptotic demise and also differentiates them into the decidualized phenotype. We propose that stromal cell survival and differentiation is mediated by a critical modulator of cell fate, Notch-1. Thus, CG is an important embryonic signal which modulates communication between the embryo and the endometrium and induces changes that are critical to successful implantation. PMID:19876822

  2. A Step Response Based Mixed-Signal BIST Approach

    NASA Technical Reports Server (NTRS)

    Walker, Alvernon

    2001-01-01

    A new Mixed-Signal Built-in Self-test approach that is based upon the step response of a reconfigurable (or multifunction) analog block is presented in this paper. The technique requires the overlapping step response of the Circuit Under Test (CUT) for two circuit configurations. Each configuration can be realized by changing the topology of the CUT or by sampling two CUT nodes with differing step responses. The technique can effectively detect both soft and hard faults and does not require an analog-to-digital converter (ADC) and/or digital-to-analog converter( DAC). It also does not require any precision voltage sources or comparators. The approach does not require any additional analog circuits to realize the test signal generator and a two input analog multiplexer for CUT test node sampling. The paper is concluded with the application of the proposed approach to a circuit found in the work of Epstein et a1 and two ITC 97 analog benchmark circuits.

  3. Purinergic Signaling to Terminate TLR Responses in Macrophages

    PubMed Central

    Hamidzadeh, Kajal; Mosser, David M.

    2016-01-01

    Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active downregulation of innate responses induced by the very PAMPs that initiated them. Here, we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR-stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the downregulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-γ. IFN-γ-treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response. PMID:26973651

  4. Purinergic Signaling to Terminate TLR Responses in Macrophages.

    PubMed

    Hamidzadeh, Kajal; Mosser, David M

    2016-01-01

    Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active downregulation of innate responses induced by the very PAMPs that initiated them. Here, we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR-stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the downregulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-γ. IFN-γ-treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response. PMID:26973651

  5. PEGylation of a Maltose Biosensor Promotes Enhanced Signal Response

    SciTech Connect

    Dattelbaum, Andrew; Baker, Gary A; Fox, John M; Iyer, Srinivas; Dattelbaum, Jonathan

    2009-01-01

    A robust method to immobilize a maltose biosensor is described using an engineered maltose periplasmic binding protein (PBP) covalently coupled to NBDamide, an environmentally sensitive fluorophore. A mesoporous silica sol-gel derived from diglycerylsilane (DGS) was constructed to embed the maltose biosensor, and the ligand reporting fluorescence properties were meas red. When sequestered in the DGS-derived silica matrix, the biosensor retained maltose-dependent fluorescence sensing capability with micromolar affinity, which is consistent with the protein free in solution. The MBP-NBD conjugate was further modified by covalent conjugation with poly(ethylene glycol)-5000 (PEG) to promote the retention of water molecules around the protein and to reduce possible steric effects between the silica matrix and protein. Bioconjugation with PEG molecules does not significantly affect the signaling response of the protein in solution. When immobilized in the DGS polymer, a consistent increase in fluorescence intensity was observed as compared to the protein not functionalized with PEG. To our knowledge, this report presents the first successful method to embed a PBP biosensor in a polymerized matrix and retain signaling response using an environmentally sensitive probe. The immobilization method presented here should be easily adaptable to all conformation-dependent biosensors.

  6. Bacterial stimulus perception and signal transduction: response to osmotic stress.

    PubMed

    Krämer, Reinhard

    2010-08-01

    When exposed to osmotic stress from the environment, bacteria act to maintain cell turgor and hydration by responding both on the level of gene transcription and protein activity. Upon a sudden decrease in external osmolality, internal solutes are released by the action of membrane embedded mechanosensitive channels. In response to an osmotic upshift, the concentration of osmolytes in the cytoplasm is increased both by de novo synthesis and by active uptake. In order to coordinate these processes of osmoregulation, cells are equipped with systems and mechanisms of sensing physical stimuli correlated to changes in the external osmolality (osmosensing), with pathways to transduce these stimuli into useful signals which can be processed in the cell (signal transduction), and mechanisms of regulating proper responses in the cell to recover from the environmental stress and to maintain all necessary physiological functions (osmoregulation). These processes will be described by a number of representative examples, mainly of osmoreactive transport systems with a focus on available data of their molecular mechanism.

  7. Myocardial survival signaling in response to stem cell transplantation

    PubMed Central

    Li, Hongzhe; Malhotra, Deepak; Yeh, Che-chung; Tu, Richard; Zhu, Bo-Qing; Birger, Noy; Wisneski, Andrew; Cha, John; Karliner, Joel S.; Mann, Michael J.

    2009-01-01

    BACKGROUND: Experimental human stem cell transplantation to the heart has begun, but the mechanisms underlying benefits seen in pre-clinical models, both at the site of cell injection and at more distant regions, remain uncertain. We hypothesize that these benefits may be best understood first at the level of key intracellular signaling cascades in the host myocardium that may be responsible for functional and structural preservation of the heart. STUDY DESIGN: Western blot and ELISA were used to assess key pathways that regulate cardiac myocyte survival and hypertrophy in both the infarct/borderzone (I/BZ) and remote myocardium (RM) of C57/B6 mouse hearts subjected to coronary artery ligation, with subsequent injection of either vehicle or bone marrow-derived adult mesenchymal stem cells (MSC). RESULTS: Improved left ventricular function with MSC transplantation was associated with a relative preservation of Akt phosphorylation (activation) and of phosphorylation of downstream mediators of cell survival and hypertrophy. There was no significant difference in activation of MAP kinase p38, and activation of the anti-apoptotic MAP kinase ERK was lower at one week after MSC treatment but rose above controls by week 2. Similar changes were observed in both the I/BZ and the RM. CONCLUSION: Stem cell transplantation in the post-MI murine myocardium is associated with preservation of Akt signaling. Together with a possible later increase in ERK activation, this signaling change may be responsible for cardioprotection. Further focused investigation may identify elements in transplantation regimens that optimize this mechanism of benefit, and that may increase the likelihood of human clinical success. PMID:19476797

  8. Testicular hyperthermia induces Unfolded Protein Response signaling activation in spermatocyte.

    PubMed

    Kim, Jung-Hak; Park, Sun-Ji; Kim, Tae-Shin; Park, Hyo-Jin; Park, Junghyung; Kim, Bo Kyung; Kim, Gyeong-Ryul; Kim, Jin-Man; Huang, Song Mei; Chae, Jung-Il; Park, Choon-Keun; Lee, Dong-Seok

    2013-05-17

    The testes of most mammals are sensitive to temperature. To survive and adapt under conditions that promote endoplasmic reticulum (ER) stress such as heat shock, cells have a self-protective mechanism against ER stress that has been termed the "Unfolded Protein Response" (UPR). However, the cellular and molecular events underlying spermatogenesis with testicular hyperthermia involved in the UPR signaling pathway under ER stress remain poorly understood. In the present study, we verified that UPR signaling via phospho-eIF2α/ATF4/GADD34, p90ATF6, and phospho-IRE1α/XBP-1 is activated with testicular hyperthermia (43 °C, 15 min/day) and induced ER stress-mediated apoptosis associated with CHOP, phospho-JNK, and caspase-3 after repetitive periods of hyperthermia. Levels of phospho-eIF2α protein of mouse spermatocytes in the testis were rapidly increased by one cycle of testicular hyperthermia. ATF4/GADD34 and p90ATF6 expression gradually increased and decreased, respectively, with repetitive cycles of hyperthermia. Spliced XBP1 mRNA as a marker of IRE1 activity was increased after one, three cycles of hyperthermia and decreased by five cycles of hyperthermia. Although the levels of anti-apoptotic phospho-JNK (p54) were gradually decreased after three cycles of hyperthermia, CHOP expression was rapidly increased. After five cycles of testicular hyperthermia, the levels of cleaved caspase-3 and TUNEL-positive apoptotic spermatocytes cells were significantly increased. Our data demonstrated that testicular hyperthermia induces UPR signaling and repetitive cycles of hyperthermia lead to apoptosis of spermatocytes in mouse testis. These results suggest a link between the UPR signaling pathway and testicular hyperthermia.

  9. Inhibitory Effects on Response Force in the Stop-Signal Paradigm

    ERIC Educational Resources Information Center

    Ko, Yao-Ting; Alsford, Toni; Miller, Jeff

    2012-01-01

    The forcefulness of key press responses was measured in stop-all and selective stopping versions of the stop-signal paradigm. When stop signals were presented too late for participants to succeed in stopping their responses, response force was nonetheless reduced relative to trials in which no stop signal was presented. This effect shows that…

  10. T cells induce extended class II MHC compartments in dendritic cells in a Toll-like receptor-dependent manner.

    PubMed

    Boes, Marianne; Bertho, Nicolas; Cerny, Jan; Op den Brouw, Marjolein; Kirchhausen, Tomas; Ploegh, Hidde

    2003-10-15

    Interaction of Ag-loaded dendritic cells with Ag-specific CD4 T cells induces the formation of long tubular class II MHC-positive compartments that polarize toward the T cell. We show involvement of a Toll-like receptor-mediated signal in this unusual form of intracellular class II MHC trafficking. First, wild-type dendritic cells loaded with LPS-free Ag failed to show formation of class II-positive tubules upon Ag-specific T cell engagement, but did so upon supplementation of the Ag with low concentrations of LPS. Second, Ag-loaded myeloid differentiation factor 88 -deficient dendritic cells failed to form these tubules upon interaction with T cells, regardless of the presence of LPS. Finally, inclusion of a cell-permeable peptide that blocks TNFR-associated factor 6 function, downstream of myeloid differentiation factor 88, blocked T cell-dependent tubulation. A Toll-like receptor-dependent signal is thus required to allow Ag-loaded dendritic cells to respond to T cell contact by formation of extended endosomal compartments. This activation does not result in massive translocation of class II MHC molecules to the cell surface.

  11. Oxidative stress response and Nrf2 signaling in aging

    PubMed Central

    Zhang, Hongqiao; Davies, Kelvin J. A.; Forman, Henry Jay

    2015-01-01

    Increasing oxidative stress, a major characteristic of aging, has been implicated in variety of age-related pathologies. In aging, oxidant production from several sources is increased while antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins also declines. Importantly, the adaptive response to oxidative stress declines with aging. Nrf2/EpRE signaling regulates the basal and inducible expression of many antioxidant enzymes and the proteasome. Nrf2/EpRE activity is regulated at several levels including transcription, post-translation, and interaction with other proteins. This review summarizes current studies on age-related impairment of Nrf2/EpRE function and discusses the change of Nrf2 regulatory mechanisms with aging. PMID:26066302

  12. Photosynthesis, photorespiration, and light signalling in defence responses.

    PubMed

    Kangasjärvi, Saijaliisa; Neukermans, Jenny; Li, Shengchun; Aro, Eva-Mari; Noctor, Graham

    2012-02-01

    Visible light is the basic energetic driver of plant biomass production through photosynthesis. The constantly fluctuating availability of light and other environmental factors means that the photosynthetic apparatus must be able to operate in a dynamic fashion appropriate to the prevailing conditions. Dynamic regulation is achieved through an array of homeostatic control mechanisms that both respond to and influence cellular energy and reductant status. In addition, light availability and quality are continuously monitored by plants through photoreceptors. Outside the laboratory growth room, it is within the context of complex changes in energy and signalling status that plants must regulate pathways to deal with biotic challenges, and this can be influenced by changes in the highly energetic photosynthetic pathways and in the turnover of the photosynthetic machinery. Because of this, defence responses are neither simple nor easily predictable, but rather conditioned by the nutritional and signalling status of the plant cell. This review discusses recent data and emerging concepts of how recognized defence pathways interact with and are influenced by light-dependent processes. Particular emphasis is placed on the potential roles of the chloroplast, photorespiration, and photoreceptor-associated pathways in regulating the outcome of interactions between plants and pathogenic organisms.

  13. Forecasting Cell Death Dose-Response from Early Signal Transduction Responses In Vitro

    PubMed Central

    Vrana, Julie A.; Currie, Holly N.; Han, Alice A.; Boyd, Jonathan

    2014-01-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure. PMID:24824809

  14. Forecasting cell death dose-response from early signal transduction responses in vitro.

    PubMed

    Vrana, Julie A; Currie, Holly N; Han, Alice A; Boyd, Jonathan

    2014-08-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure.

  15. A case of a novel mutant vasopressin receptor-dependent nephrogenic diabetes insipidus with bilateral non-obstructive hydronephrosis in a middle aged man: differentiation from aquaporin-dependent nephrogenic diabetes insipidus by response of factor VII and von Willebrand factor to 1-diamino-8-arginine vasopressin administration.

    PubMed

    Miyakoshi, Masashi; Kamoi, Kyuzi; Uchida, Shinichi; Sasaki, Sei

    2003-12-01

    We describe a case of a novel mutant vasopressin 2 receptor (V2R)-dependent nephrogenic diabetes insipidus (NDI) with bilateral non-obstructive hydronephrosis in a middle aged man. This could be distinguished from aquaporin 2 (AQP2)-dependent NDI by the response of factor VIII and von Willebrand factor (vWF) to 1-deamino-8-D-arginine vasopressin (DDAVP) administration. A 47-year-old man was admitted to hospital because of polyuria, which had been present from infancy and was suspected of causing non-obstructive hydronephrosis. His mother's father, the older brother of his mother and his second daughter also all had polyuria. Sodium concentration, osmolality and vasopressin in blood were high, while sodium concentration and osmolality in urine were low. There were no changes in urine osmolality, factor VIII and vWF in response to DDAVP infusion. Neither was heart rate, diastolic blood pressure nor facial flushing affected. These findings suggested this case was V2R-dependent NDI rather than AQP2-dependent NDI. Molecular genetic analysis demonstrated that the patient had a V2R missense mutation involving a substitution of cysteine for arginine at position 104 (R104C) located in the first extracellular loop of the V2R. It was also found that the patient's mother and his second daughter were heterozygous for this R104C mutation. PMID:14709855

  16. Effects of Response-Signal Temporal Separation on Behavior Maintained under Temporally Defined Schedules of Delayed Signaled Reinforcement

    ERIC Educational Resources Information Center

    Pulido, Marco A.; Martinez, Guillermo

    2010-01-01

    The present study assessed the effects of systematically separating the cue from the response in temporally defined schedules of delayed signaled reinforcement. Identical schedules were used to study the effects of the independent variable on response acquisition and response maintenance. In the first experiment, 8 groups of 3 naive rats were…

  17. The Arabidopsis MAP kinase kinase 7: A crosstalk point between Auxin signaling and defense responses?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant-pathogen interaction induces a complex host response that coordinates various signaling pathways through multiple signal molecules. Besides the well-documented signal molecules salicylic acid (SA), ethylene and jasmonic acid, auxin is emerging as an important player in this response. We recent...

  18. Leptin Induces a Novel Form of NMDA Receptor-Dependent LTP at Hippocampal Temporoammonic-CA1 Synapses(1,2,3).

    PubMed

    Luo, Xiao; McGregor, Gemma; Irving, Andrew J; Harvey, Jenni

    2015-01-01

    It is well documented that the hormone leptin regulates many central functions and that hippocampal CA1 pyramidal neurons are a key target for leptin action. Indeed, leptin modulates excitatory synaptic transmission and synaptic plasticity at the Schaffer-collateral input to CA1 neurons. However the impact of leptin on the direct temporoammonic (TA) input to CA1 neurons is not known. Here we show that leptin evokes a long-lasting increase [long-term potentiation (LTP)] in excitatory synaptic transmission at TA-CA1 synapses in rat juvenile hippocampus. Leptin-induced LTP was NMDA receptor-dependent and specifically involved the activation of GluN2B subunits. The signaling pathways underlying leptin-induced LTP involve the activation of phosphoinositide 3-kinase, but were independent of the ERK signaling cascade. Moreover, insertion of GluA2-lacking AMPA receptors was required for leptin-induced LTP as prior application of philanthotoxin prevented the effects of leptin. In addition, synaptic-induced LTP occluded the persistent increase in synaptic efficacy induced by leptin. In conclusion, these data indicate that leptin induces a novel form of NMDA receptor-dependent LTP at juvenile TA-CA1 synapses, which has important implications for the role of leptin in modulating hippocampal synaptic function in health and disease. PMID:26464986

  19. Epigenetic Mechanisms of Serotonin Signaling.

    PubMed

    Holloway, Terrell; González-Maeso, Javier

    2015-07-15

    Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression.

  20. Epigenetic Mechanisms of Serotonin Signaling.

    PubMed

    Holloway, Terrell; González-Maeso, Javier

    2015-07-15

    Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression. PMID:25734378

  1. Role of Standard Demand Response Signals for Advanced Automated Aggregation

    SciTech Connect

    Lawrence Berkeley National Laboratory; Kiliccote, Sila

    2011-11-18

    Emerging standards such as OpenADR enable Demand Response (DR) Resources to interact directly with Utilities and Independent System Operators to allow their facility automation equipment to respond to a variety of DR signals ranging from day ahead to real time ancillary services. In addition, there are Aggregators in today’s markets who are capable of bringing together collections of aggregated DR assets and selling them to the grid as a single resource. However, in most cases these aggregated resources are not automated and when they are, they typically use proprietary technologies. There is a need for a framework for dealing with aggregated resources that supports the following requirements: • Allows demand-side resources to participate in multiple DR markets ranging from wholesale ancillary services to retail tariffs without being completely committed to a single entity like an Aggregator; • Allow aggregated groups of demand-side resources to be formed in an ad hoc fashion to address specific grid-side issues and support the optimization of the collective response of an aggregated group along a number of different dimensions. This is important in order to taylor the aggregated performance envelope to the needs to of the grid; • Allow aggregated groups to be formed in a hierarchical fashion so that each group can participate in variety of markets from wholesale ancillary services to distribution level retail tariffs. This paper explores the issues of aggregated groups of DR resources as described above especially within the context of emerging smart grid standards and the role they will play in both the management and interaction of various grid-side entities with those resources.

  2. Allergen-encoded signals that control allergic responses

    PubMed Central

    Tung, Hui-Ying; Landers, Cameron; Li, Evan; Porter, Paul; Kheradmand, Farrah; Corry, David B.

    2016-01-01

    Purpose of review The purpose is to review the important recent advances made in how innate immune cells, microbes, and the environment contribute to the expression of allergic disease, emphasizing the allergen-related signals that drive allergic responses. Recent findings The last few years have seen crucial advances in how innate immune cells such as innate lymphoid cells group 2 and airway epithelial cells and related molecular pathways through organismal proteinases and innate immune cytokines, such as thymic stromal lymphopoietin, IL-25, and IL-33 contribute to allergy and asthma. Simultaneously with these advances, important progress has been made in our understanding of how the environment, and especially pathogenic organisms, such as bacteria, viruses, helminths, and especially fungi derived from the natural and built environments, either promote or inhibit allergic inflammation and disease. Of specific interest are how lipopolysaccharide mediates its antiallergic effect through the ubiquitin modifying factor A20 and the antiallergic activity of both helminths and protozoa. Summary Innate immune cells and molecular pathways, often activated by allergen-derived proteinases acting on airway epithelium and macrophages as well as additional unknown factors, are essential to the expression of allergic inflammation and disease. These findings suggest numerous future research opportunities and new opportunities for therapeutic intervention in allergic disease. PMID:26658015

  3. Improving OCD time to solution using Signal Response Metrology

    NASA Astrophysics Data System (ADS)

    Fang, Fang; Zhang, Xiaoxiao; Vaid, Alok; Pandev, Stilian; Sanko, Dimitry; Ramanathan, Vidya; Venkataraman, Kartik; Haupt, Ronny

    2016-03-01

    In recent technology nodes, advanced process and novel integration scheme have challenged the precision limits of conventional metrology; with critical dimensions (CD) of device reduce to sub-nanometer region. Optical metrology has proved its capability to precisely detect intricate details on the complex structures, however, conventional RCWA-based (rigorous coupled wave analysis) scatterometry has the limitations of long time-to-results and lack of flexibility to adapt to wide process variations. Signal Response Metrology (SRM) is a new metrology technique targeted to alleviate the consumption of engineering and computation resources by eliminating geometric/dispersion modeling and spectral simulation from the workflow. This is achieved by directly correlating the spectra acquired from a set of wafers with known process variations encoded. In SPIE 2015, we presented the results of SRM application in lithography metrology and control [1], accomplished the mission of setting up a new measurement recipe of focus/dose monitoring in hours. This work will demonstrate our recent field exploration of SRM implementation in 20nm technology and beyond, including focus metrology for scanner control; post etch geometric profile measurement, and actual device profile metrology.

  4. Green Leaf Volatiles in Plant Signaling and Response.

    PubMed

    Matsui, Kenji; Koeduka, Takao

    2016-01-01

    Most 'green' plants form green leaf volatiles (GLVs). GLVs are a familiar plant secondary metabolite, but knowledge of their physiological and ecological functions is limited. GLV formation is tightly suppressed when plant tissues are intact, but upon mechanical wounding, herbivore attack, or abiotic stresses, GLVs are formed rapidly, within seconds or minutes. Thus, this may be an important system for defense responses, allowing plants to protect themselves from damage as soon as possible. Because GLV formation in the natural environment is roughly related to the degree of stress in the plant life, sensing the amount of GLVs in the atmosphere might allow plants to recognize their surroundings. Because some plants respond to GLVs, they may communicate with GLVs. GLVs that contain α,β-unsaturated carbonyl groups might activate signaling systems regulated under the redox state of plant cells. Plasma membranes would also be targets of interactions with GLVs. Additionally, the metabolism of GLVs in plant cells after absorption from the atmosphere could also be classified as a plant-plant interaction.

  5. [Calmodulin inhibitors suppress a calcium signal from serotonin receptors in smooth muscle cells and remove the vasoconstrictive response upon intravenous introduction of serotonin].

    PubMed

    Kozhevnikova, L M; Zharkikh, I L; Avdonin, P V

    2013-01-01

    Comparative study of the effect of calmodulin inhibitors (trifluoperazine, W-12, and W-13) and the TRPVI channel blocker (capsazepine) on receptor-dependent calcium exchange in smooth muscle cells of the rat aorta and on the contractility of the isolated aorta was conducted. It was determined that trifluoperazine almost completely removes an increase in the concentration of calcium ions in the cytoplasm of smooth muscle cells (isolated from the rat aorta) and smooth muscle cells of the A7r5 line in response to serotonin and does not influence the cell response to vasopressin and angiotensin II. W-12 and W-13 also do not reduce calcium ion concentration increase (induced by vasopressin and angiotensin II) but reduces by two times its rise in response to serotonin. It was found that the efficiency of calcium exchange suppression by calmodulin inhibitors correlates with the intensity at which they inhibit the contractile response of the aorta on the effect of serotonin. It was detected that the inhibiting effect of calmodulin blockers on calcium exchange in smooth muscle cells and the contractility of the rat isolated aorta during the activation of serotonin vasoconstrictive receptors are realized by a TRPV1-independent mechanism. It was demonstrated in experiments in vivo that trifluoperazine does not influence hypotensive reaction in rats (normally observed in response to intravenous serotonin introduction), but removes the hypertensive effect of this neurotransmitter in rats after chronic introduction of dexamethasone. The results obtained confirm the hypothesis (that we previously stated) about the direct involvement of calmodulin in signal transmission from vasoconstrictive serotonin receptors.

  6. Within-plant signalling via volatiles overcomes vascular constraints on systemic signalling and primes responses against herbivores.

    PubMed

    Frost, Christopher J; Appel, Heidi M; Carlson, John E; De Moraes, Consuelo M; Mescher, Mark C; Schultz, Jack C

    2007-06-01

    Plant volatiles play important roles in signalling between plants and insects, but their role in communication among plants remains controversial. Previous research on plant-plant communication has focused on interactions between neighbouring plants, largely overlooking the possibility that volatiles function as signals within plants. Here, we show that volatiles released by herbivore-wounded leaves of hybrid poplar (Populus deltoides x nigra) prime defences in adjacent leaves with little or no vascular connection to the wounded leaves. Undamaged leaves exposed to volatiles from wounded leaves on the same stem had elevated defensive responses to feeding by gypsy moth larvae (Lymantria dispar L.) compared with leaves that did not receive volatiles. Volatile signals may facilitate systemic responses to localized herbivory even when the transmission of internal signals is constrained by vascular connectivity. Self-signalling via volatiles is consistent with the short distances over which plant response to airborne cues has been observed to occur and has apparent benefits for emitting plants, suggesting that within-plant signalling may have equal or greater ecological significance than signalling between plants.

  7. Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells.

    PubMed Central

    Sehgal, I; Bailey, J; Hitzemann, K; Pittelkow, M R; Maihle, N J

    1994-01-01

    Amphiregulin is a heparin-binding epidermal growth factor (EGF)-related peptide that binds to the EGF receptor (EGF-R) with high affinity. In this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhance EGF-R expression in the androgen-sensitive LNCaP human prostate carcinoma cell line, and it has been suggested that androgenic stimuli may regulate proliferation, in part, through autocrine mechanisms involving the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimulation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parallel studies using the estrogen-responsive breast carcinoma cell line, MCF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting that amphiregulin can mediate androgen-stimulated LNCaP proliferation. Together, these results implicate an androgen-regulated autocrine loop composed of amphiregulin and its receptor in prostate cancer cell growth and suggest that the mechanism of steroid hormone regulation of amphiregulin synthesis may occur through androgen upregulation of the EGF-R and subsequent receptor-dependent pathways. Images PMID:8049525

  8. Ethylene Response Factors: A Key Regulatory Hub in Hormone and Stress Signaling.

    PubMed

    Müller, Maren; Munné-Bosch, Sergi

    2015-09-01

    Ethylene is essential for many developmental processes and a key mediator of biotic and abiotic stress responses in plants. The ethylene signaling and response pathway includes Ethylene Response Factors (ERFs), which belong to the transcription factor family APETALA2/ERF. It is well known that ERFs regulate molecular response to pathogen attack by binding to sequences containing AGCCGCC motifs (the GCC box), a cis-acting element. However, recent studies suggest that several ERFs also bind to dehydration-responsive elements and act as a key regulatory hub in plant responses to abiotic stresses. Here, we review some of the recent advances in our understanding of the ethylene signaling and response pathway, with emphasis on ERFs and their role in hormone cross talk and redox signaling under abiotic stresses. We conclude that ERFs act as a key regulatory hub, integrating ethylene, abscisic acid, jasmonate, and redox signaling in the plant response to a number of abiotic stresses.

  9. Proactive adjustments of response strategies in the stop-signal paradigm.

    PubMed

    Verbruggen, Frederick; Logan, Gordon D

    2009-06-01

    In the stop-signal paradigm, fast responses are harder to inhibit than slow responses, so subjects must balance speed in the go task with successful stopping in the stop task. In theory, subjects achieve this balance by adjusting response thresholds for the go task, making proactive adjustments in response to instructions that indicate that relevant stop signals are likely to occur. The 5 experiments reported here tested this theoretical claim, presenting cues that indicated whether or not stop signals were relevant for the next few trials. Subjects made proactive response-strategy adjustments in each experiment: Diffusion-model fits showed that response threshold increased when participants expected stop signals to occur, slowing go responses and increasing accuracy. Furthermore, the results show that subjects can make proactive response-strategy adjustments on a trial-by-trial basis, suggesting a flexible cognitive system that can proactively adjust itself in changing environments. PMID:19485695

  10. Extending the impulse response in order to reduce errors due to impulse noise and signal fading

    NASA Technical Reports Server (NTRS)

    Webb, Joseph A.; Rolls, Andrew J.; Sirisena, H. R.

    1988-01-01

    A finite impulse response (FIR) digital smearing filter was designed to produce maximum intersymbol interference and maximum extension of the impulse response of the signal in a noiseless binary channel. A matched FIR desmearing filter at the receiver then reduced the intersymbol interference to zero. Signal fades were simulated by means of 100 percent signal blockage in the channel. Smearing and desmearing filters of length 256, 512, and 1024 were used for these simulations. Results indicate that impulse response extension by means of bit smearing appears to be a useful technique for correcting errors due to impulse noise or signal fading in a binary channel.

  11. Signal inference with unknown response: Calibration-uncertainty renormalized estimator

    NASA Astrophysics Data System (ADS)

    Dorn, Sebastian; Enßlin, Torsten A.; Greiner, Maksim; Selig, Marco; Boehm, Vanessa

    2015-01-01

    The calibration of a measurement device is crucial for every scientific experiment, where a signal has to be inferred from data. We present CURE, the calibration-uncertainty renormalized estimator, to reconstruct a signal and simultaneously the instrument's calibration from the same data without knowing the exact calibration, but its covariance structure. The idea of the CURE method, developed in the framework of information field theory, is to start with an assumed calibration to successively include more and more portions of calibration uncertainty into the signal inference equations and to absorb the resulting corrections into renormalized signal (and calibration) solutions. Thereby, the signal inference and calibration problem turns into a problem of solving a single system of ordinary differential equations and can be identified with common resummation techniques used in field theories. We verify the CURE method by applying it to a simplistic toy example and compare it against existent self-calibration schemes, Wiener filter solutions, and Markov chain Monte Carlo sampling. We conclude that the method is able to keep up in accuracy with the best self-calibration methods and serves as a noniterative alternative to them.

  12. Signal inference with unknown response: calibration-uncertainty renormalized estimator.

    PubMed

    Dorn, Sebastian; Enßlin, Torsten A; Greiner, Maksim; Selig, Marco; Boehm, Vanessa

    2015-01-01

    The calibration of a measurement device is crucial for every scientific experiment, where a signal has to be inferred from data. We present CURE, the calibration-uncertainty renormalized estimator, to reconstruct a signal and simultaneously the instrument's calibration from the same data without knowing the exact calibration, but its covariance structure. The idea of the CURE method, developed in the framework of information field theory, is to start with an assumed calibration to successively include more and more portions of calibration uncertainty into the signal inference equations and to absorb the resulting corrections into renormalized signal (and calibration) solutions. Thereby, the signal inference and calibration problem turns into a problem of solving a single system of ordinary differential equations and can be identified with common resummation techniques used in field theories. We verify the CURE method by applying it to a simplistic toy example and compare it against existent self-calibration schemes, Wiener filter solutions, and Markov chain Monte Carlo sampling. We conclude that the method is able to keep up in accuracy with the best self-calibration methods and serves as a noniterative alternative to them.

  13. Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline

    SciTech Connect

    Wang Jianling; Wang Gangduo; Ansari, G.A.S.; Khan, M. Firoze

    2008-07-15

    Aniline exposure causes toxicity to the spleen, which leads to a variety of sarcomas, and fibrosis appears to be an important preneoplastic lesion. However, early molecular mechanisms in aniline-induced toxicity to the spleen are not known. Previously, we have shown that aniline exposure results in iron overload and induction of oxidative stress in the spleen, which can cause transcriptional upregulation of fibrogenic/inflammatory cytokines via activation of oxidative stress (OS)-responsive signaling pathways. To test this mechanism, male SD rats were treated with aniline (1mmol/kg/day via gavage) for 7days, an experimental condition that precedes the appearance of fibrosis. Significant increases in both NF-{kappa}B and AP-1 binding activity was observed in the nuclear extracts of splenocytes from aniline-treated rats as determined by ELISAs, and supported by Western blot data showing increases in p-I{kappa}B{alpha}, p-p65 and p-c-Jun. To understand the upstream signaling events which could account for the activation of NF-{kappa}B and AP-1, phosphorylation patterns of I{kappa}B kinases (IKK{alpha} and IKK{beta}) and mitogen-activated protein kinases (MAPKs) were pursued. Our data showed remarkable increases in both p-IKK{alpha} and p-IKK{beta} in the splenocytes from aniline-treated rats, suggesting their role in the phosphorylation of both I{kappa}B{alpha} and p65 subunits. Furthermore, aniline exposure led to activation of all three classes of MAPKs, as evident from increased phosphorylation of extracellular-signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK1/2) and p38 MAPKs, which could potentially contribute to the observed activation of both AP-1 and NF-{kappa}B. Activation of upstream signaling molecules was also associated with simultaneous increases in gene transcription of cytokines IL-1, IL-6 and TNF-{alpha}. The observed sequence of events following aniline exposure could initiate a fibrogenic and/or tumorigenic response in the spleen.

  14. Proactive Adjustments of Response Strategies in the Stop-Signal Paradigm

    ERIC Educational Resources Information Center

    Verbruggen, Frederick; Logan, Gordon D.

    2009-01-01

    In the stop-signal paradigm, fast responses are harder to inhibit than slow responses, so subjects must balance speed is the go task with successful stopping in the stop task. In theory, subjects achieve this balance by adjusting response thresholds for the go task, making proactive adjustments in response to instructions that indicate that…

  15. Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion.

    PubMed

    Camp, Robert M; Johnson, John D

    2015-10-15

    Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (β-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and β-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making.

  16. Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration

    PubMed Central

    Abrahao, K.P.; Ariwodola, O.J.; Butler, T.R.; Rau, A.R.; Skelly, M.J.; Carter, E.; Alexander, N.P.; McCool, B.A.; Souza-Formigoni, M.L.O.; Weiner, J.L.

    2013-01-01

    Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. Notably, the specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In these studies, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss mice were treated daily with saline or 1.8 g/kg ethanol for 21 days. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least eleven days of withdrawal, cohorts of saline and ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor behavioral sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanolsensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol. PMID:23486954

  17. Cell Signaling in Tenocytes: Response to Load and Ligands in Health and Disease.

    PubMed

    Wall, Michelle E; Dyment, Nathaniel A; Bodle, Josie; Volmer, Jon; Loboa, Elizabeth; Cederlund, Anna; Fox, Ann M; Banes, Albert J

    2016-01-01

    Signaling in tenocytes during development, homeostasis and injury involves multiple and redundant pathways. Given that tendons transmit mechanical forces from muscle to bone to effect movement, a key function for tenocytes is the detection of and response to mechanical stimulation. Mechanotransduction involves matrix-integrin-cytoskeleton to nucleus signaling, gap junction intercellular communication, changes in intracellular calcium (Ca(2+)), activation of receptors and their pathways, and responses to biochemical factors such as hormones, growth factors, adenosine triphosphate (ATP) and its derivatives, and neuromodulators. The primary cilium also plays a key role in the detection of mechanical signals. During development, transforming growth factor-β (TGF-β), bone morphogenetic protein (BMP), and hedgehog (Hh) signaling modulate tendon differentiation and formation. The response to injury is complex and varied involving not only inflammatory mediators such as interleukin-1β but also mechanosensing. This chapter reviews the signaling pathways tenocytes use during mechanotransduction, development and in response to injury. PMID:27535250

  18. Cellular redox regulation, signaling, and stress response in plants.

    PubMed

    Shigeoka, Shigeru; Maruta, Takanori

    2014-01-01

    Cellular and organellar redox states, which are characterized by the balance between oxidant and antioxidant pool sizes, play signaling roles in the regulation of gene expression and protein function in a wide variety of plant physiological processes including stress acclimation. Reactive oxygen species (ROS) and ascorbic acid (AsA) are the most abundant oxidants and antioxidants, respectively, in plant cells; therefore, the metabolism of these redox compounds must be strictly and spatiotemporally controlled. In this review, we provided an overview of our previous studies as well as recent advances in (1) the molecular mechanisms and regulation of AsA biosynthesis, (2) the molecular and genetic properties of ascorbate peroxidases, and (3) stress acclimation via ROS-derived oxidative/redox signaling pathways, and discussed future perspectives in this field.

  19. Male Responses to Conspecific Advertisement Signals in the Field Cricket Gryllus rubens (Orthoptera: Gryllidae)

    PubMed Central

    Jang, Yikweon

    2011-01-01

    In many species males aggregate and produce long-range advertisement signals to attract conspecific females. The majority of the receivers of these signals are probably other males most of the time, and male responses to competitors' signals can structure the spatial and temporal organization of the breeding aggregation and affect male mating tactics. I quantified male responses to a conspecific advertisement stimulus repeatedly over three age classes in Gryllus rubens (Orthoptera: Gryllidae) in order to estimate the type and frequency of male responses to the broadcast stimulus and to determine the factors affecting them. Factors tested included body size, wing dimorphism, age, and intensity of the broadcast stimulus. Overall, males employed acoustic response more often than positive phonotactic response. As males aged, the frequency of positive phonotactic response decreased but that of the acoustic response increased. That is, males may use positive phonotaxis in the early stages of their adult lives, possibly to find suitable calling sites or parasitize calling males, and then later in life switch to acoustic responses in response to conspecific advertisement signals. Males with smaller body size more frequently exhibited acoustic responses. This study suggests that individual variation, more than any factors measured, is critical for age-dependent male responses to conspecific advertisement signals. PMID:21283758

  20. PGE2 released by primary sensory neurons modulates Toll-like receptor 4 activities through an EP4 receptor-dependent process.

    PubMed

    Tse, Kai-Hei; Chow, Kevin B S; Wise, Helen

    2016-04-15

    Exogenous prostaglandin E2 (PGE2) displays mixed regulatory properties with regard to inflammatory gene expression in dorsal root ganglion (DRG) cells. We show here that endogenously-produced nanomolar concentrations of PGE2, such as that generated in response to Toll-like receptor 4 (TLR4) stimulation, inhibits both cyclooxygenase-2 (COX-2) and tumour necrosis factor alpha (TNFα) mRNA expression in DRG cells in an EP4 receptor-dependent manner. DRG neurons appear to be the major source of PGE2 in the DRG and likely serve as both an autocrine and paracrine system for limiting over-activation of both DRG neurons and glial cells in response to TLR4 stimulation. PMID:27049555

  1. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling

    PubMed Central

    Watson, Oliver; Novodvorsky, Peter; Gray, Caroline; Rothman, Alexander M.K.; Lawrie, Allan; Crossman, David C.; Haase, Andrea; McMahon, Kathryn; Gering, Martin; Van Eeden, Fredericus J.M.; Chico, Timothy J.A.

    2013-01-01

    Aims The contribution of blood flow to angiogenesis is incompletely understood. We examined the effect of blood flow on Notch signalling in the vasculature of zebrafish embryos, and whether blood flow regulates angiogenesis in zebrafish with constitutively up-regulated hypoxic signalling. Methods and results Developing zebrafish (Danio rerio) embryos survive via diffusion in the absence of circulation induced by knockdown of cardiac troponin T2 or chemical cardiac cessation. The absence of blood flow increased vascular Notch signalling in 48 h post-fertilization old embryos via up-regulation of the Notch ligand dll4. Despite this, patterning of the intersegmental vessels is not affected by absent blood flow. We therefore examined homozygous vhl mutant zebrafish that have constitutively up-regulated hypoxic signalling. These display excessive and aberrant angiogenesis from 72 h post-fertilization, with significantly increased endothelial number, vessel diameter, and length. The absence of blood flow abolished these effects, though normal vessel patterning was preserved. Conclusion We show that blood flow suppresses vascular Notch signalling via down-regulation of dll4. We have also shown that blood flow is required for angiogenesis in response to hypoxic signalling but is not required for normal vessel patterning. These data indicate important differences in hypoxia-driven vs. developmental angiogenesis. PMID:23812297

  2. Defining treatment response in trichotillomania: a signal detection analysis.

    PubMed

    Houghton, David C; Capriotti, Matthew R; De Nadai, Alessandro S; Compton, Scott N; Twohig, Michael P; Neal-Barnett, Angela M; Saunders, Stephen M; Franklin, Martin E; Woods, Douglas W

    2015-12-01

    The Massachusetts General Hospital Hairpulling Scale (MGH-HPS) and the NIMH Trichotillomania Severity Scale (NIMH-TSS) are two widely used measures of trichotillomania severity. Despite their popular use, currently no empirically-supported guidelines exist to determine the degrees of change on these scales that best indicate treatment response. Determination of such criteria could aid in clinical decision-making by defining clinically significant treatment response/recovery and producing accurate power analyses for use in clinical trials research. Adults with trichotillomania (N=69) participated in a randomized controlled trial of psychotherapy and were assessed before and after treatment. Response status was measured via the Clinical Global Impressions-Improvement Scale, and remission status was measured via the Clinical Global Impressions-Severity Scale. For treatment response, a 45% reduction or 7-point raw score change on the MGH-HPS was the best indicator of clinically significant treatment response, and on the NIMH-TSS, a 30-40% reduction or 6-point raw score difference was most effective cutoff. For disorder remission, a 55-60% reduction or 7-point raw score change on the MGH-HPS was the best predictor, and on the NIMH-TSS, a 65% reduction or 6-point raw score change was the best indicator of disorder remission. Implications of these findings are discussed.

  3. Microbial Degradation of Cellular Kinases Impairs Innate Immune Signaling and Paracrine TNFα Responses

    PubMed Central

    Barth, Kenneth; Genco, Caroline Attardo

    2016-01-01

    The NFκB and MAPK signaling pathways are critical components of innate immunity that orchestrate appropriate immune responses to control and eradicate pathogens. Their activation results in the induction of proinflammatory mediators, such as TNFα a potent bioactive molecule commonly secreted by recruited inflammatory cells, allowing for paracrine signaling at the site of an infection. In this study we identified a novel mechanism by which the opportunistic pathogen Porphyromonas gingivalis dampens innate immune responses by disruption of kinase signaling and degradation of inflammatory mediators. The intracellular immune kinases RIPK1, TAK1, and AKT were selectively degraded by the P. gingivalis lysine-specific gingipain (Kgp) in human endothelial cells, which correlated with dysregulated innate immune signaling. Kgp was also observed to attenuate endothelial responsiveness to TNFα, resulting in a reduction in signal flux through AKT, ERK and NFκB pathways, as well as a decrease in downstream proinflammatory mRNA induction of cytokines, chemokines and adhesion molecules. A deficiency in Kgp activity negated decreases to host cell kinase protein levels and responsiveness to TNFα. Given the essential role of kinase signaling in immune responses, these findings highlight a unique mechanism of pathogen-induced immune dysregulation through inhibition of cell activation, paracrine signaling, and dampened cellular proinflammatory responses. PMID:27698456

  4. Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli.

    PubMed

    Jin, Xingjian; Mohieldin, Ashraf M; Muntean, Brian S; Green, Jill A; Shah, Jagesh V; Mykytyn, Kirk; Nauli, Surya M

    2014-06-01

    Primary cilia with a diameter of ~200 nm have been implicated in development and disease. Calcium signaling within a primary cilium has never been directly visualized and has therefore remained a speculation. Fluid-shear stress and dopamine receptor type-5 (DR5) agonist are among the few stimuli that require cilia for intracellular calcium signal transduction. However, it is not known if these stimuli initiate calcium signaling within the cilium or if the calcium signal originates in the cytoplasm. Using an integrated single-cell imaging technique, we demonstrate for the first time that calcium signaling triggered by fluid-shear stress initiates in the primary cilium and can be distinguished from the subsequent cytosolic calcium response through the ryanodine receptor. Importantly, this flow-induced calcium signaling depends on the ciliary polycystin-2 calcium channel. While DR5-specific agonist induces calcium signaling mainly in the cilioplasm via ciliary CaV1.2, thrombin specifically induces cytosolic calcium signaling through the IP3 receptor. Furthermore, a non-specific calcium ionophore triggers both ciliary and cytosolic calcium responses. We suggest that cilia not only act as sensory organelles but also function as calcium signaling compartments. Cilium-dependent signaling can spread to the cytoplasm or be contained within the cilioplasm. Our study thus provides the first model to understand signaling within the cilioplasm of a living cell.

  5. Brushless DC motor control system responsive to control signals generated by a computer or the like

    NASA Technical Reports Server (NTRS)

    Packard, Douglas T. (Inventor); Schmitt, Donald E. (Inventor)

    1987-01-01

    A control system for a brushless DC motor responsive to digital control signals is disclosed. The motor includes a multiphase wound stator and a permanent magnet rotor. The rotor is arranged so that each phase winding, when energized from a DC source, will drive the rotor through a predetermined angular position or step. A commutation signal generator responsive to the shaft position provides a commutation signal for each winding. A programmable control signal generator such as a computer or microprocessor produces individual digital control signals for each phase winding. The control signals and commutation signals associated with each winding are applied to an AND gate for that phase winding. Each gate controls a switch connected in series with the associated phase winding and the DC source so that each phase winding is energized only when the commutation signal and the control signal associated with that phase winding are present. The motor shaft may be advanced one step at a time to a desired position by applying a predetermined number of control signals in the proper sequence to the AND gates and the torque generated by the motor may be regulated by applying a separate control signal to each AND gate which is pulse width modulated to control the total time that each switch connects its associated winding to the DC source during each commutation period.

  6. Brushless DC motor control system responsive to control signals generated by a computer or the like

    NASA Technical Reports Server (NTRS)

    Packard, D. T. (Inventor)

    1985-01-01

    A control system for a brushless DC motor responsive to digital control signals is disclosed. The motor includes a multiphase wound stator and a permanent magnet rotor. The motor is arranged so that each phase winding, when energized from a DC source, will drive the rotor through a predetermined angular position or step. A commutation signal generator responsive to the shaft position provides a commutation signal for each winding. A programmable control signal generator such as a computer or microprocessor produces individual digital control signals for each phase winding. The control signals and commutation signals associated with each winding are applied to an AND gate for that phase winding. Each gate controls a switch connected in series with the associated phase winding and the DC source so that each phase winding is energized only when the commutation signal and the control signal associated with that phase winding are present. The motor shaft may be advanced one step at a time to a desired position by applying a predetermined number of control signals in the proper sequence to the AND gates and the torque generated by the motor be regulated by applying a separate control signal and each AND gate which is pulse width modulated to control the total time that each switch connects its associated winding to the DC source during each commutation period.

  7. Brushless DC motor control system responsive to control signals generated by a computer or the like

    NASA Astrophysics Data System (ADS)

    Packard, D. T.

    1985-04-01

    A control system for a brushless DC motor responsive to digital control signals is disclosed. The motor includes a multiphase wound stator and a permanent magnet rotor. The motor is arranged so that each phase winding, when energized from a DC source, will drive the rotor through a predetermined angular position or step. A commutation signal generator responsive to the shaft position provides a commutation signal for each winding. A programmable control signal generator such as a computer or microprocessor produces individual digital control signals for each phase winding. The control signals and commutation signals associated with each winding are applied to an AND gate for that phase winding. Each gate controls a switch connected in series with the associated phase winding and the DC source so that each phase winding is energized only when the commutation signal and the control signal associated with that phase winding are present. The motor shaft may be advanced one step at a time to a desired position by applying a predetermined number of control signals in the proper sequence to the AND gates and the torque generated by the motor be regulated by applying a separate control signal and each AND gate which is pulse width modulated to control the total time that each switch connects its associated winding to the DC source during each commutation period.

  8. Insulin signaling genes modulate nicotine-induced behavioral responses in Caenorhabditis elegans.

    PubMed

    Wescott, Seth A; Ronan, Elizabeth A; Xu, X Z Shawn

    2016-02-01

    Insulin signaling has been suggested to modulate nicotine dependence, but the underlying genetic evidence has been lacking. Here, we used the nematode, Caenorhabditis elegans, to investigate whether genetic alterations in the insulin signaling pathway affect behavioral responses to nicotine. For this, we challenged drug-naive C. elegans with an acute dose of nicotine (100 μmol/l) while recording changes in their locomotion speed. Although nicotine treatment stimulated locomotion speed in wild-type C. elegans, the same treatment reduced locomotion speed in mutants defective in insulin signaling. This phenotype could be suppressed by mutations in daf-16, a gene encoding a FOXO transcription factor that acts downstream of insulin signaling. Our data suggest that insulin signaling genes, daf-2, age-1, pdk-1, akt-1, and akt-2, modulate behavioral responses to nicotine in C. elegans, indicating a genetic link between nicotine behavior and insulin signaling.

  9. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish.

    PubMed

    Yoo, Sa Kan; Freisinger, Christina M; LeBert, Danny C; Huttenlocher, Anna

    2012-10-15

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H(2)O(2) at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H(2)O(2). A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate "wound signals" that integrate early wound responses and late epimorphic regeneration.

  10. Integrated signaling networks in plant responses to sedentary endoparasitic nematodes: a perspective.

    PubMed

    Li, Ruijuan; Rashotte, Aaron M; Singh, Narendra K; Weaver, David B; Lawrence, Kathy S; Locy, Robert D

    2015-01-01

    Sedentary plant endoparasitic nematodes can cause detrimental yield losses in crop plants making the study of detailed cellular, molecular, and whole plant responses to them a subject of importance. In response to invading nematodes and nematode-secreted effectors, plant susceptibility/resistance is mainly determined by the coordination of different signaling pathways including specific plant resistance genes or proteins, plant hormone synthesis and signaling pathways, as well as reactive oxygen signals that are generated in response to nematode attack. Crosstalk between various nematode resistance-related elements can be seen as an integrated signaling network regulated by transcription factors and small RNAs at the transcriptional, posttranscriptional, and/or translational levels. Ultimately, the outcome of this highly controlled signaling network determines the host plant susceptibility/resistance to nematodes.

  11. 5-Hydroxytryptamine type 7 receptor neuroprotection against NMDA-induced excitotoxicity is PDGFβ receptor dependent.

    PubMed

    Vasefi, Maryam S; Kruk, Jeff S; Heikkila, John J; Beazely, Michael A

    2013-04-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the hippocampus. Long-term (2-24 h) activation of 5-HT7 receptors regulates growth factor receptor expression, including the expression of platelet-derived growth factor (PDGF) β receptors. Direct activation of PDGFβ receptors in primary hippocampal and cortical neurons inhibits NMDA receptor activity and attenuates NMDA receptor-induced neurotoxicity. Our objective was to investigate whether the 5-HT7 receptor-induced increase in PDGFβ receptor expression would be similarly neuroprotective. We demonstrate that 5-HT7 receptor agonist treatment in primary hippocampal neurons also increases the expression of phospholipase C (PLC) γ, a downstream effector of PDGFβ receptors associated with the inhibition of NMDA receptor activity. To determine if the up-regulation of PDGFβ receptors is neuroprotective, primary hippocampal neurons were incubated with the 5-HT7 receptor agonist, LP 12, for 24 h. Indeed, LP 12 treatment prevented NMDA-induced neurotoxicity and this effect was dependent on PDGFβ receptor kinase activity. Treatment of primary neurons with LP 12 also differentially altered NMDA receptor subunit expression, reducing the expression of NR1 and NR2B, but not NR2A. These findings demonstrate the potential for providing growth factor receptor-dependent neuroprotective effects using small-molecule ligands of G protein-coupled receptors.

  12. Phagocytosis of aggregated lipoprotein by macrophages: Low density lipoprotein receptor-dependent foam-cell formation

    SciTech Connect

    Suits, A.G.; Chait, A.; Aviram, M.; Heinecke, J.W. )

    1989-04-01

    Low density lipoprotein (LDL) modified by incubation with phospholipase C (PLC-LDL) aggregates in solution and is rapidly taken up and degraded by human and mouse macrophages, producing foam cells in vitro. Human, mouse, and rabbit macrophages degraded {sup 125}I-labeled PLC-LDL ({sup 125}I-PLC-LDL) more rapidly than native {sup 125}I-labeled LDL ({sup 125}I-LDL), while nonphagocytic cells such as human fibroblasts and bovine aortic endothelial cells degraded {sup 125}I-PLC-LDL more slowly than {sup 125}I-LDL. This suggested the mechanism for internalization of PLC-LDL was phagocytosis. When examined by electron microscopy, mouse peritoneal macrophages appeared to be phagocytosing PLC-LDL. The uptake and degradation of {sup 125}I-PLC-LDL by human macrophages was inhibited >80% by the monoclonal antibody C7 (IgG2b) produced by hybridoma C7, which blocks the ligand binding domain of the LDL receptor. Similarly, methylation of {sup 125}I-LDL ({sup 125}I-MeLDL) prior to treatment with phospholipase C decreased its subsequent uptake and degradation by human macrophages by >90%. The uptake and degradation of phospholipase C-modified {sup 125}I-MeLDL by macrophages could be restored by incubation of the methylated lipoprotein with apoprotein E, a ligand recognized by the LDL receptor. These results indicate that macrophages internalize PLC-LDL by LDL receptor-dependent phagocytosis.

  13. NMDA receptor-dependent LTD is required for consolidation but not acquisition of fear memory.

    PubMed

    Liu, Xing; Gu, Qin-Hua; Duan, Kaizheng; Li, Zheng

    2014-06-25

    NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior.

  14. Group VII Ethylene Response Factors Coordinate Oxygen and Nitric Oxide Signal Transduction and Stress Responses in Plants.

    PubMed

    Gibbs, Daniel J; Conde, Jorge Vicente; Berckhan, Sophie; Prasad, Geeta; Mendiondo, Guillermina M; Holdsworth, Michael J

    2015-09-01

    The group VII ethylene response factors (ERFVIIs) are plant-specific transcription factors that have emerged as important regulators of abiotic and biotic stress responses, in particular, low-oxygen stress. A defining feature of ERFVIIs is their conserved N-terminal domain, which renders them oxygen- and nitric oxide (NO)-dependent substrates of the N-end rule pathway of targeted proteolysis. In the presence of these gases, ERFVIIs are destabilized, whereas an absence of either permits their accumulation; ERFVIIs therefore coordinate plant homeostatic responses to oxygen availability and control a wide range of NO-mediated processes. ERFVIIs have a variety of context-specific protein and gene interaction partners, and also modulate gibberellin and abscisic acid signaling to regulate diverse developmental processes and stress responses. This update discusses recent advances in our understanding of ERFVII regulation and function, highlighting their role as central regulators of gaseous signal transduction at the interface of ethylene, oxygen, and NO signaling.

  15. Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

    EPA Science Inventory

    Background Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immunoinflammatory function and genomic signaling in those with heightened inflammatory responsive...

  16. The Elicitation of Audiovisual Steady-State Responses: Multi-Sensory Signal Congruity and Phase Effects

    PubMed Central

    Rhone, Ariane E.; Idsardi, William J.; Simon, Jonathan Z.; Poeppel, David

    2013-01-01

    Most ecologically natural sensory inputs are not limited to a single modality. While it is possible to use real ecological materials as experimental stimuli to investigate the neural basis of multi-sensory experience, parametric control of such tokens is limited. By using artificial bimodal stimuli composed of approximations to ecological signals, we aim to observe the interactions between putatively relevant stimulus attributes. Here we use MEG as an electrophysiological tool and employ as a measure the steady-state response (SSR), an experimental paradigm typically applied to unimodal signals. In this experiment we quantify the responses to a bimodal audio-visual signal with different degrees of temporal (phase) congruity, focusing on stimulus properties critical to audiovisual speech. An amplitude modulated auditory signal (‘pseudo-speech’) is paired with a radius-modulated ellipse (‘pseudo-mouth’), with the envelope of low-frequency modulations occurring in phase or at offset phase values across modalities. We observe (i) that it is possible to elicit an SSR to bimodal signals; (ii) that bimodal signals exhibit greater response power than unimodal signals; and (iii) that the SSR power at specific harmonics and sensors differentially reflects the congruity between signal components. Importantly, we argue that effects found at the modulation frequency and second harmonic reflect differential aspects of neural coding of multisensory signals. The experimental paradigm facilitates a quantitative characterization of properties of multi-sensory speech and other bimodal computations. PMID:21380858

  17. EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling.

    PubMed

    Takeo, Makoto; Lee, Wendy; Rabbani, Piul; Sun, Qi; Hu, Hai; Lim, Chae Ho; Manga, Prashiela; Ito, Mayumi

    2016-05-10

    Delineating the crosstalk between distinct signaling pathways is key to understanding the diverse and dynamic responses of adult stem cells during tissue regeneration. Here, we demonstrate that the Edn/EdnrB signaling pathway can interact with other signaling pathways to elicit distinct stem cell functions during tissue regeneration. EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells (McSCs), dramatically enhancing the regeneration of hair and epidermal melanocytes. This effect is dependent upon active Wnt signaling that is initiated by Wnt ligand secretion from the hair follicle epithelial niche. Further, this Wnt-dependent EdnrB signaling can rescue the defects in melanocyte regeneration caused by Mc1R loss. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote photoprotective-melanocyte regeneration, which may be useful for those with increased risk of skin cancers due to Mc1R variants. PMID:27134165

  18. EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling.

    PubMed

    Takeo, Makoto; Lee, Wendy; Rabbani, Piul; Sun, Qi; Hu, Hai; Lim, Chae Ho; Manga, Prashiela; Ito, Mayumi

    2016-05-10

    Delineating the crosstalk between distinct signaling pathways is key to understanding the diverse and dynamic responses of adult stem cells during tissue regeneration. Here, we demonstrate that the Edn/EdnrB signaling pathway can interact with other signaling pathways to elicit distinct stem cell functions during tissue regeneration. EdnrB signaling promotes proliferation and differentiation of melanocyte stem cells (McSCs), dramatically enhancing the regeneration of hair and epidermal melanocytes. This effect is dependent upon active Wnt signaling that is initiated by Wnt ligand secretion from the hair follicle epithelial niche. Further, this Wnt-dependent EdnrB signaling can rescue the defects in melanocyte regeneration caused by Mc1R loss. This suggests that targeting Edn/EdnrB signaling in McSCs can be a therapeutic approach to promote photoprotective-melanocyte regeneration, which may be useful for those with increased risk of skin cancers due to Mc1R variants.

  19. The endoplasmic reticulum: structure, function and response to cellular signaling.

    PubMed

    Schwarz, Dianne S; Blower, Michael D

    2016-01-01

    The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle. PMID:26433683

  20. Ligand-Induced Protein Responses and Mechanical Signal Propagation Described by Linear Response Theories

    PubMed Central

    Yang, Lee-Wei; Kitao, Akio; Huang, Bang-Chieh; Gō, Nobuhiro

    2014-01-01

    In this study, a general linear response theory (LRT) is formulated to describe time-dependent and -independent protein conformational changes upon CO binding with myoglobin. Using the theory, we are able to monitor protein relaxation in two stages. The slower relaxation is found to occur from 4.4 to 81.2 picoseconds and the time constants characterized for a couple of aromatic residues agree with those observed by UV Resonance Raman (UVRR) spectrometry and time resolved x-ray crystallography. The faster “early responses”, triggered as early as 400 femtoseconds, can be best described by the theory when impulse forces are used. The newly formulated theory describes the mechanical propagation following ligand-binding as a function of time, space and types of the perturbation forces. The “disseminators”, defined as the residues that propagate signals throughout the molecule the fastest among all the residues in protein when perturbed, are found evolutionarily conserved and the mutations of which have been shown to largely change the CO rebinding kinetics in myoglobin. PMID:25229149

  1. Plant perception and response to the signal in gravity resistance

    NASA Astrophysics Data System (ADS)

    Hoson, Takayuki; Soga, Kouichi; Wakabayashi, Kazuyuki; Kamisaka, Seiichiro; Zhang, Yan; Otomi, Yasuhiro; Hashimoto, Takashi; Iida, Hidetoshi

    2012-07-01

    Gravity resistance, mechanical resistance to the gravitational force, is a principal graviresponse in plants, distinct from gravitropism. Plants increase the rigidity of their cell walls in the final step of gravity resistance. We studied cellular events leading to or related to the cell wall changes under hypergravity conditions produced by centrifugation and under microgravity conditions in space. The involvement of mechanosensitive ion channels (mechanoreceptors) in signal perception in gravity resistance has been suggested by experiments with inhibitors. As a candidate for the mechanoreceptor, we identified MCA1 and MCA2 in Arabidopsis. mca-null and MCA-overexpressing seedlings were normal in growth in the dark at 1 g. However, suppression by hypergravity of elongation growth was reduced in hypocotyls of mca-null seedlings. On the contrary, MCA-overexpressing seedlings were hypersensitive to hypergravity. These results suggest that MCAs act as the mechanoreceptor in signal perception of gravity resistance. Cortical microtubules play an essential role in maintenance of normal growth phenotype under hypergravity conditions. In Space Seed experiment in the Kibo Module (PI: S. Kamisaka), we examined the effects of microgravity on growth phenotypes of Arabidopsis tubulin mutant, tua6. Inflorescences of the mutant emerged earlier and elongated rapidly under microgravity conditions than under on-orbit or ground 1 g conditions. Also, the inflorescences grown under microgravity conditions showed higher cell wall extensibilities than the controls. The tubulin mutant thus grew and developed more or less normally under microgravity conditions, supporting the principal role of microtubules also in plant resistance to 1 g gravity. On the other hand, the cellular osmotic properties, as well as the cell wall properties, are important factors determining the rigidity of plant body. Azuki bean epicotyls were capable of maintaining osmoregulation even under hypergravity

  2. NMR analysis of a stress response metabolic signaling network.

    PubMed

    Zhang, Bo; Halouska, Steven; Schiaffo, Charles E; Sadykov, Marat R; Somerville, Greg A; Powers, Robert

    2011-08-01

    We previously hypothesized that Staphylococcus epidermidis senses a diverse set of environmental and nutritional factors associated with biofilm formation through a modulation in the activity of the tricarboxylic acid (TCA) cycle. Herein, we report our further investigation of the impact of additional environmental stress factors on TCA cycle activity and provide a detailed description of our NMR methodology. S. epidermidis wild-type strain 1457 was treated with stressors that are associated with biofilm formation, a sublethal dose of tetracycline, 5% NaCl, 2% glucose, and autoinducer-2 (AI-2). As controls and to integrate our current data with our previous study, 4% ethanol stress and iron-limitation were also used. Consistent with our prior observations, the effect of many environmental stress factors on the S. epidermidis metabolome was essentially identical to the effect of TCA cycle inactivation in the aconitase mutant strain 1457-acnA::tetM. A detailed quantitative analysis of metabolite concentration changes using 2D (1)H-(13)C HSQC and (1)H-(1)H TOCSY spectra identified a network of 37 metabolites uniformly affected by the stressors and TCA cycle inactivation. We postulate that the TCA cycle acts as the central pathway in a metabolic signaling network.

  3. NMR analysis of a stress response metabolic signaling network.

    PubMed

    Zhang, Bo; Halouska, Steven; Schiaffo, Charles E; Sadykov, Marat R; Somerville, Greg A; Powers, Robert

    2011-08-01

    We previously hypothesized that Staphylococcus epidermidis senses a diverse set of environmental and nutritional factors associated with biofilm formation through a modulation in the activity of the tricarboxylic acid (TCA) cycle. Herein, we report our further investigation of the impact of additional environmental stress factors on TCA cycle activity and provide a detailed description of our NMR methodology. S. epidermidis wild-type strain 1457 was treated with stressors that are associated with biofilm formation, a sublethal dose of tetracycline, 5% NaCl, 2% glucose, and autoinducer-2 (AI-2). As controls and to integrate our current data with our previous study, 4% ethanol stress and iron-limitation were also used. Consistent with our prior observations, the effect of many environmental stress factors on the S. epidermidis metabolome was essentially identical to the effect of TCA cycle inactivation in the aconitase mutant strain 1457-acnA::tetM. A detailed quantitative analysis of metabolite concentration changes using 2D (1)H-(13)C HSQC and (1)H-(1)H TOCSY spectra identified a network of 37 metabolites uniformly affected by the stressors and TCA cycle inactivation. We postulate that the TCA cycle acts as the central pathway in a metabolic signaling network. PMID:21692534

  4. Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

    PubMed

    Mayhew, S D; Mullinger, K J; Ostwald, D; Porcaro, C; Bowtell, R; Bagshaw, A P; Francis, S T

    2016-06-01

    In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of

  5. Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

    PubMed

    Mayhew, S D; Mullinger, K J; Ostwald, D; Porcaro, C; Bowtell, R; Bagshaw, A P; Francis, S T

    2016-06-01

    In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of

  6. Quorum sensing signal-response systems in Gram-negative bacteria.

    PubMed

    Papenfort, Kai; Bassler, Bonnie L

    2016-08-11

    Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy. PMID:27510864

  7. Quorum sensing signal-response systems in Gram-negative bacteria.

    PubMed

    Papenfort, Kai; Bassler, Bonnie L

    2016-08-11

    Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.

  8. The role of membrane ERα signaling in bone and other major estrogen responsive tissues

    PubMed Central

    Gustafsson, K. L.; Farman, H.; Henning, P.; Lionikaite, V.; Movérare-Skrtic, S.; Wu, J.; Ryberg, H.; Koskela, A.; Gustafsson, J.-Å.; Tuukkanen, J.; Levin, E. R.; Ohlsson, C.; Lagerquist, M. K.

    2016-01-01

    Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40–70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles. PMID:27388455

  9. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation

    PubMed Central

    Muralidharan, Sujatha; Mandrekar, Pranoti

    2013-01-01

    Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders. PMID:23990626

  10. Divergent receiver responses to components of multimodal signals in two foot-flagging frog species.

    PubMed

    Preininger, Doris; Boeckle, Markus; Sztatecsny, Marc; Hödl, Walter

    2013-01-01

    Multimodal communication of acoustic and visual signals serves a vital role in the mating system of anuran amphibians. To understand signal evolution and function in multimodal signal design it is critical to test receiver responses to unimodal signal components versus multimodal composite signals. We investigated two anuran species displaying a conspicuous foot-flagging behavior in addition to or in combination with advertisement calls while announcing their signaling sites to conspecifics. To investigate the conspicuousness of the foot-flagging signals, we measured and compared spectral reflectance of foot webbings of Micrixalus saxicola and Staurois parvus using a spectrophotometer. We performed behavioral field experiments using a model frog including an extendable leg combined with acoustic playbacks to test receiver responses to acoustic, visual and combined audio-visual stimuli. Our results indicated that the foot webbings of S. parvus achieved a 13 times higher contrast against their visual background than feet of M. saxicola. The main response to all experimental stimuli in S. parvus was foot flagging, whereas M. saxicola responded primarily with calls but never foot flagged. Together these across-species differences suggest that in S. parvus foot-flagging behavior is applied as a salient and frequently used communicative signal during agonistic behavior, whereas we propose it constitutes an evolutionary nascent state in ritualization of the current fighting behavior in M. saxicola.

  11. Divergent Receiver Responses to Components of Multimodal Signals in Two Foot-Flagging Frog Species

    PubMed Central

    Preininger, Doris; Boeckle, Markus; Sztatecsny, Marc; Hödl, Walter

    2013-01-01

    Multimodal communication of acoustic and visual signals serves a vital role in the mating system of anuran amphibians. To understand signal evolution and function in multimodal signal design it is critical to test receiver responses to unimodal signal components versus multimodal composite signals. We investigated two anuran species displaying a conspicuous foot-flagging behavior in addition to or in combination with advertisement calls while announcing their signaling sites to conspecifics. To investigate the conspicuousness of the foot-flagging signals, we measured and compared spectral reflectance of foot webbings of Micrixalus saxicola and Staurois parvus using a spectrophotometer. We performed behavioral field experiments using a model frog including an extendable leg combined with acoustic playbacks to test receiver responses to acoustic, visual and combined audio-visual stimuli. Our results indicated that the foot webbings of S. parvus achieved a 13 times higher contrast against their visual background than feet of M. saxicola. The main response to all experimental stimuli in S. parvus was foot flagging, whereas M. saxicola responded primarily with calls but never foot flagged. Together these across-species differences suggest that in S. parvus foot-flagging behavior is applied as a salient and frequently used communicative signal during agonistic behavior, whereas we propose it constitutes an evolutionary nascent state in ritualization of the current fighting behavior in M. saxicola. PMID:23383168

  12. Uncoupling High Light Responses from Singlet Oxygen Retrograde Signaling and Spatial-Temporal Systemic Acquired Acclimation.

    PubMed

    Carmody, Melanie; Crisp, Peter A; d'Alessandro, Stefano; Ganguly, Diep; Gordon, Matthew; Havaux, Michel; Albrecht-Borth, Verónica; Pogson, Barry J

    2016-07-01

    Distinct ROS signaling pathways initiated by singlet oxygen ((1)O2) or superoxide and hydrogen peroxide have been attributed to either cell death or acclimation, respectively. Recent studies have revealed that more complex antagonistic and synergistic relationships exist within and between these pathways. As specific chloroplastic ROS signals are difficult to study, rapid systemic signaling experiments using localized high light (HL) stress or ROS treatments were used in this study to uncouple signals required for direct HL and ROS perception and distal systemic acquired acclimation (SAA). A qPCR approach was chosen to determine local perception and distal signal reception. Analysis of a thylakoidal ascorbate peroxidase mutant (tapx), the (1)O2-retrograde signaling double mutant (ex1/ex2), and an apoplastic signaling double mutant (rbohD/F) revealed that tAPX and EXECUTER 1 are required for both HL and systemic acclimation stress perception. Apoplastic membrane-localized RBOHs were required for systemic spread of the signal but not for local signal induction in directly stressed tissues. Endogenous ROS treatments revealed a very strong systemic response induced by a localized 1 h induction of (1)O2 using the conditional flu mutant. A qPCR time course of (1)O2 induced systemic marker genes in directly and indirectly connected leaves revealed a direct vascular connection component of both immediate and longer term SAA signaling responses. These results reveal the importance of an EXECUTER-dependent (1)O2 retrograde signal for both local and long distance RBOH-dependent acclimation signaling that is distinct from other HL signaling pathways, and that direct vascular connections have a role in spatial-temporal SAA induction. PMID:27288360

  13. Regulation of frontline antibody responses by innate immune signals

    PubMed Central

    Chorny, Alejo; Puga, Irene; Cerutti, Andrea

    2012-01-01

    Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly “frontline” B cells located in the marginal zone of the spleen and in the intestine. PMID:22477522

  14. A receptor-like protein mediates the response to pectin modification by activating brassinosteroid signaling.

    PubMed

    Wolf, Sebastian; van der Does, Dieuwertje; Ladwig, Friederike; Sticht, Carsten; Kolbeck, Andreas; Schürholz, Ann-Kathrin; Augustin, Sebastian; Keinath, Nana; Rausch, Thomas; Greiner, Steffen; Schumacher, Karin; Harter, Klaus; Zipfel, Cyril; Höfte, Herman

    2014-10-21

    The brassinosteroid (BR) signaling module is a central regulator of plant morphogenesis, as indicated by the large number of BR-responsive cell wall-related genes and the severe growth defects of BR mutants. Despite a detailed knowledge of the signaling components, the logic of this auto-/paracrine signaling module in growth control remains poorly understood. Recently, extensive cross-talk with other signaling pathways has been shown, suggesting that the outputs of BR signaling, such as gene-expression changes, are subject to complex control mechanisms. We previously provided evidence for a role of BR signaling in a feedback loop controlling the integrity of the cell wall. Here, we identify the first dedicated component of this feedback loop: a receptor-like protein (RLP44), which is essential for the compensatory triggering of BR signaling upon inhibition of pectin de-methylesterification in the cell wall. RLP44 is required for normal growth and stress responses and connects with the BR signaling pathway, presumably through a direct interaction with the regulatory receptor-like kinase BAK1. These findings corroborate a role for BR in controlling the sensitivity of a feedback signaling module involved in maintaining the physico-chemical homeostasis of the cell wall during cell expansion.

  15. Chemical genetics reveals negative regulation of abscisic acid signaling by a plant immune response pathway.

    PubMed

    Kim, Tae-Houn; Hauser, Felix; Ha, Tracy; Xue, Shaowu; Böhmer, Maik; Nishimura, Noriyuki; Munemasa, Shintaro; Hubbard, Katharine; Peine, Nora; Lee, Byeong-Ha; Lee, Stephen; Robert, Nadia; Parker, Jane E; Schroeder, Julian I

    2011-06-01

    Coordinated regulation of protection mechanisms against environmental abiotic stress and pathogen attack is essential for plant adaptation and survival. Initial abiotic stress can interfere with disease-resistance signaling [1-6]. Conversely, initial plant immune signaling may interrupt subsequent abscisic acid (ABA) signal transduction [7, 8]. However, the processes involved in this crosstalk between these signaling networks have not been determined. By screening a 9600-compound chemical library, we identified a small molecule [5-(3,4-dichlorophenyl)furan-2-yl]-piperidine-1-ylmethanethione (DFPM) that rapidly downregulates ABA-dependent gene expression and also inhibits ABA-induced stomatal closure. Transcriptome analyses show that DFPM also stimulates expression of plant defense-related genes. Major early regulators of pathogen-resistance responses, including EDS1, PAD4, RAR1, and SGT1b, are required for DFPM-and notably also for Pseudomonas-interference with ABA signal transduction, whereas salicylic acid, EDS16, and NPR1 are not necessary. Although DFPM does not interfere with early ABA perception by PYR/RCAR receptors or ABA activation of SnRK2 kinases, it disrupts cytosolic Ca(2+) signaling and downstream anion channel activation in a PAD4-dependent manner. Our findings provide evidence that activation of EDS1/PAD4-dependent plant immune responses rapidly disrupts ABA signal transduction and that this occurs at the level of Ca(2+) signaling, illuminating how the initial biotic stress pathway interferes with ABA signaling.

  16. Early redox, Src family kinase, and calcium signaling integrate wound responses and tissue regeneration in zebrafish

    PubMed Central

    Yoo, Sa Kan; Freisinger, Christina M.; LeBert, Danny C.

    2012-01-01

    Tissue injury can lead to scar formation or tissue regeneration. How regenerative animals sense initial tissue injury and transform wound signals into regenerative growth is an unresolved question. Previously, we found that the Src family kinase (SFK) Lyn functions as a redox sensor in leukocytes that detects H2O2 at wounds in zebrafish larvae. In this paper, using zebrafish larval tail fins as a model, we find that wounding rapidly activated SFK and calcium signaling in epithelia. The immediate SFK and calcium signaling in epithelia was important for late epimorphic regeneration of amputated fins. Wound-induced activation of SFKs in epithelia was dependent on injury-generated H2O2. A SFK member, Fynb, was responsible for fin regeneration. This work provides a new link between early wound responses and late regeneration and suggests that redox, SFK, and calcium signaling are immediate “wound signals” that integrate early wound responses and late epimorphic regeneration. PMID:23045550

  17. Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells

    SciTech Connect

    Sarafian, Theodore Montes, Cindy; Harui, Airi; Beedanagari, Sudheer R.; Kiertscher, Sylvia; Stripecke, Renata; Hossepian, Derik; Kitchen, Christina; Kern, Rita; Belperio, John; Roth, Michael D.

    2008-09-15

    Marijuana smoking is associated with a number of abnormal findings in the lungs of habitual smokers. Previous studies revealed that {delta}{sup 9}-tetrahydrocannabinol (THC) caused mitochondrial injury in primary lung epithelial cells and in the cell line, A549 [Sarafian, T. A., Kouyoumjian, S., Khoshaghideh, F., Tashkin, D. P., and Roth, M. D. (2003). Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics. Am J Physiol Lung Cell Mol Physiol 284, L298-306; Sarafian, T., Habib, N., Mao, J. T., Tsu, I. H., Yamamoto, M. L., Hsu, E., Tashkin, D. P., and Roth, M. D. (2005). Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett 158, 95-107]. The role of cannabinoid receptors in this injury was unclear, as was the potential impact on cell function. In order to investigate these questions, A549 cells were engineered to over-express the type 2 cannabinoid receptor (CB2R) using a self-inactivating lentiviral vector. This transduction resulted in a 60-fold increase in CB2R mRNA relative to cells transduced with a control vector. Transduced cell lines were used to study the effects of THC on chemotactic activity and mitochondrial function. Chemotaxis in response to a 10% serum gradient was suppressed in a concentration-dependent manner by exposure to THC. CB2R-transduced cells exhibited less intrinsic chemotactic activity (p < 0.05) and were 80- to 100-fold more sensitive to the inhibitory effects of THC. Studies using SR144528, a selective CB2R antagonist, verified that these effects were mediated by the CB2R. Marijuana smoke extract, but not smoke extracts from tobacco or placebo marijuana cigarettes, reproduced these effects (p < 0.05). THC decreased ATP level and mitochondrial membrane potential ({psi}{sub m}) in both control and CB2R-transduced cells. However, these decreases did not play a significant role in chemotaxis inhibition since cyclosporine A, which protected against ATP loss

  18. Mean signal and response time influences on multivoxel signals of contextual retrieval in the medial temporal lobe

    PubMed Central

    Reas, Emilie T; Brewer, James B

    2015-01-01

    Introduction The medial temporal lobe supports integrating the “what,” “where,” and “when” of an experience into a unified memory. However, it remains unclear how representations of these contextual features are neurally encoded and distributed across medial temporal lobe subregions. Methods This study conducted functional magnetic resonance imaging of the medial temporal lobe, while participants retrieved pair, spatial, and temporal source memories. Multivoxel classifiers were trained to distinguish between retrieval conditions before and after correction for mean signal and response times, to more thoroughly characterize the multivoxel signal associated with memory context. Results Activity in perirhinal and parahippocampal cortex dissociated between memory for associated items and memory for their spatiotemporal context, and hippocampal activity was linked to memory for spatial context. However, perirhinal and hippocampal classifiers were, respectively, driven by effects of mean signal amplitude and task difficulty, whereas the parahippocampal classifier survived correction for these effects. Conclusion These findings demonstrate dissociable coding mechanisms for episodic memory context across the medial temporal lobe, and further highlight a critical distinction between multivoxel representations driven by spatially distributed activity patterns, and those driven by the regional signal. PMID:25646149

  19. Infants' responses to facial and vocal emotional signals in a social referencing paradigm.

    PubMed

    Mumme, D L; Fernald, A; Herrera, C

    1996-12-01

    The independent effects of facial and vocal emotional signals and of positive and negative signals on infant behavior were investigated in a novel toy social referencing paradigm. 90 12-month-old infants and their mothers were assigned to an expression condition (neutral, happy, or fear) nested within a modality condition (face-only or voice-only). Each infant participated in 3 trials: a baseline trial, an expression trial, and a final positive trial. We found that fearful vocal emotional signals, when presented without facial signals, were sufficient to elicit appropriate behavior regulation. Infants in the fear-voice condition looked at their mothers longer, showed less toy proximity, and tended to show more negative affect than infants in the neutral-voice condition. Happy vocal signals did not elicit differential responding. The infants' sex was a factor in the few effects that were found for infants' responses to facial emotional signals. PMID:9071778

  20. Neural Responses to Multimodal Ostensive Signals in 5-Month-Old Infants

    PubMed Central

    Parise, Eugenio; Csibra, Gergely

    2013-01-01

    Infants' sensitivity to ostensive signals, such as direct eye contact and infant-directed speech, is well documented in the literature. We investigated how infants interpret such signals by assessing common processing mechanisms devoted to them and by measuring neural responses to their compounds. In Experiment 1, we found that ostensive signals from different modalities display overlapping electrophysiological activity in 5-month-old infants, suggesting that these signals share neural processing mechanisms independently of their modality. In Experiment 2, we found that the activation to ostensive signals from different modalities is not additive to each other, but rather reflects the presence of ostension in either stimulus stream. These data support the thesis that ostensive signals obligatorily indicate to young infants that communication is directed to them. PMID:23977289

  1. Signaling the Unfolded Protein Response in primary brain cancers.

    PubMed

    Le Reste, Pierre-Jean; Avril, Tony; Quillien, Véronique; Morandi, Xavier; Chevet, Eric

    2016-07-01

    The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target. PMID:27016056

  2. Chloroplast unfolded protein response, a new plastid stress signaling pathway?

    PubMed

    Ramundo, Silvia; Rochaix, Jean-David

    2014-01-01

    A unique feature of the ATP-dependent ClpP protease of eukaryotic photosynthetic organisms is that its catalytic subunit ClpP1 is encoded by the chloroplast genome. Attempts to inactivate this subunit through chloroplast transformation have failed because it is essential for cell survival. To study the function of ClpP we have developed a repressible chloroplast gene expression system in Chlamydomonas reinhardtii. This system is based on the use of a chimeric nuclear gene in which the vitamin-repressible MetE promoter and Thi4 riboswitch have been fused to the coding sequence of Nac2. Upon entry into the chloroplast the Nac2 protein specifically interacts with the psbD 5'UTR and is required for the proper processing/translation of the psbD mRNA. This property can be conveyed to any chloroplast mRNA by replacing its 5'UTR with that of psbD. In this study we have chosen clpP1 as plastid target gene and examined the cellular events induced upon depletion of ClpP through transcriptomic, proteomic, biochemical and electron microscope analysis. Among the most striking features, a massive increase in protein abundance occurs for plastid chaperones, proteases and proteins involved in membrane assembly/disassembly strongly suggesting the existence of a chloroplast unfolded protein response. PMID:25482768

  3. Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities.

    PubMed

    Porpiglia, Ermelinda; Hidalgo, Daniel; Koulnis, Miroslav; Tzafriri, Abraham R; Socolovsky, Merav

    2012-08-01

    Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a "knocked-in" EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and

  4. The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity.

    PubMed

    Gallo, Paul M; Gallucci, Stefania

    2013-01-01

    Dendritic cells (DCs) initiate and control immune responses, participate in the maintenance of immunological tolerance and are pivotal players in the pathogenesis of autoimmunity. In patients with autoimmune disease and in experimental animal models of autoimmunity, DCs show abnormalities in both numbers and activation state, expressing immunogenic levels of costimulatory molecules and pro-inflammatory cytokines. Exogenous and endogenous danger signals activate DCs to stimulate the immune response. Classic endogenous danger signals are released, activated, or secreted by host cells and tissues experiencing stress, damage, and non-physiologic cell death; and are therefore referred to as damage-associated molecular patterns (DAMPs). Some DAMPs are released from cells, where they are normally sequestered, during necrosis (e.g., heat shock proteins, uric acid, ATP, HMGB1, mitochondria-derived molecules). Others are actively secreted, like Type I Interferons. Here we discuss important DAMPs in the context of autoimmunity. For some, there is a clear pathogenic link (e.g., nucleic acids and lupus). For others, there is less evidence. Additionally, we explore emerging danger signals. These include inorganic materials and man-made technologies (e.g., nanomaterials) developed as novel therapeutic approaches. Some nanomaterials can activate DCs and may trigger unintended inflammatory responses. Finally, we will review "homeostatic danger signals," danger signals that do not derive directly from pathogens or dying cells but are associated with perturbations of tissue/cell homeostasis and may signal pathological stress. These signals, like acidosis, hypoxia, and changes in osmolarity, also play a role in inflammation and autoimmunity.

  5. Ca2+ signal is generated only once in the mating pheromone response pathway in Saccharomyces cerevisiae.

    PubMed

    Nakajima-Shimada, J; Sakaguchi, S; Tsuji, F I; Anraku, Y; Iida, H

    2000-04-01

    The mating pheromone, alpha-factor, of the yeast Saccharomyces cerevisiae binds to the heterotrimeric G protein-coupled cell surface receptor of MATa cells and induces cellular responses necessary for mating. In higher eukaryotic cells, many hormones and growth factors rapidly mobilize a second messenger, Ca2+, by means of receptor-G protein signaling. Although striking similarities between the mechanisms of the receptor-G protein signaling in yeast and higher eukaryotes have long been known, it is still uncertain whether the pheromone rapidly mobilizes Ca2+ necessary for early events of the pheromone response. Here we reexamine this problem using sensitive methods for detecting Ca2+ fluxes and mobilization, and find no evidence that there is rapid Ca2+ influx leading to a rapid increase in the cytosolic free Ca2+ concentration. In addition, the yeast PLC1 deletion mutant lacking phosphoinositide-specific phospholipase C, a key enzyme for generating Ca2+ signals in higher eukaryotic cells, responds normally to the pheromone. These findings suggest that the receptor-G protein signaling does not utilize Ca2+ as a second messenger in the early stage of the pheromone response pathway. Since the receptor-G protein signaling does stimulate Ca2+ influx after early events have finished and this stimulation is essential for late events in the pheromone response pathway [Iida et al., (1990) J. Biol. Chem., 265: 13391-13399] Ca2+ may be used only once in the signal transduction pathway in unicellular eukaryotes such as yeast. PMID:10885582

  6. Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo

    PubMed Central

    Saunders, Abbie; Wilcockson, Scott G.; Zeef, Leo A. H.; Donaldson, Ian J.; Ashe, Hilary L.

    2016-01-01

    The BMP signaling pathway has a conserved role in dorsal-ventral axis patterning during embryonic development. In Drosophila, graded BMP signaling is transduced by the Mad transcription factor and opposed by the Brinker repressor. In this study, using the Drosophila embryo as a model, we combine RNA-seq with Mad and Brinker ChIP-seq to decipher the BMP-responsive transcriptional network underpinning differentiation of the dorsal ectoderm during dorsal-ventral axis patterning. We identify multiple new BMP target genes, including positive and negative regulators of EGF signaling. Manipulation of EGF signaling levels by loss- and gain-of-function studies reveals that EGF signaling negatively regulates embryonic BMP-responsive transcription. Therefore, the BMP gene network has a self-regulating property in that it establishes a balance between its activity and that of the antagonistic EGF signaling pathway to facilitate correct patterning. In terms of BMP-dependent transcription, we identify key roles for the Zelda and Zerknüllt transcription factors in establishing the resulting expression domain, and find widespread binding of insulator proteins to the Mad and Brinker-bound genomic regions. Analysis of embryos lacking the BEAF-32 insulator protein shows reduced transcription of a peak BMP target gene and a reduction in the number of amnioserosa cells, the fate specified by peak BMP signaling. We incorporate our findings into a model for Mad-dependent activation, and discuss its relevance to BMP signal interpretation in vertebrates. PMID:27379389

  7. The Dictyostelium MAPK ERK1 is phosphorylated in a secondary response to early developmental signaling

    PubMed Central

    Schwebs, David J.; Hadwiger, Jeffrey A.

    2014-01-01

    Previous reports have suggested that the two mitogen-activated protein kinases (MAPKs) in Dictyostelium discoideum, ERK1 and ERK2, can be directly activated in response to external cAMP even though these MAPKs play different roles in the developmental life cycle. To better characterize MAPK regulation, the levels of phosphorylated MAPKs were analyzed in response to external signals. Only ERK2 was rapidly phosphorylated in response to the chemoattractants, cAMP and folate. In contrast, the phosphorylation of ERK1 occurred as a secondary or indirect response to these stimuli and this phosphorylation was enhanced by cell-cell interactions, suggesting that other external signals can activate ERK1. The phosphorylation of ERK1 or ERK2 did not require the function of the other MAPK in these responses. Folate stimulation of a chimeric population of erk1− and gα4− cells revealed that the phosphorylation of ERK1 could be mediated through an intercellular signal other than folate. Loss of ERK1 function suppressed the developmental delay and the deficiency in anterior cell localization associated with gα5− mutants suggesting that ERK1 function can be down regulated through Gα5 subunit-mediated signaling. However, no major changes in the phosphorylation of ERK1 were observed in gα5− cells suggesting that the Gα5 subunit signaling pathway does not regulate the phosphorylation of ERK1. These findings suggest that the activation of ERK1 occurs as a secondary response to chemoattractants and that other cell-cell signaling mechanisms contribute to this activation. Gα5 subunit signaling can down regulate ERK1 function to promote prestalk cell development but not through major changes to the level of phosphorylated ERK1. PMID:25451080

  8. Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase.

    PubMed

    Davis, J N; Rock, C O; Cheng, M; Watson, J B; Ashmun, R A; Kirk, H; Kay, R J; Roussel, M F

    1997-12-01

    Substitution of phenylalanine for tyrosine at codon 809 (Y809F) of the human colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) impairs ligand-stimulated tyrosine kinase activity, prevents induction of c-MYC and cyclin D1 genes, and blocks CSF-1-dependent progression through the G1 phase of the cell cycle. We devised an unbiased genetic screen to isolate genes that restore the ability of CSF-1 to stimulate growth in cells that express mutant CSF-1R (Y809F). This screen led us to identify a truncated form of the murine type Ibeta phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta). This truncated protein lacks residues 1 to 238 of mPIP5K-Ibeta and is catalytically inactive. When we transfected cells expressing CSF-1R (Y809F) with mPIP5K-Ibeta (delta1-238), CSF-1-dependent induction of c-MYC and cyclin D1 was restored and ligand-dependent cell proliferation was sustained. CSF-1 normally triggers the rapid disappearance of CSF-1R (Y809F) from the cell surface; however, transfection of cells with mPIP5K-Ibeta (delta1-238) stabilized CSF-1R (Y809F) expression on the cell surface, resulting in elevated levels of ligand-activated CSF-1R (Y809F). These results suggest a role for PIP5K-Ibeta in receptor endocytosis and that the truncated enzyme compensated for a mitogenically defective CSF-1R by interfering with this process.

  9. Hydrogen Peroxide Signaling in Plant Development and Abiotic Responses: Crosstalk with Nitric Oxide and Calcium

    PubMed Central

    Niu, Lijuan; Liao, Weibiao

    2016-01-01

    Hydrogen peroxide (H2O2), as a reactive oxygen species, is widely generated in many biological systems. It has been considered as an important signaling molecule that mediates various physiological and biochemical processes in plants. Normal metabolism in plant cells results in H2O2 generation, from a variety of sources. Also, it is now clear that nitric oxide (NO) and calcium (Ca2+) function as signaling molecules in plants. Both H2O2 and NO are involved in plant development and abiotic responses. A wide range of evidences suggest that NO could be generated under similar stress conditions and with similar kinetics as H2O2. The interplay between H2O2 and NO has important functional implications to modulate transduction processes in plants. Moreover, close interaction also exists between H2O2 and Ca2+ in response to development and abiotic stresses in plants. Cellular responses to H2O2 and Ca2+ signaling systems are complex. There is quite a bit of interaction between H2O2 and Ca2+ signaling in responses to several stimuli. This review aims to introduce these evidences in our understanding of the crosstalk among H2O2, NO, and Ca2+ signaling which regulates plant growth and development, and other cellular and physiological responses to abiotic stresses. PMID:26973673

  10. Comparison of signaling interactions determining annual and perennial plant growth in response to low temperature

    PubMed Central

    Wingler, Astrid

    2015-01-01

    Low temperature inhibits plant growth despite the fact that considerable rates of photosynthetic activity can be maintained. Instead of lower rates of photosynthesis, active inhibition of cell division and expansion is primarily responsible for reduced growth. This results in sink limitation and enables plants to accumulate carbohydrates that act as compatible solutes or are stored throughout the winter to enable re-growth in spring. Regulation of growth in response to temperature therefore requires coordination with carbon metabolism, e.g., via the signaling metabolite trehalose-6-phosphate. The phytohormones gibberellin (GA) and jasmonate (JA) play an important role in regulating growth in response to temperature. Growth restriction at low temperature is mainly mediated by DELLA proteins, whose degradation is promoted by GA. For annual plants, it has been shown that the GA/DELLA pathway interacts with JA signaling and C-repeat binding factor dependent cold acclimation, but these interactions have not been explored in detail for perennials. Growth regulation in response to seasonal factors is, however, particularly important in perennials, especially at high latitudes. In autumn, growth cessation in trees is caused by shortening of the daylength in interaction with phytohormone signaling. In perennial grasses seasonal differences in the sensitivity to GA may enable enhanced growth in spring. This review provides an overview of the signaling interactions that determine plant growth at low temperature and highlights gaps in our knowledge, especially concerning the seasonality of signaling responses in perennial plants. PMID:25628637

  11. Spectral and spatial dependence of
diffuse optical signals in response to
peripheral nerve stimulation

    PubMed Central

    Chen, Debbie K.; Erb, M. Kelley; Tong, Yunjie; Yu, Yang; Sassaroli, Angelo; Bergethon, Peter R.; Fantini, Sergio

    2010-01-01

    Using non-invasive, near-infrared spectroscopy we have previously reported optical signals measured at or around peripheral nerves in response to their stimulation. Such optical signals featured amplitudes on the order of 0.1% and peaked about 100 ms after peripheral nerve stimulation in human subjects. Here, we report a study of the spatial and spectral dependence of the optical signals induced by stimulation of the human median and sural nerves, and observe that these optical signals are: (1) unlikely due to either dilation or constriction of blood vessels, (2) not associated with capillary bed hemoglobin, (3) likely due to blood vessel(s) displacement, and (4) unlikely due to fiber-skin optical coupling effects. We conclude that the most probable origin of the optical response to peripheral nerve stimulation is from displacement of blood vessels within the optically probed volume, as a result of muscle twitch in adjacent areas. PMID:21258519

  12. Short term signaling responses in roots of young soybean seedlings exposed to cadmium stress.

    PubMed

    Chmielowska-Bąk, Jagna; Lefèvre, Isabelle; Lutts, Stanley; Deckert, Joanna

    2013-12-15

    In the present study, the expression of fourteen genes involved in various signal transduction pathways was examined in young soybean (Glycine max) seedlings exposed to cadmium at two concentrations (10 mg L(-1) and 25 mg L(-1)) for short time periods (3, 6 and 24 h). The results show that cadmium causes induction of genes encoding proteins involved in ethylene and polyamines metabolism, nitric oxide generation, MAPK cascades and regulation of other genes' expression. The bioinformatic analysis of promoter sequences of Cd-inducible genes revealed that their promoters possess several regulative motifs associated with the plant response to stress factors and abscisic acid and ethylene signaling. The involvement of ethylene in the response of soybean seedlings to cadmium stress was further confirmed by the real-time analysis of ethylene production during 24 h of CdCl2 treatment. The role of the described signaling elements in transduction of the cadmium signal in young soybean seedlings is discussed.

  13. Characterizing the Response of Commercial and Industrial Facilities to Dynamic Pricing Signals from the Utility

    SciTech Connect

    Mathieu, Johanna L.; Gadgil, Ashok J.; Callaway, Duncan S.; Price, Phillip N.; Kiliccote, Sila

    2010-07-01

    We describe a method to generate statistical models of electricity demand from Commercial and Industrial (C&I) facilities including their response to dynamic pricing signals. Models are built with historical electricity demand data. A facility model is the sum of a baseline demand model and a residual demand model; the latter quantifies deviations from the baseline model due to dynamic pricing signals from the utility. Three regression-based baseline computation methods were developed and analyzed. All methods performed similarly. To understand the diversity of facility responses to dynamic pricing signals, we have characterized the response of 44 C&I facilities participating in a Demand Response (DR) program using dynamic pricing in California (Pacific Gas and Electric's Critical Peak Pricing Program). In most cases, facilities shed load during DR events but there is significant heterogeneity in facility responses. Modeling facility response to dynamic price signals is beneficial to the Independent System Operator for scheduling supply to meet demand, to the utility for improving dynamic pricing programs, and to the customer for minimizing energy costs.

  14. Lung cell hypoxia: role of mitochondrial reactive oxygen species signaling in triggering responses.

    PubMed

    Schumacker, Paul T

    2011-11-01

    Lung cells experience hypoxia during development, during travel to high altitude, and in acute and chronic lung diseases. The functional responses evoked by hypoxia are diverse and generally act to protect the cells from hypoxic injury, although some lung cell responses are counterproductive because they degrade normal function of the organ. The cellular O(2) sensor responsible for many of these responses involves the mitochondrial electron transport chain. Under hypoxic conditions, increased release of reactive oxygen species from the inner mitochondrial membrane to the intermembrane space leads to the activation of transcription factors, including hypoxia-inducible factor, activation of hypoxic pulmonary vasoconstriction, activation of AMP-dependent protein kinase, and internalization of the membrane Na,K-ATPase from the basolateral membrane of alveolar epithelial cells. Although the specific targets of reactive oxygen species signals are not fully understood, this signaling pathway is critical for development and for normal lung responses in the newborn and the mature lung.

  15. Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling

    PubMed Central

    Lisse, Thomas S.; Hewison, Martin; Adams, John S.

    2011-01-01

    Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as “vitamin D or estrogen response element-binding proteins”, behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. PMID:21236284

  16. A Protein Turnover Signaling Motif Controls the Stimulus-Sensitivity of Stress Response Pathways

    PubMed Central

    Loriaux, Paul Michael; Hoffmann, Alexander

    2013-01-01

    Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways. PMID:23468615

  17. Models of Response Inhibition in the Stop-Signal and Stop-Change Paradigms

    PubMed Central

    Verbruggen, Frederick; Logan, Gordon D.

    2009-01-01

    The stop-signal paradigm is very useful for the study of response inhibition. Stop-signal performance is typically described as a race between a go process, triggered by a go stimulus, and a stop process, triggered by the stop signal. Response inhibition depends on the relative finishing time of these two processes. Numerous studies have shown that the independent horse-race model of Logan and Cowan (1984) accounts for the data very well. In the present article, we review the independent horse-race model and related models, such as the interactive horse-race model (Boucher, Palmeri, Logan & Schall, 2007). We present evidence that favors the independent horse-race model but also some evidence that challenges the model. We end with a discussion of recent models that elaborate the role of a stop process in inhibiting a response. PMID:18822313

  18. Stop-signal response inhibition in schizophrenia: behavioural, event-related potential and functional neuroimaging data.

    PubMed

    Hughes, Matthew Edward; Fulham, William Ross; Johnston, Patrick James; Michie, Patricia Therese

    2012-01-01

    Inhibitory control deficits are well documented in schizophrenia, supported by impairment in an established measure of response inhibition, the stop-signal reaction time (SSRT). We investigated the neural basis of this impairment by comparing schizophrenia patients and controls matched for age, sex and education on behavioural, functional magnetic resonance imaging (fMRI) and event-related potential (ERP) indices of stop-signal task performance. Compared to controls, patients exhibited slower SSRT and reduced right inferior frontal gyrus (rIFG) activation, but rIFG activation correlated with SSRT in both groups. Go stimulus and stop-signal ERP components (N1/P3) were smaller in patients, but the peak latencies of stop-signal N1 and P3 were also delayed in patients, indicating impairment early in stop-signal processing. Additionally, response-locked lateralised readiness potentials indicated response preparation was prolonged in patients. An inability to engage rIFG may predicate slowed inhibition in patients, however multiple spatiotemporal irregularities in the networks underpinning stop-signal task performance may contribute to this deficit. PMID:22027085

  19. Cell-Based Assay for Identifying the Modulators of Antioxidant Response Element Signaling Pathway.

    PubMed

    Zhao, Jinghua; Shukla, Sunita J; Xia, Menghang

    2016-01-01

    The antioxidant response element (ARE) signaling pathway plays an important role in the amelioration of cellular oxidative stress. Thus, assays that detect this pathway can be useful for identifying chemicals that induce or inhibit oxidative stress signaling. The focus of this chapter is to describe a cell-based ARE assay in a quantitative high-throughput screening (qHTS) format to test a large collection of compounds that induce nuclear factor erythroid 2-related factor (Nrf2)/ARE signaling. The assay is described through cell handling, assay preparation, and instrument usage. PMID:27518623

  20. R26-WntVis reporter mice showing graded response to Wnt signal levels.

    PubMed

    Takemoto, Tatsuya; Abe, Takaya; Kiyonari, Hiroshi; Nakao, Kazuki; Furuta, Yasuhide; Suzuki, Hitomi; Takada, Shinji; Fujimori, Toshihiko; Kondoh, Hisato

    2016-06-01

    The canonical Wnt signaling pathway plays a major role in the regulation of embryogenesis and organogenesis, where signal strength-dependent cellular responses are of particular importance. To assess Wnt signal levels in individual cells, and to circumvent the integration site-dependent bias shown in previous Wnt reporter lines, we constructed a new Wnt signal reporter mouse line R26-WntVis. Heptameric TCF/LEF1 binding sequences were combined with a viral minimal promoter to confer a graded response to the reporter depending on Wnt signal strengths. The histone H2B-EGFP fusion protein was chosen as the fluorescent reporter to facilitate single-cell resolution analyses. This WntVis reporter gene was then inserted into the ROSA26 locus in an orientation opposite to that of the endogenous gene. The R26-WntVis allele was introduced into Wnt3a(-/-) and Wnt3a(vt/-) mutant mouse embryos and compared with wild-type embryos to assess its performance. The R26-WntVis reporter was activated in known Wnt-dependent tissues and responded in a graded fashion to signal intensity. This analysis also indicated that the major Wnt activity early in embryogenesis switched from Wnt3 to Wnt3a around E7.5. The R26-WntVis mouse line will be widely useful for the study of Wnt signal-dependent processes.

  1. R26-WntVis reporter mice showing graded response to Wnt signal levels.

    PubMed

    Takemoto, Tatsuya; Abe, Takaya; Kiyonari, Hiroshi; Nakao, Kazuki; Furuta, Yasuhide; Suzuki, Hitomi; Takada, Shinji; Fujimori, Toshihiko; Kondoh, Hisato

    2016-06-01

    The canonical Wnt signaling pathway plays a major role in the regulation of embryogenesis and organogenesis, where signal strength-dependent cellular responses are of particular importance. To assess Wnt signal levels in individual cells, and to circumvent the integration site-dependent bias shown in previous Wnt reporter lines, we constructed a new Wnt signal reporter mouse line R26-WntVis. Heptameric TCF/LEF1 binding sequences were combined with a viral minimal promoter to confer a graded response to the reporter depending on Wnt signal strengths. The histone H2B-EGFP fusion protein was chosen as the fluorescent reporter to facilitate single-cell resolution analyses. This WntVis reporter gene was then inserted into the ROSA26 locus in an orientation opposite to that of the endogenous gene. The R26-WntVis allele was introduced into Wnt3a(-/-) and Wnt3a(vt/-) mutant mouse embryos and compared with wild-type embryos to assess its performance. The R26-WntVis reporter was activated in known Wnt-dependent tissues and responded in a graded fashion to signal intensity. This analysis also indicated that the major Wnt activity early in embryogenesis switched from Wnt3 to Wnt3a around E7.5. The R26-WntVis mouse line will be widely useful for the study of Wnt signal-dependent processes. PMID:27030109

  2. Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals

    PubMed Central

    Mckenzie, Grahame; Ward, George; Stallwood, Yvette; Briend, Emmanuel; Papadia, Sofia; Lennard, Andrew; Turner, Martin; Champion, Brian; Hardingham, Giles E

    2006-01-01

    Background Notch plays a wide-ranging role in controlling cell fate, differentiation and development. The PI3K-Akt pathway is a similarly conserved signalling pathway which regulates processes such as differentiation, proliferation and survival. Mice with disrupted Notch and PI3K signalling show phenotypic similarities during haematopoietic cell development, suggesting functional interaction between these pathways. Results We show that cellular responsiveness to Notch signals depends on the activity of the PI3K-Akt pathway in cells as diverse as CHO cells, primary T-cells and hippocampal neurons. Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch-dependent responses. We propose that the PI3K-Akt pathway exerts its influence on Notch primarily via inhibition of GSK3-beta, a kinase known to phosphorylate and regulate Notch signals. Conclusion The PI3K-Akt pathway acts as a "gain control" for Notch signal responses. Since physiological levels of intracellular Notch are often low, coincidence with PI3K-activation may be crucial for induction of Notch-dependent responses. PMID:16507111

  3. Ethylene signaling pathway is not linear, however its lateral part is responsible for sensing and signaling of sulfur status in plants

    PubMed Central

    Moniuszko, Grzegorz

    2015-01-01

    A secondary, non-linear, lateral part of ethylene signaling pathway has been anticipated and speculated before. Recently, it has been found that part of the proteomic response of Eruca sativa to silver nitrate (which is an inhibitor of ethylene signaling) is related to sulfur metabolism. Using public Arabidopsis thaliana microarray data, I show that silver nitrate mimics the signal of sulfur starvation at the transcriptome level. This, combined with data mined from literature, indicates that ethylene receptors are localized at the beginning of the response to sulfur deficiency in plants. This means that the non-linear, lateral part of ethylene signaling pathway exists and is responsible for transduction of the signal of sulfur deficit. Here, I present a model of such a pathway and anticipate it to be the starting point for more detailed analysis of the lateral part of ethylene signaling pathway and the exact mechanism of sulfur status sensing in plants. PMID:26340594

  4. Ethylene signaling pathway is not linear, however its lateral part is responsible for sensing and signaling of sulfur status in plants.

    PubMed

    Moniuszko, Grzegorz

    2015-01-01

    A secondary, non-linear, lateral part of ethylene signaling pathway has been anticipated and speculated before. Recently, it has been found that part of the proteomic response of Eruca sativa to silver nitrate (which is an inhibitor of ethylene signaling) is related to sulfur metabolism. Using public Arabidopsis thaliana microarray data, I show that silver nitrate mimics the signal of sulfur starvation at the transcriptome level. This, combined with data mined from literature, indicates that ethylene receptors are localized at the beginning of the response to sulfur deficiency in plants. This means that the non-linear, lateral part of ethylene signaling pathway exists and is responsible for transduction of the signal of sulfur deficit. Here, I present a model of such a pathway and anticipate it to be the starting point for more detailed analysis of the lateral part of ethylene signaling pathway and the exact mechanism of sulfur status sensing in plants.

  5. CD47 signaling pathways controlling cellular differentiation and responses to stress

    PubMed Central

    Soto-Pantoja, David R.; Kaur, Sukhbir; Roberts, David D.

    2016-01-01

    CD47 is a widely expressed integral membrane protein that serves as the counter-receptor for the inhibitory phagocyte receptor signal-regulatory protein-α (SIRPα) and as a signaling receptor for the secreted matricellular protein thrombospondin-1. Recent studies employing mice and somatic cells lacking CD47 have revealed important pathophysiological functions of CD47 in cardiovascular homeostasis, immune regulation, resistance of cells and tissues to stress, and chronic diseases of aging including cancer. With the emergence of experimental therapeutics targeting CD47, a more thorough understanding of CD47 signal transduction is essential. CD47 lacks a substantial cytoplasmic signaling domain, but several cytoplasmic binding partners have been identified, and lateral interactions of CD47 with other membrane receptors play important roles in mediating signaling resulting from the binding of thrombospondin-1. This review addresses recent advances in identifying the lateral binding partners, signal transduction pathways, and downstream transcription networks regulated through CD47 in specific cell lineages. Major pathways regulated by CD47 signaling include calcium homeostasis, cyclic nucleotide signaling, nitric oxide and hydrogen sulfide biosynthesis and signaling, and stem cell transcription factors. These pathways and other undefined proximal mediators of CD47 signaling regulate cell death and protective autophagy responses, mitochondrial biogenesis, cell adhesion and motility, and stem cell self-renewal. Although thrombospondin-1 is the best characterized agonist of CD47, the potential roles of other members of the thrombospondin family, SIRPα and SIRPγ binding, and homotypic CD47 interactions as agonists or antagonists of signaling through CD47 should also be considered. PMID:25708195

  6. CD47 signaling pathways controlling cellular differentiation and responses to stress.

    PubMed

    Soto-Pantoja, David R; Kaur, Sukhbir; Roberts, David D

    2015-01-01

    CD47 is a widely expressed integral membrane protein that serves as the counter-receptor for the inhibitory phagocyte receptor signal-regulatory protein-α (SIRPα) and as a signaling receptor for the secreted matricellular protein thrombospondin-1. Recent studies employing mice and somatic cells lacking CD47 have revealed important pathophysiological functions of CD47 in cardiovascular homeostasis, immune regulation, resistance of cells and tissues to stress and chronic diseases of aging including cancer. With the emergence of experimental therapeutics targeting CD47, a more thorough understanding of CD47 signal transduction is essential. CD47 lacks a substantial cytoplasmic signaling domain, but several cytoplasmic binding partners have been identified, and lateral interactions of CD47 with other membrane receptors play important roles in mediating signaling resulting from the binding of thrombospondin-1. This review addresses recent advances in identifying the lateral binding partners, signal transduction pathways and downstream transcription networks regulated through CD47 in specific cell lineages. Major pathways regulated by CD47 signaling include calcium homeostasis, cyclic nucleotide signaling, nitric oxide and hydrogen sulfide biosynthesis and signaling and stem cell transcription factors. These pathways and other undefined proximal mediators of CD47 signaling regulate cell death and protective autophagy responses, mitochondrial biogenesis, cell adhesion and motility and stem cell self-renewal. Although thrombospondin-1 is the best characterized agonist of CD47, the potential roles of other members of the thrombospondin family, SIRPα and SIRPγ binding and homotypic CD47 interactions as agonists or antagonists of signaling through CD47 should also be considered.

  7. Ultrasensitivity in the Cofilin Signaling Module: A Mechanism for Tuning T Cell Responses

    PubMed Central

    Ramirez-Munoz, Rocio; Castro-Sánchez, Patricia; Roda-Navarro, Pedro

    2016-01-01

    Ultrasensitivity allows filtering weak activating signals and responding emphatically to small changes in stronger stimuli. In the presence of positive feedback loops, ultrasensitivity enables the existence of bistability, which convert graded stimuli into switch-like, sometimes irreversible, responses. In this perspective, we discuss mechanisms that can potentially generate a bistable response in the phosphorylation/dephosphorylation monocycle that regulates the activity of cofilin in dynamic actin networks. We pay particular attention to the phosphatase Slingshot-1 (SSH-1), which is involved in a reciprocal regulation and a positive feedback loop for cofilin activation. Based on these signaling properties and experimental evidences, we propose that bistability in the cofilin signaling module might be instrumental in T cell responses to antigenic stimulation. Initially, a switch-like response in the amount of active cofilin as a function of SSH-1 activation might assist in controlling the naïve T cell specificity and sensitivity. Second, high concentrations of active cofilin might endow antigen-experienced T cells with faster and more efficient responses. We discuss the cofilin function in the context of T cell receptor triggering and spatial regulation of plasma membrane signaling molecules. PMID:26925064

  8. Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries

    PubMed Central

    Slack, Daniel L.; Burnstein, Marcus J.; Errett, Lee; Bonneau, Daniel; Latter, David; Rotstein, Ori D.; Bolz, Steffen-Sebastian; Lidington, Darcy; Voigtlaender-Bolz, Julia

    2015-01-01

    We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study. PMID:26367262

  9. Inflammatory and protein metabolism signaling responses in human skeletal muscle after burn injury.

    PubMed

    Merritt, Edward K; Cross, James M; Bamman, Marcas M

    2012-01-01

    Severe burn injuries lead to a prolonged hypercatabolic state resulting in dramatic loss of skeletal muscle mass. Postburn muscle loss is well documented but the molecular signaling cascade preceding atrophy is not. The purpose of this study is to determine the response to burn injury of signaling pathways driving muscle inflammation and protein metabolism. Muscle biopsies were collected in the early flow phase after burn injury from the vastus lateralis of a noninjured leg in patients with 20 to 60% TBSA burns and compared with uninjured, matched controls. Circulating levels of proinflammatory cytokines were also compared. Immunoblotting was performed to determine the protein levels of key signaling components for translation initiation, proteolysis, and tumor necrosis factor/nuclear factor kappa B (NFκB)and interleukin (IL)-6/STAT3 signaling. Burn subjects had significantly higher levels of circulating proinflammatory cytokines, with no difference in muscle STAT3 activity and lower NFκB activity. No differences were found in any translational signaling components. Regarding proteolytic signaling in burn, calpain-2 was 47% higher, calpastatin tended to be lower, and total ubiquitination was substantially higher. Surprisingly, a systemic proinflammatory response 3 to 10 days postburn did not lead to elevated muscle STAT3 or NFκB signaling. Signaling molecules governing translation initiation were unaffected, whereas indices of calcium-mediated proteolysis and ubiquitin-proteasome activity were upregulated. These novel findings are the first in humans to suggest that the net catabolic effect of burn injury in skeletal muscle (ie, atrophy) may be mediated, at least during the early flow phase, almost entirely by an increased proteolytic activity in the absence of suppressed protein synthesis signaling.

  10. HPS4/SABRE regulates plant responses to phosphate starvation through antagonistic interaction with ethylene signalling

    PubMed Central

    Yu, Hailan; Luo, Nan; Sun, Lichao; Liu, Dong

    2012-01-01

    The phytohormone ethylene plays important roles in regulating plant responses to phosphate (Pi) starvation. To date, however, no molecular components have been identified that interact with ethylene signalling in regulating such responses. In this work, an Arabidopsis mutant, hps4, was characterized that exhibits enhanced responses to Pi starvation, including increased inhibition of primary root growth, enhanced expression of Pi starvation-induced genes, and overproduction of root-associated acid phosphatases. Molecular cloning indicated that hps4 is a new allele of SABRE, which was previously identified as an important regulator of cell expansion in Arabidopsis. HPS4/SABRE antagonistically interacts with ethylene signalling to regulate plant responses to Pi starvation. Furthermore, it is shown that Pi-starved hps4 mutants accumulate more auxin in their root tips than the wild type, which may explain the increased inhibition of their primary root growth when grown under Pi deficiency. PMID:22615140

  11. Dopamine reward prediction-error signalling: a two-component response.

    PubMed

    Schultz, Wolfram

    2016-03-01

    Environmental stimuli and objects, including rewards, are often processed sequentially in the brain. Recent work suggests that the phasic dopamine reward prediction-error response follows a similar sequential pattern. An initial brief, unselective and highly sensitive increase in activity unspecifically detects a wide range of environmental stimuli, then quickly evolves into the main response component, which reflects subjective reward value and utility. This temporal evolution allows the dopamine reward prediction-error signal to optimally combine speed and accuracy. PMID:26865020

  12. Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

    PubMed Central

    2012-01-01

    Background Exposure to ozone activates innate immune function and causes neutrophilic (PMN) airway inflammation that in some individuals is robustly elevated. The interplay between immuno-inflammatory function and genomic signaling in those with heightened inflammatory responsiveness to ozone is not well understood. Objectives Determine baseline predictors and post exposure discriminators for the immuno-inflammatory response to ozone in inflammatory responsive adult volunteers. Methods Sputum induction was performed on 27 individuals before and after a two hour chamber exposure to 0.4 ppm ozone. Subjects were classified as inflammatory responders or non-responders to ozone based on their PMN response. Innate immune function, inflammatory cell and cytokine modulation and transcriptional signaling pathways were measured in sputum. Results Post exposure, responders showed activated innate immune function (CD16: 31,004 MFI vs 8988 MFI; CD11b: 44,986 MFI vs 24,770 MFI; CD80: 2236 MFI vs 1506 MFI; IL-8: 37,603 pg/ml vs 2828 pg/ml; and IL-1β: 1380 pg/ml vs 318 pg/ml) with muted signaling of immune cell trafficking pathways. In contrast, non-responders displayed decreased innate immune activity (CD16, CD80; phagocytosis: 2 particles/PMN vs 4 particles/PMN) post exposure that was accompanied by a heightened signaling of immune cell trafficking pathways. Conclusions Inflammatory responsive and non responsive individuals to ozone show an inverse relationship between immune cell trafficking and immuno-inflammatory functional responses to ozone. These distinct genomic signatures may further our understanding about ozone-induced morbidity in individuals with different levels of inflammatory responsiveness. PMID:23033980

  13. Divergence in mating signals correlates with genetic distance and behavioural responses to playback.

    PubMed

    Sosa-López, J R; Martínez Gómez, J E; Mennill, D J

    2016-02-01

    Animals use acoustic signals to defend resources against rivals and attract breeding partners. As with many biological traits, acoustic signals may reflect ancestry; closely related species often produce more similar signals than do distantly related species. Whether this similarity in acoustic signals is biologically relevant to animals is poorly understood. We conducted a playback experiment to measure the physical and vocal responses of male songbirds to the songs of both conspecific and allopatric-congeneric animals that varied in their acoustic and genetic similarity. Our subjects were territorial males of four species of neotropical Troglodytes wrens: Brown-throated Wrens (Troglodytes brunneicollis), Cozumel Wrens (T. beani), Clarion Wrens (T. tanneri) and Socorro Wrens (T. sissonii). Our results indicate that birds respond to playback of both conspecific and allopatric-congeneric animals; that acoustic differences increase with genetic distance; and that genetic divergence predicts the strength of behavioural responses to playback, after removing the effects of acoustic similarity between subjects' songs and playback stimuli. Collectively, these results demonstrate that the most distantly related species have the most divergent songs; that male wrens perceive divergence in fine structural characteristics of songs; and that perceptual differences between species reflect evolutionary history. This study offers novel insight into the importance of acoustic divergence of learned signals and receiver responses in species recognition.

  14. Estimating the impulse response of buried objects from ground-penetrating radar signals

    NASA Astrophysics Data System (ADS)

    van der Lijn, Fedde; Roth, Friedrich; Verhaegen, Michel

    2003-09-01

    This paper presents a novel deconvolution algorithm designed to estimate the impulse response of buried objects based on ground penetrating radar (GPR) signals. The impulse response is a rich source of information about the buried object and therefore very useful for intelligent signal processing of GPR data. For example, it can be used in a target classification scheme to reduce the false alarm rate in demining operations. Estimating the target impulse response from the incident and scattered radar signals is a basic deconvolution problem. However, noise sensitivity and ground dispersion prevent the use of simple deconvolution methods like linear least squares deconvolution. Instead, a new deconvolution algorithm has been developed that computes estimates adhering to a physical impulse response model and that can be characterized by a limited number of parameters. It is shown that the new algorithm is robust with respect to noise and that it can deal with ground dispersion. The general performance of the algorithm has been tested on data generated by finite-difference time-domain (FDTD) simulations. The results demonstrate that the algorithm can distinguish between different dielectric and metal targets, making it very suitable for use in a classification scheme. Moreover, since the estimated impulse responses have physical meaning they can be related to target characteristics such as size and material properties. A direct application of this is the estimation of the permittivity of a dielectric target from its impulse response and that of a calibration target.

  15. Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses

    PubMed Central

    van Oosten-Hawle, Patricija; Morimoto, Richard I.

    2014-01-01

    The ability of each cell within a metazoan to adapt to and survive environmental and physiological stress requires cellular stress-response mechanisms, such as the heat shock response (HSR). Recent advances reveal that cellular proteostasis and stress responses in metazoans are regulated by multiple layers of intercellular communication. This ensures that an imbalance of proteostasis that occurs within any single tissue ‘at risk’ is protected by a compensatory activation of a stress response in adjacent tissues that confers a community protective response. While each cell expresses the machinery for heat shock (HS) gene expression, the HSR is regulated cell non-autonomously in multicellular organisms, by neuronal signaling to the somatic tissues, and by transcellular chaperone signaling between somatic tissues and from somatic tissues to neurons. These cell non-autonomous processes ensure that the organismal HSR is orchestrated across multiple tissues and that transmission of stress signals between tissues can also override the neuronal control to reset cell- and tissue-specific proteostasis. Here, we discuss emerging concepts and insights into the complex cell non-autonomous mechanisms that control stress responses in metazoans and highlight the importance of intercellular communication for proteostasis maintenance in multicellular organisms. PMID:24353212

  16. Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling

    PubMed Central

    Seth, Chandan; Ruiz i Altaba, Ariel

    2016-01-01

    Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti-metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective in inhibiting tumor

  17. JAK/STAT signaling in Drosophila muscles controls the cellular immune response against parasitoid infection.

    PubMed

    Yang, Hairu; Kronhamn, Jesper; Ekström, Jens-Ola; Korkut, Gül Gizem; Hultmark, Dan

    2015-12-01

    The role of JAK/STAT signaling in the cellular immune response of Drosophila is not well understood. Here, we show that parasitoid wasp infection activates JAK/STAT signaling in somatic muscles of the Drosophila larva, triggered by secretion of the cytokines Upd2 and Upd3 from circulating hemocytes. Deletion of upd2 or upd3, but not the related os (upd1) gene, reduced the cellular immune response, and suppression of the JAK/STAT pathway in muscle cells reduced the encapsulation of wasp eggs and the number of circulating lamellocyte effector cells. These results suggest that JAK/STAT signaling in muscles participates in a systemic immune defense against wasp infection.

  18. Unique Responsiveness of Angiosperm Stomata to Elevated CO2 Explained by Calcium Signalling

    PubMed Central

    Brodribb, Timothy J.; McAdam, Scott A. M.

    2013-01-01

    Angiosperm and conifer tree species respond differently when exposed to elevated CO2, with angiosperms found to dynamically reduce water loss while conifers appear insensitive. Such distinct responses are likely to affect competition between these tree groups as atmospheric CO2 concentration rises. Seeking the mechanism behind this globally important phenomenon we targeted the Ca2+-dependent signalling pathway, a mediator of stomatal closure in response to elevated CO2, as a possible explanation for the differentiation of stomatal behaviours. Sampling across the diversity of vascular plants including lycophytes, ferns, gymnosperms and angiosperms we show that only angiosperms possess the stomatal behaviour and prerequisite genetic coding, linked to Ca2+-dependent stomatal signalling. We conclude that the evolution of Ca2+-dependent stomatal signalling gives angiosperms adaptive benefits in terms of highly efficient water use, but that stomatal sensitivity to high CO2 may penalise angiosperm productivity relative to other plant groups in the current era of soaring atmospheric CO2. PMID:24278470

  19. Photodynamic therapy-induced angiogenic signaling: consequences and solutions to improve therapeutic response

    PubMed Central

    Gallagher-Colombo, Shannon M.; Maas, Amanda L.; Yuan, Min; Busch, Theresa M.

    2015-01-01

    Photodynamic therapy (PDT) can be a highly effective treatment for diseases ranging from actinic keratosis to cancer. While use of this therapy shows great promise in preclinical and clinical studies, understanding the molecular consequences of PDT is critical to designing better treatment protocols. A number of publications have documented alteration in angiogenic factors and growth factor receptors following PDT, which could abrogate treatment effect by inducing angiogenesis and re-establishment of the tumor vasculature. In response to these findings, work over the past decade has examined the efficacy of combining PDT with molecular targeting drugs, such as anti-angiogenic compounds, in an effort to combat these PDT-induced molecular changes. These combinatorial approaches increase rates of apoptosis, impair pro-tumorigenic signaling, and enhance tumor response. This report will examine the current understanding of PDT-induced angiogenic signaling and address molecular-based approaches to abrogate this signaling or its consequences thereby enhancing PDT efficacy. PMID:26109742

  20. Correction of complex nonlinear signal response from a pixel array detector

    SciTech Connect

    van Driel, Tim Brandt; Herrmann, Sven; Carini, Gabriella; Nielsen, Martin Meedom; Lemke, Henrik Till

    2015-04-22

    The pulsed free-electron laser light sources represent a new challenge to photon area detectors due to the intrinsic spontaneous X-ray photon generation process that makes single-pulse detection necessary. Intensity fluctuations up to 100% between individual pulses lead to high linearity requirements in order to distinguish small signal changes. In real detectors, signal distortions as a function of the intensity distribution on the entire detector can occur. Here a robust method to correct this nonlinear response in an area detector is presented for the case of exposures to similar signals. The method is tested for the case of diffuse scattering from liquids where relevant sub-1% signal changes appear on the same order as artifacts induced by the detector electronics.

  1. Illuminating Cell Signaling with Near-Infrared Light-Responsive Nanomaterials

    PubMed Central

    Li, Zhanjun; Ma, Guolin; Zhou, Yubin; Han, Gang

    2016-01-01

    The regulation of cellular signaling in vivo has been a challenging task owing to the lack of effective methods for tunable control of the amplitude, location, and duration of cell-signaling events at a deep-tissue level. In this issue of ACS Nano, an intriguing paper by Ambrosone et al. demonstrates that deep-tissue-penetrating near-infrared (NIR) light can be used to control the Wnt/β-catenin-signaling pathway in a single-cell organism (Hydra) by utilizing microcapsules that contain plasmonic gold nanoparticles. In parallel, in recent work, we proposed upconversion nanoparticles (UCNPs) as NIR-light-activatable “wireless” optogenetic tools, and we showed their ability to modulate cell signaling pathways in both mammalian cells and mice. We believe that these interesting NIR-light-responsive nanotechnologies will open new avenues for both basic research and clinical applications. PMID:27077481

  2. Correction of complex nonlinear signal response from a pixel array detector

    PubMed Central

    van Driel, Tim Brandt; Herrmann, Sven; Carini, Gabriella; Nielsen, Martin Meedom; Lemke, Henrik Till

    2015-01-01

    The pulsed free-electron laser light sources represent a new challenge to photon area detectors due to the intrinsic spontaneous X-ray photon generation process that makes single-pulse detection necessary. Intensity fluctuations up to 100% between individual pulses lead to high linearity requirements in order to distinguish small signal changes. In real detectors, signal distortions as a function of the intensity distribution on the entire detector can occur. Here a robust method to correct this nonlinear response in an area detector is presented for the case of exposures to similar signals. The method is tested for the case of diffuse scattering from liquids where relevant sub-1% signal changes appear on the same order as artifacts induced by the detector electronics. PMID:25931072

  3. Female Iberian wall lizards prefer male scents that signal a better cell-mediated immune response

    PubMed Central

    López, Pilar; Martín, José

    2005-01-01

    In spite of the importance of chemoreception in sexual selection of lizards, only a few studies have examined the composition of chemical signals, and it is unknown whether and how chemicals provide honest information. Chemical signals might be honest if there were a trade-off between sexual advertisement and the immune system. Here, we show that proportions of cholesta-5,7-dien-3-ol in femoral secretions of male Iberian wall lizards (Podarcis hispanica) were related to their T-cell-mediated immune response. Thus, only males with a good immune system may allocate higher amounts of this chemical to signalling. Furthermore, females selected scents of males with higher proportions of cholesta-5,7-dien-3-ol and lower proportions of cholesterol. Thus, females might base their mate choice on the males' quality as indicated by the composition of their chemical signals. PMID:17148218

  4. Very long chain fatty acid and lipid signaling in the response of plants to pathogens

    PubMed Central

    Raffaele, Sylvain; Leger, Amandine

    2009-01-01

    Recent findings indicate that lipid signaling is essential for plant resistance to pathogens. Besides oxylipins and unsaturated fatty acids known to play important signaling functions during plant-pathogen interactions, the very long chain fatty acid (VLCFA) biosynthesis pathway has been recently associated to plant defense through different aspects. VLCFAs are indeed required for the biosynthesis of the plant cuticle and the generation of sphingolipids. Elucidation of the roles of these lipids in biotic stress responses is the result of the use of genetic approaches together with the identification of the genes/proteins involved in their biosynthesis. This review focuses on recent observations which revealed the complex function of the cuticle and cuticle-derived signals, and the key role of sphingolipids as bioactive molecules involved in signal transduction and cell death regulation during plant-pathogen interactions. PMID:19649180

  5. Correction of complex nonlinear signal response from a pixel array detector

    DOE PAGES

    van Driel, Tim Brandt; Herrmann, Sven; Carini, Gabriella; Nielsen, Martin Meedom; Lemke, Henrik Till

    2015-04-22

    The pulsed free-electron laser light sources represent a new challenge to photon area detectors due to the intrinsic spontaneous X-ray photon generation process that makes single-pulse detection necessary. Intensity fluctuations up to 100% between individual pulses lead to high linearity requirements in order to distinguish small signal changes. In real detectors, signal distortions as a function of the intensity distribution on the entire detector can occur. Here a robust method to correct this nonlinear response in an area detector is presented for the case of exposures to similar signals. The method is tested for the case of diffuse scattering frommore » liquids where relevant sub-1% signal changes appear on the same order as artifacts induced by the detector electronics.« less

  6. Arm-in-Arm Response Regulator Dimers Promote Intermolecular Signal Transduction

    PubMed Central

    Baker, Anna W.; Satyshur, Kenneth A.; Moreno Morales, Neydis

    2016-01-01

    ABSTRACT Bacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis. RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRRmon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems. IMPORTANCE BphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these

  7. Calcium signaling in response to fluid flow by chondrocytes in 3D alginate culture.

    PubMed

    Degala, Satish; Williams, Rebecca; Zipfel, Warren; Bonassar, Lawrence J

    2012-05-01

    Quantifying the effects of mechanical loading on the metabolic response of chondrocytes is difficult due to complicated structure of cartilage ECM and the coupled nature of the mechanical stimuli presented to the cells. In this study we describe the effects of fluid flow, particularly hydrostatic pressure and wall shear stress, on the Ca(2+) signaling response of bovine articular chondrocytes in 3D culture. Using well-established alginate hydrogel system to maintain spherical chondrocyte morphology, we altered solid volume fraction to change scaffold mechanics. Fluid velocities in the bulk of the scaffolds were directly measured via an optical technique and scaffold permeability and aggregate modulus was characterized to quantify the mechanical stimuli presented to cells. Ca(2+) signaling response to direct perfusion of chondrocyte-seeded scaffolds increased monotonically with flow rate and was found more directly dependent on fluid velocity rather than shear stress or hydrostatic pressure. Chondrocytes in alginate scaffolds responded to fluid flow at velocities and shear stresses 2-3 orders of magnitude lower than seen in previous monolayer studies. Our data suggest that flow-induced Ca(2+) signaling response of chondrocytes in alginate culture may be due to mechanical signaling pathways, which is influenced by the 3D nature of cell shape.

  8. Reinforcement Delay Fading during Differential Reinforcement of Communication: The Effects of Signals on Response Maintenance

    ERIC Educational Resources Information Center

    Kelley, Michael E.; Lerman, Dorothea C.; Fisher, Wayne W.; Roane, Henry S.; Zangrillo, Amanda N.

    2011-01-01

    Signals during delays to reinforcement may lessen reductions in responding that typically occur when there is a delay between a response and its reinforcer. Sparse applied research has been devoted to understanding the conditions under which responding may be maintained when delays to reinforcement are introduced. We evaluated the extent to which…

  9. Development of the Poplar-Laccaria bicolor Ectomycorrhiza Modifies Root Auxin Metabolism, Signaling, and Response.

    PubMed

    Vayssières, Alice; Pěnčík, Ales; Felten, Judith; Kohler, Annegret; Ljung, Karin; Martin, Francis; Legué, Valérie

    2015-09-01

    Root systems of host trees are known to establish ectomycorrhizae (ECM) interactions with rhizospheric fungi. This mutualistic association leads to dramatic developmental modifications in root architecture, with the formation of numerous short and swollen lateral roots ensheathed by a fungal mantle. Knowing that auxin plays a crucial role in root development, we investigated how auxin metabolism, signaling, and response are affected in poplar (Populus spp.)-Laccaria bicolor ECM roots. The plant-fungus interaction leads to the arrest of lateral root growth with simultaneous attenuation of the synthetic auxin response element DR5. Measurement of auxin-related metabolites in the free-living partners revealed that the mycelium of L. bicolor produces high concentrations of the auxin indole-3-acetic acid (IAA). Metabolic profiling showed an accumulation of IAA and changes in the indol-3-pyruvic acid-dependent IAA biosynthesis and IAA conjugation and degradation pathways during ECM formation. The global analysis of auxin response gene expression and the regulation of AUXIN SIGNALING F-BOX PROTEIN5, AUXIN/IAA, and AUXIN RESPONSE FACTOR expression in ECM roots suggested that symbiosis-dependent auxin signaling is activated during the colonization by L. bicolor. Taking all this evidence into account, we propose a model in which auxin signaling plays a crucial role in the modification of root growth during ECM formation.

  10. Development of the Poplar-Laccaria bicolor Ectomycorrhiza Modifies Root Auxin Metabolism, Signaling, and Response.

    PubMed

    Vayssières, Alice; Pěnčík, Ales; Felten, Judith; Kohler, Annegret; Ljung, Karin; Martin, Francis; Legué, Valérie

    2015-09-01

    Root systems of host trees are known to establish ectomycorrhizae (ECM) interactions with rhizospheric fungi. This mutualistic association leads to dramatic developmental modifications in root architecture, with the formation of numerous short and swollen lateral roots ensheathed by a fungal mantle. Knowing that auxin plays a crucial role in root development, we investigated how auxin metabolism, signaling, and response are affected in poplar (Populus spp.)-Laccaria bicolor ECM roots. The plant-fungus interaction leads to the arrest of lateral root growth with simultaneous attenuation of the synthetic auxin response element DR5. Measurement of auxin-related metabolites in the free-living partners revealed that the mycelium of L. bicolor produces high concentrations of the auxin indole-3-acetic acid (IAA). Metabolic profiling showed an accumulation of IAA and changes in the indol-3-pyruvic acid-dependent IAA biosynthesis and IAA conjugation and degradation pathways during ECM formation. The global analysis of auxin response gene expression and the regulation of AUXIN SIGNALING F-BOX PROTEIN5, AUXIN/IAA, and AUXIN RESPONSE FACTOR expression in ECM roots suggested that symbiosis-dependent auxin signaling is activated during the colonization by L. bicolor. Taking all this evidence into account, we propose a model in which auxin signaling plays a crucial role in the modification of root growth during ECM formation. PMID:26084921

  11. The Dendritic Cell Response to Classic, Emerging, and Homeostatic Danger Signals. Implications for Autoimmunity

    PubMed Central

    Gallo, Paul M.; Gallucci, Stefania

    2013-01-01

    Dendritic cells (DCs) initiate and control immune responses, participate in the maintenance of immunological tolerance and are pivotal players in the pathogenesis of autoimmunity. In patients with autoimmune disease and in experimental animal models of autoimmunity, DCs show abnormalities in both numbers and activation state, expressing immunogenic levels of costimulatory molecules and pro-inflammatory cytokines. Exogenous and endogenous danger signals activate DCs to stimulate the immune response. Classic endogenous danger signals are released, activated, or secreted by host cells and tissues experiencing stress, damage, and non-physiologic cell death; and are therefore referred to as damage-associated molecular patterns (DAMPs). Some DAMPs are released from cells, where they are normally sequestered, during necrosis (e.g., heat shock proteins, uric acid, ATP, HMGB1, mitochondria-derived molecules). Others are actively secreted, like Type I Interferons. Here we discuss important DAMPs in the context of autoimmunity. For some, there is a clear pathogenic link (e.g., nucleic acids and lupus). For others, there is less evidence. Additionally, we explore emerging danger signals. These include inorganic materials and man-made technologies (e.g., nanomaterials) developed as novel therapeutic approaches. Some nanomaterials can activate DCs and may trigger unintended inflammatory responses. Finally, we will review “homeostatic danger signals,” danger signals that do not derive directly from pathogens or dying cells but are associated with perturbations of tissue/cell homeostasis and may signal pathological stress. These signals, like acidosis, hypoxia, and changes in osmolarity, also play a role in inflammation and autoimmunity. PMID:23772226

  12. The Yeast Sks1p Kinase Signaling Network Regulates Pseudohyphal Growth and Glucose Response

    PubMed Central

    Johnson, Cole; Kweon, Hye Kyong; Sheidy, Daniel; Shively, Christian A.; Mellacheruvu, Dattatreya; Nesvizhskii, Alexey I.; Andrews, Philip C.; Kumar, Anuj

    2014-01-01

    The yeast Saccharomyces cerevisiae undergoes a dramatic growth transition from its unicellular form to a filamentous state, marked by the formation of pseudohyphal filaments of elongated and connected cells. Yeast pseudohyphal growth is regulated by signaling pathways responsive to reductions in the availability of nitrogen and glucose, but the molecular link between pseudohyphal filamentation and glucose signaling is not fully understood. Here, we identify the glucose-responsive Sks1p kinase as a signaling protein required for pseudohyphal growth induced by nitrogen limitation and coupled nitrogen/glucose limitation. To identify the Sks1p signaling network, we applied mass spectrometry-based quantitative phosphoproteomics, profiling over 900 phosphosites for phosphorylation changes dependent upon Sks1p kinase activity. From this analysis, we report a set of novel phosphorylation sites and highlight Sks1p-dependent phosphorylation in Bud6p, Itr1p, Lrg1p, Npr3p, and Pda1p. In particular, we analyzed the Y309 and S313 phosphosites in the pyruvate dehydrogenase subunit Pda1p; these residues are required for pseudohyphal growth, and Y309A mutants exhibit phenotypes indicative of impaired aerobic respiration and decreased mitochondrial number. Epistasis studies place SKS1 downstream of the G-protein coupled receptor GPR1 and the G-protein RAS2 but upstream of or at the level of cAMP-dependent PKA. The pseudohyphal growth and glucose signaling transcription factors Flo8p, Mss11p, and Rgt1p are required to achieve wild-type SKS1 transcript levels. SKS1 is conserved, and deletion of the SKS1 ortholog SHA3 in the pathogenic fungus Candida albicans results in abnormal colony morphology. Collectively, these results identify Sks1p as an important regulator of filamentation and glucose signaling, with additional relevance towards understanding stress-responsive signaling in C. albicans. PMID:24603354

  13. Regulation of Arabidopsis defense responses against Spodoptera littoralis by CPK-mediated calcium signaling

    PubMed Central

    2010-01-01

    Background Plant Ca2+ signals are involved in a wide array of intracellular signaling pathways after pest invasion. Ca2+-binding sensory proteins such as Ca2+-dependent protein kinases (CPKs) have been predicted to mediate the signaling following Ca2+ influx after insect herbivory. However, until now this prediction was not testable. Results To investigate the roles CPKs play in a herbivore response-signaling pathway, we screened the characteristics of Arabidopsis CPK mutants damaged by a feeding generalist herbivore, Spodoptera littoralis. Following insect attack, the cpk3 and cpk13 mutants showed lower transcript levels of plant defensin gene PDF1.2 compared to wild-type plants. The CPK cascade was not directly linked to the herbivory-induced signaling pathways that were mediated by defense-related phytohormones such as jasmonic acid and ethylene. CPK3 was also suggested to be involved in a negative feedback regulation of the cytosolic Ca2+ levels after herbivory and wounding damage. In vitro kinase assays of CPK3 protein with a suite of substrates demonstrated that the protein phosphorylates transcription factors (including ERF1, HsfB2a and CZF1/ZFAR1) in the presence of Ca2+. CPK13 strongly phosphorylated only HsfB2a, irrespective of the presence of Ca2+. Furthermore, in vivo agroinfiltration assays showed that CPK3-or CPK13-derived phosphorylation of a heat shock factor (HsfB2a) promotes PDF1.2 transcriptional activation in the defense response. Conclusions These results reveal the involvement of two Arabidopsis CPKs (CPK3 and CPK13) in the herbivory-induced signaling network via HsfB2a-mediated regulation of the defense-related transcriptional machinery. This cascade is not involved in the phytohormone-related signaling pathways, but rather directly impacts transcription factors for defense responses. PMID:20504319

  14. Luminance and chromatic signals interact differently with melanopsin activation to control the pupil light response

    PubMed Central

    Barrionuevo, Pablo A.; Cao, Dingcai

    2016-01-01

    Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin. These cells receive afferent inputs from rods and cones, which provide inputs to the postreceptoral visual pathways. It is unknown, however, how melanopsin activation is integrated with postreceptoral signals to control the pupillary light reflex. This study reports human flicker pupillary responses measured using stimuli generated with a five-primary photostimulator that selectively modulated melanopsin, rod, S-, M-, and L-cone excitations in isolation, or in combination to produce postreceptoral signals. We first analyzed the light adaptation behavior of melanopsin activation and rod and cones signals. Second, we determined how melanopsin is integrated with postreceptoral signals by testing with cone luminance, chromatic blue-yellow, and chromatic red-green stimuli that were processed by magnocellular (MC), koniocellular (KC), and parvocellular (PC) pathways, respectively. A combined rod and melanopsin response was also measured. The relative phase of the postreceptoral signals was varied with respect to the melanopsin phase. The results showed that light adaptation behavior for all conditions was weaker than typical Weber adaptation. Melanopsin activation combined linearly with luminance, S-cone, and rod inputs, suggesting the locus of integration with MC and KC signals was retinal. The melanopsin contribution to phasic pupil responses was lower than luminance contributions, but much higher than S-cone contributions. Chromatic red-green modulation interacted with melanopsin activation nonlinearly as described by a “winner-takes-all” process, suggesting the integration with PC signals might be mediated by a postretinal site. PMID:27690169

  15. Phenological responses to climate change do not exhibit phylogenetic signal in a subalpine plant community.

    PubMed

    CaraDonna, Paul J; Inouye, David W

    2015-02-01

    Phylogenetic relationships may underlie species-specific phenological sensitivities to abiotic variation and may help to predict these responses to climate change. Although shared evolutionary history may mediate both phenology and phenological sensitivity to abiotic variation, few studies have explicitly investigated whether this is the case. We explore phylogenetic signal in flowering phenology and in phenological sensitivity to temperature and snowmelt using a 39-year record of flowering from the Colorado Rocky Mountains, USA that includes dates of first, peak, and last flowering, and flowering duration for 60 plant species in a subalpine plant community. Consistent with other studies, we found evidence in support of phylogenetic signal in first flowering date. However, the strength and significance of that signal were inconsistent across other measures of flowering in this plant community: peak flowering date exhibited the strongest phylogenetic signal, followed by first flowering date; last flowering date and duration of flowering exhibited patterns indistinguishable from random trait evolution. In contrast to first and peak flowering date, phenological sensitivities of all flowering measures to temperature and snowmelt did not exhibit a phylogenetic signal. These findings show that within ecological communities, phylogenetic signal in phenology does not necessarily imply phylogenetic signal in phenological sensitivities to abiotic variation.

  16. Phenological responses to climate change do not exhibit phylogenetic signal in a subalpine plant community.

    PubMed

    CaraDonna, Paul J; Inouye, David W

    2015-02-01

    Phylogenetic relationships may underlie species-specific phenological sensitivities to abiotic variation and may help to predict these responses to climate change. Although shared evolutionary history may mediate both phenology and phenological sensitivity to abiotic variation, few studies have explicitly investigated whether this is the case. We explore phylogenetic signal in flowering phenology and in phenological sensitivity to temperature and snowmelt using a 39-year record of flowering from the Colorado Rocky Mountains, USA that includes dates of first, peak, and last flowering, and flowering duration for 60 plant species in a subalpine plant community. Consistent with other studies, we found evidence in support of phylogenetic signal in first flowering date. However, the strength and significance of that signal were inconsistent across other measures of flowering in this plant community: peak flowering date exhibited the strongest phylogenetic signal, followed by first flowering date; last flowering date and duration of flowering exhibited patterns indistinguishable from random trait evolution. In contrast to first and peak flowering date, phenological sensitivities of all flowering measures to temperature and snowmelt did not exhibit a phylogenetic signal. These findings show that within ecological communities, phylogenetic signal in phenology does not necessarily imply phylogenetic signal in phenological sensitivities to abiotic variation. PMID:26240857

  17. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling

    PubMed Central

    Masyuk, Anatoliy I.; Huang, Bing Q.; Radtke, Brynn N.; Gajdos, Gabriella B.; Splinter, Patrick L.; Masyuk, Tatyana V.; Gradilone, Sergio A.

    2013-01-01

    TGR5, the G protein-coupled bile acid receptor that transmits bile acid signaling into a cell functional response via the intracellular cAMP signaling pathway, is expressed in human and rodent cholangiocytes. However, detailed information on the localization and function of cholangiocyte TGR5 is limited. We demonstrated that in human (H69 cells) and rat cholangiocytes, TGR5 is localized to multiple, diverse subcellular compartments, with its strongest expression on the apical plasma, ciliary, and nuclear membranes. To evaluate the relationship between ciliary TGR5 and the cholangiocyte functional response to bile acid signaling, we used a model of ciliated and nonciliated H69 cells and demonstrated that TGR5 agonists induce opposite changes in cAMP and ERK levels in cells with and without primary cilia. The cAMP level was increased in nonciliated cholangiocytes but decreased in ciliated cells. In contrast, ERK signaling was induced in ciliated cholangiocytes but suppressed in cells without cilia. TGR5 agonists inhibited proliferation of ciliated cholangiocytes but activated proliferation of nonciliated cells. The observed differential effects of TGR5 agonists were associated with the coupling of TGR5 to Gαi protein in ciliated cells and Gαs protein in nonciliated cholangiocytes. The functional responses of nonciliated and ciliated cholangiocytes to TGR5-mediated bile acid signaling may have important pathophysiological significance in cilia-related liver disorders (i.e., cholangiociliopathies), such as polycystic liver disease. In summary, TGR5 is expressed on diverse cholangiocyte compartments, including a primary cilium, and its ciliary localization determines the cholangiocyte functional response to bile acid signaling. PMID:23578785

  18. Analysis of Responsivity and Signal-to-Noise Ratio in PEPT

    NASA Astrophysics Data System (ADS)

    Zhou, Quan; Guo, Shu-Xu; Li, Zhao-Han; Song, Jing-Yi; Chang, Yu-Chun

    2012-11-01

    We analyze the responsivity and signal-to-noise ratio (SNR) of a punchthrough enhanced phototransistor (PEPT). Measurement results show that the PEPT exhibits a good response to light over a wide range of intensity. Because the responsivity is still as high as 106 A/W when the bias voltage is as low as 0.2 V, the device is suitable for ultra-low voltage applications. Meanwhile, with 1-10 μA bias current, the PEPT shows the best performance for the responsivity and SNR. When incident light is as low as 3.8 × 10-8 W/cm2, the responsivity reaches approximately 108 A/W. The super high responsivity of PEPTs makes it possible to fabricate small sized photodetector.

  19. Single-Cell E. coli Response to an Instantaneously Applied Chemotactic Signal

    PubMed Central

    Sagawa, Takashi; Kikuchi, Yu; Inoue, Yuichi; Takahashi, Hiroto; Muraoka, Takahiro; Kinbara, Kazushi; Ishijima, Akihiko; Fukuoka, Hajime

    2014-01-01

    In response to an attractant or repellant, an Escherichia coli cell controls the rotational direction of its flagellar motor by a chemotaxis system. When an E. coli cell senses an attractant, a reduction in the intracellular concentration of a chemotaxis protein, phosphorylated CheY (CheY-P), induces counterclockwise (CCW) rotation of the flagellar motor, and this cellular response is thought to occur in several hundred milliseconds. Here, to measure the signaling process occurring inside a single E. coli cell, including the recognition of an attractant by a receptor cluster, the inactivation of histidine kinase CheA, and the diffusion of CheY and CheY-P molecules, we applied a serine stimulus by instantaneous photorelease from a caged compound and examined the cellular response at a temporal resolution of several hundred microseconds. We quantified the clockwise (CW) and CCW durations immediately after the photorelease of serine as the response time and the duration of the response, respectively. The results showed that the response time depended on the distance between the receptor and motor, indicating that the decreased CheY-P concentration induced by serine propagates through the cytoplasm from the receptor-kinase cluster toward the motor with a timing that is explained by the diffusion of CheY and CheY-P molecules. The response time included 240 ms for enzymatic reactions in addition to the time required for diffusion of the signaling molecule. The measured response time and duration of the response also revealed that the E. coli cell senses a similar serine concentration regardless of whether the serine concentration is increasing or decreasing. These detailed quantitative findings increase our understanding of the signal transduction process that occurs inside cells during bacterial chemotaxis. PMID:25099812

  20. Dose-Response Analysis of Chemotactic Signaling Response in Salmonella typhimurium LT2 upon Exposure to Cysteine / Cystine Redox Pair

    PubMed Central

    2016-01-01

    The chemotaxis system enables motile bacteria to search for an optimum level of environmental factors. Salmonella typhimurium senses the amino acid cysteine as an attractant and its oxidized dimeric form, cystine, as a repellent. We investigated the dose-response dependence of changes in chemotactic signaling activity upon exposure to cysteine and cystine of S. typhimurium LT2 using in vivo fluorescence resonance energy transfer (FRET) measurements. The dose-response curve of the attractant response to cysteine had a sigmoidal shape, typical for receptor-ligand interactions. However, in a knockout strain of the chemoreceptor genes tsr and tar, we detected a repellent response to cysteine solutions, scaling linearly with the logarithm of the cysteine concentration. Interestingly, the magnitude of the repellent response to cystine also showed linear dependence to the logarithm of the cystine concentration. This linear dependence was observed over more than four orders of magnitude, where detection started at nanomolar concentrations. Notably, low concentrations of another oxidized compound, benzoquinone, triggered similar responses. In contrast to S. typhimurium 14028, where no response to cystine was observed in a knockout strain of chemoreceptor genes mcpB and mcpC, here we showed that McpB / McpC-independent responses to cystine existed in the strain S. typhimurium LT2 even at nanomolar concentrations. Additionally, knocking out mcpB and mcpC did not affect the linear dose-response dependence, whereas enhanced responses were only observed to solutions that where not pH neutral (>100 μM cystine) in the case of McpC overexpression. We discuss that the linear dependence of the response on the logarithm of cystine concentrations could be a result of a McpB / C-independent redox-sensing pathway that exists in S. typhimurium LT2. We supported this hypothesis with experiments with defined cysteine / cystine mixed solutions, where a transition from repellent to

  1. Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis.

    PubMed

    Corrado, Mauro; Mariotti, Francesca R; Trapani, Laura; Taraborrelli, Lucia; Nazio, Francesca; Cianfanelli, Valentina; Soriano, Maria Eugenia; Schrepfer, Emilie; Cecconi, Francesco; Scorrano, Luca; Campello, Silvia

    2016-08-15

    Mitochondrial dynamics and functionality are linked to the autophagic degradative pathway under several stress conditions. However, the interplay between mitochondria and autophagy upon cell death signalling remains unclear. The T-cell receptor pathway signals the so-called activation-induced cell death (AICD) essential for immune tolerance regulation. Here, we show that this apoptotic pathway requires the inhibition of macroautophagy. Protein kinase-A activation downstream of T-cell receptor signalling inhibits macroautophagy upon AICD induction. This leads to the accumulation of damaged mitochondria, which are fragmented, display remodelled cristae and release cytochrome c, thereby driving apoptosis. Autophagy-forced reactivation that clears the Parkin-decorated mitochondria is as effective in inhibiting apoptosis as genetic interference with cristae remodelling and cytochrome c release. Thus, upon AICD induction regulation of macroautophagy, rather than selective mitophagy, ensures apoptotic progression. PMID:27390127

  2. The complex logic of stringent response regulation in Caulobacter crescentus: starvation signalling in an oligotrophic environment.

    PubMed

    Boutte, Cara C; Crosson, Sean

    2011-05-01

    Bacteria rapidly adapt to nutritional changes via the stringent response, which entails starvation-induced synthesis of the small molecule, ppGpp, by RelA/SpoT homologue (Rsh) enzymes. Binding of ppGpp to RNA polymerase modulates the transcription of hundreds of genes and remodels the physiology of the cell. Studies of the stringent response have primarily focused on copiotrophic bacteria such as Escherichia coli; little is known about how stringent signalling is regulated in species that live in consistently nutrient-limited (i.e. oligotrophic) environments. Here we define the input logic and transcriptional output of the stringent response in the oligotroph, Caulobacter crescentus. The sole Rsh protein, SpoT(CC), binds to and is regulated by the ribosome, and exhibits AND-type control logic in which amino acid starvation is a necessary but insufficient signal for activation of ppGpp synthesis. While both glucose and ammonium starvation upregulate the synthesis of ppGpp, SpoT(CC) detects these starvation signals by two independent mechanisms. Although the logic of stringent response control in C. crescentus differs from E. coli, the global transcriptional effects of elevated ppGpp are similar, with the exception of 16S rRNA transcription, which is controlled independently of spoT(CC). This study highlights how the regulatory logic controlling the stringent response may be adapted to the nutritional niche of a bacterial species.

  3. Response of autaptic Hodgkin-Huxley neuron with noise to subthreshold sinusoidal signals

    NASA Astrophysics Data System (ADS)

    Wang, Hengtong; Chen, Yong

    2016-11-01

    In this work, we investigated the response of a stochastic Hodgkin-Huxley (HH) neuron with an autapse to subthreshold sinusoidal signals. It is found that the autapse not only adjusts the stochastic responses, but also improves the detection of subthreshold signals. In the case of weak noise, the autapse facilitates the response of neuron to the subthreshold sinusoidal signals with a small parameter region in tdelay- ω space. The increased noise intensity enlarges this parameter region and increases the corresponding response frequency in such range. As the autaptic intensity increases, however, this parameter region shrunks. We also observed that there is an optimal range of the delay time of autapse, within which the stochastic HH neuron fires action potentials with high frequency. The corresponding response spike train for the optimal delay time is nearly a regular sequence with the interspike intervals approximated to the delay time. The current results reveal a novel resonance phenomenon facilitated by autapse, named autaptic delay-induced coherence resonance.

  4. Behavioral responses of humpback whales (Megaptera novaeangliae) to full-scale ATOC signals.

    PubMed

    Frankel, A S; Clark, C W

    2000-10-01

    Loud (195 dB re 1 microPa at 1 m) 75-Hz signals were broadcast with an ATOC projector to measure ocean temperature. Respiratory and movement behaviors of humpback whales off North Kauai, Hawaii, were examined for potential changes in response to these transmissions and to vessels. Few vessel effects were observed, but there were fewer vessels operating during this study than in previous years. No overt responses to ATOC were observed for received levels of 98-109 dB re 1 microPa. An analysis of covariance, using the no-sound behavioral rate as a covariate to control for interpod variation, found that the distance and time between successive surfacings of humpbacks increased slightly with an increase in estimated received ATOC sound level. These responses are very similar to those observed in response to scaled-amplitude playbacks of ATOC signals [Frankel and Clark, Can. J. Zool. 76, 521-535 (1998)]. These similar results were obtained with different sound projectors, in different years and locations, and at different ranges creating a different sound field. The repeatability of the findings for these two different studies indicates that these effects, while small, are robust. This suggests that at least for the ATOC signal, the received sound level is a good predictor of response. PMID:11051519

  5. Elevated atmospheric CO2 impairs aphid escape responses to predators and conspecific alarm signals.

    PubMed

    Hentley, William T; Vanbergen, Adam J; Hails, Rosemary S; Jones, T Hefin; Johnson, Scott N

    2014-10-01

    Research into the impact of atmospheric change on predator-prey interactions has mainly focused on density dependent responses and trophic linkages. As yet, the chemical ecology underpinning predator-prey interactions has received little attention in environmental change research. Group living animals have evolved behavioral mechanisms to escape predation, including chemical alarm signalling. Chemical alarm signalling between conspecific prey could be susceptible to environmental change if the physiology and behavior of these organisms are affected by changes in dietary quality resulting from environmental change. Using Rubus idaeus plants, we show that elevated concentrations of atmospheric CO2 (eCO2) severely impaired escape responses of the aphid Amphorophora idaei to predation by ladybird larvae (Harmonia axyridis). Escape responses to ladybirds was reduced by >50% after aphids had been reared on plants grown under eCO2. This behavioral response was rapidly induced, occurring within 24 h of being transferred to plants grown at eCO2 and, once induced, persisted even after aphids were transferred to plants grown at ambient CO2. Escape responses were impaired due to reduced sensitivity to aphid alarm pheromone, (E)-β-farnesene, via an undefined plant-mediated mechanism. Aphid abundance often increases under eCO2, however, reduced efficacy of conspecific signalling may increase aphid vulnerability to predation, highlighting the need to study the chemical ecology of predator-prey interactions under environmental change. PMID:25273846

  6. Intramuscular Anabolic Signaling and Endocrine Response Following Resistance Exercise: Implications for Muscle Hypertrophy.

    PubMed

    Gonzalez, Adam M; Hoffman, Jay R; Stout, Jeffrey R; Fukuda, David H; Willoughby, Darryn S

    2016-05-01

    Maintaining skeletal muscle mass and function is critical for disease prevention, mobility and quality of life, and whole-body metabolism. Resistance exercise is known to be a major regulator for promoting muscle protein synthesis and muscle mass accretion. Manipulation of exercise intensity, volume, and rest elicit specific muscular adaptations that can maximize the magnitude of muscle growth. The stimulus of muscle contraction that occurs during differing intensities of resistance exercise results in varying biochemical responses regulating the rate of protein synthesis, known as mechanotransduction. At the cellular level, skeletal muscle adaptation appears to be the result of the cumulative effects of transient changes in gene expression following acute bouts of exercise. Thus, maximizing the resistance exercise-induced anabolic response produces the greatest potential for hypertrophic adaptation with training. The mechanisms involved in converting mechanical signals into the molecular events that control muscle growth are not completely understood; however, skeletal muscle protein synthesis appears to be regulated by the multi-protein phosphorylation cascade, mTORC1 (mammalian/mechanistic target of rapamycin complex 1). The purpose of this review is to examine the physiological response to resistance exercise, with particular emphasis on the endocrine response and intramuscular anabolic signaling through mTORC1. It appears that resistance exercise protocols that maximize muscle fiber recruitment, time-under-tension, and metabolic stress will contribute to maximizing intramuscular anabolic signaling; however, the resistance exercise parameters for maximizing the anabolic response remain unclear.

  7. A Step Response Based Mixed-Signal BIST Approach for Continuous-time Linear Circuits

    NASA Technical Reports Server (NTRS)

    Walker, Alvernon; Lala, P. K.

    2001-01-01

    A new Mixed-Signal Built-in self-test approach that is based upon the step response of a reconfigurable (or multifunction) analog block is presented in this paper. The technique requires the overlapping step response of the Circuit Under Test (CUT) for two circuit configurations. Each configuration can be realized by changing the topology of the CUT or by sampling two CUT nodes with differing step responses. The technique can effectively detect both soft and hard faults and does not require an analog-to-digital converter (ADC) and/or digital-to-analog converter(DAC). It also does not require any precision voltage sources or comparators. This approach does not require any additional analog circuits to realize the test signal generator and sample circuits. The paper is concluded with the application of the proposed approach to a circuit found in the work of Epstein et al and two ITC 97 analog benchmark circuits.

  8. Signals regulating myelination in peripheral nerves and the Schwann cell response to injury

    PubMed Central

    Glenn, Thomas D.; Talbot, William S.

    2013-01-01

    In peripheral nerves, Schwann cells form myelin, which facilitates the rapid conduction of action potentials along axons in the vertebrate nervous system. Myelinating Schwann cells are derived from neural crest progenitors in a step-wise process that is regulated by extracellular signals and transcription factors. In addition to forming the myelin sheath, Schwann cells orchestrate much of the regenerative response that occurs after injury to peripheral nerves. In response to injury, myelinating Schwann cells dedifferentiate into repair cells that are essential for axonal regeneration, and then redifferentiate into myelinating Schwann cells to restore nerve function. Although this remarkable plasticity has long been recognized, many questions remain unanswered regarding the signaling pathways regulating both myelination and the Schwann cell response to injury. PMID:23896313

  9. A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases

    PubMed Central

    Peineau, Stéphane; Nicolas, Céline S; Bortolotto, Zuner A; Bhat, Ratan V; Ryves, W Jonathan; Harwood, Adrian J; Dournaud, Pascal; Fitzjohn, Stephen M; Collingridge, Graham L

    2009-01-01

    Background The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons. Results Using a panel of 23 inhibitors individually loaded into the recorded neurons, we can discount the involvement of at least 57 kinases, including PKA, PKC, CaMKII, p38 MAPK and DYRK1A. However, we have been able to confirm a role for the ser/thr protein kinase, glycogen synthase kinase 3 (GSK-3). Conclusion The present study is the first to investigate the role of 58 ser/thr protein kinases in LTD in the same study. Of these 58 protein kinases, we have found evidence for the involvement of only one, GSK-3, in LTD. PMID:19583853

  10. Structure of the response regulator RPA3017 involved in red-light signaling in Rhodopseudomonas palustris.

    PubMed

    Yang, Xuefei; Zeng, Xiaoli; Moffat, Keith; Yang, Xiaojing

    2015-10-01

    Two-component signal transduction is the major signaling mechanism that enables bacteria to survive and thrive in complex environmental conditions. The photosynthetic bacterium R. palustris employs two tandem bacteriophytochromes, RpBphP2 and RpBphP3, to perceive red-light signals that regulate the synthesis of light-harvesting complexes under low-light conditions. Both RpBphP2 and RpBphP3 are photosensory histidine kinases coupled to the same response regulator RPA3017. Together, they constitute a two-component system that converts a red-light signal into a biological signal. In this work, the crystal structure of RPA3017 in the unphosphorylated form at 1.9 Å resolution is presented. This structure reveals a tightly associated dimer arrangement that is conserved among phytochrome-related response regulators. The conserved active-site architecture provides structural insight into the phosphotransfer reaction between RpBphP2/RpBphP3 and RPA3017. Based on structural comparisons and homology modeling, how specific recognition between RpBphP2/RpBphP3 and RPA3017 is achieved at the molecular level is further explored.

  11. Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.

    PubMed

    Grieder, Taryn E; Sellings, Laurie H; Vargas-Perez, Hector; Ting-A-Kee, Ryan; Siu, Eric C; Tyndale, Rachel F; van der Kooy, Derek

    2010-03-01

    The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals.

  12. Structure of the response regulator RPA3017 involved in red-light signaling in Rhodopseudomonas palustris

    PubMed Central

    Yang, Xuefei; Zeng, Xiaoli; Moffat, Keith; Yang, Xiaojing

    2015-01-01

    Two-component signal transduction is the major signaling mechanism that enables bacteria to survive and thrive in complex environmental conditions. The photosynthetic bacterium R. palustris employs two tandem bacteriophytochromes, RpBphP2 and RpBphP3, to perceive red-light signals that regulate the synthesis of light-harvesting complexes under low-light conditions. Both RpBphP2 and RpBphP3 are photosensory histidine kinases coupled to the same response regulator RPA3017. Together, they constitute a two-component system that converts a red-light signal into a biological signal. In this work, the crystal structure of RPA3017 in the unphosphorylated form at 1.9 Å resolution is presented. This structure reveals a tightly associated dimer arrangement that is conserved among phytochrome-related response regulators. The conserved active-site architecture provides structural insight into the phosphotransfer reaction between RpBphP2/RpBphP3 and RPA3017. Based on structural comparisons and homology modeling, how specific recognition between RpBphP2/RpBphP3 and RPA3017 is achieved at the molecular level is further explored. PMID:26457509

  13. Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.

    PubMed

    Grieder, Taryn E; Sellings, Laurie H; Vargas-Perez, Hector; Ting-A-Kee, Ryan; Siu, Eric C; Tyndale, Rachel F; van der Kooy, Derek

    2010-03-01

    The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. PMID:20032966

  14. Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response.

    PubMed

    Zhang, Lu; Wang, Kui; Lei, Yunlong; Li, Qifu; Nice, Edouard Collins; Huang, Canhua

    2015-12-01

    Redox signaling plays important roles in the regulation of cell death and survival in response to cancer therapy. Autophagy and apoptosis are discrete cellular processes mediated by distinct groups of regulatory and executioner molecules, and both are thought to be cellular responses to various stress conditions including oxidative stress, therefore controlling cell fate. Basic levels of reactive oxygen species (ROS) may function as signals to promote cell proliferation and survival, whereas increase of ROS can induce autophagy and apoptosis by damaging cellular components. Growing evidence in recent years argues for ROS that below detrimental levels acting as intracellular signal transducers that regulate autophagy and apoptosis. ROS-regulated autophagy and apoptosis can cross-talk with each other. However, how redox signaling determines different cell fates by regulating autophagy and apoptosis remains unclear. In this review, we will focus on understanding the delicate molecular mechanism by which autophagy and apoptosis are finely orchestrated by redox signaling and discuss how this understanding can be used to develop strategies for the treatment of cancer.

  15. Augmentation of Antigen Receptor–mediated Responses by Histamine H1 Receptor Signaling

    PubMed Central

    Banu, Yasmin; Watanabe, Takeshi

    1999-01-01

    Histamine is considered one of the important mediators of immediate hypersensitivity and inflammation, and acts via G protein–coupled receptors. Here, we report that histamine may affect antigen receptor–mediated immune responses of T and B cells via a signal(s) from histamine H1 receptors (H1Rs). Histamine exhibited enhancing effects on the in vitro proliferative responses of anti-CD3ε– or anti-IgM–stimulated spleen T and B cells, respectively, at the culture condition that the fetal calf serum was dialyzed before culture and c-kit–positive cells were depleted from the spleen cells. In studies of histamine H1R knockout mice, H1R-deficient T cells had low proliferative responses to anti-CD3ε cross-linking or antigen stimulation in vitro. B cells from H1R-deficient mice were also affected, demonstrating low proliferative responses to B cell receptor cross-linking. Antibody production against trinitrophenyl-Ficoll was reduced in H1R-deficient mice. Other aspects of T and B cell function were normal in the H1R knockout mice. H1R-deficient T and B cells showed normal responses upon stimulation with interleukin (IL)-2, IL-4, CD40 ligand, CD40 ligand plus IL-4, and lipopolysaccharide. Collectively, these results imply that the signal generated by histamine through H1R augments antigen receptor–mediated immune responses, suggesting cross-talk between G protein–coupled receptors and antigen receptor–mediated signaling. PMID:9989982

  16. A common response to common danger? Comparison of animal and plant signaling pathways involved in cadmium sensing.

    PubMed

    Chmielowska-Bąk, Jagna; Deckert, Joanna

    2012-12-01

    Exposure to cadmium results in disturbances in cell homeostasis in all living organisms. The first response to stress factors, including cadmium, is activation of signal transduction pathways that mobilize cell defense mechanisms. The aim of this review is a comparison between the signaling network triggered by Cd in plants and animals. Despite differences in the structure and physiology of plant and animal cells, their cadmium signal transduction pathways share many common elements. These elements include signaling molecules such as ROS, Ca(2+) and NO, the involvement of phospholipase C, mitogen-activated protein kinase cascades, and activation of transcription factors. Undoubtedly, both animals and plants also possess specific signaling pathways. In case of animals, Wnt/β-catenin, sonic hedgehog and oestorgen signaling are engaged in the transduction of cadmium signal. Plant specific signal transduction pathways include signaling mediated by plant hormones. The role of ethylene and jasmonic, salicylic and abscisic acid in plant response to cadmium is also discussed.

  17. Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress.

    PubMed

    Evanson, Nathan K; Herman, James P

    2015-10-15

    Glutamate is an important neurotransmitter in the regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in the regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling.

  18. Visible light communications using predistortion signal to enhance the response of passive optical receiver

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Chen, Hung-Yu; Liang, Kevin; Wei, Liang-Yu; Chow, Chi-Wai; Yeh, Chien-Hung

    2016-01-01

    Traditional visible light communication (VLC) uses positive-intrinsic-negative photodiode (PD) or avalanche PD as the optical receivers (Rx). We demonstrate using a solar cell as the VLC Rx. The solar cell is flexible and low cost and converts the optical signal into an electrical signal directly without the need of external power supply. In addition to acting as the VLC passive Rx, the converted electrical signal from the solar cell can charge up the battery of the Rx nodes. Hence, the proposed scheme can be a promising candidate for the future Internet of Things network. However, a solar cell acting as a VLC Rx is very challenging, since the response of the solar cell is limited. Here, we propose and demonstrate using predistortion to significantly enhance the solar cell Rx response for the first time up to the authors' knowledge. Experimental results show that the response of the solar cell Rx is significantly enhanced; and the original 2-kHz detection bandwidth of the solar cell can be enhanced by 250 times for receiving 500-kbit/s VLC signal at a transmission distance of 1 m. The operation principle, the generated voltage by the solar cell, and the maximum data rates achieved at different transmission distances are also studied.

  19. Uranium perturbs signaling and iron uptake response in Arabidopsis thaliana roots.

    PubMed

    Doustaly, Fany; Combes, Florence; Fiévet, Julie B; Berthet, Serge; Hugouvieux, Véronique; Bastien, Olivier; Aranjuelo, Iker; Leonhardt, Nathalie; Rivasseau, Corinne; Carrière, Marie; Vavasseur, Alain; Renou, Jean-Pierre; Vandenbrouck, Yves; Bourguignon, Jacques

    2014-04-01

    Uranium is a natural element which is mainly redistributed in the environment due to human activity, including accidents and spillages. Plants may be useful in cleaning up after incidents, although little is yet known about the relationship between metal speciation and plant response. Here, J-Chess modeling was used to predict U speciation and exposure conditions affecting U bioavailability for plants. The model was confirmed by exposing Arabidopsis thaliana plants to U under hydroponic conditions. The early root response was characterized using complete Arabidopsis transcriptome microarrays (CATMA). Expression of 111 genes was modified at the three timepoints studied. The associated biological processes were further examined by real-time quantitative RT-PCR. Annotation revealed that oxidative stress, cell wall and hormone biosynthesis, and signaling pathways (including phosphate signaling) were affected by U exposure. The main actors in iron uptake and signaling (IRT1, FRO2, AHA2, AHA7 and FIT1) were strongly down-regulated upon exposure to uranyl. A network calculated using IRT1, FRO2 and FIT1 as bait revealed a set of genes whose expression levels change under U stress. Hypotheses are presented to explain how U perturbs the iron uptake and signaling response. These results give preliminary insights into the pathways affected by uranyl uptake, which will be of interest for engineering plants to help clean areas contaminated with U.

  20. Immune signaling pathways activated in response to different pathogenic micro-organisms in Bombyx mori.

    PubMed

    Liu, Wei; Liu, Jiabin; Lu, Yahong; Gong, Yongchang; Zhu, Min; Chen, Fei; Liang, Zi; Zhu, Liyuan; Kuang, Sulan; Hu, Xiaolong; Cao, Guangli; Xue, Renyu; Gong, Chengliang

    2015-06-01

    The JAK/STAT, Toll, Imd, and RNAi pathways are the major signaling pathways associated with insect innate immunity. To explore the different immune signaling pathways triggered in response to pathogenic micro-organism infections in the silkworm, Bombyx mori, the expression levels of the signal transducer and activator of transcription (BmSTAT), spatzle-1 (Bmspz-1), peptidoglycan-recognition protein LB (BmPGRP-LB), peptidoglycan-recognition protein LE (BmPGRP-LE), argonaute 2 (Bmago2), and dicer-2 (Bmdcr2) genes after challenge with Escherichia coli (E. coli), Serratiamarcescens (Sm), Bacillus bombyseptieus (Bab), Beauveriabassiana (Beb), nucleopolyhedrovirus (BmNPV), cypovirus (BmCPV), bidensovirus (BmBDV), or Nosemabombycis (Nb) were determined using real-time PCR. We found that the JAK/STAT pathway could be activated by challenge with BmNPV and BmBDV, the Toll pathway could be most robustly induced by challenge with Beb, the Imd pathway was mainly activated in response to infection by E. coli and Sm, and the RNAi pathway was not activated by viral infection, but could be triggered by some bacterial infections. These findings yield insights into the immune signaling pathways activated in response to different pathogenic micro-organisms in the silkworm.

  1. WRKY proteins: signaling and regulation of expression during abiotic stress responses.

    PubMed

    Banerjee, Aditya; Roychoudhury, Aryadeep

    2015-01-01

    WRKY proteins are emerging players in plant signaling and have been thoroughly reported to play important roles in plants under biotic stress like pathogen attack. However, recent advances in this field do reveal the enormous significance of these proteins in eliciting responses induced by abiotic stresses. WRKY proteins act as major transcription factors, either as positive or negative regulators. Specific WRKY factors which help in the expression of a cluster of stress-responsive genes are being targeted and genetically modified to induce improved abiotic stress tolerance in plants. The knowledge regarding the signaling cascade leading to the activation of the WRKY proteins, their interaction with other proteins of the signaling pathway, and the downstream genes activated by them are altogether vital for justified targeting of the WRKY genes. WRKY proteins have also been considered to generate tolerance against multiple abiotic stresses with possible roles in mediating a cross talk between abiotic and biotic stress responses. In this review, we have reckoned the diverse signaling pattern and biological functions of WRKY proteins throughout the plant kingdom along with the growing prospects in this field of research. PMID:25879071

  2. WRKY Proteins: Signaling and Regulation of Expression during Abiotic Stress Responses

    PubMed Central

    Banerjee, Aditya

    2015-01-01

    WRKY proteins are emerging players in plant signaling and have been thoroughly reported to play important roles in plants under biotic stress like pathogen attack. However, recent advances in this field do reveal the enormous significance of these proteins in eliciting responses induced by abiotic stresses. WRKY proteins act as major transcription factors, either as positive or negative regulators. Specific WRKY factors which help in the expression of a cluster of stress-responsive genes are being targeted and genetically modified to induce improved abiotic stress tolerance in plants. The knowledge regarding the signaling cascade leading to the activation of the WRKY proteins, their interaction with other proteins of the signaling pathway, and the downstream genes activated by them are altogether vital for justified targeting of the WRKY genes. WRKY proteins have also been considered to generate tolerance against multiple abiotic stresses with possible roles in mediating a cross talk between abiotic and biotic stress responses. In this review, we have reckoned the diverse signaling pattern and biological functions of WRKY proteins throughout the plant kingdom along with the growing prospects in this field of research. PMID:25879071

  3. Guanabenz Downregulates Inflammatory Responses via eIF2α Dependent and Independent Signaling

    PubMed Central

    Takigawa, Shinya; Chen, Andy; Nishimura, Akinobu; Liu, Shengzhi; Li, Bai-Yan; Sudo, Akihiro; Yokota, Hiroki; Hamamura, Kazunori

    2016-01-01

    Integrated stress responses (ISR) may lead to cell death and tissue degeneration via eukaryotic translation initiation factor 2 α (eIF2α)-mediated signaling. Alleviating ISR by modulating eIF2α phosphorylation can reduce the symptoms associated with various diseases. Guanabenz is known to elevate the phosphorylation level of eIF2α and reduce pro-inflammatory responses. However, the mechanism of its action is not well understood. In this study, we investigated the signaling pathway through which guanabenz induces anti-inflammatory effects in immune cells, in particular macrophages. Genome-wide mRNA profiling followed by principal component analysis predicted that colony stimulating factor 2 (Csf2, or GM-CSF as granulocyte macrophage colony stimulating factor) is involved in the responses to guanabenz. A partial silencing of Csf2 or eIF2α by RNA interference revealed that Interleukin-6 (IL6), Csf2, and Cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eIF2α. Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling. Collectively, the result herein indicates that anti-inflammatory effects by guanabenz are mediated by not only eIF2α-dependent but also eIF2α-independent signaling. PMID:27164082

  4. fNIRS derived hemodynamic signals and electrodermal responses in a sequential risk-taking task.

    PubMed

    Holper, Lisa; ten Brincke, Robert H W; Wolf, Martin; Murphy, Ryan O

    2014-04-01

    The study measured cortical hemodynamic signals and peripheral correlates of decision makers during a dynamic risky task, the Just One More task (JOM), in which the risky decision entails choosing whether to incrementally increase accumulated earnings at the risk of ruin (going bust ending up with nothing). Twenty subjects participated in multiple instantiations of this task in which the probability of ruin and size of the stakes varied. Physiological correlates were simultaneously quantified by functional near-infrared spectroscopy (fNIRS) over dorsolateral prefrontal cortex (DLPFC) and electrodermal activity (EDA). First, in the task decision phase (i.e., when subjects are contemplating options before making a choice) probability of ruin had a dissociating effect on fNIRS and EDA. fNIRS derived DLPFC hemodynamic signals reflected a subjective value signal, correlating positively with individual risk attitude. Contrary, EDA reflected the probability of ruin in terms of a common affective measure, irrespective of individuals׳ risk attitude. Second, during the task outcome phase (i.e., the time after subjects have made a choice and observed the outcomes) fNIRS and EDA revealed opposite patterns. While fNIRS derived DLPFC hemodynamic signals were larger in response to gains, EDA signals were larger in response to losses; both patterns were statistically independent of individual risk attitude. Lastly, fNIRS derived DLPFC hemodynamic signals in the decision phase correlated positively with the mean round earnings, providing a measure of the quality of the individual decision-making performance. Together with the positive correlation with individual risk attitude, our findings indicate that fNIRS signals, but not EDA, could be taken as a useful method for studying individual risk attitude and task performance in dynamic risky decision-making. PMID:24530267

  5. Chloroplasts extend stromules independently and in response to internal redox signals.

    PubMed

    Brunkard, Jacob O; Runkel, Anne M; Zambryski, Patricia C

    2015-08-11

    A fundamental mystery of plant cell biology is the occurrence of "stromules," stroma-filled tubular extensions from plastids (such as chloroplasts) that are universally observed in plants but whose functions are, in effect, completely unknown. One prevalent hypothesis is that stromules exchange signals or metabolites between plastids and other subcellular compartments, and that stromules are induced during stress. Until now, no signaling mechanisms originating within the plastid have been identified that regulate stromule activity, a critical missing link in this hypothesis. Using confocal and superresolution 3D microscopy, we have shown that stromules form in response to light-sensitive redox signals within the chloroplast. Stromule frequency increased during the day or after treatment with chemicals that produce reactive oxygen species specifically in the chloroplast. Silencing expression of the chloroplast NADPH-dependent thioredoxin reductase, a central hub in chloroplast redox signaling pathways, increased chloroplast stromule frequency, whereas silencing expression of nuclear genes related to plastid genome expression and tetrapyrrole biosynthesis had no impact on stromules. Leucoplasts, which are not photosynthetic, also made more stromules in the daytime. Leucoplasts did not respond to the same redox signaling pathway but instead increased stromule formation when exposed to sucrose, a major product of photosynthesis, although sucrose has no impact on chloroplast stromule frequency. Thus, different types of plastids make stromules in response to distinct signals. Finally, isolated chloroplasts could make stromules independently after extraction from the cytoplasm, suggesting that chloroplast-associated factors are sufficient to generate stromules. These discoveries demonstrate that chloroplasts are remarkably autonomous organelles that alter their stromule frequency in reaction to internal signal transduction pathways.

  6. Chloroplasts extend stromules independently and in response to internal redox signals

    PubMed Central

    Brunkard, Jacob O.; Runkel, Anne M.; Zambryski, Patricia C.

    2015-01-01

    A fundamental mystery of plant cell biology is the occurrence of “stromules,” stroma-filled tubular extensions from plastids (such as chloroplasts) that are universally observed in plants but whose functions are, in effect, completely unknown. One prevalent hypothesis is that stromules exchange signals or metabolites between plastids and other subcellular compartments, and that stromules are induced during stress. Until now, no signaling mechanisms originating within the plastid have been identified that regulate stromule activity, a critical missing link in this hypothesis. Using confocal and superresolution 3D microscopy, we have shown that stromules form in response to light-sensitive redox signals within the chloroplast. Stromule frequency increased during the day or after treatment with chemicals that produce reactive oxygen species specifically in the chloroplast. Silencing expression of the chloroplast NADPH-dependent thioredoxin reductase, a central hub in chloroplast redox signaling pathways, increased chloroplast stromule frequency, whereas silencing expression of nuclear genes related to plastid genome expression and tetrapyrrole biosynthesis had no impact on stromules. Leucoplasts, which are not photosynthetic, also made more stromules in the daytime. Leucoplasts did not respond to the same redox signaling pathway but instead increased stromule formation when exposed to sucrose, a major product of photosynthesis, although sucrose has no impact on chloroplast stromule frequency. Thus, different types of plastids make stromules in response to distinct signals. Finally, isolated chloroplasts could make stromules independently after extraction from the cytoplasm, suggesting that chloroplast-associated factors are sufficient to generate stromules. These discoveries demonstrate that chloroplasts are remarkably autonomous organelles that alter their stromule frequency in reaction to internal signal transduction pathways. PMID:26150490

  7. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions

    PubMed Central

    Thomson, Stuart; Buck, Elizabeth; Russo, Suzanne; Petti, Filippo; Sujka-Kwok, Izabela; Eyzaguirre, Alexandra; Rosenfeld-Franklin, Maryland; Gibson, Neil W.; Miglarese, Mark; Epstein, David; Iwata, Kenneth K.; Haley, John D.

    2008-01-01

    Over 90% of all cancers are carcinomas, malignancies derived from cells of epithelial origin. As carcinomas progress, these tumors may lose epithelial morphology and acquire mesenchymal characteristics which contribute to metastatic potential. An epithelial-to-mesenchymal transition (EMT) similar to the process critical for embryonic development is thought to be an important mechanism for promoting cancer invasion and metastasis. Epithelial-to-mesenchymal transitions have been induced in vitro by transient or unregulated activation of receptor tyrosine kinase signaling pathways, oncogene signaling and disruption of homotypic cell adhesion. These cellular models attempt to mimic the complexity of human carcinomas which respond to autocrine and paracrine signals from both the tumor and its microenvironment. Activation of the epidermal growth factor receptor (EGFR) has been implicated in the neoplastic transformation of solid tumors and overexpression of EGFR has been shown to correlate with poor survival. Notably, epithelial tumor cells have been shown to be significantly more sensitive to EGFR inhibitors than tumor cells which have undergone an EMT-like transition and acquired mesenchymal characteristics, including non-small cell lung (NSCLC), head and neck (HN), bladder, colorectal, pancreas and breast carcinomas. EGFR blockade has also been shown to inhibit cellular migration, suggesting a role for EGFR inhibitors in the control of metastasis. The interaction between EGFR and the multiple signaling nodes which regulate EMT suggest that the combination of an EGFR inhibitor and other molecular targeted agents may offer a novel approach to controlling metastasis. PMID:18236164

  8. An improved response surface methodology algorithm with an application to traffic signal optimization for urban networks

    SciTech Connect

    Joshi, S.S.; Rathi, A.K.; Tew, J.D.

    1995-12-31

    This paper illustrates the use of the simulation-optimization technique of response surface methodology (RSM) in traffic signal optimization of urban networks. It also quantifies the gains of using the common random number (CRN) variance reduction strategy in such an optimization procedure. An enhanced RSM algorithm which employs conjugate gradient search techniques and successive second-order models is presented instead of the conventional approach. An illustrative example using an urban traffic network exhibits the superiority of using the CRN strategy ovr direct simulation in performing traffic signal optimization. Relative performance of the two strategies is quantified with computational results using the total network-wide delay as the measure of effectivness.

  9. Rater Drift in Constructed Response Scoring via Latent Class Signal Detection Theory and Item Response Theory

    ERIC Educational Resources Information Center

    Park, Yoon Soo

    2011-01-01

    The use of constructed response (CR) items or performance tasks to assess test takers' ability has grown tremendously over the past decade. Examples of CR items in psychological and educational measurement range from essays, works of art, and admissions interviews. However, unlike multiple-choice (MC) items that have predetermined options, CR…

  10. Development of response activation and inhibition in a selective stop-signal task.

    PubMed

    van de Laar, Maria C; van den Wildenberg, Wery P M; van Boxtel, Geert J M; van der Molen, Maurits W

    2014-10-01

    To gain more insight into the development of action control, the current brain potential study examined response selection, activation, and selective inhibition during choice- and stop-signal processing in three age groups (8-, 12-, and 21-year-olds). Results revealed that age groups differed in the implementation of proactive control; children slowed their go response and showed reduced cortical motor output compared to adults. On failed inhibition trials, children were less able than adults to suppress muscle output resulting in increased partial-inhibition rates. On invalid stop trials, all age groups initially activated, subsequently inhibited, and then reactivated the go response. Yet, children were less efficient in implementing this strategy. Then, older children recruit motor responses to a greater extent than younger children and adults, which reduced the efficiency of implementing response inhibition and proactive control. The results are discussed in relation to current notions of developmental change in proactive and reactive action control. PMID:25014630

  11. Dissociating consciousness from inhibitory control: evidence for unconsciously triggered response inhibition in the stop-signal task.

    PubMed

    van Gaal, Simon; Ridderinkhof, K Richard; van den Wildenberg, Wery P M; Lamme, Victor A F

    2009-08-01

    Theories about the functional relevance of consciousness commonly posit that higher order cognitive control functions, such as response inhibition, require consciousness. To test this assertion, the authors designed a masked stop-signal paradigm to examine whether response inhibition could be triggered and initiated by masked stop signals, which inform participants to stop an action they have begun. In 2 experiments, masked stop signals were observed to occasionally result in full response inhibition as well as to yield a slow down in the speed of responses that were not inhibited. The magnitude of this subliminally triggered response time slowing effect correlated with the efficiency measure (stop signal reaction time) of response inhibition across participants. Thus, response inhibition can be triggered unconsciously-more so in individuals who are good inhibitors and under conditions that are associated with efficient response inhibition. These results indicate that in contradiction to common theorizing, inhibitory control processes can operate outside awareness. PMID:19653754

  12. RIG-I Signaling Is Critical for Efficient Polyfunctional T Cell Responses during Influenza Virus Infection

    PubMed Central

    Kandasamy, Matheswaran; Suryawanshi, Amol; Tundup, Smanla; Perez, Jasmine T.; Schmolke, Mirco; Manicassamy, Santhakumar; Manicassamy, Balaji

    2016-01-01

    Retinoic acid inducible gene-I (RIG-I) is an innate RNA sensor that recognizes the influenza A virus (IAV) RNA genome and activates antiviral host responses. Here, we demonstrate that RIG-I signaling plays a crucial role in restricting IAV tropism and regulating host immune responses. Mice deficient in the RIG-I-MAVS pathway show defects in migratory dendritic cell (DC) activation, viral antigen presentation, and priming of CD8+ and CD4+ T cell responses during IAV infection. These defects result in decreased frequency of polyfunctional effector T cells and lowered protection against heterologous IAV challenge. In addition, our data show that RIG-I activation is essential for protecting epithelial cells and hematopoietic cells from IAV infection. These diverse effects of RIG-I signaling are likely imparted by the actions of type I interferon (IFN), as addition of exogenous type I IFN is sufficient to overcome the defects in antigen presentation by RIG-I deficient BMDC. Moreover, the in vivo T cell defects in RIG-I deficient mice can be overcome by the activation of MDA5 –MAVS via poly I:C treatment. Taken together, these findings demonstrate that RIG-I signaling through MAVS is critical for determining the quality of polyfunctional T cell responses against IAV and for providing protection against subsequent infection from heterologous or novel pandemic IAV strains. PMID:27438481

  13. The Arabidopsis LYST INTERACTING PROTEIN 5 Acts in Regulating Abscisic Acid Signaling and Drought Response.

    PubMed

    Xia, Zongliang; Huo, Yongjin; Wei, Yangyang; Chen, Qiansi; Xu, Ziwei; Zhang, Wei

    2016-01-01

    Multivesicular bodies (MVBs) are unique endosomes containing vesicles in the lumens and play essential roles in many eukaryotic cellular processes. The Arabidopsis LYST INTERACTING PROTEIN 5 (LIP5), a positive regulator of MVB biogenesis, has critical roles in biotic and abiotic stress responses. However, whether the abscisic acid (ABA) signaling is involved in LIP5-mediated stress response is largely unknown. Here, we report that LIP5 functions in regulating ABA signaling and drought response in Arabidopsis. Analyses of a LIP5 promoter-β-glucuronidase (GUS) construct revealed substantial GUS activity in whole seedlings. The expression of LIP5 was induced by ABA and drought, and overexpression of LIP5 led to ABA hypersensitivity, enhanced stomatal closure, reduced water loss, and, therefore, increased drought tolerance. On the contrary, LIP5 knockdown mutants showed ABA-insensitive phenotypes and reduced drought tolerance; suggesting that LIP5 acts in regulating ABA response. Further analysis using a fluorescent dye revealed that ABA and water stress induced cell endocytosis or vesicle trafficking in a largely LIP5-dependent manner. Furthermore, expression of several drought- or ABA-inducible marker genes was significantly down-regulated in the lip5 mutant seedlings. Collectively, our data suggest that LIP5 positively regulates drought tolerance through ABA-mediated cell signaling. PMID:27313589

  14. Induction of the unfolded protein response by constitutive G-protein signaling in rod photoreceptor cells.

    PubMed

    Wang, Tian; Chen, Jeannie

    2014-10-17

    Phototransduction is a G-protein signal transduction cascade that converts photon absorption to a change in current at the plasma membrane. Certain genetic mutations affecting the proteins in the phototransduction cascade cause blinding disorders in humans. Some of these mutations serve as a genetic source of "equivalent light" that activates the cascade, whereas other mutations lead to amplification of the light response. How constitutive phototransduction causes photoreceptor cell death is poorly understood. We showed that persistent G-protein signaling, which occurs in rod arrestin and rhodopsin kinase knock-out mice, caused a rapid and specific induction of the PERK pathway of the unfolded protein response. These changes were not observed in the cGMP-gated channel knock-out rods, an equivalent light condition that mimics light-stimulated channel closure. Thus transducin signaling, but not channel closure, triggers rapid cell death in light damage caused by constitutive phototransduction. Additionally, we show that in the albino light damage model cell death was not associated with increase in global protein ubiquitination or unfolded protein response induction. Taken together, these observations provide novel mechanistic insights into the cell death pathway caused by constitutive phototransduction and identify the unfolded protein response as a potential target for therapeutic intervention.

  15. The Arabidopsis LYST INTERACTING PROTEIN 5 Acts in Regulating Abscisic Acid Signaling and Drought Response

    PubMed Central

    Xia, Zongliang; Huo, Yongjin; Wei, Yangyang; Chen, Qiansi; Xu, Ziwei; Zhang, Wei

    2016-01-01

    Multivesicular bodies (MVBs) are unique endosomes containing vesicles in the lumens and play essential roles in many eukaryotic cellular processes. The Arabidopsis LYST INTERACTING PROTEIN 5 (LIP5), a positive regulator of MVB biogenesis, has critical roles in biotic and abiotic stress responses. However, whether the abscisic acid (ABA) signaling is involved in LIP5-mediated stress response is largely unknown. Here, we report that LIP5 functions in regulating ABA signaling and drought response in Arabidopsis. Analyses of a LIP5 promoter-β-glucuronidase (GUS) construct revealed substantial GUS activity in whole seedlings. The expression of LIP5 was induced by ABA and drought, and overexpression of LIP5 led to ABA hypersensitivity, enhanced stomatal closure, reduced water loss, and, therefore, increased drought tolerance. On the contrary, LIP5 knockdown mutants showed ABA-insensitive phenotypes and reduced drought tolerance; suggesting that LIP5 acts in regulating ABA response. Further analysis using a fluorescent dye revealed that ABA and water stress induced cell endocytosis or vesicle trafficking in a largely LIP5-dependent manner. Furthermore, expression of several drought- or ABA-inducible marker genes was significantly down-regulated in the lip5 mutant seedlings. Collectively, our data suggest that LIP5 positively regulates drought tolerance through ABA-mediated cell signaling. PMID:27313589

  16. Fuz Regulates Craniofacial Development through Tissue Specific Responses to Signaling Factors

    PubMed Central

    Zhang, Zichao; Wlodarczyk, Bogdan J.; Niederreither, Karen; Venugopalan, Shankar; Florez, Sergio; Finnell, Richard H.; Amendt, Brad A.

    2011-01-01

    The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz−/− mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh) and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz−/− mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz−/− mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling. PMID:21935430

  17. Glucose, Nitrogen, and Phosphate Repletion in Saccharomyces cerevisiae: Common Transcriptional Responses to Different Nutrient Signals

    PubMed Central

    Conway, Michael K.; Grunwald, Douglas; Heideman, Warren

    2012-01-01

    Saccharomyces cerevisiae are able to control growth in response to changes in nutrient availability. The limitation for single macronutrients, including nitrogen (N) and phosphate (P), produces stable arrest in G1/G0. Restoration of the limiting nutrient quickly restores growth. It has been shown that glucose (G) depletion/repletion very rapidly alters the levels of more than 2000 transcripts by at least 2-fold, a large portion of which are involved with either protein production in growth or stress responses in starvation. Although the signals generated by G, N, and P are thought to be quite distinct, we tested the hypothesis that depletion and repletion of any of these three nutrients would affect a common core set of genes as part of a generalized response to conditions that promote growth and quiescence. We found that the response to depletion of G, N, or P produced similar quiescent states with largely similar transcriptomes. As we predicted, repletion of each of the nutrients G, N, or P induced a large (501) common core set of genes and repressed a large (616) common gene set. Each nutrient also produced nutrient-specific transcript changes. The transcriptional responses to each of the three nutrients depended on cAMP and, to a lesser extent, the TOR pathway. All three nutrients stimulated cAMP production within minutes of repletion, and artificially increasing cAMP levels was sufficient to replicate much of the core transcriptional response. The recently identified transceptors Gap1, Mep1, Mep2, and Mep3, as well as Pho84, all played some role in the core transcriptional responses to N or P. As expected, we found some evidence of cross talk between nutrient signals, yet each nutrient sends distinct signals. PMID:22973537

  18. Model-based synthesis of locally contingent responses to global market signals

    NASA Astrophysics Data System (ADS)

    Magliocca, N. R.

    2015-12-01

    Rural livelihoods and the land systems on which they depend are increasingly influenced by distant markets through economic globalization. Place-based analyses of land and livelihood system sustainability must then consider both proximate and distant influences on local decision-making. Thus, advancing land change theory in the context of economic globalization calls for a systematic understanding of the general processes as well as local contingencies shaping local responses to global signals. Synthesis of insights from place-based case studies of land and livelihood change is a path forward for developing such systematic knowledge. This paper introduces a model-based synthesis approach to investigating the influence of local socio-environmental and agent-level factors in mediating land-use and livelihood responses to changing global market signals. A generalized agent-based modeling framework is applied to six case-study sites that differ in environmental conditions, market access and influence, and livelihood settings. The largest modeled land conversions and livelihood transitions to market-oriented production occurred in sties with relatively productive agricultural land and/or with limited livelihood options. Experimental shifts in the distributions of agents' risk tolerances generally acted to attenuate or amplify responses to changes in global market signals. Importantly, however, responses of agents at different points in the risk tolerance distribution varied widely, with the wealth gap growing wider between agents with higher or lower risk tolerance. These results demonstrate model-based synthesis is a promising approach to overcome many of the challenges of current synthesis methods in land change science, and to identify generalized as well as locally contingent responses to global market signals.

  19. Development of distortion product emissions in the gerbil: "filter" response and signal delay.

    PubMed

    Mills, D M; Rubel, E W

    1997-01-01

    Amplitude and phase responses of distortion product otoacoustic emissions as a function of stimulus frequency ratio were measured for frequencies between 2 and 48 kHz, in Mongolian gerbils (Meriones unguiculates) aged 15 to 30 days after birth. After baseline measurements, furosemide was administered to distinguish active from passive emissions. At all ages, structure in the form of multiple peaks was observed in the amplitude responses of specific odd-order emissions. This structure depended on the emission frequency, not the stimulus frequency ratio, and did not generally depend on the stimulus amplitude. Nor was it dependent on the functioning of the cochlear amplifier: At moderate stimulus levels, the observed emission distribution simply shifted to lower amplitudes when the cochlear amplifier was made temporarily dysfunctional by furosemide injection. The center frequencies and widths of the peaks in the amplitude response did not generally change with age, except that the relative amplitudes of the higher-frequency peaks were increased in younger animals. At 2 kHz, however, the distribution showed other evidence of maturation, with the frequency of maximum emission moving downward with age. The phase responses yielded estimates of the round trip signal (group or traveling wave) delay. At a given frequency, the active signal delay typically decreased substantially with increasing stimulus level. However, there was a rapid variation in delay as the stimulus level passed the normal active-passive crossover level. At stimulus levels measured relative to the active-passive crossover level, i.e., either 20 or 30 dB lower, the active signal delay decreased only slightly with age. Overall, both filter response and signal delay characteristics were found to be essentially mature near the onset of hearing. PMID:9000732

  20. Extracellular Signal-Regulated Kinase-2 within the Ventral Tegmental Area Regulates Responses to Stress

    PubMed Central

    Iñiguez, Sergio D.; Vialou, Vincent; Warren, Brandon L.; Cao, Jun-Li; Alcantara, Lyonna F.; Davis, Lindsey C.; Manojlovic, Zarko; Neve, Rachael L.; Russo, Scott J.; Han, Ming-Hu; Nestler, Eric J.; Bolaños-Guzmán, Carlos A.

    2010-01-01

    Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors. PMID:20519540

  1. Systemic and Local Responses to Repeated HL Stress-Induced Retrograde Signaling in Arabidopsis

    PubMed Central

    Gordon, Matthew J.; Carmody, Melanie; Albrecht, Verónica; Pogson, Barry

    2013-01-01

    Chloroplasts of leaves under high light stress initiate signals to the nuclei of both exposed and distal leaves in order to acclimate against the potential threat of oxidative damage: a process known as high light systemic acquired acclimation (HL SAA). This study explores the nature of HL SAA, synergistic interactions with other environmental stresses, and the impact of repeated HL stress on the acclimation response of exposed and distal leaves. This necessitated the development of novel experimental systems to investigate the initiation, perception, and response to HL SAA. These systems were used to investigate the HL SAA response by monitoring the induction of mRNA in distal leaves not exposed to the HL stress. Acclimation to HL is induced within minutes and the response is proportionally dependent on the quality and quantity of light. HL SAA treatments in conjunction with variations in temperature and humidity reveal HL SAA is influenced by fluctuations in humidity. These treatments also result in changes in auxin accumulation and auxin-responsive genes. A key question in retrograde signaling is the extent to which transient changes in light intensity result in a “memory” of the event leading to acclimation responses. Repeated exposure to short term HL resulted in acclimation of the exposed tissue and that of emerging and young leaves (but not older leaves) to HL and oxidative stress. PMID:23335929

  2. Regulation of Abscisic Acid Signaling by the Ethylene Response Pathway in Arabidopsis

    PubMed Central

    Ghassemian, Majid; Nambara, Eiji; Cutler, Sean; Kawaide, Hiroshi; Kamiya, Yuji; McCourt, Peter

    2000-01-01

    Although abscisic acid (ABA) is involved in a variety of plant growth and developmental processes, few genes that actually regulate the transduction of the ABA signal into a cellular response have been identified. In an attempt to determine negative regulators of ABA signaling, we identified mutants, designated enhanced response to ABA3 (era3), that increased the sensitivity of the seed to ABA. Biochemical and molecular analyses demonstrated that era3 mutants overaccumulate ABA, suggesting that era3 is a negative regulator of ABA synthesis. Subsequent genetic analysis of era3 alleles, however, showed that these are new alleles at the ETHYLENE INSENSITIVE2 locus. Other mutants defective in their response to ethylene also showed altered ABA sensitivity; from these results, we conclude that ethylene appears to be a negative regulator of ABA action during germination. In contrast, the ethylene response pathway positively regulates some aspects of ABA action that involve root growth in the absence of ethylene. We discuss the response of plants to ethylene and ABA in the context of how these two hormones could influence the same growth responses. PMID:10899978

  3. Thioredoxin-dependent Redox Regulation of Cellular Signaling and Stress Response through Reversible Oxidation of Methionines

    SciTech Connect

    Bigelow, Diana J.; Squier, Thomas C.

    2011-06-01

    Generation of reactive oxygen species (ROS) is a common feature of many forms of stress to which plants are exposed. Successful adaptation to changing environmental conditions requires sensitive sensors of ROS such as protein-bound methionines that are converted to their corresponding methionine sulfoxides, which in turn can influence cellular signaling pathways. Such a signaling protein is calmodulin, which represents an early and central point in calcium signaling pathways important to stress response in plants. We describe recent work elucidating fundamental mechanisms of reversible methionine oxidation within calmodulin, including the sensitivity of individual methionines within plant and animal calmodulin to ROS, the structural and functional consequences of their oxidation, and the interactions of oxidized calmodulin with methionine sulfoxide reductase enzymes.

  4. The UVR8 UV-B Photoreceptor: Perception, Signaling and Response.

    PubMed

    Tilbrook, Kimberley; Arongaus, Adriana B; Binkert, Melanie; Heijde, Marc; Yin, Ruohe; Ulm, Roman

    2013-01-01

    Ultraviolet-B radiation (UV-B) is an intrinsic part of sunlight that is accompanied by significant biological effects. Plants are able to perceive UV-B using the UV-B photoreceptor UVR8 which is linked to a specific molecular signaling pathway and leads to UV-B acclimation. Herein we review the biological process in plants from initial UV-B perception and signal transduction through to the known UV-B responses that promote survival in sunlight. The UVR8 UV-B photoreceptor exists as a homodimer that instantly monomerises upon UV-B absorption via specific intrinsic tryptophans which act as UV-B chromophores. The UVR8 monomer interacts with COP1, an E3 ubiquitin ligase, initiating a molecular signaling pathway that leads to gene expression changes. This signaling output leads to UVR8-dependent responses including UV-B-induced photomorphogenesis and the accumulation of UV-B-absorbing flavonols. Negative feedback regulation of the pathway is provided by the WD40-repeat proteins RUP1 and RUP2, which facilitate UVR8 redimerization, disrupting the UVR8-COP1 interaction. Despite rapid advancements in the field of recent years, further components of UVR8 UV-B signaling are constantly emerging, and the precise interplay of these and the established players UVR8, COP1, RUP1, RUP2 and HY5 needs to be defined. UVR8 UV-B signaling represents our further understanding of how plants are able to sense their light environment and adjust their growth accordingly.

  5. Using raw star signals in the monitoring of GOES imager visible-channel responsivities

    NASA Astrophysics Data System (ADS)

    Chang, I.-Lok; Dean, Charles; Weinreb, Michael; Wu, Xiangqian; Han, Dejiang; Mitchell, Kenneth; Li, Zhenping; Sindic-Rancic, Gordana; Yu, Fanfang

    2008-08-01

    Stars are regularly observed in the visible channels of the GOES Imagers for real-time navigation operations. However, we have been also using star observations off-line to deduce the rate of degradation of the responsivity of the visible channels. We estimate degradation rates from the time series of the intensities of the Imagers' output signals when viewing stars, available in the GOES Orbit and Attitude Tracking System (OATS). We begin by showing our latest results in monitoring the responsivities of the visible channels of the Imagers on GOES-8, -9, -10, -11 and -12. Unfortunately, the OATS computes the intensities of the star signals with approximations suitable for navigation, not for estimating accurate signal strengths, and thus we had to develop objective criteria for screening out unsuitable data. With several layers of screening, our most recent trending method yields smoother time series of star signals, but the time series are populated by a smaller pool of stars. With the goal of simplifying the task of data selection and to retrieve stars that have been rejected in the screening, we tested a technique that accessed the raw star measurements before they were processed by the OATS. We developed formulations that not only produced star signals more suitable for monitoring the changes in the Imager's outputs from views of constant-irradiance stellar sources, but also gave more information on the radiometric characteristics of the visible channels. We present specifics of this technique together with sample results. We discuss improvements in the quality of the time series that allow for more reliable inferences on the gradually changing responsivities of the visible channels. We describe further contributions of this method to monitoring of other performance characteristics of the visible channel of an Imager.

  6. Insulin secretion and signaling in response to dietary restriction and subsequent re-alimentation in cattle.

    PubMed

    Keogh, Kate; Kenny, David A; Kelly, Alan K; Waters, Sinéad M

    2015-08-01

    The objectives of this study were to examine systemic insulin response to a glucose tolerance test (GTT) and transcript abundance of genes of the insulin signaling pathway in skeletal muscle, during both dietary restriction and re-alimentation-induced compensatory growth. Holstein Friesian bulls were blocked to one of two groups: 1) restricted feed allowance for 125 days (period 1) (RES, n = 15) followed by ad libitum feeding for 55 days (period 2) or 2) ad libitum access to feed throughout (periods 1 and 2) (ADLIB, n = 15). On days 90 and 36 of periods 1 and 2, respectively, a GTT was performed. M. longissimus dorsi biopsies were harvested from all bulls on days 120 and 15 of periods 1 and 2, respectively, and RNA-Seq analysis was performed. RES displayed a lower growth rate during period 1 (RES: 0.6 kg/day, ADLIB: 1.9 kg/day; P < 0.001), subsequently gaining more during re-alimentation (RES: 2.5 kg/day, ADLIB: 1.4 kg/day; P < 0.001). Systemic insulin response to glucose administration was lower in RES in period 1 (P < 0.001) with no difference observed during period 2. The insulin signaling pathway in M. longissimus dorsi was enriched (P < 0.05) in response to dietary restriction but not during re-alimentation (P > 0.05). Genes differentially expressed in the insulin signaling pathway suggested a greater sensitivity to insulin in skeletal muscle, with pleiotropic effects of insulin signaling interrupted during dietary restriction. Collectively, these results indicate increased sensitivity to glucose clearance and skeletal muscle insulin signaling during dietary restriction; however, no overall role for insulin was apparent in expressing compensatory growth.

  7. Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

    SciTech Connect

    Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C.; Ballestas, Mary E.; Elmets, Craig A.; Robbins, David J.; Matalon, Sadis; Deshane, Jessy S.; Afaq, Farrukh; Bickers, David R.; Athar, Mohammad

    2013-11-01

    Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.

  8. Nitric Oxide Modulates the Temporal Properties of the Glutamate Response in Type 4 OFF Bipolar Cells

    PubMed Central

    Vielma, Alex H.; Agurto, Adolfo; Valdés, Joaquín; Palacios, Adrián G.; Schmachtenberg, Oliver

    2014-01-01

    Nitric oxide (NO) is involved in retinal signal processing, but its cellular actions are only partly understood. An established source of retinal NO are NOACs, a group of nNOS-expressing amacrine cells which signal onto bipolar, other amacrine and ganglion cells in the inner plexiform layer. Here, we report that NO regulates glutamate responses in morphologically and electrophysiologically identified type 4 OFF cone bipolar cells through activation of the soluble guanylyl cyclase-cGMP-PKG pathway. The glutamate response of these cells consists of two components, a fast phasic current sensitive to kainate receptor agonists, and a secondary component with slow kinetics, inhibited by AMPA receptor antagonists. NO shortened the duration of the AMPA receptor-dependent component of the glutamate response, while the kainate receptor-dependent component remained unchanged. Application of 8-Br-cGMP mimicked this effect, while inhibition of soluble guanylate cyclase or protein kinase G prevented it, supporting a mechanism involving a cGMP signaling pathway. Notably, perfusion with a NOS-inhibitor prolonged the duration of the glutamate response, while the NO precursor L-arginine shortened it, in agreement with a modulation by endogenous NO. Furthermore, NO accelerated the response recovery during repeated stimulation of type 4 cone bipolar cells, suggesting that the temporal response properties of this OFF bipolar cell type are regulated by NO. These results reveal a novel cellular mechanism of NO signaling in the retina, and represent the first functional evidence of NO modulating OFF cone bipolar cells. PMID:25463389

  9. TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity

    PubMed Central

    Ramirez-Ortiz, Zaida G.; Prasad, Amit; Griffith, Jason W.; Pendergraft, William F.; Cowley, Glenn S.; Root, David E.; Tai, Melissa; Luster, Andrew D.; Khoury, Joseph El; Hacohen, Nir; Means, Terry K.

    2015-01-01

    The genes and pathways that fine-tune TLR7-mediated innate inflammatory responses remain to be fully elucidated. Using an unbiased genome-scale shRNA screen, we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4–/– mice were hyporesponsive to TLR7 agonists and failed to produce type I interferon due to impaired phosphorylation of the transcription factor STAT1 by the MAP kinase p38 and decreased recruitment of MyD88 to TLR7. TREML4 deficiency reduced production of inflammatory cytokines and autoantibodies in SLE-prone MRL/lpr mice and inhibited the antiviral immune response to influenza. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity. PMID:25848864

  10. Jasmonates: signal transduction components and their roles in environmental stress responses.

    PubMed

    Goossens, Jonas; Fernández-Calvo, Patricia; Schweizer, Fabian; Goossens, Alain

    2016-08-01

    Jasmonates, oxylipin-type plant hormones, are implicated in diverse aspects of plant growth development and interaction with the environment. Following diverse developmental and environmental cues, jasmonate is produced, conjugated to the amino acid isoleucine and perceived by a co-receptor complex composed of the Jasmonate ZIM-domain (JAZ) repressor proteins and an E3 ubiquitin ligase complex containing the F-box CORONATINE INSENSITIVE 1 (COI1). This event triggers the degradation of the JAZ proteins and the release of numerous transcription factors, including MYC2 and its homologues, which are otherwise bound and inhibited by the JAZ repressors. Here, we will review the role of the COI1, JAZ and MYC2 proteins in the interaction of the plant with its environment, illustrating the significance of jasmonate signalling, and of the proteins involved, for responses to both biotic stresses caused by insects and numerous microbial pathogens and abiotic stresses caused by adverse climatic conditions. It has also become evident that crosstalk with other hormone signals, as well as light and clock signals, plays an important role in the control and fine-tuning of these stress responses. Finally, we will discuss how several pathogens exploit the jasmonate perception and early signalling machinery to decoy the plants defence systems. PMID:27086135

  11. Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

    PubMed Central

    Schneider, L; Fumagalli, M; d'Adda di Fagagna, F

    2012-01-01

    The impact and consequences of damage generation into genomic DNA, especially in the form of DNA double-strand breaks, and of the DNA-damage response (DDR) pathways that are promptly activated, have been elucidated in great detail. Most of this research, however, has been performed on proliferating, often cancerous, cell lines. In a mammalian body, the majority of cells are terminally differentiated (TD), and derives from a small pool of self-renewing somatic stem cells. Here, we comparatively studied DDR signaling and radiosensitivity in neural stem cells (NSC) and their TD-descendants, astrocytes – the predominant cells in the mammalian brain. Astrocytes have important roles in brain physiology, development and plasticity. We discovered that NSC activate canonical DDR upon exposure to ionizing radiation. Strikingly, astrocytes proved radioresistant, lacked functional DDR signaling, with key DDR genes such as ATM being repressed at the transcriptional level. Nevertheless, astrocytes retain the expression of non-homologous end-joining (NHEJ) genes and indeed they are DNA repair proficient. Unlike in NSC, in astrocytes DNA-PK seems to be the PI3K-like protein kinase responsible for γH2AX signal generation upon DNA damage. We also demonstrate the lack of functional DDR signaling activation in vivo in astrocytes of irradiated adult mouse brains, although adjacent neurons activate the DDR. PMID:21979466

  12. Yeast as a model system to study glucose-mediated signalling and response.

    PubMed

    Sanz, Pascual

    2007-01-01

    Glucose is the principal carbon and energy source for a wide variety of cells, ranging from unicellular microorganisms to higher eukaryotic cells. It is taken up by these cells and metabolized to obtain the energy necessary for cell viability. In addition, the presence of this sugar is able to adjust cellular metabolism, regulate gene expression and even influence cell growth. For this reason, glucose is considered as a "hormone". Specifically, it can trigger different signalling pathways that allow cells to adjust their gene expression programmes in response to glucose availability. Elucidating the molecular mechanisms of glucose response in eukaryotes has been greatly aided by studies conducted in the yeast Saccharomyces cerevisiae. This yeast shares with complex multicellular eukaryotes many of the signal transduction components that detect glucose, transmit the corresponding signals to the interior of the cell and make the needed adjustments to cellular metabolism and gene expression. In this manuscript, I will review the current knowledge of some aspects of glucose-mediated signalling in yeast and discuss how these results have contributed to the understanding of similar processes in mammalian cells.

  13. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening

    PubMed Central

    Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-01-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process. PMID:26959229

  14. [Response of arbuscular mycorrhizal fungal lipid metabolism to symbiotic signals in mycorrhiza].

    PubMed

    Tian, Lei; Li, Yuanjing; Tian, Chunjie

    2016-01-01

    Arbuscular mycorrhizal (AM) fungi play an important role in energy flow and nutrient cycling, besides their wide distribution in the cosystem. With a long co-evolution, AM fungi and host plant have formed a symbiotic relationship, and fungal lipid metabolism may be the key point to find the symbiotic mechanism in arbusculart mycorrhiza. Here, we reviewed the most recent progress on the interaction between AM fungal lipid metabolism and symbiotic signaling networks, especially the response of AM fungal lipid metabolism to symbiotic signals. Furthermore, we discussed the response of AM fungal lipid storage and release to symbiotic or non-symbiotic status, and the correlation between fungal lipid metabolism and nutrient transfer in mycorrhiza. In addition, we explored the feedback of the lipolysis process to molecular signals during the establishment of symbiosis, and the corresponding material conversion and energy metabolism besides the crosstalk of fungal lipid metabolism and signaling networks. This review will help understand symbiotic mechanism of arbuscular mycorrhiza fungi and further application in ecosystem.

  15. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening.

    PubMed

    Breitel, Dario A; Chappell-Maor, Louise; Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-03-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process. PMID:26959229

  16. Plant volatiles in a polluted atmosphere: stress response and signal degradation

    PubMed Central

    Blande, James D.; Holopainen, Jarmo K.; Niinemets, Ülo

    2014-01-01

    Plants emit a plethora of volatile organic compounds, which provide detailed information on the physiological condition of emitters. Volatiles induced by herbivore-feeding are among the best studied plant responses to stress and may constitute an informative message to the surrounding community and function in the process of plant defence. However, under natural conditions, plants are potentially exposed to multiple concurrent stresses, which can have complex effects on the volatile emissions. Atmospheric pollutants are an important facet of the abiotic environment and can impinge on a plant’s volatile-mediated defences in multiple ways at multiple temporal scales. They can exert changes in volatile emissions through oxidative stress, as is the case with ozone pollution. They may also react with volatiles in the atmosphere; such is the case for ozone, nitrogen oxides, hydroxyl radicals and other oxidizing atmospheric species. These reactions result in breakdown products, which may themselves be perceived by community members as informative signals. In this review we demonstrate the complex interplay between stress, emitted signals and modification in signal strength and composition by the atmosphere, collectively determining the responses of the biotic community to elicited signals. PMID:24738697

  17. Jasmonates: signal transduction components and their roles in environmental stress responses.

    PubMed

    Goossens, Jonas; Fernández-Calvo, Patricia; Schweizer, Fabian; Goossens, Alain

    2016-08-01

    Jasmonates, oxylipin-type plant hormones, are implicated in diverse aspects of plant growth development and interaction with the environment. Following diverse developmental and environmental cues, jasmonate is produced, conjugated to the amino acid isoleucine and perceived by a co-receptor complex composed of the Jasmonate ZIM-domain (JAZ) repressor proteins and an E3 ubiquitin ligase complex containing the F-box CORONATINE INSENSITIVE 1 (COI1). This event triggers the degradation of the JAZ proteins and the release of numerous transcription factors, including MYC2 and its homologues, which are otherwise bound and inhibited by the JAZ repressors. Here, we will review the role of the COI1, JAZ and MYC2 proteins in the interaction of the plant with its environment, illustrating the significance of jasmonate signalling, and of the proteins involved, for responses to both biotic stresses caused by insects and numerous microbial pathogens and abiotic stresses caused by adverse climatic conditions. It has also become evident that crosstalk with other hormone signals, as well as light and clock signals, plays an important role in the control and fine-tuning of these stress responses. Finally, we will discuss how several pathogens exploit the jasmonate perception and early signalling machinery to decoy the plants defence systems.

  18. Evaluating Climate Predictability Signals in Response to Forcing: Mount Pinatubo as a Case Study

    NASA Astrophysics Data System (ADS)

    Gaddis, A. L.; Drake, J.; Evans, K. J.

    2012-12-01

    Volcanic eruptions serve as a benchmark for assessing aspects of predictability because they provide a sudden global impulse to the Earth's climate system. In particular, the 1991 eruption of Mt. Pinatubo in the Philippines is of interest since it was the largest aerosol perturbation to the stratosphere in the twentieth century and the most intensely observed eruption on record. Using instrumental measurements during the eruption, the predictive capabilities of climate models may be evaluated and the predictability of climate variables under forcing may be inferred. In this study, the evolution of the climate response to volcanic forcing is simulated in the Community Earth System Model, CESM1.0, using ensembles of forced and unforced global climate model runs. The predictability signals of all atmospheric climate model variables are systematically calculated using a unitless signal to noise ratio. The signals are compared to determine the most sensitive variables. Additionally, this work examines spatial predictability patterns, important for regional predictability, by mapping the signals globally and using empirical orthogonal functions. Phase plots are employed to highlight the response of variables to forcing, and comparisons with observations of the eruption are made to provide validation of the results.

  19. [Response of arbuscular mycorrhizal fungal lipid metabolism to symbiotic signals in mycorrhiza].

    PubMed

    Tian, Lei; Li, Yuanjing; Tian, Chunjie

    2016-01-01

    Arbuscular mycorrhizal (AM) fungi play an important role in energy flow and nutrient cycling, besides their wide distribution in the cosystem. With a long co-evolution, AM fungi and host plant have formed a symbiotic relationship, and fungal lipid metabolism may be the key point to find the symbiotic mechanism in arbusculart mycorrhiza. Here, we reviewed the most recent progress on the interaction between AM fungal lipid metabolism and symbiotic signaling networks, especially the response of AM fungal lipid metabolism to symbiotic signals. Furthermore, we discussed the response of AM fungal lipid storage and release to symbiotic or non-symbiotic status, and the correlation between fungal lipid metabolism and nutrient transfer in mycorrhiza. In addition, we explored the feedback of the lipolysis process to molecular signals during the establishment of symbiosis, and the corresponding material conversion and energy metabolism besides the crosstalk of fungal lipid metabolism and signaling networks. This review will help understand symbiotic mechanism of arbuscular mycorrhiza fungi and further application in ecosystem. PMID:27305777

  20. AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening.

    PubMed

    Breitel, Dario A; Chappell-Maor, Louise; Meir, Sagit; Panizel, Irina; Puig, Clara Pons; Hao, Yanwei; Yifhar, Tamar; Yasuor, Hagai; Zouine, Mohamed; Bouzayen, Mondher; Granell Richart, Antonio; Rogachev, Ilana; Aharoni, Asaph

    2016-03-01

    The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over-expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process.

  1. Responses of macrophages to the danger signals released from necrotic cells.

    PubMed

    Kimura, Toshifumi; Kobayashi, Shuhei; Hanihara-Tatsuzawa, Fumito; Sayama, Aoi; MaruYama, Takashi; Muta, Tatsushi

    2014-12-01

    The immune system maintains homeostasis by recognizing and responding to cell death caused by various stresses. The immune response is considered to be elicited by 'danger signals' released from necrotic cells. However, the identity of the danger signals remains elusive. In this study, we focused on the expression of chemokines by macrophages stimulated with necrotic cells. In mouse bone-marrow-derived macrophages, the chemokine monocyte chemoattractant protein (MCP)-3 was induced at both the mRNA and protein levels in response to heat-killed murine cells. The induction of MCP-3 was also observed in MyD88-deficient macrophages, indicating that Toll-like receptors and the IL-1 receptor are not involved in this response. Consistent with this observation, the activation of NF-κB was not detected in RAW264.7 macrophages stimulated with necrotic cells. Treatments with proteinase K, DNaseI or RNaseA did not affect the ' STIMULATING ACTIVITY': of necrotic cells. In contrast, treatment with apyrase, which removes phosphates from nucleoside tri- and di-phosphates, abolished the inducing activity. Purified UDP at 30 µM concentration elicited similar induction of MCP-3 in RAW264.7 macrophages. Small interfering RNA-mediated knock-down of the UDP receptor P2Y6 in RAW264.7 cells significantly reduced the induction of MCP-3 in response to necrotic cells, but not its induction by lipopolysaccharide. Furthermore, ectopic expression of the P2Y6 receptor in HEK293 cells conferred responsiveness to necrotic cells. These results suggest that UDP released by necrotic cells plays a critical role as an endogenous danger signal and that P2Y6 is required for the induction of MCP-3 in response to necrotic cells.

  2. Subject specific BOLD fMRI respiratory and cardiac response functions obtained from global signal.

    PubMed

    Falahpour, Maryam; Refai, Hazem; Bodurka, Jerzy

    2013-05-15

    Subtle changes in either breathing pattern or cardiac pulse rate alter blood oxygen level dependent functional magnetic resonance imaging signal (BOLD fMRI). This is problematic because such fluctuations could possibly not be related to underlying neuronal activations of interest but instead the source of physiological noise. Several methods have been proposed to eliminate physiological noise in BOLD fMRI data. One such method is to derive a template based on average multi-subject data for respiratory response function (RRF) and cardiac response function (CRF) by simultaneously utilizing an external recording of cardiac and respiratory waveforms with the fMRI. Standard templates can then be used to model, map, and remove respiration and cardiac fluctuations from fMRI data. Utilizing these does not, however, account for intra-subject variations in physiological response. Thus, performing a more individualized approach for single subject physiological noise correction becomes more desirable, especially for clinical purposes. Here we propose a novel approach that employs subject-specific RRF and CRF response functions obtained from the whole brain or brain tissue-specific global signals (GS). Averaging multiple voxels in global signal computation ensures physiological noise dominance over thermal and system noise in even high-spatial-resolution fMRI data, making the GS suitable for deriving robust estimations of both RRF and CRF for individual subjects. Using these individualized response functions instead of standard templates based on multi-subject averages judiciously removes physiological noise from the data, assuming that there is minimal neuronal contribution in the derived individualized filters. Subject-specific physiological response functions obtained from the GS better maps individuals' physiological characteristics.

  3. Dissociating Consciousness from Inhibitory Control: Evidence for Unconsciously Triggered Response Inhibition in the Stop-Signal Task

    ERIC Educational Resources Information Center

    van Gaal, Simon; Ridderinkhof, K. Richard; van den Wildenberg, Wery P. M.; Lamme, Victor A. F.

    2009-01-01

    Theories about the functional relevance of consciousness commonly posit that higher order cognitive control functions, such as response inhibition, require consciousness. To test this assertion, the authors designed a masked stop-signal paradigm to examine whether response inhibition could be triggered and initiated by masked stop signals, which…

  4. Elevated CO2-Induced Responses in Stomata Require ABA and ABA Signaling.

    PubMed

    Chater, Caspar; Peng, Kai; Movahedi, Mahsa; Dunn, Jessica A; Walker, Heather J; Liang, Yun-Kuan; McLachlan, Deirdre H; Casson, Stuart; Isner, Jean Charles; Wilson, Ian; Neill, Steven J; Hedrich, Rainer; Gray, Julie E; Hetherington, Alistair M

    2015-10-19

    An integral part of global environment change is an increase in the atmospheric concentration of CO2 ([CO2]) [1]. Increased [CO2] reduces leaf stomatal apertures and density of stomata that plays out as reductions in evapotranspiration [2-4]. Surprisingly, given the importance of transpiration to the control of terrestrial water fluxes [5] and plant nutrient acquisition [6], we know comparatively little about the molecular components involved in the intracellular signaling pathways by which [CO2] controls stomatal development and function [7]. Here, we report that elevated [CO2]-induced closure and reductions in stomatal density require the generation of reactive oxygen species (ROS), thereby adding a new common element to these signaling pathways. We also show that the PYR/RCAR family of ABA receptors [8, 9] and ABA itself are required in both responses. Using genetic approaches, we show that ABA in guard cells or their precursors is sufficient to mediate the [CO2]-induced stomatal density response. Taken together, our results suggest that stomatal responses to increased [CO2] operate through the intermediacy of ABA. In the case of [CO2]-induced reductions in stomatal aperture, this occurs by accessing the guard cell ABA signaling pathway. In both [CO2]-mediated responses, our data are consistent with a mechanism in which ABA increases the sensitivity of the system to [CO2] but could also be explained by requirement for a CO2-induced increase in ABA biosynthesis specifically in the guard cell lineage. Furthermore, the dependency of stomatal [CO2] signaling on ABA suggests that the ABA pathway is, in evolutionary terms, likely to be ancestral.

  5. Elevated CO2-Induced Responses in Stomata Require ABA and ABA Signaling.

    PubMed

    Chater, Caspar; Peng, Kai; Movahedi, Mahsa; Dunn, Jessica A; Walker, Heather J; Liang, Yun-Kuan; McLachlan, Deirdre H; Casson, Stuart; Isner, Jean Charles; Wilson, Ian; Neill, Steven J; Hedrich, Rainer; Gray, Julie E; Hetherington, Alistair M

    2015-10-19

    An integral part of global environment change is an increase in the atmospheric concentration of CO2 ([CO2]) [1]. Increased [CO2] reduces leaf stomatal apertures and density of stomata that plays out as reductions in evapotranspiration [2-4]. Surprisingly, given the importance of transpiration to the control of terrestrial water fluxes [5] and plant nutrient acquisition [6], we know comparatively little about the molecular components involved in the intracellular signaling pathways by which [CO2] controls stomatal development and function [7]. Here, we report that elevated [CO2]-induced closure and reductions in stomatal density require the generation of reactive oxygen species (ROS), thereby adding a new common element to these signaling pathways. We also show that the PYR/RCAR family of ABA receptors [8, 9] and ABA itself are required in both responses. Using genetic approaches, we show that ABA in guard cells or their precursors is sufficient to mediate the [CO2]-induced stomatal density response. Taken together, our results suggest that stomatal responses to increased [CO2] operate through the intermediacy of ABA. In the case of [CO2]-induced reductions in stomatal aperture, this occurs by accessing the guard cell ABA signaling pathway. In both [CO2]-mediated responses, our data are consistent with a mechanism in which ABA increases the sensitivity of the system to [CO2] but could also be explained by requirement for a CO2-induced increase in ABA biosynthesis specifically in the guard cell lineage. Furthermore, the dependency of stomatal [CO2] signaling on ABA suggests that the ABA pathway is, in evolutionary terms, likely to be ancestral. PMID:26455301

  6. Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies

    PubMed Central

    2015-01-01

    Implantable biosensors are valuable scientific tools for basic neuroscience research and clinical applications. Neurotechnologies provide direct readouts of neurological signal and neurochemical processes. These tools are generally most valuable when performance capacities extend over months and years to facilitate the study of memory, plasticity, and behavior or to monitor patients’ conditions. These needs have generated a variety of device designs from microelectrodes for fast scan cyclic voltammetry (FSCV) and electrophysiology to microdialysis probes for sampling and detecting various neurochemicals. Regardless of the technology used, the breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. Changes to the tissue microenvironment surrounding the device can dramatically impact electrochemical and electrophysiological signal sensitivity and stability over time. This review summarizes the magnitude, variability, and time course of the dynamic molecular and cellular level neural tissue responses induced by state-of-the-art implantable devices. Studies show that insertion injuries and foreign body response can impact signal quality across all implanted central nervous system (CNS) sensors to varying degrees over both acute (seconds to minutes) and chronic periods (weeks to months). Understanding the underlying biological processes behind the brain tissue response to the devices at the cellular and molecular level leads to a variety of intervention strategies for improving signal sensitivity and longevity. PMID:25546652

  7. Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes

    PubMed Central

    Ruby, Maxwell A.; Nomura, Daniel K.; Hudak, Carolyn S. S.; Barber, Anne; Casida, John E.; Krauss, Ronald M.

    2011-01-01

    Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel

  8. Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses.

    PubMed

    Li, Carter; Hancock, Mark A; Sehgal, Priyanka; Zhou, Shufeng; Reinhardt, Dieter P; Philip, Anie

    2016-03-01

    Transforming growth factor-β (TGF-β) is a multifunctional cytokine implicated in many diseases, including tissue fibrosis and cancer. TGF-β mediates diverse biological responses by signalling through type I and II TGF-β receptors (TβRI and TβRII). We have previously identified CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, as a novel TGF-β co-receptor that negatively regulates TGF-β signalling and responses and demonstrated that membrane-anchored CD109 promotes TGF-β receptor degradation via a SMAD7/Smurf2-mediated mechanism. To determine whether CD109 released from the cell surface (soluble CD109 or sCD109) also acts as a TGF-β antagonist, we determined the efficacy of recombinant sCD109 to interact with TGF-β and inhibit TGF-β signalling and responses. Our results demonstrate that sCD109 binds TGF-β with high affinity as determined by surface plasmon resonance (SPR) and cell-based radioligand binding and affinity labelling competition assays. SPR detected slow dissociation kinetics between sCD109 and TGF-β at low concentrations, indicating a stable and effective interaction. In addition, sCD109 antagonizes TGF-β-induced Smad2/3 phosphorylation, transcription and cell migration. Together, our results suggest that sCD109 can bind TGF-β, inhibit TGF-β binding to its receptors and decrease TGF-β signalling and TGF-β-induced cellular responses.

  9. Somatic insulin signaling regulates a germline starvation response in Drosophila egg chambers.

    PubMed

    Burn, K Mahala; Shimada, Yuko; Ayers, Kathleen; Lu, Feiyue; Hudson, Andrew M; Cooley, Lynn

    2015-02-15

    Egg chambers from starved Drosophila females contain large aggregates of processing (P) bodies and cortically enriched microtubules. As this response to starvation is rapidly reversed upon re-feeding females or culturing egg chambers with exogenous bovine insulin, we examined the role of endogenous insulin signaling in mediating the starvation response. We found that systemic Drosophila insulin-like peptides (dILPs) activate the insulin pathway in follicle cells, which then regulate both microtubule and P body organization in the underlying germline cells. This organization is modulated by the motor proteins Dynein and Kinesin. Dynein activity is required for microtubule and P body organization during starvation, while Kinesin activity is required during nutrient-rich conditions. Blocking the ability of egg chambers to form P body aggregates in response to starvation correlated with reduced progeny survival. These data suggest a potential mechanism to maximize fecundity even during periods of poor nutrient availability, by mounting a protective response in immature egg chambers.

  10. New multiple-tap, general-response, reconfigurable photonic signal processor.

    PubMed

    Huang, Thomas X; Yi, Xiaoke; Minasian, Robert A

    2009-03-30

    A new photonic signal processor structure that can realize multiple-taps, with a general response capability, low-noise and widely tunable processor operation, is presented. It is based on a novel concept of employing positive and negative group delay slopes simultaneously by means of a dual-fed chirped fiber Bragg grating, and a new wavelength mapping scheme that enables wavelength re-use. The technique offers scalability, arbitrary responses with both positive and negative taps, tunability, and high frequency operation. Experimental results demonstrate widely tunable filters, with arbitrary bipolar tap generation, no PIIN noise, and with high FSR.

  11. Danger signals in the initiation of the inflammatory response after myocardial infarction.

    PubMed

    de Haan, J J; Smeets, M B; Pasterkamp, G; Arslan, F

    2013-01-01

    During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.

  12. Signalling of Arabidopsis thaliana response to Pieris brassicae eggs shares similarities with PAMP-triggered immunity.

    PubMed

    Gouhier-Darimont, Caroline; Schmiesing, André; Bonnet, Christelle; Lassueur, Steve; Reymond, Philippe

    2013-01-01

    Insect egg deposition activates plant defence, but very little is known about signalling events that control this response. In Arabidopsis thaliana, oviposition by Pieris brassicae triggers salicylic acid (SA) accumulation and induces the expression of defence genes. This is similar to the recognition of pathogen-associated molecular patterns (PAMPs), which are involved in PAMP-triggered immunity (PTI). Here, the involvement of known signalling components of PTI in response to oviposition was studied. Treatment with P. brassicae egg extract caused a rapid induction of early PAMP-responsive genes. In addition, expression of the defence gene PR-1 required EDS1, SID2, and, partially, NPR1, thus implicating the SA pathway downstream of egg recognition. PR-1 expression was triggered by a non-polar fraction of egg extract and by an oxidative burst modulated through the antagonistic action of EDS1 and NUDT7, but which did not depend on the NADPH oxidases RBOHD and RBOHF. Searching for receptors of egg-derived elicitors, a receptor-like kinase mutant, lecRK-I.8, was identified which shows a much reduced induction of PR-1 in response to egg extract treatment. These results demonstrate the importance of the SA pathway in response to egg-derived elicitor(s) and unravel intriguing similarities between the detection of insect eggs and PTI in Arabidopsis.

  13. Measuring stress signaling responses of stomata in isolated epidermis of graminaceous species

    PubMed Central

    Shen, Lei; Sun, Peng; Bonnell, Verity C.; Edwards, Keith J.; Hetherington, Alistair M.; McAinsh, Martin R.; Roberts, Michael R.

    2015-01-01

    Our current understanding of guard cell signaling pathways is derived from studies in a small number of model species. The ability to study stomatal responses in isolated epidermis has been an important factor in elucidating the mechanisms by which the stomata of these species respond to environmental stresses. However, such approaches have rarely been applied to study guard cell signaling in the stomata of graminaceous species (including many of the world’s major crops), in which the guard cells have a markedly different morphology to those in other plants. Our understanding of guard cell signaling in these important species is therefore much more limited. Here, we describe a procedure for the isolation of abaxial epidermal peels from barley, wheat and Brachypodium distachyon. We show that isolated epidermis from these species contains viable guard cells that exhibit typical responses to abscisic acid (ABA) and CO2, as determined by measurements of stomatal apertures. We use the epidermal peel assay technique to investigate in more detail interactions between different environmental factors in barley guard cells, and demonstrate that stomatal closure in response to external CO2 is inhibited at higher temperatures, whilst sensitivity to ABA is enhanced at 30°C compared to 20 and 40°C. PMID:26217375

  14. Regulatory function of Arabidopsis lipid transfer protein 1 (LTP1) in ethylene response and signaling.

    PubMed

    Wang, Honglin; Sun, Yue; Chang, Jianhong; Zheng, Fangfang; Pei, Haixia; Yi, Yanjun; Chang, Caren; Dong, Chun-Hai

    2016-07-01

    Ethylene as a gaseous plant hormone is directly involved in various processes during plant growth and development. Much is known regarding the ethylene receptors and regulatory factors in the ethylene signal transduction pathway. In Arabidopsis thaliana, REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1) can interact with and positively regulates the ethylene receptor ETHYLENE RESPONSE1 (ETR1). In this study we report the identification and characterization of an RTE1-interacting protein, a putative Arabidopsis lipid transfer protein 1 (LTP1) of unknown function. Through bimolecular fluorescence complementation, a direct molecular interaction between LTP1 and RTE1 was verified in planta. Analysis of an LTP1-GFP fusion in transgenic plants and plasmolysis experiments revealed that LTP1 is localized to the cytoplasm. Analysis of ethylene responses showed that the ltp1 knockout is hypersensitive to 1-aminocyclopropanecarboxylic acid (ACC), while LTP1 overexpression confers insensitivity. Analysis of double mutants etr1-2 ltp1 and rte1-3 ltp1 demonstrates a regulatory function of LTP1 in ethylene receptor signaling through the molecular association with RTE1. This study uncovers a novel function of Arabidopsis LTP1 in the regulation of ethylene response and signaling. PMID:27097903

  15. Measuring stress signaling responses of stomata in isolated epidermis of graminaceous species.

    PubMed

    Shen, Lei; Sun, Peng; Bonnell, Verity C; Edwards, Keith J; Hetherington, Alistair M; McAinsh, Martin R; Roberts, Michael R

    2015-01-01

    Our current understanding of guard cell signaling pathways is derived from studies in a small number of model species. The ability to study stomatal responses in isolated epidermis has been an important factor in elucidating the mechanisms by which the stomata of these species respond to environmental stresses. However, such approaches have rarely been applied to study guard cell signaling in the stomata of graminaceous species (including many of the world's major crops), in which the guard cells have a markedly different morphology to those in other plants. Our understanding of guard cell signaling in these important species is therefore much more limited. Here, we describe a procedure for the isolation of abaxial epidermal peels from barley, wheat and Brachypodium distachyon. We show that isolated epidermis from these species contains viable guard cells that exhibit typical responses to abscisic acid (ABA) and CO2, as determined by measurements of stomatal apertures. We use the epidermal peel assay technique to investigate in more detail interactions between different environmental factors in barley guard cells, and demonstrate that stomatal closure in response to external CO2 is inhibited at higher temperatures, whilst sensitivity to ABA is enhanced at 30°C compared to 20 and 40°C. PMID:26217375

  16. Characterization of photomorphogenic responses and signaling cascades controlled by phytochrome-A expressed in different tissues.

    PubMed

    Kirchenbauer, Daniel; Viczián, András; Ádám, Éva; Hegedűs, Zoltán; Klose, Cornelia; Leppert, Michael; Hiltbrunner, Andreas; Kircher, Stefan; Schäfer, Eberhard; Nagy, Ferenc

    2016-07-01

    The photoreceptor phytochrome A acts as a light-dependent molecular switch and regulates responses initiated by very low fluences of light (VLFR) and high fluences (HIR) of far-red light. PhyA is expressed ubiquitously, but how phyA signaling is orchestrated to regulate photomorphogenesis is poorly understood. To address this issue, we generated transgenic Arabidopsis thaliana phyA-201 mutant lines expressing the biologically active phyA-YFP photoreceptor in different tissues, and analyzed the expression of several reporter genes, including ProHY5:HY5-GFP and Pro35S:CFP-PIF1, and various FR-HIR-dependent physiological responses. We show that phyA action in one tissue is critical and sufficient to regulate flowering time and root growth; control of cotyledon and hypocotyl growth requires simultaneous phyA activity in different tissues; and changes detected in the expression of reporters are not restricted to phyA-containing cells. We conclude that FR-HIR-controlled morphogenesis in Arabidopsis is mediated partly by tissue-specific and partly by intercellular signaling initiated by phyA. Intercellular signaling is critical for many FR-HIR induced responses, yet it appears that phyA modulates the abundance and activity of key regulatory transcription factors in a tissue-autonomous fashion. PMID:27027866

  17. The role of intracellular calcium signals in inflammatory responses of polarised cystic fibrosis human airway epithelia.

    PubMed

    Ribeiro, Carla Maria Pedrosa

    2006-01-01

    Hyperinflammatory host responses to bacterial infection have been postulated to be a key step in the pathogenesis of cystic fibrosis (CF) lung disease. Previous studies have indicated that the CF airway epithelium itself contributes to the hyperinflammation of CF airways via an excessive inflammatory response to bacterial infection. However, it has been controversial whether the hyperinflammation of CF epithelia results from mutations in the CF transmembrane conductance regulator (CFTR) and/or is a consequence of persistent airways infection. Recent studies have demonstrated that intracellular calcium (Ca2+i) signals consequent to activation of apical G protein-coupled receptors (GPCRs) by pro-inflammatory mediators are increased in CF airway epithelia. Because of the relationship between Ca2+i mobilisation and inflammatory responses, the mechanism for the increased Ca2+i signals in CF was investigated and found to result from endoplasmic reticulum (ER) Ca2+ store expansion. The ER Ca2+ store expansion imparts a hyperinflammatory phenotype to chronically infected airway epithelia as a result of the larger Ca2+i mobilisation coupled to an excessive inflammatory response following GPCR activation. The ER expansion is not dependent on ER retention of misfolded DeltaF508 CFTR, but reflects an epithelial response acquired following persistent luminal airway infection. With respect to the mechanism of ER expansion in CF, the current view is that chronic airway epithelial infection triggers an unfolded protein response as a result of the increased flux of newly synthesised inflammatory mediators and defensive factors into the ER compartment. This unfolded protein response is coupled to X-box binding protein 1 (XBP-1) mRNA splicing and transcription of genes associated with the expansion of the protein-folding capacity of the ER (e.g. increases in ER chaperones and ER membranes). These studies have revealed a novel adaptive response in chronically infected airway epithelia

  18. Basic Properties of the p38 Signaling Pathway in Response to Hyperosmotic Shock

    PubMed Central

    Ben Messaoud, Nabil; Katzarova, Ilina; López, José M.

    2015-01-01

    Some properties of signaling systems, like ultrasensitivity, hysteresis (a form of biochemical memory), and all-or-none responses at a single cell level, are important to understand the regulation of irreversible processes. Xenopus oocytes are a suitable cell model to study these properties. The p38 MAPK (mitogen-activated protein kinase) pathway is activated by different stress stimuli, including osmostress, and regulates multiple biological processes, from immune response to cell cycle. Recently, we have reported that activation of p38 and JNK regulate osmostress-induced apoptosis in Xenopus oocytes and that sustained activation of p38 accelerates cytochrome c release and caspase-3 activation. However, the signaling properties of p38 in response to hyperosmotic shock have not been studied. Here we show, using Xenopus oocytes as a cell model, that hyperosmotic shock activates the p38 signaling pathway with an ultrasensitive and bimodal response in a time-dependent manner, and with low hysteresis. At a single cell level, p38 activation is not well correlated with cytochrome c release 2 h after hyperosmotic shock, but a good correlation is observed at 4 h after treatment. Interestingly, cytochrome c microinjection induces p38 phosphorylation through caspase-3 activation, and caspase inhibition reduces p38 activation induced by osmostress, indicating that a positive feedback loop is engaged by hyperosmotic shock. To know the properties of the stress protein kinases activated by hyperosmotic shock will facilitate the design of computational models to predict cellular responses in human diseases caused by perturbations in fluid osmolarity. PMID:26335493

  19. Microbiome-Derived Tryptophan Metabolites and Their Aryl Hydrocarbon Receptor-Dependent Agonist and Antagonist Activities

    PubMed Central

    Jin, Un-Ho; Lee, Syng-Ook; Sridharan, Gautham; Lee, Kyongbum; Davidson, Laurie A.; Jayaraman, Arul; Chapkin, Robert S.; Alaniz, Robert

    2014-01-01

    The tryptophan metabolites indole, indole-3-acetate, and tryptamine were identified in mouse cecal extracts and fecal pellets by mass spectrometry. The aryl hydrocarbon receptor (AHR) agonist and antagonist activities of these microbiota-derived compounds were investigated in CaCo-2 intestinal cells as a model for understanding their interactions with colonic tissue, which is highly aryl hydrocarbon (Ah)–responsive. Activation of Ah-responsive genes demonstrated that tryptamine and indole 3-acetate were AHR agonists, whereas indole was an AHR antagonist that inhibited TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)–induced CYP1A1 expression. In contrast, the tryptophan metabolites exhibited minimal anti-inflammatory activities, whereas TCDD decreased phorbol ester-induced CXCR4 [chemokine (C-X-C motif) receptor 4] gene expression, and this response was AHR dependent. These results demonstrate that the tryptophan metabolites indole, tryptamine, and indole-3-acetate modulate AHR-mediated responses in CaCo-2 cells, and concentrations of indole that exhibit AHR antagonist activity (100–250 μM) are detected in the intestinal microbiome. PMID:24563545

  20. GABA[sub A] Receptor-Dependent Synchronization Leads to Ictogenesis in the Human Dysplastic Cortex

    ERIC Educational Resources Information Center

    D'Antuono, M.; Louvel, J.; Kohling, R.; Mattia, D.; Bernasconi, A.; Olivier, A.; Turak, B.; Devaux, A.; Pumain, R.; Avoli, M.

    2004-01-01

    Patients with Taylor's type focal cortical dysplasia (FCD) present with seizures that are often medically intractable. Here, we attempted to identify the cellular and pharmacological mechanisms responsible for this epileptogenic state by using field potential and K[superscript +]-selective recordings in neocortical slices obtained from epileptic…

  1. A novel interleukin 33/ST2 signaling regulates inflammatory response in human corneal epithelium.

    PubMed

    Lin, Jing; Zhang, Lili; Zhao, Guiqiu; Su, Zhitao; Deng, Ruzhi; Pflugfelder, Stephen C; Li, De-Quan

    2013-01-01

    Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediators. This study was to identify the presence and function of ST2 and explore the role of IL-33/ST2 signaling in regulating the inflammatory cytokine production in corneal epithelial cells. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokine and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 mRNA and protein were detected in donor corneal epithelium and cultured HCECs, and ST2 signal was enhanced by exposure to IL-33. IL-33 significantly stimulated the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein phosphorylation and nuclear translocation, and also suppressed the production of these inflammatory cytokines and chemokine induced by IL-33. These findings demonstrate that ST2 is present in human corneal epithelial cells, and IL-33/ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses in ocular surface.

  2. A novel interleukin 33/ST2 signaling regulates inflammatory response in human corneal epithelium.

    PubMed

    Lin, Jing; Zhang, Lili; Zhao, Guiqiu; Su, Zhitao; Deng, Ruzhi; Pflugfelder, Stephen C; Li, De-Quan

    2013-01-01

    Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediators. This study was to identify the presence and function of ST2 and explore the role of IL-33/ST2 signaling in regulating the inflammatory cytokine production in corneal epithelial cells. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokine and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 mRNA and protein were detected in donor corneal epithelium and cultured HCECs, and ST2 signal was enhanced by exposure to IL-33. IL-33 significantly stimulated the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein phosphorylation and nuclear translocation, and also suppressed the production of these inflammatory cytokines and chemokine induced by IL-33. These findings demonstrate that ST2 is present in human corneal epithelial cells, and IL-33/ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses in ocular surface. PMID:23585867

  3. A Novel Interleukin 33/ST2 Signaling Regulates Inflammatory Response in Human Corneal Epithelium

    PubMed Central

    Lin, Jing; Zhang, Lili; Zhao, Guiqiu; Su, Zhitao; Deng, Ruzhi; Pflugfelder, Stephen C.; Li, De-Quan

    2013-01-01

    Interleukin (IL) 33, a member of IL-1 cytokine family, is well known to promote Th2 type immune responses by signaling through its receptor ST2. However, it is not clear whether ST2 is expressed by mucosal epithelium, and how it responds to IL-33 to induce inflammatory mediators. This study was to identify the presence and function of ST2 and explore the role of IL-33/ST2 signaling in regulating the inflammatory cytokine production in corneal epithelial cells. Human corneal tissues and cultured primary human corneal epithelial cells (HCECs) were treated with IL-33 in different concentrations without or with different inhibitors to evaluate the expression, location and signaling pathways of ST2 in regulating production of inflammatory cytokine and chemokine. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was measured by enzyme-linked immunosorbent assay (ELISA), immunohistochemical and immunofluorescent staining. ST2 mRNA and protein were detected in donor corneal epithelium and cultured HCECs, and ST2 signal was enhanced by exposure to IL-33. IL-33 significantly stimulated the production of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokine IL-8 by HCECs at both mRNA and protein levels. The stimulated production of inflammatory mediators by IL-33 was blocked by ST2 antibody or soluble ST2 protein. Interestingly, the IκB-α inhibitor BAY11-7082 or NF-κB activation inhibitor quinazoline blocked NF-κB p65 protein phosphorylation and nuclear translocation, and also suppressed the production of these inflammatory cytokines and chemokine induced by IL-33. These findings demonstrate that ST2 is present in human corneal epithelial cells, and IL-33/ST2 signaling plays an important role in regulating IL-33 induced inflammatory responses in ocular surface. PMID:23585867

  4. Root to leaf electrical signaling in avocado in response to light and soil water content.

    PubMed

    Gil, Pilar M; Gurovich, Luis; Schaffer, Bruce; Alcayaga, Julio; Rey, Sergio; Iturriaga, Rodrigo

    2008-07-01

    Phytomonitoring techniques for irrigation of avocado orchards indicate that plants respond very rapidly to fluctuations in soil water content. Root to leaf abscicic acid transport cannot fully explain the almost immediate response of stomata to either irrigation and/or sudden changes in climatic conditions. Therefore, we studied the existence of a fast conducting signal between roots and leaves, and the possible involvement of such a signal in the regulation of stomatal behavior. Two-year-old avocado trees were subjected to drying and re-watering cycles or changes in incident radiation (light or darkness). The difference in extracellular electrical potential between the leaf petiole and the base of stem (DeltaV(L-S)) was continuously recorded. Stomatal conductance (gs) was also recorded for the same leaves that were used for voltage difference measurements. A sudden change in soil water content induced by root drying and re-watering was accompanied by a slow, significant change in the recorded DeltaV(L-S) signal, which was fully developed at 52 and 32min for root drying and re-watering, respectively. We found an inverse correlation (r=-0.56) between the change of DeltaV(L-S) and the gs difference measured before and after each soil-drying treatment. Plants that were girdled to disrupt the phloem and then irrigated tended to have lower DeltaV(L-S) differences over time than non-girdled irrigated plants, suggesting that the electrical signal was transmitted in the phloem. The existence of a fast signal transmitted from the root to the leaf that can be measured and correlated with stomatal control opens the possibility of developing a new phytomonitoring technique and/or artificially modifying plant responses by imposing agronomic management strategies aimed at rapid stomatal adaptation to changes in soil water content.

  5. Projecting boreal bird responses to climate change: the signal exceeds the noise.

    PubMed

    Stralberg, D; Matsuoka, S M; Hamann, A; Bayne, E M; Sólymos, P; Schmiegelow, F K A; Wang, X; Cumming, S G; Song, S J

    2015-01-01

    For climate change projections to be useful, the magnitude of change must be understood relative to the magnitude of uncertainty in model predictions. We quantified the signal-to-noise ratio in projected distributional responses of boreal birds to climate change, and compared sources of uncertainty. Boosted regression tree models of abundance were generated for 80 boreal-breeding bird species using a comprehensive data set of standardized avian point counts (349,629 surveys at 122,202 unique locations) and 4-km climate, land use, and topographic data. For projected changes in abundance, we calculated signal-to-noise ratios and examined variance components related to choice of global climate model (GCM) and two sources of species distribution model (SDM) uncertainty: sampling error and variable selection. We also evaluated spatial, temporal, and interspecific variation in these sources of uncertainty. The mean signal-to-noise ratio across species increased over time to 2.87 by the end of the 21st century, with the signal greater than the noise for 88% of species. Across species, climate change represented the largest component (0.44) of variance in projected abundance change. Among sources of uncertainty evaluated, choice of GCM (mean variance component = 0.17) was most important for 66% of species, sampling error (mean= 0.12) for 29% of species, and variable selection (mean =0.05) for 5% of species. Increasing the number of GCMs from four to 19 had minor effects on these results. The range of projected changes and uncertainty characteristics across species differed markedly, reinforcing the individuality of species' responses to climate change and the challenges of one-size-fits-all approaches to climate change adaptation. We discuss the usefulness of different conservation approaches depending on the strength of the climate change signal relative to the noise, as well as the dominant source of prediction uncertainty. PMID:26255357

  6. Subthreshold membrane responses underlying sparse spiking to natural vocal signals in auditory cortex

    PubMed Central

    Perks, Krista Eva; Gentner, Timothy Q.

    2015-01-01

    Natural acoustic communication signals, such as speech, are typically high-dimensional with a wide range of co-varying spectro-temporal features at multiple timescales. The synaptic and network mechanisms for encoding these complex signals are largely unknown. We are investigating these mechanisms in high-level sensory regions of the songbird auditory forebrain, where single neurons show sparse, object-selective spiking responses to conspecific songs. Using whole-cell in-vivo patch clamp techniques in the caudal mesopallium and the caudal nidopallium of starlings, we examine song-driven subthreshold and spiking activity. We find that both the subthreshold and the spiking activity are reliable (i.e., the same song drives a similar response each time it is presented) and specific (i.e. responses to different songs are distinct). Surprisingly, however, the reliability and specificity of the sub-threshold response was uniformly high regardless of when the cell spiked, even for song stimuli that drove no spikes. We conclude that despite a selective and sparse spiking response, high-level auditory cortical neurons are under continuous, non-selective, stimulus-specific synaptic control. To investigate the role of local network inhibition in this synaptic control, we then recorded extracellularly while pharmacologically blocking local GABA-ergic transmission. This manipulation modulated the strength and the reliability of stimulus-driven spiking, consistent with a role for local inhibition in regulating the reliability of network activity and the stimulus specificity of the subthreshold response in single cells. We discuss these results in the context of underlying computations that could generate sparse, stimulus-selective spiking responses, and models for hierarchical pooling. PMID:25728189

  7. Methylglyoxal: An Emerging Signaling Molecule in Plant Abiotic Stress Responses and Tolerance

    PubMed Central

    Hoque, Tahsina S.; Hossain, Mohammad A.; Mostofa, Mohammad G.; Burritt, David J.; Fujita, Masayuki; Tran, Lam-Son P.

    2016-01-01

    The oxygenated short aldehyde methylglyoxal (MG) is produced in plants as a by-product of a number of metabolic reactions, including elimination of phosphate groups from glycolysis intermediates dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. MG is mostly detoxified by the combined actions of the enzymes glyoxalase I and glyoxalase II that together with glutathione make up the glyoxalase system. Under normal growth conditions, basal levels of MG remain low in plants; however, when plants are exposed to abiotic stress, MG can accumulate to much higher levels. Stress-induced MG functions as a toxic molecule, inhibiting different developmental processes, including seed germination, photosynthesis and root growth, whereas MG, at low levels, acts as an important signaling molecule, involved in regulating diverse events, such as cell proliferation and survival, control of the redox status of cells, and many other aspects of general metabolism and cellular homeostases. MG can modulate plant stress responses by regulating stomatal opening and closure, the production of reactive oxygen species, cytosolic calcium ion concentrations, the activation of inward rectifying potassium channels and the expression of many stress-responsive genes. MG appears to play important roles in signal transduction by transmitting and amplifying cellular signals and functions that promote adaptation of plants growing under adverse environmental conditions. Thus, MG is now considered as a potential biochemical marker for plant abiotic stress tolerance, and is receiving considerable attention by the scientific community. In this review, we will summarize recent findings regarding MG metabolism in plants under abiotic stress, and evaluate the concept of MG signaling. In addition, we will demonstrate the importance of giving consideration to MG metabolism and the glyoxalase system, when investigating plant adaptation and responses to various environmental stresses. PMID:27679640

  8. Methylglyoxal: An Emerging Signaling Molecule in Plant Abiotic Stress Responses and Tolerance

    PubMed Central

    Hoque, Tahsina S.; Hossain, Mohammad A.; Mostofa, Mohammad G.; Burritt, David J.; Fujita, Masayuki; Tran, Lam-Son P.

    2016-01-01

    The oxygenated short aldehyde methylglyoxal (MG) is produced in plants as a by-product of a number of metabolic reactions, including elimination of phosphate groups from glycolysis intermediates dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. MG is mostly detoxified by the combined actions of the enzymes glyoxalase I and glyoxalase II that together with glutathione make up the glyoxalase system. Under normal growth conditions, basal levels of MG remain low in plants; however, when plants are exposed to abiotic stress, MG can accumulate to much higher levels. Stress-induced MG functions as a toxic molecule, inhibiting different developmental processes, including seed germination, photosynthesis and root growth, whereas MG, at low levels, acts as an important signaling molecule, involved in regulating diverse events, such as cell proliferation and survival, control of the redox status of cells, and many other aspects of general metabolism and cellular homeostases. MG can modulate plant stress responses by regulating stomatal opening and closure, the production of reactive oxygen species, cytosolic calcium ion concentrations, the activation of inward rectifying potassium channels and the expression of many stress-responsive genes. MG appears to play important roles in signal transduction by transmitting and amplifying cellular signals and functions that promote adaptation of plants growing under adverse environmental conditions. Thus, MG is now considered as a potential biochemical marker for plant abiotic stress tolerance, and is receiving considerable attention by the scientific community. In this review, we will summarize recent findings regarding MG metabolism in plants under abiotic stress, and evaluate the concept of MG signaling. In addition, we will demonstrate the importance of giving consideration to MG metabolism and the glyoxalase system, when investigating plant adaptation and responses to various environmental stresses.

  9. Cardiopulmonary Bypass Down-Regulates NOD Signaling and Inflammatory Response in Children with Congenital Heart Disease.

    PubMed

    Yang, Qinghua; Liao, Jianyi; Huang, Jie; Li, Yi Ping; Huang, Shungen; Zhou, Huiting; Xie, Yi; Pan, Jian; Li, Yanhong; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatory cytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients. PMID:27622570

  10. Electrical signaling, stomatal conductance, ABA and Ethylene content in avocado trees in response to root hypoxia

    PubMed Central

    Gurovich, Luis; Schaffer, Bruce; García, Nicolás; Iturriaga, Rodrigo

    2009-01-01

    Avocado (Persea americana Mill.) trees are among the most sensitive of fruit tree species to root hypoxia as a result of flooded or poorly drained soil. Similar to drought stress, an early physiological response to root hypoxia in avocado is a reduction of stomatal conductance. It has been previously determined in avocado trees that an extracellular electrical signal between the base of stem and leaves is produced and related to reductions in stomatal conductance in response to drought stress. The current study was designed to determine if changes in the extracellular electrical potential between the base of the stem and leaves in avocado trees could also be detected in response to short-term (min) or long-term (days) root hypoxia, and if these signals could be related to stomatal conductance (gs), root and leaf ABA and ACC concentrations, ethylene emission from leaves and leaf abscission. In contrast to previous observations for drought-stressed trees, short-term or long-term root hypoxia did not stimulate an electrical potential difference between the base of the stem and leaves. Short-term hypoxia did not result in a significant decrease in gs compared with plants in the control treatment, and no differences in ABA concentration were found between plants subjected to hypoxia and control plants. Long-term hypoxia in the root zone resulted in a significant decrease in gs, increased leaf ethylene and increased leaf abscission. The results indicate that for avocado trees exposed to root hypoxia, electrical signals do not appear to be the primary root-to-shoot communication mechanism involved in signaling for stomatal closure as a result of hypoxia in the root zone. PMID:19649181

  11. Methylglyoxal: An Emerging Signaling Molecule in Plant Abiotic Stress Responses and Tolerance.

    PubMed

    Hoque, Tahsina S; Hossain, Mohammad A; Mostofa, Mohammad G; Burritt, David J; Fujita, Masayuki; Tran, Lam-Son P

    2016-01-01

    The oxygenated short aldehyde methylglyoxal (MG) is produced in plants as a by-product of a number of metabolic reactions, including elimination of phosphate groups from glycolysis intermediates dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. MG is mostly detoxified by the combined actions of the enzymes glyoxalase I and glyoxalase II that together with glutathione make up the glyoxalase system. Under normal growth conditions, basal levels of MG remain low in plants; however, when plants are exposed to abiotic stress, MG can accumulate to much higher levels. Stress-induced MG functions as a toxic molecule, inhibiting different developmental processes, including seed germination, photosynthesis and root growth, whereas MG, at low levels, acts as an important signaling molecule, involved in regulating diverse events, such as cell proliferation and survival, control of the redox status of cells, and many other aspects of general metabolism and cellular homeostases. MG can modulate plant stress responses by regulating stomatal opening and closure, the production of reactive oxygen species, cytosolic calcium ion concentrations, the activation of inward rectifying potassium channels and the expression of many stress-responsive genes. MG appears to play important roles in signal transduction by transmitting and amplifying cellular signals and functions that promote adaptation of plants growing under adverse environmental conditions. Thus, MG is now considered as a potential biochemical marker for plant abiotic stress tolerance, and is receiving considerable attention by the scientific community. In this review, we will summarize recent findings regarding MG metabolism in plants under abiotic stress, and evaluate the concept of MG signaling. In addition, we will demonstrate the importance of giving consideration to MG metabolism and the glyoxalase system, when investigating plant adaptation and responses to various environmental stresses. PMID:27679640

  12. Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila.

    PubMed

    Ajuria, Leiore; Nieva, Claudia; Winkler, Clint; Kuo, Dennis; Samper, Núria; Andreu, María José; Helman, Aharon; González-Crespo, Sergio; Paroush, Ze'ev; Courey, Albert J; Jiménez, Gerardo

    2011-03-01

    RTK/Ras/MAPK signaling pathways play key functions in metazoan development, but how they control expression of downstream genes is not well understood. In Drosophila, it is generally assumed that most transcriptional responses to RTK signal activation depend on binding of Ets-family proteins to specific cis-acting sites in target enhancers. Here, we show that several Drosophila RTK pathways control expression of downstream genes through common octameric elements that are binding sites for the HMG-box factor Capicua, a transcriptional repressor that is downregulated by RTK signaling in different contexts. We show that Torso RTK-dependent regulation of terminal gap gene expression in the early embryo critically depends on Capicua octameric sites, and that binding of Capicua to these sites is essential for recruitment of the Groucho co-repressor to the huckebein enhancer in vivo. We then show that subsequent activation of the EGFR RTK pathway in the neuroectodermal region of the embryo controls dorsal-ventral gene expression by downregulating the Capicua protein, and that this control also depends on Capicua octameric motifs. Thus, a similar mechanism of RTK regulation operates during subdivision of the anterior-posterior and dorsal-ventral embryonic axes. We also find that identical DNA octamers mediate Capicua-dependent regulation of another EGFR target in the developing wing. Remarkably, a simple combination of activator-binding sites and Capicua motifs is sufficient to establish complex patterns of gene expression in response to both Torso and EGFR activation in different tissues. We conclude that Capicua octamers are general response elements for RTK signaling in Drosophila.

  13. Electrical signaling, stomatal conductance, ABA and ethylene content in avocado trees in response to root hypoxia.

    PubMed

    Gil, Pilar M; Gurovich, Luis; Schaffer, Bruce; García, Nicolás; Iturriaga, Rodrigo

    2009-02-01

    Avocado (Persea americana Mill.) trees are among the most sensitive of fruit tree species to root hypoxia as a result of flooded or poorly drained soil. Similar to drought stress, an early physiological response to root hypoxia in avocado is a reduction of stomatal conductance. It has been previously determined in avocado trees that an extracellular electrical signal between the base of stem and leaves is produced and related to reductions in stomatal conductance in response to drought stress. The current study was designed to determine if changes in the extracellular electrical potential between the base of the stem and leaves in avocado trees could also be detected in response to short-term (min) or long-term (days) root hypoxia, and if these signals could be related to stomatal conductance (gs), root and leaf ABA and ACC concentrations, ethylene emission from leaves and leaf abscission. In contrast to previous observations for drought-stressed trees, short-term or long-term root hypoxia did not stimulate an electrical potential difference between the base of the stem and leaves. Short-term hypoxia did not result in a significant decrease in gs compared with plants in the control treatment, and no differences in ABA concentration were found between plants subjected to hypoxia and control plants. Long-term hypoxia in the root zone resulted in a significant decrease in gs, increased leaf ethylene and increased leaf abscission. The results indicate that for avocado trees exposed to root hypoxia, electrical signals do not appear to be the primary root-to-shoot communication mechanism involved in signaling for stomatal closure as a result of hypoxia in the root zone.

  14. Methylglyoxal: An Emerging Signaling Molecule in Plant Abiotic Stress Responses and Tolerance.

    PubMed

    Hoque, Tahsina S; Hossain, Mohammad A; Mostofa, Mohammad G; Burritt, David J; Fujita, Masayuki; Tran, Lam-Son P

    2016-01-01

    The oxygenated short aldehyde methylglyoxal (MG) is produced in plants as a by-product of a number of metabolic reactions, including elimination of phosphate groups from glycolysis intermediates dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. MG is mostly detoxified by the combined actions of the enzymes glyoxalase I and glyoxalase II that together with glutathione make up the glyoxalase system. Under normal growth conditions, basal levels of MG remain low in plants; however, when plants are exposed to abiotic stress, MG can accumulate to much higher levels. Stress-induced MG functions as a toxic molecule, inhibiting different developmental processes, including seed germination, photosynthesis and root growth, whereas MG, at low levels, acts as an important signaling molecule, involved in regulating diverse events, such as cell proliferation and survival, control of the redox status of cells, and many other aspects of general metabolism and cellular homeostases. MG can modulate plant stress responses by regulating stomatal opening and closure, the production of reactive oxygen species, cytosolic calcium ion concentrations, the activation of inward rectifying potassium channels and the expression of many stress-responsive genes. MG appears to play important roles in signal transduction by transmitting and amplifying cellular signals and functions that promote adaptation of plants growing under adverse environmental conditions. Thus, MG is now considered as a potential biochemical marker for plant abiotic stress tolerance, and is receiving considerable attention by the scientific community. In this review, we will summarize recent findings regarding MG metabolism in plants under abiotic stress, and evaluate the concept of MG signaling. In addition, we will demonstrate the importance of giving consideration to MG metabolism and the glyoxalase system, when investigating plant adaptation and responses to various environmental stresses.

  15. Cardiopulmonary Bypass Down-Regulates NOD Signaling and Inflammatory Response in Children with Congenital Heart Disease

    PubMed Central

    Li, Yi Ping; Huang, Shungen; Zhou, Huiting; Xie, Yi; Pan, Jian; Li, Yanhong; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatory cytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients. PMID:27622570

  16. Systems approach to characterizing cell signaling in host-pathogen response to staphylococcus toxin.

    SciTech Connect

    Ambrosiano, J. J.; Gupta, G.; Gray, P. C.; Hush, D. R.; Fugate, M. L.; Cleland, T. J.; Roberts, R. M.; Hlavacek, W. S.; Smith, J. L.

    2002-01-01

    The mammalian immune system is capable of highly sensitive and specific responses when challenged by pathogens. It is believed that the human immune repertoire - the total number of distinct antigens that can be recognized - is between 10{sup 9} and 10{sup 11}. The most specific responses are cell mediated and involve complex and subtle communications among the immune cells via small proteins known as cytokines. The details of host-pathogen response are exceedingly complex, involving both intracellular and extracellular mechanisms. These include the presentation of antigen by B cells to helper T cells and subsequent stimulation of signal transduction pathways and gene expression within both B and T-cell populations. These in turn lead to the secretion of cytokines and receptor expression. Intercellular cytokine signaling can trigger a host of immune responses including the proliferation and specialization of naive immune cells and the marshaling of effector cells to combat infection. In the ever-evolving game of threat and countermeasure played out by pathogens and their intended hosts, there are direct assaults aimed at subverting the immune system's ability to recognize antigens and respond effectively to challenge by pathogens. Staphylococcus is one of these. Staph bacteria secrete a variety of toxins known generically as superantigens. Superantigen molecules bind simultaneously to the MHC receptors of antigen presenting cells and the TCR receptors of helper T cells, locking them in place and leading to overstimulation. This strategy can effectively burn out the immune system in a matter of days.

  17. Regulation of fruit and seed response to heat and drought by sugars as nutrients and signals

    PubMed Central

    Liu, Yong-Hua; Offler, Christina E.; Ruan, Yong-Ling

    2013-01-01

    A large body of evidence shows that sugars function both as nutrients and signals to regulate fruit and seed set under normal and stress conditions including heat and drought. Inadequate sucrose import to, and its degradation within, reproductive organs cause fruit and seed abortion under heat and drought. As nutrients, sucrose-derived hexoses provide carbon skeletons and energy for growth and development of fruits and seeds. Sugar metabolism can also alleviate the impact of stress on fruit and seed through facilitating biosynthesis of heat shock proteins (Hsps) and non-enzymic antioxidants (e.g., glutathione, ascorbic acid), which collectively maintain the integrity of membranes and prevent programmed cell death (PCD) through protecting proteins and scavenging reactive oxygen species (ROS). In parallel, sugars (sucrose, glucose, and fructose), also exert signaling roles through cross-talk with hormone and ROS signaling pathways and by mediating cell division and PCD. At the same time, emerging data indicate that sugar-derived signaling systems, including trehalose-6 phosphate (T6P), sucrose non-fermenting related kinase-1 (SnRK), and the target of rapamycin (TOR) kinase complex also play important roles in regulating plant development through modulating nutrient and energy signaling and metabolic processes, especially under abiotic stresses where sugar availability is low. This review aims to evaluate recent progress of research on abiotic stress responses of reproductive organs focusing on roles of sugar metabolism and signaling and addressing the possible biochemical and molecular mechanism by which sugars regulate fruit and seed set under heat and drought. PMID:23914195

  18. Single exposure to cocaine impairs aspartate uptake in the pre-frontal cortex via dopamine D1-receptor dependent mechanisms.

    PubMed

    Sathler, Matheus Figueiredo; Stutz, Bernardo; Martins, Robertta Silva; Dos Santos Pereira, Maurício; Pecinalli, Ney Roner; Santos, Luis E; Taveira-da-Silva, Rosilane; Lowe, Jennifer; de Freitas, Isis Grigorio; de Melo Reis, Ricardo Augusto; Manhães, Alex C; Kubrusly, Regina C C

    2016-08-01

    Dopamine and glutamate play critical roles in the reinforcing effects of cocaine. We demonstrated that a single intraperitoneal administration of cocaine induces a significant decrease in [(3)H]-d-aspartate uptake in the pre-frontal cortex (PFC). This decrease is associated with elevated dopamine levels, and requires dopamine D1-receptor signaling (D1R) and adenylyl cyclase activation. The effect was observed within 10min of cocaine administration and lasted for up to 30min. This rapid response is related to D1R-mediated cAMP-mediated activation of PKA and phosphorylation of the excitatory amino acid transporters EAAT1, EAAT2 and EAAT3. We also demonstrated that cocaine exposure increases extracellular d-aspartate, l-glutamate and d-serine in the PFC. Our data suggest that cocaine activates dopamine D1 receptor signaling and PKA pathway to regulate EAATs function and extracellular EAA level in the PFC.

  19. Single exposure to cocaine impairs aspartate uptake in the pre-frontal cortex via dopamine D1-receptor dependent mechanisms.

    PubMed

    Sathler, Matheus Figueiredo; Stutz, Bernardo; Martins, Robertta Silva; Dos Santos Pereira, Maurício; Pecinalli, Ney Roner; Santos, Luis E; Taveira-da-Silva, Rosilane; Lowe, Jennifer; de Freitas, Isis Grigorio; de Melo Reis, Ricardo Augusto; Manhães, Alex C; Kubrusly, Regina C C

    2016-08-01

    Dopamine and glutamate play critical roles in the reinforcing effects of cocaine. We demonstrated that a single intraperitoneal administration of cocaine induces a significant decrease in [(3)H]-d-aspartate uptake in the pre-frontal cortex (PFC). This decrease is associated with elevated dopamine levels, and requires dopamine D1-receptor signaling (D1R) and adenylyl cyclase activation. The effect was observed within 10min of cocaine administration and lasted for up to 30min. This rapid response is related to D1R-mediated cAMP-mediated activation of PKA and phosphorylation of the excitatory amino acid transporters EAAT1, EAAT2 and EAAT3. We also demonstrated that cocaine exposure increases extracellular d-aspartate, l-glutamate and d-serine in the PFC. Our data suggest that cocaine activates dopamine D1 receptor signaling and PKA pathway to regulate EAATs function and extracellular EAA level in the PFC. PMID:27208619

  20. Simultaneous imaging of intrinsic optical signals and cerebral vessel responses during cortical spreading depression in rats

    NASA Astrophysics Data System (ADS)

    Li, Pengcheng; Chen, Shangbin; Luo, Weihua; Luo, Qingming

    2003-12-01

    Cortical spreading depression (CSD) is an important disease model for migraine and cerebral ischemia. We investigated the spatio-temporal characteristics of the intrinsic optical signals (IOS) at 570 nm and the cerebral blood vessel responses during CSD simultaneously by optical reflectance imaging in vivo. The CSD were induced by pinprick in 10 α-chloralose/urethane anesthetized Sprague-Dawley rats. A four-phasic IOS response was observed at pial arteries and parenchymal sites in all experimental animals and an initial slight pial arteries dilation (21.5%+/-13.6%) and constriction (-4.2%+/-3.5%) precedes the dramatic dilation (69.2%+/-26.1%) of pial arterioles was recorded. Our experimental results show a high correlation (r = 0.89+/-0.025) between the IOS response and the diameter changes of the cerebral blood vessels during CSD in rats.

  1. The Role of Mechanistic Target of Rapamycin (mTOR) Complexes Signaling in the Immune Responses

    PubMed Central

    Soliman, Ghada A.

    2013-01-01

    The mechanistic Target of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase which is a member of the PI3K related kinase (PIKK) family. mTOR emerged as a central node in cellular metabolism, cell growth, and differentiation, as well as cancer metabolism. mTOR senses the nutrients, energy, insulin, growth factors, and environmental cues and transmits signals to downstream targets to effectuate the cellular and metabolic response. Recently, mTOR was also implicated in the regulation of both the innate and adaptive immune responses. This paper will summarize the current knowledge of mTOR, as related to the immune microenvironment and immune responses. PMID:23783557

  2. One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament

    PubMed Central

    Cook, Peter F.; Spivak, Mark

    2014-01-01

    Having previously used functional MRI to map the response to a reward signal in the ventral caudate in awake unrestrained dogs, here we examined the importance of signal source to canine caudate activation. Hand signals representing either incipient reward or no reward were presented by a familiar human (each dog’s respective handler), an unfamiliar human, and via illustrated images of hands on a computer screen to 13 dogs undergoing voluntary fMRI. All dogs had received extensive training with the reward and no-reward signals from their handlers and with the computer images and had minimal exposure to the signals from strangers. All dogs showed differentially higher BOLD response in the ventral caudate to the reward versus no reward signals, and there was a robust effect at the group level. Further, differential response to the signal source had a highly significant interaction with a dog’s general aggressivity as measured by the C-BARQ canine personality assessment. Dogs with greater aggressivity showed a higher differential response to the reward signal versus no-reward signal presented by the unfamiliar human and computer, while dogs with lower aggressivity showed a higher differential response to the reward signal versus no-reward signal from their handler. This suggests that specific facets of canine temperament bear more strongly on the perceived reward value of relevant communication signals than does reinforcement history, as each of the dogs were reinforced similarly for each signal, regardless of the source (familiar human, unfamiliar human, or computer). A group-level psychophysiological interaction (PPI) connectivity analysis showed increased functional coupling between the caudate and a region of cortex associated with visual discrimination and learning on reward versus no-reward trials. Our findings emphasize the sensitivity of the domestic dog to human social interaction, and may have other implications and applications pertinent to the training

  3. One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament.

    PubMed

    Cook, Peter F; Spivak, Mark; Berns, Gregory S

    2014-01-01

    Having previously used functional MRI to map the response to a reward signal in the ventral caudate in awake unrestrained dogs, here we examined the importance of signal source to canine caudate activation. Hand signals representing either incipient reward or no reward were presented by a familiar human (each dog's respective handler), an unfamiliar human, and via illustrated images of hands on a computer screen to 13 dogs undergoing voluntary fMRI. All dogs had received extensive training with the reward and no-reward signals from their handlers and with the computer images and had minimal exposure to the signals from strangers. All dogs showed differentially higher BOLD response in the ventral caudate to the reward versus no reward signals, and there was a robust effect at the group level. Further, differential response to the signal source had a highly significant interaction with a dog's general aggressivity as measured by the C-BARQ canine personality assessment. Dogs with greater aggressivity showed a higher differential response to the reward signal versus no-reward signal presented by the unfamiliar human and computer, while dogs with lower aggressivity showed a higher differential response to the reward signal versus no-reward signal from their handler. This suggests that specific facets of canine temperament bear more strongly on the perceived reward value of relevant communication signals than does reinforcement history, as each of the dogs were reinforced similarly for each signal, regardless of the source (familiar human, unfamiliar human, or computer). A group-level psychophysiological interaction (PPI) connectivity analysis showed increased functional coupling between the caudate and a region of cortex associated with visual discrimination and learning on reward versus no-reward trials. Our findings emphasize the sensitivity of the domestic dog to human social interaction, and may have other implications and applications pertinent to the training and

  4. Jasmonate signaling is activated in the very early stages of iron deficiency responses in rice roots.

    PubMed

    Kobayashi, Takanori; Itai, Reiko Nakanishi; Senoura, Takeshi; Oikawa, Takaya; Ishimaru, Yasuhiro; Ueda, Minoru; Nakanishi, Hiromi; Nishizawa, Naoko K

    2016-07-01

    Under low iron availability, plants induce the expression of various genes involved in iron uptake and translocation at the transcriptional level. This iron deficiency response is affected by various plant hormones, but the roles of jasmonates in this response are not well-known. We investigated the involvement of jasmonates in rice iron deficiency responses. High rates of jasmonate-inducible genes were induced during the very early stages of iron deficiency treatment in rice roots. Many jasmonate-inducible genes were also negatively regulated by the ubiquitin ligases OsHRZ1 and OsHRZ2 and positively regulated by the transcription factor IDEF1. Ten out of 35 genes involved in jasmonate biosynthesis and signaling were rapidly induced at 3 h of iron deficiency treatment, and this induction preceded that of known iron deficiency-inducible genes involved in iron uptake and translocation. Twelve genes involved in jasmonate biosynthesis and signaling were also upregulated in HRZ-knockdown roots. Endogenous concentrations of jasmonic acid and jasmonoyl isoleucine tended to be rapidly increased in roots in response to iron deficiency treatment, whereas these concentrations were higher in HRZ-knockdown roots under iron-sufficient conditions. Analysis of the jasmonate-deficient cpm2 mutant revealed that jasmonates repress the expression of many iron deficiency-inducible genes involved in iron uptake and translocation under iron sufficiency, but this repression is partly canceled under an early stage of iron deficiency. These results indicate that jasmonate signaling is activated during the very early stages of iron deficiency, which is partly regulated by IDEF1 and OsHRZs.

  5. Multiple preprosomatostatin sorting signals mediate secretion via discrete cAMP- and tetradecanoylphorbolacetate-responsive pathways.

    PubMed

    Sevarino, K A; Stork, P

    1991-10-01

    We have previously detected a sorting signal in the amino-terminal 78 residues of rat preprosomatostatin (rPPSS) that targets the precursor into a regulated secretory pathway or pathways allowing proteolytic maturation (Sevarino, K. A., Stork, P., Ventimiglia, R., Mandel, G., and Goodman, R. H. (1989) Cell 57, 11-19). To further localize this signal, we constructed three rPPSS expression vectors that code for substitutions or mutations spanning that portion of rPPSS implicated in sorting, and the precursors were expressed in RIN 5F cells. Fractionation of the intracellular products revealed that accurate processing to somatostatin-14 (SS-14) was not affected by any of the mutations. Examination of the secreted products showed no reduction in processing efficiency, indicating that none of the mutations blocked sorting from constitutive into regulated secretion. Finally, we examined the response to two separate secretogogues, cAMP and 12-O-tetradecanoylphorbol-13-acetate (TPA). Clones expressing two of the three mutant precursors displayed the same stimulation of SS-14 secretion by exogenously administered cAMP and TPA as cells expressing wild-type rPPSS, indicating that targeting specifically to the secretory pathway, or pathways, responsive to cAMP and TPA was not disrupted. However, cells expressing the mutant precursor containing a substitution of the amino-terminal 34 residues of rPPSS by the amino terminus of the vesicular stomatitis virus G protein displayed greatly reduced stimulation of SS-14 secretion by TPA, with a less than compensatory increase in response to cAMP, when compared to cells expressing wild-type rPPSS. In conjunction with our previous studies with anglerfish preprosomatostatins, we conclude that 1) the sorting signal(s) in rPPSS necessary for cAMP-responsive secretion are redundant and probably reside within both mature peptide regions and extrapeptide regions; 2) two or more distinct regulated secretory pathways utilized by secreted

  6. Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology

    NASA Technical Reports Server (NTRS)

    Ingber, Donald E.

    2002-01-01

    Great advances have been made in the identification of the soluble angiogenic factors, insoluble extracellular matrix (ECM) molecules, and receptor signaling pathways that mediate control of angiogenesis--the growth of blood capillaries. This review focuses on work that explores how endothelial cells integrate these chemical signals with mechanical cues from their local tissue microenvironment so as to produce functional capillary networks that exhibit specialized form as well as function. These studies have revealed that ECM governs whether an endothelial cell will switch between growth, differentiation, motility, or apoptosis programs in response to a soluble stimulus based on its ability to mechanically resist cell tractional forces and thereby produce cell and cytoskeletal distortion. Transmembrane integrin receptors play a key role in this mechanochemical transduction process because they both organize a cytoskeletal signaling complex within the focal adhesion and preferentially focus mechanical forces on this site. Molecular filaments within the internal cytoskeleton--microfilaments, microtubules, and intermediate filaments--also contribute to the cell's structural and functional response to mechanical stress through their role as discrete support elements within a tensegrity-stabilized cytoskeletal array. Importantly, a similar form of mechanical control also has been shown to be involved in the regulation of contractility in vascular smooth muscle cells and cardiac myocytes. Thus, the mechanism by which cells perform mechanochemical transduction and the implications of these findings for morphogenetic control are discussed in the wider context of vascular development and cardiovascular physiology.

  7. Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet.

    PubMed

    Martínez-Micaelo, N; González-Abuín, N; Ardévol, A; Pinent, M; Petretto, E; Behmoaras, J; Blay, M

    2016-01-01

    Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar-Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.

  8. Evc regulates a symmetrical response to Shh signaling in molar development.

    PubMed

    Nakatomi, M; Hovorakova, M; Gritli-Linde, A; Blair, H J; MacArthur, K; Peterka, M; Lesot, H; Peterkova, R; Ruiz-Perez, V L; Goodship, J A; Peters, H

    2013-03-01

    Tooth morphogenesis involves patterning through the activity of epithelial signaling centers that, among other molecules, secrete Sonic hedgehog (Shh). While it is known that Shh responding cells need intact primary cilia for signal transduction, the roles of individual cilia components for tooth morphogenesis are poorly understood. The clinical features of individuals with Ellis-van Creveld syndrome include various dental anomalies, and we show here that absence of the cilial protein Evc in mice causes various hypo- and hyperplasia defects during molar development. During first molar development, the response to Shh signaling is progressively lost in Evc-deficient embryos and, unexpectedly, the response consistently disappears in a buccal to lingual direction. The important role of Evc for establishing the buccal-lingual axis of the developing first molar is also supported by a displaced activity of the Wnt pathway in Evc mutants. The observed growth abnormalities eventually manifest in first molar microdontia, disruption of molar segmentation and symmetry, root fusions, and delayed differentiation. Analysis of our data indicates that both spatially and temporally disrupted activities of the Shh pathway are the primary cause for the variable dental anomalies seen in patients with Ellis-van Creveld syndrome or Weyers acrodental dysostosis.

  9. Lysophosphatidic Acid (LPA) Receptor 5 Inhibits B Cell Antigen Receptor Signaling and Antibody Response1

    PubMed Central

    Shotts, Kristin; Donovan, Erin E.; Strauch, Pamela; Pujanauski, Lindsey M.; Victorino, Francisco; Al-Shami, Amin; Fujiwara, Yuko; Tigyi, Gabor; Oravecz, Tamas; Pelanda, Roberta; Torres, Raul M.

    2014-01-01

    Lysophospholipids have emerged as biologically important chemoattractants capable of directing lymphocyte development, trafficking and localization. Lysophosphatidic acid (LPA) is a major lysophospholipid found systemically and whose levels are elevated in certain pathological settings such as cancer and infections. Here, we demonstrate that BCR signal transduction by mature murine B cells is inhibited upon LPA engagement of the LPA5 (GPR92) receptor via a Gα12/13 – Arhgef1 pathway. The inhibition of BCR signaling by LPA5 manifests by impaired intracellular calcium store release and most likely by interfering with inositol 1,4,5-trisphosphate receptor activity. We further show that LPA5 also limits antigen-specific induction of CD69 and CD86 expression and that LPA5-deficient B cells display enhanced antibody responses. Thus, these data show that LPA5 negatively regulates BCR signaling, B cell activation and immune response. Our findings extend the influence of lysophospholipids on immune function and suggest that alterations in LPA levels likely influence adaptive humoral immunity. PMID:24890721

  10. The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B.

    PubMed

    Cohen, B Eleazar

    2016-09-01

    Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells.

  11. [RGS proteins (regulators of G protein signaling) and their roles in regulation of immune response].

    PubMed

    Lewandowicz, Anna M; Kowalski, Marek L; Pawliczak, Rafał

    2004-01-01

    RGS proteins (Regulators of G-protein Signaling) comprise a protein family responsible for regulating G proteins. By enhancing the GTPase activity of the a subunit, they speed up the reconstruction of the heterotrimeric structure of G protein, thus inhibiting its signal transduction. Sst2 protein in yeast Saccharomyces cervisiae, FlbA in fungus Aspergillus nidulans, and Egl-10 in the nematode Caenorhabditis elegans are the first native G regulators with GTPase activity (GAPs:--GTPase-activating proteins). The existence of over 30 RGS human proteins has been confirmed thus far, and they have been grouped and classified into six subfamilies. In immunocompetent cells, RGS proteins are entangled in a complicate net of different interrelating signal pathways. They are connected with B- and T-cell chemokine susceptibility, efficient T cell proliferation, and the regulation of B cell maturation. They also take an essential part in inflammation. High hopes are held for drugs, which handle would be RGS proteins and which would further provide the possibility of modifying the pharmacokinetics of drugs acting through G protein- coupled receptors. The aim of this review is to discuss the new RGS protein family and explain the potential involvement of RGS proteins in the modulation of the immune response PMID:15459549

  12. Signaling pathways involved in PDGF-evoked cellular responses in human RPE cells

    SciTech Connect

    Hollborn, Margrit . E-mail: hollbm@medizin.uni-leipzig.de; Bringmann, Andreas; Faude, Frank; Wiedemann, Peter; Kohen, Leon

    2006-06-09

    We examined whether PDGF may directly stimulate the expression of VEGF by retinal pigment epithelial (RPE) cells in vitro, and the involvement of three signal transduction pathways in the regulation of PDGF-evoked cell proliferation, migration, and production of VEGF-A was investigated. PDGF stimulated the gene and protein expression of VEGF-A by RPE cells, and increased cell proliferation and chemotaxis. PDGF activated all signaling pathways investigated, as determined by increased phosphorylation levels of ERK1/2, p38, and Akt proteins. The three signaling pathways were involved in the mediation of PDGF-evoked cell proliferation, while p38 and PI3K mediated cell migration, and PI3K mediated secretion of VEGF-A. In addition to VEGF-A, the cells expressed mRNAs for various members of the VEGF family and for their receptors, including VEGF-B, -C, -D, flt-1, and KDR. The data indicate that PDGF selectively stimulates the expression of VEGF-A in RPE cells. PDGF evokes at least three signal transduction pathways which are differentially involved in various cellular responses.

  13. Hedgehog signaling enables nutrition-responsive inhibition of an alternative morph in a polyphenic beetle

    PubMed Central

    Kijimoto, Teiya; Moczek, Armin P.

    2016-01-01

    The recruitment of modular developmental genetic components into new developmental contexts has been proposed as a central mechanism enabling the origin of novel traits and trait functions without necessitating the origin of novel pathways. Here, we investigate the function of the hedgehog (Hh) signaling pathway, a highly conserved pathway best understood for its role in patterning anterior/posterior (A/P) polarity of diverse traits, in the developmental evolution of beetle horns, an evolutionary novelty, and horn polyphenisms, a highly derived form of environment-responsive trait induction. We show that interactions among pathway members are conserved during development of Onthophagus horned beetles and have retained the ability to regulate A/P polarity in traditional appendages, such as legs. At the same time, the Hh signaling pathway has acquired a novel and highly unusual role in the nutrition-dependent regulation of horn polyphenisms by actively suppressing horn formation in low-nutrition males. Down-regulation of Hh signaling lifts this inhibition and returns a highly derived sigmoid horn body size allometry to its presumed ancestral, linear state. Our results suggest that recruitment of the Hh signaling pathway may have been a key step in the evolution of trait thresholds, such as those involved in horn polyphenisms and the corresponding origin of alternative phenotypes and complex allometries. PMID:27162357

  14. 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.

  15. Electrical signaling along the phloem and its physiological responses in the maize leaf

    PubMed Central

    Fromm, Jörg; Hajirezaei, Mohammad-Reza; Becker, Verena K.; Lautner, Silke

    2013-01-01

    To elucidate the role of electrical signaling in the phloem of maize the tips of attached leaves were stimulated by chilling and wounding. Two different signals were detected in the phloem at the middle of the leaf using the aphid stylet technique: (1) action potentials (AP) arose in the phloem after chilling; and (2) variation potentials (VPs) were evoked after wounding the leaf tip. Combined electric potential and gas exchange measurements showed that while the wound-induced VP moved rapidly towards the middle of the leaf to induce a reduction in both the net-CO2 uptake rate and the stomatal conductance, there was no response in the gas exchange to the cold-induced AP. To determine if electrical signaling had any impact on assimilate transport the middle of the leaf was exposed to 14CO2. Autoradiography of labeled assimilates provided evidence that phloem and intercellular transport of assimilates from mesophyll to bundle sheath cells was strongly reduced while the cold-induced AP moved through. In contrast, wound-induced VP did not inhibit assimilate translocation but did reduce the amount of the labeled assimilate in phloem and bundle sheath cells. Biochemical analysis revealed that callose content increased significantly in chilled leaves while starch increased in chilled but decreased in wounded leaves. The results led to the conclusion that different stimulation types incite characteristic phloem-transmitted electrical signals, each with a specific influence on gas exchange and assimilate transport. PMID:23847642

  16. Molecular hydrogen is involved in phytohormone signaling and stress responses in plants.

    PubMed

    Zeng, Jiqing; Zhang, Mingyong; Sun, Xuejun

    2013-01-01

    Molecular hydrogen (H2) metabolism in bacteria and algae has been well studied from an industrial perspective because H2 is viewed as a potential future energy source. A number of clinical trials have recently reported that H2 is a therapeutic antioxidant and signaling molecule. Although H2 metabolism in higher plants was reported in some early studies, its biological effects remain unclear. In this report, the biological effects of H2 and its involvement in plant hormone signaling pathways and stress responses were determined. Antioxidant enzyme activity was found to be increased and the transcription of corresponding genes altered when the effects of H2 on the germination of mung bean seeds treated with phytohormones was investigated. In addition, upregulation of several phytohormone receptor genes and genes that encode a few key factors involved in plant signaling pathways was detected in rice seedlings treated with HW. The transcription of putative rice hydrogenase genes, hydrogenase activity, and endogenous H2 production were also determined. H2 production was found to be induced by abscisic acid, ethylene, and jasmonate acid, salt, and drought stress and was consistent with hydrogenase activity and the expression of putative hydrogenase genes in rice seedlings. Together, these results suggest that H2 may have an effect on rice stress tolerance by modulating the output of hormone signaling pathways.

  17. Activation of the Notch signaling pathway in response to pulp capping of rat molars.

    PubMed

    Løvschall, H; Tummers, M; Thesleff, I; Füchtbauer, E-M; Poulsen, K

    2005-08-01

    Notch signaling is an evolutionarily conserved pathway that controls the developmental choices made by individual cells. Cells communicate via Notch receptors and their ligands, which direct decisions on the fate of stem cells according to the states of their neighbors. In this study we explored Notch signaling after the pulp capping of adult first upper rat molars. The wound was capped with calcium hydroxide. In situ hybridization revealed an increased expression of Notch signaling genes on day 1, which showed a tendency to decrease on day 3. Notch1 increased in the subodontoblast zone and close to the lesion limited to a few cells. Notch2 increased in pulp stroma surrounded by coronal odontoblasts. Notch1 and, especially, Notch3 expression increased, corresponding to perivascular cell groups. A low increase of ligand expression was observed near the injury with Delta1 expression along the dentin wall and Jagged1 in the stroma. Expression of the downstream target, Hes1, was observed along the lesion and adjacent dentin walls. Hes5 expression was not observed. The results indicate that Notch signaling is activated in response to injury and associated with the differentiation of pulp cells into perivascular cells and odontoblasts. The findings are consistent with the concept that the Notch pathway controls stem cell fate during pulp regeneration. PMID:16048523

  18. Molecular Hydrogen Is Involved in Phytohormone Signaling and Stress Responses in Plants

    PubMed Central

    Zeng, Jiqing; Zhang, Mingyong; Sun, Xuejun

    2013-01-01

    Molecular hydrogen (H2) metabolism in bacteria and algae has been well studied from an industrial perspective because H2 is viewed as a potential future energy source. A number of clinical trials have recently reported that H2 is a therapeutic antioxidant and signaling molecule. Although H2 metabolism in higher plants was reported in some early studies, its biological effects remain unclear. In this report, the biological effects of H2 and its involvement in plant hormone signaling pathways and stress responses were determined. Antioxidant enzyme activity was found to be increased and the transcription of corresponding genes altered when the effects of H2 on the germination of mung bean seeds treated with phytohormones was investigated. In addition, upregulation of several phytohormone receptor genes and genes that encode a few key factors involved in plant signaling pathways was detected in rice seedlings treated with HW. The transcription of putative rice hydrogenase genes, hydrogenase activity, and endogenous H2 production were also determined. H2 production was found to be induced by abscisic acid, ethylene, and jasmonate acid, salt, and drought stress and was consistent with hydrogenase activity and the expression of putative hydrogenase genes in rice seedlings. Together, these results suggest that H2 may have an effect on rice stress tolerance by modulating the output of hormone signaling pathways. PMID:23951075

  19. Phosphorylation of the fused protein kinase in response to signaling from hedgehog.

    PubMed Central

    Thérond, P P; Knight, J D; Kornberg, T B; Bishop, J M

    1996-01-01

    The hedgehog gene (hh) of Drosophila melanogaster exerts both short- and long-range effects on cell patterning during development. The product of hedgehog is a secreted protein that apparently acts by triggering an intra-cellular signaling pathway, but little is known about the details of that pathway. The Drosophila gene fused (fu) encodes a serine/threonine-protein kinase that genetic experiments have implicated in signaling initiated by hedgehog. Here we report that the fused protein is phosphorylated during the course of Drosophila embryogenesis, as a result of hedgehog activity. In cell culture, phosphorylation of fused protein occurs in response to the biologically active form of hedgehog and cannot be blocked by activation of protein kinase A, which is thought to be an antagonist of signaling from hedgehog. These results suggest that fused and protein kinase A function downstream of hedgehog but in parallel pathways that eventually converge distal to fused. The reconstruction of signaling from hedgehog in cell culture should provide further access to the mechanisms by which hedgehog acts. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8633045

  20. Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.

    PubMed

    Alaghband, Yasaman; O'Dell, Steven J; Azarnia, Siavash; Khalaj, Anna J; Guzowski, John F; Marshall, John F

    2014-12-01

    The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine

  1. Extended Synaptotagmin Interaction with the Fibroblast Growth Factor Receptor Depends on Receptor Conformation, Not Catalytic Activity.

    PubMed

    Tremblay, Michel G; Herdman, Chelsea; Guillou, François; Mishra, Prakash K; Baril, Joëlle; Bellenfant, Sabrina; Moss, Tom

    2015-06-26

    We previously demonstrated that ESyt2 interacts specifically with the activated FGF receptor and is required for a rapid phase of receptor internalization and for functional signaling via the ERK pathway in early Xenopus embryos. ESyt2 is one of the three-member family of Extended Synaptotagmins that were recently shown to be implicated in the formation of endoplasmic reticulum (ER)-plasma membrane (PM) junctions and in the Ca(2+) dependent regulation of these junctions. Here we show that ESyt2 is directed to the ER by its putative transmembrane domain, that the ESyts hetero- and homodimerize, and that ESyt2 homodimerization in vivo requires a TM adjacent sequence but not the SMP domain. ESyt2 and ESyt3, but not ESyt1, selectively interact in vivo with activated FGFR1. In the case of ESyt2, this interaction requires a short TM adjacent sequence and is independent of receptor autophosphorylation, but dependent on receptor conformation. The data show that ESyt2 recognizes a site in the upper kinase lobe of FGFR1 that is revealed by displacement of the kinase domain activation loop during receptor activation.

  2. IP receptor-dependent activation of PPAR{gamma} by stable prostacyclin analogues

    SciTech Connect

    Falcetti, Emilia; Flavell, David M.; Staels, Bart; Tinker, Andrew; Haworth, Sheila G.; Clapp, Lucie H. . E-mail: l.clapp@ucl.ac.uk

    2007-09-07

    Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors (PPARs). So far these agents have been reported to activate PPAR{alpha} and PPAR{delta} but not PPAR{gamma}. Given PPAR{gamma} agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPAR{gamma} activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPAR{gamma} in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPAR{gamma} antagonist, GW9662. We conclude that PPAR{gamma} is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues.

  3. Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

    PubMed

    Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

    2016-11-01

    Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice.

  4. Immunotoxin Therapies for the Treatment of Epidermal Growth Factor Receptor-Dependent Cancers

    PubMed Central

    Simon, Nathan; FitzGerald, David

    2016-01-01

    Many epithelial cancers rely on enhanced expression of the epidermal growth factor receptor (EGFR) to drive proliferation and survival pathways. Development of therapeutics to target EGFR signaling has been of high importance, and multiple examples have been approved for human use. However, many of the current small molecule or antibody-based therapeutics are of limited effectiveness due to the inevitable development of resistance and toxicity to normal tissues. Recombinant immunotoxins are therapeutic molecules consisting of an antibody or receptor ligand joined to a protein cytotoxin, combining the specific targeting of a cancer-expressed receptor with the potent cell killing of cytotoxic enzymes. Over the decades, many bacterial- or plant-based immunotoxins have been developed with the goal of targeting the broad range of cancers reliant upon EGFR overexpression. Many examples demonstrate excellent anti-cancer properties in preclinical development, and several EGFR-targeted immunotoxins have progressed to human trials. This review summarizes much of the past and current work in the development of immunotoxins for targeting EGFR-driven cancers. PMID:27153091

  5. Iron Mediates N-Methyl-d-aspartate Receptor-dependent Stimulation of Calcium-induced Pathways and Hippocampal Synaptic Plasticity*

    PubMed Central

    Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T.

    2011-01-01

    Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-d-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP. PMID:21296883

  6. Toll-Like Receptor-Dependent Immune Complex Activation of B Cells and Dendritic Cells.

    PubMed

    Moody, Krishna L; Uccellini, Melissa B; Avalos, Ana M; Marshak-Rothstein, Ann; Viglianti, Gregory A

    2016-01-01

    High titers of autoantibodies reactive with DNA/RNA molecular complexes are characteristic of autoimmune disorders such as systemic lupus erythematosus (SLE). In vitro and in vivo studies have implicated the endosomal Toll-like receptor 9 (TLR9) and Toll-like receptor 7 (TLR7) in the activation of the corresponding autoantibody producing B cells. Importantly, TLR9/TLR7-deficiency results in the inability of autoreactive B cells to proliferate in response to DNA/RNA-associated autoantigens in vitro, and in marked changes in the autoantibody repertoire of autoimmune-prone mice. Uptake of DNA/RNA-associated autoantigen immune complexes (ICs) also leads to activation of dendritic cells (DCs) through TLR9 and TLR7. The initial studies from our lab involved ICs formed by a mixture of autoantibodies and cell debris released from dying cells in culture. To better understand the nature of the mammalian ligands that can effectively activate TLR7 and TLR9, we have developed a methodology for preparing ICs containing defined DNA fragments that recapitulate the immunostimulatory activity of the previous "black box" ICs. As the endosomal TLR7 and TLR9 function optimally from intracellular acidic compartments, we developed a facile methodology to monitor the trafficking of defined DNA ICs by flow cytometry and confocal microscopy. These reagents reveal an important role for nucleic acid sequence, even when the ligand is mammalian DNA and will help illuminate the role of IC trafficking in the response.

  7. Notch Activity Modulates the Responsiveness of Neural Progenitors to Sonic Hedgehog Signaling

    PubMed Central

    Kong, Jennifer H.; Yang, Linlin; Dessaud, Eric; Chuang, Katherine; Moore, Destaye M.; Rohatgi, Rajat; Briscoe, James; Novitch, Bennett G.

    2015-01-01

    Summary Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination. PMID:25936505

  8. Immune response and insulin signalling alter mosquito feeding behaviour to enhance malaria transmission potential.

    PubMed

    Cator, Lauren J; Pietri, Jose E; Murdock, Courtney C; Ohm, Johanna R; Lewis, Edwin E; Read, Andrew F; Luckhart, Shirley; Thomas, Matthew B

    2015-01-01

    Malaria parasites alter mosquito feeding behaviour in a way that enhances parasite transmission. This is widely considered a prime example of manipulation of host behaviour to increase onward transmission, but transient immune challenge in the absence of parasites can induce the same behavioural phenotype. Here, we show that alterations in feeding behaviour depend on the timing and dose of immune challenge relative to blood ingestion and that these changes are functionally linked to changes in insulin signalling in the mosquito gut. These results suggest that altered phenotypes derive from insulin signalling-dependent host resource allocation among immunity, blood feeding, and reproduction in a manner that is not specific to malaria parasite infection. We measured large increases in mosquito survival and subsequent transmission potential when feeding patterns are altered. Leveraging these changes in physiology, behaviour and life history could promote effective and sustainable control of female mosquitoes responsible for transmission.

  9. Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus

    PubMed Central

    Plissonnier, Marie-Laure; Lahlali, Thomas; Michelet, Maud; Lebossé, Fanny; Cottarel, Jessica; Beer, Melanie; Neveu, Grégory; Durantel, David; Bartosch, Birke; Accardi, Rosita; Clément, Sophie; Paradisi, Andrea; Devouassoux-Shisheboran, Mojgan; Einav, Shirit; Mehlen, Patrick; Zoulim, Fabien; Parent, Romain

    2016-01-01

    Hepatitis C virus (HCV) is an oncogenic virus associated with the onset of hepatocellular carcinoma (HCC). The present study investigated the possible link between HCV infection and Netrin-1, a ligand for dependence receptors that sustains tumorigenesis, in particular in inflammation-associated tumors. We show that Netrin-1 expression is significantly elevated in HCV+ liver biopsies compared to hepatitis B virus (HBV+) and uninfected samples. Furthermore, Netrin-1 was upregulated in all histological stages of HCV+ hepatic lesions, from minimal liver fibrosis to cirrhosis and HCC, compared to histologically matched HCV- tissues. Both cirrhosis and HCV contributed to the induction of Netrin-1 expression, whereas anti-HCV treatment resulted in a reduction of Netrin-1 expression. In vitro, HCV increased the level and translation of Netrin-1 in a NS5A-La-related protein 1 (LARP1)-dependent fashion. Knockdown and forced expression experiments identified the receptor uncoordinated receptor-5 (UNC5A) as an antagonist of the Netrin-1 signal, though it did not affect the death of HCV-infected cells. Netrin-1 enhanced infectivity of HCV particles and promoted viral entry by increasing the activation and decreasing the recycling of the epidermal growth factor receptor (EGFR), a protein that is dysregulated in HCC. Netrin-1 and HCV are, therefore, reciprocal inducers in vitro and in patients, as seen from the increase in viral morphogenesis and viral entry, both phenomena converging toward an increase in the level of infectivity of HCV virions. This functional association involving a cancer-related virus and Netrin-1 argues for evaluating the implication of UNC5 receptor ligands in other oncogenic microbial species. PMID:27031829

  10. Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A

    PubMed Central

    Jones, G W; Greenhill, C J; Williams, J O; Nowell, M A; Williams, A S; Jenkins, B J; Jones, S A

    2013-01-01

    Objective Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Methods Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1−/− and gp130F/F:Il17a−/− mice. Joint pathology and associated peripheral TH-17 responses were compared. Results Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1−/−) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a−/− mice. Here, loss of IL-17A had no impact on arthritis severity. Conclusions Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent. PMID:23894061

  11. Recruitment of Prefrontal Cortical Endocannabinoid Signaling by Glucocorticoids Contributes to Termination of the Stress Response

    PubMed Central

    Hill, Matthew N.; McLaughlin, Ryan J.; Pan, Bin; Fitzgerald, Megan L.; Roberts, Christopher J.; Lee, Tiffany T-Y.; Karatsoreos, Ilia N.; Mackie, Ken; Viau, Victor; Pickel, Virginia M.; McEwen, Bruce S.; Liu, Qing-song; Gorzalka, Boris B.; Hillard, Cecilia J.

    2011-01-01

    The mechanisms subserving the ability of glucocorticoid signaling within the medial prefrontal cortex (mPFC) to terminate stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis are not well understood. We report that antagonism of the cannabinoid CB1 receptor locally within the mPFC prolonged corticosterone secretion following cessation of stress in rats. Mice lacking the CB1 receptor exhibited a similar prolonged response to stress. Exposure of rats to stress produced an elevation in the endocannabinoid 2-arachidonoylglycerol within the mPFC that was reversed by pretreatment with the glucocorticoid receptor antagonist RU-486 (20 mg/kg). Electron microscopic and electrophysiological data demonstrated the presence of CB1 receptors in inhibitory-type terminals impinging upon principal neurons within layer V of the prelimbic region of the mPFC. Bath application of corticosterone (100 nM) to prefrontal cortical slices suppressed GABA release onto principal neurons in layer V of the prelimbic region, when examined 1 h later, which was prevented by application of a CB1 receptor antagonist. Collectively, these data demonstrate that the ability of stress-induced glucocorticoid signaling within mPFC to terminate HPA axis activity is mediated by a local recruitment of endocannabinoid signaling. Endocannabinoid activation of CB1 receptors decreases GABA release within the mPFC, likely increasing the outflow of the principal neurons of the prelimbic region to contribute to termination of the stress response. These data support a model in which endocannabinoid signaling links glucocorticoid receptor engagement to activation of corticolimbic relays that inhibit corticosterone secretion. PMID:21775596

  12. Extensive and specific responses of a eukaryote to bacterial quorum-sensing signals

    PubMed Central

    Mathesius, Ulrike; Mulders, Susan; Gao, Mengsheng; Teplitski, Max; Caetano-Anollés, Gustavo; Rolfe, Barry G.; Bauer, Wolfgang D.

    2003-01-01

    Many bacteria use N-acyl homoserine lactone (AHL) signals to coordinate the behavior of individual cells in a local population. The successful infection of eukaryotic hosts by bacteria seems to depend particularly on such AHL-mediated “quorum-sensing” regulation. We have used proteome analysis to show that a eukaryotic host, the model legume Medicago truncatula, is able to detect nanomolar to micromolar concentrations of bacterial AHLs from both symbiotic (Sinorhizobium meliloti) and pathogenic (Pseudomonas aeruginosa) bacteria, and that it responds in a global manner by significant changes in the accumulation of over 150 proteins, 99 of which have been identified by peptide mass fingerprinting. The accumulation of specific proteins and isoforms depended on AHL structure, concentration, and time of exposure. AHLs were also found to induce tissue-specific activation of β-glucuronidase (GUS) reporter fusions to an auxin-responsive and three chalcone synthase promoters, consistent with AHL-induced changes in the accumulation of auxin-responsive and flavonoid synthesis proteins. In addition, exposure to AHLs was found to induce changes in the secretion of compounds by the plants that mimic quorum-sensing signals and thus have the potential to disrupt quorum sensing in associated bacteria. Our results indicate that eukaryotes have an extensive range of functional responses to AHLs that may play important roles in the beneficial or pathogenic outcomes of eukaryote–prokaryote interactions. PMID:12511600

  13. Streptozotocin induced activation of oxidative stress responsive splenic cell signaling pathways: Protective role of arjunolic acid

    SciTech Connect

    Manna, Prasenjit; Ghosh, Jyotirmoy; Das, Joydeep

    2010-04-15

    Present study investigates the beneficial role of arjunolic acid (AA) against the alteration in the cytokine levels and simultaneous activation of oxidative stress responsive signaling pathways in spleen under hyperglycemic condition. Diabetes was induced by injection of streptozotocin (STZ) (at a dose of 70 mg/kg body weight, injected in the tail vain). STZ administration elevated the levels of IL-2 as well as IFN-gamma and attenuated the level of TNF-alpha in the sera of diabetic animals. In addition, hyperglycemia is also associated with the increased production of intracellular reactive intermediates resulting with the elevation in lipid peroxidation, protein carbonylation and reduction in intracellular antioxidant defense. Investigating the oxidative stress responsive cell signaling pathways, increased expressions (immunoreactive concentrations) of phosphorylated p65 as well as its inhibitor protein phospho IkappaBalpha and phosphorylated mitogen activated protein kinases (MAPKs) have been observed in diabetic spleen tissue. Studies on isolated splenocytes revealed that hyperglycemia caused disruption of mitochondrial membrane potential, elevation in the concentration of cytosolic cytochrome c as well as activation of caspase 3 leading to apoptotic cell death. Histological examination revealed that diabetic induction depleted the white pulp scoring which is in agreement with the reduced immunological response. Treatment with AA prevented the hyperglycemia and its associated pathogenesis in spleen tissue. Results suggest that AA might act as an anti-diabetic and immunomodulatory agent against hyperglycemia.

  14. Arabidopsis PYL8 Plays an Important Role for ABA Signaling and Drought Stress Responses.

    PubMed

    Lim, Chae Woo; Baek, Woonhee; Han, Sang-Wook; Lee, Sung Chul

    2013-12-01

    Plants are frequently exposed to numerous environmental stresses such as dehydration and high salinity, and have developed elaborate mechanisms to counteract the deleterious effects of stress. The phytohormone abscisic acid (ABA) plays a critical role as an integrator of plant responses to water-limited condition to activate ABA signal transduction pathway. Although perception of ABA has been suggested to be important, the function of each ABA receptor remains elusive in dehydration condition. Here, we show that ABA receptor, pyrabactin resistance-like protein 8 (PYL8), functions in dehydration conditions. Transgenic plants overexpressing PYL8 exhibited hypersensitive phenotype to ABA in seed germination, seedling growth and establishment. We found that hypersensitivity to ABA of transgenic plants results in high degrees of stomatal closure in response to ABA leading to low transpiration rates and ultimately more vulnerable to drought than the wild-type plants. In addition, high expression of ABA maker genes also contributes to altered drought tolerance phenotype. Overall, this work emphasizes the importance of ABA signaling by ABA receptor in stomata during defense response to drought stress. PMID:25288979

  15. AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling.

    PubMed

    Shin, Jae Hoon; Lee, Seo Hyun; Kim, Yo Na; Kim, Il Yong; Kim, Youn Ju; Kyeong, Dong Soo; Lim, Hee Jung; Cho, Soo Young; Choi, Junhee; Wi, Young Jin; Choi, Jae-Hoon; Yoon, Yeo Sung; Bae, Yun Soo; Seong, Je Kyung

    2016-03-18

    In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak(-/-) mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak(-/-) mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling.

  16. AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling

    PubMed Central

    Shin, Jae Hoon; Lee, Seo Hyun; Kim, Yo Na; Kim, Il Yong; Kim, Youn Ju; Kyeong, Dong Soo; Lim, Hee Jung; Cho, Soo Young; Choi, Junhee; Wi, Young Jin; Choi, Jae-Hoon; Yoon, Yeo Sung; Bae, Yun Soo; Seong, Je Kyung

    2016-01-01

    In adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak−/− mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak−/− mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling. PMID:26987950

  17. Identifying ligand-specific signalling within biased responses: focus on δ opioid receptor ligands

    PubMed Central

    Charfi, I; Audet, N; Bagheri Tudashki, H; Pineyro, G

    2015-01-01

    Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of ‘biased agonism’ is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on δ opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24665881

  18. The Neural Feedback Response to Error As a Teaching Signal for the Motor Learning System

    PubMed Central

    Shadmehr, Reza

    2016-01-01

    When we experience an error during a movement, we update our motor commands to partially correct for this error on the next trial. How does experience of error produce the improvement in the subsequent motor commands? During the course of an erroneous reaching movement, proprioceptive and visual sensory pathways not only sense the error, but also engage feedback mechanisms, resulting in corrective motor responses that continue until the hand arrives at its goal. One possibility is that this feedback response is co-opted by the learning system and used as a template to improve performance on the next attempt. Here we used electromyography (EMG) to compare neural correlates of learning and feedback to test the hypothesis that the feedback response to error acts as a template for learning. We designed a task in which mixtures of error-clamp and force-field perturbation trials were used to deconstruct EMG time courses into error-feedback and learning components. We observed that the error-feedback response was composed of excitation of some muscles, and inhibition of others, producing a complex activation/deactivation pattern during the reach. Despite this complexity, across muscles the learning response was consistently a scaled version of the error-feedback response, but shifted 125 ms earlier in time. Across people, individuals who produced a greater feedback response to error, also learned more from error. This suggests that the feedback response to error serves as a teaching signal for the brain. Individuals who learn faster have a better teacher in their feedback control system. SIGNIFICANCE STATEMENT Our sensory organs transduce errors in behavior. To improve performance, we must generate better motor commands. How does the nervous system transform an error in sensory coordinates into better motor commands in muscle coordinates? Here we show that when an error occurs during a movement, the reflexes transform the sensory representation of error into motor

  19. Ibuprofen treatment blunts early translational signaling responses in human skeletal muscle following resistance exercise.

    PubMed

    Markworth, James F; Vella, Luke D; Figueiredo, Vandre C; Cameron-Smith, David

    2014-07-01

    Cyclooxygenase-1 and -2 pathway-derived prostaglandins (PGs) have been implicated in adaptive muscle responses to exercise, but the role of PGs in contraction-induced muscle signaling has not been determined. We investigated the effect of inhibition of cyclooxygenase-1 and -2 activities with the nonsteroidal anti-inflammatory drug ibuprofen on human muscle signaling responses to resistance exercise. Subjects orally ingested 1,200 mg ibuprofen (or placebo control) in three 400-mg doses administered ∼30 min before and ∼6 h and ∼12 h following a bout of unaccustomed resistance exercise (80% one repetition maximum). Muscle biopsies were obtained at rest (preexercise), immediately postexercise (0 h), 3 h postexercise, and at 24 h of recovery. In the placebo (PLA) group, phosphorylation of ERK1/2 (Thr202/Tyr204), ribosomal protein S6 kinase (RSK, Ser380), mitogen-activated kinase 1 (Mnk1, Thr197/202), and p70S6 kinase (p70S6K, Thr421/Ser424) increased at both 0 and 3 h postexercise, with delayed elevation of phospho (p)-p70S6K (Thr389) and p-rpS6 (Ser235/S36 and Ser240/244) at 3 h postexercise. Only p-ERK1/2 (Thr202/Tyr204) remained significantly elevated in the 24-h postexercise biopsy. Ibuprofen treatment prevented sustained elevation of MEK-ERK signaling at 3 h (p-ERK1/2, p-RSK, p-Mnk1, p-p70S6K Thr421/Ser424) and 24 h (p-ERK1/2) postexercise, and this was associated with suppressed phosphorylation of ribosomal protein S6 (Ser235/236 and Ser240/244). Early contraction-induced p-Akt (Ser473) and p-p70S6K (Thr389) were not influenced by ibuprofen, but p-p70S6K (Thr389) remained elevated 24 h postexercise only in those receiving ibuprofen treatment. Early muscle signaling responses to resistance exercise are, in part, ibuprofen sensitive, suggesting that PGs are important signaling molecules during early postexercise recovery.

  20. An Ancestral Role for CONSTITUTIVE TRIPLE RESPONSE1 Proteins in Both Ethylene and Abscisic Acid Signaling.

    PubMed

    Yasumura, Yuki; Pierik, Ronald; Kelly, Steven; Sakuta, Masaaki; Voesenek, Laurentius A C J; Harberd, Nicholas P

    2015-09-01

    Land plants have evolved adaptive regulatory mechanisms enabling the survival of environmental stresses associated with terrestrial life. Here, we focus on the evolution of the regulatory CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) component of the ethylene signaling pathway that modulates stress-related changes in plant growth and development. First, we compare CTR1-like proteins from a bryophyte, Physcomitrella patens (representative of early divergent land plants), with those of more recently diverged lycophyte and angiosperm species (including Arabidopsis [Arabidopsis thaliana]) and identify a monophyletic CTR1 family. The fully sequenced P. patens genome encodes only a single member of this family (PpCTR1L). Next, we compare the functions of PpCTR1L with that of related angiosperm proteins. We show that, like angiosperm CTR1 proteins (e.g. AtCTR1 of Arabidopsis), PpCTR1L modulates downstream ethylene signaling via direct interaction with ethylene receptors. These functions, therefore, likely predate the divergence of the bryophytes from the land-plant lineage. However, we also show that PpCTR1L unexpectedly has dual functions and additionally modulates abscisic acid (ABA) signaling. In contrast, while AtCTR1 lacks detectable ABA signaling functions, Arabidopsis has during evolution acquired another homolog that is functionally distinct from AtCTR1. In conclusion, the roles of CTR1-related proteins appear to have functionally diversified during land-plant evolution, and angiosperm CTR1-related proteins appear to have lost an ancestral ABA signaling function. Our study provides new insights into how molecular events such as gene duplication and functional differentiation may have contributed to the adaptive evolution of regulatory mechanisms in plants.

  1. Genome-Wide Transcriptional Changes in Streptococcus gordonii in Response to Competence Signaling Peptide▿ †

    PubMed Central

    Vickerman, M. M.; Iobst, S.; Jesionowski, A. M.; Gill, S. R.

    2007-01-01

    Streptococcus gordonii is a primary colonizer of the multispecies biofilm on tooth surfaces forming dental plaque and a potential agent of endocarditis. The recent completion of the genome sequence of the naturally competent strain Challis allowed the design of a spotted oligonucleotide microarray to examine a genome-wide response of this organism to environmental stimuli such as signal peptides. Based on temporal responses to synthetic competence signaling peptide (CSP) as indicated by transformation frequencies, the S. gordonii transcriptome was analyzed at various time points after CSP exposure. Microarray analysis identified 35 candidate early genes and 127 candidate late genes that were up-regulated at 5 and 15 min, respectively; these genes were often grouped in clusters. Results supported published findings on S. gordonii competence, showing up-regulation of 12 of 16 genes that have been reported to affect transformation frequencies in this species. Comparison of CSP-induced S. gordonii transcriptomes to results published for Streptococcus pneumoniae strains identified both conserved and species-specific genes. Putative intergenic regulatory sites, such as the conserved combox sequence thought to be a binding site for competence sigma factor, were found preceding S. gordonii late responsive genes. In contrast, S. gordonii early CSP-responsive genes were not preceded by the direct repeats found in S. pneumoniae. These studies provide the first insights into a genome-wide transcriptional response of an oral commensal organism. They offer an extensive analysis of transcriptional changes that accompany competence in S. gordonii and form a basis for future intra- and interspecies comparative analyses of this ecologically important phenotype. PMID:17720781

  2. Multilocus Genetic Composite Reflecting Dopamine Signaling Capacity Predicts Reward Circuitry Responsivity

    PubMed Central

    Stice, E; Yokum, S; Burger, KS; Epstein, H; Smolen, A

    2012-01-01

    Objective Test the hypotheses that humans with genotypes putatively associated with low dopamine (DA) signaling capacity, including the TaqIA A1 allele, DRD2-141C Ins/Ins genotype, DRD4 7-repeat or longer allele, DAT1 10-repeat allele, and the Met/Met COMT genotype, and with a greater number of these genotypes per a multilocus composite, show less responsivity of reward regions that primarily rely on DA-signaling. Design Functional magnetic resonance imaging (fMRI) paradigms were used to investigate activation in response to receipt and anticipated receipt of palatable food and monetary reward. DNA was extracted from saliva using standard methods. Participants One-hundred and sixty adolescents (Mean age = 15.3, SD = 1.07; Mean BMI = 20.8, SD = 1.9). Main Outcome Blood oxygen level dependent activation in the fMRI paradigms. Results Data confirmed that these fMRI paradigms activated reward, attention, somatosensory, and gustatory regions. Individuals with versus without these five genotypes did not show less activation of DA-based reward regions, but those with the Met/Met versus the Val/Val COMT genotype showed less middle temporal gyrus activation and those with the DRD4-L versus the DRD4-S genotype showed less middle occipital gyrus activation in response to monetary reward. Critically, the multilocus composite score revealed that those with a greater number of these genotypes showed less activation in reward regions, including the putamen, caudate, and insula, in response to monetary reward. Discussion Results suggest that the multilocus genetic composite is a more sensitive index of vulnerability for low reward region responsivity than individual genotypes. PMID:22815523

  3. α5-Integrin-mediated cellular signaling contributes to the myogenic response of cerebral resistance arteries.

    PubMed

    Colinas, Olaia; Moreno-Domínguez, Alejandro; Zhu, Hai-Lei; Walsh, Emma J; Pérez-García, M Teresa; Walsh, Michael P; Cole, William C

    2015-10-01

    The myogenic response of resistance arterioles and small arteries involving constriction in response to intraluminal pressure elevation and dilation on pressure reduction is fundamental to local blood flow regulation in the microcirculation. Integrins have garnered considerable attention in the context of initiating the myogenic response, but evidence indicative of mechanotransduction by integrin adhesions, for example established changes in tyrosine phosphorylation of key adhesion proteins, has not been obtained to substantiate this interpretation. Here, we evaluated the role of integrin adhesions and associated cellular signaling in the rat cerebral arterial myogenic response using function-blocking antibodies against α5β1-integrins, pharmacological inhibitors of focal adhesion kinase (FAK) and Src family kinase (SFK), an ultra-high-sensitivity western blotting technique, site-specific phosphoprotein antibodies to quantify adhesion and contractile filament protein phosphorylation, and differential centrifugation to determine G-actin levels in rat cerebral arteries at varied intraluminal pressures. Pressure-dependent increases in the levels of phosphorylation of FAK (FAK-Y397, Y576/Y577), SFK (SFK-Y416; Y527 phosphorylation was reduced), vinculin-Y1065, paxillin-Y118 and phosphoinositide-specific phospholipase C-γ1 (PLCγ1)-Y783 were detected. Treatment with α5-integrin function-blocking antibodies, FAK inhibitor FI-14 or SFK inhibitor SU6656 suppressed the changes in adhesion protein phosphorylation, and prevented pressure-dependent phosphorylation of the myosin targeting subunit of myosin light chain phosphatase (MYPT1) at T855 and 20kDa myosin regulatory light chains (LC20) at S19, as well as actin polymerization that are necessary for myogenic constriction. We conclude that mechanotransduction by integrin adhesions and subsequent cellular signaling play a fundamental role in the cerebral arterial myogenic response.

  4. Chronic social isolation suppresses proplastic response and promotes proapoptotic signalling in prefrontal cortex of Wistar rats.

    PubMed

    Djordjevic, Ana; Adzic, Miroslav; Djordjevic, Jelena; Radojcic, Marija B

    2010-08-15

    Successful adaptation to stress involves synergized actions of glucocorticoids and catecholamines at several levels of the CNS, including the prefrontal cortex (PFC). Inside the PFC, hormonal signals trigger concerted actions of transcriptional factors, such as glucocorticoid receptor (GR) and nuclear factor kappa B (NFkappaB), culminating in a balanced, proadaptive expression of their common genes, such as proplastic NCAM and/or apoptotic Bax and Bcl-2. In the present study, we hypothesized that chronic stress may compromise the balance between GR and NFkappaB signals and lead to an altered/maladaptive expression of their cognate genes in the PFC. Our results obtained with Wistar rats exposed to chronic social isolation indicated alterations of the GR relative to the NFkappaB, in favor of the GR, in both the cytoplasmic and the nuclear compartments of the PFC. Although these alterations did not affect the induction of proplastic NCAM gene, they decreased the NCAM sialylation necessary for plastic response and caused marked relocation of the mitochondrial membrane antiapoptotic Bcl-2 protein to its cytoplasmic form. Moreover, the compromised PSA-NCAM plastic response found under chronic stress was sustained after exposure of animals to the subsequent acute stress, whereas the proapoptotic signals were further emphasized. It is concluded that chronic social isolation of Wistar animals leads to a maladaptive response of the PFC, considering the diminishment of its plastic potential and potentiating of apoptosis. Such conditions in the PFC are likely to compromise its ability to interact with other CNS structures, such as the hippocampus, which is necessary for successful adaptation to stress.

  5. Regulation of the STARS signaling pathway in response to endurance and resistance exercise and training.

    PubMed

    Lamon, Séverine; Wallace, Marita A; Stefanetti, Renae J; Rahbek, Stine K; Vendelbo, Mikkel H; Russell, Aaron P; Vissing, Kristian

    2013-09-01

    The striated muscle activator of Rho signaling (STARS) protein and members of its downstream signaling pathway, including myocardin-related transcription factor-A (MRTF-A) and SRF, are increased in response to prolonged resistance exercise training but also following a single bout of endurance cycling. The aim of the present study was to measure and compare the regulation of STARS, MRTF-A and SRF mRNA and protein following 10 weeks of endurance training (ET) versus resistance training (RT), as well as before and following a single bout of endurance (EE) versus resistance exercise (RE). Following prolonged training, STARS, MRTF-A and SRF mRNA levels were all increased by similar magnitude, irrespective of training type. In the training-habituated state, STARS mRNA increased following a single-bout RE when measured 2.5 and 5 h post-exercise and had returned to resting level by 22 h following exercise. MRTF-A and SRF mRNA levels were decreased by 2.5, 5, and 22 h following a single bout of RE and EE exercise when compared to their respective basal levels, with no significant difference seen between the groups at any of the time points. No changes in protein levels were observed following the two modes of exercise training or a single bout of exercise. This study demonstrates that the stress signals elicited by ET and RT result in a comparable regulation of members of the STARS pathway. In contrast, a single bout of EE and RE, performed in the trained state, elicit different responses. These observations suggest that in the trained state, the acute regulation of the STARS pathway following EE or RE may be responsible for exercise-specific muscle adaptations.

  6. Root gravitropism in response to a signal originating outside of the cap

    NASA Technical Reports Server (NTRS)

    Wolverton, Chris; Mullen, Jack L.; Ishikawa, Hideo; Evans, Michael L.

    2002-01-01

    We have developed image analysis software linked to a rotating stage, allowing constraint of any user-selected region of a root at a prescribed angle during root gravitropism. This device allows the cap of a graviresponding root to reach vertical while maintaining a selected region within the elongation zone at a gravistimulated angle. Under these conditions gravitropic curvature of roots of Zea mays L. continues long after the root cap reaches vertical, indicating that a signal from outside of the cap can contribute to the curvature response.

  7. Root gravitropism in response to a signal originating outside of the cap.

    PubMed

    Wolverton, Chris; Mullen, Jack L; Ishikawa, Hideo; Evans, Michael L

    2002-05-01

    We have developed image analysis software linked to a rotating stage, allowing constraint of any user-selected region of a root at a prescribed angle during root gravitropism. This device allows the cap of a graviresponding root to reach vertical while maintaining a selected region within the elongation zone at a gravistimulated angle. Under these conditions gravitropic curvature of roots of Zea mays L. continues long after the root cap reaches vertical, indicating that a signal from outside of the cap can contribute to the curvature response. PMID:12012252

  8. Amiloride inhibition of gamma-aminobutyric acid(A) receptors depends upon the alpha subunit subtype.

    PubMed

    Fisher, Janet L

    2002-06-01

    gamma-Aminobutyric acid(A) (GABA(A)) receptors (GABARs) are responsible for most fast inhibitory neurotransmission in the mammalian brain. The GABARs contain several allosteric modulatory sites, many of which are useful clinically. The activity of most of these modulators depends upon the subunit composition of the receptor. The diuretic amiloride was previously reported to inhibit GABARs in frog sensory neurons. We measured its effects on recombinant GABARs to determine its mechanism of action at mammalian receptors and to examine the effect of subunit composition. Amiloride acted primarily as a competitive antagonist, reducing the sensitivity of the receptor to GABA without affecting the maximal current amplitude. Receptors containing an alpha6 subunit were about 10-fold more sensitive to amiloride than those containing other alpha subunits. In contrast, the identity of the beta or gamma subtype had little effect on amiloride sensitivity. Although several other modulators have specific effects at alpha6-containing receptors, amiloride is the first inhibitor to be reported with no additional dependence on the identity of the beta or gamma subunit. Therefore, it probably represents a unique modulatory site on the GABAR, which could be useful for developing drugs targeting these receptors. The selective activity of amiloride could also be helpful for isolating the contribution of receptors composed of alpha6 subtypes in heterogeneous native GABAR populations.

  9. Estrogen receptor dependent gene expression by osteoblasts - direct, indirect, circumspect, and speculative effects.

    PubMed

    Centrella, Michael; McCarthy, Thomas L

    2012-02-01

    Hormone activated estrogen receptors (ERs) have long been appreciated as potent mediators of gene expression in female reproductive tissues. These highly targeted responses likely evolved from more elemental roles in lower organisms, in agreement with their widespread effects in the cardiovascular, immunological, central nervous, and skeletal tissue systems. Still, despite intense investigation, the multiple and often perplexing roles of ERs retain significant attention. In the skeleton, this in part derives from apparently opposing effects by ER agonists on bone growth versus bone remodeling, and in younger versus older individuals. The complexity associated with ER activation can also derive from their interactions with other hormone and growth factor systems, and their direct and indirect effects on gene expression. We propose that part of this complexity results from essential interactions between ERs and other transcription factors, each with their own biochemical and molecular intricacies. Solving some of the many questions that persist may help to achieve better, or better directed, use of agents that can drive ER activation in focused and possibly tissue restricted ways.

  10. Histamine enhances inhibitory avoidance memory consolidation through a H2 receptor-dependent mechanism.

    PubMed

    da Silva, Weber C; Bonini, Juliana S; Bevilaqua, Lia R M; Izquierdo, Iván; Cammarota, Martín

    2006-07-01

    Several evidences suggest that brain histamine is involved in memory consolidation but the actual contribution of the hippocampal histaminergic system to this process remains controversial. Here, we show that when infused into the CA1 region of the dorsal hippocampus immediately after training in an inhibitory avoidance task, but not later, histamine induced a dose-dependent promnesic effect without altering locomotor activity, exploratory behavior, anxiety state or retrieval of the avoidance response. The facilitatory effect of intra-CA1 histamine was mimicked by the histamine N-methyltransferase inhibitor SKF-91844 as well as by the H2 receptor agonist dimaprit and it was blocked completely by the H2 receptor antagonist ranitidine. Conversely, the promnesic action of histamine was unaffected by the H1 receptor antagonist pyrilamine, the H3 receptor antagonist, thioperamide, and the NMDAr polyamine-binding site antagonist ifenprodil. By themselves, ranitidine, pyrilamine, thioperamide, and ifenprodil did not affect IA memory consolidation. Our data indicate that, when given into CA1, histamine enhances memory consolidation through a mechanism that involves activation of H2 receptors; however, endogenous CA1 histamine does not seem to participate in the consolidation of IA memory at least at the post-training times analyzed.

  11. GABAergic influences on ORX receptor-dependent abnormal motor behaviors and neurodegenerative events in fish

    SciTech Connect

    Facciolo, Rosa Maria; Crudo, Michele; Giusi, Giuseppina; Canonaco, Marcello

    2010-02-15

    At date the major neuroreceptors i.e. gamma-aminobutyric acid{sub A} (GABA{sub A}R) and orexin (ORXR) systems are beginning to be linked to homeostasis, neuroendocrine and emotional states. In this study, intraperitoneal treatment of the marine teleost Thalassoma pavo with the highly selective GABA{sub A}R agonist (muscimol, MUS; 0,1 mug/g body weight) and/or its antagonist bicuculline (BIC; 1 mug/g body weight) have corroborated a GABA{sub A}ergic role on motor behaviors. In particular, MUS induced moderate (p < 0.05) and great (p < 0.01) increases of swimming towards food sources and resting states after 24 (1 dose) and 96 (4 doses) h treatment sessions, respectively, when compared to controls. Conversely, BIC caused a very strong (p < 0.001) reduction of the former behavior and in some cases convulsive swimming. From the correlation of BIC-dependent behavioral changes to neuronal morphological and ORXR transcriptional variations, it appeared that the disinhibitory action of GABA{sub A}R was very likely responsible for very strong and strong ORXR mRNA reductions in cerebellum valvula and torus longitudinalis, respectively. Moreover these effects were linked to evident ultra-structural changes such as shrunken cell membranes and loss of cytoplasmic architecture. In contrast, MUS supplied a very low, if any, argyrophilic reaction in hypothalamic and mesencephalic regions plus a scarce level of ultra-structural damages. Interestingly, combined administrations of MUS + BIC were not related to consistent damages, aside mild neuronal alterations in motor-related areas such as optic tectum. Overall it is tempting to suggest, for the first time, a neuroprotective role of GABA{sub A}R inhibitory actions against the overexcitatory ORXR-dependent neurodegeneration and consequently abnormal swimming events in fish.

  12. Adolescent social rejection alters pain processing in a CB1 receptor dependent manner.

    PubMed

    Schneider, Peggy; Pätz, Monique; Spanagel, Rainer; Schneider, Miriam

    2016-07-01

    Experiences of social rejection represent a major source of distress and in particular peer rejection during adolescence has been implicated in various psychiatric disorders. Moreover, experimentally induced acute social rejection alters pain perception in humans, implicating overlapping neurocircuits for social and physical pains. We recently demonstrated that rearing of adolescent Wistar rats with inadequate, less playful play partners (Fischer 344) persistently decreases pain sensitivity, although the detailed mechanisms mediating the aversiveness during the social encounter remained unsettled. With the present study we examined the behavioral performance during acute interaction of female adolescent Wistar rats with either age-matched same-strain partners or rats from the Fischer 344 strain. We here identify the low responsiveness upon playful attacks, which appears to be characteristic for social play in the Fischer 344 strain, as one of the main aversive components for adolescent Wistar animals during cross-strain encounters, which subsequently diminishes thermal pain reactivity. A detailed behavioral analysis further revealed increased ultrasonic vocalization at 50kHz and an increased frequency of playful attacks for adolescent Wistar animals paired with a Fischer 344 rat compared to same-strain control pairs. Finally, an acute injection of a subthreshold dose of the cannabinoid type 1 receptor inverse agonist/antagonist SR141716 before the social encounter abolished enhanced play-soliciting behavior in Wistar/Fischer 344 pairs as well as the behavioral consequences of the rejection experience in adolescent Wistar rats, further emphasizing an important modulatory role of the endocannabinoid system in mediating the effects of social behavior and social pain. PMID:27157075

  13. RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1

    PubMed Central

    Joshi, Purna A.; Waterhouse, Paul D.; Kannan, Nagarajan; Narala, Swami; Fang, Hui; Di Grappa, Marco A.; Jackson, Hartland W.; Penninger, Josef M.; Eaves, Connie; Khokha, Rama

    2015-01-01

    Summary Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells. PMID:26095608

  14. Validated Models for Radiation Response and Signal Generation in Scintillators: Final Report

    SciTech Connect

    Kerisit, Sebastien N.; Gao, Fei; Xie, YuLong; Campbell, Luke W.; Van Ginhoven, Renee M.; Wang, Zhiguo; Prange, Micah P.; Wu, Dangxin

    2014-12-01

    This Final Report presents work carried out at Pacific Northwest National Laboratory (PNNL) under the project entitled “Validated Models for Radiation Response and Signal Generation in Scintillators” (Project number: PL10-Scin-theor-PD2Jf) and led by Drs. Fei Gao and Sebastien N. Kerisit. This project was divided into four tasks: 1) Electronic response functions (ab initio data model) 2) Electron-hole yield, variance, and spatial distribution 3) Ab initio calculations of information carrier properties 4) Transport of electron-hole pairs and scintillation efficiency Detailed information on the results obtained in each of the four tasks is provided in this Final Report. Furthermore, published peer-reviewed articles based on the work carried under this project are included in Appendix. This work was supported by the National Nuclear Security Administration, Office of Nuclear Nonproliferation Research and Development (DNN R&D/NA-22), of the U.S. Department of Energy (DOE).

  15. Remote sensing of ice phenomena from orbit by signal correlation of multiple receiver responses

    NASA Technical Reports Server (NTRS)

    Stacey, J. M.; Johnston, E. J.

    1983-01-01

    The method of signal correlation of microwave responses as applied to the measurement of Earth-surface ice temperatures from orbit is explained and summarized. Ice temperatures are estimated by a correlation function that is derived from the processes of a forward stepwise correlator. Subsets of the post-detected outputs of microwave receiving channels are combined in a multivariate cross-correlation function which operates as a spatial filter and serves to improve the spatial resolution of the thermal gradients in ice structures. The correlator is designed to selectively identify the correlative components among the microwave responses and to strongly suppress or cancel the non-correlative components appearing in the post-detected outputs.

  16. Sensor–response regulator interactions in a cross-regulated signal transduction network

    PubMed Central

    Huynh, TuAnh Ngoc; Chen, Li-Ling

    2015-01-01

    Two-component signal transduction involves phosphoryl transfer between a histidine kinase sensor and a response regulator effector. The nitrate-responsive two-component signal transduction systems in Escherichia coli represent a paradigm for a cross-regulation network, in which the paralogous sensor–response regulator pairs, NarX–NarL and NarQ–NarP, exhibit both cognate (e.g. NarX–NarL) and non-cognate (e.g. NarQ–NarL) interactions to control output. Here, we describe results from bacterial adenylate cyclase two-hybrid (BACTH) analysis to examine sensor dimerization as well as interaction between sensor–response regulator cognate and non-cognate pairs. Although results from BACTH analysis indicated that the NarX and NarQ sensors interact with each other, results from intragenic complementation tests demonstrate that they do not form functional heterodimers. Additionally, intragenic complementation shows that both NarX and NarQ undergo intermolecular autophosphorylation, deviating from the previously reported correlation between DHp (dimerization and histidyl phosphotransfer) domain loop handedness and autophosphorylation mode. Results from BACTH analysis revealed robust interactions for the NarX–NarL, NarQ–NarL and NarQ–NarP pairs but a much weaker interaction for the NarX–NarP pair. This demonstrates that asymmetrical cross-regulation results from differential binding affinities between different sensor–regulator pairs. Finally, results indicate that the NarL effector (DNA-binding) domain inhibits NarX–NarL interaction. Missense substitutions at receiver domain residue Ser-80 enhanced NarX–NarL interaction, apparently by destabilizing the NarL receiver–effector domain interface. PMID:25873583

  17. Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer.

    PubMed

    Zhang, Hua; Angelopoulos, Nicos; Xu, Yichen; Grothey, Arnhild; Nunes, Joao; Stebbing, Justin; Giamas, Georgios

    2015-06-01

    Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer. PMID:26022350

  18. Signalling mechanisms underlying the morphological responses of the root system to nitrogen in Arabidopsis thaliana.

    PubMed

    Zhang, Hanma; Rong, Honglin; Pilbeam, David

    2007-01-01

    Plants display considerable developmental plasticity in response to changing environmental conditions. The adaptations of the root system to variations in N supply are an excellent example of such developmental plasticity. In Arabidopsis, four morphological adaptations to the N supply have been characterized: (i) a localized stimulatory effect of external nitrate on lateral root elongation; (ii) a systemic inhibitory effect of high tissue nitrate concentrations on the activation of lateral root meristems; (iii) a suppression of lateral root initiation by high C:N ratios, and (iv) an inhibition of primary root growth and stimulation of root branching by external L-glutamate. These responses have provided valuable experimental systems for the study of N signalling in plants. This article will highlight some recent progress made in this direction from studies using the Arabidopsis root system. One recent development of note has been the emerging evidence of a regulatory role of nitrate transporters in some of the responses. It has been reported that the AtNRT1.1 (CHL1) dual-affinity nitrate transporter acts upstream of the ANR1 MADS box gene in mediating the stimulatory effect of a localized nitrate supply on lateral root proliferation. The AtNRT2.1 high-affinity nitrate transporter seems to be involved in the repression of lateral root initiation by high C:N ratios. The systemic inhibitory effect of high nitrate supply on lateral root development, which is mediated by abscisic acid (ABA), may be linked to the recently identified ABA receptor, FCA. The newly discovered root architectural response to external L-glutamate potentially offers a valuable experimental tool for studying the biological function of plant glutamate receptors and amino acid signalling.

  19. Electric signalling in fruit trees in response to water applications and light-darkness conditions.

    PubMed

    Gurovich, Luis A; Hermosilla, Paulo

    2009-02-15

    A fundamental property of all living organisms is the generation and conduction of electrochemical impulses throughout their different tissues and organs, resulting from abiotic and biotic changes in environmental conditions. In plants and animals, signal transmission can occur over long and short distances, and it can correspond to intra- and inter-cellular communication mechanisms that determine the physiological behaviour of the organism. Rapid plant and animal responses to environmental changes are associated with electrical excitability and signalling. The same molecules and pathways are used to drive physiological responses, which are characterized by movement (physical displacement) in animals and by continuous growth in plants. In the field of environmental plant electrophysiology, automatic and continuous measurements of electrical potential differences (DeltaEP) between plant tissues can be effectively used to study information transport mechanisms and physiological responses that result from external stimuli on plants. A critical mass of data on electrical behaviour in higher plants has accumulated in the last 5 years, establishing plant neurobiology as the most recent discipline of plant science. In this work, electrical potential differences were monitored continuously using Ag/AgCl microelectrodes, which were inserted 15mm deep into sapwood at various positions in the trunks of several fruit-bearing trees. Electrodes were referenced to an unpolarisable Ag/AgCl microelectrode, which was installed 5cm deep in the soil. Systematic patterns of DeltaEP during day-night cycles and at different conditions of soil water availability are discussed as alternative tools to assess early plant stress conditions. This research relates to the adaptive response of trees to soil water availability and light-darkness cycles.

  20. Signaling and Dynamic Actin Responses of B Cells on Topographical Substrates

    NASA Astrophysics Data System (ADS)

    Ketchum, Christina; Sun, Xiaoyu; Fourkas, John; Song, Wenxia; Upadhyaya, Arpita

    B cells become activated upon physical contact with antigen on the surface of antigen presenting cells, such as dendritic cells. Binding of the B cell receptor with antigen initiates actin-mediated spreading of B cells, signaling cascades and eventually infection fighting antibodies. Lymphocytes, including B cells and T cells, have been shown to be responsive to the physical parameters of the contact surface, such as antigen mobility and substrate stiffness. However the roll of surface topography on lymphocyte function is unknown. Here we investigate the degree to which substrate topography controls actin-mediated spreading and B cell activation using nano-fabricated surfaces and live cell imaging. The model topographical system consists of 600 nanometer tall ridges with spacing varying between 800 nanometers and 5 micrometers. Using TIRF imaging we observe actin dynamics, B cell receptor motion and calcium signaling of B cells as they spread on the ridged substrates. We show that the spacing between ridges had a strong effect on the dynamics of actin and calcium influx on B cells. Our results indicate that B cells are highly sensitive to surface topography during cell spreading and signaling activation.

  1. Stress-activated signaling responses leading to apoptosis following photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Oleinick, Nancy L.; He, Jin; Xue, Liang-yan; Separovic, Duska

    1998-05-01

    Photodynamic treatment with the phthalocyanine Pc 4, a mitochondrially localizing photosensitizer, is an efficient inducer of cell death by apoptosis, a cell suicide pathway that can be triggered by physiological stimuli as well as by various types of cellular damage. Upon exposure of the dye- loaded cells to red light, several stress signalling pathways are rapidly activated. In murine L5178Y-R lymphoblasts, caspase activation and other hallmarks of the final phase of apoptosis are observed within a few minutes post-PDT. In Chinese hamster CHO-K1 cells, the first signs of apoptosis are not observed for 1 - 2 hours. The possible involvement of three parallel mitogen-activated protein kinase (MAPK) signalling pathways has been investigated. The extracellular- regulated kinases (ERK-1 and ERK-2), that are thought to promote cell growth, are not appreciably altered by PDT. However, PDT causes marked activation of the stress-activated protein kinase (SAPK) cascade in both cell types and of the p38/HOG-type kinase in CHO cells. Both of these latter pathways have been demonstrated to be associated with apoptosis. A specific inhibitor of the ERK pathway did not alter PDT-induced apoptosis; however, an inhibitor of the p38 pathway partially blocked PDT-induced apoptosis. Blockage of the SAPK pathway is being pursued by a genetic approach. It appears that the SAPK and p38 pathways may participate in signaling apoptosis in response to PDT with Pc 4.

  2. Alpha-arrestins Aly1 and Aly2 regulate intracellular trafficking in response to nutrient signaling.

    PubMed

    O'Donnell, Allyson F; Apffel, Alex; Gardner, Richard G; Cyert, Martha S

    2010-10-15

    Extracellular signals regulate trafficking events to reorganize proteins at the plasma membrane (PM); however, few effectors of this regulation have been identified. β-Arrestins relay signaling cues to the trafficking machinery by controlling agonist-stimulated endocytosis of G-protein-coupled receptors. In contrast, we show that yeast α-arrestins, Aly1 and Aly2, control intracellular sorting of Gap1, the general amino acid permease, in response to nutrients. These studies are the first to demonstrate association of α-arrestins with clathrin and clathrin adaptor proteins (AP) and show that Aly1 and Aly2 interact directly with the γ-subunit of AP-1, Apl4. Aly2-dependent trafficking of Gap1 requires AP-1, which mediates endosome-to-Golgi transport, and the nutrient-regulated kinase, Npr1, which phosphorylates Aly2. During nitrogen starvation, Npr1 phosphorylation of Aly2 may stimulate Gap1 incorporation into AP-1/clathrin-coated vesicles to promote Gap1 trafficking from endosomes to the trans-Golgi network. Ultimately, increased Aly1-/Aly2-mediated recycling of Gap1 from endosomes results in higher Gap1 levels within cells and at the PM by diverting Gap away from trafficking pathways that lead to vacuolar degradation. This work defines a new role for arrestins in membrane trafficking and offers insight into how α-arrestins coordinate signaling events with protein trafficking.

  3. Distinct CCR7 glycosylation pattern shapes receptor signaling and endocytosis to modulate chemotactic responses.

    PubMed

    Hauser, Mark A; Kindinger, Ilona; Laufer, Julia M; Späte, Anne-Katrin; Bucher, Delia; Vanes, Sarah L; Krueger, Wolfgang A; Wittmann, Valentin; Legler, Daniel F

    2016-06-01

    The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a "swinging door" to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not naïve T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic cell-dependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses. PMID:26819318

  4. How do shared-representations and emotional processes cooperate in response to social threat signals?

    PubMed

    Grèzes, Julie; Dezecache, Guillaume

    2014-03-01

    Research in social cognition has mainly focused on the detection and comprehension of others' mental and emotional states. Doing so, past studies have adopted a "contemplative" view of the role of the observer engaged in a social interaction. However, the adaptive problem posed by the social environment is first and foremost that of coordination, which demands more of social cognition beyond mere detection and comprehension of others' hidden states. Offering a theoretical framework that takes into account the dynamical aspect of social interaction - notably by accounting for constant interplay between emotional appraisal and motor processes in socially engaged human brain - thus constitutes an important challenge for the field of social cognition. Here, we propose that our social environment can be seen as presenting opportunities for actions regarding others. Within such a framework, non-verbal social signals such as emotional displays are considered to have evolved to influence the observer in consistent ways. Consequently, social signals can modulate motor responses in observers. In line with this theoretical framework we provide evidence that emotional and motor processes are actually tightly linked during the perception of threat signals. This is ultimately reflected in the human brain by constant interplay between limbic and motor areas.

  5. The role of astrocytes in the hypothalamic response and adaptation to metabolic signals.

    PubMed

    Chowen, Julie A; Argente-Arizón, Pilar; Freire-Regatillo, Alejandra; Frago, Laura M; Horvath, Tamas L; Argente, Jesús

    2016-09-01

    The hypothalamus is crucial in the regulation of homeostatic functions in mammals, with the disruption of hypothalamic circuits contributing to chronic conditions such as obesity, diabetes mellitus, hypertension, and infertility. Metabolic signals and hormonal inputs drive functional and morphological changes in the hypothalamus in attempt to maintain metabolic homeostasis. However, the dramatic increase in the incidence of obesity and its secondary complications, such as type 2 diabetes, have evidenced the need to better understand how this system functions and how it can go awry. Growing evidence points to a critical role of astrocytes in orchestrating the hypothalamic response to metabolic cues by participating in processes of synaptic transmission, synaptic plasticity and nutrient sensing. These glial cells express receptors for important metabolic signals, such as the anorexigenic hormone leptin, and determine the type and quantity of nutrients reaching their neighboring neurons. Understanding the mechanisms by which astrocytes participate in hypothalamic adaptations to changes in dietary and metabolic signals is fundamental for understanding the neuroendocrine control of metabolism and key in the search for adequate treatments of metabolic diseases.

  6. Isorhamnetin ameliorates LPS-induced inflammatory response through downregulation of NF-κB signaling.

    PubMed

    Li, Yang; Chi, Gefu; Shen, Bingyu; Tian, Ye; Feng, Haihua

    2016-08-01

    Isorhamnetin, a flavonoid mainly found in Hippophae fhamnoides L. fruit, has been known for its antioxidant activity and its ability to regulate immune response. In this study, we investigated whether isorhamnetin exerts potent antiinflammatory effects in RAW264.7 cell and mouse model stimulated by LPS. The cytokine (TNF-α, IL-1β, and IL-6) levels were determined. In the mouse model of acute lung injury, the phosphorylation of NF-κB proteins was analyzed and inhibitor of NF-κB signaling (PDTC) was used on mice. Our results showed that isorhamnetin markedly decreased TNF-α, IL-1β, and IL-6 concentrations and suppressed the activation of NF-κB signaling. Meanwhile, isorhamnetin reduced the amount of inflammatory cells, the lung wet-to-dry weight ratio, protein leakage, and myeloperoxidase activity. Interference with specific inhibitor revealed that isorhamnetin-mediated suppression of cytokines and protein was via NF-κB signaling. So, it suggests that isorhamnetin might be a potential therapeutic agent for preventing inflammatory diseases. PMID:27138362

  7. Involvement of epidermal growth factor receptor-linked signaling responses in Pseudomonas fluorescens-infected alveolar epithelial cells.

    PubMed

    Choi, Hye Jin; Seo, Chan Hee; Park, Seong Hwan; Yang, Hyun; Do, Kee Hun; Kim, Juil; Kim, Hyung-Kab; Chung, Duk-Hwa; Ahn, Jung Hoon; Moon, Yuseok

    2011-05-01

    Pseudomonas fluorescens is an opportunistic indoor pathogen that can cause severe airway proinflammatory responses. Pulmonary epithelium, like other mucosal epithelial linings of the body, constitutes the first line of defense against airway microbial pathogens. Mucosal epithelial cells can be a sentinel of pathogenic bacteria via stimulation of specific cell surface receptors, including the epidermal growth factor receptor (EGFR) and Toll-like receptor (TLR). This study addressed the involvement of EGFR in airway epithelial pathogenesis by P. fluorescens. Human A549 pneumocytes showed prolonged production of proinflammatory interleukin-8 (IL-8) in response to infection with P. fluorescens, which was via the nuclear factor-kappa B (NF-κB) signaling pathway. Production of proinflammatory cytokine IL-8 was not mediated by P. fluorescens lipopolysaccharide, a representative TLR4 agonist, but was mediated through EGFR-linked signals activated by the opportunistic bacteria. Moreover, EGFR signals were involved in NF-κB signal-mediated production of proinflammatory cytokines. Along with persistent NF-κB activation, P. fluorescens enhanced the EGFR phosphorylation and subsequent activation of downstream mediators, including protein kinase B or extracellular-signal-regulated kinases 1/2. Blocking of EGFR-linked signals increased epithelial susceptibility to pathogen-induced epithelial cell death, suggesting protective roles of EGFR signals. Thus, airway epithelial exposure to P. fluorescens can trigger antiapoptotic responses via EGFR and proinflammatory responses via TLR4-independent NF-κB signaling pathway in human pneumocytes.

  8. Signaling through CD14 attenuates the inflammatory response to Borrelia burgdorferi, the agent of Lyme disease.

    PubMed

    Benhnia, Mohammed Rafii-El-Idrissi; Wroblewski, Danielle; Akhtar, Muhammad Naveed; Patel, Raina A; Lavezzi, Wendy; Gangloff, Sophie C; Goyert, Sanna M; Caimano, Melissa J; Radolf, Justin D; Sellati, Timothy J

    2005-02-01

    Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia burgdorferi. In vitro evidence suggests that binding of spirochetal lipoproteins to CD14, a pattern recognition receptor expressed on monocytes/macrophages and polymorphonuclear cells, is a critical requirement for cellular activation and the subsequent release of proinflammatory cytokines that most likely contribute to symptomatology and clinical manifestations. To test the validity of this notion, we assessed the impact of CD14 deficiency on Lyme disease in C3H/HeN mice. Contrary to an anticipated diminution in pathology, CD14(-/-) mice exhibited more severe and persistent inflammation than did CD14(+/+) mice. This disparity reflects altered gene regulation within immune cells that may engender the higher bacterial burden and serum cytokine levels observed in CD14(-/-) mice. Comparing their in vitro stimulatory activity, live spirochetes, but not lysed organisms, were a potent CD14-independent stimulus of cytokine production, triggering an exaggerated response by CD14(-/-) macrophages. Collectively, our in vivo and in vitro findings support the provocative notion that: 1) pattern recognition by CD14 is entirely dispensable for elaboration of an inflammatory response to B. burgdorferi, and 2) CD14-independent signaling pathways are inherently more destructive than CD14-dependent pathways. Continued study of CD14-independent signaling pathways may provide mechanistic insight into the inflammatory processes that underlie development of chronic inflammation.

  9. Characterization of Differential Protein Tethering at the Plasma Membrane in Response to Epidermal Growth Factor Signaling

    PubMed Central

    Looyenga, Brendan D.; MacKeigan, Jeffrey P.

    2013-01-01

    Physical tethering of membrane proteins to the cortical actin cytoskeleton provides functional organization to the plasma membrane and contributes to diverse cellular processes including cell signaling, vesicular trafficking, endocytosis, and migration. For these processes to occur, membrane protein tethering must be dynamically regulated in response to environmental cues. In this study, we describe a novel biochemical scheme for isolating the complement of plasma membrane proteins that are physically tethered to the actin cytoskeleton. We utilized this method in combination with tandem liquid chromatography/mass spectrometry (LC–MS/MS) to demonstrate that cytoskeletal tethering of membrane proteins is acutely regulated by epidermal growth factor (EGF) in normal human kidney (HK2) cells. Our results indicate that several proteins known to be involved in EGF signaling, as well as other proteins not traditionally associated with this pathway, are tethered to the cytoskeleton in dynamic fashion. Further analysis of one hit from our proteomic survey, the receptor phosphotyrosine phosphatase PTPRS, revealed a correlation between cytoskeletal tethering and endosomal trafficking in response to EGF. This finding parallels previous indications that PTPRS is involved in the desensitization of EGFR and provides a potential mechanism to coordinate localization of these two membrane proteins in the same compartment upon EGFR activation. PMID:22559174

  10. DNA barcodes reveal microevolutionary signals in fire response trait in two legume genera

    PubMed Central

    Bello, Abubakar; Daru, Barnabas H.; Stirton, Charles H.; Chimphango, Samson B. M.; van der Bank, Michelle; Maurin, Olivier; Muasya, A. Muthama

    2015-01-01

    Large-scale DNA barcoding provides a new technique for species identification and evaluation of relationships across various levels (populations and species) and may reveal fundamental processes in recently diverged species. Here, we analysed DNA sequence variation in the recently diverged legumes from the Psoraleeae (Fabaceae) occurring in the Cape Floristic Region (CFR) of southern Africa to test the utility of DNA barcodes in species identification and discrimination. We further explored the phylogenetic signal on fire response trait (reseeding and resprouting) at species and generic levels. We showed that Psoraleoid legumes of the CFR exhibit a barcoding gap yielding the combination of matK and rbcLa (matK + rbcLa) data set as a better barcode than single regions. We found a high score (100 %) of correct identification of individuals to their respective genera but a very low score (<50 %) in identifying them to species. We found a considerable match (54 %) between genetic species and morphologically delimited species. We also found that different lineages showed a weak but significant phylogenetic conservatism in their response to fire as reseeders or resprouters, with more clustering of resprouters than would be expected by chance. These novel microevolutionary patterns might be acting continuously over time to produce multi-scale regularities of biodiversity. This study provides the first insight into the DNA barcoding campaign of land plants in species identification and detection of the phylogenetic signal in recently diverged lineages of the CFR. PMID:26507570

  11. Vascular-mediated signalling involved in early phosphate stress response in plants.

    PubMed

    Zhang, Zhaoliang; Zheng, Yi; Ham, Byung-Kook; Chen, Jieyu; Yoshida, Akiko; Kochian, Leon V; Fei, Zhangjun; Lucas, William J

    2016-01-01

    Depletion of finite global rock phosphate (Pi) reserves will impose major limitations on future agricultural productivity and food security. Hence, modern breeding programmes seek to develop Pi-efficient crops with sustainable yields under reduced Pi fertilizer inputs. In this regard, although the long-term responses of plants to Pi stress are well documented, the early signalling events have yet to be elucidated. Here, we show plant tissue-specific responses to early Pi stress at the transcription level and a predominant role of the plant vascular system in this process. Specifically, imposition of Pi stress induces rapid and major changes in the mRNA population in the phloem translocation stream, and grafting studies have revealed that many hundreds of phloem-mobile mRNAs are delivered to specific sink tissues. We propose that the shoot vascular system acts as the site of root-derived Pi stress perception, and the phloem serves to deliver a cascade of signals to various sinks, presumably to coordinate whole-plant Pi homeostasis.

  12. Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells

    PubMed Central

    Mumby, Sharon; Ramakrishnan, Latha; Evans, Timothy W.; Griffiths, Mark J. D.

    2013-01-01

    Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-κB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases. PMID:24142518

  13. Dynamic localization of a cytoplasmic signal transduction response regulator controls morphogenesis during the Caulobacter cell cycle

    PubMed Central

    Jacobs, Christine; Hung, Dean; Shapiro, Lucy

    2001-01-01

    We present evidence that a bacterial signal transduction cascade that couples morphogenesis with cell cycle progression is regulated by dynamic localization of its components. Previous studies have implicated two histidine kinases, DivJ and PleC, and the response regulator, DivK, in the regulation of morphogenesis in the dimorphic bacterium Caulobacter crescentus. Here, we show that the cytoplasmic response regulator, DivK, exhibits a dynamic, cyclical localization that culminates in asymmetric distribution of DivK within the two cell types that are characteristic of the Caulobacter cell cycle; DivK is dispersed throughout the cytoplasm of the progeny swarmer cell and is localized to the pole of the stalked cell. The membrane-bound DivJ and PleC histidine kinases, which are asymmetrically localized at the opposite poles of the predivisional cell, control the temporal and spatial localization of DivK. DivJ mediates DivK targeting to the poles whereas PleC controls its release from one of the poles at times and places that are consistent with the activities and location of DivJ and PleC in the late predivisional cell. Thus, dynamic changes in subcellular location of multiple components of a signal transduction cascade may constitute a novel mode of prokaryotic regulation to generate and maintain cellular asymmetry. PMID:11274434

  14. Vascular-mediated signalling involved in early phosphate stress response in plants.

    PubMed

    Zhang, Zhaoliang; Zheng, Yi; Ham, Byung-Kook; Chen, Jieyu; Yoshida, Akiko; Kochian, Leon V; Fei, Zhangjun; Lucas, William J

    2016-01-01

    Depletion of finite global rock phosphate (Pi) reserves will impose major limitations on future agricultural productivity and food security. Hence, modern breeding programmes seek to develop Pi-efficient crops with sustainable yields under reduced Pi fertilizer inputs. In this regard, although the long-term responses of plants to Pi stress are well documented, the early signalling events have yet to be elucidated. Here, we show plant tissue-specific responses to early Pi stress at the transcription level and a predominant role of the plant vascular system in this process. Specifically, imposition of Pi stress induces rapid and major changes in the mRNA population in the phloem translocation stream, and grafting studies have revealed that many hundreds of phloem-mobile mRNAs are delivered to specific sink tissues. We propose that the shoot vascular system acts as the site of root-derived Pi stress perception, and the phloem serves to deliver a cascade of signals to various sinks, presumably to coordinate whole-plant Pi homeostasis. PMID:27249565

  15. Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway

    PubMed Central

    Macari, Elizabeth R.

    2011-01-01

    Although hematopoietic stem cell transplantation and gene therapy have the potential to cure β-thalassemia and sickle cell disease, they are not currently available to most people with these diseases. In the near term, pharmacologic induction of fetal hemoglobin (HbF) may offer the best possibility for safe, effective, and widely available therapy. In an effort to define new pathways for targeted drug development for HbF induction, we evaluated the nuclear factor erythroid 2–related factor 2 (NRF2) antioxidant response element signaling pathway. We found that 3 well-known activators of this pathway increased γ-globin mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most active of these compounds, increased cellular levels and nuclear translocation of NRF2 and binding of NRF2 to the γ-globin promoter. siRNA knockdown of NRF2 inhibited γ-globin induction by tBHQ. When tested in human primary erythroid cells, tBHQ induced NRF2 binding to the γ-globin promoter, increased γ-globin mRNA and HbF, and suppressed β-globin mRNA and HbA, resulting in a > 3-fold increase in the percentage of HbF. These results suggest that drugs that activate the NRF2/antioxidant response element signaling pathway have the potential to induce therapeutic levels of HbF in people with β-hemoglobinopathies. PMID:21464371

  16. Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway.

    PubMed

    Macari, Elizabeth R; Lowrey, Christopher H

    2011-06-01

    Although hematopoietic stem cell transplantation and gene therapy have the potential to cure β-thalassemia and sickle cell disease, they are not currently available to most people with these diseases. In the near term, pharmacologic induction of fetal hemoglobin (HbF) may offer the best possibility for safe, effective, and widely available therapy. In an effort to define new pathways for targeted drug development for HbF induction, we evaluated the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant response element signaling pathway. We found that 3 well-known activators of this pathway increased γ-globin mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most active of these compounds, increased cellular levels and nuclear translocation of NRF2 and binding of NRF2 to the γ-globin promoter. siRNA knockdown of NRF2 inhibited γ-globin induction by tBHQ. When tested in human primary erythroid cells, tBHQ induced NRF2 binding to the γ-globin promoter, increased γ-globin mRNA and HbF, and suppressed β-globin mRNA and HbA, resulting in a > 3-fold increase in the percentage of HbF. These results suggest that drugs that activate the NRF2/antioxidant response element signaling pathway have the potential to induce therapeutic levels of HbF in people with β-hemoglobinopathies.

  17. Geographical matching of volatile signals and pollinator olfactory responses in a cycad brood-site mutualism.

    PubMed

    Suinyuy, Terence N; Donaldson, John S; Johnson, Steven D

    2015-10-01

    Brood-site mutualisms represent extreme levels of reciprocal specialization between plants and insect pollinators, raising questions about whether these mutualisms are mediated by volatile signals and whether these signals and insect responses to them covary geographically in a manner expected from coevolution. Cycads are an ancient plant lineage in which almost all extant species are pollinated through brood-site mutualisms with insects. We investigated whether volatile emissions and insect olfactory responses are matched across the distribution range of the African cycad Encephalartos villosus. This cycad species is pollinated by the same beetle species across its distribution, but cone volatile emissions are dominated by alkenes in northern populations, and by monoterpenes and a pyrazine compound in southern populations. In reciprocal choice experiments, insects chose the scent of cones from the local region over that of cones from the other region. Antennae of beetles from northern populations responded mainly to alkenes, while those of beetles from southern populations responded mainly to pyrazine. In bioassay experiments, beetles were most strongly attracted to alkenes in northern populations and to the pyrazine compound in southern populations. Geographical matching of cone volatiles and pollinator olfactory preference is consistent with coevolution in this specialized mutualism. PMID:26446814

  18. Geographical matching of volatile signals and pollinator olfactory responses in a cycad brood-site mutualism

    PubMed Central

    Suinyuy, Terence N.; Donaldson, John S.; Johnson, Steven D.

    2015-01-01

    Brood-site mutualisms represent extreme levels of reciprocal specialization between plants and insect pollinators, raising questions about whether these mutualisms are mediated by volatile signals and whether these signals and insect responses to them covary geographically in a manner expected from coevolution. Cycads are an ancient plant lineage in which almost all extant species are pollinated through brood-site mutualisms with insects. We investigated whether volatile emissions and insect olfactory responses are matched across the distribution range of the African cycad Encephalartos villosus. This cycad species is pollinated by the same beetle species across its distribution, but cone volatile emissions are dominated by alkenes in northern populations, and by monoterpenes and a pyrazine compound in southern populations. In reciprocal choice experiments, insects chose the scent of cones from the local region over that of cones from the other region. Antennae of beetles from northern populations responded mainly to alkenes, while those of beetles from southern populations responded mainly to pyrazine. In bioassay experiments, beetles were most strongly attracted to alkenes in northern populations and to the pyrazine compound in southern populations. Geographical matching of cone volatiles and pollinator olfactory preference is consistent with coevolution in this specialized mutualism. PMID:26446814

  19. Geographical matching of volatile signals and pollinator olfactory responses in a cycad brood-site mutualism.

    PubMed

    Suinyuy, Terence N; Donaldson, John S; Johnson, Steven D

    2015-10-01

    Brood-site mutualisms represent extreme levels of reciprocal specialization between plants and insect pollinators, raising questions about whether these mutualisms are mediated by volatile signals and whether these signals and insect responses to them covary geographically in a manner expected from coevolution. Cycads are an ancient plant lineage in which almost all extant species are pollinated through brood-site mutualisms with insects. We investigated whether volatile emissions and insect olfactory responses are matched across the distribution range of the African cycad Encephalartos villosus. This cycad species is pollinated by the same beetle species across its distribution, but cone volatile emissions are dominated by alkenes in northern populations, and by monoterpenes and a pyrazine compound in southern populations. In reciprocal choice experiments, insects chose the scent of cones from the local region over that of cones from the other region. Antennae of beetles from northern populations responded mainly to alkenes, while those of beetles from southern populations responded mainly to pyrazine. In bioassay experiments, beetles were most strongly attracted to alkenes in northern populations and to the pyrazine compound in southern populations. Geographical matching of cone volatiles and pollinator olfactory preference is consistent with coevolution in this specialized mutualism.

  20. Apoplastic reactive oxygen species transiently decrease auxin signaling and cause stress-induced morphogenic response in Arabidopsis.

    PubMed

    Blomster, Tiina; Salojärvi, Jarkko; Sipari, Nina; Brosché, Mikael; Ahlfors, Reetta; Keinänen, Markku; Overmyer, Kirk; Kangasjärvi, Jaakko

    2011-12-01

    Reactive oxygen species (ROS) are ubiquitous signaling molecules in plant stress and development. To gain further insight into the plant transcriptional response to apoplastic ROS, the phytotoxic atmospheric pollutant ozone was used as a model ROS inducer in Arabidopsis (Arabidopsis thaliana) and gene expression was analyzed with microarrays. In contrast to the increase in signaling via the stress hormones salicylic acid, abscisic acid, jasmonic acid (JA), and ethylene, ROS treatment caused auxin signaling to be transiently suppressed, which was confirmed with a DR5-uidA auxin reporter construct. Transcriptomic data revealed that various aspects of auxin homeostasis and signaling were modified by apoplastic ROS. Furthermore, a detailed analysis of auxin signaling showed that transcripts of several auxin receptors and Auxin/Indole-3-Acetic Acid (Aux/IAA) transcriptional repressors were reduced in response to apoplastic ROS. The ROS-derived changes in the expression of auxin signaling genes partially overlapped with abiotic stress, pathogen responses, and salicylic acid signaling. Several mechanisms known to suppress auxin signaling during biotic stress were excluded, indicating that ROS regulated auxin responses via a novel mechanism. Using mutants defective in various auxin (axr1, nit1, aux1, tir1 afb2, iaa28-1, iaa28-2) and JA (axr1, coi1-16) responses, ROS-induced cell death was found to be regulated by JA but not by auxin. Chronic ROS treatment resulted in altered leaf morphology, a stress response known as "stress-induced morphogenic response." Altered leaf shape of tir1 afb2 suggests that auxin was a negative regulator of stress-induced morphogenic response in the rosette.

  1. Extracellular matrix hyaluronan signals via its CD44 receptor in the increased responsiveness to mechanical stimulation.

    PubMed

    Ferrari, L F; Araldi, D; Bogen, O; Levine, J D

    2016-06-01

    We propose that the extracellular matrix (ECM) signals CD44, a hyaluronan receptor, to increase the responsiveness to mechanical stimulation in the rat hind paw. We report that intradermal injection of hyaluronidase induces mechanical hyperalgesia, that is inhibited by co-administration of a CD44 receptor antagonist, A5G27. The intradermal injection of low (LMWH) but not high (HMWH) molecular weight hyaluronan also induces mechanical hyperalgesia, an effect that was attenuated by pretreatment with HMWH or A5G27. Pretreatment with HMWH also attenuated the hyperalgesia induced by hyaluronidase. Similarly, intradermal injection of A6, a CD44 receptor agonist, produced hyperalgesia that was inhibited by HMWH and A5G27. Inhibitors of protein kinase A (PKA) and Src, but not protein kinase C (PKC), significantly attenuated the hyperalgesia induced by both A6 and LMWH. Finally, to determine if CD44 receptor signaling is involved in a preclinical model of inflammatory pain, we evaluated the effect of A5G27 and HMWH on the mechanical hyperalgesia associated with the inflammation induced by carrageenan. Both A5G27 and HMWH attenuated carrageenan-induced mechanical hyperalgesia. Thus, while LMWH acts at its cognate receptor, CD44, to induce mechanical hyperalgesia, HMWH acts at the same receptor as an antagonist. That the local administration of HMWH or A5G27 inhibits carrageenan-induced hyperalgesia supports the suggestion that carrageenan produces changes in the ECM that contributes to inflammatory pain. These studies define a clinically relevant role for signaling by the hyaluronan receptor, CD44, in increased responsiveness to mechanical stimulation. PMID:26996509

  2. Regulatory Roles of Cytokinins and Cytokinin Signaling in Response to Potassium Deficiency in Arabidopsis

    PubMed Central

    Nam, Youn-Jeong; Tran, Lam-Son Phan; Kojima, Mikiko; Sakakibara, Hitoshi; Nishiyama, Rie; Shin, Ryoung

    2012-01-01

    Potassium (K) is an important plant macronutrient that has various functions throughout the whole plant over its entire life span. Cytokinins (CKs) are known to regulate macronutrient homeostasis by controlling the expression of nitrate, phosphate and sulfate transporters. Although several studies have described how CKs signal deficiencies for some macronutrients, the roles of CKs in K signaling are poorly understood. CK content has been shown to decrease under K-starved conditions. Specifically, a CK-deficient mutant was more tolerant to low K than wild-type; however, a plant with an overaccumulation of CKs was more sensitive to low K. These results suggest that K deprivation alters CK metabolism, leading to a decrease in CK content. To investigate this phenomenon further, several Arabidopsis lines, including a CK-deficient mutant and CK receptor mutants, were analyzed in low K conditions using molecular, genetic and biochemical approaches. ROS accumulation and root hair growth in low K were also influenced by CKs. CK receptor mutants lost the responsiveness to K-deficient signaling, including ROS accumulation and root hair growth, but the CK-deficient mutant accumulated more ROS and exhibited up-regulated expression of HAK5, which is a high-affinity K uptake transporter gene that is rapidly induced by low K stress in ROS- and ethylene-dependent manner in response to low K. From these results, we conclude that a reduction in CK levels subsequently allows fast and effective stimulation of low K-induced ROS accumulation, root hair growth and HAK5 expression, leading to plant adaptation to low K conditions. PMID:23112848

  3. PKCα-Mediated Signals Regulate the Motile Responses of Cochlear Outer Hair Cells.

    PubMed

    Park, Channy; Kalinec, Federico

    2015-05-01

    There is strong evidence that changes in the actin/spectrin-based cortical cytoskeleton of outer hair cells (OHCs) regulate their motile responses as well as cochlear amplification, the process that optimizes the sensitivity and frequency selectivity of the mammalian inner ear. Since a RhoA/protein kinase C (PKC)-mediated pathway is known to inhibit the actin-spectrin interaction in other cell models, we decided to investigate whether this signaling cascade could also participate in the regulation of OHC motility. We used high-speed video microscopy and confocal microscopy to explore the effects of pharmacological activation of PKCα, PKCβI, PKCβII, PKCδ, PKCε, and PKCζ with lysophosphatidic acid (LPA) and their inhibition with bisindolylmaleimide I, as well as inhibition of RhoA and Rho-associated protein kinase (ROCK) with C3 and Y-27632, respectively. Motile responses were induced in isolated guinea pig OHCs by stimulation with an 8 V/cm external alternating electrical field as 50 Hz bursts of square wave pulses (100 ms on/off). We found that LPA increased expression of PKCα and PKCζ only, with PKCα, but not PKCζ, phosphorylating the cytoskeletal protein adducin of both Ser-726 and Thr-445. Interestingly, however, inhibition of PKCα reduced adducin phosphorylation only at Ser-726. We also determined that LPA activation of a PKCα-mediated signaling pathway simultaneously enhanced OHC electromotile amplitude and cell shortening, and facilitated RhoA/ROCK/LIMK1-mediated cofilin phosphorylation. Altogether, our results suggest that PKCα-mediated signals, probably via adducin-mediated inhibition of actin-spectrin binding and cofilin-mediated depolymerization of actin filaments, play an essential role in the homeostatic regulation of OHC motility and cochlear amplification. PMID:25954875

  4. The human DEK oncogene regulates DNA damage response signaling and repair

    PubMed Central

    Kavanaugh, Gina M.; Wise-Draper, Trisha M.; Morreale, Richard J.; Morrison, Monique A.; Gole, Boris; Schwemberger, Sandy; Tichy, Elisia D.; Lu, Lu; Babcock, George F.; Wells, James M.; Drissi, Rachid; Bissler, John J.; Stambrook, Peter J.; Andreassen, Paul R.; Wiesmüller, Lisa; Wells, Susanne I.

    2011-01-01

    The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair. PMID:21653549

  5. Identification and prediction of abiotic stress responsive transcription factors involved in abiotic stress signaling in soybean.

    PubMed

    Tran, Lam-Son Phan; Mochida, Keiichi

    2010-03-01

    Abiotic stresses such as extreme temperature, drought, high salinity, cold and waterlogging often result in significant losses to the yields of economically important crops such as soybean (Glycine max L.). Transcription factors (TFs) which bind to DNA through specific cis-regulatory sequences either activate or repress gene transcription have been reported to act as control switches in stress signaling. Recent completion of the soybean genomic sequence has open wide opportunities for large-scale identification and annotations of regulatory TFs in soybean for functional studies. Within the soybean genome, we identified 5,035 TF models which grouped into 61 families. Detailed annotations of soybean TF genes can be accessed at SoybeanTFDB (soybeantfdb.psc.riken.jp). Moreover, we have reported a new idea of high throughput prediction and selection of abiotic stress responsive TFs based on the existence of known stress responsive cis-element(s) located in the promoter regions of respective TFs and GO annotations. We, therefore, have provided a basic platform for the genome-wide analysis of regulatory mechanisms underlying abiotic stress responses and a reliable tool for prediction and selection of stress responsive TFs for further functional studies and genetic engineering.

  6. Tobacco LSU-like protein couples sulphur-deficiency response with ethylene signalling pathway.

    PubMed

    Moniuszko, Grzegorz; Skoneczny, Marek; Zientara-Rytter, Katarzyna; Wawrzyńska, Anna; Głów, Dawid; Cristescu, Simona M; Harren, Frans J M; Sirko, Agnieszka

    2013-11-01

    Most genes from the plant-specific family encoding Response to Low Sulphur (LSU)-like proteins are strongly induced in sulphur (S)-deficient conditions. The exact role of these proteins remains unclear; however, some data suggest their importance for plants' adjustment to nutrient deficiency and other environmental stresses. This work established that the regulation of ethylene signalling is a part of plants' response to S deficiency and showed the interaction between UP9C, a tobacco LSU family member, and one of the tobacco isoforms of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO2A). Increase in ethylene level induced by S deficiency does not take place in tobacco plants with UP9C expressed in an antisense orientation. Based on transcriptomics data, this work also demonstrated that the majority of tobacco's response to S deficiency is misregulated in plants expressing UP9C-antisense. A link between response to S deficiency, ethylene sensing, and LSU-like proteins was emphasized by changes in expression of the genes encoding ethylene receptors and F-box proteins specific for the ethylene pathway.

  7. Host Responses to Melioidosis and Tuberculosis Are Both Dominated by Interferon-Mediated Signaling

    PubMed Central

    Koh, Gavin C. K. W.; Schreiber, M. Fernanda; Bautista, Ruben; Maude, Rapeephan R.; Dunachie, Susanna; Limmathurotsakul, Direk; Day, Nicholas P. J.; Dougan, Gordon; Peacock, Sharon J.

    2013-01-01

    Melioidosis (Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Northeast Thailand and northern Australia. B. pseudomallei is a soil saprophyte endemic to Southeast Asia and northern Australia. The clinical presentation of melioidosis may mimic tuberculosis (both cause chronic suppurative lesions unresponsive to conventional antibiotics and both commonly affect the lungs). The two diseases have overlapping risk profiles (e.g., diabetes, corticosteroid use), and both B. pseudomallei and Mycobacterium tuberculosis are intracellular pathogens. There are however important differences: the majority of melioidosis cases are acute, not chronic, and present with severe sepsis and a mortality rate that approaches 50% despite appropriate antimicrobial therapy. By contrast, tuberculosis is characteristically a chronic illness with mortality <2% with appropriate antimicrobial chemotherapy. We examined the gene expression profiles of total peripheral leukocytes in two cohorts of patients, one with acute melioidosis (30 patients and 30 controls) and another with tuberculosis (20 patients and 24 controls). Interferon-mediated responses dominate the host response to both infections, and both type 1 and type 2 interferon responses are important. An 86-gene signature previously thought to be specific for tuberculosis is also found in melioidosis. We conclude that the host responses to melioidosis and to tuberculosis are similar: both are dominated by interferon-signalling pathways and this similarity means gene expression signatures from whole blood do not distinguish between these two diseases. PMID:23383015

  8. Behavioral responses of California sea lions to mid-frequency (3250-3450 Hz) sonar signals.

    PubMed

    Houser, Dorian S; Martin, Stephen W; Finneran, James J

    2013-12-01

    Military sonar has the potential to negatively impact marine mammals. To investigate factors affecting behavioral disruption in California sea lions (Zalophus californianus), fifteen sea lions participated in a controlled exposure study using a simulated tactical sonar signal (1 s duration, 3250-3450 Hz) as a stimulus. Subjects were placed into groups of three and each group received a stimulus exposure of 125, 140, 155, 170, or 185 dB re: 1 μPa (rms). Each subject was trained to swim across an enclosure, touch a paddle, and return to the start location. Sound exposures occurred at the mid-point of the enclosure. Control and exposure sessions were run consecutively and each consisted of ten, 30-s trials. The occurrence and severity of behavioral responses were used to create acoustic dose-response and dose-severity functions. Age of the subject significantly affected the dose-response relationship, but not the dose-severity relationship. Repetitive exposures did not affect the dose-response relationship.

  9. Inhibition of TGFbeta1 Signaling Attenutates ATM Activity inResponse to Genotoxic Stress

    SciTech Connect

    Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam B.; Lavin, Martin J.; Koslov, Sergei; Shiloh, Yosef; Barcellos-Hoff, Mary Helen

    2006-09-15

    Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta}1 (TGF{beta}), which is activated by radiation, is a potent and pleiotropic mediator of physiological and pathological processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}1 null murine epithelial cells or human epithelial cells treated with a small molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17 and p53, reduced {gamma}H2AX radiation-induced foci, and increased radiosensitivity compared to TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM that directs epithelial cell stress responses, cell fate and tissue integrity. Thus, TGF{beta}1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.

  10. Theory and measurement of plasmonic terahertz detector response to large signals

    SciTech Connect

    Rudin, S.; Rupper, G.; Gutin, A.; Shur, M.

    2014-02-14

    Electron gas in the conduction channel of a Field Effect Transistor (FET) can support collective plasma oscillations tunable by the gate voltage. In the Dyakonov-Shur terahertz (THz) detector, nonlinearities in the plasma wave propagation in the gated channel of a FET lead to a constant source-to-drain voltage providing the detector output. We present the detector theory in the frame of the hydrodynamic model using the electron plasma Navier-Stokes and thermal transport equations, thus fully accounting for the hydrodynamic non-linearity, the viscosity, and pressure gradients in the detector response. Both resonant and broadband operations of the high electron mobility transistor (HEMT) based plasmonic detectors are described by this model. The relation between the electron channel density and gate voltage was modeled by the unified charge control model applicable both above and below the threshold voltage. The theoretical results are compared with the response measured in the short channel InGaAs HEMT and the analytical approximation. The THz source was operating at 1.63 THz, and the response was measured at varying signal intensities. The response of the detector operated in the open drain mode was measured above and below the threshold, and the theoretical and experimental results are shown to be in good agreement.

  11. A neural network model with dopamine-like reinforcement signal that learns a spatial delayed response task.

    PubMed

    Suri, R E; Schultz, W

    1999-01-01

    This study investigated how the simulated response of dopamine neurons to reward-related stimuli could be used as reinforcement signal for learning a spatial delayed response task. Spatial delayed response tasks assess the functions of frontal cortex and basal ganglia in short-term memory, movement preparation and expectation of environmental events. In these tasks, a stimulus appears for a short period at a particular location, and after a delay the subject moves to the location indicated. Dopamine neurons are activated by unpredicted rewards and reward-predicting stimuli, are not influenced by fully predicted rewards, and are depressed by omitted rewards. Thus, they appear to report an error in the prediction of reward, which is the crucial reinforcement term in formal learning theories. Theoretical studies on reinforcement learning have shown that signals similar to dopamine responses can be used as effective teaching signals for learning. A neural network model implementing the temporal difference algorithm was trained to perform a simulated spatial delayed response task. The reinforcement signal was modeled according to the basic characteristics of dopamine responses to novel stimuli, primary rewards and reward-predicting stimuli. A Critic component analogous to dopamine neurons computed a temporal error in the prediction of reinforcement and emitted this signal to an Actor component which mediated the behavioral output. The spatial delayed response task was learned via two subtasks introducing spatial choices and temporal delays, in the same manner as monkeys in the laboratory. In all three tasks, the reinforcement signal of the Critic developed in a similar manner to the responses of natural dopamine neurons in comparable learning situations, and the learning curves of the Actor replicated the progress of learning observed in the animals. Several manipulations demonstrated further the efficacy of the particular characteristics of the dopamine

  12. Feline mediastinal lymphoma: a retrospective study of signalment, retroviral status, response to chemotherapy and prognostic indicators.

    PubMed

    Fabrizio, Francesca; Calam, Amy E; Dobson, Jane M; Middleton, Stephanie A; Murphy, Sue; Taylor, Samantha S; Schwartz, Anita; Stell, Anneliese J

    2014-08-01

    Historically, feline mediastinal lymphoma has been associated with young age, positive feline leukaemia virus (FeLV) status, Siamese breed and short survival times. Recent studies following widespread FeLV vaccination in the UK are lacking. The aim of this retrospective multi-institutional study was to re-evaluate the signalment, retroviral status, response to chemotherapy, survival and prognostic indicators in feline mediastinal lymphoma cases in the post-vaccination era. Records of cats with clinical signs associated with a mediastinal mass and cytologically/histologically confirmed lymphoma were reviewed from five UK referral centres (1998-2010). Treatment response, survival and prognostic indicators were assessed in treated cats with follow-up data. Fifty-five cases were reviewed. The median age was 3 years (range, 0.5-12 years); 12 cats (21.8%) were Siamese; and the male to female ratio was 3.2:1.0. Five cats were FeLV-positive and two were feline immunodeficiency-positive. Chemotherapy response and survival was evaluated in 38 cats. Overall response was 94.7%; complete (CR) and partial response (PR) rates did not differ significantly between protocols: COP (cyclophosphamide, vincristine, prednisone) (n = 26, CR 61.5%, PR 34.0%); Madison-Wisconsin (MW) (n = 12, CR 66.7%, PR 25.0%). Overall median survival was 373 days (range, 20-2015 days) (COP 484 days [range, 20-980 days]; MW 211 days [range, 24-2015 days] [P = 0.892]). Cats achieving CR survived longer (980 days vs 42 days for PR; P = 0.032). Age, breed, sex, location (mediastinal vs mediastinal plus other sites), retroviral status and glucocorticoid pretreatment did not affect response or survival. Feline mediastinal lymphoma cases frequently responded to chemotherapy with durable survival times, particularly in cats achieving CR. The prevalence of FeLV-antigenaemic cats was low; males and young Siamese cats appeared to be over-represented.

  13. Vpu-Deficient HIV Strains Stimulate Innate Immune Signaling Responses in Target Cells

    PubMed Central

    Doehle, Brian P.; Chang, Kristina; Fleming, Lamar; McNevin, John; Hladik, Florian; McElrath, M. Juliana

    2012-01-01

    Acute virus infection induces a cell-intrinsic innate immune response comprising our first line of immunity to limit virus replication and spread, but viruses have developed strategies to overcome these defenses. HIV-1 is a major public health problem; however, the virus-host interactions that regulate innate immune defenses against HIV-1 are not fully defined. We have recently identified the viral protein Vpu to be a key determinant responsible for HIV-1 targeting and degradation of interferon regulatory factor 3 (IRF3), a central transcription factor driving host cell innate immunity. IRF3 plays a major role in pathogen recognition receptor (PRR) signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Here we interrogate the cellular responses to target cell infection with Vpu-deficient HIV-1 strains. Remarkably, in the absence of Vpu, HIV-1 triggers a potent intracellular innate immune response that suppresses infection. Thus, HIV-1 can be recognized by PRRs within the host cell to trigger an innate immune response, and this response is unmasked only in the absence of Vpu. Vpu modulation of IRF3 therefore prevents virus induction of specific innate defense programs that could otherwise limit infection. These observations show that HIV-1 can indeed be recognized as a pathogen in infected cells and provide a novel and effective platform for defining the native innate immune programs of target cells of HIV-1 infection. PMID:22647704

  14. Mutations of Arabidopsis in potential transduction and response components of the phototropic signaling pathway.

    PubMed Central

    Liscum, E; Briggs, W R

    1996-01-01

    Four genetic loci were recently identified by mutations that affect phototropism in Arabidopsis thaliana (L.) Heyhn. seedlings. It was hypothesized that one of these loci, NPH1, encodes the apoprotein for a phototropic photoreceptor. All of the alleles at the other three mutant loci (nph2, nph3, and nph4) contained wild-type levels of the putative NPH1 protein and exhibited normal blue-light-dependent phosphorylation of the NPH1 protein. This indicated that the NPH2, NPH3, and NPH4 proteins likely function downstream of NPH1 photoactivation. We show here that, although the nph2, nph3, and nph4 mutants are all altered with respect to their phototropic responses, only the nph4 mutants are also altered in their gravitropic responsiveness. Thus, NPH2 and NPH3 appear to act as signal carriers in a phototropism-specific pathway, whereas NPH4 is required for both phototropism and gravitropism and thus may function directly in the differential growth response. Despite their altered phototropic responses in blue and green light as etiolated seedlings, the nph2 and nph4 mutants exhibited less dramatic mutant phenotypes as de-etiolated seedlings and when etiolated seedlings were irradiated with unilateral ultraviolet-A (UV-A) light. Examination of the phototropic responses of a mutant deficient in biologically active phytochromes, hy1-100, indicated that phytochrome transformation by UV-A light mediates an increase in phototropic responsiveness, accounting for the greater phototropic curvature of the nph2 and nph4 mutants to UV-A light than to blue light. PMID:8819327

  15. Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways

    PubMed Central

    White, Jena R.; Confides, Amy L.; Moore-Reed, Stephanie; Hoch, Johanna M.; Dupont-Versteegden, Esther E.

    2015-01-01

    Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or-9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no

  16. Skeletal muscle signaling response to sprint exercise in men and women.

    PubMed

    Fuentes, Teresa; Guerra, Borja; Ponce-González, Jesús G; Morales-Alamo, David; Guadalupe-Grau, Amelia; Olmedillas, Hugo; Rodríguez-García, Lorena; Feijoo, David; De Pablos-Velasco, Pedro; Fernández-Pérez, Leandro; Santana, Alfredo; Calbet, Jose A L

    2012-05-01

    To determine if there is a sex dimorphism in the skeletal muscle signaling response to sprint exercise, 17 men and ten women performed a 30-s Wingate test. Muscle biopsies were taken before, immediately after the exercise and at 30 and 120 min during the recovery period. Thr(172)-AMPKα, Ser(221)-ACCβ, Thy(705)-STAT3, Thr(202)/Thy(204)-ERK1/2 and Thr(180)/Thy(182)-p38MAPK phosphorylation responses to sprint exercise were not statistically different between men and women. AMPKα phosphorylation was enhanced fourfold 30 min after the sprint exercise in males and females (P < 0.01). ACCβ phosphorylation was enhanced by about threefold just after the sprint test exercise and 30 min into the recovery period in males and females (P < 0.01). STAT3 phosphorylation was increased 2 h after the Wingate test compared to the value observed right after the end of the exercise (P < 0.05), and 30 min after the Wingate test there was a 2.5-fold increase in ERK1/2 phosphorylation, compared to both the pre-exercise and to the value observed right after the Wingate test (both, P < 0.05). In conclusion, the skeletal muscle signaling response to a single bout of sprint exercise mediated by AMPK, ACC, STAT3, ERK and p38MAPK is not statistically different between men and women. Marked increases in AMPKα, ACCβ, STAT3 and ERK phosphorylation were observed after a single 30-s all-out sprint (Wingate test) in the vastus lateralis.

  17. Microwave photonic filter with reconfigurable and tunable bandpass response using integrated optical signal processor based on microring resonator

    NASA Astrophysics Data System (ADS)

    Zhang, Zan; Huang, Beiju; Zhang, Zanyun; Cheng, Chuantong; Chen, Hongda

    2013-12-01

    A bandpass microwave photonic filter based on an integrated optical signal processor is proposed and demonstrated by numerical simulation. The optical signal processor consisting of double-bus-coupled and series-cascaded silicon microrings (MRs) is used to produce two bandpass responses to process optical carrier signal and sideband signal separately. Because of the tunability of MRs, variable -3 dB bandwidth and tunable operating frequency are achieved. The -3 dB bandwidth and operating frequency can be tuned from 1.5 to 12 GHz and from 15 to 34 GHz, respectively. The loss impact, tuning method, and fabrication error tolerance are also discussed.

  18. Uncoupling High Light Responses from Singlet Oxygen Retrograde Signaling and Spatial-Temporal Systemic Acquired Acclimation1[OPEN

    PubMed Central

    Gordon, Matthew; Havaux, Michel; Albrecht-Borth, Verónica

    2016-01-01

    Distinct ROS signaling pathways initiated by singlet oxygen (1O2) or superoxide and hydrogen peroxide have been attributed to either cell death or acclimation, respectively. Recent studies have revealed that more complex antagonistic and synergistic relationships exist within and between these pathways. As specific chloroplastic ROS signals are difficult to study, rapid systemic signaling experiments using localized high light (HL) stress or ROS treatments were used in this study to uncouple signals required for direct HL and ROS perception and distal systemic acquired acclimation (SAA). A qPCR approach was chosen to determine local perception and distal signal reception. Analysis of a thylakoidal ascorbate peroxidase mutant (tapx), the 1O2-retrograde signaling double mutant (ex1/ex2), and an apoplastic signaling double mutant (rbohD/F) revealed that tAPX and EXECUTER 1 are required for both HL and systemic acclimation stress perception. Apoplastic membrane-localized RBOHs were required for systemic spread of the signal but not for local signal induction in directly stressed tissues. Endogenous ROS treatments revealed a very strong systemic response induced by a localized 1 h induction of 1O2 using the conditional flu mutant. A qPCR time course of 1O2 induced systemic marker genes in directly and indirectly connected leaves revealed a direct vascular connection component of both immediate and longer term SAA signaling responses. These results reveal the importance of an EXECUTER-dependent 1O2 retrograde signal for both local and long distance RBOH-dependent acclimation signaling that is distinct from other HL signaling pathways, and that direct vascular connections have a role in spatial-temporal SAA induction. PMID:27288360

  19. Immune Modulation by Different Types of β2→1-Fructans Is Toll-Like Receptor Dependent

    PubMed Central

    Vogt, Leonie; Ramasamy, Uttara; Meyer, Diederick; Pullens, Gerdie; Venema, Koen; Faas, Marijke M.; Schols, Henk A.; de Vos, Paul

    2013-01-01

    Introduction β2→1-fructans are dietary fibers. Main objectives of this study were 1) to demonstrate direct signalling of β2→1-fructans on immune cells, 2) to study whether this is mediated by the pattern recognition receptors Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), and 3) to relate the observed effects to the chain length differences in β2→1-fructans. Methods Four different β2→1-fructan formulations were characterised for their chain length profile. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with β2→1-fructans, and production of IL-1Ra, IL-1β, IL-6, IL-10, IL-12p70, and TNF-α was analysed. Reporter cells for TLRs and NODs were incubated with β2→1-fructans and analysed for NF-κB/AP-1 activation. Results Cytokine production in human PBMCs was dose- and chain length-dependent. Strikingly, short chain enriched β2→1-fructans induced a regulatory cytokine balance compared to long chain enriched β2→1-fructans as measured by IL-10/IL-12 ratios. Activation of reporter cells showed that signalling was highly dependent on TLRs and their adapter, myeloid differentiation primary response protein 88 (MyD88). In human embryonic kidney reporter cells, TLR2 was prominently activated, while TLR4, 5, 7, 8, and NOD2 were mildly activated. Conclusions β2→1-fructans possess direct signalling capacity on human immune cells. By activating primarily TLR2, and to a lesser extent TLR4, 5, 7, 8, and NOD2, β2→1-fructan stimulation results in NF-κB/AP-1 activation. Chain length of β2→1-fructans is important for the induced activation pattern and IL-10/IL-12 ratios. PMID:23861894

  20. Coupling signalling pathways to transcriptional control: nuclear factors responsive to cAMP.

    PubMed

    Tamai, K T; Monaco, L; Nantel, F; Zazopoulos, E; Sassone-Corsi, P

    1997-01-01

    Several endocrine and neuronal functions are governed by the cAMP-dependent signalling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members that may act as activators or repressors. These factors contain the basic domain/ leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREB requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. Among the repressors, ICER (Inducible cAMP Early Repressor) deserves special mention. ICER is generated from an alternative CREM promoter and constitutes the only inducible cAMP-responsive element binding protein. Furthermore, ICER negatively autoregulates the alternative promoter, thus generating a feedback loop. In contrast to the other members of the CRE-binding protein family, ICER expression is tissue specific and developmentally regulated. The kinetics of ICER expression are characteristic of an early response gene. Our results indicate that CREM plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREM is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes that are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are

  1. Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine.

    PubMed

    Smith, Christopher T; Dang, Linh C; Cowan, Ronald L; Kessler, Robert M; Zald, David H

    2016-09-01

    Subjective responses to psychostimulants vary, the basis of which is poorly understood, especially in relation to possible cortical contributions. Here, we tested for relationships between participants' positive subjective responses to oral d-amphetamine (dAMPH) versus placebo and variability in striatal and extrastriatal dopamine (DA) receptor availability and release, measured via positron emission tomography (PET) with the radiotracer (18)F-fallypride. Analyses focused on 35 healthy adult participants showing positive subjective effects to dAMPH measured via the Drug Effects Questionnaire (DEQ) Feel, Like, High, and Want More subscales (Responders), and were repeated after inclusion of 11 subjects who lacked subjective responses. Associations between peak DEQ subscale ratings and both baseline (18)F-fallypride binding potential (BPnd; an index of D2/D3 receptor availability) and the percentage change in BPnd post dAMPH (%ΔBPnd; a measure of DA release) were assessed. Baseline BPnd in ventromedial prefrontal cortex (vmPFC) predicted the peak level of High reported following dAMPH. Furthermore, %ΔBPnd in vmPFC positively correlated with DEQ Want More ratings. DEQ Want More was also positively correlated with %ΔBPnd in right ventral striatum and left insula. This work indicates that characteristics of DA functioning in vmPFC, a cortical area implicated in subjective valuation, are associated with both subjective high and incentive (wanting) responses. The observation that insula %ΔBPnd was associated with drug wanting converges with evidence suggesting its role in drug craving. These findings highlight the importance of variability in DA signaling in specific paralimbic cortical regions in dAMPH's subjective response, which may confer risk for abusing psychostimulants. PMID:27174408

  2. A comparative analysis of signal processing methods for motion-based rate responsive pacing.

    PubMed

    Greenhut, S E; Shreve, E A; Lau, C P

    1996-08-01

    Pacemakers that augment heart rate (HR) by sensing body motion have been the most frequently prescribed rate responsive pacemakers. Many comparisons between motion-based rate responsive pacemaker models have been published. However, conclusions regarding specific signal processing methods used for rate response (e.g., filters and algorithms) can be affected by device-specific features. To objectively compare commonly used motion sensing filters and algorithms, acceleration and ECG signals were recorded from 16 normal subjects performing exercise and daily living activities. Acceleration signals were filtered (1-4 or 15-Hz band-pass), then processed using threshold crossing (TC) or integration (IN) algorithms creating four filter/algorithm combinations. Data were converted to an acceleration indicated rate and compared to intrinsic HR using root mean square difference (RMSd) and signed RMSd. Overall, the filters and algorithms performed similarly for most activities. The only differences between filters were for walking at an increasing grade (1-4 Hz superior to 15-Hz) and for rocking in a chair (15-Hz superior to 1-4 Hz). The only differences between algorithms were for bicycling (TC superior to IN), walking at an increasing grade (IN superior to TC), and holding a drill (IN superior to TC). Performance of the four filter/algorithm combinations was also similar over most activities. The 1-4/IN (filter [Hz]/algorithm) combination performed best for walking at a grade, while the 15/TC combination was best for bicycling. However, the 15/TC combination tended to be most sensitive to higher frequency artifact, such as automobile driving, downstairs walking, and hand drilling. Chair rocking artifact was highest for 1-4/IN. The RMSd for bicycling and upstairs walking were large for all combinations, reflecting the nonphysiological nature of the sensor. The 1-4/TC combination demonstrated the least intersubject variability, was the only filter/algorithm combination

  3. Equation of motion and general solution for the one-dimensional complex cell response in the signal-tuned approach.

    PubMed

    Torreão, José R A

    2015-10-01

    A signal-tuned approach has been recently introduced for modeling stimulus-dependent cortical receptive fields. The approach is based on signal-tuned Gabor functions, which are Gaussian-modulated sinusoids whose parameters are obtained from a "tuning" signal. Given a stimulus to a cell, it is taken as the tuning signal for the Gabor function modeling the cell's receptive field, and the inner product of the stimulus and the stimulus-dependent field produces the cell's response. Here, we derive and solve the equation of motion for the signal-tuned complex cell response r(x,τ), where x and τ are receptive-field parameters: its center, and the delay with which it adapts to a change in input. The motion equation can be mapped onto the Schrödinger equation for a system with time-dependent imaginary mass and time-dependent complex potential, and yields a plane-wave solution and an Airy-packet solution. The plane-wave solution replicates responses previously obtained for temporally modulated and translating signals, and yields responses which seem compatible with apparent-motion effects, when the stimulus is a pair of alternating pulses. The Airy-packet solution can lead to long-range propagating responses.

  4. Conserved versatile master regulators in signalling pathways in response to stress in plants.

    PubMed

    Balderas-Hernández, Victor E; Alvarado-Rodríguez, Miguel; Fraire-Velázquez, Saúl

    2013-01-01

    From the first land plants to the complex gymnosperms and angiosperms of today, environmental conditions have forced plants to develop molecular strategies to surpass natural obstacles to growth and proliferation, and these genetic gains have been transmitted to the following generations. In this long natural process, novel and elaborate mechanisms have evolved to enable plants to cope with environmental limitations. Elements in many signalling cascades enable plants to sense different, multiple and simultaneous ambient cues. A group of versatile master regulators of gene expression control plant responses to stressing conditions. For crop breeding purposes, the task is to determine how to activate these key regulators to enable accurate and optimal reactions to common stresses. In this review, we discuss how plants sense biotic and abiotic stresses, how and which master regulators are implied in the responses to these stresses, their evolution in the life kingdoms, and the domains in these proteins that interact with other factors to lead to a proper and efficient plant response.

  5. Multitask learning of signaling and regulatory networks with application to studying human response to flu.

    PubMed

    Jain, Siddhartha; Gitter, Anthony; Bar-Joseph, Ziv

    2014-12-01

    Reconstructing regulatory and signaling response networks is one of the major goals of systems biology. While several successful methods have been suggested for this task, some integrating large and diverse datasets, these methods have so far been applied to reconstruct a single response network at a time, even when studying and modeling related conditions. To improve network reconstruction we developed MT-SDREM, a multi-task learning method which jointly models networks for several related conditions. In MT-SDREM, parameters are jointly constrained across the networks while still allowing for condition-specific pathways and regulation. We formulate the multi-task learning problem and discuss methods for optimizing the joint target function. We applied MT-SDREM to reconstruct dynamic human response networks for three flu strains: H1N1, H5N1 and H3N2. Our multi-task learning method was able to identify known and novel factors and genes, improving upon prior methods that model each condition independently. The MT-SDREM networks were also better at identifying proteins whose removal affects viral load indicating that joint learning can still lead to accurate, condition-specific, networks. Supporting website with MT-SDREM implementation: http://sb.cs.cmu.edu/mtsdrem. PMID:25522349

  6. Tissue-Specific Regulation of Gibberellin Signaling Fine-Tunes Arabidopsis Iron-Deficiency Responses.

    PubMed

    Wild, Michael; Davière, Jean-Michel; Regnault, Thomas; Sakvarelidze-Achard, Lali; Carrera, Esther; Lopez Diaz, Isabel; Cayrel, Anne; Dubeaux, Guillaume; Vert, Grégory; Achard, Patrick

    2016-04-18

    Iron is an essential element for most living organisms. Plants acquire iron from the rhizosphere and have evolved different biochemical and developmental responses to adapt to a low-iron environment. In Arabidopsis, FIT encodes a basic helix-loop-helix transcription factor that activates the expression of iron-uptake genes in root epidermis upon iron deficiency. Here, we report that the gibberellin (GA)-signaling DELLA repressors contribute substantially in the adaptive responses to iron-deficient conditions. When iron availability decreases, DELLAs accumulate in the root meristem, thereby restraining root growth, while being progressively excluded from epidermal cells in the root differentiation zone. Such DELLA exclusion from the site of iron acquisition relieves FIT from DELLA-dependent inhibition and therefore promotes iron uptake. Consistent with this mechanism, expression of a non-GA-degradable DELLA mutant protein in root epidermis interferes with iron acquisition. Hence, spatial distribution of DELLAs in roots is essential to fine-tune the adaptive responses to iron availability.

  7. Light and circadian regulation of clock components aids flexible responses to environmental signals.

    PubMed

    Dixon, Laura E; Hodge, Sarah K; van Ooijen, Gerben; Troein, Carl; Akman, Ozgur E; Millar, Andrew J

    2014-07-01

    The circadian clock measures time across a 24 h period, increasing fitness by phasing biological processes to the most appropriate time of day. The interlocking feedback loop mechanism of the clock is conserved across species; however, the number of loops varies. Mathematical and computational analyses have suggested that loop complexity affects the overall flexibility of the oscillator, including its responses to entrainment signals. We used a discriminating experimental assay, at the transition between different photoperiods, in order to test this proposal in a minimal circadian network (in Ostreococcus tauri) and a more complex network (in Arabidopsis thaliana). Transcriptional and translational reporters in O. tauri primarily tracked dawn or dusk, whereas in A. thaliana, a wider range of responses were observed, consistent with its more flexible clock. Model analysis supported the requirement for this diversity of responses among the components of the more complex network. However, these and earlier data showed that the O. tauri network retains surprising flexibility, despite its simple circuit. We found that models constructed from experimental data can show flexibility either from multiple loops and/or from multiple light inputs. Our results suggest that O. tauri has adopted the latter strategy, possibly as a consequence of genomic reduction.

  8. Transcriptome analysis of phytohormone, transporters and signaling pathways in response to vanadium stress in rice roots.

    PubMed

    Lin, Chung-Yi; Trinh, Ngoc Nam; Lin, Chung-Wen; Huang, Hao-Jen

    2013-05-01

    Trace concentrations of vanadium (V) have several benefits for plant growth, but high concentrations are toxic. To help characterize the cellular mechanisms underlying the toxic effects of V in plants, we present the first large-scale analysis of rice root responding to V during the early stages (1 and 3 h) of toxicity. Exposure to V triggered changes in the transcript levels of several genes related to cellular metabolic process, response to stimulus and transporters. Gene expression profiling revealed upregulated levels of genes associated with signaling and biosynthesis of auxin, abscisic acid (ABA) and jasmonic acid (JA) in V-treated rice roots. In addition, V upregulated the expression of ATP-dependent GSH-conjugated transport, ATP binding cassette (ABC) transporter, and markedly downregulated of the expression of divalent cation transporters, drug/metabolite transporter (DMT) and zinc-iron permease (ZIP). Among the V-specific responsive transcription factors and protein kinases, the most predominant families were NAC (NAM, ATAF, CUC) transcription factor, receptor-like cytoplasmic kinase VII (RLCK-VII) and leucine-rich repeat kinase VIII (LRR-VIII). These microarray data provide a new insight into the molecular mechanism of the rice roots response to V toxicity.

  9. Conserved versatile master regulators in signalling pathways in response to stress in plants

    PubMed Central

    Balderas-Hernández, Victor E.; Alvarado-Rodríguez, Miguel; Fraire-Velázquez, Saúl

    2013-01-01

    From the first land plants to the complex gymnosperms and angiosperms of today, environmental conditions have forced plants to develop molecular strategies to surpass natural obstacles to growth and proliferation, and these genetic gains have been transmitted to the following generations. In this long natural process, novel and elaborate mechanisms have evolved to enable plants to cope with environmental limitations. Elements in many signalling cascades enable plants to sense different, multiple and simultaneous ambient cues. A group of versatile master regulators of gene expression control plant responses to stressing conditions. For crop breeding purposes, the task is to determine how to activate these key regulators to enable accurate and optimal reactions to common stresses. In this review, we discuss how plants sense biotic and abiotic stresses, how and which master regulators are implied in the responses to these stresses, their evolution in the life kingdoms, and the domains in these proteins that interact with other factors to lead to a proper and efficient plant response. PMID:24147216

  10. Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response.

    PubMed

    Michel, Sebastien; Canonne, Morgane; Arnould, Thierry; Renard, Patricia

    2015-03-01

    Mitochondria-to-nucleus communication, known as retrograde signaling, is important to adjust the nuclear gene expression in response to organelle dysfunction. Among the transcription factors described to respond to mitochondrial stress, CHOP-10 is activated by respiratory chain inhibition, mitochondrial accumulation of unfolded proteins and mtDNA mutations. In this study, we show that altered/impaired expression of mtDNA induces CHOP-10 expression in a signaling pathway that depends on the eIF2α/ATF4 axis of the integrated stress response rather than on the mitochondrial unfolded protein response.

  11. When infants look to their parents: II. Twelve-month-olds' response to conflicting parental emotional signals.

    PubMed

    Hirshberg, L

    1990-08-01

    12-months-olds were seen in a laboratory procedure in which they were given happy, fearful, and conflicting emotional signals by their mothers and fathers with reference to 5 unusual toy stimuli. Measures included: positive and negative affect, affect lability, and approach and proximity behavior toward the toy. Infants did not "select" a signal on the basis of a maternal or paternal primacy in emotional referencing, but responded to both signals and experienced conflict. They showed increased negative affect and decreased positive affect and toy exploration with conflicting signals compared with both happy and with fearful signals alone. Greater levels of lability were not found with conflicting signals. Marked differences among infants in capacity and style of coping with conflict were observed, as were a variety of specific conflict responses, such as agitated sucking, rocking, avoidance, extreme motor inhibition, aimless or disoriented behavior, and transient, unintegrated affect expressions. PMID:2209188

  12. Automatic and Controlled Response Inhibition: Associative Learning in the Go/No-Go and Stop-Signal Paradigms

    ERIC Educational Resources Information Center

    Verbruggen, Frederick; Logan, Gordon D.

    2008-01-01

    In 5 experiments, the authors examined the development of automatic response inhibition in the go/no-go paradigm and a modified version of the stop-signal paradigm. They hypothesized that automatic response inhibition may develop over practice when stimuli are consistently associated with stopping. All 5 experiments consisted of a training phase…

  13. Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal?##

    EPA Science Inventory

    Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? Leon Earl Gray Jr, USEPA, ORD, NHEERL, TAD, RTB. RTP, NC, USA The shape of the dose response curve in the low dose region has been debated since th...

  14. Cross Talk between Gibberellin and Cytokinin: The Arabidopsis GA Response Inhibitor SPINDLY Plays a Positive Role in Cytokinin Signaling

    PubMed Central

    Greenboim-Wainberg, Yaarit; Maymon, Inbar; Borochov, Roy; Alvarez, John; Olszewski, Neil; Ori, Naomi; Eshed, Yuval; Weiss, David

    2005-01-01

    SPINDLY (SPY) is a negative regulator of gibberellin (GA) responses; however, spy mutants exhibit various phenotypic alterations not found in GA-treated plants. Assaying for additional roles for SPY revealed that spy mutants are resistant to exogenously applied cytokinin. GA also repressed the effects of cytokinin, suggesting that there is cross talk between the two hormone-response pathways, which may involve SPY function. Two spy alleles showing severe (spy-4) and mild (spy-3) GA-associated phenotypes exhibited similar resistance to cytokinin, suggesting that SPY enhances cytokinin responses and inhibits GA signaling through distinct mechanisms. GA and spy repressed numerous cytokinin responses, from seedling development to senescence, indicating that cross talk occurs early in the cytokinin-signaling pathway. Because GA3 and spy-4 inhibited induction of the cytokinin primary-response gene, type-A Arabidopsis response regulator 5, SPY may interact with and modify elements from the phosphorelay cascade of the cytokinin signal transduction pathway. Cytokinin, on the other hand, had no effect on GA biosynthesis or responses. Our results demonstrate that SPY acts as both a repressor of GA responses and a positive regulator of cytokinin signaling. Hence, SPY may play a central role in the regulation of GA/cytokinin cross talk during plant development. PMID:15608330

  15. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading.

    PubMed

    Tu, Xiaolin; Rhee, Yumie; Condon, Keith W; Bivi, Nicoletta; Allen, Matthew R; Dwyer, Denise; Stolina, Marina; Turner, Charles H; Robling, Alexander G; Plotkin, Lilian I; Bellido, Teresita

    2012-01-01

    Sclerostin, the Wnt signaling antagonist encoded by the Sost gene, is secreted by osteocytes and inhibits bone formation by osteoblasts. Mechanical stimulation reduces sclerostin expression, suggesting that osteocytes might coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. To investigate whether sclerostin downregulation is a pre-requisite for load-induced bone formation, we conducted experiments in transgenic mice (TG) engineered to maintain high levels of SOST expression during mechanical loading. This was accomplished by introducing a human SOST transgene driven by the 8 kb fragment of the DMP1 promoter that also provided osteocyte specificity of the transgene. Right ulnae were subjected to in vivo cyclic axial loading at equivalent strains for 1 min/day at 2 Hz; left ulnae served as internal controls. Endogenous murine Sost mRNA expression measured 24 h after 1 loading bout was decreased by about 50% in TG and wild type (WT) littermates. In contrast, human SOST, only expressed in TG mice, remained high after loading. Mice were loaded on 3 consecutive days and bone formation was quantified 16 days after initiation of loading. Periosteal bone formation in control ulnae was similar in WT and TG mice. Loading induced the expected strain-dependent increase in bone formation in WT mice, resulting from increases in both mineralizing surface (MS/BS) and mineral apposition rate (MAR). In contrast, load-induced bone formation was reduced by 70-85% in TG mice, due to lower MS/BS and complete inhibition of MAR. Moreover, Wnt target gene expression induced by loading in WT mice was absent in TG mice. Thus, downregulation of Sost/sclerostin in osteocytes is an obligatory step in the mechanotransduction cascade that activates Wnt signaling and directs osteogenesis to where bone is structurally needed.

  16. Phosphate-responsive signaling pathway is a novel component of NAD+ metabolism in Saccharomyces cerevisiae.

    PubMed

    Lu, Shu-Ping; Lin, Su-Ju

    2011-04-22

    Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor involved in various cellular biochemical reactions. To date the signaling pathways that regulate NAD(+) metabolism remain unclear due to the dynamic nature and complexity of the NAD(+) metabolic pathways and the difficulty of determining the levels of the interconvertible pyridine nucleotides. Nicotinamide riboside (NmR) is a key pyridine metabolite that is excreted and re-assimilated by yeast and plays important roles in the maintenance of NAD(+) pool. In this study we establish a NmR-specific reporter system and use it to identify yeast mutants with altered NmR/NAD(+) metabolism. We show that the phosphate-responsive signaling (PHO) pathway contributes to control NAD(+) metabolism. Yeast strains with activated PHO pathway show increases in both the release rate and internal concentration of NmR. We further identify Pho8, a PHO-regulated vacuolar phosphatase, as a potential NmR production factor. We also demonstrate that Fun26, a homolog of human ENT (equilibrative nucleoside transporter), localizes to the vacuolar membrane and establishes the size of the vacuolar and cytosolic NmR pools. In addition, the PHO pathway responds to depletion of cellular nicotinic acid mononucleotide (NaMN) and mediates nicotinamide mononucleotide (NMN) catabolism, thereby contributing to both NmR salvage and phosphate acquisition. Therefore, NaMN is a putative molecular link connecting the PHO signaling and NAD(+) metabolic pathways. Our findings may contribute to the understanding of the molecular basis and regulation of NAD(+) metabolism in higher eukaryotes. PMID:21349851

  17. Hemodynamic Flow-Induced Mechanotransduction Signaling Influences the Radiation Response of the Vascular Endothelium.

    PubMed

    Natarajan, Mohan; Aravindan, Natarajan; Sprague, Eugene A; Mohan, Sumathy

    2016-08-01

    Hemodynamic shear stress is defined as the physical force exerted by the continuous flow of blood in the vascular system. Endothelial cells, which line the inner layer of blood vessels, sense this physiological force through mechanotransduction signaling and adapt to maintain structural and functional homeostasis. Hemodynamic flow, shear stress and mechanotransduction signaling are, therefore, an integral part of endothelial pathophysiology. Although this is a well-established concept in the cardiovascular field, it is largely dismissed in studies aimed at understanding radiation injury to the endothelium and subsequent cardiovascular complications. We and others have reported on the differential response of the endothelium when the cells are under hemodynamic flow shear compared with static culture. Further, we have demonstrated significant differences in the gene expression of static versus shear-stressed irradiated cells in four key pathways, reinforcing the importance of shear stress in understanding radiation injury of the endothelium. This article further emphasizes the influence of hemodynamic shear stress and the associated mechanotransduction signaling on physiological functioning of the vascular endothelium and underscores its significance in understanding radiation injury to the vasculature and associated cardiac complications. Studies of radiation effect on endothelial biology and its implication on cardiotoxicity and vascular complications thus far have failed to highlight the significance of these factors. Factoring in these integral parts of the endothelium will enhance our understanding of the contribution of the endothelium to radiation biology. Without such information, the current approaches to studying radiation-induced injury to the endothelium and its consequences in health and disease are limited. PMID:27387860

  18. New signaling pathways govern the host response to C. albicans infection in various niches.

    PubMed

    Liu, Yaoping; Shetty, Amol C; Schwartz, Jennifer A; Bradford, L Latey; Xu, Wenjie; Phan, Qyunh T; Kumari, Priti; Mahurkar, Anup; Mitchell, Aaron P; Ravel, Jacques; Fraser, Claire M; Filler, Scott G; Bruno, Vincent M

    2015-05-01

    Candida albicans, the major invasive fungal pathogen of humans, can cause both debilitating mucosal infections and fatal invasive infections. Understanding the complex nature of the host-pathogen interaction in each of these contexts is essential to developing desperately needed therapies to treat fungal infections. RNA-seq enables a systems-level understanding of infection by facilitating comprehensive analysis of transcriptomes from multiple species (e.g., host and pathogen) simultaneously. We used RNA-seq to characterize the transcriptomes of both C. albicans and human endothelial cells or oral epithelial cells during in vitro infection. Network analysis of the differentially expressed genes identified the activation of several signaling pathways that have not previously been associated with the host response to fungal pathogens. Using an siRNA knockdown approach, we demonstrate that two of these pathways-platelet-derived growth factor BB (PDGF BB) and neural precursor-cell-expressed developmentally down-regulated protein 9 (NEDD9)-govern the host-pathogen interaction by regulating the uptake of C. albicans by host cells. Using RNA-seq analysis of a mouse model of hematogenously disseminated candidiasis (HDC) and episodes of vulvovaginal candidiasis (VVC) in humans, we found evidence that many of the same signaling pathways are activated during mucosal (VVC) and/or disseminated (HDC) infections in vivo. Our analyses have uncovered several signaling pathways at the interface between C. albicans and host cells in various contexts of infection, and suggest that PDGF BB and NEDD9 play important roles in this interaction. In addition, these data provide a valuable community resource for better understanding host-fungal pathogen interactions.

  19. Small-signal transient response and turn-on delay of polariton laser diodes

    NASA Astrophysics Data System (ADS)

    Butté, Raphaël

    2016-03-01

    We present a theoretical description of the small-signal transient response of polariton laser diodes (pol-LDs) based on simplified coupled rate equations describing the exciton reservoir and the ground-state polariton populations. The analytic expressions derived for two pumping geometries, which are valid for all inorganic semiconductors suitable for the realization of pol-LDs, are compared to exact numerical calculations performed for the specific case of GaN-based devices. The two approaches show excellent agreement provided the current step transient remains within the small-signal limit. We report that the temporal attenuation of the envelopes of the oscillations matches half the value of the damping factor ({γ }{{d}}) of the pol-LDs, which is proportional to the square of the oscillation relaxation resonance frequency. An explicit expression for the dependence of {γ }{{d}} on both the exciton-photon detuning and the driving current (equivalently the optical pump power) is also obtained. In a further step, we derive the expression for the turn-on delay (t d) associated with the build-up of the exciton reservoir population up to its threshold value before coherent light emission occurs. We show that t d has the same functional form for the two pumping geometries. It is equal to the effective exciton lifetime ({τ }{x{eff}}) weighted by a logarithmic dependence on the initial and final driving currents. In addition, {τ }{x{eff}} is shown to be approximately equal to the exciton lifetime, which proves to be the main parameter governing the build-up of polariton lasing/condensation. Beyond electrically driven polariton lasers, we highlight that the temporal shape of the transients could also be easily tested by monitoring the time dependence of the output power of optically pumped polariton lasers subjected to a sudden increase in the continuous wave pump power within the small-signal limit.

  20. Evaluation of cytotoxicity and DNA damage response with analysis of intracellular ATM signaling pathways.

    PubMed

    Bandi, Sriram; Viswanathan, Preeti; Gupta, Sanjeev

    2014-06-01

    Maintenance of genome integrity by preventing and overcoming DNA damage is critical for cell survival. Deficiency or aberrancy in the DNA damage response, for example, through ataxia telangiectasia mutated (ATM) signaling, lead to pathophysiological perturbations in organs throughout the body. Therefore, control of DNA damage is of major interest for development of therapeutic agents. Such efforts will greatly benefit from convenient and simple diagnostic and/or drug development tools to demonstrate whether ATM and related genes have been activated and to then determine whether these have been returned to normal levels of activity because pathway members sense and also repair DNA damage. To overcome difficulties in analyzing differences in multitudinous ATM pathway members following DNA damage, we measured ATM promoter activity with a fluorescent td-Tomato reporter gene to interrogate the global effects of ATM signaling pathways. In cultured HuH-7 cell line derived from human hepatocellular carcinoma, cis-platinum, acetaminophen, or hydrogen peroxide caused DNA strand breaks and ATM pathway activation as shown by γH2AX expression, which in turn, led to rapid and sustained increases in ATM promoter activity. This assay of ATM promoter activity identified biological agents capable of controlling cellular DNA damage in toxin-treated HuH-7 cells and in mice after onset of drug-induced acute liver failure. Therefore, the proposed assay of ATM promoter activity in HuH-7 cells was appropriately informative for treating DNA damage. High-throughput screens using ATM promoter activation will be helpful for therapeutic development in DNA damage-associated abnormal ATM signaling in various cell types and organs. PMID:24927134

  1. Cell cycle dynamics in a response/signalling feedback system with a gap

    PubMed Central

    Gong, Xue; Buckalew, Richard; Young, Todd; Boczko, Erik

    2014-01-01

    We consider a dynamical model of cell cycles of n cells in a culture in which cells in one specific phase (S for signalling) of the cell cycle produce chemical agents that influence the growth/cell cycle progression of cells in another phase (R for responsive). In the case that the feedback is negative, it is known that subpopulations of cells tend to become clustered in the cell cycle; while for a positive feedback, all the cells tend to become synchronized. In this paper, we suppose that there is a gap between the two phases. The gap can be thought of as modelling the physical reality of a time delay in the production and action of the signalling agents. We completely analyse the dynamics of this system when the cells are arranged into two cell cycle clusters. We also consider the stability of certain important periodic solutions in which clusters of cells have a cyclic arrangement and there are just enough clusters to allow interactions between them. We find that the inclusion of a small gap does not greatly alter the global dynamics of the system; there are still large open sets of parameters for which clustered solutions are stable. Thus, we add to the evidence that clustering can be a robust phenomenon in biological systems. However, the gap does effect the system by enhancing the stability of the stable clustered solutions. We explain this phenomenon in terms of contraction rates (Floquet exponents) in various invariant subspaces of the system. We conclude that in systems for which these models are reasonable, a delay in signalling is advantageous to the emergence of clustering. PMID:24963979

  2. Life in a changing world: TCH gene regulation of expression and responses to environmental signals

    NASA Technical Reports Server (NTRS)

    Braam, J.; Sistrunk, M. L.; Polisensky, D. H.; Xu, W.; Purugganan, M. M.; Antosiewicz, D. M.; Campbell, P.; Johnson, K. A.

    1996-01-01

    The Arabidopsis TCH genes were discovered as a consequence of their marked upregulation of expression in response to seemingly innocuous stimuli such as touch. Further analyses have indicated that these genes are upregulated by a variety of diverse stimuli. Understanding the mechanism(s) and factors that control TCH gene regulation will shed light on the signaling pathways that enable plants to respond to changing environmental conditions. The TCH proteins include calmodulin, calmodulin-related proteins and a xyloglucan endotransglycosylase. Expression analyses and localization of protein accumulation indicate that the potential sites of TCH protein function include expanding cells and tissues under mechanical strain. We hypothesize that the TCH proteins may collaborate in cell wall biogenesis.

  3. Yeast as a tool to study signaling pathways in mitochondrial stress response and cytoprotection.

    PubMed

    Zdralević, Maša; Guaragnella, Nicoletta; Antonacci, Lucia; Marra, Ersilia; Giannattasio, Sergio

    2012-01-01

    Cell homeostasis results from the balance between cell capability to adapt or succumb to environmental stress. Mitochondria, in addition to supplying cellular energy, are involved in a range of processes deciding about cellular life or death. The crucial role of mitochondria in cell death is well recognized. Mitochondrial dysfunction has been associated with the death process and the onset of numerous diseases. Yet, mitochondrial involvement in cellular adaptation to stress is still largely unexplored. Strong interest exists in pharmacological manipulation of mitochondrial metabolism and signaling. The yeast Saccharomyces cerevisiae has proven a valuable model organism in which several intracellular processes have been characterized in great detail, including the retrograde response to mitochondrial dysfunction and, more recently, programmed cell death. In this paper we review experimental evidences of mitochondrial involvement in cytoprotection and propose yeast as a model system to investigate the role of mitochondria in the cross-talk between prosurvival and prodeath pathways. PMID:22454613

  4. Yeast as a Tool to Study Signaling Pathways in Mitochondrial Stress Response and Cytoprotection

    PubMed Central

    Ždralević, Maša; Guaragnella, Nicoletta; Antonacci, Lucia; Marra, Ersilia; Giannattasio, Sergio

    2012-01-01

    Cell homeostasis results from the balance between cell capability to adapt or succumb to environmental stress. Mitochondria, in addition to supplying cellular energy, are involved in a range of processes deciding about cellular life or death. The crucial role of mitochondria in cell death is well recognized. Mitochondrial dysfunction has been associated with the death process and the onset of numerous diseases. Yet, mitochondrial involvement in cellular adaptation to stress is still largely unexplored. Strong interest exists in pharmacological manipulation of mitochondrial metabolism and signaling. The yeast Saccharomyces cerevisiae has proven a valuable model organism in which several intracellular processes have been characterized in great detail, including the retrograde response to mitochondrial dysfunction and, more recently, programmed cell death. In this paper we review experimental evidences of mitochondrial involvement in cytoprotection and propose yeast as a model system to investigate the role of mitochondria in the cross-talk between prosurvival and prodeath pathways. PMID:22454613

  5. Mechanistic Basis for Plant Responses to Drought Stress : Regulatory Mechanism of Abscisic Acid Signaling

    NASA Astrophysics Data System (ADS)

    Miyakawa, Takuya; Tanokura, Masaru

    The phytohormone abscisic acid (ABA) plays a key role in the rapid adaptation of plants to environmental stresses such as drought and high salinity. Accumulated ABA in plant cells promotes stomatal closure in guard cells and transcription of stress-tolerant genes. Our understanding of ABA responses dramatically improved by the discovery of both PYR/PYL/RCAR as a soluble ABA receptor and inhibitory complex of a protein phospatase PP2C and a protein kinase SnRK2. Moreover, several structural analyses of PYR/PYL/RCAR revealed the mechanistic basis for the regulatory mechanism of ABA signaling, which provides a rational framework for the design of alternative agonists in future.

  6. Response and fluctuations of a two-state signaling module with feedback

    NASA Astrophysics Data System (ADS)

    Gopalakrishnan, Manoj; Borowski, Peter; Jülicher, Frank; Zapotocky, Martin

    2007-08-01

    We study the stochastic kinetics of a signaling module consisting of a two-state stochastic point process with negative feedback. In the active state, a product is synthesized which increases the active-to-inactive transition rate of the process. We analyze this simple autoregulatory module using a path-integral technique based on the temporal statistics of state flips of the process. We develop a systematic framework to calculate averages, autocorrelations, and response functions by treating the feedback as a weak perturbation. Explicit analytical results are obtained to first order in the feedback strength. Monte Carlo simulations are performed to test the analytical results in the weak feedback limit and to investigate the strong feedback regime. We conclude by relating some of our results to experimental observations in the olfactory and visual sensory systems.

  7. Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals

    PubMed Central

    Nakamura, Shuhei; Karalay, Özlem; Jäger, Philipp S.; Horikawa, Makoto; Klein, Corinna; Nakamura, Kayo; Latza, Christian; Templer, Sven E.; Dieterich, Christoph; Antebi, Adam

    2016-01-01

    Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival. PMID:27001890

  8. TLR2 signaling and Th2 responses drive Tannerella forsythia-induced periodontal bone loss1

    PubMed Central

    Myneni, Srinivas R.; Settem, Rajendra P.; Connell, Terry D.; Keegan, Achsah D.; Gaffen, Sarah L.; Sharma, Ashu

    2011-01-01

    Periodontal disease (PD) is a chronic inflammation of the tooth supporting soft tissue and alveolar bone due to infection by a select group of gram negative microbes, and leads to tooth loss if untreated. Since mice deficient in CD4+ cells are resistant to infection-induced alveolar bone loss, Th cells have been implicated in bone destructive processes during PD. However, the extent to which different Th-cell subtypes play roles in pathogenesis or host protection remains to be defined, and is likely to vary depending on the dominant microorganism involved. By far the best studied periodontal microbe in PD is Porphyromonas gingivalis. Even though the gram negative anaerobe Tannerella forsythia is also a vital contributor to periodontal bone loss, almost nothing is known about immune responses to this organism. Previous studies from our laboratory have revealed that T. forsythia induces periodontal bone loss in mice, and that this bone loss depends on the bacterially-expressed BspA protein. In this study, we show that T. forsythia activates murine APCs primarily through TLR2-dependent signaling via BspA. Furthermore, T. forsythia infection causes a pronounced Th2 bias, evidenced by T cell expression of IL-5 but not IFN-γ or IL-17 in draining LN. Consistently, deficiencies in TLR2 or STAT6 result in resistance to T. forsythia-induced alveolar bone loss. Thus, TLR2 signaling and Th2 cells play pathogenic roles in T. forsythia-induced alveolar bone destruction. PMID:21632710

  9. Potentiation of the early visual response to learned danger signals in adults and adolescents.

    PubMed

    Levita, Liat; Howsley, Philippa; Jordan, Jeff; Johnston, Pat

    2015-02-01

    The reinforcing effects of aversive outcomes on avoidance behaviour are well established. However, their influence on perceptual processes is less well explored, especially during the transition from adolescence to adulthood. Using electroencephalography, we examined whether learning to actively or passively avoid harm can modulate early visual responses in adolescents and adults. The task included two avoidance conditions, active and passive, where two different warning stimuli predicted the imminent, but avoidable, presentation of an aversive tone. To avoid the aversive outcome, participants had to learn to emit an action (active avoidance) for one of the warning stimuli and omit an action for the other (passive avoidance). Both adults and adolescents performed the task with a high degree of accuracy. For both adolescents and adults, increased N170 event-related potential amplitudes were found for both the active and the passive warning stimuli compared with control conditions. Moreover, the potentiation of the N170 to the warning stimuli was stable and long lasting. Developmental differences were also observed; adolescents showed greater potentiation of the N170 component to danger signals. These findings demonstrate, for the first time, that learned danger signals in an instrumental avoidance task can influence early visual sensory processes in both adults and adolescents.

  10. Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation.

    PubMed

    Aden, Konrad; Rehman, Ateequr; Falk-Paulsen, Maren; Secher, Thomas; Kuiper, Jan; Tran, Florian; Pfeuffer, Steffen; Sheibani-Tezerji, Raheleh; Breuer, Alexandra; Luzius, Anne; Jentzsch, Marlene; Häsler, Robert; Billmann-Born, Susanne; Will, Olga; Lipinski, Simone; Bharti, Richa; Adolph, Timon; Iovanna, Juan L; Kempster, Sarah L; Blumberg, Richard S; Schreiber, Stefan; Becher, Burkhard; Chamaillard, Mathias; Kaser, Arthur; Rosenstiel, Philip

    2016-08-23

    A plethora of functional and genetic studies have suggested a key role for the IL-23 pathway in chronic intestinal inflammation. Currently, pathogenic actions of IL-23 have been ascribed to specific effects on immune cells. Herein, we unveil a protective role of IL-23R signaling. Mice deficient in IL-23R expression in intestinal epithelial cells (Il23R(ΔIEC)) have reduced Reg3b expression, show a disturbed colonic microflora with an expansion of flagellated bacteria, and succumb to DSS colitis. Surprisingly, Il23R(ΔIEC) mice show impaired mucosal IL-22 induction in response to IL-23. αThy-1 treatment significantly deteriorates colitis in Il23R(ΔIEC) animals, which can be rescued by IL-22 application. Importantly, exogenous Reg3b administration rescues DSS-treated Il23R(ΔIEC) mice by recruiting neutrophils as IL-22-producing cells, thereby restoring mucosal IL-22 levels. The study identifies a critical barrier-protective immune pathway that originates from, and is orchestrated by, IL-23R signaling in intestinal epithelial cells. PMID:27524624

  11. Cross Talk between H2O2 and Interacting Signal Molecules under Plant Stress Response.

    PubMed

    Saxena, Ina; Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    It is well established that oxidative stress is an important cause of cellular damage. During stress conditions, plants have evolved regulatory mechanisms to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of reactive oxygen species, which is subsequently converted to H2O2. H2O2 is continuously produced as the byproduct of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 immerges as an important factor during many biological processes. It has been established that it acts as a secondary messenger in signal transduction networks. In this review, we discuss potential roles of H2O2 and other signaling molecules during various stress responses.

  12. Exploring motorcycle red-light violation in response to pedestrian green signal countdown device.

    PubMed

    Chen, Ping-Ling; Pai, Chih-Wei; Jou, Rong-Chang; Saleh, Wafaa; Kuo, Ming-Shin

    2015-02-01

    Literature has suggested that angle/rear-end collisions would arise from the reality that motorists and motorcyclists tended to accelerate aggressively in response to the remaining seconds of green signal countdown device (GSCD). One safety concern, while GSCD has gradually been removed for safety in Taiwan, is pedestrian green signal countdown device (PGSCD) that is used by approaching motorists and motorcyclists that may adopt the information to travel aggressively - an unintended consequence that is detrimental to safety. Research has reported that there appeared no negative effect of PGSCD on motorist behaviours but the effect on motorcyclists' behaviours has been rarely investigated. Using video/speed cameras, the current research investigates motorcyclists' RLV (red-light violation) behaviours. The descriptive analyses indicate that the percentage of RLV at PGSCD intersection is higher than that at typical intersection, and the violating motorcycles appear to have higher travelling speeds at PGSCD intersection. Several interaction terms were examined with the binary logit framework, and the results reveal that several factors are associated with RLV, notably male/young riders, moped/large motorcycle users, higher approaching speeds of motorcycles, those with tropical helmets, and lower traffic volume. Similar determinants of early-start behaviours (for those waiting at reds and could view the PGSCDs for the crossing pedestrians at the same time) were identified. Implications of the research findings, the concluding remarks, and recommendations for future research are finally provided.

  13. Signal perception, transduction, and response in gravity resistance. Another graviresponse in plants

    NASA Astrophysics Data System (ADS)

    Hoson, T.; Saito, Y.; Soga, K.; Wakabayashi, K.

    Resistance to the gravitational force is a serious problem that plants have had to solve to survive on land. Mechanical resistance to the pull of gravity is thus a principal graviresponse in plants, comparable to gravitropism. Nevertheless, only limited information has been obtained for this gravity response. We have examined the mechanism of gravity-induced mechanical resistance using hypergravity conditions produced by centrifugation. As a result, we have clarified the outline of the sequence of events leading to the development of mechanical resistance. The gravity signal may be perceived by mechanoreceptors (mechanosensitive ion channels) on the plasma membrane and it appears that amyloplast sedimentation in statocytes is not involved. Transformation and transduction of the perceived signal may be mediated by the structural or physiological continuum of microtubule-cell membrane-cell wall. As the final step in the development of mechanical resistance, plants construct a tough body by increasing cell wall rigidity. The increase in cell wall rigidity is brought about by modification of the metabolism of certain wall constituents and modification of the cell wall environment, especially pH. We need to clarify the details of each step by future space and ground-based experiments.

  14. [Salt Stress Response in Arabidopsis thaliana Plants with Defective Jasmonate Signaling].

    PubMed

    Yastreb, T O; Kolupayev, Yu E; Shvidenko, A A; Lugovaya, A A; Dmitriev, A P

    2015-01-01

    The effects of exogenous jasmonic acid (JA) on antioxidant enzymes in four-week-old leaves of wild-type Arabidopsis thaliana L. (Columbia-0) and jin1 (jasmonate insensitive 1) mutant plants with defective jasmonate signaling were investigated under normal conditions and under salt stress (200 mM NaCl, 24 h). The wild-type plants responded to JA by an increase in the activities of Cu/Zn superoxide dismutase, catalase, and guaiacol peroxidase, while there was no change in the case of the mutant plants. In response to the salt stress of both the wild-type and mutant genotypes, the activities of superoxide dismutase, catalase, and guaiacol peroxidase were unchanged, decreased, and increased, respectively. The JA-treated wild type plants showed the highest activity of all three enzymes as compared with the mutant plants. Salinity caused a decrease in chlorophyll content in the wild-type and jin 1 plants. Preliminary JA treatment of the Col-0 plants resulted in a normal content of photosynthetic pigments after the salt stress, while the positive JA effect was insignificant in the jin 1 mutants. It was concluded that the MYC2/JIN 1 protein is involved in the JA signal transduction and plant adaptation to salt stress.

  15. Insulin signalling mediates the response to male-induced harm in female Drosophila melanogaster.

    PubMed

    Sepil, Irem; Carazo, Pau; Perry, Jennifer C; Wigby, Stuart

    2016-01-01

    Genetic manipulations in nutrient-sensing pathways are known to both extend lifespan and modify responses to environmental stressors (e.g., starvation, oxidative and thermal stresses), suggesting that similar mechanisms regulate lifespan and stress resistance. However, despite being a key factor reducing female lifespan and affecting female fitness, male-induced harm has rarely been considered as a stressor mediated by nutrient sensing pathways. We explored whether a lifespan-extending manipulation also modifies female resistance to male-induced harm. To do so, we used long-lived female Drosophila melanogaster that had their insulin signalling pathway downregulated by genetically ablating the median neurosecretory cells (mNSC). We varied the level of exposure to males for control and ablated females and tested for interacting effects on female lifespan and fitness. As expected, we found that lifespan significantly declined with exposure to males. However, mNSC-ablated females maintained significantly increased lifespan across all male exposure treatments. Furthermore, lifespan extension and relative fitness of mNSC-ablated females were maximized under intermediate exposure to males, and minimized under low and high exposure to males. Overall, our results suggest that wild-type levels of insulin signalling reduce female susceptibility to male-induced harm under intense sexual conflict, and may also protect females when mating opportunities are sub-optimally low. PMID:27457757

  16. Potentiation of the early visual response to learned danger signals in adults and adolescents

    PubMed Central

    Howsley, Philippa; Jordan, Jeff; Johnston, Pat

    2015-01-01

    The reinforcing effects of aversive outcomes on avoidance behaviour are well established. However, their influence on perceptual processes is less well explored, especially during the transition from adolescence to adulthood. Using electroencephalography, we examined whether learning to actively or passively avoid harm can modulate early visual responses in adolescents and adults. The task included two avoidance conditions, active and passive, where two different warning stimuli predicted the imminent, but avoidable, presentation of an aversive tone. To avoid the aversive outcome, participants had to learn to emit an action (active avoidance) for one of the warning stimuli and omit an action for the other (passive avoidance). Both adults and adolescents performed the task with a high degree of accuracy. For both adolescents and adults, increased N170 event-related potential amplitudes were found for both the active and the passive warning stimuli compared with control conditions. Moreover, the potentiation of the N170 to the warning stimuli was stable and long lasting. Developmental differences were also observed; adolescents showed greater potentiation of the N170 component to danger signals. These findings demonstrate, for the first time, that learned danger signals in an instrumental avoidance task can influence early visual sensory processes in both adults and adolescents. PMID:24652856

  17. Cross Talk between H2O2 and Interacting Signal Molecules under Plant Stress Response

    PubMed Central

    Saxena, Ina; Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    It is well established that oxidative stress is an important cause of cellular damage. During stress conditions, plants have evolved regulatory mechanisms to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of reactive oxygen species, which is subsequently converted to H2O2. H2O2 is continuously produced as the byproduct of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 immerges as an important factor during many biological processes. It has been established that it acts as a secondary messenger in signal transduction networks. In this review, we discuss potential roles of H2O2 and other signaling molecules during various stress responses. PMID:27200043

  18. Social responsivity: judging signals of young children with and without developmental delays.

    PubMed

    Walden, T A

    1996-10-01

    This was an experimental study of the ability of adults to detect 1 social signal that is important in social interactions, children's glances or looks at their social partners. Adult judges were either parents of children with developmental delays, parents of nondelayed children, or nonparents with little experience with children. Each participant viewed 120 videotaped episode in which very young children's looks (of 2 types, either a focus on parent's face or nonface focus) occurred or no looking occurred. Half the episodes featured children with documented developmental delays and half featured nondelayed children. Participants made judgments about the occurrence of a look in each episode and rated their confidence in each judgment. Participants made more accurate and quicker responses to social looks by children without than those with developmental delays. Accuracy effects were qualified by interactions with type of look. Participants were more confident of their judgments of looks for nondelayed toddlers than those with delays. Signal detection statistics indicated that looks of delayed toddlers were harder to identify and that judges set a more stringent criterion for responding to those looks. No effects of judges' level of experience with delayed or nondelayed children were found. Implications of these findings for social interaction involving individuals with developmental delays are discussed. PMID:9022230

  19. Insulin signalling mediates the response to male-induced harm in female Drosophila melanogaster

    PubMed Central

    Sepil, Irem; Carazo, Pau; Perry, Jennifer C.; Wigby, Stuart

    2016-01-01

    Genetic manipulations in nutrient-sensing pathways are known to both extend lifespan and modify responses to environmental stressors (e.g., starvation, oxidative and thermal stresses), suggesting that similar mechanisms regulate lifespan and stress resistance. However, despite being a key factor reducing female lifespan and affecting female fitness, male-induced harm has rarely been considered as a stressor mediated by nutrient sensing pathways. We explored whether a lifespan-extending manipulation also modifies female resistance to male-induced harm. To do so, we used long-lived female Drosophila melanogaster that had their insulin signalling pathway downregulated by genetically ablating the median neurosecretory cells (mNSC). We varied the level of exposure to males for control and ablated females and tested for interacting effects on female lifespan and fitness. As expected, we found that lifespan significantly declined with exposure to males. However, mNSC-ablated females maintained significantly increased lifespan across all male exposure treatments. Furthermore, lifespan extension and relative fitness of mNSC-ablated females were maximized under intermediate exposure to males, and minimized under low and high exposure to males. Overall, our results suggest that wild-type levels of insulin signalling reduce female susceptibility to male-induced harm under intense sexual conflict, and may also protect females when mating opportunities are sub-optimally low. PMID:27457757

  20. Cross Talk between H2O2 and Interacting Signal Molecules under Plant Stress Response.

    PubMed

    Saxena, Ina; Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    It is well established that oxidative stress is an important cause of cellular damage. During stress conditions, plants have evolved regulatory mechanisms to adapt to various environmental stresses. One of the consequences of stress is an increase in the cellular concentration of reactive oxygen species, which is subsequently converted to H2O2. H2O2 is continuously produced as the byproduct of oxidative plant aerobic metabolism. Organelles with a high oxidizing metabolic activity or with an intense rate of electron flow, such as chloroplasts, mitochondria, or peroxisomes are major sources of H2O2 production. H2O2 acts as a versatile molecule because of its dual role in cells. Under normal conditions, H2O2 immerges as an important factor during many biological processes. It has been established that it acts as a secondary messenger in signal transduction networks. In this review, we discuss potential roles of H2O2 and other signaling molecules during various stress responses. PMID:27200043

  1. Exploring motorcycle red-light violation in response to pedestrian green signal countdown device.

    PubMed

    Chen, Ping-Ling; Pai, Chih-Wei; Jou, Rong-Chang; Saleh, Wafaa; Kuo, Ming-Shin

    2015-02-01

    Literature has suggested that angle/rear-end collisions would arise from the reality that motorists and motorcyclists tended to accelerate aggressively in response to the remaining seconds of green signal countdown device (GSCD). One safety concern, while GSCD has gradually been removed for safety in Taiwan, is pedestrian green signal countdown device (PGSCD) that is used by approaching motorists and motorcyclists that may adopt the information to travel aggressively - an unintended consequence that is detrimental to safety. Research has reported that there appeared no negative effect of PGSCD on motorist behaviours but the effect on motorcyclists' behaviours has been rarely investigated. Using video/speed cameras, the current research investigates motorcyclists' RLV (red-light violation) behaviours. The descriptive analyses indicate that the percentage of RLV at PGSCD intersection is higher than that at typical intersection, and the violating motorcycles appear to have higher travelling speeds at PGSCD intersection. Several interaction terms were examined with the binary logit framework, and the results reveal that several factors are associated with RLV, notably male/young riders, moped/large motorcycle users, higher approaching speeds of