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Sample records for level dependent signal

  1. Negative blood oxygen level dependent signals during speech comprehension.

    Science.gov (United States)

    Rodriguez Moreno, Diana; Schiff, Nicholas D; Hirsch, Joy

    2015-05-01

    Speech comprehension studies have generally focused on the isolation and function of regions with positive blood oxygen level dependent (BOLD) signals with respect to a resting baseline. Although regions with negative BOLD signals in comparison to a resting baseline have been reported in language-related tasks, their relationship to regions of positive signals is not fully appreciated. Based on the emerging notion that the negative signals may represent an active function in language tasks, the authors test the hypothesis that negative BOLD signals during receptive language are more associated with comprehension than content-free versions of the same stimuli. Regions associated with comprehension of speech were isolated by comparing responses to passive listening to natural speech to two incomprehensible versions of the same speech: one that was digitally time reversed and one that was muffled by removal of high frequencies. The signal polarity was determined by comparing the BOLD signal during each speech condition to the BOLD signal during a resting baseline. As expected, stimulation-induced positive signals relative to resting baseline were observed in the canonical language areas with varying signal amplitudes for each condition. Negative BOLD responses relative to resting baseline were observed primarily in frontoparietal regions and were specific to the natural speech condition. However, the BOLD signal remained indistinguishable from baseline for the unintelligible speech conditions. Variations in connectivity between brain regions with positive and negative signals were also specifically related to the comprehension of natural speech. These observations of anticorrelated signals related to speech comprehension are consistent with emerging models of cooperative roles represented by BOLD signals of opposite polarity.

  2. The Not-So-Global Blood Oxygen Level-Dependent Signal.

    Science.gov (United States)

    Billings, Jacob; Keilholz, Shella

    2018-04-01

    Global signal regression is a controversial processing step for resting-state functional magnetic resonance imaging, partly because the source of the global blood oxygen level-dependent (BOLD) signal remains unclear. On the one hand, nuisance factors such as motion can readily introduce coherent BOLD changes across the whole brain. On the other hand, the global signal has been linked to neural activity and vigilance levels, suggesting that it contains important neurophysiological information and should not be discarded. Any widespread pattern of coordinated activity is likely to contribute appreciably to the global signal. Such patterns may include large-scale quasiperiodic spatiotemporal patterns, known also to be tied to performance on vigilance tasks. This uncertainty surrounding the separability of the global BOLD signal from concurrent neurological processes motivated an examination of the global BOLD signal's spatial distribution. The results clarify that although the global signal collects information from all tissue classes, a diverse subset of the BOLD signal's independent components contribute the most to the global signal. Further, the timing of each network's contribution to the global signal is not consistent across volunteers, confirming the independence of a constituent process that comprises the global signal.

  3. Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation.

    Science.gov (United States)

    Licata, Stephanie C; Lowen, Steven B; Trksak, George H; Maclean, Robert R; Lukas, Scott E

    2011-08-15

    Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABA(A) receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 min after acute oral administration of zolpidem (0, 5, 10, or 20mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidem's modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABA(A) receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation

    Science.gov (United States)

    Licata, Stephanie C.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

    2011-01-01

    Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABAA receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess the effects of zolpidem within the brain. Healthy participants (n=12) were scanned 60 minutes after acute oral administration of zolpidem (0, 5, 10, or 20 mg), and changes in BOLD signal were measured in the visual cortex during presentation of a flashing checkerboard. Heart rate and oxygen saturation were monitored continuously throughout the session. Zolpidem (10 and 20 mg) reduced the robust visual system activation produced by presentation of this stimulus, but had no effects on physiological activity during the fMRI scan. Zolpidem’s modulation of the BOLD signal within the visual cortex is consistent with the abundant distribution of GABAA receptors localized in this region, as well as previous studies showing a relationship between increased GABA-mediated neuronal inhibition and a reduction in BOLD activation. PMID:21640782

  5. Zolpidem reduces the blood oxygen level-dependent signal during visual system stimulation

    OpenAIRE

    Licata, Stephanie C.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

    2011-01-01

    Zolpidem is a short-acting imidazopyridine hypnotic that binds at the benzodiazepine binding site on specific GABAA receptors to enhance fast inhibitory neurotransmission. The behavioral and receptor pharmacology of zolpidem has been studied extensively, but little is known about its neuronal substrates in vivo. In the present within-subject, double-blind, and placebo-controlled study, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) at 3 Tesla was used to assess...

  6. Threat-level-dependent manipulation of signaled body size: dog growls' indexical cues depend on the different levels of potential danger.

    Science.gov (United States)

    Bálint, Anna; Faragó, Tamás; Miklósi, Ádám; Pongrácz, Péter

    2016-11-01

    Body size is an important feature that affects fighting ability; however, size-related parameters of agonistic vocalizations are difficult to manipulate because of anatomical constraints within the vocal production system. Rare examples of acoustic size modulation are due to specific features that enable the sender to steadily communicate exaggerated body size. However, one could argue that it would be more adaptive if senders could adjust their signaling behavior to the fighting potential of their actual opponent. So far there has been no experimental evidence for this possibility. We tested this hypothesis by exposing family dogs (Canis familiaris) to humans with potentially different fighting ability. In a within-subject experiment, 64 dogs of various breeds consecutively faced two threateningly approaching humans, either two men or two women of different stature, or a man and a woman of similar or different stature. We found that the dogs' vocal responses were affected by the gender of the threatening stranger and the dog owner's gender. Dogs with a female owner, or those dogs which came from a household where both genders were present, reacted with growls of lower values of the Pitch-Formant component (including deeper fundamental frequency and lower formant dispersion) to threatening men. Our results are the first to show that non-human animals react with dynamic alteration of acoustic parameters related to their individual indexical features (body size), depending on the level of threat in an agonistic encounter.

  7. Systems-level identification of PKA-dependent signaling in epithelial cells.

    Science.gov (United States)

    Isobe, Kiyoshi; Jung, Hyun Jun; Yang, Chin-Rang; Claxton, J'Neka; Sandoval, Pablo; Burg, Maurice B; Raghuram, Viswanathan; Knepper, Mark A

    2017-10-17

    G protein stimulatory α-subunit (G αs )-coupled heptahelical receptors regulate cell processes largely through activation of protein kinase A (PKA). To identify signaling processes downstream of PKA, we deleted both PKA catalytic subunits using CRISPR-Cas9, followed by a "multiomic" analysis in mouse kidney epithelial cells expressing the G αs -coupled V2 vasopressin receptor. RNA-seq (sequencing)-based transcriptomics and SILAC (stable isotope labeling of amino acids in cell culture)-based quantitative proteomics revealed a complete loss of expression of the water-channel gene Aqp2 in PKA knockout cells. SILAC-based quantitative phosphoproteomics identified 229 PKA phosphorylation sites. Most of these PKA targets are thus far unannotated in public databases. Surprisingly, 1,915 phosphorylation sites with the motif x-(S/T)-P showed increased phosphooccupancy, pointing to increased activity of one or more MAP kinases in PKA knockout cells. Indeed, phosphorylation changes associated with activation of ERK2 were seen in PKA knockout cells. The ERK2 site is downstream of a direct PKA site in the Rap1GAP, Sipa1l1, that indirectly inhibits Raf1. In addition, a direct PKA site that inhibits the MAP kinase kinase kinase Map3k5 (ASK1) is upstream of JNK1 activation. The datasets were integrated to identify a causal network describing PKA signaling that explains vasopressin-mediated regulation of membrane trafficking and gene transcription. The model predicts that, through PKA activation, vasopressin stimulates AQP2 exocytosis by inhibiting MAP kinase signaling. The model also predicts that, through PKA activation, vasopressin stimulates Aqp2 transcription through induction of nuclear translocation of the acetyltransferase EP300, which increases histone H3K27 acetylation of vasopressin-responsive genes (confirmed by ChIP-seq).

  8. Blood oxygenation level dependent signal and neuronal adaptation to optogenetic and sensory stimulation in somatosensory cortex in awake animals.

    Science.gov (United States)

    Aksenov, Daniil P; Li, Limin; Miller, Michael J; Wyrwicz, Alice M

    2016-11-01

    The adaptation of neuronal responses to stimulation, in which a peak transient response is followed by a sustained plateau, has been well-studied. The blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal has also been shown to exhibit adaptation on a longer time scale. However, some regions such as the visual and auditory cortices exhibit significant BOLD adaptation, whereas other such as the whisker barrel cortex may not adapt. In the sensory cortex a combination of thalamic inputs and intracortical activity drives hemodynamic changes, although the relative contributions of these components are not entirely understood. The aim of this study is to assess the role of thalamic inputs vs. intracortical processing in shaping BOLD adaptation during stimulation in the somatosensory cortex. Using simultaneous fMRI and electrophysiology in awake rabbits, we measured BOLD, local field potentials (LFPs), single- and multi-unit activity in the cortex during whisker and optogenetic stimulation. This design allowed us to compare BOLD and haemodynamic responses during activation of the normal thalamocortical sensory pathway (i.e., both inputs and intracortical activity) vs. the direct optical activation of intracortical circuitry alone. Our findings show that whereas LFP and multi-unit (MUA) responses adapted, neither optogenetic nor sensory stimulation produced significant BOLD adaptation. We observed for both paradigms a variety of excitatory and inhibitory single unit responses. We conclude that sensory feed-forward thalamic inputs are not primarily responsible for shaping BOLD adaptation to stimuli; but the single-unit results point to a role in this behaviour for specific excitatory and inhibitory neuronal sub-populations, which may not correlate with aggregate neuronal activity. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  9. Measuring vascular reactivity with resting-state blood oxygenation level-dependent (BOLD) signal fluctuations: A potential alternative to the breath-holding challenge?

    Science.gov (United States)

    Jahanian, Hesamoddin; Christen, Thomas; Moseley, Michael E; Pajewski, Nicholas M; Wright, Clinton B; Tamura, Manjula K; Zaharchuk, Greg

    2017-07-01

    Measurement of the ability of blood vessels to dilate and constrict, known as vascular reactivity, is often performed with breath-holding tasks that transiently raise arterial blood carbon dioxide (P a CO 2 ) levels. However, following the proper commands for a breath-holding experiment may be difficult or impossible for many patients. In this study, we evaluated two approaches for obtaining vascular reactivity information using blood oxygenation level-dependent signal fluctuations obtained from resting-state functional magnetic resonance imaging data: physiological fluctuation regression and coefficient of variation of the resting-state functional magnetic resonance imaging signal. We studied a cohort of 28 older adults (69 ± 7 years) and found that six of them (21%) could not perform the breath-holding protocol, based on an objective comparison with an idealized respiratory waveform. In the subjects that could comply, we found a strong linear correlation between data extracted from spontaneous resting-state functional magnetic resonance imaging signal fluctuations and the blood oxygenation level-dependent percentage signal change during breath-holding challenge ( R 2  = 0.57 and 0.61 for resting-state physiological fluctuation regression and resting-state coefficient of variation methods, respectively). This technique may eliminate the need for subject cooperation, thus allowing the evaluation of vascular reactivity in a wider range of clinical and research conditions in which it may otherwise be impractical.

  10. The Relationship Between Dopamine Neurotransmitter Dynamics and the Blood-Oxygen-Level-Dependent (BOLD Signal: A Review of Pharmacological Functional Magnetic Resonance Imaging

    Directory of Open Access Journals (Sweden)

    Tyler J. Bruinsma

    2018-04-01

    Full Text Available Functional magnetic resonance imaging (fMRI is widely used in investigations of normal cognition and brain disease and in various clinical applications. Pharmacological fMRI (pharma-fMRI is a relatively new application, which is being used to elucidate the effects and mechanisms of pharmacological modulation of brain activity. Characterizing the effects of neuropharmacological agents on regional brain activity using fMRI is challenging because drugs modulate neuronal function in a wide variety of ways, including through receptor agonist, antagonist, and neurotransmitter reuptake blocker events. Here we review current knowledge on neurotransmitter-mediated blood-oxygen-level dependent (BOLD fMRI mechanisms as well as recently updated methodologies aimed at more fully describing the effects of neuropharmacologic agents on the BOLD signal. We limit our discussion to dopaminergic signaling as a useful lens through which to analyze and interpret neurochemical-mediated changes in the hemodynamic BOLD response. We also discuss the need for future studies that use multi-modal approaches to expand the understanding and application of pharma-fMRI.

  11. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages.

    Science.gov (United States)

    Liu, Yingying; Li, Fengna; Kong, Xiangfeng; Tan, Bie; Li, Yinghui; Duan, Yehui; Blachier, François; Hu, Chien-An A; Yin, Yulong

    2015-01-01

    Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA) pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet)- or higher/NRC (National Research Council)-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I) and longissimus dorsi muscle (LDM, type II) were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR) signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (Prelated AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05) than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K), and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05). There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05) the levels for mTOR and p70S6K in Bama mini-pigs, but repressed (P<0.05) the level for p70S6K in Landrace pigs. The higher protein-NRC diet increased ratio of p-mTOR/mTOR in

  12. Effects of Intranasal Oxytocin on the Blood Oxygenation Level-Dependent Signal in Food Motivation and Cognitive Control Pathways in Overweight and Obese Men.

    Science.gov (United States)

    Plessow, Franziska; Marengi, Dean A; Perry, Sylvia K; Felicione, Julia M; Franklin, Rachel; Holmes, Tara M; Holsen, Laura M; Makris, Nikolaos; Deckersbach, Thilo; Lawson, Elizabeth A

    2018-02-01

    Recent research indicates that the hypothalamic neuropeptide hormone oxytocin is a key central nervous system factor in the regulation of food intake and weight. However, the mechanisms underlying the anorexigenic effects of oxytocin in humans are unknown and critical to study to consider oxytocin as a neurohormonal weight loss treatment. We performed a randomized, double-blind, placebo-controlled crossover study with single-dose intranasal oxytocin (24 IU) in ten overweight or obese, otherwise healthy men. Following oxytocin/placebo administration, participants completed an established functional magnetic resonance imaging food motivation paradigm. We hypothesized that oxytocin would reduce the blood oxygenation level-dependent (BOLD) signal to high-calorie food vs non-food visual stimuli in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system. Following oxytocin administration, compared to placebo, participants showed bilateral VTA hypoactivation to high-calorie food stimuli. A secondary exploratory whole-brain analysis revealed hypoactivation in additional hedonic (orbitofrontal cortex, insula, globus pallidus, putamen, hippocampus, and amygdala) and homeostatic (hypothalamus) food motivation and hyperactivation in cognitive control (anterior cingulate and frontopolar cortex) brain regions following oxytocin administration vs placebo. Oxytocin administration reduces the BOLD signal in reward-related food motivation brain regions, providing a potential neurobiological mechanism for the anorexigenic oxytocin effects in humans. Furthermore, our data indicate that oxytocin administration reduces activation in homeostatic and increases activation in cognitive control brain regions critically involved in regulating food intake and resolving affective conflict, respectively. Future studies are required to link these changes in brain activation to oxytocin effects on food intake and weight.

  13. Signaling Pathways Related to Protein Synthesis and Amino Acid Concentration in Pig Skeletal Muscles Depend on the Dietary Protein Level, Genotype and Developmental Stages.

    Directory of Open Access Journals (Sweden)

    Yingying Liu

    Full Text Available Muscle growth is regulated by the homeostatic balance of the biosynthesis and degradation of muscle proteins. To elucidate the molecular interactions among diet, pig genotype, and physiological stage, we examined the effect of dietary protein concentration, pig genotype, and physiological stages on amino acid (AA pools, protein deposition, and related signaling pathways in different types of skeletal muscles. The study used 48 Landrace pigs and 48 pure-bred Bama mini-pigs assigned to each of 2 dietary treatments: lower/GB (Chinese conventional diet- or higher/NRC (National Research Council-protein diet. Diets were fed from 5 weeks of age to respective market weights of each genotype. Samples of biceps femoris muscle (BFM, type I and longissimus dorsi muscle (LDM, type II were collected at nursery, growing, and finishing phases according to the physiological stage of each genotype, to determine the AA concentrations, mRNA levels for growth-related genes in muscles, and protein abundances of mechanistic target of rapamycin (mTOR signaling pathway. Our data showed that the concentrations of most AAs in LDM and BFM of pigs increased (P<0.05 gradually with increasing age. Bama mini-pigs had generally higher (P<0.05 muscle concentrations of flavor-related AA, including Met, Phe, Tyr, Pro, and Ser, compared with Landrace pigs. The mRNA levels for myogenic determining factor, myogenin, myocyte-specific enhancer binding factor 2 A, and myostatin of Bama mini-pigs were higher (P<0.05 than those of Landrace pigs, while total and phosphorylated protein levels for protein kinase B, mTOR, and p70 ribosomal protein S6 kinases (p70S6K, and ratios of p-mTOR/mTOR, p-AKT/AKT, and p-p70S6K/p70S6K were lower (P<0.05. There was a significant pig genotype-dependent effect of dietary protein on the levels for mTOR and p70S6K. When compared with the higher protein-NRC diet, the lower protein-GB diet increased (P<0.05 the levels for mTOR and p70S6K in Bama mini-pigs, but

  14. What does carotenoid-dependent coloration tell? : Plasma carotenoid level signals immunocompetence and oxidative stress state in birds - A meta-analysis

    NARCIS (Netherlands)

    Simons, Mirre J. P.; Cohen, Alan A.; Verhulst, Simon

    2012-01-01

    Mechanisms maintaining honesty of sexual signals are far from resolved, limiting our understanding of sexual selection and potential important parts of physiology. Carotenoid pigmented visual signals are among the most extensively studied sexual displays, but evidence regarding hypotheses on how

  15. Identification of a c-Jun N-terminal kinase-2-dependent signal amplification cascade that regulates c-Myc levels in ras transformation

    DEFF Research Database (Denmark)

    Mathiasen, D.P.; Egebjerg, C.; Andersen, S.H.

    2012-01-01

    are essential for ras transformation. Previous studies show that ERK-mediated serine 62 phosphorylation protects c-Myc from proteasomal degradation. ERK is, however, not alone sufficient to stabilize c-Myc but requires the cooperation of cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncogene...... that counteracts protein phosphatase 2A-mediated dephosphorylation of c-Myc. Here we show that JNK2 regulates Cip2a transcription via ATF2. ATF2 and c-Myc cooperate to activate the transcription of ATF3. Remarkably, not only ectopic JNK2, but also ectopic ATF2, CIP2A, c-Myc and ATF3 are sufficient to rescue...... the defective ras transformation of JNK2-deficient cells. Thus, these data identify the key signal converging point of JNK2 and ERK pathways and underline the central role of CIP2A in ras transformation.Oncogene advance online publication, 27 June 2011; doi:10.1038/onc.2011.230....

  16. Cocaine-associated odor cue re-exposure increases blood oxygenation level dependent signal in memory and reward regions of the maternal rat brain.

    Science.gov (United States)

    Caffrey, Martha K; Febo, Marcelo

    2014-01-01

    Cue triggered relapse during the postpartum period can negatively impact maternal care. Given the high reward value of pups in maternal rats, we designed an fMRI experiment to test whether offspring presence reduces the neural response to a cocaine associated olfactory cue. Cocaine conditioned place preference was carried out before pregnancy in the presence of two distinct odors that were paired with cocaine or saline (+Cue and -Cue). The BOLD response to +Cue and -Cue was measured in dams on postpartum days 2-4. Odor cues were delivered to dams in the absence and then the presence of pups. Our data indicate that several limbic and cognitive regions of the maternal rat brain show a greater BOLD signal response to a +Cue versus -Cue. These include dorsal striatum, prelimbic cortex, parietal cortex, habenula, bed nucleus of stria terminalis, lateral septum and the mediodorsal and the anterior thalamic nucleus. Of the aforementioned brain regions, only the parietal cortex of cocaine treated dams showed a significant modulatory effect of pup presence. In this area of the cortex, cocaine exposed maternal rats showed a greater BOLD activation in response to the +Cue in the presence than in the absence of pups. Specific regions of the cocaine exposed maternal rat brain are strongly reactive to drug associated cues. The regions implicated in cue reactivity have been previously reported in clinical imaging work, and previous work supports their role in various motivational and cognitive functions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. COCAINE-ASSOCIATED ODOR CUE RE-EXPOSURE INCREASES BLOOD OXYGENATION LEVEL DEPENDENT SIGNAL IN MEMORY AND REWARD REGIONS OF THE MATERNAL RAT BRAIN*

    Science.gov (United States)

    Caffrey, Martha K.; Febo, Marcelo

    2013-01-01

    BACKGROUND Cue triggered relapse during the postpartum period can negatively impact maternal care. Given the high reward value of pups in maternal rats, we designed an fMRI experiment to test whether offspring presence reduces the neural response to a cocaine associated olfactory cue. METHODS Cocaine conditioned place preference was carried out before pregnancy in the presence of two distinct odors that were paired with cocaine or saline (+Cue and −Cue). The BOLD response to +Cue and −Cue was measured in dams on postpartum days 2–4. Odor cues were delivered to dams in the absence and then the presence of pups. RESULTS Our data indicate that several limbic and cognitive regions of the maternal rat brain show a greater BOLD signal response to a +Cue versus −Cue. These include dorsal striatum, prelimbic cortex, parietal cortex, habenula, bed nucleus of stria terminalis, lateral septum and the mediodorsal and the anterior thalamic nucleus. Of the aforementioned brain regions, only the parietal cortex of cocaine treated dams showed a significant modulatory effect of pup presence. In this area of the cortex, cocaine exposed maternal rats showed a greater BOLD activation in response to the +Cue in the presence than in the absence of pups. CONCLUSIONS Specific regions of the cocaine exposed maternal rat brain are strongly reactive to drug associated cues. The regions implicated in cue reactivity have been previously reported in clinical imaging work, and previous work supports their role in various motivational and cognitive functions. PMID:24183499

  18. Erythropoietin Receptor Signaling Is Membrane Raft Dependent

    Science.gov (United States)

    McGraw, Kathy L.; Fuhler, Gwenny M.; Johnson, Joseph O.; Clark, Justine A.; Caceres, Gisela C.; Sokol, Lubomir; List, Alan F.

    2012-01-01

    Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units. PMID:22509308

  19. Erythropoietin receptor signaling is membrane raft dependent

    NARCIS (Netherlands)

    K.L. McGraw (Kathy); G.M. Fuhler (Gwenny); J.O. Johnson (Joseph); J.A. Clark (Justine); G.C. Caceres (Gisela); L. Sokol (Lubomir); A.F. List (Alan)

    2012-01-01

    textabstractUpon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling

  20. BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zhengrong Zhang

    2017-09-01

    Full Text Available Schizophrenia is a chronic psychiatric disorder with a lifetime prevalence of about 1% in the general population. Recent studies have shown that Neuregulin-1 (Nrg1 is a candidate gene for schizophrenia. At least 15 alternative splicing of NRG1 isoforms all contain an extracellular epidermal growth factor (EGF-like domain, which is sufficient for Nrg1 biological activity including the formation of myelin sheaths and the regulation of synaptic plasticity. It is known that Nrg1 can be cleaved by β-secretase (BACE1 and the resulting N-terminal fragment (Nrg1-ntf binds to receptor tyrosine kinase ErbB4, which activates Nrg1/ErbB4 signaling. While changes in Nrg1 expression levels in schizophrenia still remain controversial, understanding the BACE1-cleaved Nrg1-ntf and Nrg1/ErbB4 signaling in schizophrenia neuropathogenesis is essential and important. In this review paper, we included three major parts: (1 Nrg1 structure and cleavage pattern by BACE1; (2 BACE1-dependent Nrg1 cleavage associated with schizophrenia in human studies; and (3 Animal studies of Nrg1 and BACE1 mutations with behavioral observations. Our review will provide a better understanding of Nrg1 in schizophrenia and a potential strategy for using BACE1 cleavage of Nrg1 as a unique biomarker for diagnosis, as well as a new therapeutic target, of schizophrenia.

  1. Diffusible signal factor-dependent quorum sensing in pathogenic bacteria and its exploitation for disease control.

    Science.gov (United States)

    Dow, J M

    2017-01-01

    Cell-to-cell signals of the diffusible signal factor (DSF) family are cis-2-unsaturated fatty acids of differing chain length and branching pattern. DSF signalling has been described in diverse bacteria to include plant and human pathogens where it acts to regulate functions such as biofilm formation, antibiotic tolerance and the production of virulence factors. DSF family signals can also participate in interspecies signalling with other bacteria and interkingdom signalling such as with the yeast Candida albicans. Interference with DSF signalling may afford new opportunities for the control of bacterial disease. Such strategies will depend in part on detailed knowledge of the molecular mechanisms underlying the processes of signal synthesis, perception and turnover. Here, I review both recent progress in understanding DSF signalling at the molecular level and prospects for translating this knowledge into approaches for disease control. © 2016 The Society for Applied Microbiology.

  2. BMP signaling regulates satellite cell-dependent postnatal muscle growth.

    Science.gov (United States)

    Stantzou, Amalia; Schirwis, Elija; Swist, Sandra; Alonso-Martin, Sonia; Polydorou, Ioanna; Zarrouki, Faouzi; Mouisel, Etienne; Beley, Cyriaque; Julien, Anaïs; Le Grand, Fabien; Garcia, Luis; Colnot, Céline; Birchmeier, Carmen; Braun, Thomas; Schuelke, Markus; Relaix, Frédéric; Amthor, Helge

    2017-08-01

    Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here, we demonstrate that postnatal satellite cells express components of the bone morphogenetic protein (BMP) signaling machinery. Overexpression of noggin in postnatal mice (to antagonize BMP ligands), satellite cell-specific knockout of Alk3 (the gene encoding the BMP transmembrane receptor) or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth, and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and upregulated the expression of cell cycle inhibitors p21 and p57 In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell-dependent myofiber growth and the generation of the adult muscle stem cell pool. © 2017. Published by The Company of Biologists Ltd.

  3. Signal restoration for NMR imaging using time-dependent gradients

    International Nuclear Information System (INIS)

    Frahm, J.; Haenicke, W.

    1984-01-01

    NMR imaging experiments that employ linear but time-dependent gradients for encoding spatial information in the time-domain signals result in distorted images when treated with conventional image reconstruction techniques. It is shown here that the phase and amplitude distortions can be entirely removed if the timeshape of the gradient is known. The method proposed is of great theoretical and experimental simplicity. It consists of a retransformation of the measured time-domain signal and corresponds to synchronisation of the signal sampling with the time-development of the gradient field strength. The procedure complements other treatments of periodically oscillating gradients in NMR imaging. (author)

  4. Signal-dependent independent component analysis by tunable mother wavelets

    International Nuclear Information System (INIS)

    Seo, Kyung Ho

    2006-02-01

    The objective of this study is to improve the standard independent component analysis when applied to real-world signals. Independent component analysis starts from the assumption that signals from different physical sources are statistically independent. But real-world signals such as EEG, ECG, MEG, and fMRI signals are not statistically independent perfectly. By definition, standard independent component analysis algorithms are not able to estimate statistically dependent sources, that is, when the assumption of independence does not hold. Therefore before independent component analysis, some preprocessing stage is needed. This paper started from simple intuition that wavelet transformed source signals by 'well-tuned' mother wavelet will be simplified sufficiently, and then the source separation will show better results. By the correlation coefficient method, the tuning process between source signal and tunable mother wavelet was executed. Gamma component of raw EEG signal was set to target signal, and wavelet transform was executed by tuned mother wavelet and standard mother wavelets. Simulation results by these wavelets was shown

  5. Linear motif atlas for phosphorylation-dependent signaling

    DEFF Research Database (Denmark)

    Miller, Martin Lee; Jensen, LJ; Diella, F

    2008-01-01

    bind to them remains a challenge. NetPhorest is an atlas of consensus sequence motifs that covers 179 kinases and 104 phosphorylation-dependent binding domains [Src homology 2 (SH2), phosphotyrosine binding (PTB), BRCA1 C-terminal (BRCT), WW, and 14-3-3]. The atlas reveals new aspects of signaling...

  6. Pseudo Asynchronous Level Crossing adc for ecg Signal Acquisition.

    Science.gov (United States)

    Marisa, T; Niederhauser, T; Haeberlin, A; Wildhaber, R A; Vogel, R; Goette, J; Jacomet, M

    2017-02-07

    A new pseudo asynchronous level crossing analogue-to-digital converter (adc) architecture targeted for low-power, implantable, long-term biomedical sensing applications is presented. In contrast to most of the existing asynchronous level crossing adc designs, the proposed design has no digital-to-analogue converter (dac) and no continuous time comparators. Instead, the proposed architecture uses an analogue memory cell and dynamic comparators. The architecture retains the signal activity dependent sampling operation by generating events only when the input signal is changing. The architecture offers the advantages of smaller chip area, energy saving and fewer analogue system components. Beside lower energy consumption the use of dynamic comparators results in a more robust performance in noise conditions. Moreover, dynamic comparators make interfacing the asynchronous level crossing system to synchronous processing blocks simpler. The proposed adc was implemented in [Formula: see text] complementary metal-oxide-semiconductor (cmos) technology, the hardware occupies a chip area of 0.0372 mm 2 and operates from a supply voltage of [Formula: see text] to [Formula: see text]. The adc's power consumption is as low as 0.6 μW with signal bandwidth from [Formula: see text] to [Formula: see text] and achieves an equivalent number of bits (enob) of up to 8 bits.

  7. Nitric oxide signaling depends on biotin in Jurkat human lymphoma cells.

    Science.gov (United States)

    Rodriguez-Melendez, Rocio; Zempleni, Janos

    2009-03-01

    Biotin affects gene expression through a diverse array of cell signaling pathways. Previous studies provided evidence that cGMP-dependent signaling also depends on biotin, but the mechanistic sequence of cGMP regulation by biotin is unknown. Here we tested the hypothesis that the effects of biotin in cGMP-dependent cell signaling are mediated by nitric oxide (NO). Human lymphoid (Jurkat) cells were cultured in media containing deficient (0.025 nmol/L), physiological (0.25 nmol/L), and pharmacological (10 nmol/L) concentrations of biotin for 5 wk. Both levels of intracellular biotin and NO exhibited a dose-dependent relationship in regard to biotin concentrations in culture media. Effects of biotin on NO levels were disrupted by the NO synthase (NOS) inhibitor N-monomethyl-arginine. Biotin-dependent production of NO was linked with biotin-dependent expression of endothelial and neuronal NOS, but not inducible NOS. Previous studies revealed that NO is an activator of guanylate cyclase. Consistent with these previous observations, biotin-dependent generation of NO increased the abundance of cGMP in Jurkat cells. Finally, the biotin-dependent generation of cGMP increased protein kinase G activity. Collectively, the results of this study are consistent with the hypothesis that biotin-dependent cGMP signaling in human lymphoid cells is mediated by NO.

  8. Microenvironment Dependent Photobiomodulation on Function-Specific Signal Transduction Pathways

    Directory of Open Access Journals (Sweden)

    Timon Cheng-Yi Liu

    2014-01-01

    Full Text Available Cellular photobiomodulation on a cellular function has been shown to be homeostatic. Its function-specific pathway mechanism would be further discussed in this paper. The signal transduction pathways maintaining a normal function in its function-specific homeostasis (FSH, resisting the activation of many other irrelative signal transduction pathways, are so sparse that it can be supposed that there may be normal function-specific signal transduction pathways (NSPs. A low level laser irradiation or monochromatic light may promote the activation of partially activated NSP and/or its redundant NSP so that it may induce the second-order phase transition of a function from its dysfunctional one far from its FSH to its normal one in a function-specific microenvironment and may also induce the first-order functional phase transition of the normal function from low level to high level.

  9. Signaling induced by hop/STI-1 depends on endocytosis

    International Nuclear Information System (INIS)

    Americo, Tatiana A.; Chiarini, Luciana B.; Linden, Rafael

    2007-01-01

    The co-chaperone hop/STI-1 is a ligand of the cell surface prion protein (PrP C ), and their interaction leads to signaling and biological effects. Among these, hop/STI-1 induces proliferation of A172 glioblastoma cells, dependent on both PrP C and activation of the Erk pathway. We tested whether clathrin-mediated endocytosis affects signaling induced by hop/STI-1. Both hyperosmolarity induced by sucrose and monodansyl-cadaverine blocked Erk activity induced by hop/STI-1, without affecting the high basal Akt activity typical of A172. The endocytosis inhibitors also affected the sub-cellular distribution of phosphorylated Erk, consistent with blockade of the latter's activity. The data indicate that signaling induced by hop/STI-1 depends on endocytosis. These findings are consistent with a role of sub-cellular trafficking in signal transduction following engagement by PrP C by ligands such as hop/STI-1, and may help help unravel both the functions of the prion protein, as well as possible loss-of-function components of prion diseases

  10. Attention-dependent modulation of cortical taste circuits revealed by Granger causality with signal-dependent noise.

    Directory of Open Access Journals (Sweden)

    Qiang Luo

    2013-10-01

    Full Text Available We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention.

  11. Time varying behavior of the loudspeaker suspension: Displacement level dependency

    DEFF Research Database (Denmark)

    Agerkvist, Finn T.; Pedersen, Bo Rohde

    2009-01-01

    The compliance of the loudspeaker suspension is known to depend on the recent excitation level history. Previous investigations have shown that the electrical power as well as displacement and velocity plays a role. In this paper the hypothesis that the changes in compliance are caused mainly...... by how much the suspension has been stretched, i.e. the maximum displacement, is investigated. For this purpose the changes in compliance are measured when exposing the speaker to different levels and types of electrical excitation signals, as well as mechanical excitation only. For sinusoidal excitation...... the change in compliance is shown to depend primarily on maximum displacement. But for square pulse excitation the duration of the excitation also plays an important role...

  12. Thylakoid redox signals are integrated into organellar-gene-expression-dependent retrograde signalling in the prors1-1 mutant

    Directory of Open Access Journals (Sweden)

    Luca eTadini

    2012-12-01

    Full Text Available Perturbations in organellar gene expression (OGE and the thylakoid redox state (TRS activate retrograde signalling pathways that adaptively modify nuclear gene expression (NGE, according to developmental and metabolic needs. The prors1-1 mutation in Arabidopsis down-regulates the expression of the nuclear gene Prolyl-tRNA Synthetase1 (PRORS1 which acts in both plastids and mitochondria, thereby impairing protein synthesis in both organelles and triggering OGE-dependent retrograde signalling. Because the mutation also affects thylakoid electron transport, TRS-dependent signals may likewise have an impact on the changes in NGE observed in this genotype. In this study, we have investigated whether signals related to TRS are actually integrated into the OGE-dependent retrograde signalling pathway. To this end, the chaos mutation (for chlorophyll a/b binding protein harvesting-organelle specific, which shows a partial loss of PSII antennae proteins and thus a reduction in PSII light absorption capability, was introduced into the prors1-1 mutant background. The resulting double mutant displayed a prors1-1-like reduction in plastid translation rate and a chaos-like decrease in PSII antenna size, whereas the hyper-reduction of the thylakoid electron transport chain, caused by the prors1-1 mutation, was alleviated, as determined by monitoring chlorophyll (Chl fluorescence and thylakoid phosphorylation. Interestingly, a substantial fraction of the nucleus-encoded photosynthesis genes down-regulated in the prors1-1 mutant are expressed at nearly wild-type rates in prors1-1 chaos leaves, and this recovery is reflected in the steady-state levels of their protein products in the chloroplast. We therefore conclude that signals related to photosynthetic electron transport and TRS, and indirectly to carbohydrate metabolism and energy balance, are indeed fed into the OGE-dependent retrograde pathway to modulate NGE and adjust the abundance of chloroplast proteins.

  13. Assuring SS7 dependability: A robustness characterization of signaling network elements

    Science.gov (United States)

    Karmarkar, Vikram V.

    1994-04-01

    Current and evolving telecommunication services will rely on signaling network performance and reliability properties to build competitive call and connection control mechanisms under increasing demands on flexibility without compromising on quality. The dimensions of signaling dependability most often evaluated are the Rate of Call Loss and End-to-End Route Unavailability. A third dimension of dependability that captures the concern about large or catastrophic failures can be termed Network Robustness. This paper is concerned with the dependability aspects of the evolving Signaling System No. 7 (SS7) networks and attempts to strike a balance between the probabilistic and deterministic measures that must be evaluated to accomplish a risk-trend assessment to drive architecture decisions. Starting with high-level network dependability objectives and field experience with SS7 in the U.S., potential areas of growing stringency in network element (NE) dependability are identified to improve against current measures of SS7 network quality, as per-call signaling interactions increase. A sensitivity analysis is presented to highlight the impact due to imperfect coverage of duplex network component or element failures (i.e., correlated failures), to assist in the setting of requirements on NE robustness. A benefit analysis, covering several dimensions of dependability, is used to generate the domain of solutions available to the network architect in terms of network and network element fault tolerance that may be specified to meet the desired signaling quality goals.

  14. Light field reconstruction robust to signal dependent noise

    Science.gov (United States)

    Ren, Kun; Bian, Liheng; Suo, Jinli; Dai, Qionghai

    2014-11-01

    Capturing four dimensional light field data sequentially using a coded aperture camera is an effective approach but suffers from low signal noise ratio. Although multiplexing can help raise the acquisition quality, noise is still a big issue especially for fast acquisition. To address this problem, this paper proposes a noise robust light field reconstruction method. Firstly, scene dependent noise model is studied and incorporated into the light field reconstruction framework. Then, we derive an optimization algorithm for the final reconstruction. We build a prototype by hacking an off-the-shelf camera for data capturing and prove the concept. The effectiveness of this method is validated with experiments on the real captured data.

  15. Filter frequency response of time dependent signal using Laplace transform

    Energy Technology Data Exchange (ETDEWEB)

    Shestakov, Aleksei I. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2018-01-16

    We analyze the effect a filter has on a time dependent signal x(t). If X(s) is the Laplace transform of x and H (s) is the filter Transfer function, the response in frequency space is X (s) H (s). Consequently, in real space, the response is the convolution (x*h) (t), where hi is the Laplace inverse of H. Effects are analyzed and analytically for functions such as (t/tc)2 e-t/t$_c$, where tc = const. We consider lowpass, highpass and bandpass filters.

  16. Association between increased EEG signal complexity and cannabis dependence.

    Science.gov (United States)

    Laprevote, Vincent; Bon, Laura; Krieg, Julien; Schwitzer, Thomas; Bourion-Bedes, Stéphanie; Maillard, Louis; Schwan, Raymund

    2017-12-01

    Both acute and regular cannabis use affects the functioning of the brain. While several studies have demonstrated that regular cannabis use can impair the capacity to synchronize neural assemblies during specific tasks, less is known about spontaneous brain activity. This can be explored by measuring EEG complexity, which reflects the spontaneous variability of human brain activity. A recent study has shown that acute cannabis use can affect that complexity. Since the characteristics of cannabis use can affect the impact on brain functioning, this study sets out to measure EEG complexity in regular cannabis users with or without dependence, in comparison with healthy controls. We recruited 26 healthy controls, 25 cannabis users without cannabis dependence and 14 cannabis users with cannabis dependence, based on DSM IV TR criteria. The EEG signal was extracted from at least 250 epochs of the 500ms pre-stimulation phase during a visual evoked potential paradigm. Brain complexity was estimated using Lempel-Ziv Complexity (LZC), which was compared across groups by non-parametric Kruskall-Wallis ANOVA. The analysis revealed a significant difference between the groups, with higher LZC in participants with cannabis dependence than in non-dependent cannabis users. There was no specific localization of this effect across electrodes. We showed that cannabis dependence is associated to an increased spontaneous brain complexity in regular users. This result is in line with previous results in acute cannabis users. It may reflect increased randomness of neural activity in cannabis dependence. Future studies should explore whether this effect is permanent or diminishes with cannabis cessation. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  17. Modelling of Signal - Level Crossing System

    Directory of Open Access Journals (Sweden)

    Daniel Novak

    2006-01-01

    Full Text Available The author presents an object-oriented model of a railway level-crossing system created for the purpose of functional requirements specification. Unified Modelling Language (UML, version 1.4, which enables specification, visualisation, construction and documentation of software system artefacts, was used. The main attention was paid to analysis and design phases. The former phase resulted in creation of use case diagrams and sequential diagrams, the latter in creation of class/object diagrams and statechart diagrams.

  18. Calcium-Dependent Protein Kinases in Phytohormone Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Wuwu Xu

    2017-11-01

    Full Text Available Calcium-dependent protein kinases (CPKs/CDPKs are Ca2+-sensors that decode Ca2+ signals into specific physiological responses. Research has reported that CDPKs constitute a large multigene family in various plant species, and play diverse roles in plant growth, development, and stress responses. Although numerous CDPKs have been exhaustively studied, and many of them have been found to be involved in plant hormone biosynthesis and response mechanisms, a comprehensive overview of the manner in which CDPKs participate in phytohormone signaling pathways, regulating nearly all aspects of plant growth, has not yet been undertaken. In this article, we reviewed the structure of CDPKs and the mechanism of their subcellular localization. Some CDPKs were elucidated to influence the intracellular localization of their substrates. Since little work has been done on the interaction between CDPKs and cytokinin signaling pathways, or on newly defined phytohormones such as brassinosteroids, strigolactones and salicylic acid, this paper mainly focused on discussing the integral associations between CDPKs and five plant hormones: auxins, gibberellins, ethylene, jasmonates, and abscisic acid. A perspective on future work is provided at the end.

  19. Distance-dependent pattern blending can camouflage salient aposematic signals.

    Science.gov (United States)

    Barnett, James B; Cuthill, Innes C; Scott-Samuel, Nicholas E

    2017-07-12

    The effect of viewing distance on the perception of visual texture is well known: spatial frequencies higher than the resolution limit of an observer's visual system will be summed and perceived as a single combined colour. In animal defensive colour patterns, distance-dependent pattern blending may allow aposematic patterns, salient at close range, to match the background to distant observers. Indeed, recent research has indicated that reducing the distance from which a salient signal can be detected can increase survival over camouflage or conspicuous aposematism alone. We investigated whether the spatial frequency of conspicuous and cryptically coloured stripes affects the rate of avian predation. Our results are consistent with pattern blending acting to camouflage salient aposematic signals effectively at a distance. Experiments into the relative rate of avian predation on edible model caterpillars found that increasing spatial frequency (thinner stripes) increased survival. Similarly, visual modelling of avian predators showed that pattern blending increased the similarity between caterpillar and background. These results show how a colour pattern can be tuned to reveal or conceal different information at different distances, and produce tangible survival benefits. © 2017 The Author(s).

  20. Delayed Dopamine Signaling of Energy Level Builds Appetitive Long-Term Memory in Drosophila

    OpenAIRE

    Pierre-Yves Musso; Paul Tchenio; Thomas Preat

    2015-01-01

    Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level t...

  1. Glycosynapses: microdomains controlling carbohydrate-dependent cell adhesion and signaling

    Directory of Open Access Journals (Sweden)

    Senitiroh Hakomori

    2004-09-01

    Full Text Available The concept of microdomains in plasma membranes was developed over two decades, following observation of polarity of membrane based on clustering of specific membrane components. Microdomains involved in carbohydrate-dependent cell adhesion with concurrent signal transduction that affect cellular phenotype are termed "glycosynapse". Three types of glycosynapse have been distinguished: "type 1" having glycosphingolipid associated with signal transducers (small G-proteins, cSrc, Src family kinases and proteolipids; "type 2" having O-linked mucin-type glycoprotein associated with Src family kinases; and "type 3" having N-linked integrin receptor complexed with tetraspanin and ganglioside. Different cell types are characterized by presence of specific types of glycosynapse or their combinations, whose adhesion induces signal transduction to either facilitate or inhibit signaling. E.g., signaling through type 3 glycosynapse inhibits cell motility and differentiation. Glycosynapses are distinct from classically-known microdomains termed "caveolae", "caveolar membrane", or more recently "lipid raft", which are not involved in carbohydrate-dependent cell adhesion. Type 1 and type 3 glycosynapses are resistant to cholesterol-binding reagents, whereas structure and function of "caveolar membrane" or "lipid raft" are disrupted by these reagents. Various data indicate a functional role of glycosynapses during differentiation, development, and oncogenic transformation.O conceito de microdomínios em membrana plasmática foi desenvolvido há mais de duas décadas, após a observação da polaridade da membrana baseada no agrupamento de componentes específicos da membrana. Microdomínios envolvidos na adesão celular dependente de carboidrato, com transdução de sinal que afeta o fenótipo celular são denominados ''glicosinapses''. Três tipos de glicosinapse foram observados: ''tipo 1'' que possue glicoesfingolipídio associado com transdutores de sinal

  2. Erythrocyte signal transduction pathways, their oxygenation dependence and functional significance.

    Science.gov (United States)

    Barvitenko, Nadezhda N; Adragna, Norma C; Weber, Roy E

    2005-01-01

    Erythrocytes play a key role in human and vertebrate metabolism. Tissue O2 supply is regulated by both hemoglobin (Hb)-O2 affinity and erythrocyte rheology, a key determinant of tissue perfusion. Oxygenation-deoxygenation transitions of Hb may lead to re-organization of the cytoskeleton and signalling pathways activation/deactivation in an O2-dependent manner. Deoxygenated Hb binds to the cytoplasmic domain of the anion exchanger band 3, which is anchored to the cytoskeleton, and is considered a major mechanism underlying the oxygenation-dependence of several erythrocyte functions. This work discusses the multiple modes of Hb-cytoskeleton interactions. In addition, it reviews the effects of Mg2+, 2,3-diphosphoglycerate, NO, shear stress and Ca2+, all factors accompanying the oxygenation-deoxygenation cycle in circulating red cells. Due to the extensive literature on the subject, the data discussed here, pertain mainly to human erythrocytes whose O2 affinity is modulated by 2,3-diphosphoglycerate, ectothermic vertebrate erythrocytes that use ATP, and to bird erythrocytes that use inositol pentaphosphate. Copyright 2005 S. Karger AG, Basel.

  3. Cell Size and Growth Rate Are Modulated by TORC2-Dependent Signals.

    Science.gov (United States)

    Lucena, Rafael; Alcaide-Gavilán, Maria; Schubert, Katherine; He, Maybo; Domnauer, Matthew G; Marquer, Catherine; Klose, Christian; Surma, Michal A; Kellogg, Douglas R

    2018-01-22

    The size of all cells, from bacteria to vertebrates, is proportional to the growth rate set by nutrient availability, but the underlying mechanisms are unknown. Here, we show that nutrients modulate cell size and growth rate via the TORC2 signaling network in budding yeast. An important function of the TORC2 network is to modulate synthesis of ceramide lipids, which play roles in signaling. TORC2-dependent control of ceramide signaling strongly influences both cell size and growth rate. Thus, cells that cannot make ceramides fail to modulate their growth rate or size in response to changes in nutrients. PP2A associated with the Rts1 regulatory subunit (PP2A Rts1 ) is embedded in a feedback loop that controls TORC2 signaling and helps set the level of TORC2 signaling to match nutrient availability. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Occupation number dependence of molecular energy levels

    International Nuclear Information System (INIS)

    Giambiagi, M.S. de; Giambiagi, M.; Ferreira, R.

    1977-08-01

    The Roothaan expression for the energy of a closed-shell molecular system is generalized in order to apply to open shells. A continuous variation from 0 to 2 is supposed for each level's occupation number, extending to this range tbe correction due to the spurious repulsion appearing in the half-electron method. The characteristic equations of the Xα method are applied to the energy expressions. The one level case is discussed in detail. Ionic and excited states of the 1,3 transbutadiene π system are analyzed

  5. Cardiac Effects of Attenuating Gsα - Dependent Signaling.

    Directory of Open Access Journals (Sweden)

    Marcus R Streit

    Full Text Available Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05 and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02. No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01 and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001. In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation.Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.

  6. Magnetic-field dependence of the signal of a uranium-scintillator calorimeter

    International Nuclear Information System (INIS)

    Bruehl, S.

    1991-11-01

    The magnetic-field dependence of the signal from 3 GeV electrons and the signal from the uranium radioactivity of a uranium-SCSN-38 test calorimeter was studied with the three in the ZEUS calorimeter implemented uranium-plate coatings 0.2 mm V2A, 0.4 mm V2A, and 0.2 mm V2A and 0.2 mm magnetic C10 in two field directions with fields between 0.01 and 1.4 tesla. In fields oriented parallel to the calorimeter axis uranium and particle signal behave equally except for the case, in which V2A and C10 are applied. At 0.01 tesla the particle signal varies by 1% and the uranium signal by 1.5%. Both signals remain up to 0.1 tesla on this level and increase from this magnetic field. The variation reaches at 1 tesla 4.5% for the particle and 6% for the uranium signal. In the application of V2A and C10 no variation of the particle signal is to be recognized within the errors, while the uranium signal increases monotoneously from 0 to 1.5%. In perpendicularly to the calorimeter axis oriented fields from ≅ 0.3 tesla a different development in the particle and uranium signal occurs. Up to this fields the behaviour of particle and uranium signal is identical with the behaviour in the other field direction. In the application of V2A and C10 the particle respectively the uranium signal increases from 0 at 0.01 tesla to 1% respectively 1.5% at 0.03 tesla. Thereafter the plateau up to 0.1 tesla with the subsequent increasement follows. Independently on the uranium-plate coating the increasement of the uranium signal decreases from 0.3 tesla, reaches at 0.5 tesla a maximum of 3 to 4% and decreases thereafter to 1% at 1 tesla. The particle signal increases as in the other field direction and reaches a signal variation of 7% at 1 tesla. The results are used in the regardment of the magnetic-field effects on the calibration of the ZEUS calorimeter. (orig.) [de

  7. Image restoration by Wiener filtering in the presence of signal-dependent noise.

    Science.gov (United States)

    Kondo, K; Ichioka, Y; Suzuki, T

    1977-09-01

    An optimum filter to restore the degraded image due to blurring and the signal-dependent noise is obtained on the basis of the theory of Wiener filtering. Computer simulations of image restoration using signal-dependent noise models are carried out. It becomes clear that the optimum filter, which makes use of a priori information on the signal-dependent nature of the noise and the spectral density of the signal and the noise showing significant spatial correlation, is potentially advantageous.

  8. Genetic variation of the ghrelin signaling system in females with severe alcohol dependence.

    Science.gov (United States)

    Landgren, Sara; Jerlhag, Elisabet; Hallman, Jarmila; Oreland, Lars; Lissner, Lauren; Strandhagen, Elisabeth; Thelle, Dag S; Zetterberg, Henrik; Blennow, Kaj; Engel, Jörgen A

    2010-09-01

    Central ghrelin signaling is required for the rewarding effects of alcohol in mice. Because ghrelin is implied in other addictive behaviors such as eating disorders and smoking, and because there is co-morbidity between these disorders and alcohol dependence, the ghrelin signaling system could be involved in mediating reward in general. Furthermore, in humans, single nucleotide polymorphisms (SNPs) and haplotypes of the pro-ghrelin gene (GHRL) and the ghrelin receptor gene (GHSR) have previously been associated with increased alcohol consumption and increased body weight. Known gender differences in plasma ghrelin levels prompted us to investigate genetic variation of the ghrelin signaling system in females with severe alcohol dependence (n = 113) and in a selected control sample of female low-consumers of alcohol from a large cohort study in southwest Sweden (n = 212). Six tag SNPs in the GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) and four tag SNPs in the GHSR (rs495225, rs2232165, rs572169, and rs2948694) were genotyped in all individuals. We found that one GHRL haplotype was associated with reports of paternal alcohol dependence as well as with reports of withdrawal symptoms in the female alcohol-dependent group. Associations with 2 GHSR haplotypes and smoking were also shown. One of these haplotypes was also negatively associated with BMI in controls, while another haplotype was associated with having the early-onset, more heredity-driven, type 2 form of alcohol dependence in the patient group. Taken together, the genes encoding the ghrelin signaling system cannot be regarded as major susceptibility genes for female alcohol dependence, but is, however, involved in paternal heritability and may affect other reward- and energy-related factors such as smoking and BMI.

  9. Brassinosteroid signaling-dependent root responses to prolonged elevated ambient temperature.

    Science.gov (United States)

    Martins, Sara; Montiel-Jorda, Alvaro; Cayrel, Anne; Huguet, Stéphanie; Roux, Christine Paysant-Le; Ljung, Karin; Vert, Grégory

    2017-08-21

    Due to their sessile nature, plants have to cope with and adjust to their fluctuating environment. Temperature elevation stimulates the growth of Arabidopsis aerial parts. This process is mediated by increased biosynthesis of the growth-promoting hormone auxin. How plant roots respond to elevated ambient temperature is however still elusive. Here we present strong evidence that temperature elevation impinges on brassinosteroid hormone signaling to alter root growth. We show that elevated temperature leads to increased root elongation, independently of auxin or factors known to drive temperature-mediated shoot growth. We further demonstrate that brassinosteroid signaling regulates root responses to elevated ambient temperature. Increased growth temperature specifically impacts on the level of the brassinosteroid receptor BRI1 to downregulate brassinosteroid signaling and mediate root elongation. Our results establish that BRI1 integrates temperature and brassinosteroid signaling to regulate root growth upon long-term changes in environmental conditions associated with global warming.Moderate heat stimulates the growth of Arabidopsis shoots in an auxin-dependent manner. Here, Martins et al. show that elevated ambient temperature modifies root growth by reducing the BRI1 brassinosteroid-receptor protein level and downregulating brassinosteroid signaling.

  10. Insulin-dependent signaling: regulation by amino acids and energy

    NARCIS (Netherlands)

    Meijer, A. J.

    2004-01-01

    Recent research has indicated that amino acids stimulate a signal-transduction pathway that is also used by insulin. Moreover, for insulin to exert its anabolic and anticatabolic effects on protein, there is an absolute requirement for amino acids. This signaling pathway becomes inhibited by

  11. Hydrogen peroxide induces activation of insulin signaling pathway via AMP-dependent kinase in podocytes

    International Nuclear Information System (INIS)

    Piwkowska, Agnieszka; Rogacka, Dorota; Angielski, Stefan; Jankowski, Maciej

    2012-01-01

    Highlights: ► H 2 O 2 activates the insulin signaling pathway and glucose uptake in podocytes. ► H 2 O 2 induces time-dependent changes in AMPK phosphorylation. ► H 2 O 2 enhances insulin signaling pathways via AMPK activation. ► H 2 O 2 stimulation of glucose uptake is AMPK-dependent. -- Abstract: Podocytes are cells that form the glomerular filtration barrier in the kidney. Insulin signaling in podocytes is critical for normal kidney function. Insulin signaling is regulated by oxidative stress and intracellular energy levels. We cultured rat podocytes to investigate the effects of hydrogen peroxide (H 2 O 2 ) on the phosphorylation of proximal and distal elements of insulin signaling. We also investigated H 2 O 2 -induced intracellular changes in the distribution of protein kinase B (Akt). Western blots showed that H 2 O 2 (100 μM) induced rapid, transient phosphorylation of the insulin receptor (IR), the IR substrate-1 (IRS1), and Akt with peak activities at 5 min (Δ 183%, P 2 O 2 >. Furthermore, H 2 O 2 inhibited phosphorylation of the phosphatase and tensin homologue (PTEN; peak activity at 10 min; Δ −32%, P 2 O 2 on IR phosphorylation by about 40% (from 2.07 ± 0.28 to 1.28 ± 0.12, P 2 O 2 increased glucose uptake in podocytes (from 0.88 ± 0.04 to 1.29 ± 0.12 nmol/min/mg protein, P 2 O 2 activated the insulin signaling pathway and glucose uptake via AMPK in cultured rat podocytes. This signaling may play a potential role in the prevention of insulin resistance under conditions associated with oxidative stress.

  12. A Real-Time Rejection Circuit to Automatically Reject Multiple Interfering Hopping Signals While Passing a Lower Level Desired Signal.

    Science.gov (United States)

    contain the low level desired frequency components that are passed through an inverse transform device for producing a frequency domain signal of the desired signal uncorrupted by unwanted signals. Patent applications. (RRH)

  13. Mean level signal crossing rate for an arbitrary stochastic process

    DEFF Research Database (Denmark)

    Yura, Harold T.; Hanson, Steen Grüner

    2010-01-01

    The issue of the mean signal level crossing rate for various probability density functions with primary relevance for optics is discussed based on a new analytical method. This method relies on a unique transformation that transforms the probability distribution under investigation into a normal...... probability distribution, for which the distribution of mean level crossings is known. In general, the analytical results for the mean level crossing rate are supported and confirmed by numerical simulations. In particular, we illustrate the present method by presenting analytic expressions for the mean level...

  14. Light Signaling-Dependent Regulation of Photoinhibition and Photoprotection in Tomato.

    Science.gov (United States)

    Wang, Feng; Wu, Nan; Zhang, Luyue; Ahammed, Golam Jalal; Chen, Xiaoxiao; Xiang, Xun; Zhou, Jie; Xia, Xiaojian; Shi, Kai; Yu, Jingquan; Foyer, Christine H; Zhou, Yanhong

    2018-02-01

    Photoreceptor-mediated light signaling plays a critical role in plant growth, development, and stress responses but its contribution to the spatial regulation of photoinhibition and photoprotection within the canopy remains unclear. Here, we show that low-red/far-red ( L - R / FR ) ratio light conditions significantly alleviate PSII and PSI photoinhibition in the shade leaves of tomato ( Solanum lycopersicum ) plants. This protection is accompanied by a phytochrome A-dependent induction of LONG HYPOCOTYL5 (HY5). HY5 binds to the promoter of ABA INSENSITIVE 5 ( ABI5 ), triggering RESPIRATORY BURST OXIDASE HOMOLOG1 ( RBOH1 )-dependent H 2 O 2 production in the apoplast. Decreased levels of HY5 , ABI5 , and RBOH1 transcripts increased cold-induced photoinhibition and abolished L - R / FR -induced alleviation of photoinhibition. L - R / FR illumination induced nonphotochemical quenching (NPQ) of chlorophyll a fluorescence and increased the activities of Foyer-Halliwell-Asada cycle enzymes and cyclic electron flux (CEF) around PSI. In contrast, decreased HY5 , ABI5 , and RBOH1 transcript levels abolished the positive effect of L - R / FR on photoprotection. Loss of PROTON GRADIENT REGULATION5 -dependent CEF led to increased photoinhibition and attenuated L - R / FR -dependent NPQ. These data demonstrate that HY5 is an important hub in the cross talk between light and cold response pathways, integrating ABA and reactive oxygen species signaling, leading to the attenuation of photoinhibition by enhanced induction of photoprotection in shade leaves. © 2018 American Society of Plant Biologists. All Rights Reserved.

  15. Time-dependent patterning of the mesoderm and endoderm by Nodal signals in zebrafish

    Directory of Open Access Journals (Sweden)

    Dougan Scott T

    2007-03-01

    Full Text Available Abstract Background The vertebrate body plan is generated during gastrulation with the formation of the three germ layers. Members of the Nodal-related subclass of the TGF-β superfamily induce and pattern the mesoderm and endoderm in all vertebrates. In zebrafish, two nodal-related genes, called squint and cyclops, are required in a dosage-dependent manner for the formation of all derivatives of the mesoderm and endoderm. These genes are expressed dynamically during the blastula stages and may have different roles at different times. This question has been difficult to address because conditions that alter the timing of nodal-related gene expression also change Nodal levels. We utilized a pharmacological approach to conditionally inactivate the ALK 4, 5 and 7 receptors during the blastula stages without disturbing earlier signaling activity. This permitted us to directly examine when Nodal signals specify cell types independently of dosage effects. Results We show that two drugs, SB-431542 and SB-505124, completely block the response to Nodal signals when added to embryos after the mid-blastula transition. By blocking Nodal receptor activity at later stages, we demonstrate that Nodal signaling is required from the mid-to-late blastula period to specify sequentially, the somites, notochord, blood, Kupffer's vesicle, hatching gland, heart, and endoderm. Blocking Nodal signaling at late times prevents specification of cell types derived from the embryo margin, but not those from more animal regions. This suggests a linkage between cell fate and length of exposure to Nodal signals. Confirming this, cells exposed to a uniform Nodal dose adopt progressively more marginal fates with increasing lengths of exposure. Finally, cell fate specification is delayed in squint mutants and accelerated when Nodal levels are elevated. Conclusion We conclude that (1 Nodal signals are most active during the mid-to-late blastula stages, when nodal-related gene

  16. Exponential signaling gain at the receptor level enhances signal-to-noise ratio in bacterial chemotaxis.

    Directory of Open Access Journals (Sweden)

    Silke Neumann

    Full Text Available Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly designed signaling architectures. Here, we report on a novel control mechanism that allows living cells to keep precision in their signaling characteristics - stationary pathway output, response amplitude, and relaxation time - in the presence of strong intracellular perturbations. The concept relies on the surprising fact that for systems showing perfect adaptation an exponential signal amplification at the receptor level suffices to eliminate slowly varying multiplicative noise. To show this mechanism at work in living systems, we quantified the response dynamics of the E. coli chemotaxis network after genetically perturbing the information flux between upstream and downstream signaling components. We give strong evidence that this signaling system results in dynamic invariance of the activated response regulator against multiplicative intracellular noise. We further demonstrate that for environmental conditions, for which precision in chemosensing is crucial, the invariant response behavior results in highest chemotactic efficiency. Our results resolve several puzzling features of the chemotaxis pathway that are widely conserved across prokaryotes but so far could not be attributed any functional role.

  17. Evidence for some signal transduction elements involved in UV-light-dependent responses in parsley protoplasts

    International Nuclear Information System (INIS)

    Frohnmeyer, H.; Bowler, C.; Schäfer, E.

    1997-01-01

    The signalling pathways used by UV-light are largely unknown. Using protoplasts from a heterotrophic parsley (Petroselinum crispum L.) cell culture that exclusively respond to UV-B light between 300 and 350 nm with a fast induction of genes encoding flavonoid biosynthetic enzymes, information was obtained about the UV-light signal transduction pathway for chalcone synthase (CHS) and phenylalanine ammonia-lyase (PAL) gene expression. Pharmacological effectors which influence intracellular calcium levels, calmodulin and the activity of serine/threonine kinases also changed the UV-light-dependent expression of these genes. This evaluation indicated the participation of these components on the UV-B-mediated signal transduction cascade to CHS. In contrast, neither membrane-permeable cyclic GMP nor the tyrosine kinase inhibitor genistein affected CHS or PAL expression. Similar results were obtained in protoplasts, which have been transiently transformed with CHS-promoter/GUS (β-glucuronidase) reporter fusion constructs. The involvement of calcium and calmodulin was further indicated in a cell-free light-responsive in vitro transcription system from evacuolated parsley protoplasts. In conclusion, there is evidence now that components of the UV-light-dependent pathway leading to the CHS-promoter are different from the previously characterized cGMP-dependent pathway to CHS utilized by phytochrome in soybean (Glycine max) and tomato seedlings (Lycopersicon esculentum). (author)

  18. Influence of Drive Level on the Fundamental Vibrator Signal

    OpenAIRE

    Noorlandt, R.P.; Drijkoningen, G.G.; Faber, C.A.M.

    2013-01-01

    In this abstract we show the influence of vibrator drive level on the signal it produces. For that purpose a field survey was carried out using an INOVA's AHV-IV vehicle with a modified 266kN (60.000 lbf) vibrator. A single linear sweep was repeated at 10 different drive levels ranging from 5 to 90% at two locations. Each drive level was repeated 10 times and each run was repeated twice per location. In total 400 sweeps were carried out. From this data set we conclude that; the vibrator signa...

  19. Presenilin dependence of phospholipase C and protein kinase C signaling

    DEFF Research Database (Denmark)

    Dehvari, Nodi; Cedazo-Minguez, Angel; Isacsson, Ola

    2007-01-01

    -stimulated phospholipase C (PLC) activity which was gamma-secretase dependent. To further evaluate the dependence of PLC on PSs we measured PLC activity and the activation of variant protein kinase C (PKC) isoforms in mouse embryonic fibroblasts (MEFs) lacking either PS1, PS2, or both. PLC activity and PKCalpha...

  20. Identification and quantitation of signal molecule-dependent protein phosphorylation

    KAUST Repository

    Groen, Arnoud J.; Thomas, Ludivine; Lilley, Kathryn S.; Marondedze, Claudius

    2013-01-01

    in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through

  1. Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets.

    Science.gov (United States)

    Keeler, Austin B; Suo, Dong; Park, Juyeon; Deppmann, Christopher D

    2017-07-01

    Postganglionic sympathetic neurons detect vascular derived neurotrophin 3 (NT3) via the axonally expressed receptor tyrosine kinase, TrkA, to promote chemo-attraction along intermediate targets. Once axons arrive to their final target, a structurally related neurotrophic factor, nerve growth factor (NGF), also acts through TrkA to promote final target innervation. Does TrkA signal differently at these different locales? We previously found that Coronin-1 is upregulated in sympathetic neurons upon exposure to NGF, thereby endowing the NGF-TrkA complex with new signaling capabilities (i.e. calcium signaling), which dampens axon growth and branching. Based on the notion that axons do not express functional levels of Coronin-1 prior to final target innervation, we developed an in vitro model for axon growth and branching along intermediate targets using Coro1a -/- neurons grown in NT3. We found that, similar to NGF-TrkA, NT3-TrkA is capable of inducing MAPK and PI3K in the presence or absence of Coronin-1. However, unlike NGF, NT3 does not induce calcium release from intracellular stores. Using a combination of pharmacology, knockout neurons and in vitro functional assays, we suggest that the NT3-TrkA complex uses Ras/MAPK and/or PI3K-AKT signaling to induce axon growth and inhibit axon branching along intermediate targets. However, in the presence of Coronin-1, these signaling pathways lose their ability to impact NT3 dependent axon growth or branching. This is consistent with a role for Coronin-1 as a molecular switch for axon behavior and suggests that Coronin-1 suppresses NT3 dependent axon behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Delayed Dopamine Signaling of Energy Level Builds Appetitive Long-Term Memory in Drosophila

    Directory of Open Access Journals (Sweden)

    Pierre-Yves Musso

    2015-02-01

    Full Text Available Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level that the activity of two pairs of dopaminergic neurons is necessary and sufficient to signal energy level to the olfactory memory center. Accordingly, we have identified in these dopaminergic neurons a delayed calcium trace that correlates with appetitive long-term memory formation. Altogether, these findings demonstrate that the Drosophila brain remembers food quality through a two-step mechanism that consists of the integration of olfactory and gustatory sensory information and then post-ingestion energetic value.

  3. Opposing effects of oxidative challenge and carotenoids on antioxidant status and condition-dependent sexual signalling.

    Science.gov (United States)

    Tomášek, Oldřich; Gabrielová, Barbora; Kačer, Petr; Maršík, Petr; Svobodová, Jana; Syslová, Kamila; Vinkler, Michal; Albrecht, Tomáš

    2016-03-22

    Several recent hypotheses consider oxidative stress to be a primary constraint ensuring honesty of condition-dependent carotenoid-based signalling. The key testable difference between these hypotheses is the assumed importance of carotenoids for redox homeostasis, with carotenoids being either antioxidant, pro-oxidant or unimportant. We tested the role of carotenoids in redox balance and sexual signalling by exposing adult male zebra finches (Taeniopygia guttata) to oxidative challenge (diquat dibromide) and manipulating carotenoid intake. As the current controversy over the importance of carotenoids as antioxidants could stem from the hydrophilic basis of commonly-used antioxidant assays, we used the novel measure of in vivo lipophilic antioxidant capacity. Oxidative challenge reduced beak pigmentation but elicited an increase in antioxidant capacity suggesting resource reallocation from signalling to redox homeostasis. Carotenoids counteracted the effect of oxidative challenge on lipophilic (but not hydrophilic) antioxidant capacity, thereby supporting carotenoid antioxidant function in vivo. This is inconsistent with hypotheses proposing that signalling honesty is maintained through either ROS-induced carotenoid degradation or the pro-oxidant effect of high levels of carotenoid-cleavage products acting as a physiological handicap. Our data further suggest that assessment of lipophilic antioxidant capacity is necessary to fully understand the role of redox processes in ecology and evolution.

  4. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

    Science.gov (United States)

    Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

    2016-01-01

    Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

  5. Inhibition of Drp-1 dependent mitochondrial fission augments alcohol-induced cardiotoxicity via dysregulated Akt signaling

    Directory of Open Access Journals (Sweden)

    Anusha Sivakumar

    2017-10-01

    Full Text Available Cardiovascular disorders (CVDs still claim high mortality in spite of advancements in prognosis and treatment strategies. Alcohol is one of the most commonly consumed drugs globally and chronic/binge consumption (BAC 0.08 g/dL in 2 hours is a risk factor for CVDs. However, the aetiology and pathophysiological mechanisms of alcohol induced cardiotoxicity are still poorly understood. Mitochondria are the prime site for the ATP demands of the heart and also ethanol metabolism. These subcellular organelles depict dynamic fusion and fission events that are vital for structure and functional integrity. While fused mitochondrial improve ATP production and cell survival, increased fragmentation can be the cause or result of apoptosis. In this study, we proposed to analyze the mechanism of mitochondrial fission protein Drp-1-dependent apoptosis during alcohol toxicity. Male Wistar rats (220-250 kg body weight were given isocaloric sucrose or ethanol for 45 days, orally, via drinking water and intermittent gavage twice a week. Histopathological examination of the heart displayed hypertrophy with mild inflammation. Drp-1 immunoblotting showed over-expression of the protein during ethanol treatment. We next hypothesized that inhibiting Drp-1 could attenuate alcohol-induced cardiotoxicity. Interestingly, silencing Drp-1 with siRNA in-vitro augmented cytotoxicity. Also, crude mitochondrial fraction showed increased Bak aggregation, reduced cytochrome c release but increased SMAC/DIABLO. We analyzed the Akt cell survival signaling and found that PTEN showed over-expression at both transcriptional and translational level with no significant change in total Akt but down-regulation of p-Akt (Ser473. In conclusion, we have shown that inhibition of Drp-1 dependent mitochondrial fission is not cardioprotective against alcohol-induced apoptotic signaling and augments the cytotoxicity. To our knowledge, this study is the first to interlink cell survival AKT signaling

  6. Quantification, modelling and design for signal history dependent effects in mixed-signal SOI/SOS circuits

    International Nuclear Information System (INIS)

    Edwards, C.F.; Redman-White, W.; Bracey, M.; Tenbroek, B.M.; Lee, M.S.; Uren, M.J.; Brunson, K.M.

    1999-01-01

    This paper deals with how the radiation hardness of mixed signal SOI/SOS CMOS circuits is taken into account at both architectural terms as well as the the transistor level cell designs. The primary issue is to deal with divergent transistor threshold shifts, and to understand the effects of large amplitude non stationary signals on analogue cell behaviour. (authors)

  7. Study of nuclear level density parameter and its temperature dependence

    International Nuclear Information System (INIS)

    Nasrabadi, M. N.; Behkami, A. N.

    2000-01-01

    The nuclear level density ρ is the basic ingredient required for theoretical studies of nuclear reaction and structure. It describes the statistical nuclear properties and is expressed as a function of various constants of motion such as number of particles, excitation energy and angular momentum. In this work the energy and spin dependence of nuclear level density will be presented and discussed. In addition the level density parameter α will be extracted from this level density information, and its temperature and mass dependence will be obtained

  8. Nox2-dependent ROS signaling protects against skeletal ageing

    Science.gov (United States)

    Bone remodeling is age-dependently regulated and changes dramatically during the course of development. Progressive accumulation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, has been suspected to be the leading cause of many inflammatory and degen...

  9. Evaluation of diagnostic thresholds dependability for tribologic signals received in the environment disturbed by vibroacoustic and functional signals

    Directory of Open Access Journals (Sweden)

    Lindstedt Paweł

    2015-12-01

    Full Text Available Determination of dependable diagnostic thresholds for tribologic signals received e.g. from antifriction bearings (in particular for insufficient number of measurements, only 4÷5 is a really difficult task due to complexity of working environment where such bearings are operated. Typical working environment for such objects must take account for operation time under various working conditions and accompanying (and disturbing signals, e.g. vibroacoustic ones. The sought assessment of the relationship between diagnostic signals and environmental noise can be determined from convolution of both diagnostic and environments signals that make up the complete set of received information. The convolution of these two series of signals can be obtained from an algorithm based on the Cauchy product. Then one has to find the coherence factor and the square of amplitude gain for the set of diagnostic signals with reference to various sets of signals received from environment, which makes it possible to evaluate cohesion of the investigated series of signals, thus their suitability to determine diagnostic threshold for tribologic signals intended for the analysis.

  10. Identification and quantitation of signal molecule-dependent protein phosphorylation

    KAUST Repository

    Groen, Arnoud J.

    2013-09-03

    Phosphoproteomics is a fast-growing field that aims at characterizing phosphorylated proteins in a cell or a tissue at a given time. Phosphorylation of proteins is an important regulatory mechanism in many cellular processes. Gel-free phosphoproteome technique involving enrichment of phosphopeptide coupled with mass spectrometry has proven to be invaluable to detect and characterize phosphorylated proteins. In this chapter, a gel-free quantitative approach involving 15N metabolic labelling in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through the identification and quantification of responsive phospho(proteins). © Springer Science+Business Media New York 2013.

  11. Photonic microwave signals with zeptosecond-level absolute timing noise

    Science.gov (United States)

    Xie, Xiaopeng; Bouchand, Romain; Nicolodi, Daniele; Giunta, Michele; Hänsel, Wolfgang; Lezius, Matthias; Joshi, Abhay; Datta, Shubhashish; Alexandre, Christophe; Lours, Michel; Tremblin, Pierre-Alain; Santarelli, Giorgio; Holzwarth, Ronald; Le Coq, Yann

    2017-01-01

    Photonic synthesis of radiofrequency (RF) waveforms revived the quest for unrivalled microwave purity because of its ability to convey the benefits of optics to the microwave world. In this work, we perform a high-fidelity transfer of frequency stability between an optical reference and a microwave signal via a low-noise fibre-based frequency comb and cutting-edge photodetection techniques. We demonstrate the generation of the purest microwave signal with a fractional frequency stability below 6.5 × 10-16 at 1 s and a timing noise floor below 41 zs Hz-1/2 (phase noise below -173 dBc Hz-1 for a 12 GHz carrier). This outperforms existing sources and promises a new era for state-of-the-art microwave generation. The characterization is achieved through a heterodyne cross-correlation scheme with the lowermost detection noise. This unprecedented level of purity can impact domains such as radar systems, telecommunications and time-frequency metrology. The measurement methods developed here can benefit the characterization of a broad range of signals.

  12. The plant natriuretic peptide receptor is a guanylyl cyclase and enables cGMP-dependent signaling

    KAUST Repository

    Turek, Ilona

    2016-03-05

    The functional homologues of vertebrate natriuretic peptides (NPs), the plant natriuretic peptides (PNPs), are a novel class of peptidic hormones that signal via guanosine 3′,5′-cyclic monophosphate (cGMP) and systemically affect plant salt and water balance and responses to biotrophic plant pathogens. Although there is increasing understanding of the complex roles of PNPs in plant responses at the systems level, little is known about the underlying signaling mechanisms. Here we report isolation and identification of a novel Leucine-Rich Repeat (LRR) protein that directly interacts with A. thaliana PNP, AtPNP-A. In vitro binding studies revealed that the Arabidopsis AtPNP-A binds specifically to the LRR protein, termed AtPNP-R1, and the active region of AtPNP-A is sufficient for the interaction to occur. Importantly, the cytosolic part of the AtPNP-R1, much like in some vertebrate NP receptors, harbors a catalytic center diagnostic for guanylyl cyclases and the recombinant AtPNP-R1 is capable of catalyzing the conversion of guanosine triphosphate to cGMP. In addition, we show that AtPNP-A causes rapid increases of cGMP levels in wild type (WT) leaf tissue while this response is significantly reduced in the atpnp-r1 mutants. AtPNP-A also causes cGMP-dependent net water uptake into WT protoplasts, and hence volume increases, whereas responses of the protoplasts from the receptor mutant are impaired. Taken together, our results suggest that the identified LRR protein is an AtPNP-A receptor essential for the PNP-dependent regulation of ion and water homeostasis in plants and that PNP- and vertebrate NP-receptors and their signaling mechanisms share surprising similarities. © 2016 Springer Science+Business Media Dordrecht

  13. Spectral analysis of highly aliased sea-level signals

    Science.gov (United States)

    Ray, Richard D.

    1998-10-01

    Observing high-wavenumber ocean phenomena with a satellite altimeter generally calls for "along-track" analyses of the data: measurements along a repeating satellite ground track are analyzed in a point-by-point fashion, as opposed to spatially averaging data over multiple tracks. The sea-level aliasing problems encountered in such analyses can be especially challenging. For TOPEX/POSEIDON, all signals with frequency greater than 18 cycles per year (cpy), including both tidal and subdiurnal signals, are folded into the 0-18 cpy band. Because the tidal bands are wider than 18 cpy, residual tidal cusp energy, plus any subdiurnal energy, is capable of corrupting any low-frequency signal of interest. The practical consequences of this are explored here by using real sea-level measurements from conventional tide gauges, for which the true oceanographic spectrum is known and to which a simulated "satellite-measured" spectrum, based on coarsely subsampled data, may be compared. At many locations the spectrum is sufficently red that interannual frequencies remain unaffected. Intra-annual frequencies, however, must be interpreted with greater caution, and even interannual frequencies can be corrupted if the spectrum is flat. The results also suggest that whenever tides must be estimated directly from the altimetry, response methods of analysis are preferable to harmonic methods, even in nonlinear regimes; this will remain so for the foreseeable future. We concentrate on three example tide gauges: two coastal stations on the Malay Peninsula where the closely aliased K1 and Ssa tides are strong and at Canton Island where trapped equatorial waves are aliased.

  14. The levels of triglyceride and total cholesterol in methamphetamine dependence.

    Science.gov (United States)

    Zhang, Meijuan; Lv, Dezhao; Zhou, Wu; Ji, Lili; Zhou, Beibei; Chen, Han; Gu, Yingying; Zhao, Jiyun; He, Jincai

    2017-04-01

    The serum triglyceride (TG) and total cholesterol (TC) levels have been reported altered in the traditional drug-dependence (such as marijuana and heroin). However, studies assessing the relationships among serum TC, TG, and methamphetamine (MA)-dependence have not been described well. In this study, our aim is to explore the serum TG and TC levels in large sample of MA-dependent patients. A retrospective study was conducted in 938 MA-dependent patients who were recruited between February 2, 2008 and March 11, 2013, with social characteristics and drug-dependence history (duration of MA use, routes of drug administration, and daily dose were collected). Then, the serum levels of TC, TG, glucose (GLU), body mass index (BMI), and blood pressure were measured among the participants. Meanwhile, 985 age- and gender-matched healthy people in the physical examination center were selected as control group. Compared with the control group, significant decreases of TC, TG, GLU, and BMI were observed in MA-dependent patients (P < 0.05). Besides, we found that the daily dose of MA use was associated with TC (β = -0.079, P = 0.015) and the duration of MA use was independently related to BMI (β = -0.071, P = 0.031). This study demonstrated that the levels of TC, TG, GLU, and BMI factors altered in the MA-dependent patients. In addition, there is a negative association between MA dependence and TC and BMI.

  15. Estrogen signalling and the DNA damage response in hormone dependent breast cancers

    Directory of Open Access Journals (Sweden)

    C Elizabeth Caldon

    2014-05-01

    Full Text Available Estrogen is necessary for the normal growth and development of breast tissue, but high levels of estrogen are a major risk factor for breast cancer. One mechanism by which estrogen could contribute to breast cancer is via the induction of DNA damage. This perspective discusses the mechanisms by which estrogen alters the DNA damage response (DDR and DNA repair through the regulation of key effector proteins including ATM, ATR, CHK1, BRCA1 and p53 and the feedback on estrogen receptor signalling from these proteins. We put forward the hypothesis that estrogen receptor signalling converges to suppress effective DNA repair and apoptosis in favour of proliferation. This is important in hormone-dependent breast cancer as it will affect processing of estrogen-induced DNA damage, as well as other genotoxic insults. DDR and DNA repair proteins are frequently mutated or altered in estrogen responsive breast cancer which will further change the processing of DNA damage. Finally the action of estrogen signalling on DNA damage is also relevant to the therapeutic setting as the suppression of a DNA damage response by estrogen has the potential to alter the response of cancers to anti-hormone treatment or chemotherapy that induces DNA damage.

  16. Dynamics of Phosphoinositide-Dependent Signaling in Sympathetic Neurons

    OpenAIRE

    Kruse, Martin; Vivas, Oscar; Traynor-Kaplan, Alexis; Hille, Bertil

    2016-01-01

    In neurons, loss of plasma membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] leads to a decrease in exocytosis and changes in electrical excitability. Restoration of PI(4,5)P2 levels after phospholipase C activation is therefore essential for a return to basal neuronal activity. However, the dynamics of phosphoinositide metabolism have not been analyzed in neurons. We measured dynamic changes of PI(4,5)P2, phosphatidylinositol 4-phosphate, diacylglycerol, inositol 1,4,5-trisphosphate...

  17. Protein Kinase C alpha (PKCα) dependent signaling mediates endometrial cancer cell growth and tumorigenesis

    Science.gov (United States)

    Haughian, James M.; Reno, Elaine M.; Thorne, Alicia M.; Bradford, Andrew P.

    2009-01-01

    Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCα, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCα protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCα knockdown increased levels of the cyclin dependent kinase (CDK) inhibitors p21Cip1/WAF1 (p21) and p27Kip1 (p27). Despite the absence of functional phosphatase and tensin homologue (PTEN) protein in Ishikawa cells, PKCα knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3β (GSK-3β). PKCα knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting PKCα regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of grade 1 endometrioid adenocarcinoma revealed aberrant PKCα expression, with foci of elevated PKCα staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCα signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK dependent proliferative pathways. Thus, targeting PKCα may provide novel therapeutic options in endometrial tumors. PMID:19672862

  18. Frequency dependence of the pump-to-signal RIN transfer in fiber optical parametric amplifiers

    DEFF Research Database (Denmark)

    Pakarzadeh Dezfuli Nezhad, Hassan; Rottwitt, Karsten; Zakery, A.

    2009-01-01

    Using a numerical model, the frequency dependence of the pump-to-signal RIN transfer in FOPAs has been investigated. The model includes fiber loss, pump depletion as well as difference in group velocity among interacting beams.......Using a numerical model, the frequency dependence of the pump-to-signal RIN transfer in FOPAs has been investigated. The model includes fiber loss, pump depletion as well as difference in group velocity among interacting beams....

  19. Signalling in international environmental agreements. Using pre-agreement emission level as a signalling device

    Energy Technology Data Exchange (ETDEWEB)

    Steiner, U.

    1997-12-31

    This paper addresses the question about strategic incentives in international environmental agreements and tries to give a positive description of how the design of the agreement influences the strategic behaviour of potential participants before they enter the treaty. A common feature of the design of agreements is that the reduction obligations (RO) are made contingent on a pre-agreement or baseline emission. As it is assumed that countries posses better information about their reduction costs than does the international body in charge of deciding the RO, countries might have incentives to signal higher costs by increasing their baseline emission, and thereby reducing the costs of entering the agreement. The appropriate analytical framework is to use a signalling game approach, where the pre-agreement emission level conveys information about the privately informed country`s reduction cost. In this paper two types of agreement design are considered, one with uniform obligations, and one with differentiated obligations. This enables us to make a comparison between two different reduction regimes. The result is that the predicted outcomes vary with regard to both the environmental effectiveness and the associated expected costs for the participating countries. This means that when private information is considered, the anticipation of a given institutional framework has significant impact on the resulting distortion of the total emission level, highlighting the necessity of taking this into consideration when future designs are proposed. (au)

  20. Signalling in international environmental agreements: Using pre-agreement emission level as a signalling device

    International Nuclear Information System (INIS)

    Steiner, U.

    1997-01-01

    This paper addresses the question about strategic incentives in international environmental agreements and tries to give a positive description of how the design of the agreement influences the strategic behaviour of potential participants before they enter the treaty. A common feature of the design of agreements is that the reduction obligations (RO) are made contingent on a pre-agreement or baseline emission. As it is assumed that countries posses better information about their reduction costs than does the international body in charge of deciding the RO, countries might have incentives to signal higher costs by increasing their baseline emission, and thereby reducing the costs of entering the agreement. The appropriate analytical framework is to use a signalling game approach, where the pre-agreement emission level conveys information about the privately informed country's reduction cost. In this paper two types of agreement design are considered, one with uniform obligations, and one with differentiated obligations. This enables us to make a comparison between two different reduction regimes. The result is that the predicted outcomes vary with regard to both the environmental effectiveness and the associated expected costs for the participating countries. This means that when private information is considered, the anticipation of a given institutional framework has significant impact on the resulting distortion of the total emission level, highlighting the necessity of taking this into consideration when future designs are proposed. (au)

  1. Masking functions and fixed-signal functions for low-level 1000-Hz tones.

    Science.gov (United States)

    Shepherd, Daniel; Hautus, Michael J; Jesteadt, Walt

    2013-06-01

    Masking functions and fixed-signal functions were constructed using a narrow range of pedestal intensities for 10-ms, 1000-Hz gated tones. Data from three experiments agreed with previously reported data, clearly demonstrating negative masking and the pedestal effect. The data extend earlier findings by showing (1) the resilience of the pedestal effect when a background noise masker is introduced; (2) a possible indifference of the fixed-signal function to stimulus duration; (3) the ability of a set of psychometric functions to produce both masking and fixed-signal functions; (4) depending on method, the impact of unit choice on the interpretation of both the pedestal effect and negative masking data. Results are discussed in relation to current psychophysical models, and suggest that accounting for the auditory system's sensitivity to differences in low-level sounds remains a challenge.

  2. Evaluating nicotine dependence levels in e-cigarette users.

    Science.gov (United States)

    González Roz, Alba; Secades Villa, Roberto; Weidberg, Sara

    2017-01-11

    Despite the fact that electronic cigarettes (e-cigarettes) are rapidly growing in popularity and use worldwide, there is scarce scientific data on abuse liability among e-cigarette users, and about whether e-cigarette use is related to nicotine dependence or not. The aim of this study is to explore nicotine dependence levels in a sample of experienced e-cigarette users (n= 39) and to compare them with current tobacco cigarette smokers (n=42). We conducted several face-to-face interviews in order to assess sociodemographic and dependence related characteristics in both e-cigarette users and in smokers. Adapted versions of both the Fagerström test for nicotine dependence (FTND) and the nicotine dependence syndrome scale (NDSS) were used to analyze nicotine dependence in each of the groups. Biochemical markers of carbon monoxide and urinary cotinine analysis were also collected. Results showed that e-cigarette users scored lower than cigarette smokers in both FTND and all NDSS subscales. Our findings extend previous research on e-cigarette use and nicotine addiction and suggest that e-cigarette users are less dependent on nicotine than current tobacco cigarette smokers. Further prospective studies are needed to better ascertain their addictiveness potential, comparing those smokers who switched to e-cigarettes from smoking cigarettes, and those who had never been tobacco cigarette smokers.

  3. Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling

    DEFF Research Database (Denmark)

    Batth, Tanveer S; Papetti, Moreno; Pfeiffer, Anamarija

    2018-01-01

    Despite its low cellular abundance, phosphotyrosine (pTyr) regulates numerous cell signaling pathways in health and disease. We applied comprehensive phosphoproteomics to unravel differential regulators of receptor tyrosine kinase (RTK)-initiated signaling networks upon activation by Pdgf-ββ, Fgf-2...... of Pdgfr pTyr signaling. Application of a recently introduced allosteric Shp-2 inhibitor revealed global regulation of the Pdgf-dependent tyrosine phosphoproteome, which significantly impaired cell migration. In addition, we present a list of hundreds of Shp-2-dependent targets and putative substrates...

  4. Frequency-dependent tACS modulation of BOLD signal during rhythmic visual stimulation.

    Science.gov (United States)

    Chai, Yuhui; Sheng, Jingwei; Bandettini, Peter A; Gao, Jia-Hong

    2018-05-01

    Transcranial alternating current stimulation (tACS) has emerged as a promising tool for modulating cortical oscillations. In previous electroencephalogram (EEG) studies, tACS has been found to modulate brain oscillatory activity in a frequency-specific manner. However, the spatial distribution and hemodynamic response for this modulation remains poorly understood. Functional magnetic resonance imaging (fMRI) has the advantage of measuring neuronal activity in regions not only below the tACS electrodes but also across the whole brain with high spatial resolution. Here, we measured fMRI signal while applying tACS to modulate rhythmic visual activity. During fMRI acquisition, tACS at different frequencies (4, 8, 16, and 32 Hz) was applied along with visual flicker stimulation at 8 and 16 Hz. We analyzed the blood-oxygen-level-dependent (BOLD) signal difference between tACS-ON vs tACS-OFF, and different frequency combinations (e.g., 4 Hz tACS, 8 Hz flicker vs 8 Hz tACS, 8 Hz flicker). We observed significant tACS modulation effects on BOLD responses when the tACS frequency matched the visual flicker frequency or the second harmonic frequency. The main effects were predominantly seen in regions that were activated by the visual task and targeted by the tACS current distribution. These findings bridge different scientific domains of tACS research and demonstrate that fMRI could localize the tACS effect on stimulus-induced brain rhythms, which could lead to a new approach for understanding the high-level cognitive process shaped by the ongoing oscillatory signal. © 2018 Wiley Periodicals, Inc.

  5. Parity dependence of the nuclear level density at high excitation

    International Nuclear Information System (INIS)

    Rao, B.V.; Agrawal, H.M.

    1995-01-01

    The basic underlying assumption ρ(l+1, J)=ρ(l, J) in the level density function ρ(U, J, π) has been checked on the basis of high quality data available on individual resonance parameters (E 0 , Γ n , J π ) for s- and p-wave neutrons in contrast to the earlier analysis where information about p-wave resonance parameters was meagre. The missing level estimator based on the partial integration over a Porter-Thomas distribution of neutron reduced widths and the Dyson-Mehta Δ 3 statistic for the level spacing have been used to ascertain that the s- and p-wave resonance level spacings D(0) and D(1) are not in error because of spurious and missing levels. The present work does not validate the tacit assumption ρ(l+1, J)=ρ(l, J) and confirms that the level density depends upon parity at high excitation. The possible implications of the parity dependence of the level density on the results of statistical model calculations of nuclear reaction cross sections as well as on pre-compound emission have been emphasized. (orig.)

  6. Hydrogen peroxide induces activation of insulin signaling pathway via AMP-dependent kinase in podocytes

    Energy Technology Data Exchange (ETDEWEB)

    Piwkowska, Agnieszka, E-mail: apiwkowska@cmdik.pan.pl [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Rogacka, Dorota; Angielski, Stefan [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Jankowski, Maciej [Mossakowski Medical Research Centre, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Gdansk (Poland); Medical University of Gdansk, Department of Therapy Monitoring and Pharmacogenetics (Poland)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer H{sub 2}O{sub 2} activates the insulin signaling pathway and glucose uptake in podocytes. Black-Right-Pointing-Pointer H{sub 2}O{sub 2} induces time-dependent changes in AMPK phosphorylation. Black-Right-Pointing-Pointer H{sub 2}O{sub 2} enhances insulin signaling pathways via AMPK activation. Black-Right-Pointing-Pointer H{sub 2}O{sub 2} stimulation of glucose uptake is AMPK-dependent. -- Abstract: Podocytes are cells that form the glomerular filtration barrier in the kidney. Insulin signaling in podocytes is critical for normal kidney function. Insulin signaling is regulated by oxidative stress and intracellular energy levels. We cultured rat podocytes to investigate the effects of hydrogen peroxide (H{sub 2}O{sub 2}) on the phosphorylation of proximal and distal elements of insulin signaling. We also investigated H{sub 2}O{sub 2}-induced intracellular changes in the distribution of protein kinase B (Akt). Western blots showed that H{sub 2}O{sub 2} (100 {mu}M) induced rapid, transient phosphorylation of the insulin receptor (IR), the IR substrate-1 (IRS1), and Akt with peak activities at 5 min ({Delta} 183%, P < 0.05), 3 min ({Delta} 414%, P < 0.05), and 10 min ({Delta} 35%, P < 0.05), respectively. Immunostaining cells with an Akt-specific antibody showed increased intensity at the plasma membrane after treatment with H{sub 2}O{sub 2}>. Furthermore, H{sub 2}O{sub 2} inhibited phosphorylation of the phosphatase and tensin homologue (PTEN; peak activity at 10 min; {Delta} -32%, P < 0.05) and stimulated phosphorylation of the AMP-dependent kinase alpha subunit (AMPK{alpha}; 78% at 3 min and 244% at 10 min). The stimulation of AMPK was abolished with an AMPK inhibitor, Compound C (100 {mu}M, 2 h). Moreover, Compound C significantly reduced the effect of H{sub 2}O{sub 2} on IR phosphorylation by about 40% (from 2.07 {+-} 0.28 to 1.28 {+-} 0.12, P < 0.05). In addition, H{sub 2}O{sub 2} increased glucose uptake in podocytes

  7. Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

    Science.gov (United States)

    Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

    2017-07-01

    The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

    Science.gov (United States)

    Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

    2015-05-20

    Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

  9. Stability of the Filter Equation for a Time-Dependent Signal on Rd

    International Nuclear Information System (INIS)

    Stannat, Wilhelm

    2005-01-01

    Stability of the pathwise filter equation for a time-dependent signal process induced by a d-dimensional stochastic differential equation and a linear observation is studied, using a variational approach. A lower bound for the rate of stability is identified in terms of the mass-gap of a parabolic ground state transform associated with the generator of the signal process and the square of the observation. The lower bound can be easily calculated a priori and provides hints on how precisely to measure the signal in order to reach a certain rate of stability. Ergodicity of the signal process is not needed

  10. Cellular chromophores and signaling in low level light therapy

    Science.gov (United States)

    Hamblin, Michael R.; Demidova-Rice, Tatiana N.

    2007-02-01

    particular, signaling cascades are initiated via cyclic adenosine monophosphate (cAMP) and nuclear factor kappa B (NF-κB). These signal transduction pathways in turn lead to increased cell proliferation and migration (particularly by fibroblasts), modulation in levels of cytokines, growth factors and inflammatory mediators, and increases in anti-apoptotic proteins. The results of these biochemical and cellular changes in animals and patients include such benefits as increased healing in chronic wounds, improvements in sports injuries and carpal tunnel syndrome, pain reduction in arthritis and neuropathies, and amelioration of damage after heart attacks, stroke, nerve injury and retinal toxicity.

  11. Recharge signal identification based on groundwater level observations.

    Science.gov (United States)

    Yu, Hwa-Lung; Chu, Hone-Jay

    2012-10-01

    This study applied a method of the rotated empirical orthogonal functions to directly decompose the space-time groundwater level variations and determine the potential recharge zones by investigating the correlation between the identified groundwater signals and the observed local rainfall records. The approach is used to analyze the spatiotemporal process of piezometric heads estimated by Bayesian maximum entropy method from monthly observations of 45 wells in 1999-2007 located in the Pingtung Plain of Taiwan. From the results, the primary potential recharge area is located at the proximal fan areas where the recharge process accounts for 88% of the spatiotemporal variations of piezometric heads in the study area. The decomposition of groundwater levels associated with rainfall can provide information on the recharge process since rainfall is an important contributor to groundwater recharge in semi-arid regions. Correlation analysis shows that the identified recharge closely associates with the temporal variation of the local precipitation with a delay of 1-2 months in the study area.

  12. Angular dependence of Auger signals from a GaAs (111) surface

    International Nuclear Information System (INIS)

    Barnard, W.O.

    1984-03-01

    This dissertation is concerned with the angular dependence of the L 3 M 4 M 4 1067 eV Ga and L 3 M 4 M 4 1228 eV As Auger electron signals from a (111) GaAs surface, using a system which is equipped with a cylindrical mirror analyser. Following a detailed discussion of the Auger process, a review is given of angular effects in the emission excitation and detection of Auger signals. Present theories are discussed and an empirical theory is developed to test the experimental results obtained in this study. The experimental procedures and equipment used are presented. It was found that the Auger signals show a strong variation with the angle of rotation about the normal of a GaAs surface. Furthermore, the nature of the angular spectra of the Ga and As signals are interchanged when the electron beam incident surface is changed from (111) to (111). The main features of the angular variation of the quasi-elastic backscattered signal is reflected in the corresponding Ga and As Auger angular spectra. The angular dependence of the quasi-elastic backscattered signal can be explained semi-quantitatively in terms of the empirical theory. Theoretical arguments are presented which suggest that the Auger signals should show an angular dependence similar to the quasi-elastic backscattered signal. Evidence was found that geometric screening-off of underlying atoms by surface and near surface atoms influence the Auger yield

  13. Time dependent auto-correlation, autospectrum and decay ratio estimation of transient signals in JET soft X-ray records

    International Nuclear Information System (INIS)

    Por, G.

    1999-08-01

    being connected with the feedback in the given system. It characterises the stability of the system i.e. the tendency (or the level) of the signal to have oscillating character. An algorithm was developed to find extrema of the ACF automatically. Upper (DR1) and lower bound (DR2) are calculated from the ratio of maxima and minima correspondingly. Calculation of time dependent APSD - The time dependent APSD is calculated from the time dependent ACF via FFT. It can follow the spectral changes with an accuracy of one time step. Details, how and why we arrived to this recipe above, are explained in this report. First we summarise the basis definitions for these parameters and then we explain why pre-processing is needed for good statistical estimations. Finally, we describe our algorithm to estimate the ACF, DR and APSD. We present also some results on test data. Hopefully, application of these algorithms on JET shots as presented proves, that; the filtering methods proposed and elaborated are adequate to prepare the signals for data processing, the DR is a good tool to find places where oscillation definitely takes place, the proposed weighting method for estimating time dependent ACF is a suitable tool to find the frequency shift of the main periodic component in the time signal, it is possible to estimate good, reliable, short range, time dependent APSD based on such ACF

  14. Vitamin A Affects Flatfish Development in a Thyroid Hormone Signaling and Metamorphic Stage Dependent Manner

    Directory of Open Access Journals (Sweden)

    Ignacio Fernández

    2017-06-01

    Full Text Available Vitamin A (VA and retinoid derivatives are known morphogens controlling vertebrate development. Despite the research effort conducted during the last decade, the precise mechanism of how VA induces post-natal bone changes, and particularly those operating through crosstalk with the thyroid hormones (THs remain to be fully understood. Since effects and mechanisms seem to be dose and time-dependent, flatfish are an interesting study model as they undergo a characteristic process of metamorphosis driven by THs that can be followed by external appearance. Here, we studied the effects of VA imbalance that might determine Senegalese sole (Solea senegalensis skeletogenetic phenotype through development of thyroid follicles, THs homeostasis and signaling when a dietary VA excess was specifically provided during pre-, pro- or post-metamorphic stages using enriched rotifers and Artemia as carriers. The increased VA content in enriched live prey was associated to a higher VA content in fish at all developmental stages. Dietary VA content clearly affected thyroid follicle development, T3 and T4 immunoreactive staining, skeletogenesis and mineralization in a dose and time-dependent fashion. Gene expression analysis showed that VA levels modified the mRNA abundance of VA- and TH-specific nuclear receptors at specific developmental stages. Present results provide new and key knowledge to better understand how VA and TH pathways interact at tissue, cellular and nuclear level at different developmental periods in Senegalese sole, unveiling how dietary modulation might determine juvenile phenotype and physiology.

  15. EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.

    Science.gov (United States)

    Demiroglu-Zergeroglu, Asuman; Candemir, Gulsife; Turhanlar, Ebru; Sagir, Fatma; Ayvali, Nurettin

    2016-12-01

    The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Inhibitory neurons modulate spontaneous signaling in cultured cortical neurons: density-dependent regulation of excitatory neuronal signaling

    International Nuclear Information System (INIS)

    Serra, Michael; Guaraldi, Mary; Shea, Thomas B

    2010-01-01

    Cortical neuronal activity depends on a balance between excitatory and inhibitory influences. Culturing of neurons on multi-electrode arrays (MEAs) has provided insight into the development and maintenance of neuronal networks. Herein, we seeded MEAs with murine embryonic cortical/hippocampal neurons at different densities ( 1000 cells mm −2 ) and monitored resultant spontaneous signaling. Sparsely seeded cultures displayed a large number of bipolar, rapid, high-amplitude individual signals with no apparent temporal regularity. By contrast, densely seeded cultures instead displayed clusters of signals at regular intervals. These patterns were observed even within thinner and thicker areas of the same culture. GABAergic neurons (25% of total neurons in our cultures) mediated the differential signal patterns observed above, since addition of the inhibitory antagonist bicuculline to dense cultures and hippocampal slice cultures induced the signal pattern characteristic of sparse cultures. Sparsely seeded cultures likely lacked sufficient inhibitory neurons to modulate excitatory activity. Differential seeding of MEAs can provide a unique model for analyses of pertubation in the interaction between excitatory and inhibitory function during aging and neuropathological conditions where dysregulation of GABAergic neurons is a significant component

  17. Angular momentum dependence of the nuclear level density parameter

    International Nuclear Information System (INIS)

    Aggarwal, Mamta; Kailas, S.

    2010-01-01

    Dependence of nuclear level density parameter on the angular momentum and temperature is investigated in a theoretical framework using the statistical theory of hot rotating nuclei. The structural effects are incorporated by including shell correction, shape, and deformation. The nuclei around Z≅50 with an excitation energy range of 30 to 40 MeV are considered. The calculations are in good agreement with the experimentally deduced inverse level density parameter values especially for 109 In, 113 Sb, 122 Te, 123 I, and 127 Cs nuclei.

  18. Temperature dependent energy levels of methylammonium lead iodide perovskite

    Science.gov (United States)

    Foley, Benjamin J.; Marlowe, Daniel L.; Sun, Keye; Saidi, Wissam A.; Scudiero, Louis; Gupta, Mool C.; Choi, Joshua J.

    2015-06-01

    Temperature dependent energy levels of methylammonium lead iodide are investigated using a combination of ultraviolet photoemission spectroscopy and optical spectroscopy. Our results show that the valence band maximum and conduction band minimum shift down in energy by 110 meV and 77 meV as temperature increases from 28 °C to 85 °C. Density functional theory calculations using slab structures show that the decreased orbital splitting due to thermal expansion is a major contribution to the experimentally observed shift in energy levels. Our results have implications for solar cell performance under operating conditions with continued sunlight exposure and increased temperature.

  19. Temperature dependent energy levels of methylammonium lead iodide perovskite

    Energy Technology Data Exchange (ETDEWEB)

    Foley, Benjamin J.; Marlowe, Daniel L.; Choi, Joshua J., E-mail: jjc6z@virginia.edu, E-mail: mgupta@virginia.edu, E-mail: scudiero@wsu.edu [Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904 (United States); Sun, Keye; Gupta, Mool C., E-mail: jjc6z@virginia.edu, E-mail: mgupta@virginia.edu, E-mail: scudiero@wsu.edu [Department of Electrical and Computer Engineering, University of Virginia, Charlottesville, Virginia 22904 (United States); Saidi, Wissam A. [Department of Mechanical Engineering and Materials Science, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 (United States); Scudiero, Louis, E-mail: jjc6z@virginia.edu, E-mail: mgupta@virginia.edu, E-mail: scudiero@wsu.edu [Chemistry Department and Materials Science and Engineering Program, Washington State University, Pullman, Washington 99164 (United States)

    2015-06-15

    Temperature dependent energy levels of methylammonium lead iodide are investigated using a combination of ultraviolet photoemission spectroscopy and optical spectroscopy. Our results show that the valence band maximum and conduction band minimum shift down in energy by 110 meV and 77 meV as temperature increases from 28 °C to 85 °C. Density functional theory calculations using slab structures show that the decreased orbital splitting due to thermal expansion is a major contribution to the experimentally observed shift in energy levels. Our results have implications for solar cell performance under operating conditions with continued sunlight exposure and increased temperature.

  20. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade

    Directory of Open Access Journals (Sweden)

    Alexandre Dumoulin

    2018-04-01

    Full Text Available Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP, the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα. In the absence of any one of these components, neurons in dorsal root ganglia (DRG and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  1. Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade.

    Science.gov (United States)

    Dumoulin, Alexandre; Ter-Avetisyan, Gohar; Schmidt, Hannes; Rathjen, Fritz G

    2018-04-24

    Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception.

  2. Decoding Signal Processing at the Single-Cell Level

    Energy Technology Data Exchange (ETDEWEB)

    Wiley, H. Steven

    2017-12-01

    The ability of cells to detect and decode information about their extracellular environment is critical to generating an appropriate response. In multicellular organisms, cells must decode dozens of signals from their neighbors and extracellular matrix to maintain tissue homeostasis while still responding to environmental stressors. How cells detect and process information from their surroundings through a surprisingly limited number of signal transduction pathways is one of the most important question in biology. Despite many decades of research, many of the fundamental principles that underlie cell signal processing remain obscure. However, in this issue of Cell Systems, Gillies et al present compelling evidence that the early response gene circuit can act as a linear signal integrator, thus providing significant insight into how cells handle fluctuating signals and noise in their environment.

  3. Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages

    Directory of Open Access Journals (Sweden)

    Reid Oldenburg

    2018-01-01

    Full Text Available Phenolic glycolipids (PGLs are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-β (TRIF protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-β and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.

  4. The dependence of signal-to-noise ratio on number of scans in covariance spectroscopy.

    Science.gov (United States)

    Qian, Yi; Shen, Ming; Amoureux, Jean-Paul; Noda, Isao; Hu, Bingwen

    2014-01-01

    The dependence of signal-to-noise ratio on the number of scans in covariance spectroscopy has been systematically analyzed for the first time with the intriguing relationship of SNRcov∝n/2, which is different from that in FT2D spectrum with SNRFT∝n. This relationship guarantees the signal-to-noise ratio when increasing the number of scans. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. The plant natriuretic peptide receptor is a guanylyl cyclase and enables cGMP-dependent signaling

    KAUST Repository

    Turek, Ilona; Gehring, Christoph A

    2016-01-01

    and water balance and responses to biotrophic plant pathogens. Although there is increasing understanding of the complex roles of PNPs in plant responses at the systems level, little is known about the underlying signaling mechanisms. Here we report

  6. Delayed dopamine signaling of energy level builds appetitive long-term memory in Drosophila.

    Science.gov (United States)

    Musso, Pierre-Yves; Tchenio, Paul; Preat, Thomas

    2015-02-24

    Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term association between an odor and a nutritious sugar depends on delayed post-ingestion signaling of energy level. We show at the neural circuit level that the activity of two pairs of dopaminergic neurons is necessary and sufficient to signal energy level to the olfactory memory center. Accordingly, we have identified in these dopaminergic neurons a delayed calcium trace that correlates with appetitive long-term memory formation. Altogether, these findings demonstrate that the Drosophila brain remembers food quality through a two-step mechanism that consists of the integration of olfactory and gustatory sensory information and then post-ingestion energetic value. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Blood oxygenation level dependent (BOLD). Renal imaging. Concepts and applications

    International Nuclear Information System (INIS)

    Nissen, Johanna C.; Haneder, Stefan; Schoenberg, Stefan O.; Michaely, Henrik J.

    2010-01-01

    Many renal diseases as well as several pharmacons cause a change in renal blood flow and/or renal oxygenation. The blood oxygenation level dependent (BOLD) imaging takes advantage of local field inhomogeneities and is based on a T2 * -weighted sequence. BOLD is a non-invasive method allowing an estimation of the renal, particularly the medullary oxygenation, and an indirect measurement of blood flow without administration of contrast agents. Thus, effects of different drugs on the kidney and various renal diseases can be controlled and observed. This work will provide an overview of the studies carried out so far and identify ways how BOLD can be used in clinical studies. (orig.)

  8. Local order dependent impurity levels in alloy semiconductors

    International Nuclear Information System (INIS)

    Silva, C.E.T.G. da; Ecole Normale Superieure, 75 - Paris

    1981-01-01

    We develop a one band/may sites model for an isoelectronic impurity in a semiconductor alloy. The cluster-Bethe-lattice approximation is used to study the dependence of the impurity energy level upon the short range order (SRO) of the alloy. The Kikuchi parametrization is used to describe the latter. We take into account diagonal disorder only, with possible off-diagonal relaxation around the impurity site. All the inequivalent clusters of the impurity site and its first nearest neighbours are considered, thus including the important short range alloy potential fluctuations. Results are presented for the local density of impurity states, for different degrees of SRO in the alloy. (Author) [pt

  9. Long-range dependence and sea level forecasting

    CERN Document Server

    Ercan, Ali; Abbasov, Rovshan K

    2013-01-01

    This study shows that the Caspian Sea level time series possess long range dependence even after removing linear trends, based on analyses of the Hurst statistic, the sample autocorrelation functions, and the periodogram of the series. Forecasting performance of ARMA, ARIMA, ARFIMA and Trend Line-ARFIMA (TL-ARFIMA) combination models are investigated. The forecast confidence bands and the forecast updating methodology, provided for ARIMA models in the literature, are modified for the ARFIMA models. Sample autocorrelation functions are utilized to estimate the differencing lengths of the ARFIMA

  10. Nuclear level density parameter 's dependence on angular momentum

    International Nuclear Information System (INIS)

    Aggarwal, Mamta; Kailas, S.

    2009-01-01

    Nuclear level densities represent a very important ingredient in the statistical Model calculations of nuclear reaction cross sections and help to understand the microscopic features of the excited nuclei. Most of the earlier experimental nuclear level density measurements are confined to low excitation energy and low spin region. A recent experimental investigation of nuclear level densities in high excitation energy and angular momentum domain with some interesting results on inverse level density parameter's dependence on angular momentum in the region around Z=50 has motivated us to study and analyse these experimental results in a microscopic theoretical framework. In the experiment, heavy ion fusion reactions are used to populate the excited and rotating nuclei and measured the α particle evaporation spectra in coincidence with ray multiplicity. Residual nuclei are in the range of Z R 48-55 with excitation energy range 30 to 40 MeV and angular momentum in 10 to 25. The inverse level density parameter K is found to be in the range of 9.0 - 10.5 with some exceptions

  11. The transcription factor ABI4 Is required for the ascorbic acid-dependent regulation of growth and regulation of jasmonate-dependent defense signaling pathways in Arabidopsis.

    Science.gov (United States)

    Kerchev, Pavel I; Pellny, Till K; Vivancos, Pedro Diaz; Kiddle, Guy; Hedden, Peter; Driscoll, Simon; Vanacker, Hélène; Verrier, Paul; Hancock, Robert D; Foyer, Christine H

    2011-09-01

    Cellular redox homeostasis is a hub for signal integration. Interactions between redox metabolism and the ABSCISIC ACID-INSENSITIVE-4 (ABI4) transcription factor were characterized in the Arabidopsis thaliana vitamin c defective1 (vtc1) and vtc2 mutants, which are defective in ascorbic acid synthesis and show a slow growth phenotype together with enhanced abscisic acid (ABA) levels relative to the wild type (Columbia-0). The 75% decrease in the leaf ascorbate pool in the vtc2 mutants was not sufficient to adversely affect GA metabolism. The transcriptome signatures of the abi4, vtc1, and vtc2 mutants showed significant overlap, with a large number of transcription factors or signaling components similarly repressed or induced. Moreover, lincomycin-dependent changes in LIGHT HARVESTING CHLOROPHYLL A/B BINDING PROTEIN 1.1 expression were comparable in these mutants, suggesting overlapping participation in chloroplast to nucleus signaling. The slow growth phenotype of vtc2 was absent in the abi4 vtc2 double mutant, as was the sugar-insensitive phenotype of the abi4 mutant. Octadecanoid derivative-responsive AP2/ERF-domain transcription factor 47 (ORA47) and AP3 (an ABI5 binding factor) transcripts were enhanced in vtc2 but repressed in abi4 vtc2, suggesting that ABI4 and ascorbate modulate growth and defense gene expression through jasmonate signaling. We conclude that low ascorbate triggers ABA- and jasmonate-dependent signaling pathways that together regulate growth through ABI4. Moreover, cellular redox homeostasis exerts a strong influence on sugar-dependent growth regulation.

  12. DEPENDENCE OF COUNTRY RISK COMPARED TO THE FOREIGN DEBT LEVEL

    Directory of Open Access Journals (Sweden)

    Angelica BĂCESCU-CĂRBUNARU

    2012-11-01

    Full Text Available The article presents some of the fundamental aspects of country risk’dependence compared to foreign debt level. Starting from external debt burden we analyze the usage of foreign loans, foreign debt bearing capacity as well as the availability of data regarding the external debt. Country risk represents the exposure to losses which may occur in a business with a foreign partner, caused by specific events that are, at least partially, controlled by the partner country’ government. Macroeconomic analysis of economic and financial component of country risk involves how this risk is influenced by government policy, by the economic role of government, bypricing strategies, investment priorities, financial structures, macroeconomic policy, by the ability to obtain foreign funds, the level of external debt as well as the liquidity and cash flows in that country.

  13. Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning.

    Science.gov (United States)

    Shaya, Oren; Binshtok, Udi; Hersch, Micha; Rivkin, Dmitri; Weinreb, Sheila; Amir-Zilberstein, Liat; Khamaisi, Bassma; Oppenheim, Olya; Desai, Ravi A; Goodyear, Richard J; Richardson, Guy P; Chen, Christopher S; Sprinzak, David

    2017-03-13

    During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise

    DEFF Research Database (Denmark)

    Rose, Adam John; Kiens, Bente; Richter, Erik

    2006-01-01

    Ca2+ signalling is proposed to play an important role in skeletal muscle function during exercise. Here, we examined the expression of multifunctional Ca2+-calmodulin-dependent protein kinases (CaMK) in human skeletal muscle and show that CaMKII and CaMKK, but not CaMKI or CaMKIV, are expressed...

  15. The mass dependence of the signal peak height of a Bragg-curve ionization chamber

    International Nuclear Information System (INIS)

    Shenhav, N.J.; Stelzer, H.

    1985-01-01

    The Bragg-curve detector of the parallel plate ionization chamber type generates a signal that is a distorted replica of the original Bragg-curve. In result of this distortion, the signal peak height is not only a function of the atomic number of the heavy ion, as it is often stated, but also of the particle mass. This mass effect was studied with the aid of computer simulation, and it was found to be dependent on the Frisch grid to anode gap width and on the detector gas. The charge resolution of the detector is affected very significantly by this mass dependence of the signal peak height. Therefore, a careful selection of the detector gas and the grid to anode gap width is necessary, if good charge resolution over a wide range of heavy ions is required. (orig.)

  16. High-level expression of nattokinase in Bacillus licheniformis by manipulating signal peptide and signal peptidase.

    Science.gov (United States)

    Cai, D; Wei, X; Qiu, Y; Chen, Y; Chen, J; Wen, Z; Chen, S

    2016-09-01

    Nattokinase is an enzyme produced by Bacillus licheniformis and has potential to be used as a drug for treating cardiovascular disease due to its beneficial effects of preventing fibrin clots etc. However, the low activity and titre of this protein produced by B. licheniformis often hinders its application of commercial production. The aim of this work is to improve the nattokinase production by manipulating signal peptides and signal peptidases in B. licheniformis. The P43 promoter, amyL terminator and AprN target gene were used to form the nattokinase expression vector, pHY-SP-NK, which was transformed into B. licheniformis and nattokinase was expressed successfully. A library containing 81 predicted signal peptides was constructed for nattokinase expression in B. licheniformis, with the maximum activity being obtained under the signal peptide of AprE. Among four type I signal peptidases genes (sipS, sipT, sipV, sipW) in B. licheniformis, the deletion of sipV resulted in a highest decrease in nattokinase activity. Overexpression of sipV in B. licheniformis led to a nattokinase activity of 35·60 FU ml(-1) , a 4·68-fold improvement over activity produced by the initial strain. This work demonstrates the potential of B. licheniformis for industrial production of nattokinase through manipulation of signal peptides and signal peptidases expression. This study has screened the signal peptides of extracellular proteins of B. licheniformis for nattokinase production. Four kinds of Type I signal peptidases genes have been detected respectively in B. licheniformis to identify which one played the vital role for nattokinase production. This study provided a promising strain for industry production of nattokinase. © 2016 The Society for Applied Microbiology.

  17. FIPSER: Performance study of a readout concept with few digitization levels for fast signals

    Energy Technology Data Exchange (ETDEWEB)

    Limyansky, B., E-mail: brent.limyansky@gatech.edu [School of Physics and Center for Relativistic Astrophysics, Georgia Institute of Technology, Atlanta (United States); Reese, R., E-mail: bobbeyreese@gmail.com [School of Physics and Center for Relativistic Astrophysics, Georgia Institute of Technology, Atlanta (United States); Cressler, J.D. [School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta (United States); Otte, A.N.; Taboada, I. [School of Physics and Center for Relativistic Astrophysics, Georgia Institute of Technology, Atlanta (United States); Ulusoy, C. [Dept. of Electrical and Computer Engineering, Michigan State University, East Lansing (United States)

    2016-11-21

    We discuss the performance of a readout system, Fixed Pulse Shape Efficient Readout (FIPSER), to digitize signals from detectors with a fixed pulse shape. In this study we are mainly interested in the readout of fast photon detectors like photomultipliers or Silicon photomultipliers. But the concept can be equally applied to the digitization of other detector signals. FIPSER is based on the flash analog to digital converter (FADC) concept, but has the potential to lower costs and power consumption by using an order of magnitude fewer discrete voltage levels. Performance is bolstered by combining the discretized signal with the knowledge of the underlying pulse shape. Simulated FIPSER data was reconstructed with two independent methods. One using a maximum likelihood method and the other using a modified χ{sup 2} test. Both methods show that utilizing 12 discrete voltage levels with a sampling rate of 4 samples per full width half maximum (FWHM) of the pulse achieves an amplitude resolution that is better than the Poisson limit for photon-counting experiments. The time resolution achieved in this configuration ranges between 0.02 and 0.16 FWHM and depends on the pulse amplitude. In a situation where the waveform is composed of two consecutive pulses the pulses can be separated if they are at least 0.05–0.30 FWHM apart with an amplitude resolution that is better than 20%.

  18. Signaling Cascades: Consequences of Varying Substrate and Phosphatase Levels

    DEFF Research Database (Denmark)

    Feliu, Elisenda; Knudsen, Michael; Wiuf, Carsten Henrik

    2012-01-01

    We study signaling cascades with an arbitrary number of layers of one-site phosphorylation cycles. Such cascades are abundant in nature and integrated parts of many pathways. Based on the Michaelis-Menten model of enzyme kinetics and the law of mass-action, we derive explicit analytic expressions...

  19. cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart.

    Science.gov (United States)

    Bockus, Lee B; Humphries, Kenneth M

    2015-12-04

    Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. cAMP-dependent Protein Kinase (PKA) Signaling Is Impaired in the Diabetic Heart*

    Science.gov (United States)

    Bockus, Lee B.; Humphries, Kenneth M.

    2015-01-01

    Diabetes mellitus causes cardiac dysfunction and heart failure that is associated with metabolic abnormalities and autonomic impairment. Autonomic control of ventricular function occurs through regulation of cAMP-dependent protein kinase (PKA). The diabetic heart has suppressed β-adrenergic responsiveness, partly attributable to receptor changes, yet little is known about how PKA signaling is directly affected. Control and streptozotocin-induced diabetic mice were therefore administered 8-bromo-cAMP (8Br-cAMP) acutely to activate PKA in a receptor-independent manner, and cardiac hemodynamic function and PKA signaling were evaluated. In response to 8Br-cAMP treatment, diabetic mice had impaired inotropic and lusitropic responses, thus demonstrating postreceptor defects. This impaired signaling was mediated by reduced PKA activity and PKA catalytic subunit content in the cytoplasm and myofilaments. Compartment-specific loss of PKA was reflected by reduced phosphorylation of discrete substrates. In response to 8Br-cAMP treatment, the glycolytic activator PFK-2 was robustly phosphorylated in control animals but not diabetics. Control adult cardiomyocytes cultured in lipid-supplemented media developed similar changes in PKA signaling, suggesting that lipotoxicity is a contributor to diabetes-induced β-adrenergic signaling dysfunction. This work demonstrates that PKA signaling is impaired in diabetes and suggests that treating hyperlipidemia is vital for proper cardiac signaling and function. PMID:26468277

  1. β-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

    Science.gov (United States)

    Jackson, Belinda M.; Eisenmann, David M.

    2012-01-01

    Wnt signaling is an evolutionarily ancient pathway used to regulate many events during metazoan development. Genetic results from Caenorhabditis elegans more than a dozen years ago suggested that Wnt signaling in this nematode worm might be different than in vertebrates and Drosophila: the worm had a small number of Wnts, too many β-catenins, and some Wnt pathway components functioned in an opposite manner than in other species. Work over the ensuing years has clarified that C. elegans does possess a canonical Wnt/β-catenin signaling pathway similar to that in other metazoans, but that the majority of Wnt signaling in this species may proceed via a variant Wnt/β-catenin signaling pathway that uses some new components (mitogen-activated protein kinase signaling enzymes), and in which some conserved pathway components (β-catenin, T-cell factor [TCF]) are used in new and interesting ways. This review summarizes our current understanding of the canonical and novel TCF/β-catenin-dependent signaling pathways in C. elegans. PMID:22745286

  2. With you or against you: social orientation dependent learning signals guide actions made for others.

    Science.gov (United States)

    Christopoulos, George I; King-Casas, Brooks

    2015-01-01

    In social environments, it is crucial that decision-makers take account of the impact of their actions not only for oneself, but also on other social agents. Previous work has identified neural signals in the striatum encoding value-based prediction errors for outcomes to oneself; also, recent work suggests that neural activity in prefrontal cortex may similarly encode value-based prediction errors related to outcomes to others. However, prior work also indicates that social valuations are not isomorphic, with social value orientations of decision-makers ranging on a cooperative to competitive continuum; this variation has not been examined within social learning environments. Here, we combine a computational model of learning with functional neuroimaging to examine how individual differences in orientation impact neural mechanisms underlying 'other-value' learning. Across four experimental conditions, reinforcement learning signals for other-value were identified in medial prefrontal cortex, and were distinct from self-value learning signals identified in striatum. Critically, the magnitude and direction of the other-value learning signal depended strongly on an individual's cooperative or competitive orientation toward others. These data indicate that social decisions are guided by a social orientation-dependent learning system that is computationally similar but anatomically distinct from self-value learning. The sensitivity of the medial prefrontal learning signal to social preferences suggests a mechanism linking such preferences to biases in social actions and highlights the importance of incorporating heterogeneous social predispositions in neurocomputational models of social behavior. Published by Elsevier Inc.

  3. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  4. RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.

    Science.gov (United States)

    Schouwey, K; Aydin, I T; Radtke, F; Beermann, F

    2011-01-20

    The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.

  5. Alterations of cAMP-dependent signaling in dystrophic skeletal muscle

    Directory of Open Access Journals (Sweden)

    Rüdiger eRudolf

    2013-10-01

    Full Text Available Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial-temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction is important for post-synaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor, PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, α-calcitonin-related peptide, as well as beta-adrenergic agonists are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of β2-adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMP-dependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity.

  6. Numerical and experimental investigations of dependence of photoacoustic signals from gold nanoparticles on the optical properties

    Science.gov (United States)

    Okawa, Shinpei; Hirasawa, Takeshi; Sato, Ryota; Kushibiki, Toshihiro; Ishihara, Miya; Teranishi, Toshiharu

    2018-04-01

    Gold nanoparticles (AuNPs) are used as a contrast agent of the photoacoustic (PA) imaging. The efficiency of AuNPs has been discussed with the absorption cross section. However, the effects of the scattering of the light by AuNPs and surrounding medium on the PA signal from AuNPs have not been discussed. The PA signals from the aqueous solution of AuNPs were examined in the numerical simulation and the experiment. In the numerical simulation, the absorption and scattering cross sections of spherical and polyhedral AuNPs were calculated by Mie theory and discrete dipole approximation. Monte Carlo simulation calculated the absorbed light energy in the aqueous solution of AuNPs. Based on the PA wave equation, the PA signals were simulated. In the experiment, the PA signal from the aqueous solution of AuNP was measured by use of a piezoelectric film and a Q-switched Nd:YAG laser operated at 532 nm. The results of the numerical simulation and the experiment agreed well. In the numerical simulation and the experiment, a single Au nanocube with 50-nm edge generated the peak value of the PA signal significantly. It was approximately 350 times and twice as large as the peak values of the spherical AuNPs with 10- and 50-nm diameters, respectively. The peak value of the PA signal depended on both the absorption and scattering coefficients of the AuNPs and the surrounding medium. The peak value increased with the scattering coefficient in a quadratic manner. The character of the temporal profile of the PA signal such as full width at half maximum depended on the scattering coefficient of the AuNPs.

  7. Five-level polybinary signaling for 10 Gbps data transmission systems

    DEFF Research Database (Denmark)

    Vegas Olmos, Juan José; Suhr, Lau Frejstrup; Li, Bomin

    2013-01-01

    This paper presents a revitalization effort towards exploiting multilevel polybinary signals for spectral efficient data links. Specifically, we present five level polybinary signaling for 10 Gbps signals. By proper coding to avoid error propagation and degeneracy of the bit error rate performance...

  8. Applied Chaos Level Test for Validation of Signal Conditions Underlying Optimal Performance of Voice Classification Methods

    Science.gov (United States)

    Liu, Boquan; Polce, Evan; Sprott, Julien C.; Jiang, Jack J.

    2018-01-01

    Purpose: The purpose of this study is to introduce a chaos level test to evaluate linear and nonlinear voice type classification method performances under varying signal chaos conditions without subjective impression. Study Design: Voice signals were constructed with differing degrees of noise to model signal chaos. Within each noise power, 100…

  9. Low level signal data acquisition for the MFTF-B superconducting magnet system

    International Nuclear Information System (INIS)

    Montoya, C.R.

    1984-01-01

    Acquisition of low level signals from sensors mounted on the superconducting magnets in the Tandem Mirror Fusion Test Facility (MFTF-B) impose very strict requirements on the magnet signal conditioning and data acquisition system. Of the various types of sensors required, thermocouples and strain gages produce very low level outputs. These low level outputs must be accurately measured in the harsh environment of slowly varying magnetic fields, cryogenic temperatures, high vacuum, 80 kV pulse power, 60 Hz, 17 MHz and 28, 35, and 56 GHz electrical noise and possible neutron radiation. Successful measurements require careful attention to grounding, shielding, signal handling and processing in the data acquisition system. The magnet instrumentation system provides a means of effectively measuring both low level signals and high level signals from all types of sensors. Various methods involved in the design and implementation of the system for signal conditioning and data gathering will be presented

  10. Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

    Science.gov (United States)

    Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

    2015-01-01

    Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. PMID:26522512

  11. Reference hearing threshold levels for short duration signals

    DEFF Research Database (Denmark)

    Poulsen, Torben; Legarth, Søren Vase

    2008-01-01

    for the determination of reference hearing threshold levels. The results are given as peak-to-peak equivalent threshold sound pressure levels (peETSPL). The results are in good agreement with other sparse results from literature and are part of the basis for the ISO 389-6 standard from 2007....

  12. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    International Nuclear Information System (INIS)

    Gandhi, Adarsh; Guo, Tao; Shah, Pranav; Moorthy, Bhagavatula; Ghose, Romi

    2013-01-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP +/+ and TIRAP −/− mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP +/+ mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP −/− mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies provide novel mechanistic

  13. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Guo, Tao, E-mail: tguo4@jhu.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Shah, Pranav [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Baylor College of Medicine, Department of Pediatrics, 1102 Bates Avenue, Suite 530, Houston, TX 77030 (United States); Ghose, Romi, E-mail: rghose@uh.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States)

    2013-02-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies

  14. Signaling profiling at the single-cell level identifies a distinct signaling signature in murine hematopoietic stem cells.

    Science.gov (United States)

    Du, Juan; Wang, Jinyong; Kong, Guangyao; Jiang, Jing; Zhang, Jingfang; Liu, Yangang; Tong, Wei; Zhang, Jing

    2012-07-01

    Hematopoietic stem cell (HSC) function is tightly regulated by cytokine signaling. Although phospho-flow cytometry allows us to study signaling in defined populations of cells, there has been tremendous hurdle to carry out this study in rare HSCs due to unrecoverable critical HSC markers, low HSC number, and poor cell recovery rate. Here, we overcame these difficulties and developed a "HSC phospho-flow" method to analyze cytokine signaling in murine HSCs at the single-cell level and compare HSC signaling profile to that of multipotent progenitors (MPPs), a cell type immediately downstream of HSCs, and commonly used Lin(-) cKit(+) cells (LK cells, enriched for myeloid progenitors). We chose to study signaling evoked from three representative cytokines, stem cell factor (SCF) and thrombopoietin (TPO) that are essential for HSC function and granulocyte macrophage-colony-stimulating factor (GM-CSF) that is dispensable for HSCs. HSCs display a distinct TPO and GM-CSF signaling signature from MPPs and LK cells, which highly correlates with receptor surface expression. In contrast, although majority of LK cells express lower levels of cKit than HSCs and MPPs, SCF-evoked ERK1/2 activation in LK cells shows a significantly increased magnitude for a prolonged period. These results suggest that specific cellular context plays a more important role than receptor surface expression in SCF signaling. Our study of HSC signaling at the homeostasis stage paves the way to investigate signaling changes in HSCs under conditions of stress, aging, and hematopoietic diseases. Copyright © 2012 AlphaMed Press.

  15. Temperature and Pressure Dependence of Signal Amplitudes for Electrostriction Laser-Induced Thermal Acoustics

    Science.gov (United States)

    Herring, Gregory C.

    2015-01-01

    The relative signal strength of electrostriction-only (no thermal grating) laser-induced thermal acoustics (LITA) in gas-phase air is reported as a function of temperature T and pressure P. Measurements were made in the free stream of a variable Mach number supersonic wind tunnel, where T and P are varied simultaneously as Mach number is varied. Using optical heterodyning, the measured signal amplitude (related to the optical reflectivity of the acoustic grating) was averaged for each of 11 flow conditions and compared to the expected theoretical dependence of a pure-electrostriction LITA process, where the signal is proportional to the square root of [P*P /( T*T*T)].

  16. Characterization of ubiquitination dependent dynamics in growth factor receptor signaling by quantitative proteomics

    DEFF Research Database (Denmark)

    Akimov, Vyacheslav; Rigbolt, Kristoffer T G; Nielsen, Mogens M

    2011-01-01

    Protein ubiquitination is a dynamic reversible post-translational modification that plays a key role in the regulation of numerous cellular processes including signal transduction, endocytosis, cell cycle control, DNA repair and gene transcription. The conjugation of the small protein ubiquitin...... investigating ubiquitination on a proteomic scale, mainly due to the inherited complexity and heterogeneity of ubiquitination. We describe here a quantitative proteomics strategy based on the specificity of ubiquitin binding domains (UBDs) and Stable Isotope Labeling by Amino acids in Cell culture (SILAC...... as ubiquitination-dependent events in signaling pathways. In addition to a detailed seven time-point profile of EGFR ubiquitination over 30 minutes of ligand stimulation, our data determined prominent involvement of Lysine-63 ubiquitin branching in EGF signaling. Furthermore, we found two centrosomal proteins, PCM1...

  17. Dynamic trafficking of STAT5 depends on an unconventional nuclear localization signal

    Science.gov (United States)

    Shin, Ha Youn; Reich, Nancy C.

    2013-01-01

    Summary Signal transducer and activator of transcription 5 (STAT5) is crucial for physiological processes that include hematopoiesis, liver metabolism and mammary gland development. However, aberrant continual activity of STAT5 has been causally linked to human leukemias and solid tumor formation. As a regulated transcription factor, precise cellular localization of STAT5 is essential. Conventional nuclear localization signals consist of short stretches of basic amino acids. In this study, we provide evidence that STAT5 nuclear import is dependent on an unconventional nuclear localization signal that functions within the conformation of an extensive coiled-coil domain. Both in vitro binding and in vivo functional assays reveal that STAT5 nuclear import is mediated by the importin-α3/β1 system independently of STAT5 activation by tyrosine phosphorylation. The integrity of the coiled-coil domain is essential for STAT5 transcriptional induction of the β-casein gene following prolactin stimulation as well as its ability to synergize with the glucocorticoid receptor. The glucocorticoid receptor accumulates in the nucleus in response to prolactin and this nuclear import is dependent on STAT5 nuclear import. STAT5 continually shuttles in and out of the nucleus and live cell imaging demonstrates that STAT5 nuclear export is mediated by both chromosome region maintenance 1 (Crm1)-dependent and Crm1-independent pathways. A Crm1-dependent nuclear export signal was identified within the STAT5 N-terminus. These findings provide insight into the fundamental mechanisms that regulate STAT5 nuclear trafficking and cooperation with the glucocorticoid receptor and provide a basis for clinical intervention of STAT5 function in disease. PMID:23704351

  18. Differential Dopamine Regulation of Ca2+ Signaling and Its Timing Dependence in the Nucleus Accumbens

    Directory of Open Access Journals (Sweden)

    Immani Swapna

    2016-04-01

    Full Text Available Dopamine action in the nucleus accumbens (NAc is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR-induced Ca2+ signaling dependent on the Ca2+- releasing messenger inositol 1,4,5-triphosphate (IP3 plays a critical role in controlling neuronal excitability and synaptic plasticity. Here, we show that transient dopamine application facilitates mGluR/IP3-induced Ca2+ signals within a time window of ∼2–10 s in a subpopulation of MSNs in the NAc core. Dopamine facilitation of IP3-induced Ca2+ signaling is mediated by D1 dopamine receptors. In dopamine-insensitive MSNs, activation of A2A adenosine receptors causes enhancement of IP3-evoked Ca2+ signals, which is reversed by D2 dopamine receptor activation. These results show that dopamine differentially regulates Ca2+ signaling on the order of seconds in two distinct MSN subpopulations.

  19. Maintenance of Taste Organs Is Strictly Dependent on Epithelial Hedgehog/GLI Signaling.

    Directory of Open Access Journals (Sweden)

    Alexandre N Ermilov

    2016-11-01

    Full Text Available For homeostasis, lingual taste papilla organs require regulation of epithelial cell survival and renewal, with sustained innervation and stromal interactions. To investigate a role for Hedgehog/GLI signaling in adult taste organs we used a panel of conditional mouse models to manipulate GLI activity within epithelial cells of the fungiform and circumvallate papillae. Hedgehog signaling suppression rapidly led to taste bud loss, papilla disruption, and decreased proliferation in domains of papilla epithelium that contribute to taste cells. Hedgehog responding cells were eliminated from the epithelium but retained in the papilla stromal core. Despite papilla disruption and loss of taste buds that are a major source of Hedgehog ligand, innervation to taste papillae was maintained, and not misdirected, even after prolonged GLI blockade. Further, vimentin-positive fibroblasts remained in the papilla core. However, retained innervation and stromal cells were not sufficient to maintain taste bud cells in the context of compromised epithelial Hedgehog signaling. Importantly taste organ disruption after GLI blockade was reversible in papillae that retained some taste bud cell remnants where reactivation of Hedgehog signaling led to regeneration of papilla epithelium and taste buds. Therefore, taste bud progenitors were either retained during epithelial GLI blockade or readily repopulated during recovery, and were poised to regenerate taste buds once Hedgehog signaling was restored, with innervation and papilla connective tissue elements in place. Our data argue that Hedgehog signaling is essential for adult tongue tissue maintenance and that taste papilla epithelial cells represent the key targets for physiologic Hedgehog-dependent regulation of taste organ homeostasis. Because disruption of GLI transcriptional activity in taste papilla epithelium is sufficient to drive taste organ loss, similar to pharmacologic Hedgehog pathway inhibition, the findings

  20. Maintenance of Taste Organs Is Strictly Dependent on Epithelial Hedgehog/GLI Signaling.

    Science.gov (United States)

    Ermilov, Alexandre N; Kumari, Archana; Li, Libo; Joiner, Ariell M; Grachtchouk, Marina A; Allen, Benjamin L; Dlugosz, Andrzej A; Mistretta, Charlotte M

    2016-11-01

    For homeostasis, lingual taste papilla organs require regulation of epithelial cell survival and renewal, with sustained innervation and stromal interactions. To investigate a role for Hedgehog/GLI signaling in adult taste organs we used a panel of conditional mouse models to manipulate GLI activity within epithelial cells of the fungiform and circumvallate papillae. Hedgehog signaling suppression rapidly led to taste bud loss, papilla disruption, and decreased proliferation in domains of papilla epithelium that contribute to taste cells. Hedgehog responding cells were eliminated from the epithelium but retained in the papilla stromal core. Despite papilla disruption and loss of taste buds that are a major source of Hedgehog ligand, innervation to taste papillae was maintained, and not misdirected, even after prolonged GLI blockade. Further, vimentin-positive fibroblasts remained in the papilla core. However, retained innervation and stromal cells were not sufficient to maintain taste bud cells in the context of compromised epithelial Hedgehog signaling. Importantly taste organ disruption after GLI blockade was reversible in papillae that retained some taste bud cell remnants where reactivation of Hedgehog signaling led to regeneration of papilla epithelium and taste buds. Therefore, taste bud progenitors were either retained during epithelial GLI blockade or readily repopulated during recovery, and were poised to regenerate taste buds once Hedgehog signaling was restored, with innervation and papilla connective tissue elements in place. Our data argue that Hedgehog signaling is essential for adult tongue tissue maintenance and that taste papilla epithelial cells represent the key targets for physiologic Hedgehog-dependent regulation of taste organ homeostasis. Because disruption of GLI transcriptional activity in taste papilla epithelium is sufficient to drive taste organ loss, similar to pharmacologic Hedgehog pathway inhibition, the findings suggest that taste

  1. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

    Science.gov (United States)

    Ma, Gang; Yu, Jiang; Xiao, Yue; Chan, Danny; Gao, Bo; Hu, Jianxin; He, Yongxing; Guo, Shengzhen; Zhou, Jian; Zhang, Lingling; Gao, Linghan; Zhang, Wenjuan; Kang, Yan; Cheah, Kathryn SE; Feng, Guoyin; Guo, Xizhi; Wang, Yujiong; Zhou, Cong-zhao; He, Lin

    2011-01-01

    Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation. PMID:21537345

  2. Real-time photonic sampling with improved signal-to-noise and distortion ratio using polarization-dependent modulators

    Science.gov (United States)

    Liang, Dong; Zhang, Zhiyao; Liu, Yong; Li, Xiaojun; Jiang, Wei; Tan, Qinggui

    2018-04-01

    A real-time photonic sampling structure with effective nonlinearity suppression and excellent signal-to-noise ratio (SNR) performance is proposed. The key points of this scheme are the polarization-dependent modulators (P-DMZMs) and the sagnac loop structure. Thanks to the polarization sensitive characteristic of P-DMZMs, the differences between transfer functions of the fundamental signal and the distortion become visible. Meanwhile, the selection of specific biases in P-DMZMs is helpful to achieve a preferable linearized performance with a low noise level for real-time photonic sampling. Compared with the quadrature-biased scheme, the proposed scheme is capable of valid nonlinearity suppression and is able to provide a better SNR performance even in a large frequency range. The proposed scheme is proved to be effective and easily implemented for real time photonic applications.

  3. Ochratoxin A Inhibits Mouse Embryonic Development by Activating a Mitochondrion-Dependent Apoptotic Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yan-Der Hsuuw

    2013-01-01

    Full Text Available Ochratoxin A (OTA, a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, both in vitro and in vivo. In the present study, we explored the cytotoxic effects exerted by OTA on the blastocyst stage of mouse embryos, on subsequent embryonic attachment, on outgrowth in vitro, and following in vivo implantation via embryo transfer. Mouse blastocysts were incubated with or without OTA (1, 5, or 10 μM for 24 h. Cell proliferation and growth were investigated using dual differential staining; apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay; and embryo implantation and post-implantation development were assessed by examination of in vitro growth and the outcome of in vivo embryo transfer, respectively. Blastocysts treated with 10 μM OTA displayed a significantly increased level of apoptosis and a reduction in total cell number. Interestingly, we observed no marked difference in implantation success rate between OTA-pretreated and control blastocysts either during in vitro embryonic development (following implantation in a fibronectin-coated culture dish or after in vivo embryo transfer. However, in vitro treatment with 10 μM OTA was associated with increased resorption of post-implantation embryos by the mouse uterus, and decreased fetal weight upon embryo transfer. Our results collectively indicate that in vitro exposure to OTA triggers apoptosis and retards early post-implantation development after transfer of embryos to host mice. In addition, OTA induces apoptosis-mediated injury of mouse blastocysts, via reactive oxygen species (ROS generation, and promotes mitochondrion-dependent apoptotic signaling processes that impair subsequent embryonic development.

  4. Dependence of accuracy of ESPRIT estimates on signal eigenvalues: the case of a noisy sum of two real exponentials.

    Science.gov (United States)

    Alexandrov, Theodore; Golyandina, Nina; Timofeyev, Alexey

    2009-02-26

    This paper is devoted to estimation of parameters for a noisy sum of two real exponential functions. Singular Spectrum Analysis is used to extract the signal subspace and then the ESPRIT method exploiting signal subspace features is applied to obtain estimates of the desired exponential rates. Dependence of estimation quality on signal eigenvalues is investigated. The special design to test this relation is elaborated.

  5. Motion-dependent levels of order in a relativistic universe.

    Science.gov (United States)

    Frieden, B Roy; Petri, Michael

    2012-09-01

    Consider a generally closed system of continuous three-space coordinates x with a differentiable amplitude function ψ(x). What is its level of order R? Define R by the property that it decreases (or stays constant) after the system is coarse grained. Then R turns out to obey R=8(-1)L(2)I,where quantity I=4∫dx[nabla]ψ(*)·[nabla]ψ is the classical Fisher information in the system and L is the longest chord that can connect two points on the system surface. In general, order R is (i) unitless, and (ii) invariant to uniform stretch or compression of the system. On this basis, the order R in the Universe was previously found to be invariant in time despite its Hubble expansion, and with value R=26.0×10(60) for flat space. By comparison, here we model the Universe as a string-based "holostar," with amplitude function ψ(x)[proportionality]1/r over radial interval r=(r(0),r(H)). Here r(0) is of order the Planck length and r(H) is the radial extension of the holostar, estimated as the known value of the Hubble radius. Curvature of space and relative motion of the observer must now be taken into account. It results that a stationary observer observes a level of order R=(8/9)(r(H)/r(0))(3/2)=0.42×10(90); while for a free-falling observer R=2(-1)(r(H)/r(0))(2)=0.85×10(120). Both order values greatly exceed the above flat-space value. Interestingly, they are purely geometric measures, depending solely upon ratio r(H)/r(0). Remarkably, the free-fall value ~10(120) of R approximates the negentropy of a universe modeled as discrete. This might mean that the Universe contains about equal amounts of continuous and discrete structure.

  6. Target-assistant Zn2+-dependent DNAzyme for signal-on electrochemiluminescent biosensing

    International Nuclear Information System (INIS)

    Huang, Yin; Lei, Jianping; Cheng, Yan; Ju, Huangxian

    2015-01-01

    Highlights: • The sensing strategy is based on cleavage reaction of target-assistant Zn 2+ -dependent DNAzyme. • A dual quenching mechanism of ECL is identified. • A sensitive and selective ECL sensor is constructed for detection of ATP. • The biosensor can detect ATP in serum samples with good accuracy. - Abstract: A signal-on electrochemiluminescent (ECL) approach for ultrasensitive ATP detection was developed using target-assistant Zn 2+ -dependent DNAzyme via a dual quenching pathway between quantum dots (QDs) and Au nanoclusters (Au NCs). The facile ECL biosensor was constructed by covalent assembly of Au NCs-labeled hairpin DNA on QDs modified glassy carbon electrode. A dual quenching ECL mechanism was identified to be via resonance energy transfer between QDs and Au NCs and electrocatalytic reduction of coreactant oxygen by Au NCs. With the assistance of two help DNAs, the G-quadruplex structure of ATP aptamer was formed, and thus narrowed the two fragments of Zn 2+ -dependent DNAzyme. In the presence of Zn 2+ , Zn 2+ -dependent DNAzyme can be generated in situ on the biosensor's surface. The as-prepared DNAzyme can cleave the substrate strand, and release the Au NCs from the electrode, resulting in the signal-on ECL state. This biosensor showed good analytical performance with 4 orders magnitude linear range, excellent specificity, and acceptable stability. The biosensor had been applied in detection of ATP in real serum sample and provided significant potential application in clinical analysis

  7. Low-level-signal data acquisition for the MFTF superconducting-magnet system

    International Nuclear Information System (INIS)

    Montoya, C.R.

    1981-01-01

    Acquisition of low level signals from sensors mounted on the superconducting yin-yang magnet in the Mirror Fusion Test Facility (MFTF) imposes very strict requirements on the magnet signal conditioning and data acquisition system. Of the various types of sensors required, thermocouples, strain gages, and voltage taps produce very low level outputs. These low level outputs must be accurately measured in the harsh environment of slowly varying magnetic fields, cryogenic temperatures, high vacuum, pulse power and 60 Hz electrical noise, possible neutron radiation, and high common mode voltage resulting from superconducting magnet quench. Successful measurements require careful attention to grounding, shielding, signal handling and processing in the data acquisition system. The magnet instrumentation system provides a means of effectively measuring both low level signals and high level signals from all types of sensors

  8. Catalase-dependent H2O2 consumption by cardiac mitochondria and redox-mediated loss in insulin signaling.

    Science.gov (United States)

    Rindler, Paul M; Cacciola, Angela; Kinter, Michael; Szweda, Luke I

    2016-11-01

    We have recently demonstrated that catalase content in mouse cardiac mitochondria is selectively elevated in response to high dietary fat, a nutritional state associated with oxidative stress and loss in insulin signaling. Catalase and various isoforms of glutathione peroxidase and peroxiredoxin each catalyze the consumption of H 2 O 2 Catalase, located primarily within peroxisomes and to a lesser extent mitochondria, has a low binding affinity for H 2 O 2 relative to glutathione peroxidase and peroxiredoxin. As such, the contribution of catalase to mitochondrial H 2 O 2 consumption is not well understood. In the current study, using highly purified cardiac mitochondria challenged with micromolar concentrations of H 2 O 2 , we found that catalase contributes significantly to mitochondrial H 2 O 2 consumption. In addition, catalase is solely responsible for removal of H 2 O 2 in nonrespiring or structurally disrupted mitochondria. Finally, in mice fed a high-fat diet, mitochondrial-derived H 2 O 2 is responsible for diminished insulin signaling in the heart as evidenced by reduced insulin-stimulated Akt phosphorylation. While elevated mitochondrial catalase content (∼50%) enhanced the capacity of mitochondria to consume H 2 O 2 in response to high dietary fat, the selective increase in catalase did not prevent H 2 O 2 -induced loss in cardiac insulin signaling. Taken together, our results indicate that mitochondrial catalase likely functions to preclude the formation of high levels of H 2 O 2 without perturbing redox-dependent signaling. Copyright © 2016 the American Physiological Society.

  9. The role of mechanical force and ROS in integrin-dependent signals.

    Directory of Open Access Journals (Sweden)

    Kathrin S Zeller

    Full Text Available Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced by integrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition of ROCK and myosin II activity, i.e. the reactions occurred independently of intracellular contractile force acting on the adhesion sites. The contraction-independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching of the adherent cells induced a robust phosphorylation only of ERK1/2 and the phosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via α5β1 or αvβ3 integrins were detected. The importance of mitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signals induced by cyclic cell stretching, it abolished the activation of AKT and reduced the actin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composed of separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and

  10. Indirect macrophage responses to ionizing radiation: implications for genotype-dependent bystander signaling.

    Science.gov (United States)

    Coates, Philip J; Rundle, Jana K; Lorimore, Sally A; Wright, Eric G

    2008-01-15

    In addition to the directly mutagenic effects of energy deposition in DNA, ionizing radiation is associated with a variety of untargeted and delayed effects that result in ongoing bone marrow damage. Delayed effects are genotype dependent with CBA/Ca mice, but not C57BL/6 mice, susceptible to the induction of damage and also radiation-induced acute myeloid leukemia. Because macrophages are a potential source of ongoing damaging signals, we have determined their gene expression profiles and we show that bone marrow-derived macrophages show widely different intrinsic expression patterns. The profiles classify macrophages derived from CBA/Ca mice as M1-like (pro-inflammatory) and those from C57BL/6 mice as M2-like (anti-inflammatory); measurements of NOS2 and arginase activity in normal bone marrow macrophages confirm these findings. After irradiation in vivo, but not in vitro, C57BL/6 macrophages show a reduction in NOS2 and an increase in arginase activities, indicating a further M2 response, whereas CBA/Ca macrophages retain an M1 phenotype. Activation of specific signal transducer and activator of transcription signaling pathways in irradiated hemopoietic tissues supports these observations. The data indicate that macrophage activation is not a direct effect of radiation but a tissue response, secondary to the initial radiation exposure, and have important implications for understanding genotype-dependent responses and the mechanisms of the hemotoxic and leukemogenic consequences of radiation exposure.

  11. Wise, a context-dependent activator and inhibitor of Wnt signalling.

    Science.gov (United States)

    Itasaki, Nobue; Jones, C Michael; Mercurio, Sara; Rowe, Alison; Domingos, Pedro M; Smith, James C; Krumlauf, Robb

    2003-09-01

    We have isolated a novel secreted molecule, Wise, by a functional screen for activities that alter the anteroposterior character of neuralised Xenopus animal caps. Wise encodes a secreted protein capable of inducing posterior neural markers at a distance. Phenotypes arising from ectopic expression or depletion of Wise resemble those obtained when Wnt signalling is altered. In animal cap assays, posterior neural markers can be induced by Wnt family members, and induction of these markers by Wise requires components of the canonical Wnt pathway. This indicates that in this context Wise activates the Wnt signalling cascade by mimicking some of the effects of Wnt ligands. Activation of the pathway was further confirmed by nuclear accumulation of beta-catenin driven by Wise. By contrast, in an assay for secondary axis induction, extracellularly Wise antagonises the axis-inducing ability of Wnt8. Thus, Wise can activate or inhibit Wnt signalling in a context-dependent manner. The Wise protein physically interacts with the Wnt co-receptor, lipoprotein receptor-related protein 6 (LRP6), and is able to compete with Wnt8 for binding to LRP6. These activities of Wise provide a new mechanism for integrating inputs through the Wnt coreceptor complex to modulate the balance of Wnt signalling.

  12. Emitter signal separation method based on multi-level digital channelization

    Science.gov (United States)

    Han, Xun; Ping, Yifan; Wang, Sujun; Feng, Ying; Kuang, Yin; Yang, Xinquan

    2018-02-01

    To solve the problem of emitter separation under complex electromagnetic environment, a signal separation method based on multi-level digital channelization is proposed in this paper. A two-level structure which can divide signal into different channel is designed first, after that, the peaks of different channels are tracked using the track filter and the coincident signals in time domain are separated in time-frequency domain. Finally, the time domain waveforms of different signals are acquired by reverse transformation. The validness of the proposed method is proved by experiment.

  13. Simulation of design dependent failure exposure levels for CMOS ICs

    International Nuclear Information System (INIS)

    Kaul, N.; Bhuva, B.L.; Rangavajjhala, V.; van der Molen, H.; Kerns, S.E.

    1990-01-01

    The total dose exposure of CMOS ICs introduces bias-dependent parameter shifts in individual devices. The bias dependency of individual parameter shifts of devices cause different designs to behave differently under identical testing conditions. This paper studies the effect of design and bias on the radiation tolerance of ICs and presents an automated design tool that produces different designs for a logic function, and presents important parameters of each design to circuit designer for trade off analysis

  14. The canonical wnt signal restricts the glycogen synthase kinase 3/fbw7-dependent ubiquitination and degradation of eya1 phosphatase.

    Science.gov (United States)

    Sun, Ye; Li, Xue

    2014-07-01

    Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1(+/-); Wnt9b(+/-) mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  15. Reducing the substrate dependent scanner leveling effect in low-k1 contact printing

    Science.gov (United States)

    Chang, C. S.; Tseng, C. F.; Huang, C. H.; Yang, Elvis; Yang, T. H.; Chen, K. C.

    2015-03-01

    As the scaling down of design rule for high-density memory device, the small depth of focus (DoF) budget may be deteriorated by focus leveling errors, which arises in unpredicted reflectivity from multilayer structures on the topographic wafer. The leveling sensors of ASML scanner use near infrared (NIR) range wavelength which can penetrate through most of films using in semiconductor fabrication such as photo-resist, bottom anti reflective coating (BARC) and dielectric materials. Consequently, the reflected light from underlying substructures would disturb leveling sensors from accurate leveling. The different pattern densities and layout characteristics between array and periphery of a memory chip are expected to result in different leveling signals. Furthermore, the process dependent variations between wafer central and edge areas are also considered to yield different leveling performances during wafer exposure. In this study, lower blind contact immunity was observed for peripheral contacts comparing to the array contacts especially around wafer edge region. In order to overcome this problem, a series of investigations have been carried out. The wafer edge leveling optimization through circuit dependent focus edge clearance (CDFEC) option doesn't get improvement. Air gauge improved process leveling (AGILE) function of ASML immersion scanner doesn't show improved result either. The ILD uniformity improvement and step height treatments around wafer edge such as edge exclusion of film deposition and bevel etching are also ineffective to mitigate the blind contact problem of peripheral patterns. Altering the etch hard-mask stack is finally found to be an effective approach to alleviate the issue. For instance, through either containing high temperature deposition advanced patterning film (APF) in the hard-mask or inserting higher opaque film such as amorphous Si in between the hard-mask stack.

  16. Determination of noise sources and space-dependent reactor transfer functions from measured output signals only

    Energy Technology Data Exchange (ETDEWEB)

    Hoogenboom, J.E.; van Dam, H.; Kleiss, E.B.J.; van Uitert, G.C.; Veldhuis, D.

    1982-01-01

    The measured cross power spectral densities of the signals from three neutron detectors and the displacement of the control rod of the 2 MW research reactor HOR at Delft have been used to determine the space-dependent reactor transfer function, the transfer function of the automatic reactor control system and the noise sources influencing the measured signals. From a block diagram of the reactor with control system and noise sources expressions were derived for the measured cross power spectral densities, which were adjusted to satisfy the requirements following from the adopted model. Then for each frequency point the required transfer functions and noise sources could be derived. The results are in agreement with those of autoregressive modelling of the reactor control feed-back loop. A method has been developed to determine the non-linear characteristics of the automatic reactor control system by analysing the non-gaussian probability density function of the power fluctuations.

  17. Determination of noise sources and space-dependent reactor transfer functions from measured output signals only

    International Nuclear Information System (INIS)

    Hoogenboom, J.E.

    1982-01-01

    The measured cross power spectral densities of the signals from three neutron detectors and the displacement of the control rod of the 2 MW research reactor HOR at Delft have been used to determine the space-dependent reactor transfer function, the transfer function of the automatic reactor control system and the noise sources influencing the measured signals. From a block diagram of the reactor with control system and noise sources expressions were derived for the measured cross power spectral densities, which were adjusted to satisfy the requirements following from the adopted model. Then for each frequency point the required transfer functions and noise sources could be derived. The results are in agreement with those of autoregressive modelling of the reactor control feed-back loop. A method has been developed to determine the non-linear characteristics of the automatic reactor control system by analysing the non-gaussian probability density function of the power fluctuations. (author)

  18. BMAL1-dependent regulation of the mTOR signaling pathway delays aging.

    Science.gov (United States)

    Khapre, Rohini V; Kondratova, Anna A; Patel, Sonal; Dubrovsky, Yuliya; Wrobel, Michelle; Antoch, Marina P; Kondratov, Roman V

    2014-01-01

    The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.

  19. IQGAP1-dependent signaling pathway regulates endothelial cell proliferation and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Rosana D Meyer

    Full Text Available Vascular endothelial growth factor receptor-2 (VEGFR-2 signaling is an obligate requirement for normal development and pathological angiogenesis such as cancer and age-related macular degeneration. Although autophosphorylation of tyrosine 1173 (Y1173 of VEGFR-2 is considered a focal point for its angiogenic signal relay, however, the mechanism of phosphorylation of Y1173, signaling proteins that are recruited to this residue and their role in angiogenesis is not fully understood.In this study we demonstrate that c-Src kinase directly through its Src homology 2 (SH2 domain and indirectly via c-Cbl binds to phospho-Y1057 of VEGFR-2. Activation of c-Src kinase by a positive feedback mechanism phosphorylates VEGFR-2 at multi-docking site, Y1173. c-Src also catalyzes tyrosine phosphorylation of IQGAP1 and acts as an adaptor to bridge IQGAP1 to VEGFR-2. In turn, IQGAP1 activates b-Raf and mediates proliferation of endothelial cells. Silencing expression of IQGAP1 and b-Raf revealed that their activity is essential for VEGF to stimulate angiogenesis in an in vivo angiogenesis model of chicken chorioallantoic membrane (CAM.Angiogenesis contributes to the pathology of numerous human diseases ranging from cancer to age-related macular degeneration. Determining molecular mechanism of tyrosine phosphorylation of VEGFR-2 and identification of molecules that are relaying its angiogenic signaling may identify novel targets for therapeutic intervention against angiogenesis-associated diseases. Our study shows that recruitment and activation of c-Src by VEGFR-2 plays a pivotal role in relaying angiogenic signaling of VEGFR-2; it phosphorylates VEGFR-2 at Y1173, facilitates association and activation of IQGAP1 and other signaling proteins to VEGFR-2. IQGAP1-dependent signaling, in part, is critically required for endothelial cell proliferation, a key step in angiogenesis. Thus, Y1057 of VEGFR-2 serves to regulate VEGFR-2 function in a combinatorial manner by

  20. Response of tobacco to the Pseudomonas syringae pv. Tomato DC3000 is mainly dependent on salicylic acid signaling pathway.

    Science.gov (United States)

    Liu, Yang; Wang, Li; Cai, Guohua; Jiang, Shanshan; Sun, Liping; Li, Dequan

    2013-07-01

    Pseudomonas syringae pv. Tomato DC3000 (Pst DC3000) was the first pathogen to be demonstrated to infect Arabidopsis and to cause disease symptoms in the laboratory setting. However, the defense response to Pst DC3000 was unclear in tobacco. In this report, the expression profiles of twelve defense response-related genes were analyzed after treatment with salicylic acid (SA), jasmonic acid (JA), and pathogen Pst DC3000 by qRT-PCR. According to our results, it could be presented that the genes primarily induced by SA were also induced to higher levels after Pst DC3000 infection. SA accumulation could be induced to a higher level than that of JA after Pst DC3000 infection. In addition, SA could result in hypersensitive response (HR), which did not completely depend on accumulation of reactive oxygen species. These results indicated that tobacco mainly depended on SA signaling pathway rather than on JA signaling pathway in response to Pst DC3000. Further study demonstrated that JA could significantly inhibit the accumulation of SA and the generation of the HR induced by Pst DC3000. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  1. A nested modeling study of elevation-dependent climate change signals in California induced by increased atmospheric CO2

    International Nuclear Information System (INIS)

    Kim, Jinwon

    2001-01-01

    Dynamically downscaled climate change signals due to increased atmospheric CO2 are investigated for three California basins. The downscaled signals show strong elevation dependence, mainly due to elevated freezing levels in the increased CO2 climate. Below 2.5 km, rainfall increases by over 150% while snowfall decreases by 20-40% in the winter. Above 2.5 km, rainfall and snowfall both increase in the winter, as the freezing levels appear mostly below this level. Winter snowmelt increases in all elevations due to warmer temperatures in the increased CO2 climate. Reduced snowfall and enhanced snowmelt during the winter decreases snowmelt-driven spring runoff below the 2.5 km level, where the peak snowmelt occurs one month earlier in the increased CO2 climate. Above 2.5km, increased winter snowfall maintains snowmelt-driven runoff through most of the warm season. The altered hydrologic characteristics in the increased CO2 climate affect the diurnal temperature variation mainly via snow-albedo-soil moisture feedback

  2. Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

    Science.gov (United States)

    Sears, James C.; Broadie, Kendal

    2018-01-01

    Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans-synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the

  3. Spatio-temporal Model of Endogenous ROS and Raft-Dependent WNT/Beta-Catenin Signaling Driving Cell Fate Commitment in Human Neural Progenitor Cells

    Science.gov (United States)

    Haack, Fiete; Lemcke, Heiko; Ewald, Roland; Rharass, Tareck; Uhrmacher, Adelinde M.

    2015-01-01

    Canonical WNT/β-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/β-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear β-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of β-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/β-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream β-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/β-catenin signal or as amplifier during continuous auto-/parcrine WNT/β-catenin signaling. In addition we provide the first stochastic computational model of WNT/β-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent β-catenin activation. The model’s predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the

  4. 4EBP-Dependent Signaling Supports West Nile Virus Growth and Protein Expression

    Directory of Open Access Journals (Sweden)

    Katherine D. Shives

    2016-10-01

    Full Text Available West Nile virus (WNV is a (+ sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an m7GpppNm 5′ cap with 2′-O-methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1 for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown. In this study, we utilize gene deletion mutants in the ribosomal protein kinase called S6 kinase (S6K and eukaryotic translation initiation factor 4E-binding protein (4EBP pathways downstream of mTORC1 to define the role of mTOR-dependent translation initiation signals in WNV gene expression and growth. We now show that WNV growth and protein expression are dependent on mTORC1 mediated-regulation of the eukaryotic translation initiation factor 4E-binding protein/eukaryotic translation initiation factor 4E-binding protein (4EBP/eIF4E interaction and eukaryotic initiation factor 4F (eIF4F complex formation to support viral growth and viral protein expression. We also show that the canonical signals of mTORC1 activation including ribosomal protein s6 (rpS6 and S6K phosphorylation are not required for WNV growth in these same conditions. Our data suggest that the mTORC1/4EBP/eIF4E signaling axis is activated to support the translation of the WNV genome.

  5. 4EBP-Dependent Signaling Supports West Nile Virus Growth and Protein Expression.

    Science.gov (United States)

    Shives, Katherine D; Massey, Aaron R; May, Nicholas A; Morrison, Thomas E; Beckham, J David

    2016-10-18

    West Nile virus (WNV) is a (+) sense, single-stranded RNA virus in the Flavivirus genus. WNV RNA possesses an m7 GpppN m 5' cap with 2'- O -methylation that mimics host mRNAs preventing innate immune detection and allowing the virus to translate its RNA genome through the utilization of cap-dependent translation initiation effectors in a wide variety of host species. Our prior work established the requirement of the host mammalian target of rapamycin complex 1 (mTORC1) for optimal WNV growth and protein expression; yet, the roles of the downstream effectors of mTORC1 in WNV translation are unknown. In this study, we utilize gene deletion mutants in the ribosomal protein kinase called S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4EBP) pathways downstream of mTORC1 to define the role of mTOR-dependent translation initiation signals in WNV gene expression and growth. We now show that WNV growth and protein expression are dependent on mTORC1 mediated-regulation of the eukaryotic translation initiation factor 4E-binding protein/eukaryotic translation initiation factor 4E-binding protein (4EBP/eIF4E) interaction and eukaryotic initiation factor 4F (eIF4F) complex formation to support viral growth and viral protein expression. We also show that the canonical signals of mTORC1 activation including ribosomal protein s6 (rpS6) and S6K phosphorylation are not required for WNV growth in these same conditions. Our data suggest that the mTORC1/4EBP/eIF4E signaling axis is activated to support the translation of the WNV genome.

  6. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression.

    Directory of Open Access Journals (Sweden)

    Eva-K Pauli

    2008-11-01

    Full Text Available The type I interferon (IFN system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNbeta gene induction via action of the viral non-structural protein 1 (NS1. Here we present data indicating that influenza A viruses not only suppress IFNbeta gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3 protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNalpha/beta, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1 was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 5' triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA- and nuclear factor kappa B (NF-kappaB-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response.

  7. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ signaling

    Directory of Open Access Journals (Sweden)

    Manuel Francisco Muñoz

    2015-03-01

    Full Text Available Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30 and channels formed by pannexins (Panx-1. The neuronal activity-initiated Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO can activate connexin hemichannel by S-nitrosylation and the Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS and neuronal NOS (nNOS are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in

  8. Indirect estimation of signal-dependent noise with nonadaptive heterogeneous samples.

    Science.gov (United States)

    Azzari, Lucio; Foi, Alessandro

    2014-08-01

    We consider the estimation of signal-dependent noise from a single image. Unlike conventional algorithms that build a scatterplot of local mean-variance pairs from either small or adaptively selected homogeneous data samples, our proposed approach relies on arbitrarily large patches of heterogeneous data extracted at random from the image. We demonstrate the feasibility of our approach through an extensive theoretical analysis based on mixture of Gaussian distributions. A prototype algorithm is also developed in order to validate the approach on simulated data as well as on real camera raw images.

  9. Study of excitation energy dependence of nuclear level density parameter

    International Nuclear Information System (INIS)

    Mohanto, G.; Nayak, B.K.; Saxena, A.

    2016-01-01

    In the present study, we have populated CN by fusion reaction and excitation energy of the intermediate nuclei is determined after first chance α-emission to investigate excitation energy dependence of the NLD parameter. Evaporated neutron spectra were measured following alpha evaporation for obtaining NLD parameter for the reaction 11 B + 197 Au, populating CN 208 Po. This CN after evaporating an α-particle populates intermediate nucleus 204 Pb. The 204 Pb has magic number of Z=82. Our aim is to study the excitation energy dependence of NLD parameter for closed shell nuclei

  10. Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

    Science.gov (United States)

    Suchankova, Petra; Jerlhag, Elisabet; Jayaram-Lindström, Nitya; Nilsson, Staffan; Toren, Kjell; Rosengren, Annika; Engel, Jörgen A; Franck, Johan

    2013-01-01

    The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL) as well as GHS-R1A (GHSR) genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs) and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104) and controls from the general population (n = 310). A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI) composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02). A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03). The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

  11. Genetic variation of the ghrelin signalling system in individuals with amphetamine dependence.

    Directory of Open Access Journals (Sweden)

    Petra Suchankova

    Full Text Available The development of amphetamine dependence largely depends on the effects of amphetamine in the brain reward systems. Ghrelin, an orexigenic peptide, activates the reward systems and is required for reward induced by alcohol, nicotine, cocaine and amphetamine in mice. Human genetic studies have shown that polymorphisms in the pre-proghrelin (GHRL as well as GHS-R1A (GHSR genes are associated with high alcohol consumption, increased weight and smoking in males. Since the heritability factor underlying drug dependence is shared between different drugs of abuse, we here examine the association between single nucleotide polymorphisms (SNPs and haplotypes in the GHRL and GHSR, and amphetamine dependence. GHRL and GHSR SNPs were genotyped in Swedish amphetamine dependent individuals (n = 104 and controls from the general population (n = 310. A case-control analysis was performed and SNPs and haplotypes were additionally tested for association against Addiction Severity Interview (ASI composite score of drug use. The minor G-allele of the GHSR SNP rs2948694, was more common among amphetamine dependent individuals when compared to controls (pc  = 0.02. A significant association between the GHRL SNP rs4684677 and ASI composite score of drug use was also reported (pc  = 0.03. The haplotype analysis did not add to the information given by the individual polymorphisms. Although genetic variability of the ghrelin signalling system is not a diagnostic marker for amphetamine dependence and problem severity of drug use, the present results strengthen the notion that ghrelin and its receptor may be involved in the development of addictive behaviours and may thus serve as suitable targets for new treatments of such disorders.

  12. Variation in regulator of G-protein signaling 17 gene (RGS17 is associated with multiple substance dependence diagnoses

    Directory of Open Access Journals (Sweden)

    Zhang Huiping

    2012-05-01

    Full Text Available Abstract Background RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. Methods The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs was examined with four substance dependence diagnoses (alcohol (AD, cocaine (CD, opioid (OD or marijuana (MjD] in 1,905 African Americans (AAs: 1,562 cases and 343 controls and 1,332 European Americans (EAs: 981 cases and 351 controls. Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Results Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤Pempirical≤0.037. The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤Pempirical≤0.019. This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002 and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185. No RGS20 SNPs were associated with any of the four dependence traits in either population. Conclusions This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations.

  13. Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway

    Directory of Open Access Journals (Sweden)

    Yeh Siang Lau

    2015-06-01

    Full Text Available Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE, also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma “antihypertensive tea” is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs. Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase, wortmannin (30 nM and LY294002 (20 µM; PI3 (phosphatidylinositol3-Kinase inhibitor, NG-nitro-l-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS and ODQ (1 µM; soluble guanylyl cyclase inhibitor. Total nitrite and nitrate (NOx level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.

  14. Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression.

    Science.gov (United States)

    Zhang, Baochun; Crankshaw, Will; Nesemeier, Ryan; Patel, Jay; Nweze, Ikenna; Lakshmanan, Jaganathan; Harbrecht, Brian G

    2015-02-01

    Induced nitric oxide synthase (iNOS) is induced in hepatocytes by shock and inflammatory stimuli. Excessive NO from iNOS mediates shock-induced hepatic injury and death, so understanding the regulation of iNOS will help elucidate the pathophysiology of septic shock. In vitro, cytokines induce iNOS expression through activation of signaling pathways including mitogen-activated protein kinases and nuclear factor κB. Cytokines also induce calcium (Ca(2+)) mobilization and activate calcium-mediated intracellular signaling pathways, typically through activation of calmodulin-dependent kinases (CaMK). Calcium regulates NO production in macrophages but the role of calcium and calcium-mediated signaling in hepatocyte iNOS expression has not been defined. Primary rat hepatocytes were isolated, cultured, and induced to produce NO with proinflammatory cytokines. Calcium mobilization and Ca(2+)-mediated signaling were altered with ionophore, Ca(2+) channel blockers, and inhibitors of CaMK. The Ca(2+) ionophore A23187 suppressed cytokine-stimulated NO production, whereas Ethylene glycol tetraacetic acid and nifedipine increased NO production, iNOS messenger RNA, and iNOS protein expression. Inhibition of CaMK with KN93 and CBD increased NO production but the calcineurin inhibitor FK 506 decreased iNOS expression. These data demonstrate that calcium-mediated signaling regulates hepatocyte iNOS expression and does so through a mechanism independent of calcineurin. Changes in intracellular calcium levels may regulate iNOS expression during hepatic inflammation induced by proinflammatory cytokines. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. High levels of Notch signaling down-regulate Numb and Numblike

    NARCIS (Netherlands)

    Chapman, G.; Liu, L.; Sahlgren, C.; Dahlqvist, C.; Lendahl, U.

    2006-01-01

    Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch,

  16. SERUM ACETYLCHOLINESTERASE LEVEL IN THE PATIENTS OF OPIOID (BROWN SUGAR) DEPENDENCE

    OpenAIRE

    Shah, Nilesh; Dave, Kirti

    1992-01-01

    The authors compared the serum acetylcholinesterase level in the patients of brown sugar dependence and the normal volunteers. Significantly lower level of serum acetylcholinesterase was found in patients of brown sugar dependence.

  17. A Plant Phytosulfokine Peptide Initiates Auxin-Dependent Immunity through Cytosolic Ca2+ Signaling in Tomato.

    Science.gov (United States)

    Zhang, Huan; Hu, Zhangjian; Lei, Cui; Zheng, Chenfei; Wang, Jiao; Shao, Shujun; Li, Xin; Xia, Xiaojian; Cai, Xinzhong; Zhou, Jie; Zhou, Yanhong; Yu, Jingquan; Foyer, Christine H; Shi, Kai

    2018-03-01

    Phytosulfokine (PSK) is a disulfated pentapeptide that is an important signaling molecule. Although it has recently been implicated in plant defenses to pathogen infection, the mechanisms involved remain poorly understood. Using surface plasmon resonance and gene silencing approaches, we showed that the tomato ( Solanum lycopersicum ) PSK receptor PSKR1, rather than PSKR2, functioned as the major PSK receptor in immune responses. Silencing of PSK signaling genes rendered tomato more susceptible to infection by the economically important necrotrophic pathogen Botrytis cinerea Analysis of tomato mutants defective in either defense hormone biosynthesis or signaling demonstrated that PSK-induced immunity required auxin biosynthesis and associated defense pathways. Here, using aequorin-expressing tomato plants, we provide evidence that PSK perception by tomato PSKR1 elevated cytosolic [Ca 2+ ], leading to auxin-dependent immune responses via enhanced binding activity between calmodulins and the auxin biosynthetic YUCs. Thus, our data demonstrate that PSK acts as a damage-associated molecular pattern and is perceived mainly by PSKR1, which increases cytosolic [Ca 2+ ] and activates auxin-mediated pathways that enhance immunity of tomato plants to B. cinerea . © 2018 American Society of Plant Biologists. All rights reserved.

  18. Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes.

    Science.gov (United States)

    Beauchemin, Hugues; Shooshtarizadeh, Peiman; Vadnais, Charles; Vassen, Lothar; Pastore, Yves D; Möröy, Tarik

    2017-03-01

    Mutations in GFI1B are associated with inherited bleeding disorders called GFI1B -related thrombocytopenias. We show here that mice with a megakaryocyte-specific Gfi1b deletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent of GFI1B -related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. Gfi1b -null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of α-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of Gfi1b -null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that Gfi1b controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient α-tubulin content. Copyright© Ferrata Storti Foundation.

  19. Satellite single-axis attitude determination based on Automatic Dependent Surveillance - Broadcast signals

    Science.gov (United States)

    Zhou, Kaixing; Sun, Xiucong; Huang, Hai; Wang, Xinsheng; Ren, Guangwei

    2017-10-01

    The space-based Automatic Dependent Surveillance - Broadcast (ADS-B) is a new technology for air traffic management. The satellite equipped with spaceborne ADS-B system receives the broadcast signals from aircraft and transfers the message to ground stations, so as to extend the coverage area of terrestrial-based ADS-B. In this work, a novel satellite single-axis attitude determination solution based on the ADS-B receiving system is proposed. This solution utilizes the signal-to-noise ratio (SNR) measurement of the broadcast signals from aircraft to determine the boresight orientation of the ADS-B receiving antenna fixed on the satellite. The basic principle of this solution is described. The feasibility study of this new attitude determination solution is implemented, including the link budget and the access analysis. On this basis, the nonlinear least squares estimation based on the Levenberg-Marquardt method is applied to estimate the single-axis orientation. A full digital simulation has been carried out to verify the effectiveness and performance of this solution. Finally, the corresponding results are processed and presented minutely.

  20. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

    International Nuclear Information System (INIS)

    Yano, Fumiko; Kugimiya, Fumitaka; Ohba, Shinsuke; Ikeda, Toshiyuki; Chikuda, Hirotaka; Ogasawara, Toru; Ogata, Naoshi; Takato, Tsuyoshi; Nakamura, Kozo; Kawaguchi, Hiroshi; Chung, Ung-il

    2005-01-01

    To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (Canada) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of β-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

  1. Dependence of the subharmonic signal from contrast agent microbubbles on ambient pressure: A theoretical analysis.

    Science.gov (United States)

    Jiménez-Fernández, J

    2018-01-01

    This paper investigates the dependence of the subharmonic response in a signal scattered by contrast agent microbubbles on ambient pressure to provide quantitative estimations of local blood pressure. The problem is formulated by assuming a gas bubble encapsulated by a shell of finite thickness with dynamic behavior modeled by a nonlinear viscoelastic constitutive equation. For ambient overpressure compatible with the clinical range, the acoustic pressure intervals where the subharmonic signal may be detected (above the threshold for the onset and below the limit value for the first chaotic transition) are determined. The analysis shows that as the overpressure is increased, all harmonic components are displaced to higher frequencies. This displacement is significant for the subharmonic of order 1/2 and explains the increase or decrease in the subharmonic amplitude with ambient pressure described in previous works. Thus, some questions related to the monotonic dependence of the subharmonic amplitude on ambient pressure are clarified. For different acoustic pressures, quantitative conditions for determining the intervals where the subharmonic amplitude is a monotonic or non-monotonic function of the ambient pressure are provided. Finally, the influence of the ambient pressure on the subharmonic resonance frequency is analyzed.

  2. Intracellular calcium levels can regulate Importin-dependent nuclear import

    International Nuclear Information System (INIS)

    Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A.

    2014-01-01

    Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca 2+ on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery

  3. Intracellular calcium levels can regulate Importin-dependent nuclear import

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A., E-mail: David.Jans@monash.edu

    2014-07-18

    Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca{sup 2+} on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 and Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery.

  4. Stat3 signaling regulates embryonic stem cell fate in a dose-dependent manner

    Directory of Open Access Journals (Sweden)

    Chih-I Tai

    2014-09-01

    Full Text Available Stat3 is essential for mouse embryonic stem cell (mESC self-renewal mediated by LIF/gp130 receptor signaling. Current understanding of Stat3-mediated ESC self-renewal mechanisms is very limited, and has heretofore been dominated by the view that Stat3 signaling functions in a binary “on/off” manner. Here, in contrast to this binary viewpoint, we demonstrate a contextual, rheostat-like mechanism for Stat3's function in mESCs. Activation and expression levels determine whether Stat3 functions in a self-renewal or a differentiation role in mESCs. We also show that Stat3 induces rapid differentiation of mESCs toward the trophectoderm (TE lineage when its activation level exceeds certain thresholds. Stat3 induces this differentiation phenotype via induction of Tfap2c and its downstream target Cdx2. Our findings provide a novel concept in the realm of Stat3, self-renewal signaling, and pluripotent stem cell biology. Ultimately, this finding may facilitate the development of conditions for the establishment of authentic non-rodent ESCs.

  5. Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks

    International Nuclear Information System (INIS)

    Fukumoto, Yasunori; Kuki, Kazumasa; Morii, Mariko; Miura, Takahito; Honda, Takuya; Ishibashi, Kenichi; Hasegawa, Hitomi; Kubota, Sho; Ide, Yudai; Yamaguchi, Noritaka; Nakayama, Yuji; Yamaguchi, Naoto

    2014-01-01

    Highlights: • Inhibition of Src family kinases decreased γ-H2AX signal. • Inhibition of Src family increased ATM-dependent phosphorylation of Chk2 and Kap1. • shRNA-mediated knockdown of Lyn increased phosphorylation of Kap1 by ATM. • Ectopic expression of Src family kinase suppressed ATM-mediated Kap1 phosphorylation. • Src is involved in upstream signaling for inactivation of ATM signaling. - Abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint

  6. Herbivore-specific, density-dependent induction of plant volatiles: honest or "cry wolf" signals?

    Directory of Open Access Journals (Sweden)

    Kaori Shiojiri

    Full Text Available Plants release volatile chemicals upon attack by herbivorous arthropods. They do so commonly in a dose-dependent manner: the more herbivores, the more volatiles released. The volatiles attract predatory arthropods and the amount determines the probability of predator response. We show that seedlings of a cabbage variety (Brassica oleracea var. capitata, cv Shikidori also show such a response to the density of cabbage white (Pieris rapae larvae and attract more (naive parasitoids (Cotesia glomerata when there are more herbivores on the plant. However, when attacked by diamondback moth (Plutella xylostella larvae, seedlings of the same variety (cv Shikidori release volatiles, the total amount of which is high and constant and thus independent of caterpillar density, and naive parasitoids (Cotesia vestalis of diamondback moth larvae fail to discriminate herbivore-rich from herbivore-poor plants. In contrast, seedlings of another cabbage variety of B. oleracea (var. acephala: kale respond in a dose-dependent manner to the density of diamondback moth larvae and attract more parasitoids when there are more herbivores. Assuming these responses of the cabbage cultivars reflect behaviour of at least some genotypes of wild plants, we provide arguments why the behaviour of kale (B. oleracea var acephala is best interpreted as an honest signaling strategy and that of cabbage cv Shikidori (B. oleracea var capitata as a "cry wolf" signaling strategy, implying a conflict of interest between the plant and the enemies of its herbivores: the plant profits from being visited by the herbivore's enemies, but the latter would be better off by visiting other plants with more herbivores. If so, evolutionary theory on alarm signaling predicts consequences of major interest to students of plant protection, tritrophic systems and communication alike.

  7. Adaptive EMG noise reduction in ECG signals using noise level approximation

    Science.gov (United States)

    Marouf, Mohamed; Saranovac, Lazar

    2017-12-01

    In this paper the usage of noise level approximation for adaptive Electromyogram (EMG) noise reduction in the Electrocardiogram (ECG) signals is introduced. To achieve the adequate adaptiveness, a translation-invariant noise level approximation is employed. The approximation is done in the form of a guiding signal extracted as an estimation of the signal quality vs. EMG noise. The noise reduction framework is based on a bank of low pass filters. So, the adaptive noise reduction is achieved by selecting the appropriate filter with respect to the guiding signal aiming to obtain the best trade-off between the signal distortion caused by filtering and the signal readability. For the evaluation purposes; both real EMG and artificial noises are used. The tested ECG signals are from the MIT-BIH Arrhythmia Database Directory, while both real and artificial records of EMG noise are added and used in the evaluation process. Firstly, comparison with state of the art methods is conducted to verify the performance of the proposed approach in terms of noise cancellation while preserving the QRS complex waves. Additionally, the signal to noise ratio improvement after the adaptive noise reduction is computed and presented for the proposed method. Finally, the impact of adaptive noise reduction method on QRS complexes detection was studied. The tested signals are delineated using a state of the art method, and the QRS detection improvement for different SNR is presented.

  8. Online Activity Levels Are Related to Caffeine Dependency.

    Science.gov (United States)

    Phillips, James G; Landhuis, C Erik; Shepherd, Daniel; Ogeil, Rowan P

    2016-05-01

    Online activity could serve in the future as behavioral markers of emotional states for computer systems (i.e., affective computing). Hence, this study considered relationships between self-reported stimulant use and online study patterns. Sixty-two undergraduate psychology students estimated their daily caffeine use, and this was related to study patterns as tracked by their use of a Learning Management System (Blackboard). Caffeine dependency was associated with less time spent online, lower rates of file access, and fewer online activities completed. Reduced breadth or depth of processing during work/study could be used as a behavioral marker of stimulant use.

  9. Loneliness depends on salivary estradiol levels in adolescent females.

    Science.gov (United States)

    Fujisawa, Takashi X; Nishitani, Shota; Obara, Tatsuro; Shinohara, Kazuyuki

    2012-01-01

    Loneliness is one of the psychological characteristics in adolescence, during which sex hormones are elevated. The elevation of sex steroid hormones is known to sculpture and remodel neuronal circuits, which cause behavioral characteristics in adolescence. The aim of the present study is to investigate the relationship between loneliness and sex steroid hormones, testosterone (T) and 17β-estradiol (E2). Fifty-eight adolescents (28 boys and 30 girls) participated in this study. The salivary levels of T and E2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Loneliness was assessed by the UCLA loneliness scale, which is widely used as a self-administered questionnaire. The results showed that Salivary E2 levels had positive relevance to loneliness in females, whereas there was no relationship in males. Salivary T level was not shown to be relevant with loneliness in either sex group. These findings suggest that E2 has gender specific effects on loneliness in adolescent females.

  10. The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae

    Science.gov (United States)

    Apostolopoulou, Anthi A.; Mazija, Lorena; Wüst, Alexander; Thum, Andreas S.

    2014-01-01

    The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs. PMID:24478653

  11. Signals for transversity and transverse-momentum-dependent quark distribution functions studied at the HERMES experiment

    Energy Technology Data Exchange (ETDEWEB)

    Diefenthaler, Markus

    2010-08-15

    Intention of the present thesis was the study of transverse-momentum dependent quark distribution functions. In the focus stood the Fourier analysis of azimutal single-spin asymmetries of pions and charged kaons performed within the HERMES experiment. These asymmetries were reconstructed from deep-inelastic scattering events on a transversely polarized proton target and decomposed in Fourier components. In the framework of quantum chromodynamics such components can be interpreted as folding of quark distribution and fragmentation functions. By the analysis of the transverse-momentum dependent quark distribution functions the study of spin-orbit correlations in the internal of the nucleon was made possible. By this conclusions on the orbital angular momentum of the quarks can be drawn. The extracted Fourier components extend the hitherto available informations on the transverse-momentum dependent quark distribution functions remarkably. The presented Fourier analysis made not only a detection of the Collins and Sivers effects possible, but beyond the extraction of the signals of the pretzelosity and worm-gear distributions. The so obtained results will conclusively contribute to the understanding of future measurements in this field and furthermore make possible a test of fundamental predictions of quantum chromodynamics.

  12. Serum Levels of the Adipokine Progranulin Depend on Renal Function

    Science.gov (United States)

    Richter, Judit; Focke, Denise; Ebert, Thomas; Kovacs, Peter; Bachmann, Anette; Lössner, Ulrike; Kralisch, Susan; Kratzsch, Jürgen; Beige, Joachim; Anders, Matthias; Bast, Ingolf; Blüher, Matthias; Stumvoll, Michael; Fasshauer, Mathias

    2013-01-01

    OBJECTIVE Progranulin has recently been introduced as a novel adipokine inducing insulin resistance and obesity. In the current study, we investigated renal elimination, as well as association of the adipokine with markers of the metabolic syndrome. RESEARCH DESIGN AND METHODS Progranulin serum levels were quantified by enzyme-linked immunosorbent assay and correlated to anthropometric and biochemical parameters of renal function and glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1–5 of chronic kidney disease (CKD). RESULTS Median serum progranulin levels adjusted for age, sex, and BMI were significantly different between CKD stages with highest values detectable in stage 5 (stage 1, 58.3 µg/L; stage 2, 63.0 µg/L; stage 3, 65.4 µg/L; stage 4, 68.8 µg/L; and stage 5, 90.6 µg/L). Furthermore, CKD stage was the strongest independent predictor of circulating progranulin in our cohort. In addition, high-sensitivity interleukin-6 and adiponectin remained significantly and independently correlated with the adipokine. CONCLUSIONS We demonstrate that progranulin serum levels increase with deteriorating renal function. These findings are in accordance with the hypothesis that renal clearance is a major elimination route for circulating progranulin. Furthermore, the adipokine is positively and independently associated with markers of inflammation and adiponectin. PMID:23033238

  13. Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats.

    Science.gov (United States)

    Pan, Bo; Huang, Xu-Feng; Deng, Chao

    2016-03-28

    Aripiprazole, a dopamine D₂ receptor (D₂R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D₂R antagonist) and bifeprunox (a D₂R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D₂Rs.

  14. TNF-α- Mediated-p38-Dependent Signaling Pathway Contributes to Myocyte Apoptosis in Rats Subjected to Surgical Trauma

    Directory of Open Access Journals (Sweden)

    Huaxing Wu

    2015-03-01

    Full Text Available Background: The accumulation of cytokines in the plasma after trauma can induce myocyte apoptosis. We aimed to identify which cytokine(s present in the plasma responsible for myocyte apoptosis, and delineated the signal transduction mechanism in rats subjected to surgical trauma. Methods: Rats were randomized into two groups: control and trauma groups, which was divided into five subgroups: posttraumatic 0, 3, 6, 12, and 24 h subgroups. Cardiomyocytes isolated from traumatized rats were incubated with one of the factors for 12 h (normal plasma; Cytomix; TNF-α; IL-1β; IFN-γ; trauma plasma; anti-TNF-α antibody; SB203580. Myocyte apoptosis, cytokine levels, and MAPKs activation, as the primary experimental outcomes, were measured by TUNEL, flow cytometry, ELISA and Western blot, respectively. Results: Myocyte apoptosis was induced by surgical trauma during the early stage after trauma. Accompanying this change, plasma TNF-α, IL-1β, and IFN-γ levels were elevated in traumatized rats. Incubation of traumatized cardiomyocytes with cytomix or TNF-α alone induced myocyte apoptosis, and increased the activation of p38 and ERK1/2. Myocyte apoptosis and p38 activation were elevated in traumatized cardiomyocytes with trauma plasma, and these increases were partly abolished by anti-TNF-α antibody or SB203580. Conclusion: Our study demonstrated that there exists the TNF-α-mediated-p38-dependent signaling pathway that contributed to posttraumatic myocyte apoptosis of rats undergoing surgical trauma.

  15. Transcriptomic Analysis Of Purified Embryonic Neural Stem Cells From Zebrafish Embryos Reveals Signalling Pathways Involved In Glycine-dependent Neurogenesis

    Directory of Open Access Journals (Sweden)

    Eric eSAMARUT

    2016-03-01

    Full Text Available How is the initial set of neurons correctly established during the development of the vertebrate central nervous system? In the embryo, glycine and GABA are depolarizing due the immature chloride gradient, which is only reversed to become hyperpolarizing later in post-natal development. We previously showed that glycine regulates neurogenesis via paracrine signalling that promotes calcium transients in neural stem cells (NSCs and their differentiation into interneurons within the spinal cord of the zebrafish embryo. However, the subjacent molecular mechanisms are not yet understood. Our previous work suggests that early neuronal progenitors were not differentiating correctly in the developing spinal cord. As a result, we aimed at identifying the downstream molecular mechanisms involved specifically in NSCs during glycine-dependent embryonic neurogenesis. Using a gfap:GFP transgenic line, we successfully purified NSCs by fluorescence-activated cell sorting (FACS from whole zebrafish embryos and in embryos in which the glycine receptor was knocked down. The strength of this approach is that it focused on the NSC population while tackling the biological issue in an in vivo context in whole zebrafish embryos. After sequencing the transcriptome by RNA-sequencing, we analyzed the genes whose expression was changed upon disruption of glycine signalling and we confirmed the differential expression by independent RTqPCR assay. While over a thousand genes showed altered expression levels, through pathway analysis we identified 14 top candidate genes belonging to five different canonical signalling pathways (signalling by calcium, TGF-beta, sonic hedgehog, Wnt and p53-related apoptosis that are likely to mediate the promotion of neurogenesis by glycine.

  16. Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs

    Science.gov (United States)

    Lindemann, Stephan W.; Yost, Christian C.; Denis, Melvin M.; McIntyre, Thomas M.; Weyrich, Andrew S.; Zimmerman, Guy A.

    2004-05-01

    The mechanisms by which neutrophils, key effector cells of the innate immune system, express new gene products in inflammation are largely uncharacterized. We found that they rapidly translate constitutive mRNAs when activated, a previously unrecognized response. One of the proteins synthesized without a requirement for transcription is the soluble IL-6 receptor , which translocates to endothelial cells and induces a temporal switch to mononuclear leukocyte recruitment. Its synthesis is regulated by a specialized translational control pathway that is inhibited by rapamycin, a bacterial macrolide with therapeutic efficacy in transplantation, inflammatory syndromes, and neoplasia. Signal-dependent translation in activated neutrophils may be a critical mechanism for alteration of the inflammatory milieu and a therapeutic target.

  17. Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate

    Science.gov (United States)

    von Erlach, Thomas C.; Bertazzo, Sergio; Wozniak, Michele A.; Horejs, Christine-Maria; Maynard, Stephanie A.; Attwood, Simon; Robinson, Benjamin K.; Autefage, Hélène; Kallepitis, Charalambos; del Río Hernández, Armando; Chen, Christopher S.; Goldoni, Silvia; Stevens, Molly M.

    2018-03-01

    Cell size and shape affect cellular processes such as cell survival, growth and differentiation1-4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications.

  18. Condition-dependent pheromone signaling by male rock lizards: more oily scents are more attractive.

    Science.gov (United States)

    Martín, José; López, Pilar

    2010-05-01

    Pheromones of vertebrates are often a mixture of several chemicals with different properties and messages, and their production seems condition dependent. Thus, pheromones are a good, but little studied, example of multiple sexual signals. Femoral gland secretions of male rock lizards Iberolacerta cyreni contain steroids that may act as pheromones, but there are also many other lipids, such as oleic acid, whose allocation to secretions may be costly because it has to be diverted from body fat reserves. This suggests that oleic acid could also have some function in secretions. Chemical analyses showed that proportions of oleic acid in femoral secretions of males were positively related to body condition of males, suggesting that the oleic acid secreted may reflect the amount of body fat reserves of a male. Tongue-flick bioassays showed that females were able to detect by chemosensory cues alone differences in proportions of oleic acid in secretions of males. Scents of males with more oleic acid elicited stronger chemosensory responses by females. Further tests with chemical standards confirmed that females distinguished oleic acid, and changes in its concentration, from other chemicals that are naturally found in secretions of males. Moreover, choice trials of scent-marked substrates showed that females were more attracted to areas that were experimentally manipulated to increase the proportion of oleic acid in natural scent marks of males. We suggest that oleic acid in femoral secretions might be a reliable advertisement of a male's body condition, which females could use to select high-quality mates in conjunction with information provided by other chemicals. Alternatively, scent marks with more oleic acid might be simply more attractive to females if chemosensory responses of females to scent of males were originated by a preexisting sensory bias for food chemicals such as the oleic acid. Nevertheless, this sensory trap might have evolved into an honest signal

  19. Assessment of peritrochanteric high T2 signal depending on the age and gender of the patients

    Energy Technology Data Exchange (ETDEWEB)

    Haliloglu, Nuray, E-mail: nurayunsal2@hotmail.co [Ankara University School of Medicine, Department of Radiology (Turkey); Inceoglu, Deniz; Sahin, Gulden [Ankara University School of Medicine, Department of Radiology (Turkey)

    2010-07-15

    Introduction: The aim of this study is to evaluate the incidence of peritrochanteric high T2 signal (peritrochanteric edema, peritendinitis) on routine MR imaging studies and to determine whether reporting peritrochanteric edema is always clinically relevant depending on the age and gender of the patients. Materials and methods: We evaluated 79 consecutive bilateral hip MR images performed in our department between January 2006 and December 2006 (57 female, 22 male patients, mean age 49 years). Each study was evaluated for areas of T2 hyperintensity representing edema around the greater trochanter. Patients with a known fracture, tumor, history of radiation therapy, history of hip surgery and prothesis were excluded from the study. Patients with signal intensity alterations within the thickened gluteus medius/minimus tendons (tendinitis) or peritrochanteric bursal fluid accumulation (bursitis) were also excluded. All patients were scanned with our routine MR imaging protocol for hip imaging. Results: In 55 of the 79 patients (70%) peritrochanteric edema was detected on MR images and 52 of these 55 patients (95%) had these changes on both hips. The median age was 56 years for the patients with peritrochanteric edema and 35.5 years for the patients without peritrochanteric edema. There was statistical significance between the median ages of the patients and a significant increased risk of peritrochanteric edema was found over 40 years of age. There was no significant difference between male and female patients. Conclusion: Bilateral peritrochanteric high T2 signal may be a part of the degeneration process and we suggest that it may not be necessarily reported if the clinical findings do not support greater trochanteric pain syndrome.

  20. Assessment of peritrochanteric high T2 signal depending on the age and gender of the patients

    International Nuclear Information System (INIS)

    Haliloglu, Nuray; Inceoglu, Deniz; Sahin, Gulden

    2010-01-01

    Introduction: The aim of this study is to evaluate the incidence of peritrochanteric high T2 signal (peritrochanteric edema, peritendinitis) on routine MR imaging studies and to determine whether reporting peritrochanteric edema is always clinically relevant depending on the age and gender of the patients. Materials and methods: We evaluated 79 consecutive bilateral hip MR images performed in our department between January 2006 and December 2006 (57 female, 22 male patients, mean age 49 years). Each study was evaluated for areas of T2 hyperintensity representing edema around the greater trochanter. Patients with a known fracture, tumor, history of radiation therapy, history of hip surgery and prothesis were excluded from the study. Patients with signal intensity alterations within the thickened gluteus medius/minimus tendons (tendinitis) or peritrochanteric bursal fluid accumulation (bursitis) were also excluded. All patients were scanned with our routine MR imaging protocol for hip imaging. Results: In 55 of the 79 patients (70%) peritrochanteric edema was detected on MR images and 52 of these 55 patients (95%) had these changes on both hips. The median age was 56 years for the patients with peritrochanteric edema and 35.5 years for the patients without peritrochanteric edema. There was statistical significance between the median ages of the patients and a significant increased risk of peritrochanteric edema was found over 40 years of age. There was no significant difference between male and female patients. Conclusion: Bilateral peritrochanteric high T2 signal may be a part of the degeneration process and we suggest that it may not be necessarily reported if the clinical findings do not support greater trochanteric pain syndrome.

  1. Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1.

    Science.gov (United States)

    Kim, Ah-Yeon; Shim, Hyun-Jin; Shin, Hyeon-Myeong; Lee, Yoo Jung; Nam, Hyeonjeong; Kim, Su Yeon; Youn, Hyung-Sun

    2018-04-01

    Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF-κB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro. These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells.

    Science.gov (United States)

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R Douglas

    2004-02-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron-glia communication are not known. Recent research shows that adenosine is a neuron-glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility that adenosine might have a similar function in communicating between axons and premyelinating SCs. Using a combination of pharmacological and molecular approaches, we found that mouse SCs in culture express functional adenosine receptors and ATP receptors, a far more complex array of purinergic receptors than thought previously. Adenosine, but not ATP, activates ERK/MAPK through stimulation of cAMP-linked A2(A) adenosine receptors. Both ATP and adenosine inhibit proliferation of SCs induced by platelet-derived growth factor (PDGF), via mechanisms that are partly independent. In contrast to ATP, adenosine failed to inhibit the differentiation of SCs to the O4+ stage. This indicates that, in addition to ATP, adenosine is an activity-dependent signaling molecule between axons and premyelinating Schwann cells, but that electrical activity, acting through adenosine, has opposite effects on the differentiation of myelinating glia in the PNS and CNS.

  3. Transmembrane collagen XVII modulates integrin dependent keratinocyte migration via PI3K/Rac1 signaling.

    Directory of Open Access Journals (Sweden)

    Stefanie Löffek

    Full Text Available The hemidesmosomal transmembrane component collagen XVII (ColXVII plays an important role in the anchorage of the epidermis to the underlying basement membrane. However, this adhesion protein seems to be also involved in the regulation of keratinocyte migration, since its expression in these cells is strongly elevated during reepithelialization of acute wounds and in the invasive front of squamous cell carcinoma, while its absence in ColXVII-deficient keratinocytes leads to altered cell motility. Using a genetic model of murine Col17a1⁻/⁻ keratinocytes we elucidated ColXVII mediated signaling pathways in cell adhesion and migration. Col17a1⁻/⁻ keratinocytes exhibited increased spreading on laminin 332 and accelerated, but less directed cell motility. These effects were accompanied by increased expression of the integrin subunits β4 and β1. The migratory phenotype, as evidenced by formation of multiple unstable lamellipodia, was associated with enhanced phosphoinositide 3-kinase (PI3K activity. Dissection of the signaling pathway uncovered enhanced phosphorylation of the β4 integrin subunit and the focal adhesion kinase (FAK as activators of PI3K. This resulted in elevated Rac1 activity as a downstream consequence. These results provide mechanistic evidence that ColXVII coordinates keratinocyte adhesion and directed motility by interfering integrin dependent PI3K activation and by stabilizing lamellipodia at the leading edge of reepithelializing wounds and in invasive squamous cell carcinoma.

  4. Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

    Energy Technology Data Exchange (ETDEWEB)

    Matoori, Simon [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Froehlich, Johannes M. [Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zurich (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Breitenstein, Stefan [Cantonal Hospital Winterthur, Department of Surgery, Clinic for Visceral and Thoracic Surgery, Winterthur (Switzerland); Doert, Aleksis [Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Pozdniakova, Viktoria [Stavanger University Hospital, Department of Radiology, Stavanger (Norway); Koh, Dow-Mu [Royal Marsden Hospital, Department of Radiology, Surrey, England (United Kingdom); Gutzeit, Andreas [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland)

    2016-06-15

    To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

  5. Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration.

    Science.gov (United States)

    Farkas, Johanna E; Freitas, Polina D; Bryant, Donald M; Whited, Jessica L; Monaghan, James R

    2016-08-01

    The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration. © 2016. Published by The Company of Biologists Ltd.

  6. Cyclic nucleotide dependent dephosphorylation of regulator of G-protein signaling 18 in human platelets.

    LENUS (Irish Health Repository)

    Gegenbauer, Kristina

    2013-11-01

    Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein that turns off Gq signaling in platelets. RGS18 is regulated by binding to the adaptor protein 14-3-3 via phosphorylated serine residues S49 and S218 on RGS18. In this study we confirm that thrombin, thromboxane A2, or ADP stimulate the interaction of RGS18 and 14-3-3 by increasing the phosphorylation of S49. Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. To understand the effect of S216 phosphorylation we studied the phosphorylation kinetics of S49, S216, and S218 using Phos-tag gels and phosphorylation site-specific antibodies in transfected cells and in platelets. Cyclic nucleotide-induced detachment of 14-3-3 from RGS18 coincides initially with double phosphorylation of S216 and S218. This is followed by dephosphorylation of S49 and S218. Dephosphorylation of S49 and S218 might be mediated by protein phosphatase 1 (PP1) which is linked to RGS18 by the regulatory subunit PPP1R9B (spinophilin). We conclude that PKA and PKG induced S216 phosphorylation triggers the dephosphorylation of the 14-3-3 binding sites of RGS18 in platelets.

  7. Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

    International Nuclear Information System (INIS)

    Matoori, Simon; Froehlich, Johannes M.; Breitenstein, Stefan; Doert, Aleksis; Pozdniakova, Viktoria; Koh, Dow-Mu; Gutzeit, Andreas

    2016-01-01

    To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

  8. Activation of cAMP-dependent signaling pathway induces mouse organic anion transporting polypeptide 2 expression.

    Science.gov (United States)

    Chen, Chuan; Cheng, Xingguo; Dieter, Matthew Z; Tanaka, Yuji; Klaassen, Curtis D

    2007-04-01

    Rodent Oatp2 is a hepatic uptake transporter for such compounds as cardiac glycosides. In the present study, we found that fasting resulted in a 2-fold induction of Oatp2 expression in liver of mice. Because the cAMP-protein kinase A (PKA) signaling pathway is activated during fasting, the role of this pathway in Oatp2 induction during fasting was examined. In Hepa-1c1c7 cells, adenylyl cyclase activator forskolin as well as two cellular membrane-permeable cAMP analogs, dibutyryl cAMP and 8-bromo-cAMP, induced Oatp2 mRNA expression in a time- and dose-dependent manner. These three chemicals induced reporter gene activity in cells transfected with a luciferase reporter gene construct containing a 7.6-kilobase (kb) 5'-flanking region of mouse Oatp2. Transient transfection of cells with 5'-deletion constructs derived from the 7.6-kb Oatp2 promoter reporter gene construct, as well as 7.6-kb constructs in which a consensus cAMP response element (CRE) half-site CGTCA (-1808/-1804 bp) was mutated or deleted, confirms that this CRE site was required for the induction of luciferase activity by forskolin. Luciferase activity driven by the Oatp2 promoter containing this CRE site was induced in cells cotransfected with a plasmid encoding the protein kinase A catalytic subunit. Cotransfection of cells with a plasmid encoding the dominant-negative CRE binding protein (CREB) completely abolished the inducibility of the reporter gene activity by forskolin. In conclusion, induction of Oatp2 expression in liver of fasted mice may be caused by activation of the cAMP-dependent signaling pathway, with the CRE site (-1808/-1804) and CREB being the cis- and trans-acting factors mediating the induction, respectively.

  9. Deep subcritical levels measurements dependents upon kinetic distortion factors

    International Nuclear Information System (INIS)

    Pan Shibiao; Li Xiang; Fu Guo'en; Huang Liyuan; Mu Keliang

    2013-01-01

    The measurement of deep subcritical levels, with the increase of subcriticality, showed that the results impact on the kinetic distortion effect, along with neutron flux strongly deteriorated. Using the diffusion theory, calculations have been carried out to quantify the kinetic distortion correction factors in subcritical systems, and these indicate that epithermal neutron distributions are strongly affected by kinetic distortion. Subcriticality measurements in four different rod-state combination at the zero power device was carried out. The test data analysis shows that, with increasing subcriticality, kinetic distortion effect correction factor gradually increases from 1.052 to 1.065, corresponding reactive correction amount of 0.78β eff ∼ 3.01β eff . Thus, it is necessary to consider the kinetic distortion effect in the deep subcritical reactivity measurements. (authors)

  10. d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ziwei Miao

    2017-01-01

    Full Text Available d,l-Sulforaphane (SFN, a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.

  11. Manganese nanoparticle activates mitochondrial dependent apoptotic signaling and autophagy in dopaminergic neuronal cells

    International Nuclear Information System (INIS)

    Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Gu, Yan; Fang, Ning; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

    2011-01-01

    The production of man-made nanoparticles for various modern applications has increased exponentially in recent years, but the potential health effects of most nanoparticles are not well characterized. Unfortunately, in vitro nanoparticle toxicity studies are extremely limited by yet unresolved problems relating to dosimetry. In the present study, we systematically characterized manganese (Mn) nanoparticle sizes and examined the nanoparticle-induced oxidative signaling in dopaminergic neuronal cells. Differential interference contrast (DIC) microscopy and transmission electron microscopy (TEM) studies revealed that Mn nanoparticles range in size from single nanoparticles (∼ 25 nM) to larger agglomerates when in treatment media. Manganese nanoparticles were effectively internalized in N27 dopaminergic neuronal cells, and they induced a time-dependent upregulation of the transporter protein transferrin. Exposure to 25–400 μg/mL Mn nanoparticles induced cell death in a time- and dose-dependent manner. Mn nanoparticles also significantly increased ROS, accompanied by a caspase-mediated proteolytic cleavage of proapoptotic protein kinase Cδ (PKCδ), as well as activation loop phosphorylation. Blocking Mn nanoparticle-induced ROS failed to protect against the neurotoxic effects, suggesting the involvement of other pathways. Further mechanistic studies revealed changes in Beclin 1 and LC3, indicating that Mn nanoparticles induce autophagy. Primary mesencephalic neuron exposure to Mn nanoparticles induced loss of TH positive dopaminergic neurons and neuronal processes. Collectively, our results suggest that Mn nanoparticles effectively enter dopaminergic neuronal cells and exert neurotoxic effects by activating an apoptotic signaling pathway and autophagy, emphasizing the need for assessing possible health risks associated with an increased use of Mn nanoparticles in modern applications. -- Highlights: ► Mn nanoparticles activate mitochondrial cell death signaling

  12. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.

    Directory of Open Access Journals (Sweden)

    Colin J Powers

    2008-10-01

    Full Text Available The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference.

  13. Ozone-induced gene expression occurs via ethylene-dependent and -independent signalling.

    Science.gov (United States)

    Grimmig, Bernhard; Gonzalez-Perez, Maria N; Leubner-Metzger, Gerhard; Vögeli-Lange, Regina; Meins, Fred; Hain, Rüdiger; Penuelas, Josep; Heidenreich, Bernd; Langebartels, Christian; Ernst, Dieter; Sandermann, Heinrich

    2003-03-01

    Recent studies suggest that ethylene is involved in signalling ozone-induced gene expression. We show here that application of ozone increased glucuronidase (GUS) expression of chimeric reporter genes regulated by the promoters of the tobacco class I beta-1,3-glucanases (GLB and Gln2) and the grapevine resveratrol synthase (Vst1) genes in transgenic tobacco leaves. 5'-deletion analysis of the class I beta-1,3-glucanase promoter revealed that ozone-induced gene regulation is mainly mediated by the distal enhancer region containing the positively acting ethylene-responsive element (ERE). In addition, application of 1-methylcyclopropene (1-MCP), an inhibitor of ethylene action, blocked ozone-induced class I beta-1,3-glucanase promoter activity. Enhancer activity and ethylene-responsiveness depended on the integrity of the GCC boxes, cis-acting elements present in the ERE of the class I beta-1,3-glucanase and the basic-type pathogenesis-related PR-1 protein (PRB-1b) gene promoters. The minimal PRB-1b promoter containing only the ERE with intact GCC boxes, was sufficient to confer 10-fold ozone inducibility to a GUS-reporter gene, while a substitution mutation in the GCC box abolished ozone responsiveness. The ERE region of the class I beta-1,3-glucanase promoter containing two intact GCC boxes confered strong ozone inducibility to a minimal cauliflower mosaic virus (CaMV) 35S RNA promoter, whereas two single-base substitution in the GCC boxes resulted in a complete loss of ozone inducibility. Taken together, these datastrongly suggest that ethylene is signalling ozone-induced expression of class I beta-l,3-glucanase and PRB-1b genes. Promoter analysis of the stilbene synthase Vst1 gene unravelled different regions for ozone and ethylene-responsiveness. Application of 1-MCP blocked ethylene-induced Vst1 induction, but ozone induction was not affected. This shows that ozone-induced gene expression occurs via at least two different signalling mechanisms and suggests an

  14. Neem leaf glycoprotein prophylaxis transduces immune dependent stop signal for tumor angiogenic switch within tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Saptak Banerjee

    Full Text Available We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation.

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

    International Nuclear Information System (INIS)

    Yonezawa, Takayuki; Hasegawa, Shin-ichi; Ahn, Jae-Yong; Cha, Byung-Yoon; Teruya, Toshiaki; Hagiwara, Hiromi; Nagai, Kazuo; Woo, Je-Tae

    2007-01-01

    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-κB 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

  16. Determination of the wavelength dependence of the differential pathlength factor from near-infrared pulse signals

    Science.gov (United States)

    Kohl, Matthias; Nolte, Christian; Heekeren, Hauke R.; Horst, Susanne; Scholz, Udo; Obrig, Hellmuth; Villringer, Arno

    1998-06-01

    For the calculation of changes in oxyhaemoglobin, deoxyhaemoglobin and the redox state of cytochrome-c-oxidase from attenuation data via a modified Beer-Lambert equation the wavelength dependence of the differential pathlength factor (DPF) has to be taken into account. The DPF, i.e. the ratio of the mean optical pathlength and the physical light source-detector separation at each wavelength, determines the crosstalk between the different concentrations and is therefore essential for a sensitive detection of chromophore changes. Here a simple method is suggested to estimate the wavelength dependence of the DPF from pulse-induced attenuation changes measured on the head of adult humans. The essence is that the DPF is the ratio of the attenuation changes over absorption coefficient changes, and that the spectral form of the pulse correlated absorption coefficient change can be assumed to be proportional to the extinction coefficient of blood. Indicators for the validity of the DPF derived for wavelengths between 700 and 970 nm are the stability of the calculated haemoglobin and cytochrome signals with variations of the wavelength range included for their calculation and its overall agreement with the data available from the literature.

  17. UDP/P2Y6 receptor signaling regulates IgE-dependent degranulation in human basophils

    Directory of Open Access Journals (Sweden)

    Manabu Nakano

    2017-10-01

    Conclusions: This study showed that UDP/P2Y6 receptor signaling is involved in the regulation of IgE-dependent degranulation in basophils, which might stimulate the P2Y6 receptor via the autocrine secretion of UTP. Thus, this receptor represents a potential target to regulate IgE-dependent degranulation in basophils during allergic diseases.

  18. Time-dependent, glucose-regulated Arabidopsis Regulator of G-protein Signaling 1 network

    Directory of Open Access Journals (Sweden)

    Dinesh Kumar Jaiswal

    2016-04-01

    Full Text Available Plants lack 7-transmembrane, G-protein coupled receptors (GPCRs because the G alpha subunit of the heterotrimeric G protein complex is “self-activating”—meaning that it spontaneously exchanges bound GDP for GTP without the need of a GPCR. In lieu of GPCRs, most plants have a seven transmembrane receptor-like regulator of G-protein signaling (RGS protein, a component of the complex that keeps G-protein signaling in its non-activated state. The addition of glucose physically uncouples AtRGS1 from the complex through specific endocytosis leaving the activated G protein at the plasma membrane. The complement of proteins in the AtRGS1/G-protein complex over time from glucose-induced endocytosis was profiled by immunoprecipitation coupled to mass spectrometry (IP-MS. A total of 119 proteins in the AtRGS1 complex were identified. Several known interactors of the complex were identified, thus validating the approach, but the vast majority (93/119 were not known previously. AtRGS1 protein interactions were dynamically modulated by d-glucose. At low glucose levels, the AtRGS1 complex is comprised of proteins involved in transport, stress and metabolism. After glucose application, the AtRGS1 complex rapidly sheds many of these proteins and recruits other proteins involved in vesicular trafficking and signal transduction. The profile of the AtRGS1 components answers several questions about the type of coat protein and vesicular trafficking GTPases used in AtRGS1 endocytosis and the function of endocytic AtRGS1.

  19. Disparity Disambiguation by Fusion of Signal and Symbolic-Level Information

    DEFF Research Database (Denmark)

    Ralli, J.; Diaz, J.; Ros, E.

    2012-01-01

    We describe a method for resolving ambiguities in low-level disparity calculations in a stereo-vision scheme by using a recurrent mechanism that we call signal-symbol loop. Due to the local nature of low-level processing it is not always possible to estimate the correct disparity values produced...... at this level. Symbolic abstraction of the signal produces robust, high confidence, multimodal image features which can be used to interpret the scene more accurately and therefore disambiguate low-level interpretations by biasing the correct disparity. The fusion process is capable of producing more accurate...... dense disparity maps than the low- and symbolic-level algorithms can produce independently. Therefore we describe an efficient fusion scheme that allows symbolic- and low-level cues to complement each other, resulting in a more accurate and dense disparity representation of the scene....

  20. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    András, Ibolya E.; Toborek, Michal

    2014-01-01

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  1. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    Energy Technology Data Exchange (ETDEWEB)

    András, Ibolya E., E-mail: iandras@med.miami; Toborek, Michal, E-mail: mtoborek@med.miami.edu

    2014-04-15

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ.

  2. Insulin Signaling Augments eIF4E-Dependent Nonsense-Mediated mRNA Decay in Mammalian Cells.

    Science.gov (United States)

    Park, Jungyun; Ahn, Seyoung; Jayabalan, Aravinth K; Ohn, Takbum; Koh, Hyun Chul; Hwang, Jungwook

    2016-07-01

    Nonsense-mediated mRNA decay (NMD) modulates the level of mRNA harboring a premature termination codon (PTC) in a translation-dependent manner. Inhibition of translation is known to impair NMD; however, few studies have investigated the correlation between enhanced translation and increased NMD. Here, we demonstrate that insulin signaling events increase translation, leading to an increase in NMD of eIF4E-bound transcripts. We provide evidence that (i) insulin-mediated enhancement of translation augments NMD and rapamycin abrogates this enhancement; (ii) an increase in AKT phosphorylation due to inhibition of PTEN facilitates NMD; (iii) insulin stimulation increases the binding of up-frameshift factor 1 (UPF1), most likely to eIF4E-bound PTC-containing transcripts; and (iv) insulin stimulation induces the colocalization of UPF1 and eIF4E in processing bodies. These results illustrate how extracellular signaling promotes the removal of eIF4E-bound NMD targets. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling.

    Science.gov (United States)

    Le Gall, Sylvain M; Szabo, Roman; Lee, Melody; Kirchhofer, Daniel; Craik, Charles S; Bugge, Thomas H; Camerer, Eric

    2016-06-23

    The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

  4. The ATM signaling cascade promotes recombination-dependent pachytene arrest in mouse spermatocytes.

    Directory of Open Access Journals (Sweden)

    Sarai Pacheco

    2015-03-01

    Full Text Available Most mutations that compromise meiotic recombination or synapsis in mouse spermatocytes result in arrest and apoptosis at the pachytene stage of the first meiotic prophase. Two main mechanisms are thought to trigger arrest: one independent of the double-strand breaks (DSBs that initiate meiotic recombination, and another activated by persistent recombination intermediates. Mechanisms underlying the recombination-dependent arrest response are not well understood, so we sought to identify factors involved by examining mutants deficient for TRIP13, a conserved AAA+ ATPase required for the completion of meiotic DSB repair. We find that spermatocytes with a hypomorphic Trip13 mutation (Trip13mod/mod arrest with features characteristic of early pachynema in wild type, namely, fully synapsed chromosomes without incorporation of the histone variant H1t into chromatin. These cells then undergo apoptosis, possibly in response to the arrest or in response to a defect in sex body formation. However, TRIP13-deficient cells that additionally lack the DSB-responsive kinase ATM progress further, reaching an H1t-positive stage (i.e., similar to mid/late pachynema in wild type despite the presence of unrepaired DSBs. TRIP13-deficient spermatocytes also progress to an H1t-positive stage if ATM activity is attenuated by hypomorphic mutations in Mre11 or Nbs1 or by elimination of the ATM-effector kinase CHK2. These mutant backgrounds nonetheless experience an apoptotic block to further spermatogenic progression, most likely caused by failure to form a sex body. DSB numbers are elevated in Mre11 and Nbs1 hypomorphs but not Chk2 mutants, thus delineating genetic requirements for the ATM-dependent negative feedback loop that regulates DSB numbers. The findings demonstrate for the first time that ATM-dependent signaling enforces the normal pachytene response to persistent recombination intermediates. Our work supports the conclusion that recombination defects trigger

  5. Physical inactivity affects skeletal muscle insulin signaling in a birth weight-dependent manner

    DEFF Research Database (Denmark)

    Mortensen, Brynjulf; Friedrichsen, Martin; Andersen, Nicoline Resen

    2014-01-01

    We investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects.......We investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects....

  6. Energy-Efficient Crowdsensing of Human Mobility and Signal Levels in Cellular Networks

    Science.gov (United States)

    Foremski, Paweł; Gorawski, Michał; Grochla, Krzysztof; Polys, Konrad

    2015-01-01

    The paper presents a practical application of the crowdsensing idea to measure human mobility and signal coverage in cellular networks. Currently, virtually everyone is carrying a mobile phone, which may be used as a sensor to gather research data by measuring, e.g., human mobility and radio signal levels. However, many users are unwilling to participate in crowdsensing experiments. This work begins with the analysis of the barriers for engaging people in crowdsensing. A survey showed that people who agree to participate in crowdsensing expect a minimum impact on their battery lifetime and phone usage habits. To address these requirements, this paper proposes an application for measuring the location and signal strength data based on energy-efficient GPS tracking, which allows one to perform the measurements of human mobility and radio signal levels with minimum energy utilization and without any engagement of the user. The method described combines measurements from the accelerometer with effective management of the GPS to monitor the user mobility with the decrease in battery lifetime by approximately 20%. To show the applicability of the proposed platform, the sample results of signal level distribution and coverage maps gathered for an LTE network and representing human mobility are shown. PMID:26340633

  7. cAMP-dependent proteolysis of GATA-6 is linked to JNK-signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ushijima, Hironori [Department of Molecular Biology, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahaba, Shiwagun, Iwate 028-3694 (Japan); Maeda, Masatomo, E-mail: mmaeda@iwate-med.ac.jp [Department of Molecular Biology, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahaba, Shiwagun, Iwate 028-3694 (Japan)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A JNK inhibitor SP600125 inhibited cAMP-dependent proteolysis of GATA-6. Black-Right-Pointing-Pointer Effect of a JNK activator anisomycin on the proteolysis was examined. Black-Right-Pointing-Pointer Anisomycin stimulated the export of nuclear GATA-6 into the cytoplasm. Black-Right-Pointing-Pointer JNK activated the CRM1 mediated nuclear export of GATA-6. Black-Right-Pointing-Pointer JNK further stimulated slowly the degradation of GATA-6 by cytoplasmic proteasomes. -- Abstract: A JNK inhibitor SP600125 inhibited cAMP-dependent proteolysis of GATA-6 by proteasomes around its IC50. We further examined the effects of SP600125 on the degradation of GATA-6 in detail, since an activator of JNK (anisomycin) is available. Interestingly, anisomycin immediately stimulated the export of nuclear GATA-6 into the cytoplasm, and then the cytoplasmic content of GATA-6 decreased slowly through degradation by proteasomes. Such an effect of anisomycin was inhibited by SP600125, indicating that the observed phenomenon might be linked to the JNK signaling pathway. The inhibitory effect of SP600125 could not be ascribed to the inhibition of PKA, since phosphorylation of CREB occurred in the presence of dbcAMP and SP600125. The nuclear export of GATA-6 was inhibited by leptomycin B, suggesting that CRM1-mediated export could be activated by anisomycin. Furthermore, it seems likely that the JNK activated by anisomycin may stimulate not only the nuclear export of GATA-6 through CRM1 but also the degradation of GATA-6 by cytoplasmic proteasomes. In contrast, A-kinase might activate only the latter process through JNK.

  8. Electron dose dependence of signal-to-noise ratio, atom contrast and resolution in transmission electron microscope images

    International Nuclear Information System (INIS)

    Lee, Z.; Rose, H.; Lehtinen, O.; Biskupek, J.; Kaiser, U.

    2014-01-01

    In order to achieve the highest resolution in aberration-corrected (AC) high-resolution transmission electron microscopy (HRTEM) images, high electron doses are required which only a few samples can withstand. In this paper we perform dose-dependent AC-HRTEM image calculations, and study the dependence of the signal-to-noise ratio, atom contrast and resolution on electron dose and sampling. We introduce dose-dependent contrast, which can be used to evaluate the visibility of objects under different dose conditions. Based on our calculations, we determine optimum samplings for high and low electron dose imaging conditions. - Highlights: • The definition of dose-dependent atom contrast is introduced. • The dependence of the signal-to-noise ratio, atom contrast and specimen resolution on electron dose and sampling is explored. • The optimum sampling can be determined according to different dose conditions

  9. One pair of hands is not like another: caudate BOLD response in dogs depends on signal source and canine temperament

    Directory of Open Access Journals (Sweden)

    Peter F. Cook

    2014-09-01

    Full Text Available 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

  10. Fenofibrate suppresses cellular metabolic memory of high glucose in diabetic retinopathy via a sirtuin 1-dependent signalling pathway.

    Science.gov (United States)

    Zhao, Shuzhi; Li, Jun; Wang, Na; Zheng, Bingqing; Li, Tao; Gu, Qing; Xu, Xun; Zheng, Zhi

    2015-10-01

    Inflammation is a major contributing factor in the development of diabetic microvascular complications, regardless of whether improved glycaemic control is achieved. Studies have increasingly indicated that fenofibrate, a lipid‑lowering therapeutic agent in clinical use, exerts a potential anti‑inflammatory effect, which is mediated by sirtuin 1 (SIRT1; an NAD+‑dependent deacetylase) in endothelial cells. The aim of the present study was to investigate the inhibitory effect of fenofibrate on metabolic memory (via the regulation of SIRT1), and inflammatory responses in cell and animal models of diabetic retinopathy (DR). The data demonstrated that high glucose treatment in human retinal endothelial cells (HRECs) inhibited the expression and deacetylase activity of SIRT1. The reduction of SIRT1 expression and deacetylase activity persisted following a return to normal glucose levels. Furthermore, nuclear factor‑κB expression was observed to be negatively correlated with SIRT1 expression and activity in HRECs under high glucose levels and the subsequent return to normal glucose levels. Fenofibrate treatment abrogated these changes. Knockdown of SIRT1 attenuated the effect of fenofibrate on high glucose‑induced NF‑κB expression. In addition, fenofibrate upregulated SIRT1 expression through peroxisome proliferator‑activated receptor α in high glucose‑induced metabolic memory. These findings indicate that fenofibrate is important in anti‑inflammatory processes and suppresses the cellular metabolic memory of high glucose‑induced stress via the SIRT1‑dependent signalling pathway. Thus, treatment with fenofibrate may offer a promising therapeutic strategy for halting the development of DR and other complications of diabetes.

  11. Distinct forms of mitochondrial TOM-TIM supercomplexes define signal-dependent states of preprotein sorting.

    Science.gov (United States)

    Chacinska, Agnieszka; van der Laan, Martin; Mehnert, Carola S; Guiard, Bernard; Mick, David U; Hutu, Dana P; Truscott, Kaye N; Wiedemann, Nils; Meisinger, Chris; Pfanner, Nikolaus; Rehling, Peter

    2010-01-01

    Mitochondrial import of cleavable preproteins occurs at translocation contact sites, where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport form containing the presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23(SORT)). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23(SORT) and TOM-TIM23-PAM. These two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import.

  12. Operational Safety Assessment of Turbo Generators with Wavelet Rényi Entropy from Sensor-Dependent Vibration Signals

    Directory of Open Access Journals (Sweden)

    Xiaoli Zhang

    2015-04-01

    Full Text Available With the rapid development of sensor technology, various professional sensors are installed on modern machinery to monitor operational processes and assure operational safety, which play an important role in industry and society. In this work a new operational safety assessment approach with wavelet Rényi entropy utilizing sensor-dependent vibration signals is proposed. On the basis of a professional sensor and the corresponding system, sensor-dependent vibration signals are acquired and analyzed by a second generation wavelet package, which reflects time-varying operational characteristic of individual machinery. Derived from the sensor-dependent signals’ wavelet energy distribution over the observed signal frequency range, wavelet Rényi entropy is defined to compute the operational uncertainty of a turbo generator, which is then associated with its operational safety degree. The proposed method is applied in a 50 MW turbo generator, whereupon it is proved to be reasonable and effective for operation and maintenance.

  13. Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction.

    Science.gov (United States)

    Bellefontaine, Nicole; Chachlaki, Konstantina; Parkash, Jyoti; Vanacker, Charlotte; Colledge, William; d'Anglemont de Tassigny, Xavier; Garthwaite, John; Bouret, Sebastien G; Prevot, Vincent

    2014-06-01

    The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.

  14. Ascorbic acid alters cell fate commitment of human neural progenitors in a WNT/β-catenin/ROS signaling dependent manner.

    Science.gov (United States)

    Rharass, Tareck; Lantow, Margareta; Gbankoto, Adam; Weiss, Dieter G; Panáková, Daniela; Lucas, Stéphanie

    2017-10-16

    Improving the neuronal yield from in vitro cultivated neural progenitor cells (NPCs) is an essential challenge in transplantation therapy in neurological disorders. In this regard, Ascorbic acid (AA) is widely used to expand neurogenesis from NPCs in cultures although the mechanisms of its action remain unclear. Neurogenesis from NPCs is regulated by the redox-sensitive WNT/β-catenin signaling pathway. We therefore aimed to investigate how AA interacts with this pathway and potentiates neurogenesis. Effects of 200 μM AA were compared with the pro-neurogenic reagent and WNT/β-catenin signaling agonist lithium chloride (LiCl), and molecules with antioxidant activities i.e. N-acetyl-L-cysteine (NAC) and ruthenium red (RuR), in differentiating neural progenitor ReNcell VM cells. Cells were supplemented with reagents for two periods of treatment: a full period encompassing the whole differentiation process versus an early short period that is restricted to the cell fate commitment stage. Intracellular redox balance and reactive oxygen species (ROS) metabolism were examined by flow cytometry using redox and ROS sensors. Confocal microscopy was performed to assess cell viability, neuronal yield, and levels of two proteins: Nucleoredoxin (NXN) and the WNT/β-catenin signaling component Dishevelled 2 (DVL2). TUBB3 and MYC gene responses were evaluated by quantitative real-time PCR. DVL2-NXN complex dissociation was measured by fluorescence resonance energy transfer (FRET). In contrast to NAC which predictably exhibited an antioxidant effect, AA treatment enhanced ROS metabolism with no cytotoxic induction. Both drugs altered ROS levels only at the early stage of the differentiation as no changes were held beyond the neuronal fate commitment stage. FRET studies showed that AA treatment accelerated the redox-dependent release of the initial pool of DVL2 from its sequestration by NXN, while RuR treatment hampered the dissociation of the two proteins. Accordingly, AA

  15. Signal-dependent Hydrolysis of Phosphatidylinositol 4,5-Bisphosphate without Activation of Phospholipase C

    Science.gov (United States)

    Lev, Shaya; Katz, Ben; Tzarfaty, Vered; Minke, Baruch

    2012-01-01

    In Drosophila, a phospholipase C (PLC)-mediated signaling cascade, couples photo-excitation of rhodopsin to the opening of the transient receptor potential (TRP) and TRP-like (TRPL) channels. A lipid product of PLC, diacylglycerol (DAG), and its metabolites, polyunsaturated fatty acids (PUFAs) may function as second messengers of channel activation. However, how can one separate between the increase in putative second messengers, change in pH, and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) depletion when exploring the TRPL gating mechanism? To answer this question we co-expressed the TRPL channels together with the muscarinic (M1) receptor, enabling the openings of TRPL channels via G-protein activation of PLC. To dissect PLC activation of TRPL into its molecular components, we used a powerful method that reduced plasma membrane-associated PI(4,5)P2 in HEK cells within seconds without activating PLC. Upon the addition of a dimerizing drug, PI(4,5)P2 was selectively hydrolyzed in the cell membrane without producing DAG, inositol trisphosphate, or calcium signals. We show that PI(4,5)P2 is not an inhibitor of TRPL channel activation. PI(4,5)P2 hydrolysis combined with either acidification or application of DAG analogs failed to activate the channels, whereas PUFA did activate the channels. Moreover, a reduction in PI(4,5)P2 levels or inhibition of DAG lipase during PLC activity suppressed the PLC-activated TRPL current. This suggests that PI(4,5)P2 is a crucial substrate for PLC-mediated activation of the channels, whereas PUFA may function as the channel activator. Together, this study defines a narrow range of possible mechanisms for TRPL gating. PMID:22065576

  16. Restoration of anatomical continuity after spinal cord transection depends on Wnt/β-catenin signaling in larval zebrafish

    Directory of Open Access Journals (Sweden)

    Daniel Wehner

    2018-02-01

    Full Text Available This data article contains descriptive and experimental data on spinal cord regeneration in larval zebrafish and its dependence on Wnt/β-catenin signaling. Analyzing spread of intraspinally injected fluorescent dextran showed that anatomical continuity is rapidly restored after complete spinal cord transection. Pharmacological interference with Wnt/β-catenin signaling (IWR-1 impaired restoration of spinal continuity. For further details and experimental findings please refer to the research article by Wehner et al. Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish (Wehner et al., 2017 [1]. Keywords: Wnt, Beta-catenin, Regeneration, Spinal cord, Zebrafish

  17. β-Arrestin-2-Dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T-Helper Type 2 Cells.

    Science.gov (United States)

    Lin, Rui; Choi, Yeon Ho; Zidar, David A; Walker, Julia K L

    2018-06-01

    Allergic asthma is a complex inflammatory disease that leads to significant healthcare costs and reduction in quality of life. Although many cell types are implicated in the pathogenesis of asthma, CD4 + T-helper cell type 2 (Th2) cells are centrally involved. We previously reported that the asthma phenotype is virtually absent in ovalbumin-sensitized and -challenged mice that lack global expression of β-arrestin (β-arr)-2 and that CD4 + T cells from these mice displayed significantly reduced CCL22-mediated chemotaxis. Because CCL22-mediated activation of CCR4 plays a role in Th2 cell regulation in asthmatic inflammation, we hypothesized that CCR4-mediated migration of CD4 + Th2 cells to the lung in asthma may use β-arr-dependent signaling. To test this hypothesis, we assessed the effect of various signaling inhibitors on CCL22-induced chemotaxis using in vitro-polarized primary CD4 + Th2 cells from β-arr2-knockout and wild-type mice. Our results show, for the first time, that CCL22-induced, CCR4-mediated Th2 cell chemotaxis is dependent, in part, on a β-arr2-dependent signaling pathway. In addition, we show that this chemotactic signaling mechanism involves activation of P-p38 and Rho-associated protein kinase. These findings point to a proinflammatory role for β-arr2-dependent signaling and support β-arr2 as a novel therapeutic target in asthma.

  18. A Busy period analysis of the level dependent PH/PH/1/K queue

    NARCIS (Netherlands)

    Al Hanbali, Ahmad

    2011-01-01

    In this paper, we study the transient behavior of a level dependent single server queuing system with a waiting room of finite size during the busy period. The focus is on the level dependent PH/PH/1/K queue. We derive in closed form the joint transform of the length of the busy period, the number

  19. The phytosulfokine (PSK) receptor is capable of guanylate cyclase activity and enabling cyclic GMP-dependent signaling in plants

    KAUST Repository

    Kwezi, Lusisizwe; Ruzvidzo, Oziniel; Wheeler, Janet I.; Govender, Kershini; Iacuone, Sylvana; Thompson, Philip E.; Gehring, Christoph A; Irving, Helen R.

    2011-01-01

    Phytosulfokines (PSKs) are sulfated pentapeptides that stimulate plant growth and differentiation mediated by the PSK receptor (PSKR1), which is a leucine-rich repeat receptor-like kinase. We identified a putative guanylate cyclase (GC) catalytic center in PSKR1 that is embedded within the kinase domain and hypothesized that the GC works in conjunction with the kinase in downstream PSK signaling. We expressed the recombinant complete kinase (cytoplasmic) domain of AtPSKR1 and show that it has serine/threonine kinase activity using the Ser/Thr peptide 1 as a substrate with an approximate Km of 7.5 μM and Vmax of 1800 nmol min-1 mg-1 of protein. This same recombinant protein also has GC activity in vitro that is dependent on the presence of either Mg2+ or Mn2+. Overexpression of the full-length AtPSKR1 receptor in Arabidopsis leaf protoplasts raised the endogenous basal cGMP levels over 20-fold, indicating that the receptor has GC activity in vivo. In addition, PSK-α itself, but not the non-sulfated backbone, induces rapid increases in cGMP levels in protoplasts. Together these results indicate that the PSKR1 contains dual GC and kinase catalytic activities that operate in vivo and that this receptor constitutes a novel class of enzymes with overlapping catalytic domains. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. The phytosulfokine (PSK) receptor is capable of guanylate cyclase activity and enabling cyclic GMP-dependent signaling in plants

    KAUST Repository

    Kwezi, Lusisizwe

    2011-04-19

    Phytosulfokines (PSKs) are sulfated pentapeptides that stimulate plant growth and differentiation mediated by the PSK receptor (PSKR1), which is a leucine-rich repeat receptor-like kinase. We identified a putative guanylate cyclase (GC) catalytic center in PSKR1 that is embedded within the kinase domain and hypothesized that the GC works in conjunction with the kinase in downstream PSK signaling. We expressed the recombinant complete kinase (cytoplasmic) domain of AtPSKR1 and show that it has serine/threonine kinase activity using the Ser/Thr peptide 1 as a substrate with an approximate Km of 7.5 μM and Vmax of 1800 nmol min-1 mg-1 of protein. This same recombinant protein also has GC activity in vitro that is dependent on the presence of either Mg2+ or Mn2+. Overexpression of the full-length AtPSKR1 receptor in Arabidopsis leaf protoplasts raised the endogenous basal cGMP levels over 20-fold, indicating that the receptor has GC activity in vivo. In addition, PSK-α itself, but not the non-sulfated backbone, induces rapid increases in cGMP levels in protoplasts. Together these results indicate that the PSKR1 contains dual GC and kinase catalytic activities that operate in vivo and that this receptor constitutes a novel class of enzymes with overlapping catalytic domains. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Vital analysis: annotating sensed physiological signals with the stress levels of first responders in action.

    Science.gov (United States)

    Gomes, P; Kaiseler, M; Queirós, C; Oliveira, M; Lopes, B; Coimbra, M

    2012-01-01

    First responders such as firefighters are exposed to extreme stress and fatigue situations during their work routines. It is thus desirable to monitor their health using wearable sensing but this is a complex and still unsolved research challenge that requires large amounts of properly annotated physiological signals data. In this paper we show that the information gathered by our Vital Analysis Framework can support the annotation of these vital signals with the stress levels perceived by the target user, confirmed by the analysis of more than 4600 hours of data collected from real firefighters in action, including 717 answers to event questionnaires from a total of 454 different events.

  2. Complexity of low-frequency blood oxygen level-dependent fluctuations covaries with local connectivity.

    Science.gov (United States)

    Anderson, Jeffrey S; Zielinski, Brandon A; Nielsen, Jared A; Ferguson, Michael A

    2014-04-01

    Very low-frequency blood oxygen level-dependent (BOLD) fluctuations have emerged as a valuable tool for describing brain anatomy, neuropathology, and development. Such fluctuations exhibit power law frequency dynamics, with largest amplitude at lowest frequencies. The biophysical mechanisms generating such fluctuations are poorly understood. Using publicly available data from 1,019 subjects of age 7-30, we show that BOLD fluctuations exhibit temporal complexity that is linearly related to local connectivity (regional homogeneity), consistently and significantly covarying across subjects and across gray matter regions. This relationship persisted independently of covariance with gray matter density or standard deviation of BOLD signal. During late neurodevelopment, BOLD fluctuations were unchanged with age in association cortex while becoming more random throughout the rest of the brain. These data suggest that local interconnectivity may play a key role in establishing the complexity of low-frequency BOLD fluctuations underlying functional magnetic resonance imaging connectivity. Stable low-frequency power dynamics may emerge through segmentation and integration of connectivity during development of distributed large-scale brain networks. Copyright © 2013 Wiley Periodicals, Inc.

  3. Application of language blood oxygenation level dependent functional MRI in the navigating operation of neurosurgery

    International Nuclear Information System (INIS)

    Liu Shuyong; Li Min; Yao Chengjun; Geng Daoying

    2011-01-01

    Objective: To verify the accuracy of blood oxygenation level dependent (BOLD)-based activation using electrocortical stimulation mapping (ESM) and explore the value of language fMRI in the navigating operation of neurosurgery. Methods: In 8 cases with brain tumors, BOLD-fMRI examinations were done before the operations. Under the state of awake anesthesia,the patients were aroused and ESM was conducted. Point-to-point comparison between the BOLD signal activations and the ESM was carried out under the surveillance of the neuro-navigation technology. In order to observe the sensibility and specificity of BOLD activations, the location of BOLD activations and the point of ESM was compared to calculate the stimulating positive points inside the regions of BOLD signals (real positive), outside BOLD regions (pseudo- negative), the stimulating negative points inside the regions of BOLD signals (pseudo-positive), and outside BOLD region (real negative). Two kinds of criteria for assessment were used. One was that the positive stimulating points were located in BOLD regions, and the other was that the positive stimulating points were located within 1 cm around the range of BOLD regions. Removal of the lesions were conducted with the tissue 1 cm around the language region preserved, and the cortex inside 0.5-1.0 cm distance from the positive points were retained. Results: Of the 8 cases, only 6 finished the tasks. Among them, 3 cases were with astrocytoma of grade 2, 2 were with astrocytoma of grade 3, and one with glioblastoma. The total number of stimulating points was 48, among which the positive points were 11. When the first criteria was applied, the sensitivity was 72.7% (8/11), and the specificity was 81.8% (30/37). When the second criteria was applied, the sensitivity was 82.0% (9/11), and the specificity was 75.6% (28/37). Follow-up after operation showed no aphasia occurred. Conclusions: BOLD-fMRI had a high sensitivity and specificity in displaying the language

  4. TIF-IA-dependent regulation of ribosome synthesis in drosophila muscle is required to maintain systemic insulin signaling and larval growth.

    Directory of Open Access Journals (Sweden)

    Abhishek Ghosh

    2014-10-01

    Full Text Available The conserved TOR kinase signaling network links nutrient availability to cell, tissue and body growth in animals. One important growth-regulatory target of TOR signaling is ribosome biogenesis. Studies in yeast and mammalian cell culture have described how TOR controls rRNA synthesis-a limiting step in ribosome biogenesis-via the RNA Polymerase I transcription factor TIF-IA. However, the contribution of TOR-dependent ribosome synthesis to tissue and body growth in animals is less clear. Here we show in Drosophila larvae that ribosome synthesis in muscle is required non-autonomously to maintain normal body growth and development. We find that amino acid starvation and TOR inhibition lead to reduced levels of TIF-IA, and decreased rRNA synthesis in larval muscle. When we mimic this decrease in muscle ribosome synthesis using RNAi-mediated knockdown of TIF-IA, we observe delayed larval development and reduced body growth. This reduction in growth is caused by lowered systemic insulin signaling via two endocrine responses: reduced expression of Drosophila insulin-like peptides (dILPs from the brain and increased expression of Imp-L2-a secreted factor that binds and inhibits dILP activity-from muscle. We also observed that maintaining TIF-IA levels in muscle could partially reverse the starvation-mediated suppression of systemic insulin signaling. Finally, we show that activation of TOR specifically in muscle can increase overall body size and this effect requires TIF-IA function. These data suggest that muscle ribosome synthesis functions as a nutrient-dependent checkpoint for overall body growth: in nutrient rich conditions, TOR is required to maintain levels of TIF-IA and ribosome synthesis to promote high levels of systemic insulin, but under conditions of starvation stress, reduced muscle ribosome synthesis triggers an endocrine response that limits systemic insulin signaling to restrict growth and maintain homeostasis.

  5. Caffeine and REM sleep deprivation: Effect on basal levels of signaling molecules in area CA1.

    Science.gov (United States)

    Alkadhi, Karim A; Alhaider, Ibrahim A

    2016-03-01

    We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treated with caffeine in drinking water (0.3g/l) for four weeks before they were REM sleep-deprived for 24h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylated- and total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Common elements in interleukin 4 and insulin signaling pathways in factor-dependent hematopoietic cells.

    Science.gov (United States)

    Wang, L M; Keegan, A D; Li, W; Lienhard, G E; Pacini, S; Gutkind, J S; Myers, M G; Sun, X J; White, M F; Aaronson, S A

    1993-05-01

    Interleukin 4 (IL-4), insulin, and insulin-like growth factor I (IGF-I) efficiently induced DNA synthesis in the IL-3-dependent murine myeloid cell lines FDC-P1 and FDC-P2. Although these factors could not individually sustain long-term growth of these lines, a combination of IL-4 with either insulin or IGF-I did support continuous growth. The principal tyrosine-phosphorylated substrate observed in FDC cells stimulated with IL-4, previously designated 4PS, was of the same size (170 kDa) as the major substrate phosphorylated in response to insulin or IGF-I. These substrates had phosphopeptides of the same size when analyzed by digestion with Staphylococcus aureus V8 protease, and each tightly associated with the 85-kDa component of phosphatidylinositol 3-kinase after factor stimulation. IRS-1, the principal substrate phosphorylated in response to insulin or IGF-I stimulation in nonhematopoietic cells, is similar in size to 4PS. However, anti-IRS-1 antibodies failed to efficiently precipitate 4PS, and some phosphopeptides generated by V8 protease digestion of IRS-1 were distinct in size from the phosphopeptides of 4PS. Nevertheless, IL-4, insulin, and IGF-I were capable of stimulating tyrosine phosphorylation of IRS-1 in FDC cells that expressed this substrate as a result of transfection. These findings indicate that (i) IL-4, insulin, and IGF-I use signal transduction pathways in FDC lines that have at least one major feature in common, the rapid tyrosine phosphorylation of 4PS, and (ii) insulin and IGF-I stimulation of hematopoietic cell lines leads to the phosphorylation of a substrate that may be related to but is not identical to IRS-1.

  7. dsRNA-Dependent Protein Kinase PKR and its Role in Stress, Signaling and HCV Infection

    Directory of Open Access Journals (Sweden)

    Eliane F. Meurs

    2012-10-01

    Full Text Available The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eIF2a. As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most viral infections, indicating that PKR may play other roles in the cell other than just acting as an antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter protein and/or using its kinase activity. Here we review the role of PKR as an eIF2a kinase, its participation in the regulation of the NF-kB, p38MAPK and insulin pathways, and we focus on its role during infection with the hepatitis C virus (HCV. PKR binds the HCV IRES RNA, cooperates with some functions of the HCV core protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter protein and as an eIF2a-kinase, and in cooperation with the di-ubiquitin-like protein ISG15. Developing pharmaceutical inhibitors of PKR may help in resolving some viral infections as well as stress-related damages.

  8. PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.

    Directory of Open Access Journals (Sweden)

    Hiroaki Ono

    Full Text Available Protein Tyrosine Kinase 6 (PTK6 is a non-receptor type tyrosine kinase that may be involved in some cancers. However, the biological role and expression status of PTK6 in pancreatic cancer is unknown. Therefore in this study, we evaluated the functional role of PTK6 on pancreatic cancer invasion. Five pancreatic cancer cell lines expressed PTK6 at varying levels. PTK6 expression was also observed in human pancreatic adenocarcinomas. PTK6 suppression by siRNA significantly reduced both cellular migration and invasion (0.59/0.49 fold for BxPC3, 0.61/0.62 for Panc1, 0.42/0.39 for MIAPaCa2, respectively, p<0.05 for each. In contrast, forced overexpression of PTK6 by transfection of a PTK6 expression vector in Panc1 and MIAPaCa2 cells increased cellular migration and invasion (1.57/1.67 fold for Panc1, 1.44/1.57 for MIAPaCa2, respectively, p<0.05. Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation. U0126, a specific inhibitor of ERK1/2, completely abolished the effect of PTK6 overexpression on cellular migration and invasion. These results suggest that PTK6 regulates cellular migration and invasion in pancreatic cancer via ERK signaling. PTK6 may be a novel therapeutic target for pancreatic cancer.

  9. Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling.

    Science.gov (United States)

    Mann, Koren K; Davison, Kelly; Colombo, Myrian; Colosimo, April L; Diaz, Zuanel; Padovani, Alessandra M S; Guo, Qi; Scrivens, P James; Gao, Wenli; Mader, Sylvie; Miller, Wilson H

    2006-01-05

    Very little is known concerning the toxicity of antimony, despite its commercial use as a flame retardant and medical use as a treatment for parasitic infections. Our previous studies show that antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived acute promyelocytic leukemia (APL) cell lines, a disease in which a related metal, arsenic trioxide (As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as differentiation markers. Sb(2)O(3)-induced reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting glutathione, ROS production and apoptosis was enhanced. Arsenic-resistant APL cells with increased glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun kinase (JNK) in the mediation of the response to As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target, AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.

  10. Traffic background level and signal duration effects on aircraft noise judgment

    Energy Technology Data Exchange (ETDEWEB)

    Johnston, G W; Haasz, A A

    1977-04-22

    The effects of background traffic noise level and signal duration on perceived aircraft noise levels during a flyover event are investigated. Tapes of traffic noise at different levels on which aircraft flyover noise events of different durations were superimposed were played to groups of observers in a room simulating indoor conditions. It is found that the presence of steady background traffic noise reduces the perceived noisiness of aircraft flyovers provided that the duration of the flyover event is sufficiently short in relation to flyover time. For a given event level, a reduction of 21 dB(A) in background noise level leads to the perception of a 5.5 dB(A) increase in peak event level. Regressions of observer response with the noise pollution index show a lower correlation than those with variables based on background noise level and peak signal level, although the data are found to exhibit a number of significant trends associated with noise pollution index variations.

  11. New Train Run Monitoring system: Getting the most out of an ERTMS level 2 Signalling system

    DEFF Research Database (Denmark)

    Richter, Troels; Landex, Alex; Andersen, Jonas Lohmann Elkjær

    . Rail Net Denmark is currently implementing ERTMS Level 2 signalling systems on the entire long distance network and a CBTC signalling system on the Copenhagen Suburban network. It is unlikely, that the current RDS will be able to function in this environment and especially be capable of taking...... advantage of the additional data delivered by the new systems. The conceptual design of a new RDS has consequently been underway since the start of the signalling program. The vision is to create an automatic system that delivers “perfect train run histories” with a cause for every time loss. The future...... ERTMS Traffic Management System will include a rescheduler: Every time a train leaves its path, a rescheduling is triggered and the train receives a new timetable. As a part of this process, other trains may also be rescheduled. A concept for converting this information into the “perfect train run...

  12. Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation

    Directory of Open Access Journals (Sweden)

    Halleskog Carina

    2012-05-01

    Full Text Available Abstract Background WNT-5A signaling in the central nervous system is important for morphogenesis, neurogenesis and establishment of functional connectivity; the source of WNT-5A and its importance for cellular communication in the adult brain, however, are mainly unknown. We have previously investigated the inflammatory effects of WNT/β-catenin signaling in microglia in Alzheimer's disease. WNT-5A, however, generally recruits β-catenin-independent signaling. Thus, we aim here to characterize the role of WNT-5A and downstream signaling pathways for the inflammatory transformation of the brain's macrophages, the microglia. Methods Mouse brain sections were used for immunohistochemistry. Primary isolated microglia and astrocytes were employed to characterize the WNT-induced inflammatory transformation and underlying intracellular signaling pathways by immunoblotting, quantitative mRNA analysis, proliferation and invasion assays. Further, measurements of G protein activation by [γ-35 S]GTP binding, examination of calcium fluxes and cyclic AMP production were used to define intracellular signaling pathways. Results Astrocytes in the adult mouse brain express high levels of WNT-5A, which could serve as a novel astroglia-microglia communication pathway. The WNT-5A-induced proinflammatory microglia response is characterized by increased expression of inducible nitric oxide synthase, cyclooxygenase-2, cytokines, chemokines, enhanced invasive capacity and proliferation. Mapping of intracellular transduction pathways reveals that WNT-5A activates heterotrimeric Gi/o proteins to reduce cyclic AMP levels and to activate a Gi/o protein/phospholipase C/calcium-dependent protein kinase/extracellular signal-regulated kinase 1/2 (ERK1/2 axis. We show further that WNT-5A-induced ERK1/2 signaling is responsible for distinct aspects of the proinflammatory transformation, such as matrix metalloprotease 9/13 expression, invasion and proliferation. Conclusions

  13. Estradiol-Induced Object Recognition Memory Consolidation Is Dependent on Activation of mTOR Signaling in the Dorsal Hippocampus

    Science.gov (United States)

    Fortress, Ashley M.; Fan, Lu; Orr, Patrick T.; Zhao, Zaorui; Frick, Karyn M.

    2013-01-01

    The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17[Beta]-estradiol (E[subscript 2]) is dependent on mTOR…

  14. An appraisal of how the vitamin A-redox hypothesis can maintain honesty of carotenoid-dependent signals

    NARCIS (Netherlands)

    Simons, Mirre J. P.; Groothuis, Ton G. G.; Verhulst, Simon

    The vitamin A-redox hypothesis provides an explanation for honest signaling of phenotypic quality by carotenoid-dependent traits. A key aspect of the vitamin A-redox hypothesis, applicable to both yellow and red coloration, is the hypothesized negative feedback of tightly regulated Vitamin A plasma

  15. Wnt signaling requires retromer-dependent recycling of MIG-14/Wntless in Wnt-producing cells.

    NARCIS (Netherlands)

    Yang, P.T.; Lorenowicz, M.J.; Silhankova, M.; Coudreuse, D.Y.M.; Betist, M.C.; Korswagen, H.C.

    2008-01-01

    Wnt proteins are secreted signaling molecules that play a central role in development and adult tissue homeostasis. We have previously shown that Wnt signaling requires retromer function in Wnt-producing cells. The retromer is a multiprotein complex that mediates endosome-to-Golgi transport of

  16. Insulin signaling regulates fatty acid catabolism at the level of CoA activation.

    Directory of Open Access Journals (Sweden)

    Xiaojun Xu

    2012-01-01

    Full Text Available The insulin/IGF signaling pathway is a highly conserved regulator of metabolism in flies and mammals, regulating multiple physiological functions including lipid metabolism. Although insulin signaling is known to regulate the activity of a number of enzymes in metabolic pathways, a comprehensive understanding of how the insulin signaling pathway regulates metabolic pathways is still lacking. Accepted knowledge suggests the key regulated step in triglyceride (TAG catabolism is the release of fatty acids from TAG via the action of lipases. We show here that an additional, important regulated step is the activation of fatty acids for beta-oxidation via Acyl Co-A synthetases (ACS. We identify pudgy as an ACS that is transcriptionally regulated by direct FOXO action in Drosophila. Increasing or reducing pudgy expression in vivo causes a decrease or increase in organismal TAG levels respectively, indicating that pudgy expression levels are important for proper lipid homeostasis. We show that multiple ACSs are also transcriptionally regulated by insulin signaling in mammalian cells. In sum, we identify fatty acid activation onto CoA as an important, regulated step in triglyceride catabolism, and we identify a mechanistic link through which insulin regulates lipid homeostasis.

  17. Head direction cell activity in mice: robust directional signal depends on intact otolith organs

    Science.gov (United States)

    Yoder, Ryan M.; Taube, Jeffrey S.

    2009-01-01

    The head direction (HD) cell signal is a representation of an animal's perceived directional heading with respect to its environment. This signal appears to originate in the vestibular system, which includes the semicircular canals and otolith organs. Preliminary studies indicate the semicircular canals provide a necessary component of the HD signal, but involvement of otolithic information in the HD signal has not been tested. The present study was designed to determine the otolithic contribution to the HD signal, as well as to compare HD cell activity of mice to that of rats. HD cell activity in the anterodorsal thalamus was assessed in wild-type C57BL/6J and otoconia-deficient tilted mice during locomotion within a cylinder containing a prominent visual landmark. HD cell firing properties in C57BL/6J mice were generally similar to those in rats. However, in C57BL/6J mice, landmark rotation failed to demonstrate dominant control of the HD signal in 36% of the sessions. In darkness, directional firing became unstable during 42% of the sessions, but landmark control was not associated with HD signal stability in darkness. HD cells were identified in tilted mice, but directional firing properties were not as robust as those of C57BL/6J mice. Most HD cells in tilted mice were controlled by landmark rotation, but showed substantial signal degradation across trials. These results support current models that suggest otolithic information is involved in the perception of directional heading. Furthermore, compared to rats, the HD signal in mice appears to be less reliably anchored to prominent environmental cues. PMID:19176815

  18. Experiments of Multi-Level Read-Only Recording Using Readout Signal Wave-Shape Modulation

    International Nuclear Information System (INIS)

    Yi, Tang; Jing, Pei; Long-Fa, Pan; Yi, Ni; Hua, Hu; Bu-Qing, Zhang

    2008-01-01

    An innovative multilevel read-only recording method is proposed. In this method, a short pit/land is deliberately inserted to the original land/pit. This modifies the wave-shape of readout signal. Taking the wave-shape as the symbol of level detection, a signal wave-shape modulation (SWSM) multilevel method is realized. This method is carried out and validated on the DVD read-only manufacture and readout system. A capacity of 15 GB can be expected, and a bit error rate of 10 −4 is achieved. The capacity can meet the demand of high definition movie publication. This method also provides a potential multi-level solution for other storage formats and systems. (fundamental areas of phenomenology (including applications))

  19. Phosphorylation-dependent signaling controls degradation of DNA mismatch repair protein PMS2.

    Science.gov (United States)

    Hinrichsen, Inga; Weßbecher, Isabel M; Huhn, Meik; Passmann, Sandra; Zeuzem, Stefan; Plotz, Guido; Biondi, Ricardo M; Brieger, Angela

    2017-12-01

    MutLα, a heterodimer consisting of MLH1 and PMS2, plays an important role in DNA mismatch repair and has been shown to be additionally involved in several other important cellular mechanisms. Previous work indicated that AKT could modulate PMS2 stability by phosphorylation. Still, the mechanisms of regulation of MutLα remain unclear. The stability of MutLα subunits was investigated by transiently overexpression of wild type and mutant forms of MLH1 and PMS2 using immunoblotting for measuring the protein levels after treatment. We found that treatment with the cell-permeable serine/threonine phosphatase inhibitor, Calyculin, leads to degradation of PMS2 when MLH1 or its C-terminal domain is missing or if amino acids of MLH1 essential for PMS2 interaction are mutated. In addition, we discovered that the C-terminal tail of PMS2 is relevant for this Calyculin-dependent degradation. A direct involvement of AKT, which was previously described to be responsible for PMS2 degradation, could not be detected. The multi-kinase inhibitor Sorafenib, in contrast, was able to avoid the degradation of PMS2 which postulates that cellular phosphorylation is involved in this process. Together, we show that pharmacologically induced phosphorylation by Calyculin can induce the selective proteasome-dependent degradation of PMS2 but not of MLH1 and that the PMS2 degradation could be blocked by Sorafenib treatment. Curiously, the C-terminal Lynch Syndrome-variants MLH1 L749P and MLH1 Y750X make PMS2 prone to Calyculin induced degradation. Therefore, we conclude that the specific degradation of PMS2 may represent a new mechanism to regulate MutLα. © 2017 Wiley Periodicals, Inc.

  20. Effect of temperature-dependent energy-level shifts on a semiconductor's Peltier heat

    International Nuclear Information System (INIS)

    Emin, D.

    1984-01-01

    The Peltier heat of a charge carrier in a semiconductor is calculated for the situation in which the electronic energy levels are temperature dependent. The temperature dependences of the electronic energy levels, generally observed optically, arise from their dependences on the vibrational energy of the lattice (e.g., as caused by thermal expansion). It has been suggested that these temperature dependences will typically have a major effect on the Peltier heat. The Peltier heat associated with a given energy level is a thermodynamic quantity; it is the product of the temperature and the change of the entropy of the system when a carrier is added in that level. As such, the energy levels cannot be treated as explicitly temperature dependent. The electron-lattice interaction causing the temperature dependence must be expressly considered. It is found that the carrier's interaction with the atomic vibrations lowers its electronic energy. However, the interaction of the carrier with the atomic vibrations also causes an infinitesimal lowering (approx.1/N) of each of the N vibrational frequencies. As a result, there is a finite carrier-induced increase in the average vibrational energy. Above the Debye temperature, this cancels the lowering of the carrier's electronic energy. Thus, the standard Peltier-heat formula, whose derivation generally ignores the temperature dependence of the electronic energy levels, is regained. This explains the apparent success of the standard formula in numerous analyses of electronic transport experiments

  1. The level of CD147 expression correlates with cyclophilin-induced signalling and chemotaxis

    Directory of Open Access Journals (Sweden)

    Constant Stephanie

    2011-10-01

    Full Text Available Abstract Background Previous studies identified CD147 as the chemotactic receptor on inflammatory leukocytes for extracellular cyclophilins (eCyp. However, CD147 is not known to associate with signal transducing molecules, so other transmembrane proteins, such as proteoglycans, integrins, and CD98, were suggested as receptor or co-receptor for eCyp. CD147 is ubiquitously expressed on many cell types, but relationship between the level of CD147 expression and cellular responses to eCyp has never been analyzed. Given the role of eCyp in pathogenesis of many diseases, it is important to know whether cellular responses to eCyp are regulated at the level of CD147 expression. Results Here, we manipulated CD147 expression levels on HeLa cells using RNAi and investigated the signalling and chemotactic responses to eCypA. Both Erk activation and chemotaxis correlated with the level of CD147 expression, with cells exhibiting low level expression being practically unresponsive to eCypA. Conclusions Our results provide the first demonstration of a chemotactic response of HeLa cells to eCypA, establish a correlation between the level of CD147 expression and the magnitude of cellular responses to eCypA, and indicate that CD147 may be a limiting factor in the receptor complex determining cyclophilin-induced Erk activation and cell migration.

  2. Nicotine Dependence and Urinary Nicotine, Cotinine and Hydroxycotinine Levels in Daily Smokers

    OpenAIRE

    Van Overmeire, Ilse P. I.; De Smedt, Tom; Dendale, Paul; Nackaerts, Kristiaan; Vanacker, Hilde; Vanoeteren, Jan F. A.; Van Laethem, Danny M. G.; Van Loco, Joris; De Cremer, Koen A. J.

    2016-01-01

    Nicotine dependence and smoking frequency are critical factors for smoking cessation. The aims of this study are (1) to determine if nicotine dependence Fagerstrom Test for Nicotine Dependence (FTND) scores are associated with urinary levels of nicotine metabolites, (2) to assess the relationship of hydroxycotinine/cotinine ratio with FTND score and cigarettes smoked per day (CPD), and (3) to identify significant predictors of cigarettes per day among biomarker concentrations and individual F...

  3. TRPP2-dependent Ca2+ signaling in dorso-lateral mesoderm is required for kidney field establishment in Xenopus.

    Science.gov (United States)

    Futel, Mélinée; Leclerc, Catherine; Le Bouffant, Ronan; Buisson, Isabelle; Néant, Isabelle; Umbhauer, Muriel; Moreau, Marc; Riou, Jean-François

    2015-03-01

    In Xenopus laevis embryos, kidney field specification is dependent on retinoic acid (RA) and coincides with a dramatic increase of Ca(2+) transients, but the role of Ca(2+) signaling in the kidney field is unknown. Here, we identify TRPP2, a member of the transient receptor potential (TRP) superfamily of channel proteins encoded by the pkd2 gene, as a central component of Ca(2+) signaling in the kidney field. TRPP2 is strongly expressed at the plasma membrane where it might regulate extracellular Ca(2+) entry. Knockdown of pkd2 in the kidney field results in the downregulation of pax8, but not of other kidney field genes (lhx1, osr1 and osr2). We further show that inhibition of Ca(2+) signaling with an inducible Ca(2+) chelator also causes downregulation of pax8, and that pkd2 knockdown results in a severe inhibition of Ca(2+) transients in kidney field explants. Finally, we show that disruption of RA results both in an inhibition of intracellular Ca(2+) signaling and of TRPP2 incorporation into the plasma membrane of kidney field cells. We propose that TRPP2-dependent Ca(2+) signaling is a key component of pax8 regulation in the kidney field downstream of RA-mediated non-transcriptional control of TRPP2. © 2015. Published by The Company of Biologists Ltd.

  4. Stiffness-dependent cellular internalization of matrix-bound BMP-2 and its relation to Smad and non-Smad signaling.

    Science.gov (United States)

    Gilde, Flora; Fourel, Laure; Guillot, Raphael; Pignot-Paintrand, Isabelle; Okada, Takaharu; Fitzpatrick, Vincent; Boudou, Thomas; Albiges-Rizo, Corinne; Picart, Catherine

    2016-12-01

    Surface coatings delivering BMP are a promising approach to render biomaterials osteoinductive. In contrast to soluble BMPs which can interact with their receptors at the dorsal side of the cell, BMPs presented as an insoluble cue physically bound to a biomimetic matrix, called here matrix-bound (bBMP-2), are presented to cells by their ventral side. To date, BMP-2 internalization and signaling studies in cell biology have always been performed by adding soluble (sBMP-2) to cells adhered on cell culture plates or glass slides, which will be considered here as a "reference" condition. However, whether and how matrix-bound BMP-2 can be internalized by cells and its relation to canonical (SMAD) and non-canonical signaling (ALP) remain open questions. In this study, we investigated the uptake and processing of BMP-2 by C2C12 myoblasts. This BMP-2 was presented either embedded in polyelectrolyte multilayer films (matrix-bound presentation) or as soluble form. Using fluorescently labeled BMP-2, we showed that the amount of matrix-bound BMP-2 internalized is dependent on the level of crosslinking of the polyelectrolyte films. Cav-1-mediated internalization is related to both SMAD and ALP signaling, while clathrin-mediated is only related to ALP signaling. BMP-2 internalization was independent of the presentation mode (sBMP-2 versus bBMP-2) for low crosslinked films (soft, EDC10) in striking contrast with high crosslinked (stiff, EDC70) films where internalization was much lower and slower for bBMP-2. As anticipated, internalization of sBMP-2 barely depended on the underlying matrix. Taken together, these results indicate that BMP-2 internalization can be tuned by the underlying matrix and activates downstream BMP-2 signaling, which is key for the effective formation of bone tissue. The presentation of growth factors from material surfaces currently presents significant challenges in academic research, clinics and industry. Being able to deliver efficiently these growth

  5. The TORC2-Dependent Signaling Network in the Yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Roelants, Françoise M; Leskoske, Kristin L; Martinez Marshall, Maria Nieves; Locke, Melissa N; Thorner, Jeremy

    2017-09-05

    To grow, eukaryotic cells must expand by inserting glycerolipids, sphingolipids, sterols, and proteins into their plasma membrane, and maintain the proper levels and bilayer distribution. A fungal cell must coordinate growth with enlargement of its cell wall. In Saccharomyces cerevisiae, a plasma membrane-localized protein kinase complex, Target of Rapamicin (TOR) complex-2 (TORC2) (mammalian ortholog is mTORC2), serves as a sensor and masterregulator of these plasma membrane- and cell wall-associated events by directly phosphorylating and thereby stimulating the activity of two types of effector protein kinases: Ypk1 (mammalian ortholog is SGK1), along with a paralog (Ypk2); and, Pkc1 (mammalian ortholog is PKN2/PRK2). Ypk1 is a central regulator of pathways and processes required for plasma membrane lipid and protein homeostasis, and requires phosphorylation on its T-loop by eisosome-associated protein kinase Pkh1 (mammalian ortholog is PDK1) and a paralog (Pkh2). For cell survival under various stresses, Ypk1 function requires TORC2-mediated phosphorylation at multiple sites near its C terminus. Pkc1 controls diverse processes, especially cell wall synthesis and integrity. Pkc1 is also regulated by Pkh1- and TORC2-dependent phosphorylation, but, in addition, by interaction with Rho1-GTP and lipids phosphatidylserine (PtdSer) and diacylglycerol (DAG). We also describe here what is currently known about the downstream substrates modulated by Ypk1-mediated and Pkc1-mediated phosphorylation.

  6. Order Level Inventory Models for Deteriorating Seasonable/Fashionable Products with Time Dependent Demand and Shortages

    OpenAIRE

    Skouri, K.; Konstantaras, I.

    2009-01-01

    An order level inventory model for seasonable/fashionable products subject to a period of increasing demand followed by a period of level demand and then by a period of decreasing demand rate (three branches ramp type demand rate) is considered. The unsatisfied demand is partially backlogged with a time dependent backlogging rate. In addition, the product deteriorates with a time dependent, namely, Weibull, deterioration rate. The model is studied under the following different replenishment p...

  7. The Transcription Factor ABI4 Is Required for the Ascorbic Acid–Dependent Regulation of Growth and Regulation of Jasmonate-Dependent Defense Signaling Pathways in Arabidopsis[C][W

    Science.gov (United States)

    Kerchev, Pavel I.; Pellny, Till K.; Vivancos, Pedro Diaz; Kiddle, Guy; Hedden, Peter; Driscoll, Simon; Vanacker, Hélène; Verrier, Paul; Hancock, Robert D.; Foyer, Christine H.

    2011-01-01

    Cellular redox homeostasis is a hub for signal integration. Interactions between redox metabolism and the ABSCISIC ACID-INSENSITIVE-4 (ABI4) transcription factor were characterized in the Arabidopsis thaliana vitamin c defective1 (vtc1) and vtc2 mutants, which are defective in ascorbic acid synthesis and show a slow growth phenotype together with enhanced abscisic acid (ABA) levels relative to the wild type (Columbia-0). The 75% decrease in the leaf ascorbate pool in the vtc2 mutants was not sufficient to adversely affect GA metabolism. The transcriptome signatures of the abi4, vtc1, and vtc2 mutants showed significant overlap, with a large number of transcription factors or signaling components similarly repressed or induced. Moreover, lincomycin-dependent changes in LIGHT HARVESTING CHLOROPHYLL A/B BINDING PROTEIN 1.1 expression were comparable in these mutants, suggesting overlapping participation in chloroplast to nucleus signaling. The slow growth phenotype of vtc2 was absent in the abi4 vtc2 double mutant, as was the sugar-insensitive phenotype of the abi4 mutant. Octadecanoid derivative-responsive AP2/ERF-domain transcription factor 47 (ORA47) and AP3 (an ABI5 binding factor) transcripts were enhanced in vtc2 but repressed in abi4 vtc2, suggesting that ABI4 and ascorbate modulate growth and defense gene expression through jasmonate signaling. We conclude that low ascorbate triggers ABA- and jasmonate-dependent signaling pathways that together regulate growth through ABI4. Moreover, cellular redox homeostasis exerts a strong influence on sugar-dependent growth regulation. PMID:21926335

  8. Detection of a dynamic topography signal in last interglacial sea-level records.

    Science.gov (United States)

    Austermann, Jacqueline; Mitrovica, Jerry X; Huybers, Peter; Rovere, Alessio

    2017-07-01

    Estimating minimum ice volume during the last interglacial based on local sea-level indicators requires that these indicators are corrected for processes that alter local sea level relative to the global average. Although glacial isostatic adjustment is generally accounted for, global scale dynamic changes in topography driven by convective mantle flow are generally not considered. We use numerical models of mantle flow to quantify vertical deflections caused by dynamic topography and compare predictions at passive margins to a globally distributed set of last interglacial sea-level markers. The deflections predicted as a result of dynamic topography are significantly correlated with marker elevations (>95% probability) and are consistent with construction and preservation attributes across marker types. We conclude that a dynamic topography signal is present in the elevation of last interglacial sea-level records and that the signal must be accounted for in any effort to determine peak global mean sea level during the last interglacial to within an accuracy of several meters.

  9. Integration and enhancement of low-level signals from air-pollution monitoring sensors

    Energy Technology Data Exchange (ETDEWEB)

    Dowd, G F; Dubois, L; Monkman, J L

    1975-09-01

    In this paper, we have demonstrated how signal enhancement techniques would be advantageous in the low-level analysis of air pollutants. We have further shown what type of signal-to-noise gain may be expected from an off-the-shelf, inexpensive run-of-the-mill mercury monitor. As long as an evoked response time constant is introduced into the measuring system, noise of a random nature may be reduced to such an extent that trace signals, buried deep in the electrical background, may be reliably measured. If we couple this type of analysis to a multi-parameter mercury analyzer, contributing factors may be evaluated. This will result in a more efficient system application. We have also reported a manner in which evoked response time is related to instrument onset time. However, there are other methods for obtaining an evoked response. Of note is the use of wavelength in the enhancement of spectrophotometric signals. In additional work now being carried out in our laboratory, there are indications that it is possible to relate this type of processing to SO/sub 2/ analyzing systems using conductometry. (auth)

  10. Acceptance noise level: effects of the speech signal, babble, and listener language.

    Science.gov (United States)

    Shi, Lu-Feng; Azcona, Gabrielly; Buten, Lupe

    2015-04-01

    The acceptable noise level (ANL) measure has gained much research/clinical interest in recent years. The present study examined how the characteristics of the speech signal and the babble used in the measure may affect the ANL in listeners with different native languages. Fifteen English monolingual, 16 Russian-English bilingual, and 24 Spanish-English bilingual listeners participated. The ANL was obtained in eight conditions varying in the language of the signal (English and Spanish), language of the babble (English and Spanish), and number of talkers in the babble (4 and 12). Test conditions were randomized across listeners. The ANL for each condition was based on a minimum of two trials. Russian-English bilinguals yielded higher ANLs than other listeners; the intergroup difference of 4-5 dB was statistically and clinically significant. Spanish signals yielded significantly higher ANLs than English signals, but this difference of 0.5 dB was clinically negligible. The language and composition of the babble had a significant effect on Russian-English bilinguals, who yielded higher ANLs with the Spanish than English 12-talker babble. The above findings do not fully support the notion that the ANL is language- and population-independent. Clinicians should be aware of possible effects on ANL measures due to listeners' linguistic/cultural background.

  11. Bifenthrin causes transcriptomic alterations in mTOR and ryanodine receptor-dependent signaling and delayed hyperactivity in developing zebrafish (Danio rerio).

    Science.gov (United States)

    Frank, Daniel F; Miller, Galen W; Harvey, Danielle J; Brander, Susanne M; Geist, Juergen; Connon, Richard E; Lein, Pamela J

    2018-04-18

    Over the last few decades, the pyrethroid insecticide bifenthrin has been increasingly employed for pest control in urban and agricultural areas, putting humans and wildlife at increased risk of exposure. Exposures to nanomolar (nM) concentrations of bifenthrin have recently been reported to alter calcium oscillations in rodent neurons. Neuronal calcium oscillations are influenced by ryanodine receptor (RyR) activity, which modulates calcium-dependent signaling cascades, including the mechanistic target of rapamycin (mTOR) signaling pathway. RyR activity and mTOR signaling play critical roles in regulating neurodevelopmental processes. However, whether environmentally relevant levels of bifenthrin alter RyR or mTOR signaling pathways to influence neurodevelopment has not been addressed. Therefore, our main objectives in this study were to examine the transcriptomic responses of genes involved in RyR and mTOR signaling pathways in zebrafish (Danio rerio) exposed to low (ng/L) concentrations of bifenthrin, and to assess the potential functional consequences by measuring locomotor responses to external stimuli. Wildtype zebrafish were exposed for 1, 3 and 5 days to 1, 10 and 50 ng/L bifenthrin, followed by a 14 d recovery period. Bifenthrin elicited significant concentration-dependent transcriptional responses in the majority of genes examined in both signaling cascades, and at all time points examined during the acute exposure period (1, 3, and 5 days post fertilization; dpf), and at the post recovery assessment time point (19 dpf). Changes in locomotor behavior were not evident during the acute exposure period, but were observed at 19 dpf, with main effects (increased locomotor behavior) detected in fish exposed developmentally to bifenthrin at 1 or 10 ng/L, but not 50 ng/L. These findings illustrate significant influences of developmental exposures to low (ng/L) concentrations of bifenthrin on neurodevelopmental processes in zebrafish. Copyright © 2018

  12. Nitric oxide-dependent vasodilation and Ca2+ signalling induced by erythrodiol in rat aorta

    Directory of Open Access Journals (Sweden)

    Fidèle Ntchapda

    2015-06-01

    Full Text Available Objective: To evaluate the pharmacological property of erythrodiol, a natural triterpenoid contained in propolis, as vasodilatory agent, and to determine its mechanism of action. Methods: Rats aortic rings were isolated and suspended in organ baths, and the effects of erythrodiol were studied by means of isometric tension recording experiments. Nitric oxide (NO was detected by ozone-induced chemiluminescence. The technique used to evaluate changes in intracellular Ca2+ concentration in intact endothelium was opened aortic ring and loaded with 16 µmol Fura-2/AM for 60 min at room temperature, washed and fixed by small pins with the luminal face up. In situ, ECs were visualized by an upright epifluorescence Axiolab microscope (Carl Zeiss, Oberkochen, Germany equipped with a Zeiss×63 Achroplan objective (water immersion, 2.0 mm working distance, 0.9 numerical apertures. ECs were excited alternately at 340 and 380 nm, and the emitted light was detected at 510 nm. Results: In aortic rings with intact endothelium pre-contracted with norepinephrine (10-4 mol/L, the addition of erythrodiol (10-8-10-4 mol/L induced vasorelaxation in a concentration-dependent manner; in endothelium-denuded rings, the relaxant response induced by erythrodiol was almost completely abolished suggesting that vasorelaxation was endothelium-dependent. They had almost no relaxant effect on depolarised or endothelium-denuded aortic segments. The relaxation was significantly attenuated by pre-treatment with the NO synthase inhibitor Nvnitro-L-arginine-methylester. Erythrodiol (10-4 mol/L was able to significantly increase NOx levels. This effect was completely abolished after removal of the vascular endothelium. Erythrodiol (100 µmol/L caused a slow, long-lasting increase in intracellular Ca2+ concentration. These results further supported the hypothesis that erythrodiol can induce activation of the NO/soluble guanylate cyclase/cyclic guanosine monophosphate pathway, as

  13. Regulation of autophagy by amino acids and MTOR-dependent signal transduction.

    Science.gov (United States)

    Meijer, Alfred J; Lorin, Séverine; Blommaart, Edward F; Codogno, Patrice

    2015-10-01

    Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.

  14. Initiation and patterning of the snake dentition are dependent on Sonic hedgehog signaling.

    Science.gov (United States)

    Buchtová, Marcela; Handrigan, Gregory R; Tucker, Abigail S; Lozanoff, Scott; Town, Liam; Fu, Katherine; Diewert, Virginia M; Wicking, Carol; Richman, Joy M

    2008-07-01

    Here we take the first look at cellular dynamics and molecular signaling in the developing snake dentition. We found that tooth formation differs from rodents in several respects. The majority of snake teeth bud off of a deep, ribbon-like dental lamina rather than as separate tooth germs. Prior to and after dental lamina ingrowth, we observe asymmetries in cell proliferation and extracellular matrix distribution suggesting that localized signaling by a secreted protein is involved. We cloned Sonic hedgehog from the African rock python Python sebae and traced its expression in the species as well as in two other snakes, the closely-related Python regius and the more derived corn snake Elaphe guttata (Colubridae). We found that expression of Shh is first confined to the odontogenic band and defines the position of the future dental lamina. Shh transcripts in pythons are progressively restricted to the oral epithelium on one side of the dental lamina and remain in this position throughout the prehatching period. Shh is expressed in the inner enamel epithelium and the stellate reticulum of the tooth anlagen, but is absent from the outer enamel epithelium and its derivative, the successional lamina. This suggests that signals other than Shh are responsible for replacement tooth formation. Functional studies using cyclopamine to block Hh signaling during odontogenesis prevented initiation and extension of the dental lamina into the mesenchyme, and also affected the directionality of this process. Further, blocking Hh signaling led to disruptions of the inner enamel epithelium. To explore the role of Shh in lamina extension, we looked at its expression in the premaxillary teeth, which form closer to the oral surface than elsewhere in the mouth. Oral ectodermal Shh expression in premaxillary teeth is lost soon after the teeth form reinforcing the idea that Shh is controlling the depth of the dental lamina. In summary, we have found diverse roles for Shh in patterning the

  15. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T.Y.; Sadat, U. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom); Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Miller, S.R. [GlaxoSmithKline, Biostatistics and Data Sciences, Harlow (United Kingdom); Walsh, S.R.; Boyle, J.R.; Gaunt, M.E. [Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom)

    2009-07-15

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T{sub 1}-weighted (T{sub 1}w), T{sub 2}*-weighted (T{sub 2}*w) and quantitative T{sub 2}* (qT{sub 2}*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T{sub 1}w, T{sub 2}*w and qT{sub 2}* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T{sub 1}w, T{sub 2}*w and qT{sub 2}* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T{sub 1}w, T{sub 2}*w and qT{sub 2}*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T{sub 1}w, T{sub 2}*w and qT{sub 2}* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  16. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    International Nuclear Information System (INIS)

    Tang, T.Y.; Sadat, U.; Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H.; Miller, S.R.; Walsh, S.R.; Boyle, J.R.; Gaunt, M.E.

    2009-01-01

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T 1 -weighted (T 1 w), T 2 *-weighted (T 2 *w) and quantitative T 2 * (qT 2 *) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T 1 w, T 2 *w and qT 2 * MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T 1 w, T 2 *w and qT 2 * sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T 1 w, T 2 *w and qT 2 *, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T 1 w, T 2 *w and qT 2 * signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  17. Ethylene Regulates Levels of Ethylene Receptor/CTR1 Signaling Complexes in Arabidopsis thaliana*

    Science.gov (United States)

    Shakeel, Samina N.; Gao, Zhiyong; Amir, Madiha; Chen, Yi-Feng; Rai, Muneeza Iqbal; Haq, Noor Ul; Schaller, G. Eric

    2015-01-01

    The plant hormone ethylene is perceived by a five-member family of receptors in Arabidopsis thaliana. The receptors function in conjunction with the Raf-like kinase CTR1 to negatively regulate ethylene signal transduction. CTR1 interacts with multiple members of the receptor family based on co-purification analysis, interacting more strongly with receptors containing a receiver domain. Levels of membrane-associated CTR1 vary in response to ethylene, doing so in a post-transcriptional manner that correlates with ethylene-mediated changes in levels of the ethylene receptors ERS1, ERS2, EIN4, and ETR2. Interactions between CTR1 and the receptor ETR1 protect ETR1 from ethylene-induced turnover. Kinetic and dose-response analyses support a model in which two opposing factors control levels of the ethylene receptor/CTR1 complexes. Ethylene stimulates the production of new complexes largely through transcriptional induction of the receptors. However, ethylene also induces turnover of receptors, such that levels of ethylene receptor/CTR1 complexes decrease at higher ethylene concentrations. Implications of this model for ethylene signaling are discussed. PMID:25814663

  18. Improved signal model for confocal sensors accounting for object depending artifacts.

    Science.gov (United States)

    Mauch, Florian; Lyda, Wolfram; Gronle, Marc; Osten, Wolfgang

    2012-08-27

    The conventional signal model of confocal sensors is well established and has proven to be exceptionally robust especially when measuring rough surfaces. Its physical derivation however is explicitly based on plane surfaces or point like objects, respectively. Here we show experimental results of a confocal point sensor measurement of a surface standard. The results illustrate the rise of severe artifacts when measuring curved surfaces. On this basis, we present a systematic extension of the conventional signal model that is proven to be capable of qualitatively explaining these artifacts.

  19. Frequency response testing at Experimental Breeder Reactor II using discrete-level periodic signals

    International Nuclear Information System (INIS)

    Rhodes, W.D.; Larson, H.A.

    1990-01-01

    The Experimental Breeder Reactor 2 (EBR-2) reactivity-to-power frequency-response function was measured with pseudo-random, discrete-level, periodic signals. The reactor power deviation was small with insignificant perturbation of normal operation and in-place irradiation experiments. Comparison of results with measured rod oscillator data and with theoretical predictions show good agreement. Moreover, measures of input signal quality (autocorrelation function and energy spectra) confirm the ability to enable this type of frequency response determination at EBR-2. Measurements were made with the pseudo-random binary sequence, quadratic residue binary sequence, pseudo-random ternary sequence, and the multifrequency binary sequence. 10 refs., 7 figs., 3 tabs

  20. Hybrid Scheduling/Signal-Level Coordination in the Downlink of Multi-Cloud Radio-Access Networks

    KAUST Repository

    Douik, Ahmed; Dahrouj, Hayssam; Al-Naffouri, Tareq Y.; Alouini, Mohamed-Slim

    2016-01-01

    results suggest that the proposed hybrid scheduling strategy provides appreciable gain as compared to the scheduling-level coordinated networks, with a negligible degradation to signal-level coordination.

  1. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.

    Science.gov (United States)

    Durocher, D; Taylor, I A; Sarbassova, D; Haire, L F; Westcott, S L; Jackson, S P; Smerdon, S J; Yaffe, M B

    2000-11-01

    Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 A resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes.

  2. Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis.

    Science.gov (United States)

    Lin, Neng-Yu; Distler, Alfiya; Beyer, Christian; Philipi-Schöbinger, Ariella; Breda, Silvia; Dees, Clara; Stock, Michael; Tomcik, Michal; Niemeier, Andreas; Dell'Accio, Francesco; Gelse, Kolja; Mattson, Mark P; Schett, Georg; Distler, Jörg Hw

    2016-11-01

    Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis.

    Directory of Open Access Journals (Sweden)

    Lakshmi Pillai-Kastoori

    2014-07-01

    Full Text Available Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.

  4. Dependence centrality similarity: Measuring the diversity of profession levels of interests

    Science.gov (United States)

    Yan, Deng-Cheng; Li, Ming; Wang, Bing-Hong

    2017-08-01

    To understand the relations between developers and software, we study a collaborative coding platform from the perspective of networks, including follower networks, dependence networks and developer-project bipartite networks. Through the analyzing of degree distribution, PageRank and degree-dependent nearest neighbors' centrality, we find that the degree distributions of all networks have a power-law form except the out-degree distributions of dependence networks. The nearest neighbors' centrality is negatively correlated with degree for developers but fluctuates around the average for projects. In order to measure the diversity of profession levels of interests, a new index called dependence centrality similarity is proposed and the correlation between dependence centrality similarity and degree is investigated. The result shows an obvious negative correlations between dependence centrality similarity and degree.

  5. A density-dependent switch drives stochastic clustering and polarization of signaling molecules.

    Directory of Open Access Journals (Sweden)

    Alexandra Jilkine

    2011-11-01

    Full Text Available Positive feedback plays a key role in the ability of signaling molecules to form highly localized clusters in the membrane or cytosol of cells. Such clustering can occur in the absence of localizing mechanisms such as pre-existing spatial cues, diffusional barriers, or molecular cross-linking. What prevents positive feedback from amplifying inevitable biological noise when an un-clustered "off" state is desired? And, what limits the spread of clusters when an "on" state is desired? Here, we show that a minimal positive feedback circuit provides the general principle for both suppressing and amplifying noise: below a critical density of signaling molecules, clustering switches off; above this threshold, highly localized clusters are recurrently generated. Clustering occurs only in the stochastic regime, suggesting that finite sizes of molecular populations cannot be ignored in signal transduction networks. The emergence of a dominant cluster for finite numbers of molecules is partly a phenomenon of random sampling, analogous to the fixation or loss of neutral mutations in finite populations. We refer to our model as the "neutral drift polarity model." Regulating the density of signaling molecules provides a simple mechanism for a positive feedback circuit to robustly switch between clustered and un-clustered states. The intrinsic ability of positive feedback both to create and suppress clustering is a general mechanism that could operate within diverse biological networks to create dynamic spatial organization.

  6. Regulation of autophagy by amino acids and MTOR-dependent signal transduction

    NARCIS (Netherlands)

    Meijer, Alfred J.; Lorin, Séverine; Blommaart, Edward F.; Codogno, Patrice

    2015-01-01

    Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins

  7. A postsynaptic PI3K-cII dependent signaling controller for presynaptic homeostatic plasticity

    Science.gov (United States)

    Hauswirth, Anna G; Ford, Kevin J; Wang, Tingting; Fetter, Richard D; Tong, Amy

    2018-01-01

    Presynaptic homeostatic plasticity stabilizes information transfer at synaptic connections in organisms ranging from insect to human. By analogy with principles of engineering and control theory, the molecular implementation of PHP is thought to require postsynaptic signaling modules that encode homeostatic sensors, a set point, and a controller that regulates transsynaptic negative feedback. The molecular basis for these postsynaptic, homeostatic signaling elements remains unknown. Here, an electrophysiology-based screen of the Drosophila kinome and phosphatome defines a postsynaptic signaling platform that includes a required function for PI3K-cII, PI3K-cIII and the small GTPase Rab11 during the rapid and sustained expression of PHP. We present evidence that PI3K-cII localizes to Golgi-derived, clathrin-positive vesicles and is necessary to generate an endosomal pool of PI(3)P that recruits Rab11 to recycling endosomal membranes. A morphologically distinct subdivision of this platform concentrates postsynaptically where we propose it functions as a homeostatic controller for retrograde, trans-synaptic signaling. PMID:29303480

  8. CCR5 internalisation and signalling have different dependence on membrane lipid raft integrity.

    Science.gov (United States)

    Cardaba, Clara Moyano; Kerr, Jason S; Mueller, Anja

    2008-09-01

    The chemokine receptor, CCR5, acts as a co-receptor for human immunodeficiency virus entry into cells. CCR5 has been shown to be targeted to cholesterol- and sphingolipid-rich membrane microdomains termed lipid rafts or caveolae. Cholesterol is essential for CCL4 binding to CCR5 and for keeping the conformational integrity of the receptor. Filipin treatment leads to loss of caveolin-1 from the membrane and therefore to a collapse of the caveolae. We have found here that sequestration of membrane cholesterol with filipin did not affect receptor signalling, however a loss of ligand-induced internalisation of CCR5 was observed. Cholesterol extraction with methyl-beta-cyclodextrin (MCD) reduced signalling through CCR5 as measured by release of intracellular Ca(2+) and completely abolished the inhibition of forskolin-stimulated cAMP accumulation with no effect on internalisation. Pertussis toxin (PTX) treatment inhibited the intracellular release of calcium that is transduced via Galphai G-proteins. Depletion of cholesterol destroyed microdomains in the membrane and switched CCR5/G-protein coupling to a PTX-independent G-protein. We conclude that cholesterol in the membrane is essential for CCR5 signalling via the Galphai G-protein subunit, and that integrity of lipid rafts is not essential for effective CCR5 internalisation however it is crucial for proper CCR5 signal transduction via Galphai G-proteins.

  9. PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

    NARCIS (Netherlands)

    Sjöqvist, M.; Antfolk, D.; Ferraris, S.; Rraklli, V.; Haga, C.; Antila, C.; Mutvei, A.; Imanishi, S.Y.; Holmberg, J.; Jin, S.; Eriksson, J.E.; Lendahl, U.; Sahlgren, C.M.

    Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick

  10. GPER1-mediated IGFBP-1 induction modulates IGF-1-dependent signaling in tamoxifen-treated breast cancer cells.

    Science.gov (United States)

    Vaziri-Gohar, Ali; Houston, Kevin D

    2016-02-15

    Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant therapy for estrogen receptor-α (ERα)-positive breast cancer patients. To determine if extracellular factors contribute to the modulation of IGF-1 signaling after tamoxifen treatment, MCF-7 cells were treated with IGF-1 in conditioned medium (CM) obtained from 4-OHT-treated MCF-7 cells and the accumulation of phospho-Akt (S473) was measured. CM inhibited IGF-1-dependent cell signaling and suggesting the involvement of extracellular factors (ie. IGFBPs). A significant increase in IGFBP-1 mRNA and extracellular IGFBP-1 protein was observed in 4-OHT-treated MCF-7 cells. Knockdown experiments demonstrated that both GPER1 and CREB mediate IGFBP-1 induction. Furthermore, experiments showed that 4-OHT-dependent IGFBP-1 transcription is downstream of GPER1-activation in breast cancer cells. Additionally, neutralization and knockdown experiments demonstrated a role for IGFBP-1 in the observed inhibition of IGF-1 signaling. These results suggested that 4-OHT inhibits IGF-1 signaling via GPER1 and CREB mediated extracellular IGFBP-1 accumulation in breast cancer cells. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  11. Dependence levels in users of electronic cigarettes, nicotine gums and tobacco cigarettes.

    Science.gov (United States)

    Etter, Jean-François; Eissenberg, Thomas

    2015-02-01

    To assess dependence levels in users of e-cigarettes, and compare them with dependence levels in users of nicotine gums and tobacco cigarettes. Self-reports from cross-sectional Internet and mail surveys. Comparisons of: (a) 766 daily users of nicotine-containing e-cigarettes with 30 daily users of nicotine-free e-cigarettes; (b) 911 former smokers who used the e-cigarette daily with 451 former smokers who used the nicotine gum daily (but no e-cigarette); (c) 125 daily e-cigarette users who smoked daily (dual users) with two samples of daily smokers who did not use e-cigarettes (2206 enrolled on the Internet and 292 enrolled by mail from the general population of Geneva). We used the Fagerström test for nicotine dependence, the nicotine dependence syndrome scale, the cigarette dependence scale and versions of these scales adapted for e-cigarettes and nicotine gums. Dependence ratings were slightly higher in users of nicotine-containing e-cigarettes than in users of nicotine-free e-cigarettes. In former smokers, long-term (>3 months) users of e-cigarettes were less dependent on e-cigarettes than long-term users of the nicotine gum were dependent on the gum. There were few differences in dependence ratings between short-term (≤3 months) users of gums or e-cigarettes. Dependence on e-cigarettes was generally lower in dual users than dependence on tobacco cigarettes in the two other samples of daily smokers. Some e-cigarette users were dependent on nicotine-containing e-cigarettes, but these products were less addictive than tobacco cigarettes. E-cigarettes may be as or less addictive than nicotine gums, which themselves are not very addictive. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Nutritional status-dependent endocannabinoid signalling regulates the integration of rat visceral information.

    Science.gov (United States)

    Khlaifia, Abdessattar; Matias, Isabelle; Cota, Daniela; Tell, Fabien

    2017-06-01

    Vagal sensory inputs transmit information from the viscera to brainstem neurones located in the nucleus tractus solitarii to set physiological parameters. These excitatory synapses exhibit a CB1 endocannabinoid-induced long-term depression (LTD) triggered by vagal fibre stimulation. We investigated the impact of nutritional status on long-term changes in this long-term synaptic plasticity. Food deprivation prevents LTD induction by disrupting CB1 receptor signalling. Short-term refeeding restores the capacity of vagal synapses to express LTD. Ghrelin and cholecystokinin, respectively released during fasting and refeeding, play a key role in the control of LTD via the activation of energy sensing pathways such as AMPK and the mTOR and ERK pathways. Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarii, a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB)-induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reversed by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding, restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and

  13. Relationship between nitric oxide- and calcium-dependent signal transduction pathways in growth hormone release from dispersed goldfish pituitary cells.

    Science.gov (United States)

    Chang, John P; Sawisky, Grant R; Davis, Philip J; Pemberton, Joshua G; Rieger, Aja M; Barreda, Daniel R

    2014-09-15

    Nitric oxide (NO) and Ca(2+) are two of the many intracellular signal transduction pathways mediating the control of growth hormone (GH) secretion from somatotropes by neuroendocrine factors. We have previously shown that the NO donor sodium nitroprusside (SNP) elicits Ca(2+) signals in identified goldfish somatotropes. In this study, we examined the relationships between NO- and Ca(2+)-dependent signal transduction mechanisms in GH secretion from primary cultures of dispersed goldfish pituitary cells. Morphologically identified goldfish somatotropes stained positively for an NO-sensitive dye indicating they may be a source of NO production. In 2h static incubation experiments, GH release responses to the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) were attenuated by CoCl2, nifedipine, verapamil, TMB-8, BHQ, and KN62. In column perifusion experiments, the ability of SNP to induce GH release was impaired in the presence of TMB-8, BHQ, caffeine, and thapsigargin, but not ryanodine. Caffeine-elicited GH secretion was not affected by the NO scavenger PTIO. These results suggest that NO-stimulated GH release is dependent on extracellular Ca(2+) availability and voltage-sensitive Ca(2+) channels, as well as intracellular Ca(2+) store(s) that possess BHQ- and/or thapsigargin-inhibited sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases, as well as TMB-8- and/or caffeine-sensitive, but not ryanodine-sensitive, Ca(2+)-release channels. Calmodulin kinase-II also likely participates in NO-elicited GH secretion but caffeine-induced GH release is not upstream of NO production. These findings provide insights into how NO actions many integrate with Ca(2+)-dependent signalling mechanisms in goldfish somatotropes and how such interactions may participate in the GH-releasing actions of regulators that utilize both NO- and Ca(2+)-dependent transduction pathways. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Digital timing: sampling frequency, anti-aliasing filter and signal interpolation filter dependence on timing resolution

    International Nuclear Information System (INIS)

    Cho, Sanghee; Grazioso, Ron; Zhang Nan; Aykac, Mehmet; Schmand, Matthias

    2011-01-01

    The main focus of our study is to investigate how the performance of digital timing methods is affected by sampling rate, anti-aliasing and signal interpolation filters. We used the Nyquist sampling theorem to address some basic questions such as what will be the minimum sampling frequencies? How accurate will the signal interpolation be? How do we validate the timing measurements? The preferred sampling rate would be as low as possible, considering the high cost and power consumption of high-speed analog-to-digital converters. However, when the sampling rate is too low, due to the aliasing effect, some artifacts are produced in the timing resolution estimations; the shape of the timing profile is distorted and the FWHM values of the profile fluctuate as the source location changes. Anti-aliasing filters are required in this case to avoid the artifacts, but the timing is degraded as a result. When the sampling rate is marginally over the Nyquist rate, a proper signal interpolation is important. A sharp roll-off (higher order) filter is required to separate the baseband signal from its replicates to avoid the aliasing, but in return the computation will be higher. We demonstrated the analysis through a digital timing study using fast LSO scintillation crystals as used in time-of-flight PET scanners. From the study, we observed that there is no significant timing resolution degradation down to 1.3 Ghz sampling frequency, and the computation requirement for the signal interpolation is reasonably low. A so-called sliding test is proposed as a validation tool checking constant timing resolution behavior of a given timing pick-off method regardless of the source location change. Lastly, the performance comparison for several digital timing methods is also shown.

  15. Excitation energy and angular momentum dependence of the nuclear level densities

    International Nuclear Information System (INIS)

    Razavi, R.; Kakavand, T.; Behkami, A. N.

    2007-01-01

    We have investigated the excitation energy (E) dependence of nuclear level density for Bethe formula and constant temperature model. The level density parameter aa nd the back shifted energy from the Bethe formula are obtained by fitting the complete level schemes. Also the level density parameters from the constant temperature model have been determined for several nuclei. we have shown that the microscopic theory provides more precise information on the nuclear level densities. On the other hand, the spin cut-off parameter and effective moment of inertia are determined by studying of the angular momentum (J) dependence of the nuclear level density, and effective moment of inertia is compared with rigid body value.

  16. A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.

    Science.gov (United States)

    Uno, Kenji; Yamada, Tetsuya; Ishigaki, Yasushi; Imai, Junta; Hasegawa, Yutaka; Sawada, Shojiro; Kaneko, Keizo; Ono, Hiraku; Asano, Tomoichiro; Oka, Yoshitomo; Katagiri, Hideki

    2015-08-13

    Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.

  17. Current and sea-level signals in periplatform ooze (Neogene, Maldives, Indian Ocean)

    Science.gov (United States)

    Betzler, Christian; Lüdmann, Thomas; Hübscher, Christian; Fürstenau, Jörn

    2013-05-01

    Periplatform ooze is an admixture of pelagic carbonate and sediment derived from neritic carbonate platforms. Compositional variations of periplatform ooze allow the reconstruction of past sea-level changes. Periplatform ooze formed during sea-level highstands is finer grained and richer in aragonite through the elevated input of material from the flooded platform compared to periplatform ooze formed during the episodes of lowered sea level. In many cases, however, the sea floor around carbonate platforms is subjected to bottom currents which are expected to affect sediment composition, i.e. through winnowing of the fine fraction. The interaction of sea-level driven highstand shedding and current impact on the formation of periplatform ooze has hitherto not been analyzed. To test if a sea-level driven input signal in periplatform ooze is influenced or even distorted by changing current activity, an integrated study using seismic, hydroacoustic and sedimentological data has been performed on periplatform ooze deposited in the Inner Sea of the Maldives. The Miocene to Pleistocene succession of drift deposits is subdivided into nine units; limits of seismostratigraphic units correspond to changes or turnarounds in grain size trends in cores recovered at ODP Site 716 and NEOMA Site 1143. For the Pleistocene it can be shown how changes in grain size occur in concert with sea-level changes and changes of the monsoonal system, which is thought to be a major driver of bottom currents in the Maldives. A clear highstand shedding pattern only appears in the data at a time of relaxation of monsoonal strength during the last 315 ky. Results imply (1) that drift sediments provide a potential target for analyzing past changes in oceanic currents and (2) that the ooze composition bears a mixed signal of input and physical winnowing at the sea floor.

  18. A noise reconfigurable current-reuse resistive feedback amplifier with signal-dependent power consumption for fetal ECG monitoring

    NARCIS (Netherlands)

    Song, Shuang; Rooijakkers, M.J.; Harpe, P.; Rabotti, C.; Mischi, M.; Van Roermund, A.H.M.; Cantatore, E.

    2016-01-01

    This paper presents a noise-reconfigurable resistive feedback amplifier with current-reuse technique for fetal ECG monitoring. The proposed amplifier allows for both tuning of the noise level and changing the power consumption according to the signal properties, minimizing the total power

  19. The APC/C Coordinates Retinal Differentiation with G1 Arrest through the Nek2-Dependent Modulation of Wingless Signaling.

    Science.gov (United States)

    Martins, Torcato; Meghini, Francesco; Florio, Francesca; Kimata, Yuu

    2017-01-09

    The cell cycle is coordinated with differentiation during animal development. Here we report a cell-cycle-independent developmental role for a master cell-cycle regulator, the anaphase-promoting complex or cyclosome (APC/C), in the regulation of cell fate through modulation of Wingless (Wg) signaling. The APC/C controls both cell-cycle progression and postmitotic processes through ubiquitin-dependent proteolysis. Through an RNAi screen in the developing Drosophila eye, we found that partial APC/C inactivation severely inhibits retinal differentiation independently of cell-cycle defects. The differentiation inhibition coincides with hyperactivation of Wg signaling caused by the accumulation of a Wg modulator, Drosophila Nek2 (dNek2). The APC/C degrades dNek2 upon synchronous G1 arrest prior to differentiation, which allows retinal differentiation through local suppression of Wg signaling. We also provide evidence that decapentaplegic signaling may posttranslationally regulate this APC/C function. Thus, the APC/C coordinates cell-fate determination with the cell cycle through the modulation of developmental signaling pathways. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Recalled first reactions to inhaling nicotine predict the level of physical dependence.

    Science.gov (United States)

    Wellman, Robert J; DiFranza, Joseph R; O'Loughlin, Jennifer

    2014-10-01

    The level of physical dependence is a measure of addiction that correlates highly with addiction-associated changes in brain structure. We sought to determine whether age at first inhalation and initial reactions to inhaling nicotine are related to level of physical dependence in early adulthood. Young adults (n=312; mean age=24 years; 51% female) from the Nicotine Dependence in Teens study who had smoked at least once in the preceding three months completed self-report questionnaires in 2011-12. We assessed level of physical dependence with three validated self-report items assessing 'wanting,' 'craving' and 'needing' triggered by nicotine deprivation. Survey items assessed smoking behavior, including age at first inhalation, and recalled first reactions to inhaling nicotine. After adjusting for covariates, experiencing relaxation, heart racing/pounding, rush or "buzz" (OR=1.45; 95% CI: 1.08, 1.94) and dizziness (OR=1.58; 95% CI: 1.15, 2.18) at first nicotine inhalation were associated with an increased odds of being at a higher level of physical dependence in young adulthood; the association for experiencing relaxation (OR=1.78; 95% CI: 1.20, 2.64) and heart racing/pounding (OR=1.51; 95% CI: 1.00, 2.28) persisted after additionally controlling for all other first reactions. Neither age at first inhalation nor unpleasant first reactions predicted level of physical dependence. In accordance with prior research, our findings suggest that smokers who are particularly sensitive to the pleasant, "buzz-related" and generally arousing effects of nicotine may be more likely to attain higher levels of physical dependence. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Fatigue Level Estimation of Bill Based on Acoustic Signal Feature by Supervised SOM

    Science.gov (United States)

    Teranishi, Masaru; Omatu, Sigeru; Kosaka, Toshihisa

    Fatigued bills have harmful influence on daily operation of Automated Teller Machine(ATM). To make the fatigued bills classification more efficient, development of an automatic fatigued bill classification method is desired. We propose a new method to estimate bending rigidity of bill from acoustic signal feature of banking machines. The estimated bending rigidities are used as continuous fatigue level for classification of fatigued bill. By using the supervised Self-Organizing Map(supervised SOM), we estimate the bending rigidity from only the acoustic energy pattern effectively. The experimental result with real bill samples shows the effectiveness of the proposed method.

  2. Adenosine: an activity-dependent axonal signal regulating MAP kinase and proliferation in developing Schwann cells

    OpenAIRE

    Stevens, Beth; Ishibashi, Tomoko; Chen, Jiang-Fan; Fields, R. Douglas

    2004-01-01

    Nonsynaptic release of ATP from electrically stimulated dorsal root gangion (DRG) axons inhibits Schwann cell (SC) proliferation and arrests SC development at the premyelinating stage, but the specific types of purinergic receptor(s) and intracellular signaling pathways involved in this form of neuron–glia communication are not known. Recent research shows that adenosine is a neuron–glial transmitter between axons and myelinating glia of the CNS. The present study investigates the possibility...

  3. Audiovisual integration of emotional signals from music improvisation does not depend on temporal correspondence.

    Science.gov (United States)

    Petrini, Karin; McAleer, Phil; Pollick, Frank

    2010-04-06

    In the present study we applied a paradigm often used in face-voice affect perception to solo music improvisation to examine how the emotional valence of sound and gesture are integrated when perceiving an emotion. Three brief excerpts expressing emotion produced by a drummer and three by a saxophonist were selected. From these bimodal congruent displays the audio-only, visual-only, and audiovisually incongruent conditions (obtained by combining the two signals both within and between instruments) were derived. In Experiment 1 twenty musical novices judged the perceived emotion and rated the strength of each emotion. The results indicate that sound dominated the visual signal in the perception of affective expression, though this was more evident for the saxophone. In Experiment 2 a further sixteen musical novices were asked to either pay attention to the musicians' movements or to the sound when judging the perceived emotions. The results showed no effect of visual information when judging the sound. On the contrary, when judging the emotional content of the visual information, a worsening in performance was obtained for the incongruent condition that combined different emotional auditory and visual information for the same instrument. The effect of emotionally discordant information thus became evident only when the auditory and visual signals belonged to the same categorical event despite their temporal mismatch. This suggests that the integration of emotional information may be reinforced by its semantic attributes but might be independent from temporal features. Copyright 2010 Elsevier B.V. All rights reserved.

  4. IL-6 trans-Signaling-Dependent Rapid Development of Cytotoxic CD8+ T Cell Function

    Directory of Open Access Journals (Sweden)

    Jan P. Böttcher

    2014-09-01

    Full Text Available Immune control of infections with viruses or intracellular bacteria relies on cytotoxic CD8+ T cells that use granzyme B (GzmB for elimination of infected cells. During inflammation, mature antigen-presenting dendritic cells instruct naive T cells within lymphoid organs to develop into effector T cells. Here, we report a mechanistically distinct and more rapid process of effector T cell development occurring within 18 hr. Such rapid acquisition of effector T cell function occurred through cross-presenting liver sinusoidal endothelial cells (LSECs in the absence of innate immune stimulation and known costimulatory signaling. Rather, interleukin-6 (IL-6 trans-signaling was required and sufficient for rapid induction of GzmB expression in CD8+ T cells. Such LSEC-stimulated GzmB-expressing CD8+ T cells further responded to inflammatory cytokines, eliciting increased and protracted effector functions. Our findings identify a role for IL-6 trans-signaling in rapid generation of effector function in CD8+ T cells that may be beneficial for vaccination strategies.

  5. Rapid stress-induced transcriptomic changes in the brain depend on beta-adrenergic signaling.

    Science.gov (United States)

    Roszkowski, Martin; Manuella, Francesca; von Ziegler, Lukas; Durán-Pacheco, Gonzalo; Moreau, Jean-Luc; Mansuy, Isabelle M; Bohacek, Johannes

    2016-08-01

    Acute exposure to stressful experiences can rapidly increase anxiety and cause neuropsychiatric disorders. The effects of stress result in part from the release of neurotransmitters and hormones, which regulate gene expression in different brain regions. The fast neuroendocrine response to stress is largely mediated by norepinephrine (NE) and corticotropin releasing hormone (CRH), followed by a slower and more sustained release of corticosterone. While corticosterone is an important regulator of gene expression, it is not clear which stress-signals contribute to the rapid regulation of gene expression observed immediately after stress exposure. Here, we demonstrate in mice that 45 min after an acute swim stress challenge, large changes in gene expression occur across the transcriptome in the hippocampus, a region sensitive to the effects of stress. We identify multiple candidate genes that are rapidly and transiently altered in both males and females. Using a pharmacological approach, we show that most of these rapidly induced genes are regulated by NE through β-adrenergic receptor signaling. We find that CRH and corticosterone can also contribute to rapid changes in gene expression, although these effects appear to be restricted to fewer genes. These results newly reveal a widespread impact of NE on the transcriptome and identify novel genes associated with stress and adrenergic signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Inhibition of cell migration by focal adhesion kinase: Time-dependent difference in integrin-induced signaling between endothelial and hepatoblastoma cells.

    Science.gov (United States)

    Yu, Hongchi; Gao, Min; Ma, Yunlong; Wang, Lijuan; Shen, Yang; Liu, Xiaoheng

    2018-05-01

    angiogenesis plays an important role in the development and progression of tumors, and it involves a series of signaling pathways contributing to the migration of endothelial cells for vascularization and to the invasion of cancer cells for secondary tumor formation. Among these pathways, the focal adhesion kinase (FAK) signaling cascade has been implicated in a variety of human cancers in connection with cell adhesion and migration events leading to tumor angiogenesis, metastasis and invasion. Therefore, the inhibition of FAK in endothelial and/or cancer cells is a potential target for anti‑angiogenic therapy. In the present study, a small‑molecule FAK inhibitor, 1,2,4,5-benzenetetramine tetrahydrochloride (Y15), was used to study the effects of FAK inhibition on the adhesion and migration behaviors of vascular endothelial cells (VECs) and human hepatoblastoma cells. Furthermore, the time-dependent differences in proteins associated with the integrin-mediated FAK/Rho GTPases signaling pathway within 2 h were examined. The results indicated that the inhibition of FAK significantly decreased the migration ability of VECs and human hepatoblastoma cells in a dose-dependent manner. Inhibition of FAK promoted cell detachment by decreasing the expression of focal adhesion components, and blocked cell motility by reducing the level of Rho GTPases. However, the expression of crucial proteins involved in integrin-induced signaling in two cell lines exhibited a time-dependent difference with increased duration of FAK inhibitor treatment, suggesting different mechanisms of FAK-mediated cell migration behavior. These results suggest that the mechanism underlying FAK-mediated adhesion and migration behavior differs among various cells, which is expected to provide evidence for future FAK therapy targeted against tumor angiogenesis.

  7. Aminoacylation of the N-terminal cysteine is essential for Lol-dependent release of lipoproteins from membranes but does not depend on lipoprotein sorting signals.

    Science.gov (United States)

    Fukuda, Ayumu; Matsuyama, Shin-Ichi; Hara, Takashi; Nakayama, Jiro; Nagasawa, Hiromichi; Tokuda, Hajime

    2002-11-08

    Lipoproteins are present in a wide variety of bacteria and are anchored to membranes through lipids attached to the N-terminal cysteine. The Lol system of Escherichia coli mediates the membrane-specific localization of lipoproteins. Aspartate at position 2 functions as a Lol avoidance signal and causes the retention of lipoproteins in the inner membrane, whereas lipoproteins having residues other than aspartate at position 2 are released from the inner membrane and localized to the outer membrane by the Lol system. Phospholipid:apolipoprotein transacylase, Lnt, catalyzes the last step of lipoprotein modification, converting apolipoprotein into mature lipoprotein. To reveal the importance of this aminoacylation for the Lol-dependent membrane localization, apolipoproteins were prepared by inhibiting lipoprotein maturation. Lnt was also purified and used to convert apolipoprotein into mature lipoprotein in vitro. The release of these lipoproteins was examined in proteoliposomes. We show here that the aminoacylation is essential for the Lol-dependent release of lipoproteins from membranes. Furthermore, lipoproteins with aspartate at position 2 were found to be aminoacylated both in vivo and in vitro, indicating that the lipoprotein-sorting signal does not affect lipid modification.

  8. Defects level evaluation of LiTiZn ferrite ceramics using temperature dependence of initial permeability

    Science.gov (United States)

    Malyshev, A. V.; Petrova, A. B.; Sokolovskiy, A. N.; Surzhikov, A. P.

    2018-06-01

    The method for evaluating the integral defects level and chemical homogeneity of ferrite ceramics based on temperature dependence analysis of initial permeability is suggested. A phenomenological expression for the description of such dependence was suggested and an interpretation of its main parameters was given. It was shown, that the main criterion of the integral defects level of ferrite ceramics is relation of two parameters correlating with elastic stress value in a material. An indicator of structural perfection can be a maximum value of initial permeability close to Curie point as well. The temperature dependences of initial permeability have analyzed for samples sintered in laboratory conditions and for the ferrite industrial product. The proposed method allows controlling integral defects level of the soft ferrite products and has high sensitivity compare to typical X-ray methods.

  9. Activation of the Cph1-dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans.

    Directory of Open Access Journals (Sweden)

    Bernardo Ramírez-Zavala

    Full Text Available Depending on the environmental conditions, the pathogenic yeast Candida albicans can undergo different developmental programs, which are controlled by dedicated transcription factors and upstream signaling pathways. C. albicans strains that are homozygous at the mating type locus can switch from the normal yeast form (white to an elongated cell type (opaque, which is the mating-competent form of this fungus. Both white and opaque cells use the Ste11-Hst7-Cek1/Cek2 MAP kinase signaling pathway to react to the presence of mating pheromone. However, while opaque cells employ the transcription factor Cph1 to induce the mating response, white cells recruit a different downstream transcription factor, Tec1, to promote the formation of a biofilm that facilitates mating of opaque cells in the population. The switch from the white to the opaque cell form is itself induced by environmental signals that result in the upregulation of the transcription factor Wor1, the master regulator of white-opaque switching. To get insight into the upstream signaling pathways controlling the switch, we expressed all C. albicans protein kinases from a tetracycline-inducible promoter in a switching-competent strain. Screening of this library of strains showed that a hyperactive form of Ste11 lacking its N-terminal domain (Ste11(ΔN467 efficiently stimulated white cells to switch to the opaque phase, a behavior that did not occur in response to pheromone. Ste11(ΔN467-induced switching specifically required the downstream MAP kinase Cek1 and its target transcription factor Cph1, but not Cek2 and Tec1, and forced expression of Cph1 also promoted white-opaque switching in a Wor1-dependent manner. Therefore, depending on the activation mechanism, components of the pheromone-responsive MAP kinase pathway can be reconnected to stimulate an alternative developmental program, switching of white cells to the mating-competent opaque phase.

  10. Levels of physical dependence on tobacco among adolescent smokers in Cyprus.

    Science.gov (United States)

    Christophi, Costas A; Pampaka, Despina; Paisi, Martha; Ioannou, Solonas; DiFranza, Joseph R

    2016-09-01

    The purpose of this study is to assess tobacco dependence among Cypriot adolescents and examine its association to cigarette consumption and attitudes towards smoking. The current study used cross-sectional data from the 2011 Cyprus Global Youth Tobacco Survey which adopted multistage cluster sampling methods to select adolescents registered in middle and high schools in Cyprus. Tobacco use, physical dependence on tobacco, and attitudes towards tobacco use were measured in 187 adolescents aged 13-18years old who reported that they had smoked at least once in the preceding 30days. Physical dependence was assessed using the Levels of Physical Dependence scale. Physical dependence was present in 86% of the adolescent smokers. The mean latency to needing among smokers in the highest dependence group was 101h. Significant associations were observed between physical dependence and the perceived difficulty in quitting (OR=13.1, 95% CI: 4.0, 43.0) as well as the expectation to continue smoking for the next five years (OR=3.3, 95% CI: 1.3, 8.4). Significant associations were also observed between physical dependence and the number of smoking days per month, daily smoking, daily cigarette consumption, lifetime cigarette consumption, and perceived difficulty in abstaining from smoking for one week. Physical dependence provides a symptom-based approach to assess dependence and it is a strong predictor of adolescents' perceptions of their ability to quit or to refrain from smoking for a week. Physical dependence on tobacco was highly prevalent among adolescent smokers in Cyprus and it was associated with greater perceived difficulty in quitting. Interventions targeting adolescent smoking must account for the high prevalence of physical dependence. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Influence of time dependent effects on the disposal environments of low and intermediate level radioactive wastes

    International Nuclear Information System (INIS)

    1984-12-01

    Reviews are presented firstly of potential events and processes which may affect the evolution of the disposal environments of low and intermediate level radioactive wastes in Britain and secondly of previous studies carried out worldwide in the field of time dependent effects. From the latter review available methodologies for incorporating time dependence into radiological assessments are identified. Finally, proposals are presented for the design and development of a time dependent effects model, based on the existing far field state model (FFSM) developed for ONWI in USA. (author)

  12. The Arabidopsis Mitochondrial Protease FtSH4 Is Involved in Leaf Senescence via Regulation of WRKY-Dependent Salicylic Acid Accumulation and Signaling.

    Science.gov (United States)

    Zhang, Shengchun; Li, Cui; Wang, Rui; Chen, Yaxue; Shu, Si; Huang, Ruihua; Zhang, Daowei; Li, Jian; Xiao, Shi; Yao, Nan; Yang, Chengwei

    2017-04-01

    Mitochondria and autophagy play important roles in the networks that regulate plant leaf senescence and cell death. However, the molecular mechanisms underlying the interactions between mitochondrial signaling and autophagy are currently not well understood. This study characterized the function of the Arabidopsis ( Arabidopsis thaliana ) mitochondrial AAA-protease gene FtSH4 in regulating autophagy and senescence, finding that FtSH4 mediates WRKY-dependent salicylic acid (SA) accumulation and signaling. Knockout of FtSH4 in the ftsh4-4 mutant resulted in severe leaf senescence, cell death, and high autophagy levels. The level of SA increased dramatically in the ftsh4-4 mutant. Expression of nahG in the ftsh4-4 mutant led to decreased SA levels and suppressed the leaf senescence and cell death phenotypes. The transcript levels of several SA synthesis and signaling genes, including SALICYLIC ACID INDUCTION DEFICIENT2 ( SID2 ), NON-RACE-SPECIFIC DISEASE RESISTANCE1 ( NDR1 ), and NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 ( NPR1 ), increased significantly in the ftsh4-4 mutants compared with the wild type. Loss of function of SID2 , NDR1 , or NPR1 in the ftsh4-4 mutant reversed the ftsh4-4 senescence and autophagy phenotypes. Furthermore, ftsh4-4 mutants had elevated levels of transcripts of several WRKY genes, including WRKY40 , WRKY46 , WRKY51 , WRKY60 , WRKY63 , and WRKY75 ; all of these WRKY proteins can bind to the promoter of SID2 Loss of function of WRKY75 in the ftsh4-4 mutants decreased the levels of SA and reversed the senescence phenotype. Taken together, these results suggest that the mitochondrial ATP-dependent protease FtSH4 may regulate the expression of WRKY genes by modifying the level of reactive oxygen species and the WRKY transcription factors that control SA synthesis and signaling in autophagy and senescence. © 2017 American Society of Plant Biologists. All Rights Reserved.

  13. Multi-level reputation signals in service industries in Latin America

    Directory of Open Access Journals (Sweden)

    William Newburry

    2011-03-01

    Full Text Available This study uses signaling theory to investigate industry -firm- and individual-level determinants of individual-level corporate reputation assessments in the context of Latin America. In a hierarchical linear model, we test our theory using 76,419 individual evaluations of 80 companies in five Latin American countries collected by the Reputation Institute in conjunction with the Foro de Reputación Corporativa. Results show that across our Latin American sample, reputations of firms in the telecom and energy industries are significantly lower than those of manufacturing firms. Additionally, we find consistent evidence across marginalized groups (e.g., women, lower social class, education and income that they assess telecom industry reputations relatively higher than their less marginalized counterparts do. Results are mixed with regards to marginalized group assessments of firms from other service industries. Additionally, counter to expectations, we do not find evidence that firm size or financial performance impact reputation assessments.

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

    Science.gov (United States)

    2012-01-01

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

  15. The position dependent influence that sensitivity correction processing gives the signal-to-noise ratio measurement in parallel imaging

    International Nuclear Information System (INIS)

    Murakami, Koichi; Yoshida, Koji; Yanagimoto, Shinichi

    2012-01-01

    We studied the position dependent influence that sensitivity correction processing gave the signal-to-noise ratio (SNR) measurement of parallel imaging (PI). Sensitivity correction processing that referred to the sensitivity distribution of the body coil improved regional uniformity more than the sensitivity uniformity correction filter with a fixed correction factor. In addition, the position dependent influence to give the SNR measurement in PI was different from the sensitivity correction processing. Therefore, if we divide SNR of the sensitivity correction processing image by SNR of the original image in each pixel and calculate SNR ratio, we can show the position dependent influence that sensitivity correction processing gives the SNR measurement in PI. It is with an index of the sensitivity correction processing precision. (author)

  16. Classification of a Driver's cognitive workload levels using artificial neural network on ECG signals.

    Science.gov (United States)

    Tjolleng, Amir; Jung, Kihyo; Hong, Wongi; Lee, Wonsup; Lee, Baekhee; You, Heecheon; Son, Joonwoo; Park, Seikwon

    2017-03-01

    An artificial neural network (ANN) model was developed in the present study to classify the level of a driver's cognitive workload based on electrocardiography (ECG). ECG signals were measured on 15 male participants while they performed a simulated driving task as a primary task with/without an N-back task as a secondary task. Three time-domain ECG measures (mean inter-beat interval (IBI), standard deviation of IBIs, and root mean squared difference of adjacent IBIs) and three frequencydomain ECG measures (power in low frequency, power in high frequency, and ratio of power in low and high frequencies) were calculated. To compensate for individual differences in heart response during the driving tasks, a three-step data processing procedure was performed to ECG signals of each participant: (1) selection of two most sensitive ECG measures, (2) definition of three (low, medium, and high) cognitive workload levels, and (3) normalization of the selected ECG measures. An ANN model was constructed using a feed-forward network and scaled conjugate gradient as a back-propagation learning rule. The accuracy of the ANN classification model was found satisfactory for learning data (95%) and testing data (82%). Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Potassium conductances mediate bidirectional state-dependent modulation of action potential evoked dendritic calcium signals in dentate gyrus granule cells

    Directory of Open Access Journals (Sweden)

    János Brunner

    2014-03-01

    resulted in faster repolarization and increased AP related calcium signals relative to the control (i. e. in the absence of the extra conductance at the same membrane potential. In conclusion, our results revealed that activation of potassium currents can profoundly enhance dendritic bAP-evoked calcium signals in GC dendrites, thus providing a previously unknown state-dependent modulatory mechanism in dendritic signalization.

  18. Order Level Inventory Models for Deteriorating Seasonable/Fashionable Products with Time Dependent Demand and Shortages

    Directory of Open Access Journals (Sweden)

    K. Skouri

    2009-01-01

    Full Text Available An order level inventory model for seasonable/fashionable products subject to a period of increasing demand followed by a period of level demand and then by a period of decreasing demand rate (three branches ramp type demand rate is considered. The unsatisfied demand is partially backlogged with a time dependent backlogging rate. In addition, the product deteriorates with a time dependent, namely, Weibull, deterioration rate. The model is studied under the following different replenishment policies: (a starting with no shortages and (b starting with shortages. The optimal replenishment policy for the model is derived for both the above mentioned policies.

  19. Prefrontal Neurons Represent Motion Signals from Across the Visual Field But for Memory-Guided Comparisons Depend on Neurons Providing These Signals.

    Science.gov (United States)

    Wimmer, Klaus; Spinelli, Philip; Pasternak, Tatiana

    2016-09-07

    Visual decisions often involve comparisons of sequential stimuli that can appear at any location in the visual field. The lateral prefrontal cortex (LPFC) in nonhuman primates, shown to play an important role in such comparisons, receives information about contralateral stimuli directly from sensory neurons in the same hemisphere, and about ipsilateral stimuli indirectly from neurons in the opposite hemisphere. This asymmetry of sensory inputs into the LPFC poses the question of whether and how its neurons incorporate sensory information arriving from the two hemispheres during memory-guided comparisons of visual motion. We found that, although responses of individual LPFC neurons to contralateral stimuli were stronger and emerged 40 ms earlier, they carried remarkably similar signals about motion direction in the two hemifields, with comparable direction selectivity and similar direction preferences. This similarity was also apparent around the time of the comparison between the current and remembered stimulus because both ipsilateral and contralateral responses showed similar signals reflecting the remembered direction. However, despite availability in the LPFC of motion information from across the visual field, these "comparison effects" required for the comparison stimuli to appear at the same retinal location. This strict dependence on spatial overlap of the comparison stimuli suggests participation of neurons with localized receptive fields in the comparison process. These results suggest that while LPFC incorporates many key aspects of the information arriving from sensory neurons residing in opposite hemispheres, it continues relying on the interactions with these neurons at the time of generating signals leading to successful perceptual decisions. Visual decisions often involve comparisons of sequential visual motion that can appear at any location in the visual field. We show that during such comparisons, the lateral prefrontal cortex (LPFC) contains

  20. High spatial correspondence at a columnar level between activation and resting state fMRI signals and local field potentials.

    Science.gov (United States)

    Shi, Zhaoyue; Wu, Ruiqi; Yang, Pai-Feng; Wang, Feng; Wu, Tung-Lin; Mishra, Arabinda; Chen, Li Min; Gore, John C

    2017-05-16

    Although blood oxygenation level-dependent (BOLD) fMRI has been widely used to map brain responses to external stimuli and to delineate functional circuits at rest, the extent to which BOLD signals correlate spatially with underlying neuronal activity, the spatial relationships between stimulus-evoked BOLD activations and local correlations of BOLD signals in a resting state, and whether these spatial relationships vary across functionally distinct cortical areas are not known. To address these critical questions, we directly compared the spatial extents of stimulated activations and the local profiles of intervoxel resting state correlations for both high-resolution BOLD at 9.4 T and local field potentials (LFPs), using 98-channel microelectrode arrays, in functionally distinct primary somatosensory areas 3b and 1 in nonhuman primates. Anatomic images of LFP and BOLD were coregistered within 0.10 mm accuracy. We found that the point spread functions (PSFs) of BOLD and LFP responses were comparable in the stimulus condition, and both estimates of activations were slightly more spatially constrained than local correlations at rest. The magnitudes of stimulus responses in area 3b were stronger than those in area 1 and extended in a medial to lateral direction. In addition, the reproducibility and stability of stimulus-evoked activation locations within and across both modalities were robust. Our work suggests that the intrinsic resolution of BOLD is not a limiting feature in practice and approaches the intrinsic precision achievable by multielectrode electrophysiology.

  1. Identification of a functional, CRM-1-dependent nuclear export signal in hepatitis C virus core protein.

    Directory of Open Access Journals (Sweden)

    Andrea Cerutti

    Full Text Available Hepatitis C virus (HCV infection is a major cause of chronic liver disease worldwide. HCV core protein is involved in nucleocapsid formation, but it also interacts with multiple cytoplasmic and nuclear molecules and plays a crucial role in the development of liver disease and hepatocarcinogenesis. The core protein is found mostly in the cytoplasm during HCV infection, but also in the nucleus in patients with hepatocarcinoma and in core-transgenic mice. HCV core contains nuclear localization signals (NLS, but no nuclear export signal (NES has yet been identified.We show here that the aa(109-133 region directs the translocation of core from the nucleus to the cytoplasm by the CRM-1-mediated nuclear export pathway. Mutagenesis of the three hydrophobic residues (L119, I123 and L126 in the identified NES or in the sequence encoding the mature core aa(1-173 significantly enhanced the nuclear localisation of the corresponding proteins in transfected Huh7 cells. Both the NES and the adjacent hydrophobic sequence in domain II of core were required to maintain the core protein or its fragments in the cytoplasmic compartment. Electron microscopy studies of the JFH1 replication model demonstrated that core was translocated into the nucleus a few minutes after the virus entered the cell. The blockade of nucleocytoplasmic export by leptomycin B treatment early in infection led to the detection of core protein in the nucleus by confocal microscopy and coincided with a decrease in virus replication.Our data suggest that the functional NLS and NES direct HCV core protein shuttling between the cytoplasmic and nuclear compartments, with at least some core protein transported to the nucleus. These new properties of HCV core may be essential for virus multiplication and interaction with nuclear molecules, influence cell signaling and the pathogenesis of HCV infection.

  2. Identification of a functional, CRM-1-dependent nuclear export signal in hepatitis C virus core protein.

    Science.gov (United States)

    Cerutti, Andrea; Maillard, Patrick; Minisini, Rosalba; Vidalain, Pierre-Olivier; Roohvand, Farzin; Pecheur, Eve-Isabelle; Pirisi, Mario; Budkowska, Agata

    2011-01-01

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. HCV core protein is involved in nucleocapsid formation, but it also interacts with multiple cytoplasmic and nuclear molecules and plays a crucial role in the development of liver disease and hepatocarcinogenesis. The core protein is found mostly in the cytoplasm during HCV infection, but also in the nucleus in patients with hepatocarcinoma and in core-transgenic mice. HCV core contains nuclear localization signals (NLS), but no nuclear export signal (NES) has yet been identified.We show here that the aa(109-133) region directs the translocation of core from the nucleus to the cytoplasm by the CRM-1-mediated nuclear export pathway. Mutagenesis of the three hydrophobic residues (L119, I123 and L126) in the identified NES or in the sequence encoding the mature core aa(1-173) significantly enhanced the nuclear localisation of the corresponding proteins in transfected Huh7 cells. Both the NES and the adjacent hydrophobic sequence in domain II of core were required to maintain the core protein or its fragments in the cytoplasmic compartment. Electron microscopy studies of the JFH1 replication model demonstrated that core was translocated into the nucleus a few minutes after the virus entered the cell. The blockade of nucleocytoplasmic export by leptomycin B treatment early in infection led to the detection of core protein in the nucleus by confocal microscopy and coincided with a decrease in virus replication.Our data suggest that the functional NLS and NES direct HCV core protein shuttling between the cytoplasmic and nuclear compartments, with at least some core protein transported to the nucleus. These new properties of HCV core may be essential for virus multiplication and interaction with nuclear molecules, influence cell signaling and the pathogenesis of HCV infection.

  3. Synthetic generation of myocardial blood-oxygen-level-dependent MRI time series via structural sparse decomposition modeling.

    Science.gov (United States)

    Rusu, Cristian; Morisi, Rita; Boschetto, Davide; Dharmakumar, Rohan; Tsaftaris, Sotirios A

    2014-07-01

    This paper aims to identify approaches that generate appropriate synthetic data (computer generated) for cardiac phase-resolved blood-oxygen-level-dependent (CP-BOLD) MRI. CP-BOLD MRI is a new contrast agent- and stress-free approach for examining changes in myocardial oxygenation in response to coronary artery disease. However, since signal intensity changes are subtle, rapid visualization is not possible with the naked eye. Quantifying and visualizing the extent of disease relies on myocardial segmentation and registration to isolate the myocardium and establish temporal correspondences and ischemia detection algorithms to identify temporal differences in BOLD signal intensity patterns. If transmurality of the defect is of interest pixel-level analysis is necessary and thus a higher precision in registration is required. Such precision is currently not available affecting the design and performance of the ischemia detection algorithms. In this work, to enable algorithmic developments of ischemia detection irrespective to registration accuracy, we propose an approach that generates synthetic pixel-level myocardial time series. We do this by 1) modeling the temporal changes in BOLD signal intensity based on sparse multi-component dictionary learning, whereby segmentally derived myocardial time series are extracted from canine experimental data to learn the model; and 2) demonstrating the resemblance between real and synthetic time series for validation purposes. We envision that the proposed approach has the capacity to accelerate development of tools for ischemia detection while markedly reducing experimental costs so that cardiac BOLD MRI can be rapidly translated into the clinical arena for the noninvasive assessment of ischemic heart disease.

  4. Squalene Inhibits ATM-Dependent Signaling in γIR-Induced DNA Damage Response through Induction of Wip1 Phosphatase.

    Directory of Open Access Journals (Sweden)

    Naoto Tatewaki

    Full Text Available Ataxia telangiectasia mutated (ATM kinase plays a crucial role as a master controller in the cellular DNA damage response. Inhibition of ATM leads to inhibition of the checkpoint signaling pathway. Hence, addition of checkpoint inhibitors to anticancer therapies may be an effective targeting strategy. A recent study reported that Wip1, a protein phosphatase, de-phosphorylates serine 1981 of ATM during the DNA damage response. Squalene has been proposed to complement anticancer therapies such as chemotherapy and radiotherapy; however, there is little mechanistic information supporting this idea. Here, we report the inhibitory effect of squalene on ATM-dependent DNA damage signals. Squalene itself did not affect cell viability and the cell cycle of A549 cells, but it enhanced the cytotoxicity of gamma-irradiation (γIR. The in vitro kinase activity of ATM was not altered by squalene. However, squalene increased Wip1 expression in cells and suppressed ATM activation in γIR-treated cells. Consistent with the potential inhibition of ATM by squalene, IR-induced phosphorylation of ATM effectors such as p53 (Ser15 and Chk1 (Ser317 was inhibited by cell treatment with squalene. Thus, squalene inhibits the ATM-dependent signaling pathway following DNA damage through intracellular induction of Wip1 expression.

  5. Conflict anticipation in alcohol dependence - A model-based fMRI study of stop signal task.

    Science.gov (United States)

    Hu, Sien; Ide, Jaime S; Zhang, Sheng; Sinha, Rajita; Li, Chiang-Shan R

    2015-01-01

    Our previous work characterized altered cerebral activations during cognitive control in individuals with alcohol dependence (AD). A hallmark of cognitive control is the ability to anticipate changes and adjust behavior accordingly. Here, we employed a Bayesian model to describe trial-by-trial anticipation of the stop signal and modeled fMRI signals of conflict anticipation in a stop signal task. Our goal is to characterize the neural correlates of conflict anticipation and its relationship to response inhibition and alcohol consumption in AD. Twenty-four AD and 70 age and gender matched healthy control individuals (HC) participated in the study. fMRI data were pre-processed and modeled with SPM8. We modeled fMRI signals at trial onset with individual events parametrically modulated by estimated probability of the stop signal, p(Stop), and compared regional responses to conflict anticipation between AD and HC. To address the link to response inhibition, we regressed whole-brain responses to conflict anticipation against the stop signal reaction time (SSRT). Compared to HC (54/70), fewer AD (11/24) showed a significant sequential effect - a correlation between p(Stop) and RT during go trials - and the magnitude of sequential effect is diminished, suggesting a deficit in proactive control. Parametric analyses showed decreased learning rate and over-estimated prior mean of the stop signal in AD. In fMRI, both HC and AD responded to p(Stop) in bilateral inferior parietal cortex and anterior pre-supplementary motor area, although the magnitude of response increased in AD. In contrast, HC but not AD showed deactivation of the perigenual anterior cingulate cortex (pgACC). Furthermore, deactivation of the pgACC to increasing p(Stop) is positively correlated with the SSRT in HC but not AD. Recent alcohol consumption is correlated with increased activation of the thalamus and cerebellum in AD during conflict anticipation. The current results highlight altered proactive

  6. Dependency of high coastal water level and river discharge at the global scale

    Science.gov (United States)

    Ward, P.; Couasnon, A.; Haigh, I. D.; Muis, S.; Veldkamp, T.; Winsemius, H.; Wahl, T.

    2017-12-01

    It is widely recognized that floods cause huge socioeconomic impacts. From 1980-2013, global flood losses exceeded $1 trillion, with 220,000 fatalities. These impacts are particularly hard felt in low-lying densely populated deltas and estuaries, whose location at the coast-land interface makes them naturally prone to flooding. When river and coastal floods coincide, their impacts in these deltas and estuaries are often worse than when they occur in isolation. Such floods are examples of so-called `compound events'. In this contribution, we present the first global scale analysis of the statistical dependency of high coastal water levels (and the storm surge component alone) and river discharge. We show that there is statistical dependency between these components at more than half of the stations examined. We also show time-lags in the highest correlation between peak discharges and coastal water levels. Finally, we assess the probability of the simultaneous occurrence of design discharge and design coastal water levels, assuming both independence and statistical dependence. For those stations where we identified statistical dependency, the probability is between 1 and 5 times greater, when the dependence structure is accounted for. This information is essential for understanding the likelihood of compound flood events occurring at locations around the world as well as for accurate flood risk assessments and effective flood risk management. The research was carried out by analysing the statistical dependency between observed coastal water levels (and the storm surge component) from GESLA-2 and river discharge using gauged data from GRDC stations all around the world. The dependence structure was examined using copula functions.

  7. The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qing [Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (United States); Yang, Haifeng, E-mail: qing_zhang@dfci.harvard.edu [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH (United States); Haifeng Yang, E-mail: yangh2@ccf.org [Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, NB-40, 9500 Euclid Avenue, Cleveland, OH 44195 (United States)

    2012-04-12

    The function of tumor suppressor VHL is compromised in the vast majority of clear cell renal cell carcinoma, and its mutations or loss of expression was causal for this disease. pVHL was found to be a substrate recognition subunit of an E3 ubiquitin ligase, and most of the tumor-derived mutations disrupt this function. pVHL was found to bind to the alpha subunits of hypoxia-inducible factor (HIF) and promote their ubiquitination and proteasomal degradation. Proline hydroxylation on key sites of HIFα provides the binding signal for pVHL E3 ligase complex. Beside HIFα, several other VHL targets have been identified, including activated epidermal growth factor receptor (EGFR), RNA polymerase II subunits RPB1 and hsRPB7, atypical protein kinase C (PKC), Sprouty2, β-adrenergic receptor II, and Myb-binding protein p160. HIFα is the most well studied substrate and has been proven to be critical for pVHL’s tumor suppressor function, but the activated EGFR and PKC and other pVHL substrates might also be important for tumor growth and drug response. Their regulations by pVHL and their relevance to signaling and cancer are discussed.

  8. Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling

    Science.gov (United States)

    Wassum, Kate M.; Ostlund, Sean B.; Balleine, Bernard W.; Maidment, Nigel T.

    2011-01-01

    Here we attempted to clarify the role of dopamine signaling in reward seeking. In Experiment 1, we assessed the effects of the dopamine D1/D2 receptor antagonist flupenthixol (0.5 mg/kg i.p.) on Pavlovian incentive motivation and found that flupenthixol blocked the ability of a conditioned stimulus to enhance both goal approach and instrumental performance (Pavlovian-to-instrumental transfer). In Experiment 2 we assessed the effects of flupenthixol on reward palatability during post-training noncontingent re-exposure to the sucrose reward in either a control 3-h or novel 23-h food-deprived state. Flupenthixol, although effective in blocking the Pavlovian goal approach, was without effect on palatability or the increase in reward palatability induced by the upshift in motivational state. This noncontingent re-exposure provided an opportunity for instrumental incentive learning, the process by which rats encode the value of a reward for use in updating reward-seeking actions. Flupenthixol administered prior to the instrumental incentive learning opportunity did not affect the increase in subsequent off-drug reward-seeking actions induced by that experience. These data suggest that although dopamine signaling is necessary for Pavlovian incentive motivation, it is not necessary for changes in reward experience, or for the instrumental incentive learning process that translates this experience into the incentive value used to drive reward-seeking actions, and provide further evidence that Pavlovian and instrumental incentive learning processes are dissociable. PMID:21693635

  9. Gender Differences in the Effect of Tobacco Use on Brain Phosphocreatine Levels in Methamphetamine Dependent Subjects

    Science.gov (United States)

    Sung, Young-Hoon; Yurgelun-Todd, Deborah A.; Kondo, Douglas G.; Shi, Xian-Feng; Lundberg, Kelly J.; Hellem, Tracy L.; Huber, Rebekah S.; McGlade, Erin C.; Jeong, Eun-Kee; Renshaw, Perry F.

    2015-01-01

    Background A high prevalence of tobacco smoking has been observed in methamphetamine users, but there have been no in vivo brain neurochemistry studies addressing gender effects of tobacco smoking in methamphetamine users. Methamphetamine addiction is associated with increased risk of depression and anxiety in females. There is increasing evidence that selective analogues of nicotine, a principal active component of tobacco smoking, may improve depression and cognitive performance in animals and humans. Objectives To investigate the effects of tobacco smoking and gender on brain phosphocreatine (PCr) levels, a marker of brain energy metabolism reported to be reduced in methamphetamine-dependent subjects. Methods Thirty female and twenty-seven male methamphetamine-dependent subjects were evaluated with phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to measure PCr levels within the pregenual anterior cingulate, which has been implicated in methamphetamine neurotoxicity. Results Analysis of covariance revealed that there were statistically significant slope (PCr versus lifetime amount of tobacco smoking) differences between female and male methamphetamine-dependent subjects (p=0.03). In females, there was also a statistically significant interaction between lifetime amounts of tobacco smoking and methamphetamine in regard to PCr levels (p=0.01), which suggests that tobacco smoking may have a more significant positive impact on brain PCr levels in heavy, as opposed to light to moderate, methamphetamine-dependent females. Conclusion These results indicate that tobacco smoking has gender-specific effects in terms of increased anterior cingulate high energy PCr levels in methamphetamine-dependent subjects. Cigarette smoking in methamphetamine-dependent women, particularly those with heavy methamphetamine use, may have a potentially protective effect upon neuronal metabolism. PMID:25871447

  10. Photosynthesis-dependent H2O2 transfer from chloroplasts to nuclei provides a high-light signalling mechanism.

    Science.gov (United States)

    Exposito-Rodriguez, Marino; Laissue, Pierre Philippe; Yvon-Durocher, Gabriel; Smirnoff, Nicholas; Mullineaux, Philip M

    2017-06-29

    Chloroplasts communicate information by signalling to nuclei during acclimation to fluctuating light. Several potential operating signals originating from chloroplasts have been proposed, but none have been shown to move to nuclei to modulate gene expression. One proposed signal is hydrogen peroxide (H 2 O 2 ) produced by chloroplasts in a light-dependent manner. Using HyPer2, a genetically encoded fluorescent H 2 O 2 sensor, we show that in photosynthetic Nicotiana benthamiana epidermal cells, exposure to high light increases H 2 O 2 production in chloroplast stroma, cytosol and nuclei. Critically, over-expression of stromal ascorbate peroxidase (H 2 O 2 scavenger) or treatment with DCMU (photosynthesis inhibitor) attenuates nuclear H 2 O 2 accumulation and high light-responsive gene expression. Cytosolic ascorbate peroxidase over-expression has little effect on nuclear H 2 O 2 accumulation and high light-responsive gene expression. This is because the H 2 O 2 derives from a sub-population of chloroplasts closely associated with nuclei. Therefore, direct H 2 O 2 transfer from chloroplasts to nuclei, avoiding the cytosol, enables photosynthetic control over gene expression.Multiple plastid-derived signals have been proposed but not shown to move to the nucleus to promote plant acclimation to fluctuating light. Here the authors use a fluorescent hydrogen peroxide sensor to provide evidence that H 2 O 2 is transferred directly from chloroplasts to nuclei to control nuclear gene expression.

  11. Are greenhouse gas signals of Northern Hemisphere winter extra-tropical cyclone activity dependent on the identification and tracking algorithm?

    Energy Technology Data Exchange (ETDEWEB)

    Ulbrich, Uwe; Grieger, Jens [Freie Univ. Berlin (Germany). Inst. of Meteorology; Leckebusch, Gregor C. [Birmingham Univ. (United Kingdom). School of Geography, Earth and Environmental Sciences] [and others

    2013-02-15

    For Northern Hemisphere extra-tropical cyclone activity, the dependency of a potential anthropogenic climate change signal on the identification method applied is analysed. This study investigates the impact of the used algorithm on the changing signal, not the robustness of the climate change signal itself. Using one single transient AOGCM simulation as standard input for eleven state-of-the-art identification methods, the patterns of model simulated present day climatologies are found to be close to those computed from re-analysis, independent of the method applied. Although differences in the total number of cyclones identified exist, the climate change signals (IPCC SRES A1B) in the model run considered are largely similar between methods for all cyclones. Taking into account all tracks, decreasing numbers are found in the Mediterranean, the Arctic in the Barents and Greenland Seas, the mid-latitude Pacific and North America. Changing patterns are even more similar, if only the most severe systems are considered: the methods reveal a coherent statistically significant increase in frequency over the eastern North Atlantic and North Pacific. We found that the differences between the methods considered are largely due to the different role of weaker systems in the specific methods. (orig.)

  12. The effect of hearing aid signal-processing schemes on acceptable noise levels: perception and prediction.

    Science.gov (United States)

    Wu, Yu-Hsiang; Stangl, Elizabeth

    2013-01-01

    The acceptable noise level (ANL) test determines the maximum noise level that an individual is willing to accept while listening to speech. The first objective of the present study was to systematically investigate the effect of wide dynamic range compression processing (WDRC), and its combined effect with digital noise reduction (DNR) and directional processing (DIR), on ANL. Because ANL represents the lowest signal-to-noise ratio (SNR) that a listener is willing to accept, the second objective was to examine whether the hearing aid output SNR could predict aided ANL across different combinations of hearing aid signal-processing schemes. Twenty-five adults with sensorineural hearing loss participated in the study. ANL was measured monaurally in two unaided and seven aided conditions, in which the status of the hearing aid processing schemes (enabled or disabled) and the location of noise (front or rear) were manipulated. The hearing aid output SNR was measured for each listener in each condition using a phase-inversion technique. The aided ANL was predicted by unaided ANL and hearing aid output SNR, under the assumption that the lowest acceptable SNR at the listener's eardrum is a constant across different ANL test conditions. Study results revealed that, on average, WDRC increased (worsened) ANL by 1.5 dB, while DNR and DIR decreased (improved) ANL by 1.1 and 2.8 dB, respectively. Because the effects of WDRC and DNR on ANL were opposite in direction but similar in magnitude, the ANL of linear/DNR-off was not significantly different from that of WDRC/DNR-on. The results further indicated that the pattern of ANL change across different aided conditions was consistent with the pattern of hearing aid output SNR change created by processing schemes. Compared with linear processing, WDRC creates a noisier sound image and makes listeners less willing to accept noise. However, this negative effect on noise acceptance can be offset by DNR, regardless of microphone mode

  13. cAMP-dependent signaling regulates the adipogenic effect of n-6 polyunsaturated fatty acids

    DEFF Research Database (Denmark)

    Madsen, Lise; Pedersen, Lone Møller; Liaset, Bjørn

    2008-01-01

    The effect of n-6 polyunsaturated fatty acids (n-6 PUFAs) on adipogenesis and obesity is controversial. Using in vitro cell culture models, we show that n-6 PUFAs was pro-adipogenic under conditions with base-line levels of cAMP, but anti-adipogenic when the levels of cAMP were elevated. The anti...

  14. Polydatin Restores Endothelium-Dependent Relaxation in Rat Aorta Rings Impaired by High Glucose: A Novel Insight into the PPARβ-NO Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Yang Wu

    Full Text Available Polydatin, a natural component from Polygonum Cuspidatum, has important therapeutic effects on metabolic syndrome. A novel therapeutic strategy using polydatin to improve vascular function has recently been proposed to treat diabetes-related cardiovascular complications. However, the biological role and molecular basis of polydatin's action on vascular endothelial cells (VECs-mediated vasodilatation under diabetes-related hyperglycemia condition remain elusive. The present study aimed to assess the contribution of polydatin in restoring endothelium-dependent relaxation and to determine the details of its underlying mechanism. By measuring endothelium-dependent relaxation, we found that acetylcholine-induced vasodilation was impaired by elevated glucose (55 mmol/L; however, polydatin (1, 3, 10 μmol/L could restore the relaxation in a dose-dependent manner. Polydatin could also improve the histological damage to endothelial cells in the thoracic aorta. Polydatin's effects were mediated via promoting the expression of endothelial NO synthase (eNOS, enhancing eNOS activity and decreasing the inducible NOS (iNOS level, finally resulting in a beneficial increase in NO release, which probably, at least in part, through activation of the PPARβ signaling pathway. The results provided a novel insight into polydatin action, via PPARβ-NO signaling pathways, in restoring endothelial function in high glucose conditions. The results also indicated the potential utility of polydatin to treat diabetes related cardiovascular diseases.

  15. Level of khat dependence, use patterns, and psychosocial correlates in Yemen: a cross-sectional investigation.

    Science.gov (United States)

    Nakajima, Motohiro; Hoffman, Richard; al'Absi, Mustafa

    2017-05-01

    Chronic khat use is associated with negative health consequences. However, no study has fully characterized individuals who are khat dependent. This paper examines socio-demographic and psychosocial correlates of adult khat dependence. A total of 270 khat users (129 women) in Yemen completed face-to-face interviews and provided demographic information and data on patterns of khat use, subjective mood, and sleep quality. The Severity of Dependence Scale-Khat (SDS-khat) was used to assess level of khat dependence. A series of analysis of variance was conducted. Khat users, on average, used khat for 5.2 hours a day (SD = 2.3) for 5.7 days a week (SD = 2.0). Individuals who screened positive for khat dependence reported longer duration of khat sessions per day, higher frequency of khat use per week, greater levels of negative mood and sleep disturbances, and were more likely to endorse physical symptoms after khat use (P < 0.05). Future research should elucidate mechanisms responsible for khat dependence symptomatology.

  16. An integrated framework for high level design of high performance signal processing circuits on FPGAs

    Science.gov (United States)

    Benkrid, K.; Belkacemi, S.; Sukhsawas, S.

    2005-06-01

    This paper proposes an integrated framework for the high level design of high performance signal processing algorithms' implementations on FPGAs. The framework emerged from a constant need to rapidly implement increasingly complicated algorithms on FPGAs while maintaining the high performance needed in many real time digital signal processing applications. This is particularly important for application developers who often rely on iterative and interactive development methodologies. The central idea behind the proposed framework is to dynamically integrate high performance structural hardware description languages with higher level hardware languages in other to help satisfy the dual requirement of high level design and high performance implementation. The paper illustrates this by integrating two environments: Celoxica's Handel-C language, and HIDE, a structural hardware environment developed at the Queen's University of Belfast. On the one hand, Handel-C has been proven to be very useful in the rapid design and prototyping of FPGA circuits, especially control intensive ones. On the other hand, HIDE, has been used extensively, and successfully, in the generation of highly optimised parameterisable FPGA cores. In this paper, this is illustrated in the construction of a scalable and fully parameterisable core for image algebra's five core neighbourhood operations, where fully floorplanned efficient FPGA configurations, in the form of EDIF netlists, are generated automatically for instances of the core. In the proposed combined framework, highly optimised data paths are invoked dynamically from within Handel-C, and are synthesized using HIDE. Although the idea might seem simple prima facie, it could have serious implications on the design of future generations of hardware description languages.

  17. Quantification of modulated blood oxygenation levels in single cerebral veins by investigating their MR signal decay

    Energy Technology Data Exchange (ETDEWEB)

    Sedlacik, Jan [St. Jude Children' s Research Hospital, Memphis, TN (United States). Div. of Translational Imaging Research; University Clinics Jena (Germany). Medical Physics Group; Rauscher, Alexander [University Clinics Jena (Germany). Medical Physics Group; British Columbia Univ., Vancouver (Canada). MRI Research Centre; Reichenbach, Juergen R. [University Clinics Jena (Germany). Medical Physics Group

    2009-07-01

    The transverse magnetization of a single vein and its surrounding tissue is subject to spin dephasing caused by the local magnetic field inhomogeneity which is induced by the very same vessel. This phenomenon can be approximated and simulated by applying the model of an infinitely long and homogeneously magnetized cylinder embedded in a homogeneous tissue background. It is then possible to estimate the oxygenation level of the venous blood by fitting the simulated magnetization-time-course to the measured signal decay. In this work we demonstrate the ability of this approach to quantify the blood oxygenation level (Y) of small cerebral veins in vivo, not only under normal physiologic conditions (Y{sub native}=0.5-0.55) but also during induced changes of physiologic conditions which affect the cerebral venous blood oxygenation level. Changes of blood's oxygenation level induced by carbogen (5% CO{sub 2}, 95% O{sub 2}) and caffeine were observed and quantified, resulting in values of Y{sub carbogen}=0.7 and Y{sub caffeine}=0.42, respectively. The proposed technique may ultimately help to better understand local changes in cerebral physiology during neuronal activation by quantifying blood oxygenation in veins draining active brain areas. It may also be beneficial in clinical applications where it may improve diagnosis of cerebral pathologies as well as monitoring of responses to therapy. (orig.)

  18. Detection of Cracking Levels in Brittle Rocks by Parametric Analysis of the Acoustic Emission Signals

    Science.gov (United States)

    Moradian, Zabihallah; Einstein, Herbert H.; Ballivy, Gerard

    2016-03-01

    Determination of the cracking levels during the crack propagation is one of the key challenges in the field of fracture mechanics of rocks. Acoustic emission (AE) is a technique that has been used to detect cracks as they occur across the specimen. Parametric analysis of AE signals and correlating these parameters (e.g., hits and energy) to stress-strain plots of rocks let us detect cracking levels properly. The number of AE hits is related to the number of cracks, and the AE energy is related to magnitude of the cracking event. For a full understanding of the fracture process in brittle rocks, prismatic specimens of granite containing pre-existing flaws have been tested in uniaxial compression tests, and their cracking process was monitored with both AE and high-speed video imaging. In this paper, the characteristics of the AE parameters and the evolution of cracking sequences are analyzed for every cracking level. Based on micro- and macro-crack damage, a classification of cracking levels is introduced. This classification contains eight stages (1) crack closure, (2) linear elastic deformation, (3) micro-crack initiation (white patch initiation), (4) micro-crack growth (stable crack growth), (5) micro-crack coalescence (macro-crack initiation), (6) macro-crack growth (unstable crack growth), (7) macro-crack coalescence and (8) failure.

  19. Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

    Science.gov (United States)

    Endo, Yoko; Suzuki, Masashi; Yamada, Hideomi; Horita, Shoko; Kunimi, Motoei; Yamazaki, Osamu; Shirai, Ayumi; Nakamura, Motonobu; Iso-O, Naoyuki; Li, Yuehong; Hara, Masumi; Tsukamoto, Kazuhisa; Moriyama, Nobuo; Kudo, Akihiko; Kawakami, Hayato; Yamauchi, Toshimasa; Kubota, Naoto; Kadowaki, Takashi; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George; Fujita, Toshiro

    2011-05-04

    Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. The cis-acting replication signal at the 3' end of Flock House virus RNA2 is RNA3-dependent

    International Nuclear Information System (INIS)

    Albarino, Cesar G.; Eckerle, Lance D.; Ball, L. Andrew

    2003-01-01

    The nodavirus Flock House virus has a bipartite positive-sense RNA genome consisting of RNAs 1 and 2, which encode the viral RNA-dependent RNA polymerase (RdRp) and capsid protein precursor, respectively. The RdRp catalyzes replication of both genome segments and produces from RNA1 a subgenomic RNA (RNA3) that transactivates RNA2 replication. Here, we replaced internal sequences of RNAs 1 and 2 with a common heterologous core and were thereby able to test the RNA termini for compatibility in supporting the replication of chimeric RNAs. The results showed that the 3' 50 nt of RNA2 contained an RNA3-dependent cis-acting replication signal. Since covalent RNA dimers can direct the synthesis of monomeric replication products, the RdRp can evidently respond to cis-acting replication signals located internally. Accordingly, RNA templates containing the 3' termini of both RNAs 1 and 2 in tandem generated different replication products depending on the presence or absence of RNA3

  1. Volume fraction dependence of transient absorption signal and nonlinearities in metal nanocolloids

    International Nuclear Information System (INIS)

    Jayabalan, J; Singh, Asha; Khan, Salahuddin; Chari, Rama

    2013-01-01

    Electron–lattice thermalization dynamics in metal nanoparticles or in bulk metal is usually estimated by measuring the decay time of the change in transmission following an optical excitation. Such measurements can be performed in transient absorption geometry using a femtosecond laser. We find that for silver nanoplatelet/water colloids, the decay time of the transient absorption depends on the volume fraction of silver in water. By estimating the volume fraction dependence of nonlinearities in the same samples, we show that the variation in the measured decay time is due to pump-depletion effects present in the sample. The correct correction factor for taking into account pump-depletion effects in fifth- and higher-order nonlinearities is also presented. (paper)

  2. On the Perpetual American Put Options for Level Dependent Volatility Models with Jumps

    OpenAIRE

    Bayraktar, Erhan

    2007-01-01

    We prove that the perpetual American put option price of level dependent volatility model with compound Poisson jumps is convex and is the classical solution of its associated quasi-variational inequality, that it is $C^2$ except at the stopping boundary and that it is $C^1$ everywhere (i.e. the smooth pasting condition always holds).

  3. Analysis of Two-Level Support Systems with Time-Dependent Overflow - A Banking Application

    DEFF Research Database (Denmark)

    Barth, Wolfgang; Manitz, Michael; Stolletz, Raik

    2010-01-01

    In this paper, we analyze the performance of call centers of financial service providers with two levels of support and a time-dependent overflow mechanism. Waiting calls from the front-office queue flow over to the back office if a waiting-time limit is reached and at least one back-office agent...

  4. p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals

    DEFF Research Database (Denmark)

    Epifano, Carolina; Megias, Diego; Perez-Moreno, Mirna

    2014-01-01

    The adherens junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120 catenin regulates the intrinsic...... migratory properties of primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell...... motility via an increase in actin stress fibers, reduction in integrin turnover and an increase in the robustness of focal adhesions. The other is coupled to the secretion of inflammatory cytokines including interleukin-24, which causally enhances randomized cell movements. Taken together, our results...

  5. ERK2 dependent signaling contributes to wound healing after a partial-thickness burn

    International Nuclear Information System (INIS)

    Satoh, Yasushi; Saitoh, Daizoh; Takeuchi, Atsuya; Ojima, Kenichiro; Kouzu, Keita; Kawakami, Saki; Ito, Masataka; Ishihara, Masayuki; Sato, Shunichi; Takishima, Kunio

    2009-01-01

    Burn healing is a complex physiological process involving multiple cell activities, such as cell proliferation, migration and differentiation. Although extracellular signal-regulated kinases (ERK) have a pivotal role in regulating a variety of cellular responses, little is known about the individual functions of ERK isoform for healing in vivo. This study investigated the role of ERK2 in burn healing. To assess this, Erk2 +/- mice generated by gene targeting were used. The resultant mice exhibited significant delay in re-epithelization of partial-thickness burns in the skin in comparison to wild-type. An in vitro proliferation assay revealed that keratinocytes from Erk2 +/- mice grew significantly slower than those prepared from wild-type. These results highlight the importance of ERK2 in the process of burn healing.

  6. In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

    Science.gov (United States)

    Miller, Peter G.; Al-Shahrour, Fatima; Hartwell, Kimberly A.; Chu, Lisa P.; Järås, Marcus; Puram, Rishi V.; Puissant, Alexandre; Callahan, Kevin P.; Ashton, John; McConkey, Marie E.; Poveromo, Luke P.; Cowley, Glenn S.; Kharas, Michael G.; Labelle, Myriam; Shterental, Sebastian; Fujisaki, Joji; Silberstein, Lev; Alexe, Gabriela; Al-Hajj, Muhammad A.; Shelton, Christopher A.; Armstrong, Scott A.; Root, David E.; Scadden, David T.; Hynes, Richard O.; Mukherjee, Siddhartha; Stegmaier, Kimberly; Jordan, Craig T.; Ebert, Benjamin L.

    2013-01-01

    SUMMARY We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. PMID:23770013

  7. Blood oxygenation level dependent (BOLD). Renal imaging. Concepts and applications; Blood Oxygenation Level Dependent (BOLD). Bildgebung der Nieren. Konzepte und Anwendungen

    Energy Technology Data Exchange (ETDEWEB)

    Nissen, Johanna C.; Haneder, Stefan; Schoenberg, Stefan O.; Michaely, Henrik J. [Heidelberg Univ. Medizinische Fakultaet Mannheim (Germany). Inst. fuer Klinische Radiologie und Nuklearmedizin; Mie, Moritz B.; Zoellner, Frank G. [Heidelberg Univ. Medizinische Fakultaet Mannheim (DE). Inst. fuer Computerunterstuetzte Klinische Medizin (CKM)

    2010-07-01

    Many renal diseases as well as several pharmacons cause a change in renal blood flow and/or renal oxygenation. The blood oxygenation level dependent (BOLD) imaging takes advantage of local field inhomogeneities and is based on a T2{sup *}-weighted sequence. BOLD is a non-invasive method allowing an estimation of the renal, particularly the medullary oxygenation, and an indirect measurement of blood flow without administration of contrast agents. Thus, effects of different drugs on the kidney and various renal diseases can be controlled and observed. This work will provide an overview of the studies carried out so far and identify ways how BOLD can be used in clinical studies. (orig.)

  8. The cAMP-dependent protein kinase inhibitor H-89 attenuates the bioluminescence signal produced by Renilla Luciferase.

    Directory of Open Access Journals (Sweden)

    Katie J Herbst

    2009-05-01

    Full Text Available Investigations into the regulation and functional roles of kinases such as cAMP-dependent protein kinase (PKA increasingly rely on cellular assays. Currently, there are a number of bioluminescence-based assays, for example reporter gene assays, that allow the study of the regulation, activity, and functional effects of PKA in the cellular context. Additionally there are continuing efforts to engineer improved biosensors that are capable of detecting real-time PKA signaling dynamics in cells. These cell-based assays are often utilized to test the involvement of PKA-dependent processes by using H-89, a reversible competitive inhibitor of PKA.We present here data to show that H-89, in addition to being a competitive PKA inhibitor, attenuates the bioluminescence signal produced by Renilla luciferase (RLuc variants in a population of cells and also in single cells. Using 10 microM of luciferase substrate and 10 microM H-89, we observed that the signal from RLuc and RLuc8, an eight-point mutation variant of RLuc, in cells was reduced to 50% (+/-15% and 54% (+/-14% of controls exposed to the vehicle alone, respectively. In vitro, we showed that H-89 decreased the RLuc8 bioluminescence signal but did not compete with coelenterazine-h for the RLuc8 active site, and also did not affect the activity of Firefly luciferase. By contrast, another competitive inhibitor of PKA, KT5720, did not affect the activity of RLuc8.The identification and characterization of the adverse effect of H-89 on RLuc signal will help deconvolute data previously generated from RLuc-based assays looking at the functional effects of PKA signaling. In addition, for the current application and future development of bioluminscence assays, KT5720 is identified as a more suitable PKA inhibitor to be used in conjunction with RLuc-based assays. These principal findings also provide an important lesson to fully consider all of the potential effects of experimental conditions on a cell

  9. Equation of State Dependent Dynamics and Multi-messenger Signals from Stellar-mass Black Hole Formation

    Science.gov (United States)

    Pan, Kuo-Chuan; Liebendörfer, Matthias; Couch, Sean M.; Thielemann, Friedrich-Karl

    2018-04-01

    We investigate axisymmetric black hole (BH) formation and its gravitational wave (GW) and neutrino signals with self-consistent core-collapse supernova simulations of a non-rotating 40 M ⊙ progenitor star using the isotropic diffusion source approximation for the neutrino transport and a modified gravitational potential for general relativistic effects. We consider four different neutron star (NS) equations of state (EoS): LS220, SFHo, BHBΛϕ, and DD2, and study the impact of the EoS on BH formation dynamics and GW emission. We find that the BH formation time is sensitive to the EoS from 460 to >1300 ms and is delayed in multiple dimensions for ∼100–250 ms due to the finite entropy effects. Depending on the EoS, our simulations show the possibility that shock revival can occur along with the collapse of the proto-neutron star (PNS) to a BH. The gravitational waveforms contain four major features that are similar to previous studies but show extreme values: (1) a low-frequency signal (∼300–500 Hz) from core-bounce and prompt convection, (2) a strong signal from the PNS g-mode oscillation among other features, (3) a high-frequency signal from the PNS inner-core convection, and (4) signals from the standing accretion shock instability and convection. The peak frequency at the onset of BH formation reaches to ∼2.3 kHz. The characteristic amplitude of a 10 kpc object at peak frequency is detectable but close to the noise threshold of the Advanced LIGO and KAGRA, suggesting that the next-generation GW detector will need to improve the sensitivity at the kHz domain to better observe stellar-mass BH formation from core-collapse supernovae or failed supernovae.

  10. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

    OpenAIRE

    Lim, Chae-Seok; Hoang, Elizabeth T.; Viar, Kenneth E.; Stornetta, Ruth L.; Scott, Michael M.; Zhu, J. Julius

    2014-01-01

    Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation. Lim et al. find that compounds activating serotonin (5HT) subtype 2B receptors or dopamine (DA) subtype 1-like receptors and those inhibiting 5HT2A-Rs or D2-Rs enhance Ras signaling, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Combining 5HT and DA compounds at low doses synergistically restored normal learning. This suggests that properly dosed an...

  11. Panel Data with Cross-Sectional Dependence Characterized by a Multi-Level Factor Structure

    DEFF Research Database (Denmark)

    Rodríguez-Caballero, Carlos Vladimir

    A panel data model with a multi-level cross-sectional dependence is proposed. The factor structure is driven by top-level common factors as well as non-pervasive factors. I propose a simple method to filter out the full factor structure that overcomes limitations in standard procedures which may...... mix up both levels of unobservable factors and may hamper the identification of the model. The model covers both stationary and non-stationary cases and takes into account other relevant features that make the model well suited to the analysis of many types of time series frequently addressed...

  12. Simultaneous reflection masking: dependency on direct sound level and hearing-impairment

    DEFF Research Database (Denmark)

    Buchholz, Jörg; Mihai, Paul Glad

    2008-01-01

    B-SL direct sound level, NH-listeners showed a binaural suppression effect for delays smaller than 7-10 ms and a binaural enhancement effect for larger delays. When decreasing the direct sound level to 15 dB-SL, the only significant change observed was that the dichotic RMT increased for delays larger than...... expected from changed auditory filter bandwidth and audi-bility. However, the stimulus level-dependency of the auditory filters’ bandwidth was not reflected in the SRMT data....

  13. Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic

    Energy Technology Data Exchange (ETDEWEB)

    Allison, Patrick; Huang, Tianfang; Broka, Derrick; Parker, Patti [Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children' s Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721 (United States); Barnett, Joey V. [Department of Pharmacology, Vanderbilt Medical University, Nashville, TN (United States); Camenisch, Todd D., E-mail: camenisch@pharmacy.arizona.edu [Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children' s Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721 (United States)

    2013-10-01

    Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18 hour exposure to 1.34 μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34 μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity. - Highlights: • Arsenic blocks TGFβ2 induced expression of EMT genes. • Arsenic blocks TGFβ2 triggered Smad2/3 phosphorylation and nuclear translocation. • Arsenic blocks epicardial cell differentiation into cardiac mesenchyme.

  14. Fermi level dependent native defect formation: Consequences for metal-semiconductor and semiconductor-semiconductor interfaces

    International Nuclear Information System (INIS)

    Walukiewicz, W.

    1988-02-01

    The amphoteric native defect model of the Schottky barrier formation is used to analyze the Fermi level pinning at metal/semiconductor interfaces for submonolayer metal coverages. It is assumed that the energy required for defect generation is released in the process of surface back-relaxation. Model calculations for metal/GaAs interfaces show a weak dependence of the Fermi level pinning on the thickness of metal deposited at room temperature. This weak dependence indicates a strong dependence of the defect formation energy on the Fermi level, a unique feature of amphoteric native defects. This result is in very good agreement with experimental data. It is shown that a very distinct asymmetry in the Fermi level pinning on p- and n-type GaAs observed at liquid nitrogen temperatures can be understood in terms of much different recombination rates for amphoteric native defects in those two types of materials. Also, it is demonstrated that the Fermi level stabilization energy, a central concept of the amphoteric defect system, plays a fundamental role in other phenomena in semiconductors such as semiconductor/semiconductor heterointerface intermixing and saturation of free carrier concentration. 33 refs., 6 figs

  15. Light-Triggered Soft Artificial Muscles: Molecular-Level Amplification of Actuation Control Signals.

    Science.gov (United States)

    Dicker, Michael P M; Baker, Anna B; Iredale, Robert J; Naficy, Sina; Bond, Ian P; Faul, Charl F J; Rossiter, Jonathan M; Spinks, Geoffrey M; Weaver, Paul M

    2017-08-23

    The principle of control signal amplification is found in all actuation systems, from engineered devices through to the operation of biological muscles. However, current engineering approaches require the use of hard and bulky external switches or valves, incompatible with both the properties of emerging soft artificial muscle technology and those of the bioinspired robotic systems they enable. To address this deficiency a biomimetic molecular-level approach is developed that employs light, with its excellent spatial and temporal control properties, to actuate soft, pH-responsive hydrogel artificial muscles. Although this actuation is triggered by light, it is largely powered by the resulting excitation and runaway chemical reaction of a light-sensitive acid autocatalytic solution in which the actuator is immersed. This process produces actuation strains of up to 45% and a three-fold chemical amplification of the controlling light-trigger, realising a new strategy for the creation of highly functional soft actuating systems.

  16. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins.

    Science.gov (United States)

    Seong, Hyun-A; Jung, Haiyoung; Kim, Kyong-Tai; Ha, Hyunjung

    2007-04-20

    We have reported previously that PDK1 physically interacts with STRAP, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and enhances STRAP-induced inhibition of TGF-beta signaling. In this study we show that PDK1 coimmunoprecipitates with Smad proteins, including Smad2, Smad3, Smad4, and Smad7, and that this association is mediated by the pleckstrin homology domain of PDK1. The association between PDK1 and Smad proteins is increased by insulin treatment but decreased by TGF-beta treatment. Analysis of the interacting proteins shows that Smad proteins enhance PDK1 kinase activity by removing 14-3-3, a negative regulator of PDK1, from the PDK1-14-3-3 complex. Knockdown of endogenous Smad proteins, including Smad3 and Smad7, by transfection with small interfering RNA produced the opposite trend and decreased PDK1 activity, protein kinase B/Akt phosphorylation, and Bad phosphorylation. Moreover, coexpression of Smad proteins and wild-type PDK1 inhibits TGF-beta-induced transcription, as well as TGF-beta-mediated biological functions, such as apoptosis and cell growth arrest. Inhibition was dose-dependent on PDK1, but no inhibition was observed in the presence of an inactive kinase-dead PDK1 mutant. In addition, confocal microscopy showed that wild-type PDK1 prevents translocation of Smad3 and Smad4 from the cytoplasm to the nucleus, as well as the redistribution of Smad7 from the nucleus to the cytoplasm in response to TGF-beta. Taken together, our results suggest that PDK1 negatively regulates TGF-beta-mediated signaling in a PDK1 kinase-dependent manner via a direct physical interaction with Smad proteins and that Smad proteins can act as potential positive regulators of PDK1.

  17. Vitamin D Status in Population of Bukovyna and Subcarpathia Depending on Residence above Sea Level

    Directory of Open Access Journals (Sweden)

    V.V. Povoroznyuk

    2016-04-01

    ding on the residence above sea level. Objective: to determine the level of vitamin D in the blood serum of people, who live in different regions of the Subcarpathia and Bukovyna, depending on the location of the settlement above sea le-vel. Material and methods. In the cross-sectional study, we have examined 353 individuals, aged 18 to 86 years, permanently residing in different parts of the Subcarpathia (Kolomyia, Kosiv, Verhovyna districts and Bukovyna (Vyzhny-tsia district. Results. Only in 28 cases (7.9 %, the content of 25(OHD in the blood serum was in the normal range, and in other cases (92.1 %, there was a deficiency and a lack of vitamin D. The severe form of vitamin D deficiency has been detected in 7 (1.9 % patients. When comparing the performance of 25(OHD in the areas of inspection, it was found that the level of vitamin D in the blood serum was significantly higher in residents of Verkhovyna and Kosiv districts (located higher than 450 meters above sea level as compared with residents of Vyzhnytsia and Kolomyia. Conclusion. The average level of vitamin D in the blood serum of the adult population depends on residence and increases with height above sea level.

  18. Seasonal dependence of the predictable low-level circulation patterns over the tropical Indo-Pacific domain

    Science.gov (United States)

    Zhang, Tuantuan; Huang, Bohua; Yang, Song; Laohalertchai, Charoon

    2018-06-01

    The seasonal dependence of the prediction skill of 850-hPa monthly zonal wind over the tropical Indo-Pacific domain is examined using the ensemble reforecasts for 1983-2010 from the National Centers for Environmental Prediction (NCEP) Climate Forecast System Reanalysis and Reforecast (CFSRR) project. According to a maximum signal-to-noise empirical orthogonal function analysis, the most predictable patterns of atmospheric low-level circulation are associated with the developing and maturing phases of El Niño-Southern Oscillation (ENSO). The CFSv2 is capable of predicting these ENSO-related patterns up to 9-months in advance for all months, except for May-June when the effect of the spring barrier is strong. The other predictable climate processes associated with the low-level atmospheric circulation are more seasonally dependent. For winter and spring, the second most predictable patterns are associated with the ENSO decaying phase. Within these seasons, the monthly evolution of the predictable patterns is characterized by a southward shift of westerly wind anomalies, generated by the interaction between the annual cycle and the ENSO signals (i.e., the combination-mode). In general, the CFSv2 hindcast well predicts these patterns at least 5 months in advance for spring, while shows much lower skills for winter months. In summer, the second predictable patterns are associated with the western North Pacific (WNP) monsoon (i.e., the WNP anticyclone/cyclone) in short leads while associated with ENSO in longer leads (after 4-month lead). The second predictable patterns in fall are mainly associated with tropical Indian Ocean Dipole, which can be predicted 3 months in advance.

  19. Butein Inhibits Angiogenesis of Human Endothelial Progenitor Cells via the Translation Dependent Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ching-Hu Chung

    2013-01-01

    Full Text Available Compelling evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs can contribute to postnatal neovascularization and tumor angiogenesis. EPCs have been shown to play a “catalytic” role in metastatic progression by mediating the angiogenic switch. Understanding the pharmacological functions and molecular targets of natural products is critical for drug development. Butein, a natural chalcone derivative, has been reported to exert potent anticancer activity. However, the antiangiogenic activity of butein has not been addressed. In this study, we found that butein inhibited serum- and vascular endothelial growth factor- (VEGF- induced cell proliferation, migration, and tube formation of human EPCs in a concentration dependent manner without cytotoxic effect. Furthermore, butein markedly abrogated VEGF-induced vessels sprouting from aortic rings and suppressed microvessel formation in the Matrigel implant assay in vivo. In addition, butein concentration-dependently repressed the phosphorylation of Akt, mTOR, and the major downstream effectors, p70S6K, 4E-BP1, and eIF4E in EPCs. Taken together, our results demonstrate for the first time that butein exhibits the antiangiogenic effect both in vitro and in vivo by targeting the translational machinery. Butein is a promising angiogenesis inhibitor with the potential for treatment of cancer and other angiogenesis-related diseases.

  20. Growth of intestinal epithelium in organ culture is dependent on EGF signalling

    International Nuclear Information System (INIS)

    Abud, Helen E.; Watson, Nadine; Heath, Joan K.

    2005-01-01

    Differentiation of endoderm into intestinal epithelium is initiated at E13.5 of mouse development when there are significant changes in morphology resulting in the conversion of undifferentiated stratified epithelium into a mature epithelial monolayer. Here we demonstrate that monolayer formation is associated with the selective apoptosis of superficial cells lining the lumen while cell proliferation is progressively restricted to cells adjacent to the basement membrane. We describe an innovative embryonic gut culture system that maintains the three-dimensional architecture of gut and in which these processes are recapitulated in vitro. Explants taken from specific regions of the gut and placed into organ culture develop and express molecular markers (Cdx1, Cdx2 and A33 antigen) in the same spatial and temporal pattern observed in vivo indicating that regional specification is maintained. Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase using the specific inhibitor AG1478 significantly reduced the proliferation and survival of cells within the epithelial cell layer of cultured gut explants. This demonstrates an essential role for the EGF signalling pathway during the early stages of intestinal development

  1. Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation

    Science.gov (United States)

    Wu, Haitao; Barik, Arnab; Lu, Yisheng; Shen, Chengyong; Bowman, Andrew; Li, Lei; Sathyamurthy, Anupama; Lin, Thiri W; Xiong, Wen-Cheng; Mei, Lin

    2015-01-01

    Neuromuscular junction formation requires proper interaction between motoneurons and muscle cells. β-Catenin (Ctnnb1) in muscle is critical for motoneuron differentiation; however, little is known about the relevant retrograde signal. In this paper, we dissected which functions of muscle Ctnnb1 are critical by an in vivo transgenic approach. We show that Ctnnb1 mutant without the transactivation domain was unable to rescue presynaptic deficits of Ctnnb1 mutation, indicating the involvement of transcription regulation. On the other hand, the cell-adhesion function of Ctnnb1 is dispensable. We screened for proteins that may serve as a Ctnnb1-directed retrograde factor and identified Slit2. Transgenic expression of Slit2 specifically in the muscle was able to diminish presynaptic deficits by Ctnnb1 mutation in mice. Slit2 immobilized on beads was able to induce synaptophysin puncta in axons of spinal cord explants. Together, these observations suggest that Slit2 serves as a factor utilized by muscle Ctnnb1 to direct presynaptic differentiation. DOI: http://dx.doi.org/10.7554/eLife.07266.001 PMID:26159615

  2. Lamellipodia nucleation by filopodia depends on integrin occupancy and downstream Rac1 signaling

    International Nuclear Information System (INIS)

    Guillou, Herve; Depraz-Depland, Adeline; Planus, Emmanuelle; Vianay, Benoit; Chaussy, Jacques; Grichine, Alexei; Albiges-Rizo, Corinne; Block, Marc R.

    2008-01-01

    Time-lapse video-microscopy unambiguously shows that fibroblast filopodia are the scaffold of lamellipodia nucleation that allows anisotropic cell spreading. This process was dissected into elementary stages by monitoring cell adhesion on micropatterned extracellular matrix arrays of various pitches. Adhesion structures are stabilized by contact with the adhesive plots and subsequently converted into lamellipodia-like extensions starting at the filopodia tips. This mechanism progressively leads to full cell spreading. Stable expression of the dominant-negative Rac1 N17 impairs this change in membrane extension mode and stops cell spreading on matrix arrays. Similar expression of the dominant-negative Cdc42 N17 impairs cell spreading on homogenous and structured substrate, suggesting that filopodia extension is a prerequisite for cell spreading in this model. The differential polarity of the nucleation of lamellipodial structures by filopodia on homogenous and structured surfaces starting from the cell body and of filopodia tip, respectively, suggested that this process is triggered by areas that are in contact with extracellular matrix proteins for longer times. Consistent with this view, wild-type cells cannot spread on microarrays made of function blocking or neutral anti-β 1 integrin antibodies. However, stable expression of a constitutively active Rac1 mutant rescues the cell ability to spread on these integrin microarrays. Thereby, lamellipodia nucleation by filopodia requires integrin occupancy by matrix substrate and downstream Rac1 signaling

  3. BMP signaling protects telencephalic fate by repressing eye identity and its Cxcr4-dependent morphogenesis.

    Science.gov (United States)

    Bielen, Holger; Houart, Corinne

    2012-10-16

    Depletion of Wnt signaling is a major requirement for the induction of the anterior prosencephalon. However, the molecular events driving the differential regionalization of this area into eye-field and telencephalon fates are still unknown. Here we show that the BMP pathway is active in the anterior neural ectoderm during late blastula to early gastrula stage in zebrafish. Bmp2b mutants and mosaic loss-of-function experiments reveal that BMP acts as a repressor of eye-field fate through inhibition of its key transcription factor Rx3, thereby protecting the future telencephalon from acquiring eye identity. This BMP-driven mechanism initiates the establishment of the telencephalon prior to the involvement of Wnt antagonists from the anterior neural border. Furthermore, we demonstrate that Rx3 and BMP are respectively required to maintain and restrict the chemokine receptor cxcr4a, which in turn contributes to the morphogenetic separation of eye-field and telencephalic cells during early neurulation. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Control of biotin biosynthesis in mycobacteria by a pyruvate carboxylase dependent metabolic signal.

    Science.gov (United States)

    Lazar, Nathaniel; Fay, Allison; Nandakumar, Madhumitha; Boyle, Kerry E; Xavier, Joao; Rhee, Kyu; Glickman, Michael S

    2017-12-01

    Biotin is an essential cofactor utilized by all domains of life, but only synthesized by bacteria, fungi and plants, making biotin biosynthesis a target for antimicrobial development. To understand biotin biosynthesis in mycobacteria, we executed a genetic screen in Mycobacterium smegmatis for biotin auxotrophs and identified pyruvate carboxylase (Pyc) as required for biotin biosynthesis. The biotin auxotrophy of the pyc::tn strain is due to failure to transcriptionally induce late stage biotin biosynthetic genes in low biotin conditions. Loss of bioQ, the repressor of biotin biosynthesis, in the pyc::tn strain reverted biotin auxotrophy, as did reconstituting the last step of the pathway through heterologous expression of BioB and provision of its substrate DTB. The role of Pyc in biotin regulation required its catalytic activities and could be supported by M. tuberculosis Pyc. Quantitation of the kinetics of depletion of biotinylated proteins after biotin withdrawal revealed that Pyc is the most rapidly depleted biotinylated protein and metabolomics revealed a broad metabolic shift in wild type cells upon biotin withdrawal which was blunted in cell lacking Pyc. Our data indicate that mycobacterial cells monitor biotin sufficiency through a metabolic signal generated by dysfunction of a biotinylated protein of central metabolism. © 2017 John Wiley & Sons Ltd.

  5. The dependence level analysis between the human actions in NPP Operation

    International Nuclear Information System (INIS)

    Farcasiu, M.; Nitoi, M.; Apostol, M.; Florescu, G.; Prisecaru, Ilie

    2009-01-01

    The Human Reliability Analysis (HRA) is an important method in Probabilistic Safety Assessment (PSA) studies and offers desirability for concrete improvement of the man - machine - organization interfaces, reliability and safety. An important step in HRA is the dependence level analysis between the human actions performed by the same person or between the actions performed by different persons, step in quantitative analysis of the human errors probabilities. The purpose of this paper is to develop a model to analyze the dependence level between human actions for Nuclear Power Plant (NPP) operation. The model estimates the conditional human error probabilities (CHEP) and joint human error probabilities (JHEP). The achieved sensitivity analyses determine human performance sensibility to systematic variations for dependence level between human actions. The human error probabilities estimated in this paper are adequate values for integration both in HRA and in PSA realized for NPP. This type of analysis helps in finding and analyzing the ways of reducing the likelihood of human errors, so that the impact of human factor to systems availability, reliability and safety can be realistically estimated. In order to demonstrate the usability of this model an analysis is performed upon the dependences between the necessary human actions in mitigating the consequences of LOCA events, particularly for the case of Cernavoda NPP. (authors)

  6. Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

    International Nuclear Information System (INIS)

    Chen, Chien-Liang; Chou, Kang-Ju; Lee, Po-Tsang; Chen, Ying-Shou; Chang, Tsu-Yuan; Hsu, Chih-Yang; Huang, Wei-Chieh; Chung, Hsiao-Min; Fang, Hua-Chang

    2010-01-01

    Purpose: Tumor growth factor-β1 (TGF-β1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-β1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-β1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-β1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-β1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-β1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-β1-mediated apoptosis and also partially inhibited TGF-β1-mediated EMT. We showed that EPO treatment suppressed TGF-β1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-β1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-β1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.

  7. Astrocyte IP3R2-dependent Ca2+ signaling is not a major modulator of neuronal pathways governing behavior.

    Directory of Open Access Journals (Sweden)

    Jeremy ePetravicz

    2014-11-01

    Full Text Available Calcium-dependent release of gliotransmitters by astrocytes is reported to play a critical role in synaptic transmission and be necessary for long-term potentiation (LTP, long-term depression (LTD and other forms of synaptic modulation that are correlates of learning and memory . Further, physiological processes reported to be dependent on Ca2+ fluxes in astrocytes include functional hyperemia, sleep, and regulation of breathing. The preponderance of findings indicate that most, if not all, receptor dependent Ca2+ fluxes within astrocytes are due to release of Ca2+ through IP3 receptor/channels in the endoplasmic reticulum. Findings from several laboratories indicate that astrocytes only express IP3 receptor type 2 (IP3R2 and that a knockout of IP3R2 obliterates the GPCR-dependent astrocytic Ca2+ responses. Assuming that astrocytic Ca2+ fluxes play a critical role in synaptic physiology, it would be predicted that eliminating of astrocytic Ca2+ fluxes would lead to marked changes in behavioral tests. Here, we tested this hypothesis by conducting a broad series of behavioral tests that recruited multiple brain regions, on an IP3R2 conditional knockout mouse model. We present the novel finding that behavioral processes are unaffected by lack of astrocyte IP3R-mediated Ca2+ signals. IP3R2 cKO animals display no change in anxiety or depressive behaviors, and no alteration to motor and sensory function. Morris water maze testing, a behavioral correlate of learning and memory, was unaffected by lack of astrocyte IP3R2-mediated Ca2+-signaling. Therefore, in contrast to the prevailing literature, we find that neither receptor-driven astrocyte Ca2+ fluxes nor, by extension, gliotransmission is likely to be a major modulating force on the physiological processes underlying behavior.

  8. Relations between vegetation and water level in groundwater dependent terrestrial ecosystems (GWDTEs)

    DEFF Research Database (Denmark)

    Munch Johansen, Ole; Andersen, Dagmar Kappel; Ejrnæs, Rasmus

    2018-01-01

    , management and conservation of fens are constrained by limited knowledge on the relations between vegetation and measurable hydrological conditions. This study investigates the relations between vegetation and water level dynamics in groundwater dependent wetlands in Denmark. A total of 35 wetland sites...... across Denmark were included in the study. The sites represent a continuum of wetlands with respect to vegetation and hydrological conditions. Water level was measured continuously using pressure transducers at each site. Metrics expressing different hydrological characteristics, such as mean water level...... and low and high water level periods, were calculated based on the water level time series. A complete plant species list was recorded in plots covering 78.5 m2 at each site. Community metrics such as total number of species and the number of bryophytes were generated from the species lists and Ellenberg...

  9. Decreased serum level of NGF in alcohol-dependent patients with declined executive function

    Directory of Open Access Journals (Sweden)

    Bae H

    2014-11-01

    Full Text Available Hwallip Bae,1 Youngsun Ra,1 Changwoo Han,2 Dai-Jin Kim3 1Department of Psychiatry, Myongji Hospital, Goyang, 2Department of Psychiatry, Keyo Hospital, Uiwang, 3Department of Psychiatry, Seoul St Mary’s Hospital, College of Medicine, Catholic University of Korea, Seoul, South Korea Abstract: The role of neurotrophic factors has been highlighted as a cause of decline in the cognitive function of alcohol-dependent patients. It is known that nerve-growth factor (NGF, one of the neurotrophins, is related to the growth and differentiation of nerve cells, as well as to a decline in cognitive function. The purpose of this study was to investigate the relationship between decreased NGF levels and cognitive decline in alcohol-dependent patients. The serum concentration of NGF was measured in 38 patients with chronic alcohol dependence, and several neuropsychological tests were also performed for cognitive function assessment. The results indicated a significant correlation between serum NGF level and the trail-making test part B, which evaluates executive function, but did not show a significant correlation with other cognitive function tests. An increased serum level of NGF was associated with a decreased completion time in the trail-making test B, and this finding indicates that a high serum level of NGF is related to greater executive function. This finding may imply a protective role of NGF in preventing neuron damage among patients with alcohol dependence. Larger controlled studies will be necessary in the future to investigate this issue further. Keywords: nerve-growth factor, alcohol dependence, executive function, trail-making test

  10. Ca2+-Dependent Regulations and Signaling in Skeletal Muscle: From Electro-Mechanical Coupling to Adaptation

    Science.gov (United States)

    Gehlert, Sebastian; Bloch, Wilhelm; Suhr, Frank

    2015-01-01

    Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca2+ is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca2+ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca2+-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca2+ ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca2+ ions in adult muscle but also highlight recent findings of critical Ca2+-dependent mechanisms essential for skeletal muscle-regulation and maintenance. PMID:25569087

  11. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts.

    Directory of Open Access Journals (Sweden)

    Gilles M Leclerc

    Full Text Available The outcome of patients with resistant phenotypes of acute lymphoblastic leukemia (ALL or those who relapse remains poor. We investigated the mechanism of cell death induced by metformin in Bp- and T-ALL cell models and primary cells, and show that metformin effectively induces apoptosis in ALL cells. Metformin activated AMPK, down-regulated the unfolded protein response (UPR demonstrated by significant decrease in the main UPR regulator GRP78, and led to UPR-mediated cell death via up-regulation of the ER stress/UPR cell death mediators IRE1α and CHOP. Using shRNA, we demonstrate that metformin-induced apoptosis is AMPK-dependent since AMPK knock-down rescued ALL cells, which correlated with down-regulation of IRE1α and CHOP and restoration of the UPR/GRP78 function. Additionally rapamycin, a known inhibitor of mTOR-dependent protein synthesis, rescued cells from metformin-induced apoptosis and down-regulated CHOP expression. Finally, metformin induced PIM-2 kinase activity and co-treatment of ALL cells with a PIM-1/2 kinase inhibitor plus metformin synergistically increased cell death, suggesting a buffering role for PIM-2 in metformin's cytotoxicity. Similar synergism was seen with agents targeting Akt in combination with metformin, supporting our original postulate that AMPK and Akt exert opposite regulatory roles on UPR activity in ALL. Taken together, our data indicate that metformin induces ALL cell death by triggering ER and proteotoxic stress and simultaneously down-regulating the physiologic UPR response responsible for effectively buffering proteotoxic stress. Our findings provide evidence for a role of metformin in ALL therapy and support strategies targeting synthetic lethal interactions with Akt and PIM kinases as suitable for future consideration for clinical translation in ALL.

  12. Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice.

    Science.gov (United States)

    Oberkofler, Christian E; Limani, Perparim; Jang, Jae-Hwi; Rickenbacher, Andreas; Lehmann, Kuno; Raptis, Dimitri A; Ungethuem, Udo; Tian, Yinghua; Grabliauskaite, Kamile; Humar, Rok; Graf, Rolf; Humar, Bostjan; Clavien, Pierre-Alain

    2014-10-01

    Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological responses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1(-) (/) (-) mice, and through neutralizing antibodies, respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet-derived serotonin. Downstream of serotonin, systemic protection was spread through up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up-regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet-dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm. © 2014 by the American Association for the Study of Liver Diseases.

  13. Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.

    Science.gov (United States)

    Ma, Yonggang; Chiao, Ying Ann; Clark, Ryan; Flynn, Elizabeth R; Yabluchanskiy, Andriy; Ghasemi, Omid; Zouein, Fouad; Lindsey, Merry L; Jin, Yu-Fang

    2015-06-01

    Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing. Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state. Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  14. Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters.

    Science.gov (United States)

    Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong; Alexandre, Gladys

    2016-06-15

    The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  15. Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity

    Science.gov (United States)

    Cai, Chenxu; Liu, Guangao; Wang, Yuande; Du, Juan; Lin, Xin; Yang, Meixiang

    2017-01-01

    Signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (TFH) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in TFH cell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient TFH cells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP. PMID:28049627

  16. Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Sota Iwatani

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs are a heterogeneous cell population that is isolated initially from the bone marrow (BM and subsequently almost all tissues including umbilical cord (UC. UC-derived MSCs (UC-MSCs have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA. These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation.

  17. Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

    Science.gov (United States)

    Shono, Akemi; Yoshida, Makiko; Yamana, Keiji; Thwin, Khin Kyae Mon; Kuroda, Jumpei; Kurokawa, Daisuke; Koda, Tsubasa; Nishida, Kosuke; Ikuta, Toshihiko; Mizobuchi, Masami; Taniguchi-Ikeda, Mariko

    2017-01-01

    Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation. PMID:29138639

  18. Dissection of SAP-dependent and SAP-independent SLAM family signaling in NKT cell development and humoral immunity.

    Science.gov (United States)

    Chen, Shasha; Cai, Chenxu; Li, Zehua; Liu, Guangao; Wang, Yuande; Blonska, Marzenna; Li, Dan; Du, Juan; Lin, Xin; Yang, Meixiang; Dong, Zhongjun

    2017-02-01

    Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) mutations in X-linked lymphoproliferative disease (XLP) lead to defective NKT cell development and impaired humoral immunity. Because of the redundancy of SLAM family receptors (SFRs) and the complexity of SAP actions, how SFRs and SAP mediate these processes remains elusive. Here, we examined NKT cell development and humoral immunity in mice completely deficient in SFR. We found that SFR deficiency severely impaired NKT cell development. In contrast to SAP deficiency, SFR deficiency caused no apparent defect in follicular helper T (T FH ) cell differentiation. Intriguingly, the deletion of SFRs completely rescued the severe defect in T FH cell generation caused by SAP deficiency, whereas SFR deletion had a minimal effect on the defective NKT cell development in SAP-deficient mice. These findings suggest that SAP-dependent activating SFR signaling is essential for NKT cell selection; however, SFR signaling is inhibitory in SAP-deficient T FH cells. Thus, our current study revises our understanding of the mechanisms underlying T cell defects in patients with XLP. © 2017 Chen et al.

  19. Maximum magnitude in bias-dependent spin accumulation signals of CoFe/MgO/Si on insulator devices

    International Nuclear Information System (INIS)

    Ishikawa, M.; Sugiyama, H.; Inokuchi, T.; Tanamoto, T.; Saito, Y.; Hamaya, K.; Tezuka, N.

    2013-01-01

    We study in detail how the bias voltage (V bias ) and interface resistance (RA) depend on the magnitude of spin accumulation signals (|ΔV| or |ΔV|/I, where I is current) as detected by three-terminal Hanle measurements in CoFe/MgO/Si on insulator (SOI) devices with various MgO layer thicknesses and SOI carrier densities. We find the apparent maximum magnitude of spin polarization as a function of V bias and the correlation between the magnitude of spin accumulation signals and the shape of differential conductance (dI/dV) curves within the framework of the standard spin diffusion model. All of the experimental results can be explained by taking into account the density of states (DOS) in CoFe under the influence of the applied V bias and the quality of MgO tunnel barrier. These results indicate that it is important to consider the DOS of the ferromagnetic materials under the influence of an applied V bias and the quality of tunnel barrier when observing large spin accumulation signals in Si

  20. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling

    Directory of Open Access Journals (Sweden)

    Elizabeth Allen

    2016-05-01

    Full Text Available Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.

  1. Modulation of adhesion-dependent cAMP signaling by echistatin and alendronate

    Science.gov (United States)

    Fong, J. H.; Ingber, D. E.

    1996-01-01

    We measured intracellular cAMP levels in cells during attachment and spreading on different extracellular matrix (ECM) proteins. Increases in cAMP were observed within minutes when cells attached to fibronectin, vitronectin, and a synthetic RGD-containing fibronectin peptide (Petite 2000), but not when they adhered to another integrin alpha nu beta 3 ligand, echistatin. Because echistatin also inhibits bone resorption, we measured the effects of adding another osteoporosis inhibitor, alendronate, in this system. Alendronate inhibited the cAMP increase induced by ligands that primarily utilize integrin alpha nu beta 3 (vitronectin, Peptite 2000), but not by fibronectin which can also use integrin alpha 5 beta 1. These results show that cell adhesion to ECM can increase intracellular cAPM levels and raise the possibility that inhibitors of osteoporosis may act, in part, by preventing activation of this pathway by integrins.

  2. Mono-(2-ethylhexyl)-phthalate (MEHP) affects ERK-dependent GDNF signalling in mouse stem-progenitor spermatogonia

    International Nuclear Information System (INIS)

    Lucas, Benjamin E.G.; Fields, Christopher; Joshi, Neeraj; Hofmann, Marie-Claude

    2012-01-01

    Highlights: ► MEHP affects SSC proliferation in a dose- and time-dependent manner. ► MEHP does not increase apoptosis, necrosis or the production of ROS in SSCs. ► MEHP reduces the activity of the GDNF/ERK1/2/FOS signalling pathway in SSCs. ► MEHP does not affect the GDNF/SRC/MYCN signalling pathway in SSCs. -- Abstract: Many commercial and household products such as lubricants, cosmetics, plastics, and paint contain phthalates, in particular bis-(2-ethyhexyl)-phthalate (DEHP). As a consequence, phthalates have been found in a number of locations and foods (streambeds, household dust, bottled water and dairy products). Epidemiological and animal studies analysing phthalate exposure in males provide evidence of degradation in sperm quality, associated to an increase in the incidence of genital birth defects and testicular cancers. In the testis, spermatogenesis is maintained throughout life by a small number of spermatogonial stem cells (SSCs) that self-renew or differentiate to produce adequate numbers of spermatozoa. Disruption or alteration of SSC self-renewal induce decreased sperm count and sperm quality, or may potentially lead to testicular cancer. GDNF, or glial cell-line-derived neurotrophic factor, is a growth factor that is essential for the self-renewal of SSCs and continuous spermatogenesis. In the present study, the SSC-derived cell line C18-4 was used as a model for preliminary assessment of the effects of mono-(2-ethylhexyl)-phthalate (MEHP, main metabolite of DEHP) on spermatogonial stem cells. Our data demonstrate that MEHP disrupts one of the known GDNF signalling pathways in these cells. MEHP induced a decrease of C18-4 cell viability in a time- and dose-dependent manner, as well as a disruption of ERK1/2 activation but not of SRC signalling. As a result, we observed a decrease of expression of the transcription factor FOS, which is downstream of the GDNF/ERK1/2 axis in these cells. Taken together, our data suggest that MEHP exposure

  3. Population-Level Density Dependence Influences the Origin and Maintenance of Parental Care.

    Directory of Open Access Journals (Sweden)

    Elijah Reyes

    Full Text Available Parental care is a defining feature of animal breeding systems. We now know that both basic life-history characteristics and ecological factors influence the evolution of care. However, relatively little is known about how these factors interact to influence the origin and maintenance of care. Here, we expand upon previous work and explore the relationship between basic life-history characteristics (stage-specific rates of mortality and maturation and the fitness benefits associated with the origin and the maintenance of parental care for two broad ecological scenarios: the scenario in which egg survival is density dependent and the case in which adult survival is density dependent. Our findings suggest that high offspring need is likely critical in driving the origin, but not the maintenance, of parental care regardless of whether density dependence acts on egg or adult survival. In general, parental care is more likely to result in greater fitness benefits when baseline adult mortality is low if 1 egg survival is density dependent or 2 adult mortality is density dependent and mutant density is relatively high. When density dependence acts on egg mortality, low rates of egg maturation and high egg densities are less likely to lead to strong fitness benefits of care. However, when density dependence acts on adult mortality, high levels of egg maturation and increasing adult densities are less likely to maintain care. Juvenile survival has relatively little, if any, effect on the origin and maintenance of egg-only care. More generally, our results suggest that the evolution of parental care will be influenced by an organism's entire life history characteristics, the stage at which density dependence acts, and whether care is originating or being maintained.

  4. Population-Level Density Dependence Influences the Origin and Maintenance of Parental Care.

    Science.gov (United States)

    Reyes, Elijah; Thrasher, Patsy; Bonsall, Michael B; Klug, Hope

    2016-01-01

    Parental care is a defining feature of animal breeding systems. We now know that both basic life-history characteristics and ecological factors influence the evolution of care. However, relatively little is known about how these factors interact to influence the origin and maintenance of care. Here, we expand upon previous work and explore the relationship between basic life-history characteristics (stage-specific rates of mortality and maturation) and the fitness benefits associated with the origin and the maintenance of parental care for two broad ecological scenarios: the scenario in which egg survival is density dependent and the case in which adult survival is density dependent. Our findings suggest that high offspring need is likely critical in driving the origin, but not the maintenance, of parental care regardless of whether density dependence acts on egg or adult survival. In general, parental care is more likely to result in greater fitness benefits when baseline adult mortality is low if 1) egg survival is density dependent or 2) adult mortality is density dependent and mutant density is relatively high. When density dependence acts on egg mortality, low rates of egg maturation and high egg densities are less likely to lead to strong fitness benefits of care. However, when density dependence acts on adult mortality, high levels of egg maturation and increasing adult densities are less likely to maintain care. Juvenile survival has relatively little, if any, effect on the origin and maintenance of egg-only care. More generally, our results suggest that the evolution of parental care will be influenced by an organism's entire life history characteristics, the stage at which density dependence acts, and whether care is originating or being maintained.

  5. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

    Science.gov (United States)

    Lim, Chae-Seok; Hoang, Elizabeth T; Viar, Kenneth E; Stornetta, Ruth L; Scott, Michael M; Zhu, J Julius

    2014-02-01

    Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

  6. Clathrin-dependent internalization, signaling, and metabolic processing of guanylyl cyclase/natriuretic peptide receptor-A.

    Science.gov (United States)

    Somanna, Naveen K; Mani, Indra; Tripathi, Satyabha; Pandey, Kailash N

    2018-04-01

    Cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP), have pivotal roles in renal hemodynamics, neuroendocrine signaling, blood pressure regulation, and cardiovascular homeostasis. Binding of ANP and BNP to the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) induces rapid internalization and trafficking of the receptor via endolysosomal compartments, with concurrent generation of cGMP. However, the mechanisms of the endocytotic processes of NPRA are not well understood. The present study, using 125 I-ANP binding assay and confocal microscopy, examined the function of dynamin in the internalization of NPRA in stably transfected human embryonic kidney-293 (HEK-293) cells. Treatment of recombinant HEK-293 cells with ANP time-dependently accelerated the internalization of receptor from the cell surface to the cell interior. However, the internalization of ligand-receptor complexes of NPRA was drastically decreased by the specific inhibitors of clathrin- and dynamin-dependent receptor internalization, almost 85% by monodansylcadaverine, 80% by chlorpromazine, and 90% by mutant dynamin, which are specific blockers of endocytic vesicle formation. Visualizing the internalization of NPRA and enhanced GFP-tagged NPRA in HEK-293 cells by confocal microscopy demonstrated the formation of endocytic vesicles after 5 min of ANP treatment; this effect was blocked by the inhibitors of clathrin and by mutant dynamin construct. Our results suggest that NPRA undergoes internalization via clathrin-mediated endocytosis as part of its normal itinerary, including trafficking, signaling, and metabolic degradation.

  7. Agonist-mediated activation of Bombyx mori diapause hormone receptor signals to extracellular signal-regulated kinases 1 and 2 through Gq-PLC-PKC-dependent cascade.

    Science.gov (United States)

    Jiang, Xue; Yang, Jingwen; Shen, Zhangfei; Chen, Yajie; Shi, Liangen; Zhou, Naiming

    2016-08-01

    Diapause is a developmental strategy adopted by insects to survive in challenging environments such as the low temperatures of a winter. This unique process is regulated by diapause hormone (DH), which is a neuropeptide hormone that induces egg diapause in Bombyx mori and is involved in terminating pupal diapause in heliothis moths. An G protein-coupled receptor from the silkworm, B. mori, has been identified as a specific cell surface receptor for DH. However, the detailed information on the DH-DHR system and its mechanism(s) involved in the induction of embryonic diapause remains unknown. Here, we combined functional assays with various specific inhibitors to elucidate the DHR-mediated signaling pathways. Upon activation by DH, B. mori DHR is coupled to the Gq protein, leading to a significant increase of intracellular Ca(2+) and cAMP response element-driven luciferase activity in an UBO-QIC, a specific Gq inhibitor, sensitive manner. B. mori DHR elicited ERK1/2 phosphorylation in a dose- and time-dependent manner in response to DH. This effect was almost completely inhibited by co-incubation with UBO-QIC and was also significantly suppressed by PLC inhibitor U73122, PKC inhibitors Gö6983 and the Ca(2+) chelator EGTA. Moreover, DHR-induced activation of ERK1/2 was significantly attenuated by treatment with the Gβγ specific inhibitors gallein and M119K and the PI3K specific inhibitor Wortmannin, but not by the Src specific inhibitor PP2. Our data also demonstrates that the EGFR-transactivation pathway is not involved in the DHR-mediated ERK1/2 phosphorylation. Future efforts are needed to clarify the role of the ERK1/2 signaling pathway in the DH-mediated induction of B. mori embryonic diapause. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. IL-27 Receptor Signalling Restricts the Formation of Pathogenic, Terminally Differentiated Th1 Cells during Malaria Infection by Repressing IL-12 Dependent Signals

    Science.gov (United States)

    Villegas-Mendez, Ana; de Souza, J. Brian; Lavelle, Seen-Wai; Gwyer Findlay, Emily; Shaw, Tovah N.; van Rooijen, Nico; Saris, Christiaan J.; Hunter, Christopher A.; Riley, Eleanor M.; Couper, Kevin N.

    2013-01-01

    The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4+ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1+) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4+ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1−/− and IL-10−/− mice and the numbers and phenotype of Foxp3+ cells were largely unaltered in WSX-1−/− mice during infection. As expected, depletion of Foxp3+ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection. PMID:23593003

  9. Quantitative simulation of intracellular signaling cascades in a Virtual Liver: estimating dose dependent changes in hepatocellular proliferation and apoptosis

    Science.gov (United States)

    The US EPA Virtual Liver (v-Liver™) is developing an approach to predict dose-dependent hepatotoxicity as an in vivo tissue level response using in vitro data. The v-Liver accomplishes this using an in silico agent-based systems model that dynamically integrates environmental exp...

  10. Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

    Science.gov (United States)

    Ferrario, Juan E.; Baskaran, Pranetha; Clark, Christopher; Hendry, Aenea; Lerner, Oleg; Hintze, Mark; Allen, James; Chilton, John K.; Guthrie, Sarah

    2012-01-01

    Eye movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human eye movement disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3–PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway. PMID:22912401

  11. Regulator of calcineurin 1 differentially regulates TLR-dependent MyD88 and TRIF signaling pathways.

    Directory of Open Access Journals (Sweden)

    Zheng Pang

    Full Text Available Toll-like receptors (TLRs recognize the conserved molecular patterns in microorganisms and trigger myeloid differentiation primary response 88 (MyD88 and/or TIR-domain-containing adapter-inducing interferon-β (TRIF pathways that are critical for host defense against microbial infection. However, the molecular mechanisms that govern TLR signaling remain incompletely understood. Regulator of calcineurin-1 (RCAN1, a small evolutionarily conserved protein that inhibits calcineurin phosphatase activity, suppresses inflammation during Pseudomonas aeruginosa infection. Here, we define the roles for RCAN1 in P. aeruginosa lipopolysaccharide (LPS-activated TLR4 signaling. We compared the effects of P. aeruginosa LPS challenge on bone marrow-derived macrophages from both wild-type and RCAN1-deficient mice and found that RCAN1 deficiency increased the MyD88-NF-κB-mediated cytokine production (IL-6, TNF and MIP-2, whereas TRIF-interferon-stimulated response elements (ISRE-mediated cytokine production (IFNβ, RANTES and IP-10 was suppressed. RCAN1 deficiency caused increased IκBα phosphorylation and NF-κB activity in the MyD88-dependent pathway, but impaired ISRE activation and reduced IRF7 expression in the TRIF-dependent pathway. Complementary studies of a mouse model of P. aeruginosa LPS-induced acute pneumonia confirmed that RCAN1-deficient mice displayed greatly enhanced NF-κB activity and MyD88-NF-κB-mediated cytokine production, which correlated with enhanced pulmonary infiltration of neutrophils. By contrast, RCAN1 deficiency had little effect on the TRIF pathway in vivo. These findings demonstrate a novel regulatory role of RCAN1 in TLR signaling, which differentially regulates MyD88 and TRIF pathways.

  12. Neuronal extracellular signal-regulated kinase (ERK activity as marker and mediator of alcohol and opioid dependence

    Directory of Open Access Journals (Sweden)

    Eva R. Zamora-Martinez

    2014-03-01

    Full Text Available Early pioneering work in the field of biochemistry identified phosphorylation as a crucial post-translational modification of proteins with the ability to both indicate and arbitrate complex physiological processes. More recent investigations have functionally linked phosphorylation of extracellular signal-regulated kinase (ERK to a variety of neurophysiological mechanisms ranging from acute neurotransmitter action to long-term gene expression. ERK phosphorylation serves as an intracellular bridging mechanism that facilitates neuronal communication and plasticity. Drugs of abuse, including alcohol and opioids, act as artificial yet powerful rewards that impinge upon natural reinforcement processes critical for survival. The graded progression from initial exposure to addiction (or substance dependence is believed to result from drug- and drug context-induced adaptations in neuronal signaling processes across brain reward and stress circuits following excessive drug use. In this regard, commonly abused drugs as well as drug-associated experiences are capable of modifying the phosphorylation of ERK within central reinforcement systems. In addition, chronic drug and alcohol exposure may drive ERK-regulated epigenetic and structural alterations that underlie a long-term propensity for escalating drug use. Under the influence of such a neurobiological vulnerability, encountering drug-associated cues and contexts can produce subsequent alterations in ERK signaling that drive relapse to drug and alcohol seeking. Current studies are determining precisely which molecular and regional ERK phosphorylation-associated events contribute to the addiction process, as well as which neuroadaptations need to be targeted in order to return dependent individuals to a healthy state.

  13. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

    Directory of Open Access Journals (Sweden)

    Zhao-Jun Liu

    Full Text Available Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM. They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox embryonic fibroblasts (MEFs. Notch1-deficient (Notch1(-/- MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1 in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441, which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1. Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4 in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

  14. Nicotine Dependence and Urinary Nicotine, Cotinine and Hydroxycotinine Levels in Daily Smokers.

    Science.gov (United States)

    Van Overmeire, Ilse P I; De Smedt, Tom; Dendale, Paul; Nackaerts, Kristiaan; Vanacker, Hilde; Vanoeteren, Jan F A; Van Laethem, Danny M G; Van Loco, Joris; De Cremer, Koen A J

    2016-09-01

    Nicotine dependence and smoking frequency are critical factors for smoking cessation. The aims of this study are (1) to determine if nicotine dependence Fagerström Test for Nicotine Dependence (FTND) scores are associated with urinary levels of nicotine metabolites, (2) to assess the relationship of hydroxycotinine/cotinine ratio with FTND score and cigarettes smoked per day (CPD), and (3) to identify significant predictors of cigarettes per day among biomarker concentrations and individual FTND items. Urine samples and questionnaire data of 239 daily smokers were obtained. Nicotine, cotinine and hydroxycotinine urinary levels were determined by UPLC MS/MS.Multiple linear regression models were developed to explore the relationship between nicotine, cotinine, hydroxycotinine levels and separate FTND scores (for all six items). We found significant correlations between the different urinary biomarker concentrations, and the FTND score. The time before the first cigarette after waking (TTFC) was significantly associated with the nicotine, cotinine and hydroxycotinine concentrations. No association was found between the ratio of hydroxycotinine to cotinine and either the FTND or the CPD. A model including four FTND questions, sex, age, and the cotinine concentration, accounted for 45% of the variance of CPD. There are significant relationships between urinary levels of nicotine, cotinine, and hydroxycotinine and the FTND score. Especially the FTND question about TTFC is relevant for explaining the biomarker concentrations. CPD (below 15) was significantly explained by four FTND dependence items and urinary cotinine levels in a regression model. We investigated associations between urinary levels of nicotine, cotinine, and hydroxycotinine in daily smokers and the FTND scores for nicotine dependence. We did not find association between the hydroxycotinine/cotinine ratio and CPD. We developed a model that explains the cigarettes smoked daily (CPD) in a group of light

  15. Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1-Independent Manners in Mouse Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    Jan Kučera

    2017-01-01

    Full Text Available Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1 is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES cell maintenance. We employed wild-type and HIF-1α-deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1-independent manner, while STAT3 phosphorylation remained unaffected. Downregulation of ERK could not be mimicked either by pharmacologically induced hypoxia or by the overexpression. Dual-specificity phosphatases (DUSP 1, 5, and 6 are hypoxia-sensitive MAPK-specific phosphatases involved in ERK downregulation, and protein phosphatase 2A (PP2A regulates both ERK and Akt. However, combining multiple approaches, we revealed the limited significance of DUSPs and PP2A in the hypoxia-mediated attenuation of ERK signaling. Interestingly, we observed a decreased reactive oxygen species (ROS level in hypoxia and a similar phosphorylation pattern for ERK when the cells were supplemented with glutathione. Therefore, we suggest a potential role for the ROS-dependent attenuation of ERK signaling in hypoxia, without the involvement of HIF-1.

  16. Carbon Monoxide Protects against Hepatic Ischemia/Reperfusion Injury via ROS-Dependent Akt Signaling and Inhibition of Glycogen Synthase Kinase 3β

    Directory of Open Access Journals (Sweden)

    Hyo Jeong Kim

    2013-01-01

    Full Text Available Carbon monoxide (CO may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3 and phosphatidylinositol 3-kinase (PI3K-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  17. Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.

    Science.gov (United States)

    Kim, Hyo Jeong; Joe, Yeonsoo; Kong, Jin Sun; Jeong, Sun-Oh; Cho, Gyeong Jae; Ryter, Stefan W; Chung, Hun Taeg

    2013-01-01

    Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

  18. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Fang, E-mail: fhua2@emory.edu [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States); Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G. [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States)

    2009-12-18

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.

  19. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

    International Nuclear Information System (INIS)

    Hua, Fang; Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G.

    2009-01-01

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-κB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-κB signaling and brain injury after acute cerebral I/R.

  20. Iron-dependent regulation of hepcidin in Hjv-/- mice: evidence that hemojuvelin is dispensable for sensing body iron levels.

    Directory of Open Access Journals (Sweden)

    Konstantinos Gkouvatsos

    Full Text Available Hemojuvelin (Hjv is a bone morphogenetic protein (BMP co-receptor involved in the control of systemic iron homeostasis. Functional inactivation of Hjv leads to severe iron overload in humans and mice due to marked suppression of the iron-regulatory hormone hepcidin. To investigate the role of Hjv in body iron sensing, Hjv-/- mice and isogenic wild type controls were placed on a moderately low, a standard or a high iron diet for four weeks. Hjv-/- mice developed systemic iron overload under all regimens. Transferrin (Tf was highly saturated regardless of the dietary iron content, while liver iron deposition was proportional to it. Hepcidin mRNA expression responded to fluctuations in dietary iron intake, despite the absence of Hjv. Nevertheless, iron-dependent upregulation of hepcidin was more than an order of magnitude lower compared to that seen in wild type controls. Likewise, iron signaling via the BMP/Smad pathway was preserved but substantially attenuated. These findings suggest that Hjv is not required for sensing of body iron levels and merely functions as an enhancer for iron signaling to hepcidin.

  1. Peripheral Signals of Food Intake in Response to Low Leptin Levels Induced by Centrifugation

    Science.gov (United States)

    Moran, M. M.; Wade, Charles E.; Stein, T. P.; Dalton, Bonnie P. (Technical Monitor)

    2001-01-01

    The focus of the study was to examine leptin and other peripheral signals of energy balance, following hypergravity. The study was conducted in two experiments. In experiment 1 rats were centrifuged at either 1.5, 2, or remained at 1 G. During days 8 to 14 of experiment 1, mean body mass of the 1.5 and 2 G groups was significantly (p<0.05) lower than controls. No differences were found in food intake (g/day/100 g body mass). Epididymal fat in the 2 G group was 21% lower than controls and 14% lower than the 1.5 G group. Plasma leptin was reduced from controls in the 1.5 and 2 G groups by 45 and 63%, respectively. A significant correlation was found between G load and urinary catecholamines. In experiment 2, rats were centrifuged at either 1.25, 1.5, or remained at 1 G. During days 8 to 14, body mass and food intake were similar between the 1, 1.25, and 1.5 G groups. Epididymal fat was reduced from controls in the 1.25 (14%) and 1.5 (19%) G groups. Leptin was reduced from controls in the 1.25 (45%) and 1.5 (46%) G groups. No differences were found in urinary epinephrine. Urinary norepinephrine levels were significantly higher than controls in each centrifuge group. During hypergravity exposure, food intake is the result of a complex relationship between multiple pathways, which abates the importance of leptin as a primary signal.

  2. Multi-Level Simulated Fault Injection for Data Dependent Reliability Analysis of RTL Circuit Descriptions

    Directory of Open Access Journals (Sweden)

    NIMARA, S.

    2016-02-01

    Full Text Available This paper proposes data-dependent reliability evaluation methodology for digital systems described at Register Transfer Level (RTL. It uses a hybrid hierarchical approach, combining the accuracy provided by Gate Level (GL Simulated Fault Injection (SFI and the low simulation overhead required by RTL fault injection. The methodology comprises the following steps: the correct simulation of the RTL system, according to a set of input vectors, hierarchical decomposition of the system into basic RTL blocks, logic synthesis of basic RTL blocks, data-dependent SFI for the GL netlists, and RTL SFI. The proposed methodology has been validated in terms of accuracy on a medium sized circuit – the parallel comparator used in Check Node Unit (CNU of the Low-Density Parity-Check (LDPC decoders. The methodology has been applied for the reliability analysis of a 128-bit Advanced Encryption Standard (AES crypto-core, for which the GL simulation was prohibitive in terms of required computational resources.

  3. DIFFERENCES REGARDING SELF-ESTEEM AND THE COMMUNICATION STYLE DEPENDING ON THE LEVEL OF EDUCATION

    Directory of Open Access Journals (Sweden)

    Georgeta PÂNIȘOARĂ

    2015-12-01

    Full Text Available The present paper aims to study the differences in self-esteem and the communication style, depending on the level of education (at high school and university subjects. It is analyzed also how the positive self-esteem can correlate with a style of communication and assertively-positive approach. The participants are 120 subjects, 60 high school students and 60 students. The data was collected using two instruments: the Rosenberg questionnaire and a questionnaire on communication style. The data analyzed using a t test for independent samples and a Pearson correlation test with SPSS statistical software. The results show that there are differences regarding the self-esteem and the communication style depending on the level of education.

  4. Elevated carbon dioxide blunts mammalian cAMP signaling dependent on inositol 1,4,5-triphosphate receptor-mediated Ca2+ release.

    Science.gov (United States)

    Cook, Zara C; Gray, Michael A; Cann, Martin J

    2012-07-27

    Elevated CO(2) is generally detrimental to animal cells, suggesting an interaction with core processes in cell biology. We demonstrate that elevated CO(2) blunts G protein-activated cAMP signaling. The effect of CO(2) is independent of changes in intracellular and extracellular pH, independent of the mechanism used to activate the cAMP signaling pathway, and is independent of cell context. A combination of pharmacological and genetic tools demonstrated that the effect of elevated CO(2) on cAMP levels required the activity of the IP(3) receptor. Consistent with these findings, CO(2) caused an increase in steady state cytoplasmic Ca(2+) concentrations not observed in the absence of the IP(3) receptor or under nonspecific acidotic conditions. We examined the well characterized cAMP-dependent inhibition of the isoform 3 Na(+)/H(+) antiporter (NHE3) to demonstrate a functional relevance for CO(2)-mediated reductions in cellular cAMP. Consistent with the cellular biochemistry, elevated CO(2) abrogated the inhibitory effect of cAMP on NHE3 function via an IP(3) receptor-dependent mechanism.

  5. Elevated Carbon Dioxide Blunts Mammalian cAMP Signaling Dependent on Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Release*

    Science.gov (United States)

    Cook, Zara C.; Gray, Michael A.; Cann, Martin J.

    2012-01-01

    Elevated CO2 is generally detrimental to animal cells, suggesting an interaction with core processes in cell biology. We demonstrate that elevated CO2 blunts G protein-activated cAMP signaling. The effect of CO2 is independent of changes in intracellular and extracellular pH, independent of the mechanism used to activate the cAMP signaling pathway, and is independent of cell context. A combination of pharmacological and genetic tools demonstrated that the effect of elevated CO2 on cAMP levels required the activity of the IP3 receptor. Consistent with these findings, CO2 caused an increase in steady state cytoplasmic Ca2+ concentrations not observed in the absence of the IP3 receptor or under nonspecific acidotic conditions. We examined the well characterized cAMP-dependent inhibition of the isoform 3 Na+/H+ antiporter (NHE3) to demonstrate a functional relevance for CO2-mediated reductions in cellular cAMP. Consistent with the cellular biochemistry, elevated CO2 abrogated the inhibitory effect of cAMP on NHE3 function via an IP3 receptor-dependent mechanism. PMID:22654111

  6. Integrative curriculum reform, domain dependent knowing, and teachers` epistemological theories: Implications for middle-level teaching

    Energy Technology Data Exchange (ETDEWEB)

    Powell, R.R. [Texas Tech Univ., Lubbock, TX (United States). College of Education

    1998-12-01

    Integrative curriculum as both a theoretical construct and a practical reality, and as a theme-based, problem-centered, democratic way of schooling, is becoming more widely considered as a feasible alternative to traditional middle-level curricula. Importantly for teaching and learning, domain dependence requires teachers to view one area of knowledge as fully interdependent with other areas of knowledge during the learning process. This requires teachers to adopt personal epistemological theories that reflect integrative, domain dependent knowing. This study explored what happened when teachers from highly traditional domain independent school settings encountered an ambitious college-level curriculum project that was designed to help the teachers understand the potential that integrative, domain dependent teaching holds for precollege settings. This study asked: What influence does an integrative, domain dependent curriculum project have on teachers` domain independent, epistemological theories for teaching and learning? Finding an answer to this question is essential if we, as an educational community, are to understand how integrative curriculum theory is transformed by teachers into systemic curriculum reform. The results suggest that the integrative curriculum project that teachers participated in did not explicitly alter their classroom practices in a wholesale manner. Personal epistemological theories of teachers collectively precluded teachers from making any wholesale changes in their individual classroom teaching. However, teachers became aware of integrative curriculum as an alternative, and they expressed interest in infusing integrative practices into their classrooms as opportunities arise.

  7. NAD+-Dependent Deacetylase Hst1p Controls Biosynthesis and Cellular NAD+ Levels in Saccharomyces cerevisiae

    OpenAIRE

    Bedalov, Antonio; Hirao, Maki; Posakony, Jeffrey; Nelson, Melisa; Simon, Julian A.

    2003-01-01

    Nicotine adenine dinucleotide (NAD+) performs key roles in electron transport reactions, as a substrate for poly(ADP-ribose) polymerase and NAD+-dependent protein deacetylases. In the latter two processes, NAD+ is consumed and converted to ADP-ribose and nicotinamide. NAD+ levels can be maintained by regeneration of NAD+ from nicotinamide via a salvage pathway or by de novo synthesis of NAD+ from tryptophan. Both pathways are conserved from yeast to humans. We describe a critical role of the ...

  8. Association between tobacco industry denormalization beliefs, tobacco control community discontent and smokers' level of nicotine dependence.

    Science.gov (United States)

    Kushnir, Vladyslav; Selby, Peter; Cunningham, John A

    2013-07-01

    Tobacco industry denormalization (TID) informs the public about the tobacco industry's role in the tobacco epidemic and is an important component of a comprehensive tobacco control strategy. Although TID beliefs have been noted in adult smokers and associated with intent to quit, research has not evaluated whether they are affected by smokers' level of nicotine dependence. The present article sought to concurrently examine how attitudes towards the tobacco industry and tobacco control groups may differ among smokers of varying levels of nicotine dependence. In addition, it evaluated how these attitudes and beliefs may be associated with smokers' intentions to reduce or quit smoking. A random digit dialing telephone survey was conducted of 889 Canadian current daily smokers, 18 years and older. Attitudes towards the tobacco industry were mixed among the entire cohort and differences in beliefs towards the tobacco industry were not found among smokers of varying levels of nicotine dependence. However, smokers that held strong TID beliefs were 5 times more intent to quit smoking than those without such beliefs. Compared to smokers with low level of nicotine dependence, heavy smokers were more likely to report strong overall displeasure with the tobacco control community (OR=1.98, 95% CI=1.23-3.19, p=0.005), however there were no differences with regards to future intent to quit. The absence of strong negative sentiment toward the tobacco industry among smokers as a whole suggests that more targeted anti-industry messages are needed, raising greater awareness of tobacco industry practices within smokers and non-smokers alike. As heavier smokers' discontent with the tobacco control community highlights increasing social disapproval and pressure to quit smoking, future educational and media strategies used for smoking cessation purposes may benefit from emphasizing more of the positive attributes associated with quitting smoking, as opposed to the negative features of

  9. Neurophysiological model of tinnitus: dependence of the minimal masking level on treatment outcome.

    Science.gov (United States)

    Jastreboff, P J; Hazell, J W; Graham, R L

    1994-11-01

    Validity of the neurophysiological model of tinnitus (Jastreboff, 1990), outlined in this paper, was tested on data from multicenter trial of tinnitus masking (Hazell et al., 1985). Minimal masking level, intensity match of tinnitus, and the threshold of hearing have been evaluated on a total of 382 patients before and after 6 months of treatment with maskers, hearing aids, or combination devices. The data has been divided into categories depending on treatment outcome and type of approach used. Results of analysis revealed that: i) the psychoacoustical description of tinnitus does not possess a predictive value for the outcome of the treatment; ii) minimal masking level changed significantly depending on the treatment outcome, decreasing on average by 5.3 dB in patients reporting improvement, and increasing by 4.9 dB in those whose tinnitus remained the same or worsened; iii) 73.9% of patients reporting improvement had their minimal masking level decreased as compared with 50.5% for patients not showing improvement, which is at the level of random change; iv) the type of device used has no significant impact on the treatment outcome and minimal masking level change; v) intensity match and threshold of hearing did not exhibit any significant changes which can be related to treatment outcome. These results are fully consistent with the neurophysiological interpretation of mechanisms involved in the phenomenon of tinnitus and its alleviation.

  10. Power law scaling in synchronization of brain signals depends on cognitive load

    Directory of Open Access Journals (Sweden)

    Jose Luis ePerez Velazquez

    2014-05-01

    Full Text Available As it has several features that optimize information processing, it has been proposed that criticality governs the dynamics of nervous system activity. Indications of such dynamics have been reported for a variety of in vitro and in vivo recordings, ranging from in vitro slice electrophysiology to human functional magnetic resonance imaging. However, there still remains considerable debate as to whether the brain actually operates close to criticality or in another governing state such as stochastic or oscillatory dynamics. A tool used to investigate the criticality of nervous system data is the inspection of power-law distributions. Although the findings are controversial, such power-law scaling has been found in different types of recordings. Here, we studied whether there is a power law scaling in the distribution of the phase synchronization derived from magnetoencephalographic recordings during executive function tasks performed by children with and without autism. Characterizing the brain dynamics that is different between autistic and non-autistic individuals is important in order to find differences that could either aid diagnosis or provide insights as to possible therapeutic interventions in autism. We report in this study that power law scaling in the distributions of a phase synchrony index is not very common and its frequency of occurrence is similar in the control and the autism group. In addition, power law scaling tends to diminish with increased cognitive load (difficulty or engagement in the task. There were indications of changes in the probability distribution functions for the phase synchrony that were associated with a transition from power law scaling to lack of power law (or vice versa, which suggests the presence of phenomenological bifurcations in brain dynamics associated with cognitive load. Hence, brain dynamics may fluctuate between criticality and other regimes depending upon context and behaviours.

  11. Phytochrome-dependent coordinate control of distinct aspects of nuclear and plastid gene expression during anterograde signalling and photomorphogenesis

    Directory of Open Access Journals (Sweden)

    Sookyung eOh

    2014-04-01

    Full Text Available Light perception by photoreceptors impacts plastid transcription, development, and differentiation. This photoreceptor-dependent activity suggests a mechanism for photoregulation of gene expression in the nucleus and plastid that serves to coordinate expression of critical genes of these two organelles. This coordinate expression is required for proper stoichiometric accumulation of components needed for assembly of plastids, photosynthetic light-harvesting complexes and components such as phytochromes. Chloroplast-targeted sigma factors, which function together with the plastid-encoded RNA polymerase to regulate expression of plastid-encoded genes, and nuclear-encoded plastid development factors, such as GLK1 and GLK2, are targets of phytochrome regulation. Such phytochrome-dependent functions are hypothesized to allow light-dependent regulation, and feasibly tuning, of plastid components and function in response to changes in the external environment, which directly affects photosynthesis and the potential for light-induced damage. When the size and protein composition of the light-harvesting complexes are not tuned to the external environment, imbalances in electron transport can impact the cellular redox state and cause cellular damage. We show that phytochromes specifically regulate the expression of multiple factors that function to modulate plastid transcription and, thus, provide a paradigm for coordinate expression of the nuclear and plastid genomes in response to changes in external light conditions. As phytochromes respond to changes in the prevalent wavelengths of light and light intensity, we propose that specific phytochrome-dependent molecular mechanisms are used during light-dependent signaling between the nucleus and chloroplast during photomorphogenesis to coordinate chloroplast development with plant developmental stage and the external environment.

  12. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    He, Miao, E-mail: hemiao@mail.cmu.edu.cn [Environment and Non-communicable Disease Research Center, School of Public Health, China Medical University, Shenyang 110122 (China); Ichinose, Takamichi, E-mail: ichinose@oita-nhs.ac.jp [Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita 870-1201 (Japan); Song, Yuan; Yoshida, Yasuhiro [Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Fukuoka 807-8555 (Japan); Bekki, Kanae [Department of Environmental Health, National Institute of Public Health, Saitama 351-0197 (Japan); Arashidani, Keiichi [Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Fukuoka 807-8555 (Japan); Yoshida, Seiichi [Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita 870-1201 (Japan); Nishikawa, Masataka [Environmental Chemistry Division, National Institute for Environmental Studies, Ibaraki 305-8506 (Japan); Takano, Hirohisa [Environmental Health Division, Department of Environmental Engineering, Graduate School of Engineering, Kyoto University, Kyoto 615-8530 (Japan); Shibamoto, Takayuki [Department of Environmental Toxicology, University of California, Davis, CA 95616, USA. (United States); Sun, Guifan [Environment and Non-communicable Disease Research Center, School of Public Health, China Medical University, Shenyang 110122 (China)

    2016-04-01

    Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2{sup −/−}, TLR4{sup −/−}, and MyD88{sup −/−} BALB/c mice and BMDMs from WT, TLR2{sup −/−}, TLR4{sup −/−}, TLR2/4{sup −/−}, TLR7/9{sup −/−}, and MyD88{sup −/−} C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2{sup −/−} cells than in TLR4{sup −/−} cells, whereas it was lower or undetectable in TLR2/4{sup −/−} and MyD88{sup −/−} cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2{sup −/−}, 4{sup −/−}, and MyD88{sup −/−} BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2{sup −/−}, 4{sup −/−} mice, but not in MyD88{sup −/−} mice. The Th2 responses in TLR2{sup −/−} mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like β-glucan may be strong candidates for exacerbation of lung eosinophilia. - Highlights: • ASD enhanced Th2 response in TLR2{sup −/−}, TLR4{sup −/−} and WT mice, but not in MyD88{sup −/−}. • Th2 responses in TLR2{sup −/−} mice were attenuated by LPS inhibitor polymyxin B. • TLR2

  13. Desert dust induces TLR signaling to trigger Th2-dominant lung allergic inflammation via a MyD88-dependent signaling pathway

    International Nuclear Information System (INIS)

    He, Miao; Ichinose, Takamichi; Song, Yuan; Yoshida, Yasuhiro; Bekki, Kanae; Arashidani, Keiichi; Yoshida, Seiichi; Nishikawa, Masataka; Takano, Hirohisa; Shibamoto, Takayuki; Sun, Guifan

    2016-01-01

    Asian sand dust (ASD) is known to exacerbate asthma, although its mechanism is not yet well understood. In this study, when the effects on inflammatory response by LPS present in ASD was investigated by measuring the gene expression of cytokines and chemokines in RAW264.7 cells treated with ASD and/or polymyxin B (PMB), the ASD effects were attenuated by PMB, but not completely. When an in vitro study was performed using bone marrow-derived macrophages (BMDMs) from WT, TLR2 −/− , TLR4 −/− , and MyD88 −/− BALB/c mice and BMDMs from WT, TLR2 −/− , TLR4 −/− , TLR2/4 −/− , TLR7/9 −/− , and MyD88 −/− C57BL/6J mice, cytokine (IL-6, IL-12) production in BMDMs was higher in ASD-stimulated TLR2 −/− cells than in TLR4 −/− cells, whereas it was lower or undetectable in TLR2/4 −/− and MyD88 −/− cells. These results suggest that ASD causes cytokine production predominantly in a TLR4/MyD88-dependent pathway. When WT and TLRs 2 −/− , 4 −/− , and MyD88 −/− BALB/c mice were intratracheally challenged with OVA and/or ASD, ASD caused exacerbation of lung eosinophilia along with Th2 cytokine and eosinophil-relevant chemokine production. Serum OVA-specific IgE and IgG1 similar to WT was observed in TLRs 2 −/− , 4 −/− mice, but not in MyD88 −/− mice. The Th2 responses in TLR2 −/− mice were attenuated remarkably by PMB. These results indicate that ASD exacerbates lung eosinophilia in a MyD88-dependent pathway. TLRs 2 and 4 signaling may be important in the increase in lung eosinophilia. Also, the TLR4 ligand LPS and TLR2 ligand like β-glucan may be strong candidates for exacerbation of lung eosinophilia. - Highlights: • ASD enhanced Th2 response in TLR2 −/− , TLR4 −/− and WT mice, but not in MyD88 −/− . • Th2 responses in TLR2 −/− mice were attenuated by LPS inhibitor polymyxin B. • TLR2 and TLR4 signaling is important in allergic lung disease aggravation by ASD. • MyD88 is the key

  14. Control of density-dependent, cell state-specific signal transduction by the cell adhesion molecule CEACAM1, and its influence on cell cycle regulation

    International Nuclear Information System (INIS)

    Scheffrahn, Inka; Singer, Bernhard B.; Sigmundsson, Kristmundur; Lucka, Lothar; Oebrink, Bjoern

    2005-01-01

    Growth factor receptors, extracellular matrix receptors, and cell-cell adhesion molecules co-operate in regulating the activities of intracellular signaling pathways. Here, we demonstrate that the cell adhesion molecule CEACAM1 co-regulates growth-factor-induced DNA synthesis in NBT-II epithelial cells in a cell-density-dependent manner. CEACAM1 exerted its effects by regulating the activity of the Erk 1/2 MAP kinase pathway and the expression levels of the cyclin-dependent kinase inhibitor p27 Kip1 . Interestingly, both inhibitory and stimulatory effects were observed. Confluent cells continuously exposed to fetal calf serum showed little Erk activity and DNA synthesis compared with sparse cells. Under these conditions, anti-CEACAM1 antibodies strongly stimulated Erk activation, decreased p27 expression, and induced DNA synthesis. In serum-starved confluent cells, re-addition of 10% fetal calf serum activated the Erk pathway, decreased p27 expression, and stimulated DNA synthesis to the same levels as in sparse cells. Under these conditions anti-CEACAM1 antibodies de-activated Erk, restored the level of p27, and inhibited DNA synthesis. These data indicate that CEACAM1 mediates contact inhibition of proliferation in cells that are constantly exposed to growth factors, but co-activates growth-factor-induced proliferation in cells that have been starved for growth factors; exposure to extracellular CEACAM1 ligands reverts these responses

  15. Study of time dependence and spectral composition of the signal in circuit of ac electric point motors

    Directory of Open Access Journals (Sweden)

    S. Yu. Buryak

    2014-12-01

    Full Text Available Purpose. The paper is aimed to establish the dependence of changes in the time domain and spectral components of the current in the circuit of the AC electric point motor on its technical condition, to identify the common features for the same type of damage. It is necessary using the analysis of the received signals to carry out the remote diagnosis and determination of faults and defects of electric point motors. In addition it suggested to accelerate the process of the failure, malfunction and damage search. Authors propose the automated approach to the service of remote floor automation equipment, which is located in the envelope of trains. Reduction of the threat to life and health of staff by reducing the residence time in the zone of train movement. Reduce the impact of human factors on the result of service. Methodology. The paper studies the structure, parameters and characteristics, the operation and maintenance characteristics of the AC electric point motors. Determination of the main types of possible faults in the process depending on the operating conditions. Presentation of the electric motor as an object of diagnosis. Findings. The time dependences of the current in the circuit of electric point motor for its various states was obtained. The connection between the technical condition of electric point motor and the performance of current curve in time and spectral domains was established. The revealed deviations from the reference signal were justified. According to the obtained results it was made the conclusion. Originality. A method for diagnosing the state of the AC electric point motor by the time dependence and the spectral composition of the current in its circuit was proposed. The connection diagram to the motor windings based on non-infringement of electric parameters of connection circuit in the actual operating conditions was applied. Practical value. The obtained results suggest the possibility and feasibility of

  16. GATA-Dependent Glutaminolysis Drives Appressorium Formation in Magnaporthe oryzae by Suppressing TOR Inhibition of cAMP/PKA Signaling.

    Science.gov (United States)

    Marroquin-Guzman, Margarita; Wilson, Richard A

    2015-04-01

    Fungal plant pathogens are persistent and global food security threats. To invade their hosts they often form highly specialized infection structures, known as appressoria. The cAMP/ PKA- and MAP kinase-signaling cascades have been functionally delineated as positive-acting pathways required for appressorium development. Negative-acting regulatory pathways that block appressorial development are not known. Here, we present the first detailed evidence that the conserved Target of Rapamycin (TOR) signaling pathway is a powerful inhibitor of appressorium formation by the rice blast fungus Magnaporthe oryzae. We determined TOR signaling was activated in an M. oryzae mutant strain lacking a functional copy of the GATA transcription factor-encoding gene ASD4. Δasd4 mutant strains could not form appressoria and expressed GLN1, a glutamine synthetase-encoding orthologue silenced in wild type. Inappropriate expression of GLN1 increased the intracellular steady-state levels of glutamine in Δasd4 mutant strains during axenic growth when compared to wild type. Deleting GLN1 lowered glutamine levels and promoted appressorium formation by Δasd4 strains. Furthermore, glutamine is an agonist of TOR. Treating Δasd4 mutant strains with the specific TOR kinase inhibitor rapamycin restored appressorium development. Rapamycin was also shown to induce appressorium formation by wild type and Δcpka mutant strains on non-inductive hydrophilic surfaces but had no effect on the MAP kinase mutant Δpmk1. When taken together, we implicate Asd4 in regulating intracellular glutamine levels in order to modulate TOR inhibition of appressorium formation downstream of cPKA. This study thus provides novel insight into the metabolic mechanisms that underpin the highly regulated process of appressorium development.

  17. GATA-Dependent Glutaminolysis Drives Appressorium Formation in Magnaporthe oryzae by Suppressing TOR Inhibition of cAMP/PKA Signaling.

    Directory of Open Access Journals (Sweden)

    Margarita Marroquin-Guzman

    2015-04-01

    Full Text Available Fungal plant pathogens are persistent and global food security threats. To invade their hosts they often form highly specialized infection structures, known as appressoria. The cAMP/ PKA- and MAP kinase-signaling cascades have been functionally delineated as positive-acting pathways required for appressorium development. Negative-acting regulatory pathways that block appressorial development are not known. Here, we present the first detailed evidence that the conserved Target of Rapamycin (TOR signaling pathway is a powerful inhibitor of appressorium formation by the rice blast fungus Magnaporthe oryzae. We determined TOR signaling was activated in an M. oryzae mutant strain lacking a functional copy of the GATA transcription factor-encoding gene ASD4. Δasd4 mutant strains could not form appressoria and expressed GLN1, a glutamine synthetase-encoding orthologue silenced in wild type. Inappropriate expression of GLN1 increased the intracellular steady-state levels of glutamine in Δasd4 mutant strains during axenic growth when compared to wild type. Deleting GLN1 lowered glutamine levels and promoted appressorium formation by Δasd4 strains. Furthermore, glutamine is an agonist of TOR. Treating Δasd4 mutant strains with the specific TOR kinase inhibitor rapamycin restored appressorium development. Rapamycin was also shown to induce appressorium formation by wild type and Δcpka mutant strains on non-inductive hydrophilic surfaces but had no effect on the MAP kinase mutant Δpmk1. When taken together, we implicate Asd4 in regulating intracellular glutamine levels in order to modulate TOR inhibition of appressorium formation downstream of cPKA. This study thus provides novel insight into the metabolic mechanisms that underpin the highly regulated process of appressorium development.

  18. GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Aβ production

    Science.gov (United States)

    Toh, Wei Hong; Chia, Pei Zhi Cheryl; Hossain, Mohammed Iqbal; Gleeson, Paul A.

    2018-01-01

    The diversion of the membrane-bound β-site amyloid precursor protein–(APP) cleaving enzyme (BACE1) from the endolysosomal pathway to recycling endosomes represents an important transport step in the regulation of amyloid beta (Aβ) production. However, the mechanisms that regulate endosome sorting of BACE1 are poorly understood. Here we assessed the transport of BACE1 from early to recycling endosomes and have identified essential roles for the sorting nexin 4 (SNX4)-mediated, signal-independent pathway and for a novel signal-mediated pathway. The signal-mediated pathway is regulated by the phosphorylation of the DXXLL-motif sequence DISLL in the cytoplasmic tail of BACE1. The phosphomimetic S498D BACE1 mutant was trafficked to recycling endosomes at a faster rate compared with wild-type BACE1 or the nonphosphorylatable S498A mutant. The rapid transit of BACE1 S498D from early endosomes was coupled with reduced levels of amyloid precursor protein processing and Aβ production, compared with the S498A mutant. We show that the adaptor, GGA1, and retromer are essential to mediate rapid trafficking of phosphorylated BACE1 to recycling endosomes. In addition, the BACE1 DISLL motif is phosphorylated and regulates endosomal trafficking, in primary neurons. Therefore, post-translational phosphorylation of DISLL enhances the exit of BACE1 from early endosomes, a pathway mediated by GGA1 and retromer, which is important in regulating Aβ production. PMID:29142073

  19. Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Eun-Mi Noh

    2016-01-01

    Full Text Available Reactive oxygen species (ROS play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3 metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.

  20. Effects of Varying Gravity Levels on fNIRS Headgear Performance and Signal Recovery

    Science.gov (United States)

    Mackey, Jeffrey R.; Harrivel, Angela R.; Adamovsky, Grigory; Lewandowski, Beth E.; Gotti, Daniel J.; Tin, Padetha; Floyd, Bertram M.

    2013-01-01

    This paper reviews the effects of varying gravitational levels on functional Near-Infrared Spectroscopy (fNIRS) headgear. The fNIRS systems quantify neural activations in the cortex by measuring hemoglobin concentration changes via optical intensity. Such activation measurement allows for the detection of cognitive state, which can be important for emotional stability, human performance and vigilance optimization, and the detection of hazardous operator state. The technique depends on coupling between the fNIRS probe and users skin. Such coupling may be highly susceptible to motion if probe-containing headgear designs are not adequately tested. The lack of reliable and self-applicable headgear robust to the influence of motion artifact currently inhibits its operational use in aerospace environments. Both NASAs Aviation Safety and Human Research Programs are interested in this technology as a method of monitoring cognitive state of pilots and crew.

  1. Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice.

    Science.gov (United States)

    Seong, Hyun-A; Manoharan, Ravi; Ha, Hyunjung

    2016-03-10

    To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-β (TGF-β) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role. We provide evidence that the ASK1 and TGF-β signaling pathways are interconnected by a multiprotein complex harboring murine protein serine-threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc-finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-β activity is sufficient to activate both the redox-dependent ASK1 and TGF-β signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-β signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis. Our data suggest that the multiprotein complex linking ASK1 and TGF-β signaling pathways may be a potential target for redox-mediated metabolic complications.

  2. Effects of traffic noise on tree frog stress levels, immunity, and color signaling.

    Science.gov (United States)

    Troïanowski, Mathieu; Mondy, Nathalie; Dumet, Adeline; Arcanjo, Caroline; Lengagne, Thierry

    2017-10-01

    During the last decade, many studies have focused on the detrimental effects of noise pollution on acoustic communication. Surprisingly, although it is known that noise exposure strongly influences health in humans, studies on wildlife remain scarce. In order to gain insight into the consequences of traffic noise exposure, we experimentally manipulated traffic noise exposure as well as the endocrine status of animals to investigate physiological and phenotypic consequences of noise pollution in an anuran species. We showed that noise exposure increased stress hormone level and induced an immunosuppressive effect. In addition, both traffic noise exposure and stress hormone application negatively impacted H. arborea vocal sac coloration. Moreover, our results suggest profound changes in sexual selection processes because the best quality males with initial attractive vocal sac coloration were the most impacted by noise. Hence, our study suggests that the recent increases in anthropogenic noise worldwide might affect a broader range of animal species than previously thought, because of alteration of visual signals and immunity. Generalizing these results to other taxa is crucial for the conservation of biodiversity in an increasingly noisy world. © 2017 Society for Conservation Biology.

  3. The roles of DNA damage-dependent signals and MAPK cascades in tributyltin-induced germline apoptosis in Caenorhabditis elegans.

    Science.gov (United States)

    Wang, Yun; Wang, Shunchang; Luo, Xun; Yang, Yanan; Jian, Fenglei; Wang, Xuemin; Xie, Lucheng

    2014-08-01

    The induction of apoptosis is recognized to be a major mechanism of tributyltin (TBT) toxicity. However, the underlying signaling pathways for TBT-induced apoptosis remain unclear. In this study, using the nematode Caenorhabditis elegans, we examined whether DNA damage response (DDR) pathway and mitogen-activated protein kinase (MAPK) signaling cascades are involved in TBT-induced germline apoptosis and cell cycle arrest. Our results demonstrated that exposing worms to TBT at the dose of 10nM for 6h significantly increased germline apoptosis in N2 strain. Germline apoptosis was absent in strains that carried ced-3 or ced-4 loss-of-function alleles, indicating that both caspase protein CED-3 and Apaf-1 protein CED-4 were required for TBT-induced apoptosis. TBT-induced apoptosis was blocked in the Bcl-2 gain-of-function strain ced-9(n1950), whereas TBT induced a minor increase in the BH3-only protein EGL-1 mutated strain egl-1(n1084n3082). Checkpoint proteins HUS-1 and CLK-2 exerted proapoptotic effects, and the null mutation of cep-1, the homologue of tumor suppressor gene p53, significantly inhibited TBT-induced apoptosis. Apoptosis in the loss-of-function strains of ERK, JNK and p38 MAPK signaling pathways were completely or mildly suppressed under TBT stress. These results were supported by the results of mRNA expression levels of corresponding genes. The present study indicated that TBT-induced apoptosis required the core apoptotic machinery, and that DDR genes and MAPK pathways played essential roles in signaling the processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Signal dependence of inter-pixel capacitance in hybridized HgCdTe H2RG arrays for use in James Webb space telescope's NIRcam

    Science.gov (United States)

    Donlon, Kevan; Ninkov, Zoran; Baum, Stefi

    2016-08-01

    Interpixel capacitance (IPC) is a deterministic electronic coupling by which signal generated in one pixel is measured in neighboring pixels. Examination of dark frames from test NIRcam arrays corroborates earlier results and simulations illustrating a signal dependent coupling. When the signal on an individual pixel is larger, the fractional coupling to nearest neighbors is lesser than when the signal is lower. Frames from test arrays indicate a drop in average coupling from approximately 1.0% at low signals down to approximately 0.65% at high signals depending on the particular array in question. The photometric ramifications for this non-uniformity are not fully understood. This non-uniformity intro-duces a non-linearity in the current mathematical model for IPC coupling. IPC coupling has been mathematically formalized as convolution by a blur kernel. Signal dependence requires that the blur kernel be locally defined as a function of signal intensity. Through application of a signal dependent coupling kernel, the IPC coupling can be modeled computationally. This method allows for simultaneous knowledge of the intrinsic parameters of the image scene, the result of applying a constant IPC, and the result of a signal dependent IPC. In the age of sub-pixel precision in astronomy these effects must be properly understood and accounted for in order for the data to accurately represent the object of observation. Implementation of this method is done through python scripted processing of images. The introduction of IPC into simulated frames is accomplished through convolution of the image with a blur kernel whose parameters are themselves locally defined functions of the image. These techniques can be used to enhance the data processing pipeline for NIRcam.

  5. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence

    Directory of Open Access Journals (Sweden)

    Pierre eTrifilieff

    2013-06-01

    Full Text Available Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the Positron Emission Tomography (PET imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.

  6. The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling

    CSIR Research Space (South Africa)

    Wheeler, J

    2017-06-01

    Full Text Available ) with the ll PickUp Injection mode using the loading pump at 15 ll min�1 flow rate for 3 min. Samples were then loaded on a RSLC, 75 lm 9 500 mm, nanoVi- per, C18, 2 lm, 100 �A column (Acclaim, PepMap) retrofitted to an EASY-spray source with a flow rate of 300... receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling Janet I. Wheeler1,2,†, Aloysius Wong3,4, Claudius Marondedze3,5, Arnoud J. Groen5, Lusisizwe Kwezi1,6, Lubna Freihat1, Jignesh Vyas1, Misjudeen A. Raji7, Helen R. Irving1...

  7. Activation of Host IRE1α-Dependent Signaling Axis Contributes the Intracellular Parasitism of Brucella melitensis

    Directory of Open Access Journals (Sweden)

    Aseem Pandey

    2018-04-01

    Full Text Available Brucella spp. are intracellular vacuolar pathogens that causes brucellosis, a worldwide zoonosis of profound importance. We previously demonstrated that the activity of host unfolded protein response (UPR sensor IRE1α (inositol-requiring enzyme 1 and ER-associated autophagy confer susceptibility to Brucella melitensis and Brucella abortus intracellular replication. However, the mechanism by which host IRE1α regulates the pathogen intracellular lifestyle remains elusive. In this study, by employing a diverse array of molecular approaches, including biochemical analyses, fluorescence microscopy imaging, and infection assays using primary cells derived from Ern1 (encoding IRE1 conditional knockout mice, we address this gap in our understanding by demonstrating that a novel IRE1α to ULK1, an important component for autophagy initiation, signaling axis confers susceptibility to Brucella intracellular parasitism. Importantly, deletion or inactivation of key signaling components along this axis, including IRE1α, BAK/BAX, ASK1, and JNK as well as components of the host autophagy system ULK1, Atg9a, and Beclin 1, resulted in striking disruption of Brucella intracellular trafficking and replication. Host kinases in the IRE1α-ULK1 axis, including IRE1α, ASK1, JNK1, and/or AMPKα as well as ULK1, were also coordinately phosphorylated in an IRE1α-dependent fashion upon the pathogen infection. Taken together, our findings demonstrate that the IRE1α-ULK1 signaling axis is subverted by the bacterium to promote intracellular parasitism, and provide new insight into our understanding of the molecular mechanisms of intracellular lifestyle of Brucella.

  8. An Elk transcription factor is required for Runx-dependent survival signaling in the sea urchin embryo.

    Science.gov (United States)

    Rizzo, Francesca; Coffman, James A; Arnone, Maria Ina

    2016-08-01

    Elk proteins are Ets family transcription factors that regulate cell proliferation, survival, and differentiation in response to ERK (extracellular-signal regulated kinase)-mediated phosphorylation. Here we report the embryonic expression and function of Sp-Elk, the single Elk gene of the sea urchin Strongylocentrotus purpuratus. Sp-Elk is zygotically expressed throughout the embryo beginning at late cleavage stage, with peak expression occurring at blastula stage. Morpholino antisense-mediated knockdown of Sp-Elk causes blastula-stage developmental arrest and embryo disintegration due to apoptosis, a phenotype that is rescued by wild-type Elk mRNA. Development is also rescued by Elk mRNA encoding a serine to aspartic acid substitution (S402D) that mimics ERK-mediated phosphorylation of a conserved site that enhances DNA binding, but not by Elk mRNA encoding an alanine substitution at the same site (S402A). This demonstrates both that the apoptotic phenotype of the morphants is specifically caused by Elk depletion, and that phosphorylation of serine 402 of Sp-Elk is critical for its anti-apoptotic function. Knockdown of Sp-Elk results in under-expression of several regulatory genes involved in cell fate specification, cell cycle control, and survival signaling, including the transcriptional regulator Sp-Runt-1 and its target Sp-PKC1, both of which were shown previously to be required for cell survival during embryogenesis. Both Sp-Runt-1 and Sp-PKC1 have sequences upstream of their transcription start sites that specifically bind Sp-Elk. These results indicate that Sp-Elk is the signal-dependent activator of a feed-forward gene regulatory circuit, consisting also of Sp-Runt-1 and Sp-PKC1, which actively suppresses apoptosis in the early embryo. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Protein kinase C-dependent signaling controls the midgut epithelial barrier to malaria parasite infection in anopheline mosquitoes.

    Directory of Open Access Journals (Sweden)

    Nazzy Pakpour

    Full Text Available Anopheline mosquitoes are the primary vectors of parasites in the genus Plasmodium, the causative agents of malaria. Malaria parasites undergo a series of complex transformations upon ingestion by the mosquito host. During this process, the physical barrier of the midgut epithelium, along with innate immune defenses, functionally restrict parasite development. Although these defenses have been studied for some time, the regulatory factors that control them are poorly understood. The protein kinase C (PKC gene family consists of serine/threonine kinases that serve as central signaling molecules and regulators of a broad spectrum of cellular processes including epithelial barrier function and immunity. Indeed, PKCs are highly conserved, ranging from 7 isoforms in Drosophila to 16 isoforms in mammals, yet none have been identified in mosquitoes. Despite conservation of the PKC gene family and their potential as targets for transmission-blocking strategies for malaria, no direct connections between PKCs, the mosquito immune response or epithelial barrier integrity are known. Here, we identify and characterize six PKC gene family members--PKCδ, PKCε, PKCζ, PKD, PKN, and an indeterminate conventional PKC--in Anopheles gambiae and Anopheles stephensi. Sequence and phylogenetic analyses of the anopheline PKCs support most subfamily assignments. All six PKCs are expressed in the midgut epithelia of A. gambiae and A. stephensi post-blood feeding, indicating availability for signaling in a tissue that is critical for malaria parasite development. Although inhibition of PKC enzymatic activity decreased NF-κB-regulated anti-microbial peptide expression in mosquito cells in vitro, PKC inhibition had no effect on expression of a panel of immune genes in the midgut epithelium in vivo. PKC inhibition did, however, significantly increase midgut barrier integrity and decrease development of P. falciparum oocysts in A. stephensi, suggesting that PKC-dependent

  10. Platelet-derived-growth-factor-induced signalling in human platelets: phosphoinositide-3-kinase-dependent inhibition of platelet activation.

    Science.gov (United States)

    Selheim, F; Fukami, M H; Holmsen, H; Vassbotn, F S

    2000-09-01

    Human platelets release platelet-derived growth factor (PDGF) from alpha-granules during platelet activation. We have previously shown that platelets have PDGF alpha-receptors, a transmembrane tyrosine kinase that takes part in negative feedback regulation during platelet activation. Here we have described a study of PDGF-induced tyrosine phosphorylation of platelet substrates and phosphoinositide 3-kinase (PI-3K) activity in collagen-stimulated platelets. By immunoblotting with phosphotyrosine antibodies of collagen-activated platelets we found that PDGF increased the phosphorylation of several platelet substrates, e.g. pp140, pp120 and pp85. PDGF inhibited collagen-induced platelet activation in the presence of inhibitors of autocrine stimulation, thus blocking the pure collagen-induced signal transduction. PDGF enhanced the collagen-induced formation of PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) as measured by HPLC. Wortmannin and LY294002, two unrelated inhibitors of PI-3K, were used to investigate the role of PI-3K in PDGF-induced platelet signalling. Incubation of platelets with wortmannin and LY294002 blocked the formation of three phosphorylated inositides as well as the inhibitory effect of PDGF on collagen-induced platelet activation. We conclude that the inhibitory effect of PDGF on platelet activation is PI-3K dependent. This is the first demonstration of a negative regulatory function of 3-phosphorylated inositides in platelets.

  11. Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling

    Science.gov (United States)

    Zhao, Zhongfu; Koltai, Erika; Ohno, Hideki; Atalay, Mustafa

    2013-01-01

    Abstract The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1α activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and protein–protein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROS-mediated activation of hypoxia-inducible factor 1α. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling. Antioxid. Redox Signal. 18, 1208–1246. PMID:22978553

  12. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

    Science.gov (United States)

    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

  13. Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription

    Energy Technology Data Exchange (ETDEWEB)

    Kusano, Shuichi, E-mail: skusano@m2.kufm.kagoshima-u.ac.jp [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Eizuru, Yoshito [Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    2010-06-04

    Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3{beta} (GSK-3{beta}) and to negatively regulate its activity, leading to stimulation of GSK-3{beta}-dependent {beta}-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a {beta}-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3{beta} complex. These data reveal for the first time that I-mfa domain proteins interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3{beta} complex.

  14. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    Science.gov (United States)

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Determination of dependence of feed intake level on functional and technological parameters of prescription mixture

    Directory of Open Access Journals (Sweden)

    Aksenova O. I.

    2016-12-01

    Full Text Available The problem of the development of pet food formulations in the conditions of information uncertainty which is characteristic of an actual business enterprise engaged in production of feed has been considered in the paper. The analysis of the literature [1–4] has shown that the main works are devoted to the extrusion of plastics and cereal products, with the temperature conditions equal to 130–200 ºC. This temperature range is not suitable for the production of pet food, and researches on this issue are virtually absent. This study is devoted to defining the functional and technological parameters of prescription mixture depending on the level of feed intake by unproductive animals; this knowledge will allow manufacturers to simplify the development of new formulations of balanced feed. Identification of this relationship has been carried out on the basis of modeling methods of mathematical statistics in Excel and Mathcad packages, as well as on the basis of fuzzy logic set theory in MatLAB package, as the construction of a complete mathematical model is complicated by absence of an explicit numerical form of the result received on the basis of sensory analysis. The research has revealed the dependence of feed intake level on functional and technological parameters of prescription mix for non-productive animals, in particular, the highest level of animal feed intake will be achieved at the following values of the main parameters: pH – 6.5; the moisture – 9 %; the protein concentration – 85 %; the particle size – 0.55 mm; the energy value – 267 kcal/100 g feed. The adequacy of the dependence for the input variables – the moisture feed and concentration of the protein component – is confirmed by the experimental investigations. This paper can be used to generate the optimal prescription composition for functional and technological characteristics of the samples in order to create balanced extruded feeds.

  16. Ethanol extract of seeds of Oenothera odorata induces vasorelaxation via endothelium-dependent NO-cGMP signaling through activation of Akt-eNOS-sGC pathway.

    Science.gov (United States)

    Kim, Hye Yoom; Oh, Hyuncheol; Li, Xiang; Cho, Kyung Woo; Kang, Dae Gill; Lee, Ho Sub

    2011-01-27

    The vasorelaxant effect of ethanol extract of seeds of Oenothera odorata (Onagraceae) (one species of evening primroses) (ESOO) and its mechanisms involved were defined. Changes in vascular tension, guanosine 3',5'-cyclic monophosphate (cGMP) levels, and Akt expression were measured in carotid arterial rings from rats. Seeds of Oenothera odorata were extracted with ethanol (94%) and the extract was filtered, concentrated and stored at -70°C. ESOO relaxed endothelium-intact, but not endothelium-denuded, carotid arterial rings in a concentration-dependent manner. Similarly, ESOO increased cGMP levels of the carotid arterial rings. Pretreatment of endothelium-intact arterial rings with L-NAME, an inhibitor of nitric oxide synthase (NOS), or ODQ, an inhibitor of soluble guanylyl cyclase (sGC), blocked the ESOO-induced vasorelaxation and increase in cGMP levels. Nominally Ca(2+)-free but not L-typed Ca(2+) channel inhibition attenuated the ESOO-induced vasorelaxation. Thapsigargin, Gd(3+), and 2-aminoethyl diphenylborinate, modulators of store-operated Ca(2+) entry (SOCE), significantly attenuated the ESOO-induced vasorelaxation and increase in cGMP levels. Further, wortmannin, an inhibitor of Akt, attenuated the ESOO-induced vasorelaxation and increases in cGMP levels and phosphorylated Akt2 expression. K(+) channel blockade with TEA, 4-aminopyridine, and glibenclamide attenuated the ESOO-induced vascular relaxation. Taken together, the present study demonstrates that ESOO relaxes vascular smooth muscle via endothelium-dependent NO-cGMP signaling through activation of the Akt-eNOS-sGC pathway. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  17. Two models of the sound-signal frequency dependence on the animal body size as exemplified by the ground squirrels of Eurasia (mammalia, rodentia).

    Science.gov (United States)

    Nikol'skii, A A

    2017-11-01

    Dependence of the sound-signal frequency on the animal body length was studied in 14 ground squirrel species (genus Spermophilus) of Eurasia. Regression analysis of the total sample yielded a low determination coefficient (R 2 = 26%), because the total sample proved to be heterogeneous in terms of signal frequency within the dimension classes of animals. When the total sample was divided into two groups according to signal frequency, two statistically significant models (regression equations) were obtained in which signal frequency depended on the body size at high determination coefficients (R 2 = 73 and 94% versus 26% for the total sample). Thus, the problem of correlation between animal body size and the frequency of their vocal signals does not have a unique solution.

  18. A preliminary study of murine walker-256 tumor hypoxia detected by blood oxygen level dependent-MR

    International Nuclear Information System (INIS)

    Zhang Shengjian; Mao Jian; Wu Bin; Peng Weijun

    2013-01-01

    Objective: To establish Walker-256 transplantation tumor model in SD Rats. To study of R_2"* signal changes on murine Walker-256 tumor after inhaling Carbogen by blood oxygen level dependent (BOLD)-MR, and to explore the feasibility of BOLD-MRI on detecting tumor hypoxia. Methods: Walker-256 tumor cell implanted subcutaneously in right lower abdomen of 95 female SD rats. MR was performed on the tumor-forming rats when the maximum diameter of tumor reached 1-3 cm, using a 3.0 T MR scanner equipped with a 3 inch animal surface coil. BOLD-MRI was done by using a multiecho SPGR sequence during inhaling air and at 10 minute after inhaling Carbogen, respectively. All images were transferred to GE ADW 4.3 workstation, then a baseline R_2"* (R_2"* a) and R_2"* (R_2"* b) after inhaling Carbogen of tumor was calculated using R_2 Star analysis software and ΔR_2"* was calculated through ΔR_2"* = R_2"* b -R_2"* a", meanwhile the volume of tumor were calculated as well. The difference of R_2"* signal pre and post-inhaling of Carbogen was compared with a paired t test, Pearson correlation was calculated between R_2"* a, ΔR_2"* and the volume of tumor, respectively. The correlation between ΔR_2"* and R_2"* a was also assessed by Pearson correlation. Results: Sixty-eight of ninety-five female SD rats formed the tumor (71.6%). The volume of tumor was from 352 to 13 173 mm"3. Mean ΔR_2"* decreased significantly (-2.26 ± 3.90) s"-"1 from (41.18 ± 22.29) s"-"1 during breathing air to (38.91 ± 21.35) s"-"1 10 min after inhaling Carbogen (t = 4.01, P 0.05). Conclusions: BOLD-MRI can detect the R_2"* signal change of murine Walker-256 tumor pre-and post-inhaling of Carbogen. The R_2"* signal showed significant decrease after inhaling Carbogen, however, the individual variation was remarkable. (authors)

  19. Vascular Steal Explains Early Paradoxical Blood Oxygen Level-Dependent Cerebrovascular Response in Brain Regions with Delayed Arterial Transit Times

    Directory of Open Access Journals (Sweden)

    Julien Poublanc

    2013-04-01

    Full Text Available Introduction: Blood oxygen level-dependent (BOLD magnetic resonance imaging (MRI during manipulation of inhaled carbon dioxide (CO2 can be used to measure cerebrovascular reactivity (CVR and map regions of exhausted cerebrovascular reserve. These regions exhibit a reduced or negative BOLD response to inhaled CO2. In this study, we sought to clarify the mechanism behind the negative BOLD response by investigating its time delay (TD. Dynamic susceptibility contrast (DSC MRI with the injection of a contrast agent was used as the gold standard in order to provide measurement of the blood arrival time to which CVR TD could be compared. We hypothesize that if negative BOLD responses are the result of a steal phenomenon, they should be synchronized with positive BOLD responses from healthy brain tissue, even though the blood arrival time would be delayed. Methods: On a 3-tesla MRI system, BOLD CVR and DSC images were collected in a group of 19 patients with steno-occlusive cerebrovascular disease. For each patient, we generated a CVR magnitude map by regressing the BOLD signal with the end-tidal partial pressure of CO2 (PETCO2, and a CVR TD map by extracting the time of maximum cross-correlation between the BOLD signal and PETCO2. In addition, a blood arrival time map was generated by fitting the DSC signal with a gamma variate function. ROI masks corresponding to varying degrees of reactivity were constructed. Within these masks, the mean CVR magnitude, CVR TD and DSC blood arrival time were extracted and averaged over the 19 patients. CVR magnitude and CVR TD were then plotted against DSC blood arrival time. Results: The results show that CVR magnitude is highly correlated to DSC blood arrival time. As expected, the most compromised tissues with the longest blood arrival time have the lowest (most negative CVR magnitude. However, CVR TD shows a noncontinuous relationship with DSC blood arrival time. CVR TD is well correlated to DSC blood arrival time

  20. Aspects of two-level systems under external time-dependent fields

    Energy Technology Data Exchange (ETDEWEB)

    Bagrov, V.G.; Wreszinski, W.F. [Tomsk State University and Tomsk Institute of High Current Electronics (Russian Federation); Barata, J.C.A.; Gitman D.M. [Universidade de Sao Paulo, Instituto de Fisica (Brazil)]. E-mails: jbarata@fma.if.usp.br; gitman@fma.if.usp.br

    2001-12-14

    The dynamics of two-level systems in time-dependent backgrounds is under consideration. We present some new exact solutions in special backgrounds decaying in time. On the other hand, following ideas of Feynman et al, we discuss in detail the possibility of reducing the quantum dynamics to a classical Hamiltonian system. This, in particular, opens the possibility of directly applying powerful methods of classical mechanics (e.g. KAM methods) to study the quantum system. Following such an approach, we draw conclusions of relevance for 'quantum chaos' when the external background is periodic or quasi-periodic in time. (author)

  1. Models of consumer behavior of households depending on the income level

    Directory of Open Access Journals (Sweden)

    Melnikova A.S.

    2016-11-01

    Full Text Available the consumer behavior of households is defined by a complex of internal and external factors: income of the population, motives and incentives of behavior, behavioral norms and personal preferences. As the example of structure analysis of the income and expenses of households of Sverdlovsk region during research models of consumer behavior of households are allocated, characteristics and structure of the population depending on their welfare are allocated. Author's approach allows forecasting of the consumer market, proceeding from the socio-economic factors forming the level of the population income in the region.

  2. Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI Cerebrovascular Reactivity in Cerebrovascular Disease

    DEFF Research Database (Denmark)

    Smeeing, Diederik P J; Hendrikse, Jeroen; Petersen, Esben T

    2016-01-01

    BACKGROUND: The cerebrovascular reactivity (CVR) results of blood oxygen level-dependent (BOLD) and arterial spin labeling (ASL) MRI studies performed in patients with cerebrovascular disease (steno-occlusive vascular disease or stroke) were systematically reviewed. SUMMARY: Thirty-one articles...... found a significant lower ASL CVR in the ipsilateral hemispheres of patients compared to controls. KEY MESSAGES: This review brings support for a reduced BOLD and ASL CVR in the ipsilateral hemisphere of patients with cerebrovascular disease. We suggest that future studies will be performed in a uniform...... way so reference values can be established and could be used to guide treatment decisions in patients with cerebrovascular disease....

  3. Hemispheric lateralization for early auditory processing of lexical tones: dependence on pitch level and pitch contour.

    Science.gov (United States)

    Wang, Xiao-Dong; Wang, Ming; Chen, Lin

    2013-09-01

    In Mandarin Chinese, a tonal language, pitch level and pitch contour are two dimensions of lexical tones according to their acoustic features (i.e., pitch patterns). A change in pitch level features a step change whereas that in pitch contour features a continuous variation in voice pitch. Currently, relatively little is known about the hemispheric lateralization for the processing of each dimension. To address this issue, we made whole-head electrical recordings of mismatch negativity in native Chinese speakers in response to the contrast of Chinese lexical tones in each dimension. We found that pre-attentive auditory processing of pitch level was obviously lateralized to the right hemisphere whereas there is a tendency for that of pitch contour to be lateralized to the left. We also found that the brain responded faster to pitch level than to pitch contour at a pre-attentive stage. These results indicate that the hemispheric lateralization for early auditory processing of lexical tones depends on the pitch level and pitch contour, and suggest an underlying inter-hemispheric interactive mechanism for the processing. © 2013 Elsevier Ltd. All rights reserved.

  4. Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling.

    Science.gov (United States)

    Kling, Jessica C; Jordan, Margaret A; Pitt, Lauren A; Meiners, Jana; Thanh-Tran, Thao; Tran, Le Son; Nguyen, Tam T K; Mittal, Deepak; Villani, Rehan; Steptoe, Raymond J; Khosrotehrani, Kiarash; Berzins, Stuart P; Baxter, Alan G; Godfrey, Dale I; Blumenthal, Antje

    2018-01-01

    roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.

  5. Equation-of-state dependent features in shock-oscillation modulated neutrino and gravitational-wave signals from supernovae

    Science.gov (United States)

    Marek, A.; Janka, H.-T.; Müller, E.

    2009-03-01

    We present two-dimensional (axisymmetric) neutrino-hydrodynamic simulations of the long-time accretion phase of a 15 M_⊙ progenitor star after core bounce and before the launch of a supernova explosion, when non-radial hydrodynamic instabilities like convection occur in different regions of the collapsing stellar core and the standing accretion shock instability (SASI) leads to large-amplitude oscillations of the stalled shock with a period of tens of milliseconds. Our simulations were performed with the Prometheus-Vertex code, which includes a multi-flavor, energy-dependent neutrino transport scheme and employs an effective relativistic gravitational potential. Testing the influence of a stiff and a soft equation of state for hot neutron star matter, we find that the non-radial mass motions in the supernova core impose a time variability on the neutrino and gravitational-wave signals with larger amplitudes, as well as higher frequencies in the case of a more compact nascent neutron star. After the prompt shock-breakout burst of electron neutrinos, a more compact accreting remnant produces higher neutrino luminosities and higher mean neutrino energies. The observable neutrino emission in the SASI sloshing direction exhibits a modulation of several ten percent in the luminosities and around 1 MeV in the mean energies with most power at typical SASI frequencies between roughly 20 and 100 Hz. The modulation is caused by quasi-periodic variations in the mass accretion rate of the neutron star in each hemisphere. At times later than ~50-100 ms after bounce, the gravitational-wave amplitude is dominated by the growing low-frequency (⪉200 Hz) signal associated with anisotropic neutrino emission. A high-frequency wave signal results from nonradial gas flows in the outer layers of the anisotropically accreting neutron star. Right after bounce such nonradial mass motions occur due to prompt post-shock convection in both considered cases and contribute mostly to the early

  6. Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling

    Directory of Open Access Journals (Sweden)

    Jessica C. Kling

    2018-03-01

    complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.

  7. Opposing roles of RNF8/RNF168 and deubiquitinating enzymes in ubiquitination-dependent DNA double-strand break response signaling and DNA-repair pathway choice

    International Nuclear Information System (INIS)

    Nakada, Shinichiro

    2016-01-01

    The E3 ubiquitin ligases ring finger protein (RNF) 8 and RNF168 transduce the DNA double-strand break (DSB) response (DDR) signal by ubiquitinating DSB sites. The depletion of RNF8 or RNF168 suppresses the accumulation of DNA-repair regulating factors such as 53BP1 and RAP80 at DSB sites, suggesting roles for RNF8- and RNF168-mediated ubiquitination in DSB repair. This mini-review provides a brief overview of the RNF8- and RNF168-dependent DDR-signaling and DNA-repair pathways. The choice of DNA-repair pathway when RNF8- and RNF168-mediated ubiquitination-dependent DDR signaling is negatively regulated by deubiquitinating enzymes (DUBs) is reviewed to clarify how the opposing roles of RNF8/RNF168 and DUBs regulate ubiquitination-dependent DDR signaling and the choice of DNA-repair pathway

  8. Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

    Science.gov (United States)

    Turner, Mark J.; Saint‐Criq, Vinciane; Patel, Waseema; Ibrahim, Salam H.; Verdon, Bernard; Ward, Christopher; Garnett, James P.; Tarran, Robert; Cann, Martin J.

    2015-01-01

    Key points Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases.CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+.Hypercapnia reduced cAMP‐stimulated cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid transport in Calu‐3 cells and primary human airway epithelia but did not affect cAMP‐regulated HCO3 − transport via pendrin or Na+/HCO3 − cotransporters.These results further support the role of CO2 as a cell signalling molecule and suggests CO2‐induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs. Abstract Hypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist‐stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP‐regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin‐stimulated elevations in intracellular cAMP as well as both adenosine‐ and forskolin‐stimulated increases in CFTR‐dependent transepithelial short‐circuit current, in polarised cultures of Calu‐3 human airway cells. This CO2‐induced reduction in anion secretion was not due to a decrease in HCO3 − transport given that neither a change in CFTR‐dependent HCO3 − efflux nor Na+/HCO3 − cotransporter‐dependent HCO3 − influx were CO2‐sensitive. Hypercapnia also reduced the volume of forskolin‐stimulated fluid

  9. Rare sugar D-allose suppresses gibberellin signaling through hexokinase-dependent pathway in Oryza sativa L.

    Science.gov (United States)

    Fukumoto, Takeshi; Kano, Akihito; Ohtani, Kouhei; Yamasaki-Kokudo, Yumiko; Kim, Bong-Gyu; Hosotani, Kouji; Saito, Miu; Shirakawa, Chikage; Tajima, Shigeyuki; Izumori, Ken; Ohara, Toshiaki; Shigematsu, Yoshio; Tanaka, Keiji; Ishida, Yutaka; Nishizawa, Yoko; Tada, Yasuomi; Ichimura, Kazuya; Gomi, Kenji; Akimitsu, Kazuya

    2011-12-01

    One of the rare sugars, D-allose, which is the epimer of D-glucose at C3, has an inhibitory effect on rice growth, but the molecular mechanisms of the growth inhibition by D-allose were unknown. The growth inhibition caused by D-allose was prevented by treatment with hexokinase inhibitors, D-mannoheptulose and N-acetyl-D-glucosamine. Furthermore, the Arabidopsis glucose-insensitive2 (gin2) mutant, which is a loss-of-function mutant of the glucose sensor AtHXK1, showed a D-allose-insensitive phenotype. D-Allose strongly inhibited the gibberellin-dependent responses such as elongation of the second leaf sheath and induction of α-amylase in embryo-less half rice seeds. The growth of the slender rice1 (slr1) mutant, which exhibits a constitutive gibberellin-responsive phenotype, was also inhibited by D-allose, and the growth inhibition of the slr1 mutant by D-allose was also prevented by D-mannoheptulose treatment. The expressions of gibberellin-responsive genes were down-regulated by D-allose treatment, and the down-regulations of gibberellin-responsive genes were also prevented by D-mannoheptulose treatment. These findings reveal that D-allose inhibits the gibberellin-signaling through a hexokinase-dependent pathway.

  10. Shock, stress or signal? Implications of freshwater flows for a top-level estuarine predator.

    Directory of Open Access Journals (Sweden)

    Matthew D Taylor

    Full Text Available Physicochemical variability in estuarine systems plays an important role in estuarine processes and in the lifecycles of estuarine organisms. In particular, seasonality of freshwater inflow to estuaries may be important in various aspects of fish lifecycles. This study aimed to further understand these relationships by studying the movements of a top-level estuarine predator in response to physicochemical variability in a large, temperate south-east Australian estuary (Shoalhaven River. Mulloway (Argyrosomus japonicus, 47-89 cm total length were surgically implanted with acoustic transmitters, and their movements and migrations monitored over two years via fixed-position VR2W acoustic receivers configured in a linear array along the length of the estuary. The study period included a high degree of abiotic variability, with multiple pulses (exponentially high flows over a short period of time in fresh water to the estuary, as well as broader seasonal variation in flow, temperature and conductivity. The relative deviation of fish from their modal location in the estuary was affected primarily by changes in conductivity, and smaller fish (n = 4 tended to deviate much further downstream from their modal position in the estuary than larger fish (n = 8. High-flow events which coincided with warmer temperatures tended to drive mature fish down the estuary and potentially provided a spawning signal to stimulate aggregation of adults near the estuary mouth; however, this relationship requires further investigation. These findings indicate that pulse and press effects of freshwater inflow and associated physicochemical variability play a role in the movements of mulloway, and that seasonality of large freshwater flows may be important in spawning. The possible implications of river regulation and the extraction of freshwater for consumptive uses on estuarine fishes are discussed.

  11. CVTresh: R Package for Level-Dependent Cross-Validation Thresholding

    Directory of Open Access Journals (Sweden)

    Donghoh Kim

    2006-04-01

    Full Text Available The core of the wavelet approach to nonparametric regression is thresholding of wavelet coefficients. This paper reviews a cross-validation method for the selection of the thresholding value in wavelet shrinkage of Oh, Kim, and Lee (2006, and introduces the R package CVThresh implementing details of the calculations for the procedures. This procedure is implemented by coupling a conventional cross-validation with a fast imputation method, so that it overcomes a limitation of data length, a power of 2. It can be easily applied to the classical leave-one-out cross-validation and K-fold cross-validation. Since the procedure is computationally fast, a level-dependent cross-validation can be developed for wavelet shrinkage of data with various sparseness according to levels.

  12. CVTresh: R Package for Level-Dependent Cross-Validation Thresholding

    Directory of Open Access Journals (Sweden)

    Donghoh Kim

    2006-04-01

    Full Text Available The core of the wavelet approach to nonparametric regression is thresholding of wavelet coefficients. This paper reviews a cross-validation method for the selection of the thresholding value in wavelet shrinkage of Oh, Kim, and Lee (2006, and introduces the R package CVThresh implementing details of the calculations for the procedures.This procedure is implemented by coupling a conventional cross-validation with a fast imputation method, so that it overcomes a limitation of data length, a power of 2. It can be easily applied to the classical leave-one-out cross-validation and K-fold cross-validation. Since the procedure is computationally fast, a level-dependent cross-validation can be developed for wavelet shrinkage of data with various sparseness according to levels.

  13. Interaural Level Difference Dependent Gain Control and Synaptic Scaling Underlying Binaural Computation

    Science.gov (United States)

    Xiong, Xiaorui R.; Liang, Feixue; Li, Haifu; Mesik, Lukas; Zhang, Ke K.; Polley, Daniel B.; Tao, Huizhong W.; Xiao, Zhongju; Zhang, Li I.

    2013-01-01

    Binaural integration in the central nucleus of inferior colliculus (ICC) plays a critical role in sound localization. However, its arithmetic nature and underlying synaptic mechanisms remain unclear. Here, we showed in mouse ICC neurons that the contralateral dominance is created by a “push-pull”-like mechanism, with contralaterally dominant excitation and more bilaterally balanced inhibition. Importantly, binaural spiking response is generated apparently from an ipsilaterally-mediated scaling of contralateral response, leaving frequency tuning unchanged. This scaling effect is attributed to a divisive attenuation of contralaterally-evoked synaptic excitation onto ICC neurons with their inhibition largely unaffected. Thus, a gain control mediates the linear transformation from monaural to binaural spike responses. The gain value is modulated by interaural level difference (ILD) primarily through scaling excitation to different levels. The ILD-dependent synaptic scaling and gain adjustment allow ICC neurons to dynamically encode interaural sound localization cues while maintaining an invariant representation of other independent sound attributes. PMID:23972599

  14. The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels.

    Science.gov (United States)

    Singh, Jaskirat; Wen, Xiaohui; Scales, Suzie J

    2015-12-04

    The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Ck2-Dependent Phosphorylation Is Required to Maintain Pax7 Protein Levels in Proliferating Muscle Progenitors.

    Directory of Open Access Journals (Sweden)

    Natalia González

    Full Text Available Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (reacquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.

  16. Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling

    International Nuclear Information System (INIS)

    Kumar, B N Prashanth; Rajput, Shashi; Dey, Kaushik Kumar; Parekh, Aditya; Das, Subhasis; Mazumdar, Abhijit; Mandal, Mahitosh

    2013-01-01

    Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed. Here, we elucidated how the combination of TAM and CXB at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1α activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive

  17. Operator dependency of the radiation exposure in cardiac interventions: feasibility of ultra low dose levels

    International Nuclear Information System (INIS)

    Emre Ozpelit, Mehmet; Ercan, Ertugrul; Pekel, Nihat; Tengiz, Istemihan; Yilmaz, Akar; Ozpelit, Ebru; Ozyurtlu, Ferhat

    2017-01-01

    Introduction: Mean radiation exposure in invasive cardiology varies greatly between different centres and interventionists. The International Commission on Radiological Protection and the EURATOM Council stipulate that, despite reference values, 'All medical exposure for radiodiagnostic purposes shall be kept as low as reasonably achievable' (ALARA). The purpose of this study is to establish the effects of the routine application of ALARA principles and to determine operator and procedure impact on radiation exposure in interventional cardiology. Materials and methods: A total of 240 consecutive cardiac interventional procedures were analysed. Five operators performed the procedures, two of whom were working in accordance with ALARA principles (Group 1 operators) with the remaining three working in a standard manner (Group 2 operators). Radiation exposure levels of these two groups were compared. Results: Total fluoroscopy time and the number of radiographic runs were similar between groups. However, dose area product and cumulative dose were significantly lower in Group 1 when compared with Group 2. Radiation levels of Group 1 were far below even the reference levels in the literature, thus representing an ultra-low-dose radiation exposure in interventional cardiology. Conclusion: By use of simple radiation reducing techniques, ultra-low-dose radiation exposure is feasible in interventional cardiology. Achievability of such levels depends greatly on operator awareness, desire, knowledge and experience of radiation protection. (authors)

  18. Relationship between systemic hemodynamics and ambulatory blood pressure level are sex dependent.

    Science.gov (United States)

    Alfie, J; Waisman, G D; Galarza, C R; Magi, M I; Vasvari, F; Mayorga, L M; Cámera, M I

    1995-12-01

    Sex-related differences in systemic hemodynamics were analyzed by means of cardiac index and systemic vascular resistance according to the level of daytime ambulatory blood pressure. In addition, we assessed the relations between ambulatory blood pressure measurements and systemic hemodynamics in male and female patients. We prospectively included 52 women and 53 men referred to our unit for evaluation of arterial hypertension. Women and men were grouped according to the level of daytime mean arterial pressure: or = 110 mm Hg. Patients underwent noninvasive evaluation of resting hemodynamics (impedance cardiography) and 24-hour ambulatory blood pressure monitoring. Compared with women men with lower daytime blood pressure had a 12% higher systemic vascular resistance index (P = NS) and a 14% lower cardiac index (P < .02), whereas men with higher daytime blood pressure had a 25% higher vascular resistance (P < .003) and a 21% lower cardiac index (P < .0004). Furthermore, in men systemic vascular resistance correlated positively with both daytime and nighttime systolic and diastolic blood pressures, whereas cardiac index correlated negatively only with daytime diastolic blood pressure. In contrast, women did not exhibit any significant correlation between hemodynamic parameters and ambulatory blood pressure measurements. In conclusion, sex-related differences in systemic hemodynamics were more pronounced in the group with higher daytime hypertension. The relations between systemic hemodynamics and ambulatory blood pressure level depended on the sex of the patient. In men a progressive circulatory impairment underlies the increasing level of ambulatory blood pressure, but this was not observed in women.

  19. Age and dosage-level dependence of radium retention in beagles

    International Nuclear Information System (INIS)

    Parks, N.J.; Pool, R.R.; Williams, J.R.; Wolf, H.G.

    1978-01-01

    Radium retention was measured over the lifespan of 46 beagles exposed by eight semimonthly injections at 60 to 160, 120 to 220, or 435 to 535 days of age. Injection dosage levels ranged from 0.37 to 10 μCi of 226 Ra/kg. The fractional retention of each animal is described in terms of a modified power function, R = [(t + d)/d] - /sup b/. Young adult beagles (approximately equal to 10 kg) injected at a mean age (A) of 485 days with 226 Ra at dosage levels of 10, 3.3, 1.11, and 0.37 μCi/kg had mean values for d and b of [0.897; 0.187], [2.015; 0.206], [2.778; 0.257], and [3.894; 0.274], respectively. Juvenile beagles injected with 10 μCi/kg at A = 110 days (average weight approximately equal to 6 kg) and at A = 170 days (average weight approximately equal to 10 kg) had mean values for d and b of [137; 0.277] and [5.53; 0.086], respectively. The d values are geometric means and the units are days; b values are arithmetic means. The formula for deriving the age-dependent retention function for dogs is given. The beagle results were correlated with human data in terms of age-to-equivalent fraction of adult body calcium content and were used to construct a similar age-dependent retention function for chronically exposed people. The correlation of age-dependent retention functions for beagles and humans is used to estimate scaling factors between the two species for the fraction of injected dosage associated with bone for various ages of exposure

  20. Quantification, modelling and design for signal history dependent effects in mixed-signal SOI/SOS circuits; Quantification, modelisation et conception prenant en compte les etats anterieurs des signaux dans les circuits mixtes SOI/SOS

    Energy Technology Data Exchange (ETDEWEB)

    Edwards, C.F.; Redman-White, W.; Bracey, M.; Tenbroek, B.M.; Lee, M.S. [Southampton Univ., Dept. of Electronics and Computer Sciences (United Kingdom); Uren, M.J.; Brunson, K.M. [DERA Farnborough, GU, Hants (United Kingdom)

    1999-07-01

    This paper deals with how the radiation hardness of mixed signal SOI/SOS CMOS circuits is taken into account at both architectural terms as well as the the transistor level cell designs. The primary issue is to deal with divergent transistor threshold shifts, and to understand the effects of large amplitude non stationary signals on analogue cell behaviour. (authors)