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Sample records for activating danger signal

  1. Danger Signals Activating the Immune Response after Trauma

    Stefanie Hirsiger

    2012-01-01

    Full Text Available Sterile injury can cause a systemic inflammatory response syndrome (SIRS that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins as well as exogenous pathogen-associated molecular patterns (PAMPs play a crucial role in the initiation of the immune response. With popularization of the “danger theory,” numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1, interleukin-1α (IL-1α, and interleukin-33 (IL-33 as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.

  2. Danger signals activating the immune response after trauma

    Stefanie Hirsiger; Hans-Peter Simmen; Werner, Clément M. L.; Wanner, Guido A; Daniel Rittirsch

    2012-01-01

    Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immun...

  3. Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors

    Rossol, Manuela; Pierer, Matthias; Raulien, Nora; Quandt, Dagmar; Meusch, Undine; Rothe, Kathrin; Schubert, Kristin; Schöneberg, Torsten; Schaefer, Michael; Krügel, Ute; Smajilovic, Sanela; Bräuner-Osborne, Hans; Baerwald, Christoph; Wagner, Ulf

    2012-01-01

    calcium activates the NLRP3 inflammasome via stimulation of G protein-coupled calcium sensing receptors. Activation is mediated by signalling through the calcium-sensing receptor and GPRC6A via the phosphatidyl inositol/Ca(2+) pathway. The resulting increase in the intracellular calcium concentration...... this effect was inhibited in GPRC6A(-/-) mice. Our results demonstrate that G-protein-coupled receptors can activate the inflammasome, and indicate that increased extracellular calcium has a role as a danger signal and amplifier of inflammation....

  4. Eccrine sweat contains IL-1α, IL-1β and IL-31 and activates epidermal keratinocytes as a danger signal.

    Xiuju Dai

    Full Text Available Eccrine sweat is secreted onto the skin's surface and is not harmful to normal skin, but can exacerbate eczematous lesions in atopic dermatitis. Although eccrine sweat contains a number of minerals, proteins, and proteolytic enzymes, how it causes skin inflammation is not clear. We hypothesized that it stimulates keratinocytes directly, as a danger signal. Eccrine sweat was collected from the arms of healthy volunteers after exercise, and levels of proinflammatory cytokines in the sweat were quantified by ELISA. We detected the presence of IL-1α, IL-1β, and high levels of IL-31 in sweat samples. To investigate whether sweat activates keratinocytes, normal human keratinocytes were stimulated with concentrated sweat. Western blot analysis demonstrated the activation of NF-κB, ERK, and JNK signaling in sweat-stimulated keratinocytes. Real-time PCR using total RNA and ELISA analysis of supernatants showed the upregulation of IL-8 and IL-1β by sweat. Furthermore, pretreatment with IL-1R antagonist blocked sweat-stimulated cytokine production and signal activation, indicating that bioactive IL-1 is a major factor in the activation of keratinocytes by sweat. Moreover, IL-31 seems to be another sweat stimulator that activates keratinocytes to produce inflammatory cytokine, CCL2. Sweat is secreted onto the skin's surface and does not come into contact with keratinocytes in normal skin. However, in skin with a defective cutaneous barrier, such as atopic dermatitis-affected skin, sweat cytokines can directly act on epidermal keratinocytes, resulting in their activation. In conclusion, eccrine sweat contains proinflammatory cytokines, IL-1 and IL-31, and activates epidermal keratinocytes as a danger signal.

  5. Eccrine sweat contains IL-1α, IL-1β and IL-31 and activates epidermal keratinocytes as a danger signal.

    Dai, Xiuju; Okazaki, Hidenori; Hanakawa, Yasushi; Murakami, Masamoto; Tohyama, Mikiko; Shirakata, Yuji; Sayama, Koji

    2013-01-01

    Eccrine sweat is secreted onto the skin's surface and is not harmful to normal skin, but can exacerbate eczematous lesions in atopic dermatitis. Although eccrine sweat contains a number of minerals, proteins, and proteolytic enzymes, how it causes skin inflammation is not clear. We hypothesized that it stimulates keratinocytes directly, as a danger signal. Eccrine sweat was collected from the arms of healthy volunteers after exercise, and levels of proinflammatory cytokines in the sweat were quantified by ELISA. We detected the presence of IL-1α, IL-1β, and high levels of IL-31 in sweat samples. To investigate whether sweat activates keratinocytes, normal human keratinocytes were stimulated with concentrated sweat. Western blot analysis demonstrated the activation of NF-κB, ERK, and JNK signaling in sweat-stimulated keratinocytes. Real-time PCR using total RNA and ELISA analysis of supernatants showed the upregulation of IL-8 and IL-1β by sweat. Furthermore, pretreatment with IL-1R antagonist blocked sweat-stimulated cytokine production and signal activation, indicating that bioactive IL-1 is a major factor in the activation of keratinocytes by sweat. Moreover, IL-31 seems to be another sweat stimulator that activates keratinocytes to produce inflammatory cytokine, CCL2. Sweat is secreted onto the skin's surface and does not come into contact with keratinocytes in normal skin. However, in skin with a defective cutaneous barrier, such as atopic dermatitis-affected skin, sweat cytokines can directly act on epidermal keratinocytes, resulting in their activation. In conclusion, eccrine sweat contains proinflammatory cytokines, IL-1 and IL-31, and activates epidermal keratinocytes as a danger signal. PMID:23874436

  6. Preferred levels of auditory danger signals.

    Zera, J; Nagórski, A

    2000-01-01

    An important issue at the design stage of the auditory danger signal for a safety system is the signal audibility under various conditions of background noise. The auditory danger signal should be clearly audible but it should not be too loud to avoid fright, startling effects, and nuisance complaints. Criteria for designing auditory danger signals are the subject of the ISO 7731 (International Organization for Standardization [ISO], 1986) international standard and the EN 457 European standard (European Committee for Standardization [CEN], 1992). It is required that the A-weighted sound pressure level of the auditory danger signal is higher in level than the background noise by 15 dB. In this paper, the results of an experiment are reported, in which listeners adjusted most preferred levels of 3 danger signals (tone, sweep, complex sound) in the presence of a noise background (pink noise and industrial noise). The measurements were done for 60-, 70-, 80-, and 90-dB A-weighted levels of noise. Results show that for 60-dB level of noise the most preferred level of the danger signal is 10 to 20 dB above the noise level. However, for 90-dB level of noise, listeners selected a level of the danger signal that was equal to the noise level. Results imply that the criterion in the existing standards is conservative as it requires the level of the danger signal to be higher than the level of noise regardless of the noise level. PMID:10828157

  7. Eccrine Sweat Contains IL-1α, IL-1β and IL-31 and Activates Epidermal Keratinocytes as a Danger Signal

    Xiuju Dai; Hidenori Okazaki; Yasushi Hanakawa; Masamoto Murakami; Mikiko Tohyama; Yuji Shirakata; Koji Sayama

    2013-01-01

    Eccrine sweat is secreted onto the skin's surface and is not harmful to normal skin, but can exacerbate eczematous lesions in atopic dermatitis. Although eccrine sweat contains a number of minerals, proteins, and proteolytic enzymes, how it causes skin inflammation is not clear. We hypothesized that it stimulates keratinocytes directly, as a danger signal. Eccrine sweat was collected from the arms of healthy volunteers after exercise, and levels of proinflammatory cytokines in the sweat were ...

  8. Penicillin binding proteins as danger signals: meningococcal penicillin binding protein 2 activates dendritic cells through Toll-like receptor 4.

    Marcelo Hill

    Full Text Available Neisseria meningitidis is a human pathogen responsible for life-threatening inflammatory diseases. Meningococcal penicillin-binding proteins (PBPs and particularly PBP2 are involved in bacterial resistance to β-lactams. Here we describe a novel function for PBP2 that activates human and mouse dendritic cells (DC in a time and dose-dependent manner. PBP2 induces MHC II (LOGEC50 = 4.7 µg/ml ± 0.1, CD80 (LOGEC50 = 4.88 µg/ml ± 0.15 and CD86 (LOGEC50 = 5.36 µg/ml ± 0.1. This effect was abolished when DCs were co-treated with anti-PBP2 antibodies. PBP2-treated DCs displayed enhanced immunogenic properties in vitro and in vivo. Furthermore, proteins co-purified with PBP2 showed no effect on DC maturation. We show through different in vivo and in vitro approaches that this effect is not due to endotoxin contamination. At the mechanistic level, PBP2 induces nuclear localization of p65 NF-kB of 70.7 ± 5.1% cells versus 12 ± 2.6% in untreated DCs and needs TLR4 expression to mature DCs. Immunoprecipitation and blocking experiments showed thatPBP2 binds TLR4. In conclusion, we describe a novel function of meningococcal PBP2 as a pathogen associated molecular pattern (PAMP at the host-pathogen interface that could be recognized by the immune system as a danger signal, promoting the development of immune responses.

  9. Danger-signaler og inflammasomer ved autoinflammatoriske og autoimmune sygdomme

    Bendtzen, Klaus

    2011-01-01

    Cytoplasmic inflammasomes are formed through activation of pattern recognition receptors (PRR) of the innate immune system. Endogenous and exogenous danger signals, e.g. DNA- and RNA-fragments, urate- and cholesterol crystals, silica and asbestos, ß-amyloid, UV-light and skin irritants, may induce...

  10. Innate danger signals in acute injury: From bench to bedside.

    Fontaine, Mathieu; Lepape, Alain; Piriou, Vincent; Venet, Fabienne; Friggeri, Arnaud

    2016-08-01

    The description of the systemic inflammatory response syndrome (SIRS) as a reaction to numerous insults marked a turning point in the understanding of acute critical states, which are intensive care basic cases. This concept highlighted the final inflammatory response features whichever the injury mechanism is: infectious, or non-infectious such as extensive burns, traumas, major surgery or acute pancreatitis. In these cases of severe non-infectious insult, many endogenous mediators are released. Like infectious agents components, they can activate the immune system (via common signaling pathways) and initiate an inflammatory response. They are danger signals or alarmins. These molecules generally play an intracellular physiological role and acquire new functions when released in extracellular space. Many progresses brought new information on these molecules and on their function in infectious and non-infectious inflammation. These danger signals can be used as biomarkers and provide new pathophysiological and therapeutic approaches, particularly for immune dysfunctions occurring after an acute injury. We present herein the danger model, the main danger signals and the clinical consequences. PMID:26987739

  11. Staphylococcal Superantigens Spark Host-Mediated Danger Signals

    Terry eKrakauer

    2016-02-01

    Full Text Available Staphylococcal enterotoxin B (SEB of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal toxic shock. These protein toxins bind directly to specific V regions of T-cell receptors (TCR and major histocompatibility complex (MHC class II on antigen-presenting cells, resulting in hyperactivation of T lymphocytes and monocytes / macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1, IL-2, interferon γ (IFNγ, and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. Because of superantigen-induced T cells skewed towards TH1 helper cells, and the induction of proinflammatory cytokines, superantigens can exacerbate autoimmune diseases. Upon TCR / MHC ligation, pathways induced by superantigens include the mitogen-activated protein kinase cascades and cytokine receptor signaling, resulting in activation of NFκB and the phosphoinositide 3-kinase / mammalian target of rapamycin pathways. Various mouse models exist to study SEB-induced shock including those with potentiating agents, transgenic mice and an SEB-only model. However, therapeutics to treat toxic shock remain elusive as host response genes central to pathogenesis of superantigens have only been identified recently. Gene profiling of a murine model for SEB-induced shock reveals novel molecules upregulated in multiple organs not previously associated with SEB-induced responses. The pivotal genes include intracellular DNA / RNA sensors, apoptosis / DNA damage-related molecules, immunoproteasome components, as well as anti-viral and IFN-stimulated genes. The host-wide induction of these, and other, anti-microbial defense genes provide evidence that SEB elicits danger signals resulting in multi

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

    Paul Matthew Gallo

    2013-06-01

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

  13. High-resolution mass spectrometry driven discovery of peptidic danger signals in insect immunity.

    Berisha, Arton; Mukherjee, Krishnendu; Vilcinskas, Andreas; Spengler, Bernhard; Römpp, Andreas

    2013-01-01

    The 'danger model' is an alternative concept for immune response postulating that the immune system reacts to entities that do damage (danger associated molecular patterns, DAMP) and not only to entities that are foreign (pathogen-associated molecular patterns, PAMP) as proposed by classical immunology concepts. In this study we used Galleria mellonella to validate the danger model in insects. Hemolymph of G. mellonella was digested with thermolysin (as a representative for virulence-associated metalloproteinases produced by humanpathogens) followed by chromatographic fractionation. Immune-stimulatory activity was tested by measuring lysozyme activity with the lytic zone assays against Micrococcus luteus cell wall components. Peptides were analyzed by nano-scale liquid chromatography coupled to high-resolution Fourier transform mass spectrometers. Addressing the lack of a genome sequence we complemented the rudimentary NCBI protein database with a recently established transcriptome and de novo sequencing methods for peptide identification. This approach led to identification of 127 peptides, 9 of which were identified in bioactive fractions. Detailed MS/MS experiments in comparison with synthetic analogues confirmed the amino acid sequence of all 9 peptides. To test the potential of these putative danger signals to induce immune responses we injected the synthetic analogues into G. mellonella and monitored the anti-bacterial activity against living Micrococcus luteus. Six out of 9 peptides identified in the bioactive fractions exhibited immune-stimulatory activity when injected. Hence, we provide evidence that small peptides resulting from thermolysin-mediated digestion of hemolymph proteins function as endogenous danger signals which can set the immune system into alarm. Consequently, our study indicates that the danger model also plays a role in insect immunity. PMID:24303012

  14. DMPD: Innate immune sensing of pathogens and danger signals by cell surface Toll-likereceptors. [Dynamic Macrophage Pathway CSML Database

    Full Text Available 17275324 Innate immune sensing of pathogens and danger signals by cell surface Toll... Show Innate immune sensing of pathogens and danger signals by cell surface Toll-likereceptors. PubmedID 172...75324 Title Innate immune sensing of pathogens and danger signals by cell surface

  15. Various Forms of Tissue Damage and Danger Signals Following Hematopoietic Stem-Cell Transplantation

    Ramadan, Abdulraouf; Paczesny, Sophie

    2014-01-01

    Hematopoietic stem-cell transplantation (HSCT) is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD), which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T-cells and recipient’s antigen-presenting cells). This tissue damage leads to the release of alarmins and the triggering of pathogen-recognition receptors that activate the innate immune system and subsequently the adaptive immune system. Alarmins, which are of endogenous origin, together with the exogenous pathogen-associated molecular patterns (PAMPs) elicit similar responses of danger signals and represent the group of damage-associated molecular patterns (DAMPs). Effector cells of innate and adaptive immunity that are activated by PAMPs or alarmins can secrete other alarmins and amplify the immune responses. These complex interactions and loops between alarmins and PAMPs are particularly potent at inducing and then aggravating the GVHD reaction. In this review, we highlight the role of these tissue damaging molecules and their signaling pathways. Interestingly, some DAMPs and PAMPs are organ specific and GVHD-induced and have been shown to be interesting biomarkers. Some of these molecules may represent potential targets for novel therapeutic approaches. PMID:25674088

  16. Various forms of tissue damage and danger signals following hematopoietic stem cell transplantation

    Abdulraouf eRamadan

    2015-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD, which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T cells and recipient’s antigen-presenting cells. This tissue damage leads to the release of alarmins and the triggering of pathogen-recognition receptors that activate the innate immune system and subsequently the adaptive immune system. Alarmins, which are of endogenous origin, together with the exogenous pathogen-associated molecular patterns (PAMPs elicit similar responses of danger signals and represent the group of damage-associated molecular patterns (DAMPs. Effector cells of innate and adaptive immunity that are activated by PAMPs or alarmins can secrete other alarmins and amplify the immune responses. These complex interactions and loops between alarmins and PAMPs are particularly potent at inducing and then aggravating the GVHD reaction. In this review, we highlight the role of these tissue damaging molecules and their signaling pathways. Interestingly, some DAMPs and PAMPs are organ specific and GVHD-induced and have been shown to be interesting biomarkers. Some of these molecules even represent potential targets for novel therapeutic approaches.

  17. Railway signals passed at danger. Situational and personal factors underlying stop signal abuse.

    van der Flier, H; Schoonman, W

    1988-06-01

    Based upon a systematic registration of cases of unauthorised passing through signals at danger (SPD cases) during the period 1 January 1983 to 1 January 1985, the contribution of situational and personal factors to the occurrence of this kind of safety error was studied. Exposural deviances were taken into account by presenting the relevant exposural details as well as the SPD frequencies. To study the effect of personal factors, the group of drivers involved was compared with an individually matched control group. Data analysis indicated that SPD cases tended to be fairly evenly dispersed over the months of the year. The distribution of incidents throughout the days of the week corresponded rather closely to the numbers of train driver shifts. Neither technical nor mechanical faults nor weather nor visibility conditions seemed to be significant contributory factors. SPD cases were relatively many during the morning hours (midnight till 6 am and 8 am till noon) and at the start of duty periods. At a number of (black) spots two or more cases were recorded accounting for a relatively high percentage of all cases. The most frequently mentioned hazard was that of the signal being situated behind a bend. About 90% of the cases took place at or near stations and most were with arriving trains. The direct cause of an SPD case often seemed to be that a signal was overlooked or not anticipated. Personal factors (age, time on duty, length of service or track and rolling-stock experience) did not seem to be important variables. However, it was proven that previous incidents, worse performance with multiple choice reaction tests, and less job satisfaction are predictive of a future SPD case. In this study the consequences of SPD cases were not as serious as they could be. Most damage was to points (forced open). Other consequences include level crossings not closed and a very small number of crashes. There were no fatalities and only one person was injured as a result of stop

  18. Release of Danger Signals during Ischemic Storage of the Liver: A Potential Marker of Organ Damage?

    Anding Liu

    2010-01-01

    Full Text Available Liver grafts suffer from unavoidable injury due to ischemia and manipulation before implantation. Danger signals such as high-mobility group box -1(HMGB1 and macrophage migration inhibitory factor (MIF play a pivotal role in the immune response. We characterized the kinetics of their release into the effluent during cold/warm ischemia and additional manipulation-induced mechanical damage. Furthermore, we evaluated the relationship between HMGB1/MIF release and ischemic/mechanical damage. Liver enzymes and protein in the effluent increased with increasing ischemia time. HMGB1/MIF- release correlated with the extent of hepatocellular injury. With increasing ischemia time and damage, HMGB1 was translocated from the nucleus to the cytoplasma as indicated by weak nuclear and strong cytoplasmic staining. Enhancement of liver injury by mechanical damage was indicated by an earlier HMGB1 translocation into the cytoplasm and earlier release of danger signals into the effluent. Our results suggest that determination of HMGB1 and MIF reflects the extent of ischemic injury. Furthermore, HMGB1and MIF are more sensitive than liver enzymes to detect the additional mechanical damage inflicted on the organ graft during surgical manipulation.

  19. STAT3 Activities and Energy Metabolism: Dangerous Liaisons

    STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3C/C) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3C/C MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3C/C MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms

  20. STAT3 Activities and Energy Metabolism: Dangerous Liaisons

    Camporeale, Annalisa, E-mail: annalisa.camporeale@unito.it [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy); Demaria, Marco [Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945 (United States); Monteleone, Emanuele [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy); Giorgi, Carlotta [Department of Experimental and Diagnostic Medicine, Section of General Pathology, Laboratory for Technologies of Advances Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121 (Italy); Wieckowski, Mariusz R. [Nencki Institute of Experimental Biology, Department of Biochemistry, Pasteur Str. 3, Warsaw 02-093 (Poland); Pinton, Paolo [Department of Experimental and Diagnostic Medicine, Section of General Pathology, Laboratory for Technologies of Advances Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121 (Italy); Poli, Valeria, E-mail: annalisa.camporeale@unito.it [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy)

    2014-07-31

    STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3{sup C/C}) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3{sup C/C} MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3{sup C/C} MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms.

  1. Using an Activity to Simulate the Dangers of Multitasking with Technology while Walking

    Lazaros, Edward J.; Xu, Renmei; Londt, Susan

    2012-01-01

    People are increasingly trying to multitask while walking. Text messaging while walking is a significant area for concern. The number of text messages sent is expected to be more than 8 trillion in 2012. Texting is becoming so commonplace that people use this technology while engaged in other activities. The dangers of multitasking have hit the…

  2. DMPD: Regulation of TLR4 signaling and the host interface with pathogens and danger:the role of RP105. [Dynamic Macrophage Pathway CSML Database

    Full Text Available 17470533 Regulation of TLR4 signaling and the host interface with pathogens and dan...tion of TLR4 signaling and the host interface with pathogens and danger:the role ...of RP105. PubmedID 17470533 Title Regulation of TLR4 signaling and the host interface with pathogens and dan

  3. Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway

    WANG Hui; LI Zhuo-ya; WU He-shui; WANG Yang; JIANG Chun-fang; ZHENG Qi-chang; ZHANG Jin-xiang

    2007-01-01

    Background Restoration of blood flow to the ischemic liver lobes may paradoxically exacerbate tissue injury, which is called hepatic ischemia/reperfusion injury (IRI). Toll-like receptor 4 (TLR4), expressed on several liver cell types, and the nuclear factor-kappa B (NF-κB) signaling pathway are crucial to mediating hepatic inflammatory response. Because IRI is essentially a kind of profound acute inflammatory reaction evoked by many kinds of danger signals, we investigated TLR4/NF-κB signaling pathway activation in a murine model of partial hepatic IRI.Methods Wild-type mice (Wr, C3H/HeN) or TLR4 mutant mice (C3H/HeJ) were subjected to 45 minutes of partial hepatic ischemia followed by 1 hour, 3 hours of reperfusion. Sham group accepted the same procedure without the obstruction of blood supply. At the end of reperfusion, the compromise of liver function and the histological change of liver sections were measured as the severity of liver injury. The level of endotoxin in the portal vein was measured by limulus assay. NF-κB activation was determined by electrophoretic mobility shift assay (EMSA). The levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in systemic blood after hepatic IRI were assessed by enzyme-linked immunosorbent assay (ELISA).Results The compromise of liver function and the morphological injuries in mutant mice were relieved more markedly than those in WT mice after partial hepatic IRI. NF-κB activation in WT mice was stronger than that in TLR4 mutant mice,and both were stronger than those in the sham operated mice (P<0.01). Endotoxin in each group was undetectable. The levels of TNF-α and IL-1β in systemic blood were elevated in both strains, but lower in the sham operated group. These mediators were significantly decreased in TLR4 mutant mice compared with those in WT mice (P<0.01).Conclusions The TLR4/NF-κB signaling pathway may mediate hepatic IRI triggered by endogenous danger signals.Inhibition of the TLR4/NF

  4. Short-term memory of danger signals or environmental stimuli in mesenchymal stem cells: implications for therapeutic potential.

    Liu, Guang-Yang; Liu, Yang; Lu, Ying; Qin, Ya-Ru; Di, Guo-Hu; Lei, Yong-Hong; Liu, Hu-Xian; Li, Yan-Qi; Wu, Chutse; Hu, Xian-Wen; Duan, Hai-Feng

    2016-05-01

    Mesenchymal stem/stromal cells (MSCs) possess some characteristics of immune cells, including a pro-inflammatory phenotype, an immunosuppressive phenotype, antibacterial properties and the expression of Toll-like receptor proteins. Here we show that, similar to immune cells, MSCs retain information from danger signals or environmental stimuli for a period of time. When treated with the pro-inflammatory factors lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), MSCs display increased expression of IL-6, IL-8 and MCP-1. Following re-plating and several rounds of cell division in the absence of stimulating factors, the expression of IL-6, IL-8 and MCP-1 remained higher than in untreated cells for over 7 days. A spike in cytokine secretion occurred when cells were exposed to a second round of stimulation. We primed MSCs with LPS and LPS-primed MSCs had better therapeutic efficacy at promoting skin flap survival in a diabetic rat model than did unprimed MSCs. Finally, we found that several microRNAs, including miR146a, miR150 and miR155, along with the modification of DNA by 5-hydroxymethylcytosine (5hmC), mediate the MSC response to LPS and TNF-α stimulation. Collectively, our data suggest that MSCs have a short-term memory of environmental signals, which may impact their therapeutic potential. PMID:25942600

  5. Various Forms of Tissue Damage and Danger Signals Following Hematopoietic Stem-Cell Transplantation

    Ramadan, Abdulraouf; Paczesny, Sophie

    2015-01-01

    Hematopoietic stem-cell transplantation (HSCT) is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD), which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T-cells and recipient’s antigen-presenting cells). This tissue damage leads to the release of alarmins and the trigger...

  6. Divergence of canonical danger signals: The genome-level expression patterns of human mononuclear cells subjected to heat shock or lipopolysaccharide

    Sakthivel Bhuvaneswari

    2008-05-01

    Full Text Available Abstract Background Peripheral blood mononuclear cells (PBMC serve a sentinel role allowing the host to efficiently sense and adapt to the presence of danger signals. Herein we have directly compared the genome-level expression patterns (microarray of a human PBMC model (THP-1 cells subjected to one of two canonical danger signals, heat shock or lipopolysaccharide (LPS. Results and Discussion Based on sequential expression and statistical filters, and in comparison to control cells, we found that 3,988 genes were differentially regulated in THP-1 cells subjected to LPS stress, and 2,921 genes were differentially regulated in THP-1 cells subjected to heat shock stress. Venn analyses demonstrated that the majority of differentially regulated genes (≥ 70% were uniquely expressed in response to one of the two danger signals. Functional analyses demonstrated that the two danger signals induced expression or repression of genes corresponding to unique pathways, molecular functions, biological processes, and gene networks. In contrast, there were 184 genes that were commonly upregulated by both stress signals, and 430 genes that were commonly downregulated by both stress signals. Interestingly, the 184 commonly upregulated genes corresponded to a gene network broadly related to inflammation, and more specifically to chemokine signaling. Conclusion These data demonstrate that the mononuclear cell responses to the canonical stress signals, heat shock and LPS, are highly divergent. However, there is a heretofore unrecognized common pattern of gene network expression corresponding to chemokine-related biology. The data also serve as a reference database for investigators in the field of stress signaling.

  7. Death-associated Protein Kinase Mediated Cell Death Modulated by Interaction with DANGER

    Kang, Bingnan N.; Ahmad, Abdullah S.; Saleem, Sofiyan; Patterson, Randen L.; Hester, Lynda; Doré, Sylvain; Snyder, Solomon H.

    2010-01-01

    Death-associated protein kinase (DAPK) is a key player in multiple cell death signaling pathways. We report that DAPK is regulated by DANGER, a partial MAB-21-domain containing protein. DANGER binds directly to DAPK and inhibits DAPK catalytic activity. DANGER-deficient mouse embryonic fibroblasts and neurons exhibit greater DAPK activity and increased sensitivity to cell death stimuli than do wild-type control cells. In addition, DANGER-deficient mice manifest more severe brain damage after ...

  8. Does Pedestrian Danger Mediate the Relationship between Local Walkability and Active Travel to Work?

    Sandy J Slater

    2016-05-01

    Full Text Available Background: Environmental and policy factors play an important role in influencing people’s lifestyles, physical activity (PA, and risks for developing obesity. Research suggests that more walkable communities are needed to sustain lifelong PA behavior, but there is a need to determine what local built environment features facilitate making being active the easy choice.Purpose: This county-level study examined the association between local walkability (walkability and traffic calming scales, pedestrian danger, and the percent of adults who used active transport to work. Methods: Built environment and PA outcome measures were constructed for the 496 most populous counties representing 74 percent of the U.S. population. GIS-based walkability scales were constructed and include a census of roads located within the counties using 2011 Navteq data. The pedestrian danger index (PDI includes data collected from the Fatality Analysis Reporting System 2009-2011, and measures the likelihood of a pedestrian being hit and killed by a vehicle. Four continuous outcome measures were constructed using 2009-2013 American Community Survey county-level 5-year estimates. The measures represent the percentage of workers living in a county who worked away from home and: 1 walked to work; 2 biked to work; 3 took public transit; and 4 used any form of active transport. Linear regression and mediation analyses were conducted to examine the association between walkability, PDI and active transport. Models accounted for clustering within state with robust standard errors, and controlled for median household income, families with children in poverty, race, ethnicity, urbanicity and region.Results: The walkability scale was significantly negatively associated with the PDI (β=-0.06, 95% CI=-0.111, -0.002. In all models, the PDI was significantly negatively associated with all active travel-related outcomes at the p<0.01 level. The walkability scale was positively

  9. Bacterial danger sensing.

    LeRoux, Michele; Peterson, S Brook; Mougous, Joseph D

    2015-11-20

    Here we propose that bacteria detect and respond to threats posed by other bacteria via an innate immune-like process that we term danger sensing. We find support for this contention by reexamining existing literature from the perspective that intermicrobial antagonism, not opportunistic pathogenesis, is the major evolutionary force shaping the defensive behaviors of most bacteria. We conclude that many bacteria possess danger sensing pathways composed of a danger signal receptor and corresponding signal transduction mechanism that regulate pathways important for survival in the presence of the perceived competitor. PMID:26434507

  10. Signal Processing under Active Monitoring

    Mostovyi, Oleksii

    2005-01-01

    This paper describes a method of signal preprocessing under active monitoring. Suppose we want to solve the inverse problem of getting the response of a medium to one powerful signal, which is equivalent to obtaining the transmission function of the medium, but do not have an opportunity to conduct such an experiment (it might be too expensive or harmful for the environment). Practically the problem can be reduced to obtaining the transmission function of the medium. In this case ...

  11. Electroporated Antigen-Encoding mRNA Is Not a Danger Signal to Human Mature Monocyte-Derived Dendritic Cells

    Stefanie Hoyer

    2015-01-01

    Full Text Available For therapeutic cancer vaccination, the adoptive transfer of mRNA-electroporated dendritic cells (DCs is frequently performed, usually with monocyte-derived, cytokine-matured DCs (moDCs. However, DCs are rich in danger-sensing receptors which could recognize the exogenously delivered mRNA and induce DC activation, hence influencing the DCs’ immunogenicity. Therefore, we examined whether electroporation of mRNA with a proper cap and a poly-A tail of at least 64 adenosines had any influence on cocktail-matured moDCs. We used 16 different RNAs, encoding tumor antigens (MelanA, NRAS, BRAF, GNAQ, GNA11, and WT1, and variants thereof. None of those RNAs induced changes in the expression of CD25, CD40, CD83, CD86, and CD70 or the secretion of the cytokines IL-8, IL-6, and TNFα of more than 1.5-fold compared to the control condition, while an mRNA encoding an NF-κB-activation protein as positive control induced massive secretion of the cytokines. To determine whether mRNA electroporation had any effect on the whole transcriptome of the DCs, we performed microarray analyses of DCs of 6 different donors. None of 60,000 probes was significantly different between mock-electroporated DCs and MelanA-transfected DCs. Hence, we conclude that no transcriptional programs were induced within cocktail-matured DCs by electroporation of single tumor-antigen-encoding mRNAs.

  12. Contesting danger

    Heathershaw, John; Megoran, Nick

    2011-01-01

    of danger is contested within the region. The example of urban violence in Osh, Kyrgyzstan and Jalalabad, Afghanistan in 2010 demonstrates how opportunities to mitigate conflict may have been lost due to the distortions of this discourse of danger. It concludes by raising the challenge to policy...... and subsequent considerations of the region in terms of the war on terror. It considers several examples of this discourse of danger including the popular US TV drama about presidential politics, The West Wing, the policy texts of ‘Washingtonian security analysis’ and accounts of danger, insecurity and urban...... violence in the Ferghana Valley. It is argued that popular policy and academic texts are relatively consistent across the three dimensions of endangerment. This argument is demonstrated through a discussion of how policy-making and practice is informed by this discourse of danger and of how the discourse...

  13. Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin-1 beta production in peripheral blood mononuclear cell.

    Pitanga, Thassila N; Oliveira, Ricardo R; Zanette, Dalila L; Guarda, Caroline C; Santiago, Rayra P; Santana, Sanzio S; Nascimento, Valma M L; Lima, Jonilson B; Carvalho, Graziele Q; Maffili, Vitor V; Carvalho, Magda O S; Alcântara, Luiz C J; Borges, Valéria M; Goncalves, Marilda S

    2016-07-01

    This study tested the hypothesis that sickle red blood cell (SS-RBC) induce Toll-like receptors (TLR) and Nod-like receptor family, pyrin domain containing 3 (NLRP3)- inflammasome expression in peripheral blood mononuclear cells (PBMC). TLR and NLRP3 inflammasome could contribute to the maintenance of the inflammatory status in sickle cell anemia (SCA) patients, since SS-RBC act as danger signals activating these pathways. In this study, first, we evaluated TLR (2, 4, 5 and 9), NLRP3, Caspase-1, interleukin (IL)-1β and IL-18 expression in PBMC freshly isolated from SCA patients (SS-PBMC) in comparison with PBMC from healthy individuals (AA-PBMC). In the second moment, we investigated whether SS-RBC could interfere with the expression of these molecules in PBMC from healthy donor, in the absence or presence of hydroxyurea (HU) in vitro. TLRs and NLRP3 inflammasome expression were investigated by qPCR. IL-1β, Leukotriene-B4 (LTB4) and nitrite production were measured in PBMC (from healthy donor) culture supernatants. TLR2, TLR4, TLR5, NLRP3 and IL-1β were highly expressed in SS-PBMC when compared to AA-PBMC. Additionally, SS-RBC induced TLR9, NLRP3, Caspase-1, IL-1β and IL-18 expression and induced IL-1β, LTB4 and nitrite production in PBMC cultures. HU did not prevent TLR and NLRP3 inflammasome expression, but increased TLR2 and IL-18 expression and reduced nitrite production. In conclusion, our data suggest that TLR and inflammasome complexes may be key inducers of inflammation in SCA patients, probably through SS-RBC; also, HU does not prevent NLRP3 inflammasome- and TLR-dependent inflammation, indicating the need to develop new therapeutic strategies to SCA patients that act with different mechanisms of those observed for HU. PMID:27045344

  14. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases

    Amna Abderrazak

    2015-04-01

    An ever increasing number of studies link the sensing of cellular stress signals to a direct pathophysiological role of NLRP3 activation in a wide range of autoinflammatory and autoimmune disorders, and thus provide a novel mechanistic rational, on how molecules trigger and support sterile inflammatory diseases. A vast interest has created to unravel how NLRP3 becomes activated, since mechanistic insight is the prerequisite for a knowledge-based development of therapeutic intervention strategies that specifically target the NLRP3 triggered IL-1β production. In this review, we have updated knowledge on NLRP3 inflammasome assembly and activation and on the pyrin domain in NLRP3 that could represent a drug target to treat sterile inflammatory diseases. We have reported mutations in NLRP3 that were found to be associated with certain diseases. In addition, we have reviewed the functional link between NLRP3 inflammasome, the regulator of cellular redox status Trx/TXNIP complex, endoplasmic reticulum stress and the pathogenesis of diseases such as type 2 diabetes. Finally, we have provided data on NLRP3 inflammasome, as a critical regulator involved in the pathogenesis of obesity and cardiovascular diseases.

  15. Trauma is danger

    Porterfield Nancy

    2011-06-01

    Full Text Available Abstract Background Trauma is one of the leading causes of death in young adult patients. Many pre-clinical and clinical studies attempt to investigate the immunological pathways involved, however the true mediators remain to be elucidated. Herein, we attempt to describe the immunologic response to systemic trauma in the context of the Danger model. Data Sources A literature search using PubMed was used to identify pertinent articles describing the Danger model in relation to trauma. Conclusions Our knowledge of Danger signals in relation to traumatic injury is still limited. Danger/alarmin signals are the most proximal molecules in the immune response that have many possibilities for effector function in the innate and acquired immune systems. Having a full understanding of these molecules and their pathways would give us the ability to intervene at such an early stage and may prove to be more effective in blunting the post-injury inflammatory response unlike previously failed cytokine experiments.

  16. ATP release and purinergic signaling in NLRP3 inflammasome activation

    Isabelle eCOUILLIN

    2013-01-01

    Full Text Available The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing that senses pathogen- and danger-associated molecular patterns. One step- or two step- models have been proposed to explain the tight regulation of IL-1β production during inflammation. Moreover, cellular stimulation triggers ATP release and subsequent activation of purinergic receptors at the cell surface. Importantly some studies have reported roles for extracellular ATP (eATP, in NLRP3 inflammasome activation in response to PAMPs and DAMPs. In this mini review, we will discuss the link between active ATP release, purinergic signaling and NLRP3 inflammasome activation. We will focus on the role of autocrine or paracrine ATP export in particle-induced NLRP3 inflammasome activation and discuss how particle activators are competent to induce maturation and secretion of IL-1β through a process that involves, as a first event, extracellular release of endogenous ATP through hemichannel opening, and as a second event, signaling through purinergic receptors that trigger NLRP3 inflammasome activation. Finally, we will review the evidence for ATP as a key proinflammatory mediator released by dying cells. In particular we will discuss how cancer cells dying via autophagy trigger ATP-dependent NLRP3 inflammasome activation in the macrophages engulfing them, eliciting an immunogenic response against tumors.

  17. [Dangerous animals].

    Hasle, Gunnar

    2002-06-30

    As travellers seek ever more exotic destinations they are more likely to encounter dangerous animals. Compared to risks such as AIDS, traffic accidents and malaria, the risk is not so great; many travellers are, however, concerned about this and those who give pre-travel vaccines and advice should know something about it. This article is mainly based on medical and zoological textbooks. Venomous stings and bites may be prevented by adequate clothing and by keeping safe distance to the animals. Listening to those who live in the area is of course important. Travellers should not carry antisera with them, but antisera should be available at local hospitals. It should be borne in mind that plant eaters cause just as many deaths as large predators. In some cases it is necessary to carry a sufficiently powerful firearm. PMID:12555616

  18. Dangerous surplus

    As a result of existing arms control reduction commitments, approximately 50 metric tons of weapon-grade plutonium is expected to become surplus in the United States--and a similar or larger amount in Russia--over the next 10 years. It is crucial that this surplus weapons plutonium be managed in a way that minimizes the danger that it will be re-used for weapons, does not lead to increased accessibility of civilian plutonium for weapons use, and meets reasonable standards for cost and human and environmental safety. The Committee on International Security and Arms Control (CISAC) of the National Academy of Sciences recently conducted an 18-month study for the U.S. government for methods of weapons plutonium management. This article summarizes the resulting report, which was released on January 24. The special security problems posed by plutonium are outlined. Three early phases of plutonium management emphasized by the report are discussed. Two candidate approaches for reducing the accessibility of weapons plutonium are described. One is to fabricate the weapons plutonium into mixed oxide fuel for reactors; the other is to mix the weapons plutonium with already reprocessed high-level radioactive waste for vitrification and long-term disposal. In either of the two approaches, the end result would be the dilution and the contamination of the weapons plutonium with a radioactive waste form. For both approaches, the ultimate destination of the plutonium would be a geologic repository

  19. DMPD: Macrophage activation by endogenous danger signals. [Dynamic Macrophage Pathway CSML Database

    Full Text Available G File (.svg) HTML File (.html) CSML File (.csml) Open .csml file with CIOPlayer Open .csml file with CIOPla...yer - ※CIO Playerのご利用上の注意 Open .csml file with CIO Open .csml file with CIO - ※CIOのご利用上の注意 ...

  20. Myocardial infarction following recombinant tissue plasminogen activator treatment for acute ischemic stroke: a dangerous complication

    ZHOU Zhi-gang; WANG Rui-lan; YU Kang-long

    2012-01-01

    Thrombolysis with intravenous tissue plasminogen activator (t-PA) is currently an approved therapy for patients with acute ischemic stroke.Acute myocardial infarction (AMI) immediately following t-PA treatment for stroke is a rare but serious complication.A case of acute myocardial infarction (MI) following IV t-PA infusion for acute stroke was observed.This is a 52-year-old male with a known history of hypertension and chest pain,who subsequently developed MI four hours after IV t-PA was administered for acute ischemic stroke.The disruption of intra-cardiac thrombus and subsequent embolization to the coronary arteries may be an important mechanism.In addition.spontaneous recanalization of infarct-related arteries may be associated with 9reater myocardial salvage and better prognosis.

  1. Dangerous Forms – Playing by the Visual Rules. Ecological Approach to Videogames as Activity

    Meldgaard, Betty Li Malvang

    2011-01-01

    The purpose of the dissertation is to investigate the role of perception while palying videogames. The main thesis is that theories of perception have been largely overlooked within the videogame research field. The basic assumption is that to address the perceptual implications of game play, the...... typical notions of videogames with a focus on the narrative or ludic aspects, which have dominated the field, are not an appropriate outset for this type of study. The attempt her will be to look at videogames from a systemic framework in order to address the interdependent functionality of the elements...... understanding of the reciprocality of videogame - player system. The approach will be interdiciplinary with respect to an integrational view of videogames as human - computer systems wich afford specific types of activities and perceptual awareness. Eventually a new concept will emerge....

  2. Biased Signaling of Protease-activated Receptors

    PeishenZhao; NigelWilliamBunnett

    2014-01-01

    In addition to their role in protein degradation and digestion, proteases can also function as hormone-like signaling molecules that regulate vital patho-physiological processes, including inflammation, hemostasis, pain and repair mechanisms. Certain proteases can signal to cells by cleaving protease-activated receptors (PARs), a family of four G protein-coupled receptors. PARs are expressed by almost all cell types, control important physiological and disease-relevant processes, and are an e...

  3. Lung carcinoma signaling pathways activated by smoking

    Jing Wen; Jian-Hua Fu; Wei Zhang; Ming Guo

    2011-01-01

    Lung cancer is the leading cause of cancer death in men and women worldwide, with over a million deaths annually. Tobacco smoke is the major etiologic risk factor for lung cancer in current or previous smokers and has been strongly related to certain types of lung cancer, such as small cell lung carcinoma and squamous cell lung carcinoma. In recent years, there has been an increased incidence of lung adenocarcinoma. This change is strongly associated with changes in smoking behavior and cigarette design. Carcinogens present in tobacco products and their intermediate metabolites can activate multiple signaling pathways that contribute to lung cancer carcinogenesis. In this review, we summarize the smoking-activated signaling pathways involved in lung cancer.

  4. Disentangling stellar activity and planetary signals

    Santos N.C.

    2011-02-01

    Full Text Available Photospheric stellar activity (i.e. dark spots or bright plages might be an important source of noise and confusion in the radial-velocity (RV measurements. Radial-velocimetry planet search surveys as well as follow-up of photometric transit surveys require a deep understanding and precise characterization of the effects of stellar activity, in order to disentangle it from planetary signals. We simulate dark spots on a rotating stellar photosphere. The variations of the RV are characterized and analyzed according to the stellar inclination, the latitude and the number of spots. The Lomb-Scargle periodograms of the RV variations induced by activity present power at the rotational period Prot of the star and its two-first harmonics Prot/2 and Prot/3. Three adjusted sinusoids fixed at the fundamental period and its two-first harmonics allow to remove about 90% of the RV jitter amplitude. We apply and validate our approach on four known active planet-host stars: HD 189733, GJ 674, CoRoT-7 and ι Hor.

  5. Heat dissipation guides activation in signaling proteins.

    Weber, Jeffrey K; Shukla, Diwakar; Pande, Vijay S

    2015-08-18

    Life is fundamentally a nonequilibrium phenomenon. At the expense of dissipated energy, living things perform irreversible processes that allow them to propagate and reproduce. Within cells, evolution has designed nanoscale machines to do meaningful work with energy harnessed from a continuous flux of heat and particles. As dictated by the Second Law of Thermodynamics and its fluctuation theorem corollaries, irreversibility in nonequilibrium processes can be quantified in terms of how much entropy such dynamics produce. In this work, we seek to address a fundamental question linking biology and nonequilibrium physics: can the evolved dissipative pathways that facilitate biomolecular function be identified by their extent of entropy production in general relaxation processes? We here synthesize massive molecular dynamics simulations, Markov state models (MSMs), and nonequilibrium statistical mechanical theory to probe dissipation in two key classes of signaling proteins: kinases and G-protein-coupled receptors (GPCRs). Applying machinery from large deviation theory, we use MSMs constructed from protein simulations to generate dynamics conforming to positive levels of entropy production. We note the emergence of an array of peaks in the dynamical response (transient analogs of phase transitions) that draw the proteins between distinct levels of dissipation, and we see that the binding of ATP and agonist molecules modifies the observed dissipative landscapes. Overall, we find that dissipation is tightly coupled to activation in these signaling systems: dominant entropy-producing trajectories become localized near important barriers along known biological activation pathways. We go on to classify an array of equilibrium and nonequilibrium molecular switches that harmonize to promote functional dynamics. PMID:26240354

  6. New Constitutively Active Phytochromes Exhibit Light-Independent Signaling Activity.

    Jeong, A-Reum; Lee, Si-Seok; Han, Yun-Jeong; Shin, Ah-Young; Baek, Ayoung; Ahn, Taeho; Kim, Min-Gon; Kim, Young Soon; Lee, Keun Woo; Nagatani, Akira; Kim, Jeong-Il

    2016-08-01

    Plant phytochromes are photoreceptors that mediate a variety of photomorphogenic responses. There are two spectral photoisomers, the red light-absorbing Pr and far-red light-absorbing Pfr forms, and the photoreversible transformation between the two forms is important for the functioning of phytochromes. In this study, we isolated a Tyr-268-to-Val mutant of Avena sativa phytochrome A (AsYVA) that displayed little photoconversion. Interestingly, transgenic plants of AsYVA showed light-independent phytochrome signaling with a constitutive photomorphogenic (cop) phenotype that is characterized by shortened hypocotyls and open cotyledons in the dark. In addition, the corresponding Tyr-303-to-Val mutant of Arabidopsis (Arabidopsis thaliana) phytochrome B (AtYVB) exhibited nuclear localization and interaction with phytochrome-interacting factor 3 (PIF3) independently of light, conferring a constitutive photomorphogenic development to its transgenic plants, which is comparable to the first constitutively active version of phytochrome B (YHB; Tyr-276-to-His mutant). We also found that chromophore ligation was required for the light-independent interaction of AtYVB with PIF3. Moreover, we demonstrated that AtYVB did not exhibit phytochrome B activity when it was localized in the cytosol by fusion with the nuclear export signal and that AsYVA exhibited the full activity of phytochrome A when localized in the nucleus by fusion with the nuclear localization signal. Furthermore, the corresponding Tyr-269-to-Val mutant of Arabidopsis phytochrome A (AtYVA) exhibited similar cop phenotypes in transgenic plants to AsYVA. Collectively, these results suggest that the conserved Tyr residues in the chromophore-binding pocket play an important role during the Pr-to-Pfr photoconversion of phytochromes, providing new constitutively active alleles of phytochromes by the Tyr-to-Val mutation. PMID:27325667

  7. Industry and dangerous wastes

    The serious danger present tailing dumps of functioning and closed mineral resource industry in consequence of their weak security from natural disasters, proximity to water-ways, towns and state boundaries and also considering of past accidents

  8. Colored Contact Lens Dangers

    Full Text Available ... Uveitis Focus On Pediatric Ophthalmology Education Center Oculofacial Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center Global ... Halloween Hazard: The Hidden Dangers of Buying Decorative Contact Lenses Without a Prescription ...

  9. Trauma is danger

    Porterfield Nancy; Hwang Paul F; Pannell Dylan; Davis Thomas A; Elster Eric A

    2011-01-01

    Abstract Background Trauma is one of the leading causes of death in young adult patients. Many pre-clinical and clinical studies attempt to investigate the immunological pathways involved, however the true mediators remain to be elucidated. Herein, we attempt to describe the immunologic response to systemic trauma in the context of the Danger model. Data Sources A literature search using PubMed was used to identify pertinent articles describing the Danger model in relation to trauma. Conclusi...

  10. A dangerous mixture

    Anna Piva

    2014-03-01

    Full Text Available A 59-year old woman was admitted for fatigue and arm paresthesias with Trousseau sign. Her medical history included thyroidectomy and hypercholesterolemia recently treated with simvastatin. Laboratory tests showed severe hypokalemia and hypocalcemia, severe increase in muscle enzymes, metabolic alkalosis; low plasma renin activity, increased thyroid-stimulating hormone, normal free thyroxine, increased parathyroid hormone, decreased vitamin D3; alterations in electrolyte urinary excretion, cortisol and aldosterone were excluded. Hypothesizing a statin-related myopathy, simvastatin was suspended; the patient reported use of laxatives containing licorice. Electrolytes normalized with intravenous supplementation. Among many biochemical alterations, none stands out as a major cause for muscular and electrolyte disorders. All co-factors are inter-connected, starting with statin-induced myopathy, worsened by hypothyroidism, secondary hyperaldosteronism and vitamin D deficiency, leading to hypocalcemia and hypokalemia, perpetrating muscular and electrolyte disorders. The importance of considering clinical conditions as a whole emerges with multiple co-factors involved. Another issue concerns herbal products and their potential dangerous effects.

  11. ЕSTIMATION AND OPTIMIZATION OF THE ACTIVE BASIS RATIO FOR SYNTHETIC WASHING POWDERS WITH LOWERED ECOLOGICAL DANGER

    Tihonova, Yu; Lomakin, S.; Filatova, E.; Habibullin, R.

    2009-01-01

    The problem of work selection of an active basis for a synthetic washing powder with the lowered foaming. The active basis is consist of 3 components: anionic surface-active substances sodium soap of fat acids, nonionic surface-active substances cyntanol ALM-10 and amphoteric surface-active substances a product of dissolution of collagen. Pure surface-active substances and 3 various ratio of these components have been taken with concentration 3 g/l for studying. The superficial tension and wa...

  12. Activation of endothelial β-catenin signaling induces heart failure

    Nakagawa, Akito; Naito, Atsuhiko T.; Sumida, Tomokazu; Nomura, Seitaro; Shibamoto, Masato; Higo, Tomoaki; Okada, Katsuki; Sakai, Taku; Hashimoto, Akihito; Kuramoto, Yuki; Oka, Toru; Lee, Jong-Kook; Harada, Mutsuo; Ueda, Kazutaka; Shiojima, Ichiro

    2016-01-01

    Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-cat...

  13. The danger of engagement: Behavioral observations of online community activity and service spending in the online gaming

    Kaptein, M.C.; Parvinen, P.; Pöyri, E.

    2015-01-01

    Research indicates that customer engagement in online communities has positive effects on related businesses, and that, on an aggregated level, community activity and service spending are positively related. Therefore, marketing efforts tend to focus on promoting the community activity of customers.

  14. Human ECG signal parameters estimation during controlled physical activity

    Maciejewski, Marcin; Surtel, Wojciech; Dzida, Grzegorz

    2015-09-01

    ECG signal parameters are commonly used indicators of human health condition. In most cases the patient should remain stationary during the examination to decrease the influence of muscle artifacts. During physical activity, the noise level increases significantly. The ECG signals were acquired during controlled physical activity on a stationary bicycle and during rest. Afterwards, the signals were processed using a method based on Pan-Tompkins algorithms to estimate their parameters and to test the method.

  15. Mitogen-activated protein kinase signaling in plants

    Rodriguez, Maria Cristina Suarez; Petersen, Morten; Mundy, John

    2010-01-01

    Eukaryotic mitogen-activated protein kinase (MAPK) cascades have evolved to transduce environmental and developmental signals into adaptive and programmed responses. MAPK cascades relay and amplify signals via three types of reversibly phosphorylated kinases leading to the phosphorylation of...... substrate proteins, whose altered activities mediate a wide array of responses, including changes in gene expression. Cascades may share kinase components, but their signaling specificity is maintained by spaciotemporal constraints and dynamic protein-protein interactions and by mechanisms that include...

  16. Network Proactive Defense Model Based on Immune Danger Theory

    Zhenxing Wang; Liancheng Zhang; Yazhou Kong; Yu Wang

    2016-01-01

    Recent investigations into proactive network defense have not produced a systematic methodology and structure; in addition, issues including multi-source information fusion and attacking behavior analysis have not been resolved. Borrowing ideas of danger sensing and immune response from danger theory, a proactive network defense model based on danger theory is proposed. This paper defines the signals and antigens in the network environment as well as attacking behavior analysis algorithm, pro...

  17. Dangerous Raw Oysters

    2013-08-05

    Dr. Duc Vugia, chief of the Infectious Diseases Branch at the California Department of Public Health, discusses the dangers of eating raw oysters.  Created: 8/5/2013 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 8/7/2013.

  18. Colored Contact Lens Dangers

    Full Text Available ... Halloween Hazard: The Hidden Dangers of Buying Decorative Contact Lenses Without a Prescription Sep. 26, 2013 It started ... vampire eyes to glow-in-the-dark lizard lenses, costume contacts can certainly add a spooky, eye-popping touch. ...

  19. Heat dissipation guides activation in signaling proteins

    Weber, Jeffrey K.; Shukla, Diwakar; Pande, Vijay S.

    2015-01-01

    As with their macroscopic counterparts, the moving parts of nanoscale protein machines grow hot while in operation. A portion of the energy biomolecules harness to perform meaningful work is always dissipated as heat into the surroundings. Here, we feature a methodology by which dominant dissipative trajectories can be extracted from detailed models of protein dynamics. In two important classes of signaling proteins [kinases and G-protein–coupled receptors (GPCRs)], we find that the regions o...

  20. How dangerous are atomic power stations?

    This article takes a look at potential dangers presented by atomic power stations and measures taken to ensure safety. Since the accident in Chernobyl, atomic power stations represent, from the point of view of the general public, a considerable danger. The article analyses the actual risks presented by atom power stations and asks the question, if these risks can even be assessed. Basic considerations on the stability and safety of reactors are discussed. Safety precautions implemented for the world's first nuclear reactor in the USA are discussed. The various safety precautions taken for various types of reactor are examined in detail. Also, the dangers presented by emissions that occur during normal operation are examined. The danger of a nuclear meltdown caused by external factors such as earthquakes, fire, aircraft crashes and terrorist activity is discussed

  1. Wnt Signaling in Neurogenesis during Aging and Physical Activity

    Michael Chen

    2012-12-01

    Full Text Available Over the past decade, much progress has been made regarding our understanding of neurogenesis in both young and old animals and where it occurs throughout the lifespan, although the growth of new neurons declines with increasing age. In addition, physical activity can reverse this age-dependent decline in neurogenesis. Highly correlated with this decline is the degree of inter and intracellular Wnt signaling, the molecular mechanisms of which have only recently started to be elucidated. So far, most of what we know about intracellular signaling during/following exercise centers around the CREB/CRE initiated transcriptional events. Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway. Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals. Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity.

  2. Sources of increased danger

    The present and future facts of absolute liability under specific laws will have to be supplemented by the legislator, and the claims for damages will have to be limited to physical and material damage. The formulation should be about as follows: 'If a person is killed by a source of increased danger or damage done to his/her body or health or material damage done, the owner of that source will be liable for payment of damages'. A standard of this kind has good chances of being realized and applied in German or even European technical and social developments of the future. The general clause of absolute reliability for sources of increased danger depends on the judge's decision and models so far, also of other countries, give no cause to doubt this. (orig./HP)

  3. Semantic Gaps Are Dangerous

    Ejstrup, Michael; le Fevre Jakobsen, Bjarne

    2014-01-01

    constantely. Recently both media and migrations have accelerated considerably in speed. In Europe and thus in Denmark homogenous populations have developed into multicultural ones. Language has not kept pace with this development, and millions of people have to adapt to this new situation with lightning speed...... tools at hand. But we have not these tools of communication, and we are in a situation today where media and specially digital and social media, supported by new possibilities of migration, create dangerous situations....

  4. Dangerous Energy : Atomic

    This book describes the disaster in Chernobyl, Russia. Through the accident It reveals the dangerous nuclear energy with a lot of problems on the nuclear power plants which includes four reasons about propelling development of atomic and criticism about that, eight reasons against development of atomic, the problem in 11 -12 nuclear power plant, the movement of antagonism towards nuclear waste in Anmyon island, cases of antinuclear in foreign country and building of new energy system.

  5. The dangerous story

    This book describes of the dangerous accident i Chernobyl, which includes what happen in Chernobyl, report of the soviet union and secret conversation between IAEA and Kremlin. It deals with presupposition of disasters and reality like atomic soldier's leukemia and pollution in West Europe and Poland Next, it reports of a great accident caused defect of nuclear power plant in Japan and nuclear power industry and stagnation of journalism.

  6. A Dangerous Awakening

    Enwerem, Iheanyi M.; Ikime, Obaro

    2013-01-01

    Students of religion and interested observers of politics in Africa will cherish this book for providing a thorough analysis of the origin and politics of the Christian Association of Nigeria (CAN). A Dangerous Awakening chronicles the religious clashes in Nigeria, and shows how religion has been used in the struggle for political power. Dr. Enwerem bases his study on interviews and unpublished memos, papers and letters not otherwise accessible to the public. This book is an invaluable contri...

  7. Activation of endothelial β-catenin signaling induces heart failure.

    Nakagawa, Akito; Naito, Atsuhiko T; Sumida, Tomokazu; Nomura, Seitaro; Shibamoto, Masato; Higo, Tomoaki; Okada, Katsuki; Sakai, Taku; Hashimoto, Akihito; Kuramoto, Yuki; Oka, Toru; Lee, Jong-Kook; Harada, Mutsuo; Ueda, Kazutaka; Shiojima, Ichiro; Limbourg, Florian P; Adams, Ralf H; Noda, Tetsuo; Sakata, Yasushi; Akazawa, Hiroshi; Komuro, Issei

    2016-01-01

    Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/β-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/β-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure. PMID:27146149

  8. La mesure du danger

    Manceron, Vanessa; Revet, Sandrine

    2014-01-01

    La mesure du danger permet d’explorer des dangers de nature aussi diverse que la délinquance, la pollution, l’écueil maritime, la maladie ou l’attaque sorcellaire, l’extinction d’espèces animales ou végétales, voire de la Planète tout entière. Au croisement de la sociologie, de l’anthropologie et de l’histoire, les différents articles analysent les pratiques concrètes de mesure pour tenter de comprendre ce qui se produit au cours de l’opération d’évaluation du danger sans préjuger de la nature de celui-ci. L’anthropologie a contribué à la réflexion sur l’infortune en s’intéressant aux temporalités de l’après : maladies, catastrophes, pandémies, etc. et en cherchant à rendre compte de l’expérience des victimes, de leur vie ordinaire bouleversée, de la recomposition du quotidien. Elle s’intéresse aussi aux autres types de mesures, les savoirs incorporés, qui reposent sur l’odorat, la vue ou le toucher et ceux qui ressortent d’une épistémologie « non ...

  9. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

    Marina Pasca di Magliano

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma.

  10. Sorafenib Inhibits Signal Transducer and Activator of Transcription-3 Signaling in Cholangiocarcinoma Cells by Activating the Phosphatase Shatterproof 2

    Blechacz, Boris R. A.; Smoot, Rory L.; Bronk, Steven F; Werneburg, Nathan W.; Sirica, Alphonse E.; Gores, Gregory J.

    2009-01-01

    The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is one of the key signaling cascades in cholangiocarcinoma (CCA) cells, mediating their resistance to apoptosis. Our aim was to ascertain if sorafenib, a multikinase inhibitor, may also inhibit JAK/STAT signaling and, therefore, be efficacious for CCA. Sorafenib treatment of three human CCA cell lines resulted in Tyr705 phospho-STAT3 dephosphorylation. Similar results were obtained with the Raf-kinase inhibit...

  11. Insulin-like growth factor induced signals activate mitochondrial respiration

    Hütter, E.; Unterluggauer, H.; Viertler, H.P.; Jansen-Dürr, P

    2008-01-01

    From experiments with lower eukaryotes it is known that the metabolic rate and also the rate of aging are tightly controlled by the IGF / insulin signal transduction pathway. The mitochondrial theory of aging implies that an increased metabolic rate leads to increased mitochondrial activity; increased production of reactive oxygen species due to these alterations would speed up the aging process. To address the question if mitochondrial activity is influenced by insulin / IGF signalling, we h...

  12. Wnt signaling and the activation of myogenesis in mammals.

    Cossu, G.; Borello, U

    1999-01-01

    In the amniote embryos, specification of skeletal myoblasts occurs in the paraxial mesoderm in response to a number of signaling molecules produced by neighboring tissues such as neural tube, notochord and dorsal ectoderm. Candidate molecules for this complex signaling activity include Sonic hedgehog, Wnts and Noggin as positive activators and BMP4 as a possible inhibitor. Recently, the receptors and the post-receptor pathways for Sonic hedgehog and Wnts have been characterized, and this has ...

  13. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

    Choudhary, Chuna Ram; Olsen, Jesper V; Brandts, Christian;

    2009-01-01

    Inappropriate activation of oncogenic kinases at intracellular locations is frequently observed in human cancers, but its effects on global signaling are incompletely understood. Here, we show that the oncogenic mutant of Flt3 (Flt3-ITD), when localized at the endoplasmic reticulum (ER), aberrant...... patterns of the receptor itself. Thus, intracellular activation of RTKs by oncogenic mutations in the biosynthetic route may exploit cellular architecture to initiate aberrant signaling cascades, thus evading negative regulation....

  14. Dangers and Pleasures

    Järvinen, Margaretha Maria; Østergaard, Jeanette

    2011-01-01

    This is a study of young people’s conceptions of illegal drug use as dangerous and/or pleasurable and an analysis of the relationship between attitudes to drugs, drinking, friends’ reported drug use and own experience with drug use and drinking. The article applies a mixed methods approach using......-old Danes: the anti-drug position, usually held by youths who do not use illegal drugs and do not have drug-using friends; the ambivalent position, occupied by non-users who report that they have drug-using friends; the transitory position, held by cannabis users, some of whom express positive attitudes to...

  15. Reducing Nuclear Dangers

    Bunn, Matthew G.

    2012-01-01

    Ron Rosenbaum wants us to be worried. His book How the End Begins: The Road to a Nuclear World War III is intended as an urgent warning that the terrifying dangers of nuclear weapons did not disappear when the Cold War ended two decades ago. There are still many thousands of nuclear weapons in the world—about 95% of them in the U.S. and Russian arsenals—and thousands of them are constantly poised for launch within minutes.

  16. Activation of the Canonical Wnt Signaling Pathway Induces Cementum Regeneration.

    Han, Pingping; Ivanovski, Saso; Crawford, Ross; Xiao, Yin

    2015-07-01

    Canonical Wnt signaling is important in tooth development but it is unclear whether it can induce cementogenesis and promote the regeneration of periodontal tissues lost because of disease. Therefore, the aim of this study is to investigate the influence of canonical Wnt signaling enhancers on human periodontal ligament cell (hPDLCs) cementogenic differentiation in vitro and cementum repair in a rat periodontal defect model. Canonical Wnt signaling was induced by (1) local injection of lithium chloride; (2) local injection of sclerostin antibody; and (3) local injection of a lentiviral construct overexpressing β-catenin. The results showed that the local activation of canonical Wnt signaling resulted in significant new cellular cementum deposition and the formation of well-organized periodontal ligament fibers, which was absent in the control group. In vitro experiments using hPDLCs showed that the Wnt signaling pathway activators significantly increased mineralization, alkaline phosphatase (ALP) activity, and gene and protein expression of the bone and cementum markers osteocalcin (OCN), osteopontin (OPN), cementum protein 1 (CEMP1), and cementum attachment protein (CAP). Our results show that the activation of the canonical Wnt signaling pathway can induce in vivo cementum regeneration and in vitro cementogenic differentiation of hPDLCs. PMID:25556853

  17. G protein activation stimulates phospholipase D signaling in plants

    Munnik, T.; Arisz, S.A.; Vrije, de T.; Musgrave, A.

    1995-01-01

    We provide direct evidence for phospholipase D (PLD) signaling in plants by showing that this enzyme is stimulated by the G protein activators mastoparan, ethanol, and cholera toxin. An in vivo assay for PLD activity in plant cells was developed based on the use of a "reporter alcohol" rather than w

  18. Modulation of β-catenin signaling by glucagon receptor activation.

    Jiyuan Ke

    Full Text Available The glucagon receptor (GCGR is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin-mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R and glucagon-like peptide 1 (GLP-1R receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5 is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1 or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.

  19. Adipocyte activation of cancer stem cell signaling in breast cancer

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

    2015-01-01

    Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment,have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6(IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activatorof transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.

  20. Glucose Enhances Leptin Signaling through Modulation of AMPK Activity

    Haoran Su; Lin Jiang; Christin Carter-Su; Liangyou Rui

    2012-01-01

    Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk bet...

  1. Activity-dependent neuronal signalling and autism spectrum disorder

    Ebert, Daniel H.; Greenberg, Michael E.

    2013-01-01

    Neuronal activity induces the post-translational modification of synaptic molecules, promotes localized protein synthesis within dendrites and activates gene transcription, thereby regulating synaptic function and allowing neuronal circuits to respond dynamically to experience. Evidence indicates that many of the genes that are mutated in autism spectrum disorders are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity. Dysregulati...

  2. [GABA-NO interaction in the N. Accumbens during danger-induced inhibition of exploratory behavior].

    2013-01-01

    In Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, it was shown that presentation to rats during exploratory activity of a tone previously pared with footshock inhibited the exploration and prevented the exploration-induced increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. Intra-accumbal infusions of 20 μM bicuculline, a GABA(A)-receptor antagonist, firstly, partially restored the exploration-induced increase of extracellular citrulline levels in this brain area, which was inhibited by presentation of the tone, previously paired with foot-shock and, secondly, prevented the inhibition of exploratory behavior produced by this sound signal of danger. The data obtained indicate for the first time that signals of danger inhibit exploratory behavior and exploration-induced activation of the accumbal nitrergic system via GABA(A)-receptor mechanisms. PMID:25508395

  3. Is Brain Emulation Dangerous?

    Eckersley, Peter; Sandberg, Anders

    2013-12-01

    Brain emulation is a hypothetical but extremely transformative technology which has a non-zero chance of appearing during the next century. This paper investigates whether such a technology would also have any predictable characteristics that give it a chance of being catastrophically dangerous, and whether there are any policy levers which might be used to make it safer. We conclude that the riskiness of brain emulation probably depends on the order of the preceding research trajectory. Broadly speaking, it appears safer for brain emulation to happen sooner, because slower CPUs would make the technology`s impact more gradual. It may also be safer if brains are scanned before they are fully understood from a neuroscience perspective, thereby increasing the initial population of emulations, although this prediction is weaker and more scenario-dependent. The risks posed by brain emulation also seem strongly connected to questions about the balance of power between attackers and defenders in computer security contests. If economic property rights in CPU cycles1 are essentially enforceable, emulation appears to be comparatively safe; if CPU cycles are ultimately easy to steal, the appearance of brain emulation is more likely to be a destabilizing development for human geopolitics. Furthermore, if the computers used to run emulations can be kept secure, then it appears that making brain emulation technologies ―open‖ would make them safer. If, however, computer insecurity is deep and unavoidable, openness may actually be more dangerous. We point to some arguments that suggest the former may be true, tentatively implying that it would be good policy to work towards brain emulation using open scientific methodology and free/open source software codebases

  4. PFP dangerous waste training plan

    This document establishes the minimum training requirements for the Plutonium Finishing Plant (PFP) personnel who are responsible for management of dangerous waste. The training plan outlines training requirements for handling of solid dangerous waste during generator accumulation and liquid dangerous waste during treatment and storage operations. The implementation of this training plan will ensure the PFP facility compliance with the training plan requirements of Dangerous Waste Regulation. Chapter 173-303-330. Washington Administrative Code (WAC). The requirements for such compliance is described in Section 11.0 of WHC-CM-7-5 Environmental Compliance Manual

  5. WNT signaling in activated microglia is pro-inflammatory: WNT/β-catenin signaling in microglia

    Halleskog, Carina; Mulder, Jan; Dahlström, Jenny; Mackie, Ken; Hortobágyi, Tibor; Tanila, Heikki; Puli, Lakshman Kumar; Färber, Katrin; Harkany, Tibor; Schulte, Gunnar

    2010-01-01

    Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly since activated microglia are often a source of pro-inflammatory cytokines. Despite decades-long research, the molecular cascade of pro-inflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased β–catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a pro-inflammatory morphogenic t...

  6. Wnt signaling and the activation of myogenesis in mammals.

    Cossu, G; Borello, U

    1999-12-15

    In the amniote embryos, specification of skeletal myoblasts occurs in the paraxial mesoderm in response to a number of signaling molecules produced by neighboring tissues such as neural tube, notochord and dorsal ectoderm. Candidate molecules for this complex signaling activity include Sonic hedgehog, Wnts and Noggin as positive activators and BMP4 as a possible inhibitor. Recently, the receptors and the post-receptor pathways for Sonic hedgehog and Wnts have been characterized, and this has opened up the possibility of linking these signaling events to the activation of myogenic regulatory factor genes such as Myf5 and MyoD and functionally related genes such as Pax3. Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis. However, the fact that both Wnts and Sonic hedgehog have a strong effect on cell proliferation and survival suggests that they may contribute to the overall process of myogenesis by a combination of these different biological activities. PMID:10601008

  7. MEKK1/JNK signaling stabilizes and activates p53

    Fuchs, Serge Y.; Adler, Victor; Pincus, Matthew R.; Ronai, Ze’ev

    1998-01-01

    Activation of the tumor suppressor p53 by stress and damage stimuli often correlates with induction of stress kinases, Jun-NH2 kinase (JNK). As JNK association with p53 plays an important role in p53 stability, in the present study we have elucidated the relationship between the JNK-signaling pathway and p53 stability and activity. Expression of a constitutively active form of JNKK upstream kinase, mitogen-activated protein kinase kinase kinase (ΔMEKK1), increased the level of the exogenously...

  8. Identification of small molecule activators of BMP signaling.

    Karen Vrijens

    Full Text Available Bone Morphogenetic Proteins (BMPs are morphogens that play a major role in regulating development and homeostasis. Although BMPs are used for the treatment of bone and kidney disorders, their clinical use is limited due to the supra-physiological doses required for therapeutic efficacy causing severe side effects. Because recombinant BMPs are expensive to produce, small molecule activators of BMP signaling would be a cost-effective alternative with the added benefit of being potentially more easily deliverable. Here, we report our efforts to identify small molecule activators of BMP signaling. We have developed a cell-based assay to monitor BMP signaling by stably transfecting a BMP-responsive human cervical carcinoma cell line (C33A with a reporter construct in which the expression of luciferase is driven by a multimerized BMP-responsive element from the Id1 promoter. A BMP-responsive clone C33A-2D2 was used to screen a bioactive library containing ∼5,600 small molecules. We identified four small molecules of the family of flavonoids all of which induced luciferase activity in a dose-dependent manner and ventralized zebrafish embryos. Two of the identified compounds induced Smad1, 5 phosphorylation (P-Smad, Id1 and Id2 expression in a dose-dependent manner demonstrating that our assays identified small molecule activators of BMP signaling.

  9. Active Harmonic Load–Pull With Realistic Wideband Communications Signals

    Marchetti, M.; Pelk, M.J.; Buisman, K.; Neo, W.C.E.; Spirito, M.; De Vreede, L.C.N.

    2008-01-01

    A new wideband open-loop active harmonic load–pull measurement approach is presented. The proposed method is based on wideband data-acquisition and wideband signal-injection of the incident and device generated power waves at the frequencies of interest. The system provides full, user defined, in-ba

  10. Steroid signaling activation and intracellular localization of sex steroid receptors

    Giraldi, Tiziana; Giovannelli, Pia; Di Donato, Marzia; Castoria, Gabriella; Migliaccio, Antimo; Auricchio, Ferdinando

    2010-01-01

    In addition to stimulating gene transcription, sex steroids trigger rapid, non-genomic responses in the extra-nuclear compartment of target cells. These events take place within seconds or minutes after hormone administration and do not require transcriptional activity of sex steroid receptors. Depending on cell systems, activation of extra-nuclear signaling pathways by sex steroids fosters cell cycle progression, prevents apoptosis, leads to epigenetic modifications and increases cell migrat...

  11. Joint analysis of infrasound and seismic signals by cross wavelet transform: detection of Mt. Etna explosive activity

    A. Cannata

    2013-06-01

    Full Text Available The prompt detection of explosive volcanic activity is crucial since this kind of activity can release copious amounts of volcanic ash and gases into the atmosphere, causing severe dangers to aviation. In this work, we show how the joint analysis of seismic and infrasonic data by wavelet transform coherence (WTC can be useful to detect explosive activity, significantly enhancing its recognition that is normally done by video cameras and thermal sensors. Indeed, the efficiency of these sensors can be reduced (or inhibited in the case of poor visibility due to clouds or gas plumes. In particular, we calculated the root mean square (RMS of seismic and infrasonic signals recorded at Mt. Etna during 2011. This interval was characterised by several episodes of lava fountains, accompanied by lava effusion, and minor strombolian activities. WTC analysis showed significantly high values of coherence between seismic and infrasonic RMS during explosive activity, with infrasonic and seismic series in phase with each other, hence proving to be sensitive to both weak and strong explosive activity. The WTC capability of automatically detecting explosive activity was compared with the potential of detection methods based on fixed thresholds of seismic and infrasonic RMS. Finally, we also calculated the cross correlation function between seismic and infrasonic signals, which showed that the wave types causing such seismo-acoustic relationship are mainly incident seismic and infrasonic waves, likely with a common source.

  12. Survey of activated FLT3 signaling in leukemia.

    Ting-lei Gu

    Full Text Available Activating mutations of FMS-like tyrosine kinase-3 (FLT3 are found in approximately 30% of patients with acute myeloid leukemia (AML. FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3 and B cell acute lymphoblastic leukemia (normal and amplification of FLT3 cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC, we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.

  13. Manifesto for a Dangerous Sociology

    Cisneros, César

    2008-05-01

    Full Text Available Based on my experience as a Mexican sociologist, I argue for the practice of a "Dangerous Sociology". I examine the process of sociological observation to show the need for such a practice. Some dimensions of this "Dangerous Sociology" are defined.

  14. Semantic Gaps are Dangerous

    Ejstrup, Michael; le Fevre Jakobsen, Bjarne

    Language adapts to the environment where it serves as a tool to communication. Language is a social agreement, and we all have to stick to both grammaticalized and non-grammaticalized rules in order to pass information about the world around us. As such language develops and adapts constantely. R...... we do not have these tools of communication, and we are in a situation today where media and specially digital and social media, supported by new possibilities of migration, create dangerous situations.......Language adapts to the environment where it serves as a tool to communication. Language is a social agreement, and we all have to stick to both grammaticalized and non-grammaticalized rules in order to pass information about the world around us. As such language develops and adapts constantely....... Recently both media and migrations have accelerated considerably. In Europe and thus in Denmark homogenous populations have developed into multicultural ones. Language has not kept pace with this development, and millions of people have to adapt to this new situation with lightning speed. That seems not to...

  15. BMP2 Transfer to Neighboring Cells and Activation of Signaling.

    Alborzinia, Hamed; Shaikhkarami, Marjan; Hortschansky, Peter; Wölfl, Stefan

    2016-09-01

    Morphogen gradients and concentration are critical features during early embryonic development and cellular differentiation. Previously we reported the preparation of biologically active, fluorescently labeled BMP2 and quantitatively analyzed their binding to the cell surface and followed BMP2 endocytosis over time on the level of single endosomes. Here we show that this internalized BMP2 can be transferred to neighboring cells and, moreover, also activates downstream BMP signaling in adjacent cells, indicated by Smad1/5/8 phosphorylation and activation of the downstream target gene id1. Using a 3D matrix to modulate cell-cell contacts in culture we could show that direct cell-cell contact significantly increased BMP2 transfer. Using inhibitors of vesicular transport, transfer was strongly inhibited. Interestingly, cotreatment with the physiological BMP inhibitor Noggin increased BMP2 uptake and transfer, albeit activation of Smad signaling in neighboring cells was completely suppressed. Our findings present a novel and interesting mechanism by which morphogens such as BMP2 can be transferred between cells and how this is modulated by BMP antagonists such as Noggin, and how this influences activation of Smad signaling by BMP2 in neighboring cells. PMID:27306974

  16. Chemokines: a new dendritic cell signal for T cell activation

    Christoph A Thaiss

    2011-08-01

    Full Text Available Dendritic cells (DCs are the main inducers and regulators of cytotoxic T lymphocyte (CTL responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and licensed by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4+ T helper cells (classical licensing or by NKT cells (alternative licensing. Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.

  17. Angiotensin II activates different calcium signaling pathways in adipocytes.

    Dolgacheva, Lyudmila P; Turovskaya, Maria V; Dynnik, Vladimir V; Zinchenko, Valery P; Goncharov, Nikolay V; Davletov, Bazbek; Turovsky, Egor A

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades:In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2diabetes. PMID:26850364

  18. Activation and signaling of the p38 MAP kinase pathway

    Tyler ZARUBIN; Jiahuai HAN

    2005-01-01

    The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

  19. Artifact suppression and analysis of brain activities with electroencephalography signals

    Md. Rashed-Al-Mahfuz; Md. Rabiul Islam; Keikichi Hirose; Md. Khademul Islam Molla

    2013-01-01

    Brain-computer interface is a communication system that connects the brain with computer (or other devices) but is not dependent on the normal output of the brain (i.e., peripheral nerve and muscle). Electro-oculogram is a dominant artifact which has a significant negative influence on further analysis of real electroencephalography data. This paper presented a data adaptive technique for artifact suppression and brain wave extraction from electroencephalography signals to detect regional brain activities. Empirical mode decomposition based adaptive thresholding approach was employed here to suppress the electro-oculogram artifact. Fractional Gaussian noise was used to determine the threshold level derived from the analysis data without any training. The purified electroencephalography signal was composed of the brain waves also called rhythmic components which represent the brain activities. The rhythmic components were extracted from each electroencephalography channel using adaptive wiener filter with the original scale. The regional brain activities were mapped on the basis of the spatial distribution of rhythmic components, and the results showed that different regions of the brain are activated in response to different stimuli. This research analyzed the activities of a single rhythmic component, alpha with respect to different motor imaginations. The experimental results showed that the proposed method is very efficient in artifact suppression and identifying individual motor imagery based on the activities of alpha component.

  20. Intrinsic optical signals of the nervous tissue during neuronal activation

    Konopková, Renata; Otáhal, Jakub

    Brno : Brno University of Technology, 2006 - (Burša, J.; Fuis, V.). s. 124-125 ISBN 80-214-3232-2. [Human Biomechanics 2006 : international conference /11./. 13.11.2006-16.11.2006, Hrotovice] R&D Projects: GA AV ČR(CZ) 1QS501210509 Institutional research plan: CEZ:AV0Z50110509 Keywords : intrinsic optical signals * neuronal activation * light transmission Subject RIV: ED - Physiology

  1. Chemical Signaling and Functional Activation in Colloidosome-Based Protocells.

    Sun, Shiyong; Li, Mei; Dong, Faqin; Wang, Shengjie; Tian, Liangfei; Mann, Stephen

    2016-04-01

    An aqueous-based microcompartmentalized model involving the integration of partially hydrophobic Fe(III)-rich montmorillonite (FeM) clay particles as structural and catalytic building blocks for colloidosome membrane assembly, self-directed membrane remodeling, and signal-induced protocell communication is described. The clay colloidosomes exhibit size- and charge-selective permeability, and show dual catalytic functions involving spatially confined enzyme-mediated dephosphorylation and peroxidase-like membrane activity. The latter is used for the colloidosome-mediated synthesis and assembly of a temperature-responsive poly(N-isopropylacrylamide)(PNIPAM)/clay-integrated hybrid membrane. In situ PNIPAM elaboration of the membrane is coupled to a glucose oxidase (GOx)-mediated signaling pathway to establish a primitive model of chemical communication and functional activation within a synthetic "protocell community" comprising a mixed population of GOx-containing silica colloidosomes and alkaline phosphatase (ALP)-containing FeM-clay colloidosomes. Triggering the enzyme reaction in the silica colloidosomes gives a hydrogen peroxide signal that induces polymer wall formation in a coexistent population of the FeM-clay colloidosomes, which in turn generates self-regulated membrane-gated ALP-activity within the clay microcompartments. The emergence of new functionalities in inorganic colloidosomes via chemical communication between different protocell populations provides a first step toward the realization of interacting communities of synthetic functional microcompartments. PMID:26923794

  2. Dangerous scorpion fauna of Mali

    M Goyffon

    2012-01-01

    Full Text Available Although the main Malian scorpion species of medical interest, Androctonus amoreuxi, is responsible for severe envenomings and perhaps some deaths, it has hitherto been considered not dangerous for humans. This population is located in the Saharian North-Eastern regions of Mali where it is accompanied by Leiurus quinquestriatus, a well known dangerous species of the Sahara. In the Gao district, divided by the Niger River, less desolate than the Tessalit and Kidal regions, one specimen of the dangerous species Androctonus australis was found. To summarize, Mali harbors at least three dangerous scorpion species: Leiurus quinquestriatus, Androctonus amoreuxi and A. australis, the latter recently having been identified in Mali for the first time. The absence of Androctonus aeneas is surprising in this context because it is found in neighboring countries (Algeria, Niger and should be detected by new surveys. The possibility of preparing a single scorpion antivenom intended for Saharian and sub-Saharian populations is discussed.

  3. Financial Consolidation: Dangers and Opportunities

    Frederic S. Mishkin

    1999-01-01

    This paper argues that although financial consolidation creates some dangers because it is leading to larger institutions who might expose the U.S. financial system to increased systemic risk, these dangers can be handled by vigilant supervision and a government safety net with an appropriate amount of constructive ambiguity. Financial consolidation also opens up opportunities to dramatically reduce the scope of deposit insurance and limit it to narrow bank accounts, thus substantially reduci...

  4. Disentangling stellar activity from exoplanetary signals with interferometry

    Ligi Roxanne

    2015-01-01

    Full Text Available Stellar activity can express as many forms at stellar surfaces: dark spots, convective cells, bright plages. Particularly, dark spots and bright plages add noise on photometric data or radial velocity measurements used to detect exoplanets, and thus lead to false detection or disrupt their derived parameters. Since interferometry provides a very high angular resolution, it may constitute an interesting solution to distinguish the signal of a transiting exoplanet and that of stellar activity. It has also been shown that granulation adds bias in visibility and closure phase measurements, affecting in turn the derived stellar parameters. We analyze the noises generated by dark spots on interferometric observables and compare them to exoplanet signals. We investigate the current interferometric instruments able to measure and disentangle these signals, and show that there is a lack in spatial resolution. We thus give a prospective of the improvements to be brought on future interferometers, which would also significantly extend the number of available targets.

  5. Artificial Immune Danger Theory Based Model for Network Security Evaluation

    Feixian Sun

    2011-02-01

    Full Text Available Inspired by the principles of immune danger theory, a danger theory based model for network security risk assessment is presented in this paper. Firstly, the principle of the danger theory is introduced. And then, with the improved concepts and formal definitions of antigen, antibody, danger signal, and detection lymphocyte for network security risk assessment presented, the distributed architecture of the proposed model is described. Following that, the principle of network intrusion detection is expounded. Finally, the method of network security risk assessment is given. Theoretical analysis and simulation results show that the proposed model can evaluate the network attack threats in real time. Thus, it provides an effective risk evaluation solution to network security.

  6. Negativity Bias in Dangerous Drivers.

    Chai, Jing; Qu, Weina; Sun, Xianghong; Zhang, Kan; Ge, Yan

    2016-01-01

    The behavioral and cognitive characteristics of dangerous drivers differ significantly from those of safe drivers. However, differences in emotional information processing have seldom been investigated. Previous studies have revealed that drivers with higher anger/anxiety trait scores are more likely to be involved in crashes and that individuals with higher anger traits exhibit stronger negativity biases when processing emotions compared with control groups. However, researchers have not explored the relationship between emotional information processing and driving behavior. In this study, we examined the emotional information processing differences between dangerous drivers and safe drivers. Thirty-eight non-professional drivers were divided into two groups according to the penalty points that they had accrued for traffic violations: 15 drivers with 6 or more points were included in the dangerous driver group, and 23 drivers with 3 or fewer points were included in the safe driver group. The emotional Stroop task was used to measure negativity biases, and both behavioral and electroencephalograph data were recorded. The behavioral results revealed stronger negativity biases in the dangerous drivers than in the safe drivers. The bias score was correlated with self-reported dangerous driving behavior. Drivers with strong negativity biases reported having been involved in mores crashes compared with the less-biased drivers. The event-related potentials (ERPs) revealed that the dangerous drivers exhibited reduced P3 components when responding to negative stimuli, suggesting decreased inhibitory control of information that is task-irrelevant but emotionally salient. The influence of negativity bias provides one possible explanation of the effects of individual differences on dangerous driving behavior and traffic crashes. PMID:26765225

  7. Danger of zooplankton feeding

    Kiørboe, Thomas; Jiang, H.; Colin, S.P.

    2010-01-01

    therefore perform occasional upward repositioning jumps. We quantified the fluid disturbance generated by repositioning jumps in a millimetre-sized copepod (Re ∼ 40). The kick of the swimming legs generates a viscous vortex ring in the wake; another ring of similar intensity but opposite rotation is formed...... around the decelerating copepod. A simple analytical model, that of an impulsive point force, properly describes the observed flow field as a function of the momentum of the copepod, including the translation of the vortex and its spatial extension and temporal decay. We show that the time-averaged fluid...... signal and the consequent predation risk is much less for an ambush-feeding than a cruising or hovering copepod for small individuals, while the reverse is true for individuals larger than about 1 mm. This makes inefficient ambush feeding feasible in small copepods, and is consistent with the observation...

  8. Role of Calcium Signaling in B Cell Activation and Biology.

    Baba, Yoshihiro; Kurosaki, Tomohiro

    2016-01-01

    Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases. PMID:26369772

  9. Main Dangers of Our Times.

    Synek, Miroslav

    2003-03-01

    Terrorism and threatening dictatorships are the main, man-made, dangers of our times. They are run by master demagogues, or, brain-washing manipulators. ----- Our next step in coping with terrorism is to counter master demagoguery. Therefore, supporting EDUCATION that would emphasize the most unifying (and the least controversial), yet, BASIC CIVIC RESPECT for lives of people in a civilian human society, is a priority everywhere on our planet. ----- At the same time we start facing mostly small, threatening, dictatorships, capable of producing weapons of mass destruction. Therefore, we have to try to contribute to developing systems of FREE ELECTIONS, controlling weapons of mass destruction, wherever such dangers exist. ----- In a foreseeable future, unfortunately, we are facing a danger even by orders of magnitude greater. We are facing a possibility of a mass-produced heavy accumulation of inter-continental nuclear missiles, on a computerized "push-button" control, by a very powerful (and, quite possibly, miscalculating, or, suicidal) dictator, dangerous to the very existence of humanity on our planet. Therefore, it is a historical urgency that such a technological power be under the control by a government of the people, by the people and for the people, based on a sufficiently reliable system of FREE ELECTIONS, wherever, on our planet, such a potential danger may originate.

  10. Monocyte Signal Transduction Receptors in Active and Latent Tuberculosis

    Magdalena Druszczynska

    2013-01-01

    Full Text Available The mechanisms that promote either resistance or susceptibility to TB disease remain insufficiently understood. Our aim was to compare the expression of cell signaling transduction receptors, CD14, TLR2, CD206, and β2 integrin LFA-1 on monocytes from patients with active TB or nonmycobacterial lung disease and healthy individuals with M.tb latency and uninfected controls to explain the background of the differences between clinical and subclinical forms of M.tb infection. A simultaneous increase in the expression of the membrane bound mCD14 receptor and LFA-1 integrin in patients with active TB may be considered a prodrome of breaking immune control by M.tb bacilli in subjects with the latent TB and absence of clinical symptoms.

  11. Immune challenge and satiety-related activation of both distinct and overlapping neuronal populations in the brainstem indicate parallel pathways for viscerosensory signaling.

    Gaykema, Ronald P A; Daniels, Teresa E; Shapiro, Nathan J; Thacker, Gregory C; Park, Su-Mi; Goehler, Lisa E

    2009-10-19

    Caudal brainstem viscerosensory nuclei convey information about the body's internal state to forebrain regions implicated in feeding behavior and responses to immune challenge, and may modulate ingestive behavior following immune activation. Illness-induced appetite loss might be attributed to accentuated "satiety" pathways, activation of a distinct "danger channel" separate from satiety pathways, or both. To evaluate neural substrates that could mediate the effects of illness on ingestive behavior, we analyzed the pattern and phenotypes of medullary neurons responsive to consumption of a preferred food, sweetened milk, and to intraperitoneal lipopolysaccharide challenge that reduced sweetened milk intake. Brainstem sections were stained for c-Fos, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, and glucagon-like peptide-1 (GLP-1) immunoreactivity. Sweetened milk intake activated many neurons throughout the nucleus of the solitary tract (NTS), including A2 noradrenergic neurons in the caudal half of the NTS. LPS challenge activated a similar population of neurons in the NTS, in addition to rostral C2 adrenergic and mid-level A2 noradrenergic neurons in the NTS, many C1 and A1 neurons in the ventrolateral medulla, and in GLP-1 neurons in the dorsal medullary reticular nucleus. Increased numbers of activated GLP-1 neurons in the NTS were only associated with sweetened milk ingestion. Evidence for parallel processing was reflected in the parabrachial nucleus, where sweetened milk intake resulted in activation of the inner external lateral, ventrolateral and central medial portions, whereas LPS challenge induced c-Fos expression in the outer external lateral portions. Thus, signals generated in response to potentially dangerous physiological conditions seem to be propagated via specific populations of catecholaminergic neurons in the NTS and VLM, and likely include a pathway through the external lateral PBN. The data indicate that immune challenge

  12. Carbon dioxide dangers demonstration model

    Venezky, Dina; Wessells, Stephen

    2010-01-01

    Carbon dioxide is a dangerous volcanic gas. When carbon dioxide seeps from the ground, it normally mixes with the air and dissipates rapidly. However, because carbon dioxide gas is heavier than air, it can collect in snowbanks, depressions, and poorly ventilated enclosures posing a potential danger to people and other living things. In this experiment we show how carbon dioxide gas displaces oxygen as it collects in low-lying areas. When carbon dioxide, created by mixing vinegar and baking soda, is added to a bowl with candles of different heights, the flames are extinguished as if by magic.

  13. DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

    Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathwa...ys activated by microorganisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

  14. Activation of Wnt signaling bypasses the requirement for RTK/Ras signaling during C. elegans vulval induction

    Gleason, Julie E.; Korswagen, Hendrik C.; Eisenmann, David M

    2002-01-01

    During Caenorhabditis elegans vulval development, activation of receptor tyrosine kinase/Ras and Notch signaling pathways causes three vulval precursor cells (VPCs) to adopt induced cell fates. A Wnt signaling pathway also acts in cell fate specification by the VPCs, via regulation of the Hox gene lin-39. We show here that either mutation of pry-1 or expression of an activated BAR-1 β-catenin protein causes an Overinduced phenotype, in which greater than three VPCs adopt induced cell fates. T...

  15. Antithrombotic activities of ferulic acid via intracellular cyclic nucleotide signaling.

    Hong, Qian; Ma, Zeng-Chun; Huang, Hao; Wang, Yu-Guang; Tan, Hong-Ling; Xiao, Cheng-Rong; Liang, Qian-De; Zhang, Han-Ting; Gao, Yue

    2016-04-15

    Ferulic acid (FA) produces protective effects against cardiovascular dysfunctions. However, the mechanisms of FA is still not known. Here we examined the antithrombotic effects of FA and its potential mechanisms. Anticoagulation assays and platelet aggregation was evaluated in vitro and in vivo. Thromboxane B2 (TXB2), cyclic adenosine monophosphate(cAMP), and cyclic guanosine monophosphate (cGMP) was determined using enzyme immunoassay kits. Nitric oxide (NO) production was measured using the Griess reaction. Protein expression was detected by Western blotting analysis. Oral administration of FA prevented death caused by pulmonary thrombosis and prolonged the tail bleeding and clotting time in mice,while, it did not alter the coagulation parameters, including the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). In addition, FA (50-200µM) dose-dependently inhibited platelet aggregation induced by various platelet agonists, including adenosine diphosphate (ADP), thrombin, collagen, arachidonic acid (AA), and U46619. Further, FA attenuated intracellular Ca(2)(+) mobilization and TXB2 production induced by the platelet agonists. FA increased the levels of cAMP and cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP) while decreased phospho-MAPK (mitogen-activated protein kinase) and phosphodiesterase (PDE) in washed rat platelets, VASP is a substrate of cyclic nucleotide and PDE is an enzyme family responsible for hydrolysis of cAMP/cGMP. These results suggest that antithrombotic activities of FA may be regulated by inhibition of platelet aggregation, rather than through inhibiting the release of thromboplastin or formation of thrombin. The mechanism of this action may involve activation of cAMP and cGMP signaling. PMID:26948317

  16. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity.

    Wicher, Dieter; Derst, Christian; Gautier, Hélène; Lapied, Bruno; Heinemann, Stefan H; Agricola, Hans-Jürgen

    2007-01-01

    The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK) in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK) in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR), we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM) neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC(50)=11pM) due to reduction of a pacemaker Ca(2+) current through cAMP-inhibited pTRPgamma channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca(2+) concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH): PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPgamma channel that is activated by AKH under conditions of food shortage. PMID:18946521

  17. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

    Dieter Wicher

    2007-12-01

    Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

  18. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    Qia, Zhi

    2010-11-18

    A family of peptide signaling molecules (AtPeps) and their plasma membrane receptor AtPepR1 are known to act in pathogendefense signaling cascades in plants. Little is currently known about the molecular mechanisms that link these signaling peptides and their receptor, a leucine-rich repeat receptor-like kinase, to downstream pathogen-defense responses. We identify some cellular activities of these molecules that provide the context for a model for their action in signaling cascades. AtPeps activate plasma membrane inwardly conducting Ca 2+ permeable channels in mesophyll cells, resulting in cytosolic Ca 2+ elevation. This activity is dependent on their receptor as well as a cyclic nucleotide-gated channel (CNGC2). We also show that the leucine-rich repeat receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33) is mediated by the Ca 2+ signaling pathway associated with AtPep peptides and their receptor. The work presented here indicates that extracellular AtPeps, which can act as danger-associated molecular patterns, signal by interaction with their receptor, AtPepR1, a plasma membrane protein that can generate cGMP. Downstream from AtPep and AtPepR1 in a signaling cascade, the cGMP-activated channel CNGC2 is involved in AtPep- and AtPepR1-dependent inward Ca 2+ conductance and resulting cytosolic Ca 2+ elevation. The signaling cascade initiated by AtPeps leads to expression of pathogen- defense genes in a Ca 2+-dependent manner.

  19. Danger.

    Clay, Allyson

    1993-01-01

    The paintings in Allyson Clay’s series "Some places in the world a woman could walk" combine abstraction, photo silkscreen, and text to describe the experiences of women in the city. The works call up Baudelaire’s idea of the flâneur; far from being detached observers, Clay’s flâneuses reflect on their relationship to others and to public spaces. In each diptych text divulges the experiences, predilections and desires of individual women as they navigate public and private spaces within the...

  20. Dangerous Dogs, Constructivism and Normativity

    Hansen, Allan Dreyer

    2010-01-01

    This article argues that although there is no necessary link between constructivism and particular sets of norms, constructivism opens up a space for normativity and can be articulated through particular normative or political programs. I show how Laclau’s deconstructive constructivism can be art...... articulated within the framework of an ethos of democratization. The article takes its empirical point of departure in debates over dangerous dogs....

  1. Signal transduction and activator of transcription (STAT) protein-dependent activation of angiotensinogen promoter: A cellular signal for hypertrophy in cardiac muscle

    Mascareno, Eduardo; Dhar, Manya; M.A.Q. SIDDIQUI

    1998-01-01

    The role of the peptide hormone angiotensin (AngII) in promoting myocardial hypertrophy is well documented. Our studies demonstrate that AngII uses a signaling pathway in cardiac myocytes in which the promoter of the gene encoding its prohormone, angiotensinogen, serves as the target site for activated signal transduction and activator of transcription (STAT) proteins. Gel mobility-shift assay revealed that STAT3 and STAT6 are selectively activated by AngII treatment of cardiomyocytes in cult...

  2. Unique catalytic activities and scaffolding of p21 activated kinase-1 in cardiovascular signaling

    YunboKe

    2013-09-01

    Full Text Available P21 activated kinase-1 has diverse functions in mammalian cells. Although a large number of phosphoproteins have been designated as Pak1 substrates from in vitro studies,emerging evidence has indicated that Pak1 may function as a signaling molecule through a unique molecular mechanism—scaffolding. By scaffolding, Pak1 delivers signals through an auto-phosphorylation-induced conformational change without transfer of a phosphate group to its immediate downstream effector(s. Here we review evidence for this regulatory mechanism based on structural and functional studies of Pak1 in different cell types and research models as well as in vitro biochemical assays. We also discuss the implications of Pak1 scaffolding in disease-related signaling processes and the potential in cardiovascular drug development.

  3. Hypoxia activated EGFR signaling induces epithelial to mesenchymal transition (EMT.

    Ashish Misra

    Full Text Available Metastasis is a multi-step process which requires the conversion of polarized epithelial cells to mesenchymal cells, Epithelial-Mesenchymal Transition (EMT. EMT is essential during embryonic morphogenesis and has been implicated in the progression of primary tumors towards metastasis. Hypoxia is known to induce EMT; however the molecular mechanism is still poorly understood. Using the A431 epithelial cancer cell line, we show that cells grown under hypoxic conditions migrated faster than cells grown under normal oxygen environment. Cells grown under hypoxia showed reduced adhesion to the extracellular matrix (ECM probably due to reduced number of Vinculin patches. Growth under hypoxic conditions also led to down regulation of E-cadherin and up regulation of vimentin expression. The increased motility of cells grown under hypoxia could be due to redistribution of Rac1 to the plasma membrane as opposed to increased expression of Rac1. EGF (Epidermal Growth Factor is a known inducer of EMT and growth of A431 cells in the absence of oxygen led to increased expression of EGFR (EGF Receptor. Treatment of A431 cells with EGF led to reduced cell adhesion to ECM, increased cell motility and other EMT characteristics. Furthermore, this transition was blocked by the monoclonal antibody Cetuximab. Cetuximab also blocked the hypoxia-induced EMT suggesting that cell growth under hypoxic conditions led to activation of EGFR signaling and induction of EMT phenotype.

  4. Activation of hedgehog signaling is not a frequent event in ovarian cancers

    Zhang Xiaoli; Huang Shuhong; He Jing; Yang Ling; Bian Yuehong; He Nonggao; Zhang Hongwei; Xie Jingwu

    2009-01-01

    Abstract The hedgehog (Hh) signaling pathway regulates many processes of development and tissue homeostasis. Activation of hedgehog signaling has been reported in about 30% of human cancer including ovarian cancer. Inhibition of hedgehog signaling has been pursued as an effective strategy for cancer treatment including an ongoing phase II clinical trial in ovarian cancer. However, the rate of hedgehog signaling activation in ovarian cancer was reported differently by different groups. To pred...

  5. Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

    Atsuhiko T. Naito; Sumida, Tomokazu; Nomura, Seitaro; Liu, Mei-Lan; Higo, Tomoaki; NAKAGAWA, AKITO; Okada, Katsuki; Sakai, Taku; Hashimoto, Akihito; Hara, Yurina; Shimizu, Ippei; Zhu, Weidong; Toko, Haruhiro; Katada, Akemi; Akazawa, Hiroshi

    2012-01-01

    Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice,...

  6. Deregulated inflammasome signaling in disease

    Lamkanfi, Mohamed; Walle, Lieselotte Vande; Kanneganti, Thirumala-Devi

    2011-01-01

    Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding inflamm...

  7. Sunitinib activates Axl signaling in renal cell cancer.

    van der Mijn, Johannes C; Broxterman, Henk J; Knol, Jaco C; Piersma, Sander R; De Haas, Richard R; Dekker, Henk; Pham, Thang V; Van Beusechem, Victor W; Halmos, Balazs; Mier, James W; Jiménez, Connie R; Verheul, Henk M W

    2016-06-15

    Mass spectrometry-based phosphoproteomics provides a unique unbiased approach to evaluate signaling network in cancer cells. The tyrosine kinase inhibitor sunitinib is registered as treatment for patients with renal cell cancer (RCC). We investigated the effect of sunitinib on tyrosine phosphorylation in RCC tumor cells to get more insight in its mechanism of action and thereby to find potential leads for combination treatment strategies. Sunitinib inhibitory concentrations of proliferation (IC50) of 786-O, 769-p and A498 RCC cells were determined by MTT-assays. Global tyrosine phosphorylation was measured by LC-MS/MS after immunoprecipitation with the antiphosphotyrosine antibody p-TYR-100. Phosphoproteomic profiling of 786-O cells yielded 1519 phosphopeptides, corresponding to 675 unique proteins including 57 different phosphorylated protein kinases. Compared to control, incubation with sunitinib at its IC50 of 2 µM resulted in downregulation of 86 phosphopeptides including CDK5, DYRK3, DYRK4, G6PD, PKM and LDH-A, while 94 phosphopeptides including Axl, FAK, EPHA2 and p38α were upregulated. Axl- (y702), FAK- (y576) and p38α (y182) upregulation was confirmed by Western Blot in 786-O and A498 cells. Subsequent proliferation assays revealed that inhibition of Axl with a small molecule inhibitor (R428) sensitized 786-O RCC cells and immortalized endothelial cells to sunitinib up to 3 fold. In conclusion, incubation with sunitinib of RCC cells causes significant upregulation of multiple phosphopeptides including Axl. Simultaneous inhibition of Axl improves the antitumor activity of sunitinib. We envision that evaluation of phosphoproteomic changes by TKI treatment enables identification of new targets for combination treatment strategies. PMID:26815723

  8. A third-order active-R filter with feedforward input signal

    G N Shinde; P B Patil; P R Mirkute

    2003-12-01

    A realization of voltage-mode transfer functions with feedforward input signal for third-order active-R filter using an oprational amplifier has been presented. This filter is useful for high frequency operation, monolithic IC implementation and is easy to design. The single circuit gives three filter functions, low pass, high pass and band pass. This filter circuit can be used for different and f0 with high passband gain. This gives better stop band attenuation and sharper cut-off at the edge of the passband.

  9. Conformational transition in signal transduction: metastable states and transition pathways in the activation of a signaling protein.

    Banerjee, Rahul; Yan, Honggao; Cukier, Robert I

    2015-06-01

    Signal transduction is of vital importance to the growth and adaptation of living organisms. The key to understand mechanisms of biological signal transduction is elucidation of the conformational dynamics of its signaling proteins, as the activation of a signaling protein is fundamentally a process of conformational transition from an inactive to an active state. A predominant form of signal transduction for bacterial sensing of environmental changes in the wild or inside their hosts is a variety of two-component systems, in which the conformational transition of a response regulator (RR) from an inactive to an active state initiates responses to the environmental changes. Here, RR activation has been investigated using RR468 as a model system by extensive unbiased all-atom molecular dynamics (MD) simulations in explicit solvent, starting from snapshots along a targeted MD trajectory that covers the conformational transition. Markov state modeling, transition path theory, and geometric analyses of the wealth of the MD data have provided a comprehensive description of the RR activation. It involves a network of metastable states, with one metastable state essentially the same as the inactive state and another very similar to the active state that are connected via a small set of intermediates. Five major pathways account for >75% of the fluxes of the conformational transition from the inactive to the active-like state. The thermodynamic stability of the states and the activation barriers between states are found, to identify rate-limiting steps. The conformal transition is initiated predominantly by movements of the β3α3 loop, followed by movements of the β4α4-loop and neighboring α4 helix region, and capped by additional movements of the β3α3 loop. A number of transient hydrophobic and hydrogen bond interactions are revealed, and they may be important for the conformational transition. PMID:25945797

  10. Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

    Sengupta, T K; Schmitt, E M; Ivashkiv, L B

    1996-01-01

    An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation of genes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals ...

  11. Crosstalk between signaling pathways of adrenoreceptors and signal transducers and activators of transcription 3 (STAT3) in heart

    Kai-zheng GONG; Hui ZHANG; Jian-hai DU; You-yi ZHANG

    2007-01-01

    Recently, there have been important advancements in our understanding of the signaling mechanisms of adrenoreceptors (AR) and signal transducers and activators of transcription 3 (STAT3). While their crucial roles in the pathological processes of the heart are well established, accumulating evidence suggests there is a complex pattern of crosstalk between these 2 signaling pathways. Moreover, the potential for crosstalk occurs at multiple levels in each signaling cascade and involves receptor transactivation, G proteins, small GTPases, cyclic adenosine 3',5'-monophosphate/protein kinase A, protein kinase C, scaffold/adaptor proteins, protein tyrosine kinases, and mitogen-activated protein kinases. In addition, post-translational modification (eg acetylation) of STAT3 may provide a link betweenSTAT3 and AR signaling. In particular, crosstalk between these 2 systems in the heart would appear to be dependent upon the species/tissue studied, develop-mental stage, and eliciting stimulus. This at least partly accounts for the epigenetic effects on biological function that is mediated by the 2 signaling pathways. Elucidation of these mechanisms will provide new targets in the development of novel clinical strategies for heart disorders.

  12. Understanding disease mechanisms with models of signaling pathway activities

    Sebastian-Leon, Patricia; Vidal, Enrique; Minguez, Pablo; Conesa, Ana; Tarazona, Sonia; Amadoz, Alicia; Armero, Carmen; Salavert, Francisco; VIDAL-PUIG, Antonio; Montaner, David; Dopazo, Joaquín

    2014-01-01

    Background Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine. Results Here we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements in...

  13. The Search for signals of technological activities in the galaxy

    Lemarchand, Guillermo A

    2010-01-01

    In this article an analysis of the fundamentals used to search for extraterrestrial artificial signals in the galaxy, which have been developing for more than five decades, is presented. It is shown that the key factor for the success of these research projects is given by the technological civilizations lifetimes. Assuming the Principle of Mediocrity, estimations are made to determine the minimum number of civilizations that may co-exist in the galaxy and the probability of detecting a signal from them.

  14. Decree 2211: Standards to control the generation and handling of dangerous wastes

    This Decree has for object to establish the conditions under which should be carried out the activities of generation and handling of dangerous waste, in order to prevent damages to health and to the atmosphere. It includes: definitions; a list of sources of waste; a list of constituent of dangerous waste; the characteristics of danger; a lists of maximum permissible concentrations in leachates, handling of dangerous waste, criterion for transport, monitoring form, storage areas, treatment and final disposition, storage, elimination, incineration, recycling, reuse and recovery, installation and operation of security backfilling, book of waste record, control of activities, obligations in charge of those who manage dangerous waste, and trans border movements of dangerous waste

  15. Dangerousness and mental health policy.

    Hewitt, J L

    2008-04-01

    Mental health policy development in the UK has become increasingly dominated by the assumed need to prevent violence and alleviate public concerns about the dangers of the mentally ill living in the community. Risk management has become the expected focus of contemporary mental health services, and responsibility has increasingly been devolved to individual service professionals when systems fail to prevent violence. This paper analyses the development of mental health legislation and its impact on services users and mental health professionals at the micro level of service delivery. Historical precedence, media influence and public opinion are explored, and the reification of risk is questioned in practical and ethical terms. The government's newest proposals for compulsory treatment in the community are discussed in terms of practical efficacy and therapeutic impact. Dangerousness is far from being an objectively observable phenomenon arising from clinical pathology, but is a formulation of what is partially knowable through social analysis and unknowable by virtue of its situation in individual psychic motivation. Risk assessment can therefore never be completely accurate, and the solution of a 'better safe than sorry' approach to mental health policy is ethically and pragmatically flawed. PMID:18307647

  16. Temporal variations and change of forest fire danger in Europe in 1960–2012

    A. Venäläinen; N. Korhonen; N. Koutsias; Xystrakis, F.; Urbieta, I. R.; J. M. Moreno

    2013-01-01

    Understanding how fire-weather danger indices changed in the past, and detecting how changes affected forest fire activity is important in changing climate. We used the Canadian Fire Weather Index (FWI), calculated from two reanalysis datasets, ERA 40 and ERA Interim, to examine the temporal variation of forest fire danger in Europe in 1960–2012. Additionally, we used national forest-fires statistical data from Greece and Spain to relate fire danger and fire ...

  17. Temporal variations and change in forest fire danger in Europe for 1960–2012

    Venäläinen, A.; Korhonen, N.; O. Hyvärinen; Koutsias, N.; Xystrakis, F.; I. R. Urbieta; Moreno, J.M.

    2014-01-01

    Understanding how fire weather danger indices changed in the past and how such changes affected forest fire activity is important in a changing climate. We used the Canadian Fire Weather Index (FWI), calculated from two reanalysis data sets, ERA-40 and ERA Interim, to examine the temporal variation of forest fire danger in Europe in 1960–2012. Additionally, we used national forest fire statistics from Greece, Spain and Finland to examine the relationship between fire danger ...

  18. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland

    Joanna Pyczek; Rolf Buslei; David Schult; Annett Hölsken; Michael Buchfelder; Ina Heß; Heidi Hahn; Anja Uhmann

    2016-01-01

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2+ and Sox...

  19. A Transcriptional Mechanism Integrating Inputs from Extracellular Signals to Activate Hippocampal Stem Cells

    Andersen, Jimena; Urbán, Noelia; Achimastou, Angeliki; Ito, Ayako; Simic, Milesa; Ullom, Kristy; Martynoga, Ben; Lebel, Mélanie; Göritz, Christian; Frisén, Jonas; Nakafuku, Masato; Guillemot, François

    2014-01-01

    Summary The activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate...

  20. Active transport improves the precision of linear long distance molecular signalling

    Godec, Aljaz; Metzler, Ralf

    2016-01-01

    Molecular signalling in living cells occurs at low copy numbers and is thereby inherently limited by the noise imposed by thermal diffusion. The precision at which biochemical receptors can count signalling molecules is intimately related to the noise correlation time. In addition to passive thermal diffusion, messenger RNA and vesicle-engulfed signalling molecules can transiently bind to molecular motors and are actively transported across biological cells. Active transport is most beneficia...

  1. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

  2. Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou, E-mail: xinzhou_yang@hotmail.com

    2014-12-01

    Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals.

  3. A Gaussian process framework for modelling stellar activity signals in radial velocity data

    Rajpaul, Vinesh; Osborne, Michael A; Reece, Steven; Roberts, Stephen J

    2015-01-01

    To date, the radial velocity (RV) method has been one of the most productive techniques for detecting and confirming extrasolar planetary candidates. Unfortunately, stellar activity can induce RV variations which can drown out or even mimic planetary signals - and it is notoriously difficult to model and thus mitigate the effects of these activity-induced nuisance signals. This is expected to be a major obstacle to using next-generation spectrographs to detect lower mass planets, planets with longer periods, and planets around more active stars. Enter Gaussian processes (GPs) which, we note, have a number of attractive features that make them very well suited to disentangling stellar activity signals from planetary signals. We present here a GP framework we developed to model RV time series jointly with ancillary activity indicators (e.g. bisector velocity spans, line widths, chromospheric activity indices), allowing the activity component of RV time series to be constrained and disentangled from e.g. planeta...

  4. Artifact suppression and analysis of brain activities with electroencephalography signals

    Rashed-Al-Mahfuz, Md.; Islam, Md. Rabiul; Hirose, Keikichi; Molla, Md. Khademul Islam

    2013-01-01

    Brain-computer interface is a communication system that connects the brain with computer (or other devices) but is not dependent on the normal output of the brain (i.e., peripheral nerve and muscle). Electro-oculogram is a dominant artifact which has a significant negative influence on further analysis of real electroencephalography data. This paper presented a data adaptive technique for artifact suppression and brain wave extraction from electroencephalography signals to detect regional bra...

  5. Determination of Sphingosine Kinase Activity for Cellular Signaling Studies

    Lee, Katherine J.; Mwongela, Simon M.; Kottegoda, Sumith; Borland, Laura; Nelson, Allison R.; Sims, Christopher E.; Allbritton, Nancy L.

    2008-01-01

    Regulation of sphingosine and sphingosine-1-phosphate concentrations is of growing interest due to their importance in cellular signal transduction. Furthermore, new pharmaceutical agents moderating the intracellular and extracellular levels of sphingosine metabolites are showing promise in preclinical and clinical trials. In the present work, a quantitative assay relying on capillary electrophoresis with laser-induced fluorescence detection was developed to measure the interconversion of sph...

  6. Human ZCCHC12 activates AP-1 and CREB signaling as a transcriptional co-activator

    Hong Li; Qian Liu; Xiang Hu; Du Feng; Shuanglin Xiang; Zhicheng He; Xingwang Hu; Jianlin Zhou; Xiaofeng Ding; Chang Zhou; Jian Zhang

    2009-01-01

    Mouse zinc finger CCHC domain containing 12 gene (ZCCHC12) has been identified as a transcriptional co-activator of bone morphogenetic protein (BMP) sig-naling,and human ZCCHC12 was reported to be related to non-syndromic X-linked mental retardation (NS-XLMR).However,the details of how human ZCCHCI2 involve in the NS-XLMR still remain unclear.In this study,we identified a novel nuclear localization signal (NLS) in the middle of human ZCCHC12 protein which is responsible for the nuclear localization.Multiple-tissue northern blot analysis indi-cated that ZCCHC12 is highly expressed in human brain.Furthermore,in situ hybridization showed that ZCCHC12 is specifically expressed in neuroepithelium of forebrain,midbrain,and diencephalon regions of mouse E10.5 embryos.Luciferase reporter assays demonstrated that ZCCHC12 enhanced the transcrip-tional activities of activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as a co-activator.In conclusion,we identified a new NLS in ZCCHC12 and figured out that ZCCHC12 functions as a transcriptional co-activator of AP-1 and CREB.

  7. Angiogenic activity of sesamin through the activation of multiple signal pathways

    The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125FAK-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.

  8. Surfactant Protein A integrates activation signal strength to differentially modulate T cell proliferation

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; GOTO, HISATSUGU; Ledford, Julie G.; Hsia, Bethany; Pastva, Amy M.; Wright, Jo Rae

    2012-01-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar:airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A mediated modulation of T cell activation depends upon the strength, duration and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex and in vivo in different mouse models, ...

  9. The Dangers of Educated Girls and Women

    John, Vaughn M.

    2016-01-01

    Why do educated girls and women constitute a danger in some societies and for this face extreme danger in their educational endeavours? This article argues that historical and contemporary educational discrimination of girls and women is the hallmark of a violently patriarchal society, and this stubborn injustice is exacerbated under conditions of…

  10. Suppression of epithelial signal transducer and activator of transcription 1 activation by extracts of Aspergillus fumigatus.

    Bhushan, Bharat; Homma, Tetsuya; Norton, James E; Sha, Quan; Siebert, Jason; Gupta, Dave S; Schroeder, James W; Schleimer, Robert P

    2015-07-01

    Aspergillus fumigatus (AF) is often pathogenic in immune-deficient individuals and can cause life-threatening infections such as invasive aspergillosis. The pulmonary epithelial response to AF infection and the signaling pathways associated with it have not been completely studied. BEAS-2B cells or primary human bronchial epithelial cells were exposed to extracts of AF and challenged with IFN-β or the Toll-like receptor 3 agonist double-stranded RNA (dsRNA). Cytokine release (B-cell activating factor of the TNF family [BAFF], IFN-γ-induced protein-10 [IP-10], etc.) was assessed. AF extract was separated into low-molecular-weight (LMW) and high-molecular-weight (HMW) fractions using ultra 4 centrifugal force filters to characterize the activity. Real-time PCR was performed with a TaqMan method, and protein estimation was performed using ELISA techniques. Western blot was performed to assess phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-β and dsRNA induced messenger RNA (mRNA) expression of BAFF (350- and 452-fold, respectively [n = 3]) and IP-10 (1,081- and 3,044-fold, respectively [n = 3]) in BEAS-2B cells. When cells were pretreated with AF extract for 1 hour and then stimulated with IFN-β or dsRNA for 6 hours, induction of BAFF and IP-10 mRNA was strongly suppressed relative to levels produced by IFN-β and dsRNA alone. When compared with control, soluble BAFF and IP-10 protein levels were maximally suppressed in dsRNA-stimulated wells treated with 1:320 wt/vol AF extract (P < 0.005). Upon molecular size fractionation, a LMW fraction of AF extract had no measurable suppressive effect on IP-10 mRNA expression. However, a HMW fraction of the AF extract significantly suppressed IP-10 expression in BEAS-2B cells that were stimulated with dsRNA or IFN-β. When BEAS-2B cells were pretreated with AF extract and then stimulated with IFN-β, reduced levels of pSTAT1 were observed, with maximum suppression at 4 and 6

  11. Extracellular signal-regulated kinase 1/2 signalling in SLE T cells is influenced by oestrogen and disease activity.

    Gorjestani, S; Rider, V; Kimler, B F; Greenwell, C; Abdou, N I

    2008-06-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs primarily in women of reproductive age. The disease is characterized by exaggerated T-cell activity and abnormal T-cell signalling. The mitogen-activated protein kinase (MAPK) pathway is involved in the maintenance of T-cell tolerance that fails in patients with SLE. Oestrogen is a female sex hormone that binds to nuclear receptors and alters the rate of gene transcription. Oestrogen can also act through the plasma membrane and rapidly stimulate second messengers including calcium flux and kinase activation. In this study, we investigated whether oestrogen influences the activation of MAPK signalling through the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in activated SLE T cells. SLE and control T cells were cultured in serum-free medium without and with oestradiol (10(-7) M) for 18 h. The T cells were activated with phorbol 12 myristate 13-acetate and ionomycin for various time points (0-60 min), and the amount of phosphorylated ERK1/2 was measured by immunoblotting. There were no differences in ERK1/2 phosphorylation between SLE and control T cells at 5 and 15 min after the activation stimulus. However, comparison between the amount of phosphorylated ERK1/2 in SLE T cells from the same patients cultured without and with oestradiol showed a significant oestrogen-dependent suppression (P=0.48) of ERK1/2 in patients with inactive/mild systemic lupus erythematosus disease activity index (SLEDAI) (0-2) compared with patients with moderate (4-6) or active (8-12) SLEDAI scores. These results suggest that the suppression of MAPK through ERK1/2 phosphorylation is sensitive to oestradiol in patients with inactive or mild disease, but the sensitivity is not maintained when disease activity increases. Furthermore, studies are now necessary to understand the mechanisms by which oestrogen influences MAPK activation in SLE T cells. PMID:18539708

  12. Sunlight UV-induced skin cancer relies upon activation of the p38α signaling pathway

    LIU, KANGDONG; Yu, Donghoon; Cho, Yong-Yeon; Ann M Bode; Ma, Weiya; Yao, Ke; Li, Shengqing; Li, Jixia; Bowden, G. Tim; Dong, Ziming; Dong, Zigang

    2013-01-01

    The activation of cellular signal transduction pathways by solar ultraviolet (SUV) irradiation plays a vital role in skin tumorigenesis. Although many pathways have been studied using pure ultraviolet A (UVA) or ultraviolet B (UVB) irradiation, the signaling pathways induced by SUV (i.e., sunlight) are not understood well enough to permit improvements for prevention, prognosis and treatment. Here we report parallel protein kinase array studies aimed at determining the dominant signaling pathw...

  13. An Apodized Kepler Periodogram for Separating Planetary and Stellar Activity Signals

    Gregory, Philip C

    2016-01-01

    A new apodized Keplerian (AK) model is proposed for the analysis of precision radial velocity (RV) data to model both planetary and stellar activity (SA) induced RV signals. A symmetrical Gaussian apodization function with unknown width and center can distinguish planetary signals from SA signals on the basis of the span of the apodization window. The general model for $m$ apodized Keplerian signals includes a linear regression term between RV and the stellar activity diagnostic $\\log(R'hk)$, as well as an extra Gaussian noise term with unknown standard deviation. The model parameters are explored using a Bayesian fusion MCMC code. A differential version of the Generalized Lomb-Scargle periodogram that employs a control diagnostic provides an additional way of distinguishing SA signals and helps guide the choice of new periods. Results are reported for a recent international RV blind challenge which included multiple state of the art simulated data sets supported by a variety of stellar activity diagnostics. ...

  14. Discovery of novel small molecule activators of β-catenin signaling.

    Folkert Verkaar

    Full Text Available Wnt/β-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/β-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed bona fide activators of β-catenin signaling. The compounds stabilized cytoplasmic β-catenin and activated β-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate β-catenin signaling has yet to be determined, several key regulators of Wnt/β-catenin signaling, including glycogen synthase kinase 3 and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they only induced β-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined. Our data indicate that differences in cellular Wnt/β-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/β-catenin signaling.

  15. Remote activation of the Wnt/β-catenin signalling pathway using functionalised magnetic particles.

    Michael Rotherham

    Full Text Available Wnt signalling pathways play crucial roles in developmental biology, stem cell fate and tissue patterning and have become an attractive therapeutic target in the fields of tissue engineering and regenerative medicine. Wnt signalling has also been shown to play a role in human Mesenchymal Stem Cell (hMSC fate, which have shown potential as a cell therapy in bone and cartilage tissue engineering. Previous work has shown that biocompatible magnetic nanoparticles (MNP can be used to stimulate specific mechanosensitive membrane receptors and ion channels in vitro and in vivo. Using this strategy, we determined the effects of mechano-stimulation of the Wnt Frizzled receptor on Wnt pathway activation in hMSC. Frizzled receptors were tagged using anti-Frizzled functionalised MNP (Fz-MNP. A commercially available oscillating magnetic bioreactor (MICA Biosystems was used to mechanically stimulate Frizzled receptors remotely. Our results demonstrate that Fz-MNP can activate Wnt/β-catenin signalling at key checkpoints in the signalling pathway. Immunocytochemistry indicated nuclear localisation of the Wnt intracellular messenger β-catenin after treatment with Fz-MNP. A Wnt signalling TCF/LEF responsive luciferase reporter transfected into hMSC was used to assess terminal signal activation at the nucleus. We observed an increase in reporter activity after treatment with Fz-MNP and this effect was enhanced after mechano-stimulation using the magnetic array. Western blot analysis was used to probe the mechanism of signalling activation and indicated that Fz-MNP signal through an LRP independent mechanism. Finally, the gene expression profiles of stress response genes were found to be similar when cells were treated with recombinant Wnt-3A or Fz-MNP. This study provides proof of principle that Wnt signalling and Frizzled receptors are mechanosensitive and can be remotely activated in vitro. Using magnetic nanoparticle technology it may be possible to modulate

  16. Hemodynamic activation of β-catenin and TCF signaling in vascular endothelium regulates fibronectin expression

    Gelfand, Bradley D.; Meller, Julia; Pryor, Andrew W.; Kahn, Michael; Schoppee Bortz, Pamela D.; Wamhoff, Brian R.; Blackman, Brett R.

    2011-01-01

    β-catenin/TCF signaling regulates a varied set of cellular functions including development and remodeling. Fibronectin is a TCF-regulated gene that is highly expressed in arterial endothelium during atherosclerosis development and contributes to the pathophysiology of the disease. However, the activation of endothelial β-catenin/TCF signaling and its role in fibronectin expression in atherosclerosis are not currently known.

  17. FEATURES FOR TRANSPORT AND AIR MECHANICAL SYSTEMS OF DANGEROUS GOODS

    Eugen Dumitru BUSA

    2012-05-01

    Full Text Available Transport of dangerous goods are regulated activities, they take place under the direction and control of the authorities and specialized bodies in an institutional framework determined by national and international law. Of economic, transport infrastructure is the crucial element without which both production and trade would become meaningless, it is an essential element of a civilization, is also a necessary accessory of other economic activities.

  18. Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling

    Hanselman Keaton B

    2006-10-01

    Full Text Available Abstract Background In the nematode, Caenorhabditis elegans, a conserved insulin-like signaling pathway controls larval development, stress resistance and adult lifespan. AGE-1, a homolog of the p110 catalytic subunit of phosphoinositide 3-kinases (PI3K comprises the major known effector pathway downstream of the insulin receptor, DAF-2. Phospholipid products of AGE-1/PI3K activate AKT/PKB kinase signaling via PDK-1. AKT/PKB signaling antagonizes nuclear translocation of the DAF-16/FOXO transcription factor. Reduced AGE-1/PI3K signaling permits DAF-16 to direct dauer larval arrest and promote long lifespan in adult animals. In order to study the downstream effectors of AGE-1/PI3K signaling in C. elegans, we conducted a genetic screen for mutations that suppress the constitutive dauer arrest phenotype of age-1(mg109 animals. Results This report describes mutations recovered in a screen for suppressors of the constitutive dauer arrest (daf-C phenotype of age-1(mg109. Two mutations corresponded to alleles of daf-16. Two mutations were gain-of-function alleles in the genes, akt-1 and pdk-1, encoding phosphoinositide-dependent serine/threonine kinases. A fifth mutation, mg227, located on chromosome X, did not correspond to any known dauer genes, suggesting that mg227 may represent a new component of the insulin pathway. Genetic epistasis analysis by RNAi showed that reproductive development in age-1(mg109;akt-1(mg247 animals was dependent on the presence of pdk-1. Similarly, reproductive development in age-1(mg109;pdk-1(mg261 animals was dependent on akt-1. However, reproductive development in age-1(mg109; mg227 animals required only akt-1, and pdk-1 activity was dispensable in this background. Interestingly, while mg227 suppressed dauer arrest in age-1(mg109 animals, it enhanced the long lifespan phenotype. In contrast, akt-1(mg247 and pdk-1(mg261 did not affect lifespan or stress resistance, while both daf-16 alleles fully suppressed these

  19. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression

    Highlights: → Nerve transection increased Notch signaling in paralyzed muscle. → Nandrolone prevented denervation-induced Notch signaling. → Nandrolone induced the expression of an inhibitor of the Notch signaling, Numb. → Reduction of denervation-induced Notch signaling by nandrolone is likely through upregulation of Numb. -- Abstract: Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy.

  20. Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression

    Liu, Xin-Hua [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Yao, Shen; Qiao, Rui-Fang; Levine, Alice C. [Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Kirschenbaum, Alexander [Department of Urology, Mount Sinai School of Medicine, New York, NY 10029 (United States); Pan, Jiangping; Wu, Yong [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Qin, Weiping [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Bauman, William A. [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Cardozo, Christopher P., E-mail: chris.cardozo@mssm.edu [Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peter VA Medical Center, Bronx, NY 10468 (United States); Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States); Rehabilitation Medicine, Mount Sinai School of Medicine, New York, NY 10029 (United States)

    2011-10-14

    Highlights: {yields} Nerve transection increased Notch signaling in paralyzed muscle. {yields} Nandrolone prevented denervation-induced Notch signaling. {yields} Nandrolone induced the expression of an inhibitor of the Notch signaling, Numb. {yields} Reduction of denervation-induced Notch signaling by nandrolone is likely through upregulation of Numb. -- Abstract: Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy.

  1. Bi-Static Active Microwave Remote Sensing of Reflected Signals-of-Opportunity Project

    National Aeronautics and Space Administration — We propose to demonstrate the use of these so-called signals-of-opportunity (SOP) to perform bi-static active microwave remote sensing of land surfaces. Specially,...

  2. Stopping Accidents before They Happen: Perceiving Lane-Level Moving Vehicle Danger Regions to Warn Surrounding Drivers and Pedestrians

    Chi Guo

    2016-01-01

    Full Text Available Perceiving the location of dangerous moving vehicles and broadcasting this information to vehicles nearby are essential to achieve active safety in the Internet of Vehicles (IOV. To address this issue, we implement a real-time high-precision lane-level danger region service for moving vehicles. A traditional service depends on static geofencing and fails to deal with dynamic vehicles. To overcome this defect, we devised a new type of IOV service that manages to track dangerous moving vehicles in real time and recognize their danger regions quickly and accurately. Next, we designed algorithms to distinguish the vehicles in danger regions and broadcast the information to these vehicles. Our system can simultaneously manipulate a mass of danger regions for various dangerous vehicles and broadcast this information to surrounding vehicles at a large scale. This new system was tested in Shanghai, Guangzhou, Wuhan, and other cities; the data analysis is presented in this paper as well.

  3. Active transport improves the precision of linear long distance molecular signalling

    Godec, Aljaž; Metzler, Ralf

    2016-09-01

    Molecular signalling in living cells occurs at low copy numbers and is thereby inherently limited by the noise imposed by thermal diffusion. The precision at which biochemical receptors can count signalling molecules is intimately related to the noise correlation time. In addition to passive thermal diffusion, messenger RNA and vesicle-engulfed signalling molecules can transiently bind to molecular motors and are actively transported across biological cells. Active transport is most beneficial when trafficking occurs over large distances, for instance up to the order of 1 metre in neurons. Here we explain how intermittent active transport allows for faster equilibration upon a change in concentration triggered by biochemical stimuli. Moreover, we show how intermittent active excursions induce qualitative changes in the noise in effectively one-dimensional systems such as dendrites. Thereby they allow for significantly improved signalling precision in the sense of a smaller relative deviation in the concentration read-out by the receptor. On the basis of linear response theory we derive the exact mean field precision limit for counting actively transported molecules. We explain how intermittent active excursions disrupt the recurrence in the molecular motion, thereby facilitating improved signalling accuracy. Our results provide a deeper understanding of how recurrence affects molecular signalling precision in biological cells and novel medical-diagnostic devices.

  4. Mitogen-activated protein kinase signaling in plants under abiotic stress.

    Sinha, Alok Krishna; Jaggi, Monika; Raghuram, Badmi; Tuteja, Narendra

    2011-02-01

    Mitogen-activated protein kinase cascade is evolutionarily conserved signal transduction module involved in transducing extracellular signals to the nucleus for appropriate cellular adjustment. This cascade consists essentially of three components, a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK) and a MAPK connected to each other by the event of phosphorylation. These kinases play various roles in intra- and extra-cellular signaling in plants by transferring the information from sensors to responses. Signaling through MAP kinase cascade can lead to cellular responses including cell division, differentiation as well as responses to various stresses. MAPK signaling has also been associated with hormonal responses. In plants, MAP kinases are represented by multigene families and are involved in efficient transmission of specific stimuli and also involved in the regulation of the antioxidant defense system in response to stress signaling. In the current review we summarize and investigate the participation of MAPKs as possible mediators of various abiotic stresses in plants. PMID:21512321

  5. Active regulation of receptor ratios controls integration of quorum-sensing signals in Vibrio harveyi

    Teng, Shu-Wen; Schaffer, Jessica N; Tu, Kimberly C; Mehta, Pankaj; Lu, Wenyun; Ong, N P; Bassler, Bonnie L; Wingreen, Ned S

    2011-01-01

    Quorum sensing is a chemical signaling mechanism used by bacteria to communicate and orchestrate group behaviors. Multiple feedback loops exist in the quorum-sensing circuit of the model bacterium Vibrio harveyi. Using fluorescence microscopy of individual cells, we assayed the activity of the quorum-sensing circuit, with a focus on defining the functions of the feedback loops. We quantitatively investigated the signaling input–output relation both in cells with all feedback loops present as well as in mutants with specific feedback loops disrupted. We found that one of the feedback loops regulates receptor ratios to control the integration of multiple signals. Together, the feedback loops affect the input–output dynamic range of signal transmission and the noise in the output. We conclude that V. harveyi employs multiple feedback loops to simultaneously control quorum-sensing signal integration and to ensure signal transmission fidelity. PMID:21613980

  6. Active control of shocks and sonic boom ground signal

    Yagiz, Bedri

    The manipulation of a flow field to obtain a desired change is a much heightened subject. Active flow control has been the subject of the major research areas in fluid mechanics for the past two decades. It offers new solutions for mitigation of shock strength, sonic boom alleviation, drag minimization, reducing blade-vortex interaction noise in helicopters, stall control and the performance maximization of existing designs to meet the increasing requirements of the aircraft industries. Despite the wide variety of the potential applications of active flow control, the majority of studies have been performed at subsonic speeds. The active flow control cases were investigated in transonic speed in this study. Although the active flow control provides significant improvements, the sensibility of aerodynamic performance to design parameters makes it a nontrivial and expensive problem, so the designer has to optimize a number of different parameters. For the purpose of gaining understanding of the active flow control concepts, an automated optimization cycle process was generated. Also, the optimization cycle reduces cost and turnaround time. The mass flow coefficient, location, width and angle were chosen as design parameters to maximize the aerodynamic performance of an aircraft. As the main contribution of this study, a detailed parametric study and optimization process were presented. The second step is to appraise the practicability of weakening the shock wave and thereby reducing the wave drag in transonic flight regime using flow control devices such as two dimensional contour bump, individual jet actuator, and also the hybrid control which includes both control devices together, thereby gaining the desired improvements in aerodynamic performance of the air-vehicle. After this study, to improve the aerodynamic performance, the flow control and shape parameters are optimized separately, combined, and in a serial combination. The remarkable part of all these

  7. Methanol and ethanol modulate responses to danger- and microbe-associated molecular patterns

    Claire T Hann

    2014-10-01

    Full Text Available Methanol is a byproduct of cell wall modification, released through the action of pectin methylesterases (PMEs, which demethylesterify cell wall pectins. Plant PMEs play not only a role in developmental processes but also in responses to herbivory and infection by fungal or bacterial pathogens. Molecular mechanisms that explain how methanol affects plant defenses are poorly understood. Here we show that exogenously supplied methanol alone has weak effects on defense signaling in three dicot species, however it profoundly alters signaling responses to danger- and microbe-associated molecular patterns (DAMPs, MAMPs such as the alarm hormone systemin, the bacterial flagellum-derived flg22 peptide, and the fungal cell wall-derived oligosaccharide chitosan. In the presence of methanol the kinetics and amplitudes of DAMP/MAMP-induced MAP kinase (MAPK activity and oxidative burst are altered in tobacco and tomato suspension-cultured cells, in Arabidopsis seedlings and tomato leaf tissue. As a possible consequence of altered DAMP/MAMP signaling, methanol suppressed the expression of the defense genes PR-1 and PI-1 in tomato. In cell cultures of the grass tall fescue (Festuca arundinacea, Poaceae, Monocots, methanol alone activates MAPKs and increases chitosan-induced MAPK activity, and in the darnel grass Lolium temulentum (Poaceae, it alters wound-induced MAPK signaling. We propose that methanol can be recognized by plants as a sign of the damaged self. In dicots, methanol functions as a DAMP-like alarm signal with little elicitor activity on its own, whereas it appears to function as an elicitor-active DAMP in monocot grasses. Ethanol had been implicated in plant stress responses, although the source of ethanol in plants is not well established. We found that it has a similar effect as methanol on responses to MAMPs and DAMPs.

  8. DMPD: Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3. [Dynamic Macrophage Pathway CSML Database

    Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regulatoryfactor...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of... interferon regulatoryfactor 3. Authors Servant MJ, Grandvaux N, Hiscott J. Publication Biochem Pharmacol. 2

  9. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

    Hirose, Yoshikazu [Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Itoh, Tohru, E-mail: itohru@iam.u-tokyo.ac.jp [Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan); Miyajima, Atsushi [Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan)

    2009-09-10

    Hedgehog (Hh) signaling plays crucial roles in development and homeostasis of various organs. In the adult liver, it regulates proliferation and/or viability of several types of cells, particularly under injured conditions, and is also implicated in stem/progenitor cell maintenance. However, the role of this signaling pathway during the normal developmental process of the liver remains elusive. Although Sonic hedgehog (Shh) is expressed in the ventral foregut endoderm from which the liver derives, the expression disappears at the onset of the liver bud formation, and its possible recurrence at the later stages has not been investigated. Here we analyzed the activation and functional relevance of Hh signaling during the mouse fetal liver development. At E11.5, Shh and an activation marker gene for Hh signaling, Gli1, were expressed in Dlk{sup +} hepatoblasts, the fetal liver progenitor cells, and the expression was rapidly decreased thereafter as the development proceeded. In the culture of Dlk{sup +} hepatoblasts isolated from the E11.5 liver, activation of Hh signaling stimulated their proliferation and this effect was cancelled by a chemical Hh signaling inhibitor, cyclopamine. In contrast, hepatocyte differentiation of Dlk{sup +} hepatoblasts in vitro as manifested by the marker gene expression and acquisition of ammonia clearance activity was significantly inhibited by forced activation of Hh signaling. Taken together, these results demonstrate the temporally restricted manner of Hh signal activation and its role in promoting the hepatoblast proliferation, and further suggest that the pathway needs to be shut off for the subsequent hepatic differentiation of hepatoblasts to proceed normally.

  10. Teens and Steroids: A Dangerous Combo

    ... warns teens and parents about the dangers of steroid use. Q: What are anabolic steroids and how many ... but the truth is that the frequency of steroid use in this age group is far greater than ...

  11. Xylitol and Your Dog: Danger, Paws Off

    ... Products For Consumers Home For Consumers Consumer Updates Xylitol and Your Dog: Danger, Paws Off Share Tweet ... containing xylitol. back to top Other Foods Containing Xylitol But gum isn’t the only product containing ...

  12. Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.

    Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning; Zhang, Robin; Searle, Jennifer S; Pei, Xun; Li, Xuan; Ryoo, Hyung Don; Ji, Jun-Yuan; Du, Wei

    2014-05-01

    Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor. PMID:24809668

  13. Signal transducer and activator of transcription 3 activation is associated with bladder cancer cell growth and survival

    Hsieh Fu-Chuan

    2008-10-01

    Full Text Available Abstract Background Constitutive activation of signal transducer and activator of transcription 3 (Stat3 signaling pathway plays an important role in several human cancers. Activation of Stat3 is dependent on the phosphorylation at the tyrosine residue 705 by upstream kinases and subsequent nuclear translocation after dimerization. It remains unclear whether oncogenic Stat3 signaling pathway is involved in the oncogenesis of bladder cancer. Results We found that elevated Stat3 phosphorylation in 19 of 100 (19% bladder cancer tissues as well as bladder cancer cell lines, WH, UMUC-3 and 253J. To explore whether Stat3 activation is associated with cell growth and survival of bladder cancer, we targeted the Stat3 signaling pathway in bladder cancer cells using an adenovirus-mediated dominant-negative Stat3 (Y705F and a small molecule compound, STA-21. Both prohibited cell growth and induction of apoptosis in these bladder cancer cell lines but not in normal bladder smooth muscle cell (BdSMC. The survival inhibition might be mediated through apoptotic caspase 3, 8 and 9 pathways. Moreover, down-regulation of anti-apoptotic genes (Bcl-2, Bcl-xL and survivin and a cell cycle regulating gene (cyclin D1 was associated with the cell growth inhibition and apoptosis. Conclusion These results indicated that activation of Stat3 is crucial for bladder cancer cell growth and survival. Therefore, interference of Stat3 signaling pathway emerges as a potential therapeutic approach for bladder cancer.

  14. 77 FR 25952 - Oregon Army National Guard, Camp Rilea, Clatsop County, OR; Danger Zone

    2012-05-02

    ... boundaries of the Camp. If a vessel is detected in the danger zone, a cease fire will be called on all active weapons ranges and Camp Rilea will attempt to contact the vessel using marine VHF radio. Cease fire...

  15. How Dangerous are 'Dirty Bombs'?

    dangerous, contrary to the 'threshold' model, according to which small or even moderate increases in background radiation may be safe. b) National and international radiation-safety organizations set differing safety levels. c) The bigger the conventional bomb that distributes the radioactive material, the better it will disperse. Thus, for a given amount of a particular isotope, a smaller explosion will expose a few people to a higher dose. A larger explosion will expose more people to a lower dose. d) A steady wind will carry the radiation in one direction. A changing wind will spread it more widely, increasing the affected area and population, but reducing the individual dose. e) The higher the radiation in the bomb, the better the chance it will be detected before detonation. Many relatively low cost practical steps can be taken to reduce risks from radiological weapons and minimize the effects if an attack should occur. The first step is ensuring that the radioactive materials are safe, secure and out of reach of possible terrorists. The coherent response plan should be prepared in advance. Ability to detect lost and stolen materials should be developed. Radiation detection devices should be installed on key points such as frontier passages, airports etc. Training of population and experts should be continuously implemented etc. (author)

  16. Nuclear threat. A clear and present danger

    It was disappointed at the discussion in the review conference of the NPT held in 2005. The fact may be caused by the estrangement between the international urgent issues related to the non-proliferation and the effectiveness of archaic measures through the NPT. However, it should not be recognized that the international obligation and worth of NPT has been gone. The NPT referred the typical international situation under the cold war era. Although several permanent issues of the nuclear non-proliferation exist in current discussions, the activities relevant to the NPT may not be effect against newly unstable situations after the September 11th of 2001. Urgent challenges to be taken are that we must strictly analyze the interventions between 'the clear and present danger' of our world and the nuclear herms, and must take appropriate actions toward them without influences from previous international situations that might be subsisted in current international treaties and agreements. This paper identified the features of nuclear threats based on the four categories and examined the possibilities of nuclear terrorism from previous facts with the inductive inference. The results identified the possibility of nuclear facility attack and of radioactive materials theft by the Polico-Religious Groups and others are stood out. The authors would suggest the important of urgent recognition to establish the certain security system against nuclear terrorism. (author)

  17. Vitamin D controls T cell antigen receptor signaling and activation of human T cells

    von Essen, Marina Rode; Kongsbak, Martin; Schjerling, Peter;

    2010-01-01

    Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering...... led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR...... signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation....

  18. Prediction of vehicle activity for emissions estimation under oversaturated conditions along signalized arterials

    Skabardonis, Alexander; Geroliminis, Nikolaos; Christofa, Eleni

    2013-01-01

    The traditional methodology for estimating vehicle emissions based on vehicle miles traveled and average speed is not reliable because it does not consider the effects of congestion, control devices, and driving mode (cruise, acceleration, deceleration, and idle). We developed an analytical model to predict vehicle activity on signalized arterials with emphasis on oversaturated traffic conditions. The model depends only on loop detector data and signal settings as inputs and provides estimate...

  19. The functional activity of hypothalamic signaling systems in rats with neonatal diabetes mellitus treated with metformin.

    Derkach, K V; Sukhov, I B; Kuznetsova, L A; Buzanakov, D M; Shpakov, A O

    2016-03-01

    The effect of the two-month metformin treatment (200 mg/kg/day) of rats with the neonatal model of type 2 diabetes mellitus on the functional activity of hypothalamic signaling systems was studied. It was shown that metformin treatment restored the sensitivity of hypothalamic adenylyl cyclase signaling system to agonists of the type 4 melanocortin receptor and the type 2 dopamine receptor but did not influence significantly the functions of the insulin signaling system. These data suggest new targets and mechanisms of metformin action in the CNS, which may mediate its restoring effect on energy homeostasis impaired in diabetic pathology. PMID:27193707

  20. Biased signalling from the glucocorticoid receptor: Renewed opportunity for tailoring glucocorticoid activity.

    Keenan, Christine R; Lew, Michael J; Stewart, Alastair G

    2016-07-15

    Recent landmark studies applying analytical pharmacology approaches to the glucocorticoid receptor (GR) have demonstrated that different ligands can cause differential activation of distinct GR-regulated genes. Drawing on concepts of signalling bias from the field of G protein-coupled receptor (GPCR) biology, we speculate that ligand-dependent differences in GR signalling can be considered analogous to GPCR biased signalling, and thus can be quantitatively analysed in a similar way. This type of approach opens up the possibility of using rational structure-based drug optimisation strategies to improve the therapeutic selectivity of glucocorticoid drugs to maximise their efficacy and minimise adverse effects. PMID:26898958

  1. A Gaussian process framework for modelling stellar activity signals in radial velocity data

    Rajpaul, V.; Aigrain, S.; Osborne, M. A.; Reece, S.; Roberts, S.

    2015-09-01

    To date, the radial velocity (RV) method has been one of the most productive techniques for detecting and confirming extrasolar planetary candidates. Unfortunately, stellar activity can induce RV variations which can drown out or even mimic planetary signals - and it is notoriously difficult to model and thus mitigate the effects of these activity-induced nuisance signals. This is expected to be a major obstacle to using next-generation spectrographs to detect lower mass planets, planets with longer periods, and planets around more active stars. Enter Gaussian processes (GPs) which, we note, have a number of attractive features that make them very well suited to disentangling stellar activity signals from planetary signals. We present here a GP framework we developed to model RV time series jointly with ancillary activity indicators (e.g. bisector velocity spans, line widths, chromospheric activity indices), allowing the activity component of RV time series to be constrained and disentangled from e.g. planetary components. We discuss the mathematical details of our GP framework, and present results illustrating its encouraging performance on both synthetic and real RV data sets, including the publicly available Alpha Centauri B data set.

  2. Task control signals in pediatric Tourette syndrome show evidence of immature and anomalous functional activity

    Francis M Miezin

    2009-11-01

    Full Text Available Tourette Syndrome (TS is a pediatric movement disorder that may affect control signaling in the brain. Previous work has proposed a dual-networks architecture of control processing involving a task-maintenance network and an adaptive control network (Dosenbach et al., 2008. A prior resting-state functional connectivity MRI (rs-fcMRI analysis in TS has revealed functional immaturity in both putative control networks, with “anomalous” correlations (i.e. correlations outside the typical developmental range limited to the adaptive control network (Church et al., 2009. The present study used functional MRI (fMRI to study brain activity related to adaptive control (by studying start-cues signals, and to task-maintenance (by studying signals sustained across a task set. Two hypotheses from the previous rs-fcMRI results were tested. First, adaptive control (i.e., start-cue activity will be altered in TS, including activity inconsistent with typical development (“anomalous”. Second, group differences found in task maintenance (i.e., sustained activity will be consistent with functional immaturity in TS. We examined regions found through a direct comparison of adolescents with and without TS, as well as regions derived from a previous investigation that showed differences between unaffected children and adults. The TS group showed decreased start-cue signal magnitude in regions where start-cue activity is unchanged over typical development, consistent with anomalous adaptive control. The TS group also had higher magnitude sustained signals in frontal cortex regions that overlapped with regions showing differences over typical development, consistent with immature task maintenance in TS. The results demonstrate task-related fMRI signal differences anticipated by the atypical functional connectivity found previously in adolescents with TS, strengthening the evidence for functional immaturity and anomalous signaling in control networks in adolescents

  3. Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells

    Our proteomical analysis of osteoblasts exposed to fluoride revealed a distinctive upregulation of proteins in osteoblast. These upregulated proteins play key roles in the protein folding. The PRK-like ER kinase (PERK) signaling, one branch of unfolded protein response (UPR) to combat ER stress, is a transcription factor needed for osteoblast proliferation and differentiation. The mechanism of skeletal fluorosis by which fluoride regulates osteoblast is not fully defined. Here we studied the effect of fluoride on PERK signaling genes and x-box binding protein 1 (xbp-1) in OS7232 cells (human osteoblast-like cell line). Meantime, genes associated with bone turnover were examined in this study. We found that early and continuous fluoride exposure increased the binding immunoglobulin protein (BiP) expression and activated the PERK signaling pathway, resulting in activation of transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The altered expression of cbfa1, osteoprotegerin (OPG)/nuclear factor kappa B ligand (RANKL) were viewed in this study. These results showed fluoride impelled a distinctive ER stress response in OS732 cells, primarily by activating PERK and PERK-dependent signaling. Little effects were viewed for activating xbp-1, a common target of the other two canonical sensors of ER stress, ATF6 and IRE1. In this study the altered expression of bone turnover genes were consistent with activation of ER stress and PERK signaling. This study proved that PERK signaling play major roles in action of fluoride on osteoblast, and suggested that bone response in skeletal fluorosis may be due in part to PERK signaling pathway.

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

    Highlights: ► H2O2 activates the insulin signaling pathway and glucose uptake in podocytes. ► H2O2 induces time-dependent changes in AMPK phosphorylation. ► H2O2 enhances insulin signaling pathways via AMPK activation. ► H2O2 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 (H2O2) on the phosphorylation of proximal and distal elements of insulin signaling. We also investigated H2O2-induced intracellular changes in the distribution of protein kinase B (Akt). Western blots showed that H2O2 (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 2O2>. Furthermore, H2O2 inhibited phosphorylation of the phosphatase and tensin homologue (PTEN; peak activity at 10 min; Δ −32%, P 2O2 on IR phosphorylation by about 40% (from 2.07 ± 0.28 to 1.28 ± 0.12, P 2O2 increased glucose uptake in podocytes (from 0.88 ± 0.04 to 1.29 ± 0.12 nmol/min/mg protein, P 2O2 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.

  5. Recombinant TCR ligand induces early TCR signaling and a unique pattern of downstream activation.

    Wang, Chunhe; Mooney, Jeffery L; Meza-Romero, Roberto; Chou, Yuan K; Huan, Jianya; Vandenbark, Arthur A; Offner, Halina; Burrows, Gregory G

    2003-08-15

    Recombinant TCR ligands (RTLs) consisting of covalently linked alpha(1) and beta(1) domains of MHC class II molecules tethered to specific antigenic peptides represent minimal TCR ligands. In a previous study we reported that the rat RTL201 construct, containing RT1.B MHC class II domains covalently coupled to the encephalitogenic guinea pig myelin basic protein (Gp-MBP(72-89)) peptide, could prevent and treat actively and passively induced experimental autoimmune encephalomyelitis in vivo by selectively inhibiting Gp-MBP(72-89) peptide-specific CD4(+) T cells. To evaluate the inhibitory signaling pathway, we tested the effects of immobilized RTL201 on T cell activation of the Gp-MBP(72-89)-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP(72-89) peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3zeta p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3epsilon treatment produced stronger activation of these cellular events with additional activation of NF-kappaB and extracellular signal-regulated kinases as well as long term increased IL-2 production. These results demonstrate that RTLs can bind directly to the TCR and modify T cell behavior through a partial activation mechanism, triggering specific downstream signaling events that deplete intracellular calcium stores without fully activating T cells. The resulting Ag-specific activation of the transcription factor NFAT uncoupled from the activation of NF-kappaB or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4(+) T cells. PMID:12902496

  6. Mammary cells with active Wnt signaling resist ErbB2-induced tumorigenesis.

    Wen Bu

    Full Text Available Aberrant activation of Wnt signaling is frequent in human malignancies. In normal epithelial tissues, including the breast, Wnt signaling is active only in a subset of cells, but it is unknown whether this subset of Wnt signaling-active cells is at increased risk of carcinogenesis. We created transgenic mice (TOP-tva in which the synthetic Wnt-responsive promoter TOP controlled the gene encoding TVA, which confers susceptibility to infection by the retroviral vector RCAS. Thus, only cells in which Wnt signaling is active will express tva and be targeted by RCAS. Surprisingly, we found that RCAS-mediated delivery of cDNA encoding a constitutively activated version of ErbB2 (HER2/Neu into the small number of TVA+ mammary epithelial cells in TOP-tva mice failed to induce tumor, while the same virus readily induced mammary tumors after it was delivered into a comparable number of cells in our previously reported mouse line MMTV-tva, whose tva is broadly expressed in mammary epithelium. Furthermore, we could not even detect any early lesions or infected cells in TOP-tva mice at the time of necropsy. Therefore, we conclude that the Wnt pathway-active cell subset in the normal mammary epithelium does not evolve into tumors following ErbB2 activation-rather, they apparently die due to apoptosis, an anticancer "barrier" that we have reported to be erected in some mammary cells followed ErbB2 activation. In accord with these mouse model data, we found that unlike the basal subtype, ErbB2+ human breast cancers rarely involve aberrant activation of Wnt signaling. This is the first report of a defined sub-population of mammalian cells that is "protected" from tumorigenesis by a potent oncogene, and provides direct in vivo evidence that mammary epithelial cells are not equal in their response to oncogene-initiated transformation.

  7. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution.

    Luo, Bangwei; Wang, Jinsong; Liu, Zongwei; Shen, Zigang; Shi, Rongchen; Liu, Yu-Qi; Liu, Yu; Jiang, Man; Wu, Yuzhang; Zhang, Zhiren

    2016-01-01

    Inflammation resolution is an active process, the failure of which causes uncontrolled inflammation which underlies many chronic diseases. Therefore, endogenous pathways that regulate inflammation resolution are fundamental and of wide interest. Here, we demonstrate that phagocyte respiratory burst-induced hypoxia activates macrophage erythropoietin signalling to promote acute inflammation resolution. This signalling is activated following acute but not chronic inflammation. Pharmacological or genetical inhibition of the respiratory burst suppresses hypoxia and macrophage erythropoietin signalling. Macrophage-specific erythropoietin receptor-deficient mice and chronic granulomatous disease (CGD) mice, which lack the capacity for respiratory burst, display impaired inflammation resolution, and exogenous erythropoietin enhances this resolution in WT and CGD mice. Mechanistically, erythropoietin increases macrophage engulfment of apoptotic neutrophils via PPARγ, promotes macrophage removal of debris and enhances macrophage migration to draining lymph nodes. Together, our results provide evidences of an endogenous pathway that regulates inflammation resolution, with important implications for treating inflammatory conditions. PMID:27397585

  8. Signal intensity, clinical activity and cross-sectional areas on MRI scans in thyroid eye disease

    The signal intensity from inflamed extra-ocular muscles on short tau inversion recovery (STIR)-sequence magnetic resonance imaging (MRI) is known to correlate with clinical scores of thyroid eye disease (TED) severity. Twenty-one patients who had undergone repeated MRI scanning for TED were studied retrospectively. Signal intensity of extra-ocular muscles (from STIR-sequence MRI) and cross-sectional area (from STIR and T1 MRI) were correlated with Mourits' clinical activity score (CAS). The area of highest signal intensity within the most inflamed extra-ocular muscle, and the average cross-sectional signal intensity of the most inflamed extra-ocular muscle reliably correlated with CAS, and this was maintained as disease activity changed over time. In contrast, isolated measures of muscle cross-sectional area did not correlate with CAS. The extra-ocular muscle cross-sectional area calculated from STIR-sequence MR images was greater than that measured on T1 images. This suggests that muscle area from STIR-sequence MRI may also detect peri-muscular inflammation. We conclude that the peak signal intensity from the most inflamed extra-ocular muscle remains the most reliable correlate of clinical disease activity obtained from these images. STIR-sequence MRI scans provide a number of useful measures of disease activity in TED

  9. Investigations on Inhibitors of Hedgehog Signal Pathway: A Quantitative Structure-Activity Relationship Study

    Zhiwei Cao

    2011-05-01

    Full Text Available The hedgehog signal pathway is an essential agent in developmental patterning, wherein the local concentration of the Hedgehog morphogens directs cellular differentiation and expansion. Furthermore, the Hedgehog pathway has been implicated in tumor/stromal interaction and cancer stem cell. Nowadays searching novel inhibitors for Hedgehog Signal Pathway is drawing much more attention by biological, chemical and pharmological scientists. In our study, a solid computational model is proposed which incorporates various statistical analysis methods to perform a Quantitative Structure-Activity Relationship (QSAR study on the inhibitors of Hedgehog signaling. The whole QSAR data contain 93 cyclopamine derivatives as well as their activities against four different cell lines (NCI-H446, BxPC-3, SW1990 and NCI-H157. Our extensive testing indicated that the binary classification model is a better choice for building the QSAR model of inhibitors of Hedgehog signaling compared with other statistical methods and the corresponding in silico analysis provides three possible ways to improve the activity of inhibitors by demethylation, methylation and hydroxylation at specific positions of the compound scaffold respectively. From these, demethylation is the best choice for inhibitor structure modifications. Our investigation also revealed that NCI-H466 served as the best cell line for testing the activities of inhibitors of Hedgehog signal pathway among others.

  10. The lack of autophagy triggers precocious activation of Notch signaling during Drosophila oogenesis

    Barth Julia MI

    2012-12-01

    Full Text Available Abstract Background The proper balance of autophagy, a lysosome-mediated degradation process, is indispensable for oogenesis in Drosophila. We recently demonstrated that egg development depends on autophagy in the somatic follicle cells (FC, but not in the germline cells (GCs. However, the lack of autophagy only affects oogenesis when FCs are autophagy-deficient but GCs are wild type, indicating that a dysfunctional signaling between soma and germline may be responsible for the oogenesis defects. Thus, autophagy could play an essential role in modulating signal transduction pathways during egg development. Results Here, we provide further evidence for the necessity of autophagy during oogenesis and demonstrate that autophagy is especially required in subsets of FCs. Generation of autophagy-deficient FCs leads to a wide range of phenotypes that are similar to mutants with defects in the classical cell-cell signaling pathways in the ovary. Interestingly, we observe that loss of autophagy leads to a precocious activation of the Notch pathway in the FCs as monitored by the expression of Cut and Hindsight, two downstream effectors of Notch signaling. Conclusion Our findings point to an unexpected function for autophagy in the modulation of the Notch signaling pathway during Drosophila oogenesis and suggest a function for autophagy in proper receptor activation. Egg development is affected by an imbalance of autophagy between signal sending (germline and signal receiving cell (FC, thus the lack of autophagy in the germline is likely to decrease the amount of active ligand and accordingly compensates for increased signaling in autophagy-defective follicle cells.

  11. Hanford Facility Annual Dangerous Waste Report Calendar Year 2002

    Hanford CY 2002 dangerous waste generation and management forms. The Hanford Facility Annual Dangerous Waste Report (ADWR) is prepared to meet the requirements of Washington Administrative Code Sections 173-303-220, Generator Reporting, and 173-303-390, Facility Reporting. In addition, the ADWR is required to meet Hanford Facility RCRA Permit Condition I.E.22, Annual Reporting. The ADWR provides summary information on dangerous waste generation and management activities for the Calendar Year for the Hanford Facility EPA ID number assigned to the Department of Energy for RCRA regulated waste, as well as Washington State only designated waste and radioactive mixed waste. The Solid Waste Information and Tracking System (SWITS) database is utilized to collect and compile the large array of data needed for preparation of this report. Information includes details of waste generated on the Hanford Facility, waste generated offsite and sent to Hanford for management, and other waste management activities conducted at Hanford, including treatment, storage, and disposal. Report details consist of waste descriptions and weights, waste codes and designations, and waste handling codes. In addition, for waste shipped to Hanford for treatment and/or disposal, information on manifest numbers, the waste transporter, the waste receiving facility, and the original waste generators are included. In addition to paper copies, electronic copies of the report are also transmitted to the regulatory agency

  12. Radiation danger of exclusion zone objects

    Kholosha, V.I.; Proskura, N.I.; Ivanov, Yu.A.; Kazakov, S.V.; Arkhipov, A.N. [Ministry of Ukraine of Emergencies and Affairs of Population Protection from the Consequences of Chornobyl Catastrophe (Ukraine)

    2001-03-01

    The analysis of radiation danger of the Exclusion Zone objects was made. Here, the Zone is defined as the territory from which the population has been evacuated in 1986 owing to the Chernobyl accident and possible outflow of the contaminated substances out of the borders is potentially dangerous to the Ukraine. In the present work were analyzed such problems as sources of radiation danger in the Zone, ways of radionuclide migration out of the borders of the Zone in normal and emergency situations, the non-radiation (ecological) danger factors of the Zone objects, doses (individual and collective) from various sources and on separate ways of their formation, and the characteristics of radiation danger of the Zone objects. The conclusions are: (1) Radionuclide flows both from technologic and natural sources exceed those from Shelter objects, (2) Under emergency conditions, radionuclide flows and doze loading remain comparable with those from emergency sources, (3) To solve some management tasks in radiation situation, the basic works on the Shelter objects should be oriented to decrease probability of emergency occurrence and to reduce radiation influence (prevention wash-outs during high waters, fire-prevention measures in forests and strengthening of the control behind non-authorized use of objects in the Zone). (S. Ohno)

  13. Radiation danger of exclusion zone objects

    The analysis of radiation danger of the Exclusion Zone objects was made. Here, the Zone is defined as the territory from which the population has been evacuated in 1986 owing to the Chernobyl accident and possible outflow of the contaminated substances out of the borders is potentially dangerous to the Ukraine. In the present work were analyzed such problems as sources of radiation danger in the Zone, ways of radionuclide migration out of the borders of the Zone in normal and emergency situations, the non-radiation (ecological) danger factors of the Zone objects, doses (individual and collective) from various sources and on separate ways of their formation, and the characteristics of radiation danger of the Zone objects. The conclusions are: (1) Radionuclide flows both from technologic and natural sources exceed those from Shelter objects, (2) Under emergency conditions, radionuclide flows and doze loading remain comparable with those from emergency sources, (3) To solve some management tasks in radiation situation, the basic works on the Shelter objects should be oriented to decrease probability of emergency occurrence and to reduce radiation influence (prevention wash-outs during high waters, fire-prevention measures in forests and strengthening of the control behind non-authorized use of objects in the Zone). (S. Ohno)

  14. Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

    House, Carrie D.; Wang, Bi-Dar; Ceniccola, Kristin; Williams, Russell; Simaan, May; Olender, Jacqueline; Patel, Vyomesh; Baptista-Hon, Daniel T.; Annunziata, Christina M.; Silvio Gutkind, J.; Hales, Tim G.; Lee, Norman H.

    2015-06-01

    Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.

  15. Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells

    Meininger, Isabel; Griesbach, Richard A.; Hu, Desheng; Gehring, Torben; Seeholzer, Thomas; Bertossi, Arianna; Kranich, Jan; Oeckinghaus, Andrea; Eitelhuber, Andrea C; Greczmiel, Ute; Gewies, Andreas; Schmidt-Supprian, Marc; Ruland, Jürgen; Brocker, Thomas; Heissmeyer, Vigo

    2016-01-01

    MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4+ T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify...

  16. Active Elements for Analog Signal Processing: Classification, Review, and New Proposals

    Z. Kolka

    2008-12-01

    Full Text Available In the paper, an analysis of the state-of-the-art of active elements for analog signal processing is presented which support – in contrast to the conventional operational amplifiers – not only the voltage-mode but also the current- and mixed-mode operations. Several problems are addressed which are associated with the utilization of these elements in linear applications, particularly in frequency filters. A methodology is proposed which generates a number of fundamentally new active elements with their potential utilization in various areas of signal processing.

  17. Aurora A drives early signalling and vesicle dynamics during T-cell activation

    Blas-Rus, Noelia; Bustos-Morán, Eugenio; Pérez de Castro, Ignacio; de Cárcer, Guillermo; Borroto, Aldo; Camafeita, Emilio; Jorge, Inmaculada; Vázquez, Jesús; Alarcón, Balbino; Malumbres, Marcos; Martín-Cófreces, Noa B.; Sánchez-Madrid, Francisco

    2016-01-01

    Aurora A is a serine/threonine kinase that contributes to the progression of mitosis by inducing microtubule nucleation. Here we have identified an unexpected role for Aurora A kinase in antigen-driven T-cell activation. We find that Aurora A is phosphorylated at the immunological synapse (IS) during TCR-driven cell contact. Inhibition of Aurora A with pharmacological agents or genetic deletion in human or mouse T cells severely disrupts the dynamics of microtubules and CD3ζ-bearing vesicles at the IS. The absence of Aurora A activity also impairs the activation of early signalling molecules downstream of the TCR and the expression of IL-2, CD25 and CD69. Aurora A inhibition causes delocalized clustering of Lck at the IS and decreases phosphorylation levels of tyrosine kinase Lck, thus indicating Aurora A is required for maintaining Lck active. These findings implicate Aurora A in the propagation of the TCR activation signal. PMID:27091106

  18. Activation of aryl hydrocarbon receptor signaling by extracts of teak and other wood dusts.

    Wilson, Mark J; Sabbioni, Gabriele; Rando, Roy; Miller, Charles A

    2015-12-01

    Wood dusts, as a group, are categorized as known human carcinogens, but the risks of exposure to specific types of wood dusts and the carcinogenic chemicals they contain are not well studied. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is linked to the carcinogenic action of specific classes of chemicals. Here we examined whether chemicals in various wood dusts had the potential to activate AhR signaling as a potential toxic mechanism of action. We found that methanol extracts of teak, walnut, mahogany, and poplar dusts contained a wide range of AhR ligand activity, whereas extracts of oak, pine, and other softwoods did not contain appreciable activity. Teak dust extract, being particularly potent, was subjected to chemical analysis. The 2-methylanthraquinone (2-MAQ) accounted for the AhR ligand activity and was present at an average concentration of 0.27 parts per hundred in teak dust. Pure 2-MAQ potently induced AhR signaling (EC50 115 nM), confirming that this was the active ligand. Aqueous extracts of teak dust made using yeast or mammalian cell culture medium also contained robust AhR activity, suggesting the 2-MAQ ligand is soluble at bioactive concentrations in physiologically relevant fluids. The high concentration and potency of 2-MAQ in teak wood suggest it may mediate toxic effects through activation of AhR signaling in exposed wood workers. PMID:24898320

  19. Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland.

    Pyczek, Joanna; Buslei, Rolf; Schult, David; Hölsken, Annett; Buchfelder, Michael; Heß, Ina; Hahn, Heidi; Uhmann, Anja

    2016-01-01

    Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2(+) and Sox9(+) adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors. PMID:27109116

  20. Clicks, whistles and pulses: Passive and active signal use in dolphin communication

    Herzing, Denise L.

    2014-12-01

    The search for signals out of noise is a problem not only with radio signals from the sky but in the study of animal communication. Dolphins use multiple modalities to communicate including body postures, touch, vision, and most elaborately sound. Like SETI radio signal searches, dolphin sound analysis includes the detection, recognition, analysis, and interpretation of signals. Dolphins use both passive listening and active production to communicate. Dolphins use three main types of acoustic signals: frequency modulated whistles (narrowband with harmonics), echolocation (broadband clicks) and burst pulsed sounds (packets of closely spaced broadband clicks). Dolphin sound analysis has focused on frequency-modulated whistles, yet the most commonly used signals are burst-pulsed sounds which, due to their graded and overlapping nature and bimodal inter-click interval (ICI) rates are hard to categorize. We will look at: 1) the mechanism of sound production and categories of sound types, 2) sound analysis techniques and information content, and 3) examples of lessons learned in the study of dolphin acoustics. The goal of this paper is to provide perspective on how animal communication studies might provide insight to both passive and active SETI in the larger context of searching for life signatures.

  1. False Alarm Reduction in BSN-Based Cardiac Monitoring Using Signal Quality and Activity Type Information

    Tanatorn Tanantong

    2015-02-01

    Full Text Available False alarms in cardiac monitoring affect the quality of medical care, impacting on both patients and healthcare providers. In continuous cardiac monitoring using wireless Body Sensor Networks (BSNs, the quality of ECG signals can be deteriorated owing to several factors, e.g., noises, low battery power, and network transmission problems, often resulting in high false alarm rates. In addition, body movements occurring from activities of daily living (ADLs can also create false alarms. This paper presents a two-phase framework for false arrhythmia alarm reduction in continuous cardiac monitoring, using signals from an ECG sensor and a 3D accelerometer. In the first phase, classification models constructed using machine learning algorithms are used for labeling input signals. ECG signals are labeled with heartbeat types and signal quality levels, while 3D acceleration signals are labeled with ADL types. In the second phase, a rule-based expert system is used for combining classification results in order to determine whether arrhythmia alarms should be accepted or suppressed. The proposed framework was validated on datasets acquired using BSNs and the MIT-BIH arrhythmia database. For the BSN dataset, acceleration and ECG signals were collected from 10 young and 10 elderly subjects while they were performing ADLs. The framework reduced the false alarm rate from 9.58% to 1.43% in our experimental study, showing that it can potentially assist physicians in diagnosing a vast amount of data acquired from wireless sensors and enhance the performance of continuous cardiac monitoring.

  2. Transport of dangerous substances by road

    This book is a collection of the Finnish acts and regulations concerning transport of dangerous substances by road as of 31st March 1985. Included are: Act and Decree on the Transport of Dangerous Substances by Road (Nos 510/74 and 861/74), both as amended; Decree setting up a related Commission (No. 862/74), as amended; Act on the Contract for Carriage of Goods by Road (No. 345/79); Decree bringing into force the ADR (No. 289/79); and Decision of the Ministry of Communications on the Transport of Dangerous Substances by Road (No. 610/78) as amended by Decisions No. 344/79, 995/79, 218/82 and 935/83. (NEA)

  3. Effects of anesthesia on BOLD signal and neuronal activity in the somatosensory cortex.

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

    2015-11-01

    Most functional magnetic resonance imaging (fMRI) animal studies rely on anesthesia, which can induce a variety of drug-dependent physiological changes, including depression of neuronal activity and cerebral metabolism as well as direct effects on the vasculature. The goal of this study was to characterize the effects of anesthesia on the BOLD signal and neuronal activity. Simultaneous fMRI and electrophysiology were used to measure changes in single units (SU), multi-unit activity (MUA), local field potentials (LFP), and the blood oxygenation level-dependent (BOLD) response in the somatosensory cortex during whisker stimulation of rabbits before, during and after anesthesia with fentanyl or isoflurane. Our results indicate that anesthesia modulates the BOLD signal as well as both baseline and stimulus-evoked neuronal activity, and, most significantly, that the relationship between the BOLD and electrophysiological signals depends on the type of anesthetic. Specifically, the behavior of LFP observed under isoflurane did not parallel the behavior of BOLD, SU, or MUA. These findings suggest that the relationship between these signals may not be straightforward. BOLD may scale more closely with the best measure of the excitatory subcomponents of the underlying neuronal activity, which may vary according to experimental conditions that alter the excitatory/inhibitory balance in the cortex. PMID:26104288

  4. Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation.

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; Goto, Hisatsugu; Ledford, Julie G; Hsia, Bethany; Pastva, Amy M; Wright, Jo Rae

    2012-02-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation. PMID:22219327

  5. Opposing Activities of Notch and Wnt Signaling Regulate Intestinal Stem Cells and Gut Homeostasis

    Hua Tian

    2015-04-01

    Full Text Available Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology.

  6. Sleep loss activates cellular inflammation and signal transducer and activator of transcription (STAT) family proteins in humans

    Irwin, DE; Witarama, T; Caudill, M; Olmstead, R; Breen, EC

    2015-01-01

    © 2014 Elsevier Inc.. Sleep disturbance and short sleep duration are associated with inflammation and related disorders including cardiovascular disease, arthritis, diabetes mellitus, and certain cancers. This study was undertaken to test the effects of experimental sleep loss on spontaneous cellular inflammation and activation of signal transducer and activator of transcription (STAT) family proteins, which together promote an inflammatory microenvironment. In 24 healthy adults (16 females; ...

  7. Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells

    Lee, Joomin; Hahm, Eun-Ryeong; Singh, Shivendra V

    2010-01-01

    We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor act...

  8. Distinct neural circuits underlie assessment of a diversity of natural dangers by American crows.

    Cross, Donna J; Marzluff, John M; Palmquist, Ila; Minoshima, Satoshi; Shimizu, Toru; Miyaoka, Robert

    2013-08-22

    Social animals encountering natural dangers face decisions such as whether to freeze, flee or harass the threat. The American crow, Corvus brachyrhynchos, conspicuously mobs dangers. We used positron emission tomography to test the hypothesis that distinct neuronal substrates underlie the crow's consistent behavioural response to different dangers. We found that crows activated brain regions associated with attention and arousal (nucleus isthmo-opticus/locus coeruleus), and with motor response (arcopallium), as they fixed their gaze on a threat. However, despite this consistent behavioural and neural response, the sight of a person who previously captured the crow, a person holding a dead crow and a taxidermy-mounted hawk activated distinct forebrain regions (amygdala, hippocampus and portion of the caudal nidopallium, respectively). We suggest that aspects of mobbing behaviour are guided by unique neural circuits that respond to differences in mental processing-learning, memory formation and multisensory discrimination-required to appropriately nuance a risky behaviour to specific dangers. PMID:23825209

  9. Activation of the wnt/β-Catenin Signaling Pathway in Polymyositis, Dermatomyositis and Duchenne Muscular Dystrophy

    Liu, Fuchen; Liang, Zonglai; Xu, Jingwen; Li, Wei; Zhao, Dandan; Zhao, Yuying

    2016-01-01

    Background and Purpose The wnt/β-catenin signaling pathway plays a critical role in embryonic development and adult-tissue homeostasis. Recent investigations implicate the importance of wnt/β-catenin signaling in normal wound healing and its sustained activation being associated with fibrogenesis. We investigated the immunolocalization and activation of wnt/β-catenin in polymyositis (PM), dermatomyositis (DM), and Duchenne muscular dystrophy (DMD). Methods Immunofluorescence staining and Western blot analysis of β-catenin were performed in muscle specimens from 6 PM, 8 DM, and 6 DMD subjects. The β-catenin/Tcf4 DNA-binding activity in muscle was studied using an electrophoretic mobility shift assay (EMSA), and serum wnt/β-catenin/Tcf transcriptional activity was measured using a luciferase reporter gene assay. Results Immunoreactivity for β-catenin was found in the cytoplasm and nuclei of muscle fibers in PM, DM, and DMD. The protein level of β-catenin was elevated, and EMSA analysis confirmed the activation of wnt/β-catenin signaling. The transcriptional activities of β-catenin/Tcf in the circulation were increased in patients with PM, DM, and DMD, especially in those with interstitial lung disease, and these transcriptional activities decreased when PM or DM patients exhibited obvious clinical improvements. Conclusions Our findings indicate that wnt/β-catenin signaling is activated in PM, DM, and DMD. Its activation in muscle tissue and the circulation may play a role in modulating muscle regeneration and be at least partly involved in the process of muscle and pulmonary fibrosis. PMID:27165423

  10. Principles of estimation of Radiative danger

    Korogodin, V. I.

    1990-08-01

    The main principles of the estimation of Radiative danger has been discussed. Two main particularities of the danger were pointed out: negatve consequencies of small doses, which does not lead to radiation sickness, but lead to disfunctions of sanguine organs and thin intestines; absolute estimation of biological anomalies, which was forwarded by A.D. Sakharov (1921-1989). The ethic aspects of the use of Nuclear weapons on the fate of Human civilization were pointed out by A.D. Sakharov (1921-1990).

  11. Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway.

    Donyo, Maya; Hollander, Dror; Abramovitch, Ziv; Naftelberg, Shiran; Ast, Gil

    2016-04-01

    Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD. PMID:26769675

  12. Signal transducer and activator of transcription 5 is implicated in disease activity in adult and juvenile onset systemic lupus erythematosus.

    Meshaal, Safa; El Refai, Rasha; El Saie, Ahmed; El Hawary, Rabab

    2016-06-01

    The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in humans. It is the principal signaling mechanism for a wide array of cytokines and growth factors. Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE). In this study, we tried to assess the role of STAT5 in systemic lupus erythematosus and correlate its phosphorylation level with the disease activity. The activation of the STAT5 was assessed by measuring the level of expression of phosphorylated STAT5 (pSTAT5) using flow cytometry on the peripheral blood T and B cells in 58 SLE patients (40 adult and 18 juvenile onset) and on 23 healthy age- and sex-matched controls for both groups. Serum prolactin level was also assessed in the patients and control by ELISA. The study revealed that the level of pSTAT5 was higher in adult SLE patients than in healthy control (p = 0.001) and in juvenile-onset SLE patients versus age-matched control (p = 0.031). A positive correlation existed between the pSTAT5 levels and Systemic Lupus Activity Measure (SLAM) score and also with multiple clinical manifestations indicating a potential role of STAT5 signaling in pathogenesis SLE. The pSTAT5 signaling is implicated in the disease activity of SLE and may be a useful target of therapy by correcting the dysregulation of cytokines involved in the disease pathogenesis. PMID:27041383

  13. Chemical Signals of Synthetic Disaccharide Derivatives Dominate Rhamnolipids at Controlling Multiple Bacterial Activities.

    Singh, Nischal; Shetye, Gauri S; Zheng, Hewen; Sun, Jiayue; Luk, Yan-Yeung

    2016-01-01

    Microbes secrete molecules that modify their environment. Here, we demonstrate a class of synthetic disaccharide derivatives (DSDs) that mimics and dominates the activity of naturally secreted rhamnolipids by Pseudomonas aeruginosa. The DSDs exhibit the dual function of activating and inhibiting the swarming motility through a concentration-dependent activity reversal that is characteristic of signaling molecules. Whereas DSDs tethered with a saturated farnesyl group exhibit inhibition of both biofilm formation and swarming motility, with higher activities than rhamnolipids, a saturated farnesyl tethered with a sulfonate group only inhibits swarming motility but promote biofilm formation. These results identified important structural elements for controlling swarming motility, biofilm formation, and bacterial adhesion and suggest an effective chemical approach to control intertwined signaling processes that are important for biofilm formation and motilities. PMID:26511780

  14. Detecting stable phase structures in EEG signals to classify brain activity amplitude patterns

    Yusely RUIZ; Guang LI; Walter J. FREEMAN; Eduardo GONZALEZ

    2009-01-01

    Obtaining an electrocorticograms (ECoG) signal requires an invasive procedure in which brain activity is recorded from the cortical surface. In contrast, obtaining electroencephalograms (EEG) recordings requires the non-invasive procedure of recording the brain activity from the scalp surface, which allows EEG recordings to be performed more easily on healthy humans. In this work, a technique previously used to study spatial-temporal patterns of brain activity on animal ECoG was adapted for use on EEG. The main issues are centered on solving the problems introduced by the increment on the interelectrode distance and the procedure to detect stable frames. The results showed that spatial patterns of beta and gamma activity can also be extracted from the EEG signal by using stable frames as time markers for feature extraction. This adapted technique makes it possible to take advantage of the cognitive and phenomenological awareness of a normal healthy subject.

  15. Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor.

    Kota, Kokila; Kuzhikandathil, Eldo V; Afrasiabi, Milad; Lacy, Brett; Kontoyianni, Maria; Crider, A Michael; Song, Daniel

    2015-09-01

    The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH-PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior. PMID:26116441

  16. TRACKING AND TRACING SOLUTION FOR DANGEROUS GOODS CARRIED BY INTERMODAL TRANSPORT

    Marek Kvet

    2014-03-01

    Full Text Available This paper deals with the problem of designing a complex tracking and tracing solution for dangerous goods transportation with the support of modern information technologies. This research activity presents a part of the “ChemLogTT” [2] project solved at the University of Žilina. The main goal of our contribution is to present basic conception of a complex developed software tool for monitoring and analyzing mentioned dangerous goods transportation.

  17. NF-kB activation by ultraviolet light not dependent on a nuclear signal

    Devary, Y.; Rosette, C.; DiDonato, J.A.; Karin, M. (Univ. of California, San Diego, CA (United States))

    1993-09-10

    Exposure of mammalian cells to radiation triggers the ultraviolet (UV) response, which includes activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB). This was postulated to occur by induction of a nuclear signaling cascade by damaged DNA. Recently, induction of AP-1 by UV was shown to be mediated by a pathway involving Src tyrosine kinases and the Ha-Ras small guanosine triphosphate-binding protein, proteins located at the plasma membrane. It is demonstrated here that the same pathway mediates induction of NF-kB by UV. Because inactive NF-kB is stored in the cytosol, analysis of its activation directly tests the involvement of a nuclear-initiated signaling cascade. Enucleated cells are fully responsive to UV both in NF-kB induction and in activation of another key signaling event. Therefore, the UV response does not require a signal generated in the nucleus and is likely to be initiated at or near the plasma membrane.

  18. NF-kB activation by ultraviolet light not dependent on a nuclear signal

    Exposure of mammalian cells to radiation triggers the ultraviolet (UV) response, which includes activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kB). This was postulated to occur by induction of a nuclear signaling cascade by damaged DNA. Recently, induction of AP-1 by UV was shown to be mediated by a pathway involving Src tyrosine kinases and the Ha-Ras small guanosine triphosphate-binding protein, proteins located at the plasma membrane. It is demonstrated here that the same pathway mediates induction of NF-kB by UV. Because inactive NF-kB is stored in the cytosol, analysis of its activation directly tests the involvement of a nuclear-initiated signaling cascade. Enucleated cells are fully responsive to UV both in NF-kB induction and in activation of another key signaling event. Therefore, the UV response does not require a signal generated in the nucleus and is likely to be initiated at or near the plasma membrane

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

    Wasternack, Claus; Strnad, Miroslav

    2016-09-25

    Jasmonates (JAs) are lipid-derived signals mediating plant responses to biotic and abiotic stresses and in plant development. Following the elucidation of each step in their biosynthesis and the important components of perception and signaling, several activators, repressors and co-repressors have been identified which contribute to fine-tuning the regulation of JA-induced gene expression. Many of the metabolic reactions in which JA participates, such as conjugation with amino acids, glucosylation, hydroxylation, carboxylation, sulfation and methylation, lead to numerous compounds with different biological activities. These metabolites may be highly active, partially active in specific processes or inactive. Hydroxylation, carboxylation and sulfation inactivate JA signaling. The precursor of JA biosynthesis, 12-oxo-phytodienoic acid (OPDA), has been identified as a JA-independent signaling compound. An increasing number of OPDA-specific processes is being identified. To conclude, the numerous JA compounds and their different modes of action allow plants to respond specifically and flexibly to alterations in the environment. PMID:26581489

  20. Reduced endogenous Ca2+ buffering speeds active zone Ca2+ signaling.

    Delvendahl, Igor; Jablonski, Lukasz; Baade, Carolin; Matveev, Victor; Neher, Erwin; Hallermann, Stefan

    2015-06-01

    Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission. PMID:26015575

  1. Epigenetic regulator Lid maintains germline stem cells through regulating JAK-STAT signaling pathway activity

    Lama Tarayrah

    2015-11-01

    Full Text Available Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid maintains germline stem cell (GSC mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities.

  2. Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis

    Zheng, Wenjing; Gorre, Nagaraju; Shen, Yan; Noda, Tetsuo; Ogawa, Wataru; Lundin, Eva; Liu, Kui

    2010-01-01

    Maternal effect factors derived from oocytes are important for sustaining early embryonic development. This report shows that PI3K/PTEN-PDK1-AKT signaling in oocytes, as a novel maternal effect factor, is crucial for embryonic genome activation and preimplantation embryogenesis in mice.

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

    M.C. van de Laar; W.P.M. van den Wildenberg; G.J.M. van Boxtel; M.W. van der Molen

    2014-01-01

    To gain more insight into the development of action control, the current brain potential study examined response selection, activation, and selective inhibition during choice- and stop-signal processing in three age groups (8-, 12-, and 21-year-olds). Results revealed that age groups differed in the

  4. A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway

    Zheng, Ying; Qin, Hongwei; Frank, Stuart J.; Deng, Luqin; Litchfield, David W.; Tefferi, Ayalew; Pardanani, Animesh; Lin, Fang-Tsyr; Li, Jingzhi; Sha, Bingdong; Benveniste, Etty N.

    2011-01-01

    JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present...

  5. Activation of MAP kinase signaling pathway in the mussel Mytilus galloprovincialis as biomarker of environmental pollution.

    Châtel, A; Hamer, B; Talarmin, H; Dorange, G; Schröder, H C; Müller, W E G

    2010-03-01

    Stimulation of MAP kinase signal transduction pathway by various stressful stimuli was investigated in the marine bivalve Mytilus galloprovincialis. Analyses were performed in animals exposed in laboratory to selected pollutants and in mussels collected in winter and summer along the eastern Adriatic coast (Croatia). Effects of oxidative stress, induced by tributyltin, hydrogen peroxide and water soluble fraction of diesel fuel on the activation/phosphorylation of the three Mitogen-Activated Protein Kinases (MAPKs) p38, JNK and ERK using a newly developed ELISA procedure were evaluated. MAP kinase activation was analyzed 1h after exposure of mussels to chemical agents, and after recovery periods of 6 and 24h. Our results clearly indicated that pollutants generated different patterns of induction of the MAPK phosphorylation. Indeed, only pp38 and pJNK were activated with 11, 33 and 100 microg/L TBT, reaching a maximum activation after 6h in seawater following treatment of mussels with 11 microg/L TBT. Treatment with 0.074 and 0.222 mM H2O2 enhanced activation of both p38 and ERK. These two kinases were activated after 1h exposure, followed by a diminution after 6h of recovery in seawater and a reactivation after 24h. The levels of phosphorylated P38 and JNK were increased after mussel exposure with 7.5, 15 and 30% of water soluble fraction of diesel oil. P38 was activated concentration dependently at 1h exposure. Additionally, field study pointed out seasonal differences in MAP kinases activation as mussels collected during summer had a higher enzyme activation state than in winter, as well as sampling site differences which could be correlated to the industrial/tourism activity and environmental stresses (salinity). All the results converge towards MAP kinase signaling pathway being induced by various pollutants in M. galloprovincialis. This signaling cascade should be considered as a possible biomarker of environmental stress and pollution. PMID:19948362

  6. Active site coupling in PDE:PKA complexes promotes resetting of mammalian cAMP signaling.

    Krishnamurthy, Srinath; Moorthy, Balakrishnan Shenbaga; Xin Xiang, Lim; Xin Shan, Lim; Bharatham, Kavitha; Tulsian, Nikhil Kumar; Mihalek, Ivana; Anand, Ganesh S

    2014-09-16

    Cyclic 3'5' adenosine monophosphate (cAMP)-dependent-protein kinase (PKA) signaling is a fundamental regulatory pathway for mediating cellular responses to hormonal stimuli. The pathway is activated by high-affinity association of cAMP with the regulatory subunit of PKA and signal termination is achieved upon cAMP dissociation from PKA. Although steps in the activation phase are well understood, little is known on how signal termination/resetting occurs. Due to the high affinity of cAMP to PKA (KD ∼ low nM), bound cAMP does not readily dissociate from PKA, thus begging the question of how tightly bound cAMP is released from PKA to reset its signaling state to respond to subsequent stimuli. It has been recently shown that phosphodiesterases (PDEs) can catalyze dissociation of bound cAMP and thereby play an active role in cAMP signal desensitization/termination. This is achieved through direct interactions with the regulatory subunit of PKA, thereby facilitating cAMP dissociation and hydrolysis. In this study, we have mapped direct interactions between a specific cyclic nucleotide phosphodiesterase (PDE8A) and a PKA regulatory subunit (RIα isoform) in mammalian cAMP signaling, by a combination of amide hydrogen/deuterium exchange mass spectrometry, peptide array, and computational docking. The interaction interface of the PDE8A:RIα complex, probed by peptide array and hydrogen/deuterium exchange mass spectrometry, brings together regions spanning the phosphodiesterase active site and cAMP-binding sites of RIα. Computational docking combined with amide hydrogen/deuterium exchange mass spectrometry provided a model for parallel dissociation of bound cAMP from the two tandem cAMP-binding domains of RIα. Active site coupling suggests a role for substrate channeling in the PDE-dependent dissociation and hydrolysis of cAMP bound to PKA. This is the first instance, to our knowledge, of PDEs directly interacting with a cAMP-receptor protein in a mammalian system, and

  7. mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration.

    Deng, Zhili; Lei, Xiaohua; Zhang, Xudong; Zhang, Huishan; Liu, Shuang; Chen, Qi; Hu, Huimin; Wang, Xinyue; Ning, Lina; Cao, Yujing; Zhao, Tongbiao; Zhou, Jiaxi; Chen, Ting; Duan, Enkui

    2015-02-01

    Hair follicles (HFs) undergo cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) phases. Anagen begins when the hair follicle stem cells (HFSCs) obtain sufficient activation cues to overcome suppressive signals, mainly the BMP pathway, from their niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSC activation at the telogen-to-anagen transition. By using both an inducible conditional gene targeting strategy and a pharmacological inhibition method to ablate or inhibit mTOR signaling in adult skin epithelium before anagen initiation, we demonstrate that HFs that cannot respond to mTOR signaling display significantly delayed HFSC activation and extended telogen. Unexpectedly, BMP signaling activity is dramatically prolonged in mTOR signaling-deficient HFs. Through both gain- and loss-of-function studies in vitro, we show that mTORC1 signaling negatively affects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitates HFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-null skin. Our findings reveal a critical role for mTOR signaling in regulating stem cell activation through counterbalancing BMP-mediated repression during hair regeneration. PMID:25609845

  8. An apodized Kepler periodogram for separating planetary and stellar activity signals

    Gregory, Philip C.

    2016-05-01

    A new apodized Keplerian (AK) model is proposed for the analysis of precision radial velocity (RV) data to model both planetary and stellar activity (SA) induced RV signals. A symmetrical Gaussian apodization function with unknown width and centre can distinguish planetary signals from SA signals on the basis of the span of the apodization window. The general model for m AK signals includes a linear regression term between RV and the SA diagnostic log (R'hk), as well as an extra Gaussian noise term with unknown standard deviation. The model parameters are explored using a Bayesian fusion Markov chain Monte Carlo code. A differential version of the generalized Lomb-Scargle periodogram that employs a control diagnostic provides an additional way of distinguishing SA signals and helps guide the choice of new periods. Results are reported for a recent international RV blind challenge which included multiple state-of-the-art simulated data sets supported by a variety of SA diagnostics. In the current implementation, the AK method achieved a reduction in SA noise by a factor of approximately 6. Final parameter estimates for the planetary candidates are derived from fits that include AK signals to model the SA components and simple Keplerians to model the planetary candidates. Preliminary results are also reported for AK models augmented by a moving average component that allows for correlations in the residuals.

  9. Quorum activation at a distance: spatiotemporal patterns of gene regulation from diffusion of an autoinducer signal

    Dilanji, Gabriel; Langebrake, Jessica; Deleenheer, Patrick; Hagen, Stephen J.

    2012-02-01

    Bacteria in colonies coordinate gene regulation through the exchange of diffusible signal molecules known as autoinducers (AI). This ``quorum signaling'' often occurs in physically heterogeneous and spatially extended environments such as biofilms. Under these conditions the space and time scales for diffusion of the signal limit the range and timing of effective gene regulation. We expect that spatial and temporal patterns of gene expression will reflect physical environmental constraints as well as nonlinear transcriptional activation and feedback within the gene regulatory system. We have combined experiments and modeling to investigate how these spatiotemporal patterns develop. We embed engineered plasmid/GFP quorum sensor strains or wild type strains in a long narrow agar lane, and then introduce AI signal at one terminus of the lane. Diffusion of the AI initiates reporter expression along the length of the lane, extending to macroscopic distances of mm-cm. Resulting patterns are captured quantitatively by a mathematical model that incorporates logistic growth of the population, diffusion of AI, and nonlinear transcriptional activation. Our results show that a diffusing quorum signal can coordinate gene expression over distances of order 1cm on time scales of order 10 hrs.

  10. Is Low Blood Glucose (Hypoglycemia) Dangerous?

    ... Diabetes Sign Up forJoslin Newsletters Is Low Blood Glucose (Hypoglycemia) Dangerous? Low blood glucose or hypoglycemia is one of the most common ... In general, hypoglycemia is defined as a blood glucose level below 70 mg/dl. Low blood glucose ...

  11. The dangers of non-empirical confirmation

    Rovelli, Carlo

    2016-01-01

    In the book "String Theory and the Scientific Method", Richard Dawid describes a few of the many non-empirical arguments that motivate theoretical physicists' confidence in a theory, taking string theory as case study. I argue that excessive reliance on non-empirical evidence compromises the reliability of science, and that precisely the case of string theory well illustrates this danger.

  12. Transport of dangerous goods through road tunnels

    Jørgensen, N O; Lacroix, Didier; Amundsen, F.H.;

    1999-01-01

    A paper which describes the work of an OECD research group. The group has suggested a grouping of dangerous materials, a quantitative risk assessment model and a decision support model which should allow tunnel operators to determine if a given material should be allowed throug a given tunnel...

  13. The wind energy in danger in France

    The law project of march 2005, concerning the energy policy in France is dangerous for the wind power development. The new regulation favor the big installations in order to protect the environment. In fact this decision will limit the wind turbines installations. (A.L.B.)

  14. (Neuro)predictions, Dangerousness, and Retributivism

    Petersen, Thomas Søbirk

    2014-01-01

    Through the criminal justice system so-called dangerous offenders are, besides the offence that they are being convicted of and sentenced to, also punished for acts that they have not done but that they are believe to be likely to commit in the future. The aim of this paper is to critically discuss...

  15. Grout treatment facility dangerous waste permit application

    This section briefly describes the Hanford Site, provides a general description of the site operations and administration, provides an overview of the contents of this Grout Treatment Facility (GTF) Permit Application, and gives a list of acronyms and abbreviations used in the document. The decision was made to use the checklist as a locator reference instead of using the checklist section numbers as paragraph section numbers because several different types of waste management units, some of which are not addressed in the checklists, are part of the GTF. The GTF is a waste management unit within the Hanford Site facility. In May 1988, permit application was filed that identified the GTF as an existing facility. The GTF mixes dry cementitious solids with liquid mixed wastes (containing both dangerous and radioactive constituents) produced by Hanford Site operations. In addition to the design and operating features of the GTF that are intended to meet the requirements of dangerous waste regulations, many additional design and operating features are necessary to comply with radioactive waste management practices. The GTF design features and practices are intended to keep operational exposure to radionuclides and dangerous substances ''as low as reasonably achievable'' (ALARA) and to provide a disposal system that protects the environment for at least 10,000 yr. In some instances, ALARA practices present difficulties when complying with requirements of dangerous waste regulations

  16. Grout Treatment Facility dangerous waste permit application

    This section briefly describes the Hanford Site, provides a general description of the site operations and administration, provides an overview of the contents of this Grout Treatment Facility (GTF) Permit Application, and gives a list of acronyms and abbreviations used in the document. The decision was made to use the checklist as a locator reference instead of using the checklist section numbers as paragraph section numbers because several different types of waste management units, some of which are not addressed in the checklists, are part of the GTF. The GTF is a waste management unit within the Hanford Site facility. In May 1988, a permit application was filed that identified the GTF as an existing facility. The GTF mixes dry cementitious solids with liquid wastes (containing both dangerous and radioactive constituents) produced by Hanford Site operations. In addition to the design and operating features of the GTF that are intended to meet the requirements of dangerous waste regulations, many additional design and operating features are necessary to comply with radioactive waste management practices. The GTF design features and practices are intended to keep operational exposure to radionuclides and dangerous substances ''as low as reasonably achievable'' (ALARA) and to provide a disposal system that protects the environment for at least 10,000 yr. In some instances, ALARA practices present difficulties when complying with requirements of dangerous waste regulations. This volume contains 14 Appendices. Topics include Engineering Drawings, Maps, Roads, Toxicity Testing, and Pilot-Scale Testing

  17. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  18. Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

    Emri Zsuzsa

    2011-10-01

    Full Text Available Abstract Background Accumulating evidence suggests that glial signalling is activated by different brain functions. However, knowledge regarding molecular mechanisms of activation or their relation to neuronal activity is limited. The purpose of the present study is to identify the characteristics of ATP-evoked glial signalling in the brain reward area, the nucleus accumbens (NAc, and thereby to explore the action of citric acid cycle intermediate succinate (SUC. Results We described the burst-like propagation of Ca2+ transients evoked by ATP in acute NAc slices from rat brain. Co-localization of the ATP-evoked Ca2+ signalling with immunoreactivities of the astroglia-specific gap junction forming channel protein connexin43 (Cx43 and the glial fibrillary acidic protein (GFAP indicated that the responsive cells were a subpopulation of Cx43 and GFAP immunoreactive astrocytes. The ATP-evoked Ca2+ transients were present under the blockade of neuronal activity, but were inhibited by Ca2+ store depletion and antagonism of the G protein coupled purinergic P2Y1 receptor subtype-specific antagonist MRS2179. Similarly, Ca2+ transients evoked by the P2Y1 receptor subtype-specific agonist 2-(Methylthioadenosine 5'-diphosphate were also blocked by MRS2179. These characteristics implied that intercellular Ca2+ signalling originated from the release of Ca2+ from internal stores, triggered by the activation of P2Y1 receptors. Inhibition by the gap junction blockers carbenoxolone and flufenamic acid and by an antibody raised against the gating-associated segment of Cx43 suggested that intercellular Ca2+ signalling proceeded through gap junctions. We demonstrated for the first time that extracellular SUC also evoked Ca2+ transients (EC50 = 50-60 μM in about 15% of the ATP-responsive NAc astrocytes. By contrast to glial cells, electrophysiologically identified NAc neurons surrounded by ATP-responsive astrocytes were not activated simultaneously. Conclusions We

  19. Convergence of dopamine and glutamate signalling onto striatal ERK activation in response to drugs of abuse.

    JocelyneCaboche

    2014-01-01

    Full Text Available Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA concentration within the striatum. The main DA G-Protein Coupled Receptors (GPCRs expressed by medium-sized spiny neurons (MSNs of the striatum are the D1R and D2R, which are positively and negatively coupled to cAMP/protein kinase A (PKA signalling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behaviour induced by drugs of abuse. A major downstream target of striatal D1R is the Extracellular signal-Regulated Kinase (ERK kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signalling. Once activated, ERK can trigger chromatin remodelling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioural changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signalling and is liable to prove relevant for addictive drug-induced signalling, plasticity and behaviour. Herein, we review the evidence that built our understanding of the consequences of this synergistic signalling for the actions of drugs of abuse.

  20. Resistance of Cancer Cells to Targeted Therapies Through the Activation of Compensating Signaling Loops.

    von Manstein, Viktoria; Yang, Chul Min; Richter, Diane; Delis, Natalia; Vafaizadeh, Vida; Groner, Bernd

    2013-12-01

    The emergence of low molecular weight kinase inhibitors as "targeted" drugs has led to remarkable advances in the treatment of cancer patients. The clinical benefits of these tumor therapies, however, vary widely in patient populations and with duration of treatment. Intrinsic and acquired resistance against such drugs limits their efficacy. In addition to the well studied mechanisms of resistance based upon drug transport and metabolism, genetic alterations in drug target structures and the activation of compensatory cell signaling have received recent attention. Adaptive responses can be triggered which counteract the initial dependence of tumor cells upon a particular signaling molecule and allow only a transient inhibition of tumor cell growth. These compensating signaling mechanisms are often based upon the relief of repression of regulatory feedback loops. They might involve cell autonomous, intracellular events or they can be mediated via the secretion of growth factor receptor ligands into the tumor microenvironment and signal induction in an auto- or paracrine fashion. The transcription factors Stat3 and Stat5 mediate the biological functions of cytokines, interleukins and growth factors and can be considered as endpoints of multiple signaling pathways. In normal cells this activation is transient and the Stat molecules return to their non-phosphorylated state within a short time period. In tumor cells the balance between activating and de-activating signals is disturbed resulting in the persistent activation of Stat3 or Stat5. The constant activation of Stat3 induces the expression of target genes, which cause the proliferation and survival of cancer cells, as well as their migration and invasive behavior. Activating components of the Jak-Stat pathway have been recognized as potentially valuable drug targets and important principles of compensatory signaling circuit induction during targeted drug treatment have been discovered in the context of kinase

  1. Suppression of hedgehog signaling regulates hepatic stellate cell activation and collagen secretion

    Li, Tao; Leng, Xi-Sheng; Zhu, Ji-Ye; Wang, Gang

    2015-01-01

    Hepatic stellate cells (HSCs) play an important role in liver fibrosis. This study investigates the expression of hedgehog in HSC and the role of hedgehog signaling on activation and collagen secretion of HSC. Liver ex vivo perfusion with collagenase IV and density gradient centrifugation were used to isolate HSC. Expression of hedgehog signaling components Ihh, Smo, Ptc, Gli2 and Gli3 in HSC were detected by RT-PCR. Hedgehog siRNA vectors targeting Ihh, Smo and Gli2 were constructed and tran...

  2. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

    Tian, Yuan; Mok, Myth T.S.; Yang, Pengyuan; Cheng, Alfred S.L.

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients. PMID:27556491

  3. Periostin Responds to Mechanical Stress and Tension by Activating the MTOR Signaling Pathway

    Rosselli-Murai, Luciana K.; Galindo-Moreno, Pablo; Padial-Molina, Miguel; Volk, Sarah L.; Murai, Marcelo J.; Rios, Hector F.; Squarize, Cristiane H.; Castilho, Rogerio M.

    2013-01-01

    Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade. PMID:24349533

  4. Periostin responds to mechanical stress and tension by activating the MTOR signaling pathway.

    Luciana K Rosselli-Murai

    Full Text Available Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade.

  5. Personalizing energy expenditure estimation using physiological signals normalization during activities of daily living

    In this paper we propose a generic approach to reduce inter-individual variability of different physiological signals (HR, GSR and respiration) by automatically estimating normalization parameters (e.g. baseline and range). The proposed normalization procedure does not require a dedicated personal calibration during system setup. On the other hand, normalization parameters are estimated at system runtime from sedentary and low intensity activities of daily living (ADLs), such as lying and walking. When combined with activity-specific energy expenditure (EE) models, our normalization procedure improved EE estimation by 15 to 33% in a study group of 18 participants, compared to state of the art activity-specific EE models combining accelerometer and non-normalized physiological signals. (paper)

  6. [Review on the associations of signal transducer and activators of transcription 3 with hepatocellular carcinoma].

    Xie, J X; Gao, Q J

    2016-05-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies with high fatality rate in China. To investigate the related risk factors and therapeutic targets, and actively carry out the prevention and early treatment is of great public health value. Signal transducer and activators of transcription 3 (STAT3) is the key molecule of multiple inflammation-associated signaling pathways. Recent studies have found that HCC patients have high expressing levels of STAT3 in tumor tissues, and aberrant activation of STAT3 is closely associated with the occurrence, development, invasion, metastasis, and prognosis of HCC. In this paper, we reviewed the researches on the associations of STAT3 with the occurrence and prognosis of HCC and prospected on the issues of causal prophylaxis and targeted therapy for HCC which could offer reference for the protection strategy of HCC. PMID:27141908

  7. An adaptive synchronization strategy based on active control for demodulating message hidden in chaotic signals

    In the field of secure communication, it is very important to demodulate the message hidden in chaotic signals. In this paper, an adaptive synchronization strategy based on active control is proposed, which is used to design an active controller and an appropriate adaptive demodulator at the receiver to recover the transmitted message hidden in chaotic signals of a drive system. Based on Lyapunov stability theory, it is shown that the transmitted message can be theoretically recovered by using the proposed strategy. Numerical simulations based on the Chua's circuit are also presented to verify the effectiveness of the proposed strategy. In addition, it is shown via simulations that, by increasing the gain of the active controller the message error caused by the external noise and the discontinuous property of the message can be reduced

  8. Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.

    Giordano, Cinzia; Barone, Ines; Vircillo, Valentina; Panza, Salvatore; Malivindi, Rocco; Gelsomino, Luca; Pellegrino, Michele; Rago, Vittoria; Mauro, Loredana; Lanzino, Marilena; Panno, Maria Luisa; Bonofiglio, Daniela; Catalano, Stefania; Andò, Sebastiano

    2016-01-01

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment. PMID:26899873

  9. Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension.

    Smith, Kimberly A; Voiriot, Guillaume; Tang, Haiyang; Fraidenburg, Dustin R; Song, Shanshan; Yamamura, Hisao; Yamamura, Aya; Guo, Qiang; Wan, Jun; Pohl, Nicole M; Tauseef, Mohammad; Bodmer, Rolf; Ocorr, Karen; Thistlethwaite, Patricia A; Haddad, Gabriel G; Powell, Frank L; Makino, Ayako; Mehta, Dolly; Yuan, Jason X-J

    2015-09-01

    Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca(2+) entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6(-/-) mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca(2+) concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia. PMID:25569851

  10. A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.

    Han, Shuxin; Li, Tiangang; Ellis, Ewa; Strom, Stephen; Chiang, John Y L

    2010-06-01

    Vitamin D receptor (VDR) is activated by natural ligands, 1alpha, 25-dihydroxy-vitamin D(3) [1alpha,25(OH)(2)-D(3)] and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1alpha,25(OH)(2)-D(3) activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1alpha, 25(OH)(2)-D(3) induced intracellular translocation of VDR from the cytosol to the nucleus and also plasma membrane where VDR colocalized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/extracellular signal-regulated kinase (ERK) 1/2 pathway, which stimulates serine phosphorylation of VDR and hepatocyte nuclear factor-4alpha, and their interaction. Mammalian two-hybrid assays showed a VDR ligand-dependent interaction of nuclear receptor corepressor-1 and silencing mediator of retinoid and thyroid with VDR/retinoid X receptor-alpha (RXRalpha). Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRalpha, and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRalpha recruitment of corepressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR-signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury. PMID:20371703